WorldWideScience

Sample records for based dose-response models

  1. Experimental data and dose-response models

    International Nuclear Information System (INIS)

    Ullrich, R.L.

    1985-01-01

    Dose-response relationships for radiation carcinogenesis have been of interest to biologists, modelers, and statisticians for many years. Despite his interest there are few instances in which there are sufficient experimental data to allow the fitting of various dose-response models. In those experimental systems for which data are available the dose-response curves for tumor induction for the various systems cannot be described by a single model. Dose-response models which have been observed following acute exposures to gamma rays include threshold, quadratic, and linear models. Data on sex, age, and environmental influences of dose suggest a strong role of host factors on the dose response. With decreasing dose rate the effectiveness of gamma ray irradiation tends to decrease in essentially every instance. In those cases in which the high dose rate dose response could be described by a quadratic model, the effect of dose rate is consistent with predictions based on radiation effects on the induction of initial events. Whether the underlying reasons for the observed dose-rate effect is a result of effects on the induction of initial events or is due to effects on the subsequent steps in the carcinogenic process is unknown. Information on the dose response for tumor induction for high LET (linear energy transfer) radiations such as neutrons is even more limited. The observed dose and dose rate data for tumor induction following neutron exposure are complex and do not appear to be consistent with predictions based on models for the induction of initial events

  2. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose response (BBDR) Model***

    Science.gov (United States)

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (HPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the 1-IPT axis. Model calibrations, carried out by adjusting key model...

  3. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model

    Science.gov (United States)

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (BPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model p...

  4. Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system.

    Science.gov (United States)

    Lumen, Annie; McNally, Kevin; George, Nysia; Fisher, Jeffrey W; Loizou, George D

    2015-01-01

    A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources and contributions of uncertainties in the predicted model output. The workflow and methodologies suitable for computationally expensive models, such as the Morris screening method and Gaussian Emulation processes, were used for the implementation of the global sensitivity analysis. Sensitivity indices, such as main, total and interaction effects, were computed for a screened set of the total thyroidal system descriptive model input parameters. Furthermore, a narrower sub-set of the most influential parameters affecting the model output of maternal thyroid hormone levels were identified in addition to the characterization of their overall and pair-wise parameter interaction quotients. The characteristic trends of influence in model output for each of these individual model input parameters over their plausible ranges were elucidated using Gaussian Emulation processes. Through global sensitivity analysis we have gained a better understanding of the model behavior and performance beyond the domains of observation by the simultaneous variation in model inputs over their range of plausible uncertainties. The sensitivity analysis helped identify parameters that determine the driving mechanisms of the maternal and fetal iodide kinetics, thyroid function and their interactions, and contributed to an improved understanding of the system modeled. We have thus demonstrated the use and application of global sensitivity analysis for a biologically based dose-response model for sensitive life-stages such as pregnancy that provides richer information on the model and the thyroidal system modeled compared to local sensitivity analysis.

  5. Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system

    Directory of Open Access Journals (Sweden)

    Annie eLumen

    2015-05-01

    Full Text Available A deterministic biologically based dose-response model for the thyroidal system in a near-term pregnant woman and the fetus was recently developed to evaluate quantitatively thyroid hormone perturbations. The current work focuses on conducting a quantitative global sensitivity analysis on this complex model to identify and characterize the sources and contributions of uncertainties in the predicted model output. The workflow and methodologies suitable for computationally expensive models, such as the Morris screening method and Gaussian Emulation processes, were used for the implementation of the global sensitivity analysis. Sensitivity indices, such as main, total and interaction effects, were computed for a screened set of the total thyroidal system descriptive model input parameters. Furthermore, a narrower sub-set of the most influential parameters affecting the model output of maternal thyroid hormone levels were identified in addition to the characterization of their overall and pair-wise parameter interaction quotients. The characteristic trends of influence in model output for each of these individual model input parameters over their plausible ranges were elucidated using Gaussian Emulation processes. Through global sensitivity analysis we have gained a better understanding of the model behavior and performance beyond the domains of observation by the simultaneous variation in model inputs over their range of plausible uncertainties. The sensitivity analysis helped identify parameters that determine the driving mechanisms of the maternal and fetal iodide kinetics, thyroid function and their interactions, and contributed to an improved understanding of the system modeled. We have thus demonstrated the use and application of global sensitivity analysis for a biologically based dose-response model for sensitive life-stages such as pregnancy that provides richer information on the model and the thyroidal system modeled compared to local

  6. Single toxin dose-response models revisited

    Energy Technology Data Exchange (ETDEWEB)

    Demidenko, Eugene, E-mail: eugened@dartmouth.edu [Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH03756 (United States); Glaholt, SP, E-mail: sglaholt@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States); Kyker-Snowman, E, E-mail: ek2002@wildcats.unh.edu [Department of Natural Resources and the Environment, University of New Hampshire, Durham, NH03824 (United States); Shaw, JR, E-mail: joeshaw@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Chen, CY, E-mail: Celia.Y.Chen@dartmouth.edu [Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States)

    2017-01-01

    The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.

  7. A Generalized QMRA Beta-Poisson Dose-Response Model.

    Science.gov (United States)

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

    2016-10-01

    Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0Poisson model, PI(d|α,β), is a special case of the generalized model with K min = 1 (which implies r*=1). The generalized beta-Poisson model is based on a conceptual model with greater detail in the dose-response mechanism. Since a maximum likelihood solution is not easily available, a likelihood-free approximate Bayesian computation (ABC) algorithm is employed for parameter estimation. By fitting the generalized model to four experimental data sets from the literature, this study reveals that the posterior median r* estimates produced fall short of meeting the required condition of r* = 1 for single-hit assumption. However, three out of four data sets fitted by the generalized models could not achieve an improvement in goodness of fit. These combined results imply that, at least in some cases, a single-hit assumption for characterizing the dose-response process may not be appropriate, but that the more complex models may be difficult to support especially if the sample size is small. The three-parameter generalized model provides a possibility to investigate the mechanism of a dose-response process in greater detail than is possible under a single-hit model. © 2016 Society for Risk Analysis.

  8. Theory of thermoluminescence gamma dose response: The unified interaction model

    International Nuclear Information System (INIS)

    Horowitz, Y.S.

    2001-01-01

    We describe the development of a comprehensive theory of thermoluminescence (TL) dose response, the unified interaction model (UNIM). The UNIM is based on both radiation absorption stage and recombination stage mechanisms and can describe dose response for heavy charged particles (in the framework of the extended track interaction model - ETIM) as well as for isotropically ionising gamma rays and electrons (in the framework of the TC/LC geminate recombination model) in a unified and self-consistent conceptual and mathematical formalism. A theory of optical absorption dose response is also incorporated in the UNIM to describe the radiation absorption stage. The UNIM is applied to the dose response supralinearity characteristics of LiF:Mg,Ti and is especially and uniquely successful in explaining the ionisation density dependence of the supralinearity of composite peak 5 in TLD-100. The UNIM is demonstrated to be capable of explaining either qualitatively or quantitatively all of the major features of TL dose response with many of the variable parameters of the model strongly constrained by ancilliary optical absorption and sensitisation measurements

  9. Model for dose-response with alternative change of sign

    International Nuclear Information System (INIS)

    Osovets, S.V.

    1998-01-01

    A new mathematical model of dose-response relationships is proposed, suitable for calculating stochastic effects of low level exposure. The corresponding differential equations are presented as well as their solution. (A.K.)

  10. Skull base chordomas: analysis of dose-response characteristics

    International Nuclear Information System (INIS)

    Niemierko, Andrzej; Terahara, Atsuro; Goitein, Michael

    1997-01-01

    Objective: To extract dose-response characteristics from dose-volume histograms and corresponding actuarial survival statistics for 115 patients with skull base chordomas. Materials and Methods: We analyzed data for 115 patients with skull base chordoma treated with combined photon and proton conformal radiotherapy to doses in the range 66.6Gy - 79.2Gy. Data set for each patient included gender, histology, age, tumor volume, prescribed dose, overall treatment time, time to recurrence or time to last observation, target dose-volume histogram, and several dosimetric parameters (minimum/mean/median/maximum target dose, percent of the target volume receiving the prescribed dose, dose to 90% of the target volume, and the Equivalent Uniform Dose (EUD). Data were analyzed using the Kaplan-Meier survivor function estimate, the proportional hazards (Cox) model, and parametric modeling of the actuarial probability of recurrence. Parameters of dose-response characteristics were obtained using the maximum likelihood method. Results: Local failure developed in 42 (36%) of patients, with actuarial local control rates at 5 years of 59.2%. The proportional hazards model revealed significant dependence of gender on the probability of recurrence, with female patients having significantly poorer prognosis (hazard ratio of 2.3 with the p value of 0.008). The Wilcoxon and the log-rank tests of the corresponding Kaplan-Meier recurrence-free survival curves confirmed statistical significance of this effect. The Cox model with stratification by gender showed significance of tumor volume (p=0.01), the minimum target dose (p=0.02), and the EUD (p=0.02). Other parameters were not significant at the α level of significance of 0.05, including the prescribed dose (p=0.21). Parametric analysis using a combined model of tumor control probability (to account for non-uniformity of target dose distribution) and the Weibull failure time model (to account for censoring) allowed us to estimate

  11. Proposal of a probabilistic dose-response model

    International Nuclear Information System (INIS)

    Barrachina, M.

    1997-01-01

    A biologically updated dose-response model is presented as an alternative to the linear-quadratic model currently in use for cancer risk assessment. The new model is based on the probability functions for misrepair and/or unrepair of DNA lesions, in terms of the radiation damage production rate in the cell (supposedly, a stem cell) and its repair-rate constant. The model makes use, interpreting it on the basis of misrepair probabilities, of the ''dose and dose-rate effectiveness factor'' of ICRP, and provides the way for a continuous extrapolation between the high and low dose-rate regions, ratifying the ''linear non-threshold hypothesis'' as the main option. Anyhow, the model throws some doubts about the additive property of the dose. (author)

  12. Categorical regression dose-response modeling

    Science.gov (United States)

    The goal of this training is to provide participants with training on the use of the U.S. EPA’s Categorical Regression soft¬ware (CatReg) and its application to risk assessment. Categorical regression fits mathematical models to toxicity data that have been assigned ord...

  13. TESS-based dose-response using pediatric clonidine exposures

    International Nuclear Information System (INIS)

    Benson, Blaine E.; Spyker, Daniel A.; Troutman, William G.; Watson, William A.

    2006-01-01

    Objective: The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. Methods: 3458 single-substance clonidine exposures in children <6 years of age reported to TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a 'taste or lick' (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) μg/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). Results: The logistic model describing medical outcome (P < 0.0001) included Log dose/kg (P 0.0000) and Certainty (P = 0.045). Conclusion: TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures

  14. TESS-based dose-response using pediatric clonidine exposures.

    Science.gov (United States)

    Benson, Blaine E; Spyker, Daniel A; Troutman, William G; Watson, William A

    2006-06-01

    The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. 3,458 single-substance clonidine exposures in children TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a "taste or lick" (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) microg/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). The logistic model describing medical outcome (P TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures.

  15. Bayesian Dose-Response Modeling in Sparse Data

    Science.gov (United States)

    Kim, Steven B.

    This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a

  16. Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model.

    Science.gov (United States)

    Chuang, Shu-Chun; Rota, Matteo; Gunter, Marc J; Zeleniuch-Jacquotte, Anne; Eussen, Simone J P M; Vollset, Stein Emil; Ueland, Per Magne; Norat, Teresa; Ziegler, Regina G; Vineis, Paolo

    2013-10-01

    Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors.

  17. Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model.

    Science.gov (United States)

    Lumen, Annie; Mattie, David R; Fisher, Jeffrey W

    2013-06-01

    A biologically based dose-response model (BBDR) for the hypothalamic pituitary thyroid (HPT) axis was developed in the near-term pregnant mother and fetus. This model was calibrated to predict serum levels of iodide, total thyroxine (T4), free thyroxine (fT4), and total triiodothyronine (T3) in the mother and fetus for a range of dietary iodide intake. The model was extended to describe perchlorate, an environmental and food contaminant, that competes with the sodium iodide symporter protein for thyroidal uptake of iodide. Using this mode-of-action framework, simulations were performed to determine the daily ingestion rates of perchlorate that would be associated with hypothyroxinemia or onset of hypothyroidism for varying iodide intake. Model simulations suggested that a maternal iodide intake of 75 to 250 µg/day and an environmentally relevant exposure of perchlorate (~0.1 µg/kg/day) did not result in hypothyroxinemia or hypothyroidism. For a daily iodide-sufficient intake of 200 µg/day, the dose of perchlorate required to reduce maternal fT4 levels to a hypothyroxinemic state was estimated at 32.2 µg/kg/day. As iodide intake was lowered to 75 µg/day, the model simulated daily perchlorate dose required to cause hypothyroxinemia was reduced by eightfold. Similarly, the perchlorate intake rates associated with the onset of subclinical hypothyroidism ranged from 54.8 to 21.5 µg/kg/day for daily iodide intake of 250-75 µg/day. This BBDR-HPT axis model for pregnancy provides an example of a novel public health assessment tool that may be expanded to address other endocrine-active chemicals found in food and the environment.

  18. Some hybrid models applicable to dose-response relationships

    International Nuclear Information System (INIS)

    Kumazawa, Shigeru

    1992-01-01

    A new type of models of dose-response relationships has been studied as an initial stage to explore a reliable extrapolation of the relationships decided by high dose data to the range of low dose covered by radiation protection. The approach is to use a 'hybrid scale' of linear and logarithmic scales; the first model is that the normalized surviving fraction (ρ S > 0) in a hybrid scale decreases linearly with dose in a linear scale, and the second is that the induction in a log scale increases linearly with the normalized dose (τ D > 0) in a hybrid scale. The hybrid scale may reflect an overall effectiveness of a complex system against adverse events caused by various agents. Some data of leukemia in the atomic bomb survivors and of rodent experiments were used to show the applicability of hybrid scale models. The results proved that proposed models fit these data not less than the popular linear-quadratic models, providing the possible interpretation of shapes of dose-response curves, e.g. shouldered survival curves varied by recovery time. (author)

  19. Ingestion risks of metals in groundwater based on TIN model and dose-response assessment - A case study in the Xiangjiang watershed, central-south China

    International Nuclear Information System (INIS)

    Chai, Liyuan; Wang, Zhenxing; Wang, Yunyan; Yang, Zhihui; Wang, Haiying; Wu, Xie

    2010-01-01

    Groundwater samples were collected in the Xiangjiang watershed in China from 2002 to 2008 to analyze concentrations of arsenic, cadmium, chromium, copper, iron, lead, mercury, manganese, and zinc. Spatial and seasonal trends of metal concentrations were then discussed. Combined with geostatistics, an ingestion risk assessment of metals in groundwater was performed using the dose-response assessment method and the triangulated irregular network (TIN) model. Arsenic concentration in groundwater had a larger variation from year to year, while the variations of other metal concentrations were minor. Meanwhile, As concentrations in groundwater over the period of 2002-2004 were significantly higher than that over the period of 2005-2007, indicating the improvement of groundwater quality within the later year. The hazard index (HI) in 2002 was also significantly higher than that in 2005, 2006, 2007 and 2008. Moreover, more than 80% of the study area recorded an HI of more than 1.0 for children, suggesting that some people will experience deleterious health effects from drinking groundwater in the Xiangjiang watershed. Arsenic and manganese were the largest contributors to human health risks (HHRs). This study highlights the value of long-term health risk evaluation and the importance of geographic information system (GIS) technologies in the assessment of watershed-scale human health risk.

  20. A comparison of dose-response models for death from hematological depression

    International Nuclear Information System (INIS)

    Morris, M.D.; Jones, T.D.

    1987-01-01

    Many radiation-induced lethality experiments that have been published for various mammalian species have been compiled into a database suitable to study interspecific variability of radiosensitivity, dose-rate dependence of sensitivity, dose-response behavior within each experiment, etc. The data compiled were restricted to continuous and nearly continuous exposures to photon radiations having source energies above 100 keV. Also, photon source energy, exposure geometry, and body weight considerations were used to select studies where the dose to hematopoietic marrow was nearly uniform, i.e., < +- 20%. The data base reflects 13 mammalian test species ranging from mouse to cattle. Some 211 studies were compiled but only 105 were documented in adequate detail to be useful in development and evaluation of dose-response models of interest to practical human exposures. Of the 105 studies, 70 were for various rodent species, and 35 were for nonrodent groups ranging from standard laboratory primates (body weight ∼5 kg) to cattle (body weight 375 kg). This paper considers seven different dose-response models which are tested for validity against those 105 studies. The dose-response models included: a right-skewed extreme value, a left-skewed extreme value model, log-logistic, log-probit, logistic, probit, and Weibull models. In general, the log transformed models did not improve model performance and the extreme value models did not seem consistent with the preponderance of the data. Overall, the probit and the logistic models seemed preferable over the Weibull model. 30 refs., 8 tabs

  1. Toward a unified approach to dose-response modeling in ecotoxicology.

    Science.gov (United States)

    Ritz, Christian

    2010-01-01

    This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

  2. Research toward the development of a biologically based dose response assessment for inorganic arsenic carcinogenicity: A progress report

    International Nuclear Information System (INIS)

    Clewell, Harvey J.; Thomas, Russell S.; Gentry, P. Robinan; Crump, Kenny S.; Kenyon, Elaina M.; El-Masri, Hisham A.; Yager, Janice W.

    2007-01-01

    Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an adequate biologically based dose response (BBDR) model that could provide a quantitative basis for an alternative nonlinear approach. This paper describes elements of an ongoing collaborative research effort between the CIIT Centers for Health Research, the U.S. Environmental Protection Agency, ENVIRON International, and EPRI to develop BBDR modeling approaches that could be used to inform a nonlinear cancer dose response assessment for inorganic arsenic. These efforts are focused on: (1) the refinement of physiologically based pharmacokinetic (PBPK) models of the kinetics of inorganic arsenic and its metabolites in the mouse and human; (2) the investigation of mathematical solutions for multi-stage cancer models involving multiple pathways of cell transformation; (3) the review and evaluation of the literature on the dose response for the genomic effects of arsenic; and (4) the collection of data on the dose response for genomic changes in the urinary bladder (a human target tissue for arsenic carcinogenesis) associated with in vivo drinking water exposures in the mouse as well as in vitro exposures of both mouse and human cells. An approach is proposed for conducting a biologically based margin of exposure risk assessment for inorganic arsenic using the in vitro dose response for the expression of genes associated with the obligatory precursor events for arsenic tumorigenesis

  3. Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

    Science.gov (United States)

    González, S J; Pozzi, E C C; Monti Hughes, A; Provenzano, L; Koivunoro, H; Carando, D G; Thorp, S I; Casal, M R; Bortolussi, S; Trivillin, V A; Garabalino, M A; Curotto, P; Heber, E M; Santa Cruz, G A; Kankaanranta, L; Joensuu, H; Schwint, A E

    2017-10-03

    Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed

  4. Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer

    Science.gov (United States)

    González, S. J.; Pozzi, E. C. C.; Monti Hughes, A.; Provenzano, L.; Koivunoro, H.; Carando, D. G.; Thorp, S. I.; Casal, M. R.; Bortolussi, S.; Trivillin, V. A.; Garabalino, M. A.; Curotto, P.; Heber, E. M.; Santa Cruz, G. A.; Kankaanranta, L.; Joensuu, H.; Schwint, A. E.

    2017-10-01

    Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson’s correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed

  5. Dose-response models for the radiation-induction of skin tumours in mice

    International Nuclear Information System (INIS)

    Papworth, D.G.; Hulse, E.V.

    1983-01-01

    Extensive data on radiation-induced skin tumours in mice were examined using 8 models, all based on the concept that incidences of radiation-induced tumours depend on a combination of two radiation effects: a tumour induction process and the loss of reproductive integrity by the potential tumour cells. Models with and without a threshold were used, in spite of theoretical objections to threshold models. No model fitted well both the epidermal and the dermal tumour data and models which proved to be statistically satisfactory for some of the data were rejected for biological reasons. It is concluded that, for skin tumours, dose-response curves depending on a combination of cancer induction and loss of cellular reproductive integrity are distorted by some special, relatively radio-resistant, factor which we have previously postulated as being involved in radiation skin carcinogenesis. (author)

  6. Computational Modeling of Micrometastatic Breast Cancer Radiation Dose Response

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Daniel L.; Debeb, Bisrat G. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Thames, Howard D. [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Woodward, Wendy A., E-mail: wwoodward@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2016-09-01

    Purpose: Prophylactic cranial irradiation (PCI) involves giving radiation to the entire brain with the goals of reducing the incidence of brain metastasis and improving overall survival. Experimentally, we have demonstrated that PCI prevents brain metastases in a breast cancer mouse model. We developed a computational model to expand on and aid in the interpretation of our experimental results. Methods and Materials: MATLAB was used to develop a computational model of brain metastasis and PCI in mice. Model input parameters were optimized such that the model output would match the experimental number of metastases per mouse from the unirradiated group. An independent in vivo–limiting dilution experiment was performed to validate the model. The effect of whole brain irradiation at different measurement points after tumor cells were injected was evaluated in terms of the incidence, number of metastases, and tumor burden and was then compared with the corresponding experimental data. Results: In the optimized model, the correlation between the number of metastases per mouse and the experimental fits was >95. Our attempt to validate the model with a limiting dilution assay produced 99.9% correlation with respect to the incidence of metastases. The model accurately predicted the effect of whole-brain irradiation given 3 weeks after cell injection but substantially underestimated its effect when delivered 5 days after cell injection. The model further demonstrated that delaying whole-brain irradiation until the development of gross disease introduces a dose threshold that must be reached before a reduction in incidence can be realized. Conclusions: Our computational model of mouse brain metastasis and PCI correlated strongly with our experiments with unirradiated mice. The results further suggest that early treatment of subclinical disease is more effective than irradiating established disease.

  7. Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    Energy Technology Data Exchange (ETDEWEB)

    Calabrese, Edward J. [Environmental Health Sciences, School of Public Health, Morrill I, N344, University of Massachusetts, Amherst, MA 01003 (United States)]. E-mail: edwardc@schoolph.umass.edu

    2005-12-15

    This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted. - The quantitative features of the hormetic dose/response are described and placed within the context of toxicology.

  8. Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    International Nuclear Information System (INIS)

    Calabrese, Edward J.

    2005-01-01

    This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted. - The quantitative features of the hormetic dose/response are described and placed within the context of toxicology

  9. Biological profiling and dose-response modeling tools ...

    Science.gov (United States)

    Through its ToxCast project, the U.S. EPA has developed a battery of in vitro high throughput screening (HTS) assays designed to assess the potential toxicity of environmental chemicals. At present, over 1800 chemicals have been tested in up to 600 assays, yielding a large number of concentration-response data sets. Standard processing of these data sets involves finding a best fitting mathematical model and set of model parameters that specify this model. The model parameters include quantities such as the half-maximal activity concentration (or “AC50”) that have biological significance and can be used to inform the efficacy or potency of a given chemical with respect to a given assay. All of this data is processed and stored in an online-accessible database and website: http://actor.epa.gov/dashboard2. Results from these in vitro assays are used in a multitude of ways. New pathways and targets can be identified and incorporated into new or existing adverse outcome pathways (AOPs). Pharmacokinetic models such as those implemented EPA’s HTTK R package can be used to translate an in vitro concentration into an in vivo dose; i.e., one can predict the oral equivalent dose that might be expected to activate a specific biological pathway. Such predicted values can then be compared with estimated actual human exposures prioritize chemicals for further testing.Any quantitative examination should be accompanied by estimation of uncertainty. We are developing met

  10. Mathematical modeling improves EC50 estimations from classical dose-response curves.

    Science.gov (United States)

    Nyman, Elin; Lindgren, Isa; Lövfors, William; Lundengård, Karin; Cervin, Ida; Sjöström, Theresia Arbring; Altimiras, Jordi; Cedersund, Gunnar

    2015-03-01

    The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time-resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180-525 nm) is higher than the classically interpreted EC50 (46-191 nm). Mathematical modeling thus makes it possible to re-interpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible. The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman. © 2015 FEBS.

  11. Droplet-based microfluidics for dose-response assay of enzyme inhibitors by electrochemical method.

    Science.gov (United States)

    Gu, Shuqing; Lu, Youlan; Ding, Yaping; Li, Li; Zhang, Fenfen; Wu, Qingsheng

    2013-09-24

    A simple but robust droplet-based microfluidic system was developed for dose-response enzyme inhibition assay by combining concentration gradient generation method with electrochemical detection method. A slotted-vials array and a tapered tip capillary were used for reagents introduction and concentration gradient generation, and a polydimethylsiloxane (PDMS) microfluidic chip integrated with microelectrodes was used for droplet generation and electrochemical detection. Effects of oil flow rate and surfactant on electrochemical sensing were investigated. This system was validated by measuring dose-response curves of three types of acetylcholinesterase (AChE) inhibitors, including carbamate pesticide, organophosphorus pesticide, and therapeutic drugs regulating Alzheimer's disease. Carbaryl, chlorpyrifos, and tacrine were used as model analytes, respectively, and their IC50 (half maximal inhibitory concentration) values were determined. A whole enzyme inhibition assay was completed in 6 min, and the total consumption of reagents was less than 5 μL. This microfluidic system is applicable to many biochemical reactions, such as drug screening and kinetic studies, as long as one of the reactants or products is electrochemically active. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Addressing model uncertainty in dose-response: The case of chloroform

    International Nuclear Information System (INIS)

    Evans, J.S.

    1994-01-01

    This paper discusses the issues involved in addressing model uncertainty in the analysis of dose-response relationships. A method for addressing model uncertainty is described and applied to characterize the uncertainty in estimates of the carcinogenic potency of chloroform. The approach, which is rooted in Bayesian concepts of subjective probability, uses probability trees and formally-elicited expert judgments to address model uncertainty. It is argued that a similar approach could be used to improve the characterization of model uncertainty in the dose-response relationships for health effects from ionizing radiation

  13. Estimating adolescent sleep need using dose-response modeling.

    Science.gov (United States)

    Short, Michelle A; Weber, Nathan; Reynolds, Chelsea; Coussens, Scott; Carskadon, Mary A

    2018-04-01

    This study will (1) estimate the nightly sleep need of human adolescents, (2) determine the time course and severity of sleep-related deficits when sleep is reduced below this optimal quantity, and (3) determine whether sleep restriction perturbs the circadian system as well as the sleep homeostat. Thirty-four adolescents aged 15 to 17 years spent 10 days and nine nights in the sleep laboratory. Between two baseline nights and two recovery nights with 10 hours' time in bed (TIB) per night, participants experienced either severe sleep restriction (5-hour TIB), moderate sleep restriction (7.5-hour TIB), or no sleep restriction (10-hour TIB) for five nights. A 10-minute psychomotor vigilance task (PVT; lapse = response after 500 ms) and the Karolinska Sleepiness Scale were administered every 3 hours during wake. Salivary dim-light melatonin onset was calculated at baseline and after four nights of each sleep dose to estimate circadian phase. Dose-dependent deficits to sleep duration, circadian phase timing, lapses of attention, and subjective sleepiness occurred. Less TIB resulted in less sleep, more lapses of attention, greater subjective sleepiness, and larger circadian phase delays. Sleep need estimated from 10-hour TIB sleep opportunities was approximately 9 hours, while modeling PVT lapse data suggested that 9.35 hours of sleep is needed to maintain optimal sustained attention performance. Sleep restriction perturbs homeostatic and circadian systems, leading to dose-dependent deficits to sustained attention and sleepiness. Adolescents require more sleep for optimal functioning than typically obtained.

  14. Evaluation of the risk of perchlorate exposure in a population of late-gestation pregnant women in the United States: Application of probabilistic biologically-based dose response modeling

    International Nuclear Information System (INIS)

    Lumen, A; George, N I

    2017-01-01

    The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15 μg/L, 20 μg/L, or 24.5 μg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198 μg/kg/day). We determined that a daily intake of 0.45 to 0.50 μg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25–0.3 μg/kg/day. Assuming a drinking water intake rate of 0.033 L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6–9.2 μg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher. - Highlights: • Probabilistic risk assessment for perchlorate in U.S. pregnant women was conducted. • No significant change in maternal fT4 predicted due to perchlorate from food alone. • Drinking water concentration allowance for perchlorate estimated as 7.6–9.2 μg/L

  15. Evaluation of the risk of perchlorate exposure in a population of late-gestation pregnant women in the United States: Application of probabilistic biologically-based dose response modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lumen, A, E-mail: Annie.Lumen@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Rd, HFT-110, Jefferson, AR 72079 (United States); George, N I, E-mail: Nysia.George@fda.hhs.gov [Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Rd, HFT-20, Jefferson, AR 72079 (United States)

    2017-05-01

    The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15 μg/L, 20 μg/L, or 24.5 μg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198 μg/kg/day). We determined that a daily intake of 0.45 to 0.50 μg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25–0.3 μg/kg/day. Assuming a drinking water intake rate of 0.033 L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6–9.2 μg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher. - Highlights: • Probabilistic risk assessment for perchlorate in U.S. pregnant women was conducted. • No significant change in maternal fT4 predicted due to perchlorate from food alone. • Drinking water concentration allowance for perchlorate estimated as 7.6–9.2 μg/L.

  16. IRSL dating of K-feldspars: Modelling natural dose response curves to deal with anomalous fading and trap competition

    International Nuclear Information System (INIS)

    Kars, Romee H.; Wallinga, Jakob

    2009-01-01

    We recently proposed a model that reconstructs the natural dose response curve for K-rich feldspars, using laboratory fading measurements and dose response as input parameters. The model is based on the relationship between recombination centre density and trap lifetime. In this study we test the working of the model by comparing modelled feldspar ages with known quartz OSL ages of the same samples and with anomalous fading-corrected feldspar ages. The modelled feldspar ages are in good agreement with quartz OSL ages and corrected feldspar ages, opening possibilities for future use of the model on samples without independent age constraints. Furthermore, we investigate the effects of trap competition on the build-up of IRSL signal using two new variations of the model. Results show that incorporating trap competition into the model reduces the agreement between feldspar IRSL ages and quartz OSL ages.

  17. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    DEFF Research Database (Denmark)

    Appelt, A. L.; Ploen, J.; Vogelius, I. R.

    2013-01-01

    estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination...... of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect...... of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D-50,D-i, and the normalized dose-response gradient, gamma(50,i). Results: A highly...

  18. Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.

    Science.gov (United States)

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

    2017-07-01

    For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 (22α̂)0.50 for 0.020.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 Poisson model dose-response curve. © 2016 Society for Risk Analysis.

  19. Dose-response relationships for environmentally mediated infectious disease transmission models.

    Directory of Open Access Journals (Sweden)

    Andrew F Brouwer

    2017-04-01

    Full Text Available Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose-response relationship. Much of the work characterizing the functional forms of dose-response relationships has used statistical fit to experimental data. However, there has been little research examining the consequences of the choice of functional form in the context of transmission dynamics. To this end, we identify four properties of dose-response functions that should be considered when selecting a functional form: low-dose linearity, scalability, concavity, and whether it is a single-hit model. We find that i middle- and high-dose data do not constrain the low-dose response, and different dose-response forms that are equally plausible given the data can lead to significant differences in simulated outbreak dynamics; ii the choice of how to aggregate continuous exposure into discrete doses can impact the modeled force of infection; iii low-dose linear, concave functions allow the basic reproduction number to control global dynamics; and iv identifiability analysis offers a way to manage multiple sources of uncertainty and leverage environmental monitoring to make inference about infectivity. By applying an environmentally mediated infectious disease model to the 1993 Milwaukee Cryptosporidium outbreak, we demonstrate that environmental monitoring allows for inference regarding the infectivity of the pathogen and thus improves our ability to identify outbreak characteristics such as pathogen strain.

  20. The Key Events Dose-Response Framework: a cross-disciplinary mode-of-action based approach to examining dose-response and thresholds.

    Science.gov (United States)

    Julien, Elizabeth; Boobis, Alan R; Olin, Stephen S

    2009-09-01

    The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents-food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework-the Key Events Dose-Response Framework (KEDRF)-for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents.

  1. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    International Nuclear Information System (INIS)

    Appelt, Ane L.; Pløen, John; Vogelius, Ivan R.; Bentzen, Søren M.; Jakobsen, Anders

    2013-01-01

    Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D 50,i , and the normalized dose-response gradient, γ 50,i . Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D 50,TRG1 = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), γ 50,TRG1 = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D 50,TRG1 and 2 = 72.1 Gy (CI 65.3-94.0 Gy), γ 50,TRG1 and 2 = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.

  2. Basic dose response of fluorescent screen-based portal imaging device

    International Nuclear Information System (INIS)

    Yeo, In Hwan; Yonannes, Yonas; Zhu, Yunping

    1999-01-01

    The purpose of this study is to investigate fundamental aspects of the dose response of fluorescent screen-based electronic portal imaging devices (EPIDs). We acquired scanned signal across portal planes as we varied the radiation that entered the EPID by changing the thickness and anatomy of the phantom as well as the air gap between the phantom and the EPID. In addition, we simulated the relative contribution of the scintillation light signal in the EPID system. We have shown that the dose profile across portal planes is a function of the air gap and phantom thickness. We have also found that depending on the density change within the phantom geometry, errors associated with dose response based on the EPID scan can be as high as 7%. We also found that scintillation light scattering within the EPID system is an important source of error. This study revealed and demonstrated fundamental characteristics of dose response of EPID, as relative to that of ion chambers. This study showed that EPID based on fluorescent screen cannot be an accurate dosimetry system

  3. Dose-response model of Rocky Mountain spotted fever (RMSF) for human.

    Science.gov (United States)

    Tamrakar, Sushil B; Haas, Charles N

    2011-10-01

    Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae, which is found in North, Central, and South America. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through tick bites; however, some cases of aerosol transmission also have been reported. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment, it can be fatal. This article develops dose-response models of different routes of exposure for RMSF in primates and humans. The beta-Poisson model provided the best fit to the dose-response data of aerosol-exposed rhesus monkeys, and intradermally inoculated humans (morbidity as end point of response). The average 50% infectious dose among (ID₅₀) exposed human population, N₅₀, is 23 organisms with 95% confidence limits of 1 to 89 organisms. Similarly, ID₁₀ and ID₂₀ are 2.2 and 5.0, respectively. Moreover, the data of aerosol-exposed rhesus monkeys and intradermally inoculated humans could be pooled. This indicates that the dose-response models fitted to different data sets are not significantly different and can be described by the same relationship. © 2011 Society for Risk Analysis.

  4. Comparison of Dose Response Models for Predicting Normal Tissue Complications from Cancer Radiotherapy: Application in Rat Spinal Cord

    Energy Technology Data Exchange (ETDEWEB)

    Adamus-Górka, Magdalena; Mavroidis, Panayiotis, E-mail: panayiotis.mavroidis@ki.se; Lind, Bengt K.; Brahme, Anders [Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm S-17176 (Sweden)

    2011-05-18

    Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. The other three models: the Lyman (Gaussian distribution), the parallel architecture and the Weibull distribution models are semi-empirical and rather based on statistical distributions. The maximum likelihood estimation was used to fit the models to experimental data and the χ{sup 2}-distribution, AIC criterion and F-test were applied to compare the goodness-of-fit of the models. The comparison was performed using experimental data for rat spinal cord injury. Both the shape of the dose-response curve and the ability of handling the volume dependence were separately compared for each model. All the models were found to be acceptable in describing the present experimental dataset (p > 0.05). For the white matter necrosis dataset, the Weibull and Lyman models were clearly superior to the other models, whereas for the vascular damage case, the Relative Seriality model seems to have the best performance although the Critical volume, Inverse tumor, Critical element and Parallel architecture models gave similar results. Although the differences between many of the investigated models are rather small, they still may be of importance in indicating the advantages and limitations of each particular model. It appears that most of the models have favorable properties for describing dose-response data, which indicates that they may be suitable to be used in biologically optimized intensity modulated radiation therapy planning, provided a proper estimation of their radiobiological parameters had been performed for every tissue and clinical endpoint.

  5. Comparison of Dose Response Models for Predicting Normal Tissue Complications from Cancer Radiotherapy: Application in Rat Spinal Cord

    International Nuclear Information System (INIS)

    Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Lind, Bengt K.; Brahme, Anders

    2011-01-01

    Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. The other three models: the Lyman (Gaussian distribution), the parallel architecture and the Weibull distribution models are semi-empirical and rather based on statistical distributions. The maximum likelihood estimation was used to fit the models to experimental data and the χ 2 -distribution, AIC criterion and F-test were applied to compare the goodness-of-fit of the models. The comparison was performed using experimental data for rat spinal cord injury. Both the shape of the dose-response curve and the ability of handling the volume dependence were separately compared for each model. All the models were found to be acceptable in describing the present experimental dataset (p > 0.05). For the white matter necrosis dataset, the Weibull and Lyman models were clearly superior to the other models, whereas for the vascular damage case, the Relative Seriality model seems to have the best performance although the Critical volume, Inverse tumor, Critical element and Parallel architecture models gave similar results. Although the differences between many of the investigated models are rather small, they still may be of importance in indicating the advantages and limitations of each particular model. It appears that most of the models have favorable properties for describing dose-response data, which indicates that they may be suitable to be used in biologically optimized intensity modulated radiation therapy planning, provided a proper estimation of their radiobiological parameters had been performed for every tissue and clinical endpoint

  6. Fractional poisson--a simple dose-response model for human norovirus.

    Science.gov (United States)

    Messner, Michael J; Berger, Philip; Nappier, Sharon P

    2014-10-01

    This study utilizes old and new Norovirus (NoV) human challenge data to model the dose-response relationship for human NoV infection. The combined data set is used to update estimates from a previously published beta-Poisson dose-response model that includes parameters for virus aggregation and for a beta-distribution that describes variable susceptibility among hosts. The quality of the beta-Poisson model is examined and a simpler model is proposed. The new model (fractional Poisson) characterizes hosts as either perfectly susceptible or perfectly immune, requiring a single parameter (the fraction of perfectly susceptible hosts) in place of the two-parameter beta-distribution. A second parameter is included to account for virus aggregation in the same fashion as it is added to the beta-Poisson model. Infection probability is simply the product of the probability of nonzero exposure (at least one virus or aggregate is ingested) and the fraction of susceptible hosts. The model is computationally simple and appears to be well suited to the data from the NoV human challenge studies. The model's deviance is similar to that of the beta-Poisson, but with one parameter, rather than two. As a result, the Akaike information criterion favors the fractional Poisson over the beta-Poisson model. At low, environmentally relevant exposure levels (Poisson model; however, caution is advised because no subjects were challenged at such a low dose. New low-dose data would be of great value to further clarify the NoV dose-response relationship and to support improved risk assessment for environmentally relevant exposures. © 2014 Society for Risk Analysis Published 2014. This article is a U.S. Government work and is in the public domain for the U.S.A.

  7. Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system.

    Science.gov (United States)

    Aldelaijan, Saad; Devic, Slobodan

    2018-05-01

    Different dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation. Pieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis. Response functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy. Although reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  8. Dose-response study of the hematological toxicity induced by vectorized radionuclides in a mouse model

    International Nuclear Information System (INIS)

    Rousseau-Poivet, J.; Sas, N.; Nguyen, F.; Abadie, J.; Chouin, N.; Barbet, J.

    2015-01-01

    studied progenitor and blood cells. As compared to 0.8 Gy, one more week was necessary at 1.4 Gy. A mild anemia (21% erythrocyte depletion) was noticed only at this higher absorbed dose between D3 and D10. Conclusion: absorbed doses to the BM between 0.8 and 1.4 Gy induced hematological toxicity expressed by transient BM aplasia, neutropenia, thrombocytopenia and inconsistent anemia. These depletions and time to recovery were both dose-dependent. Higher absorbed doses will be achieved to better investigate the dose-response relationship and to further develop our compartmental model for platelets. Neutrophils and erythrocytes kinetics are also under investigation to generate satisfying simulations with the model. (authors)

  9. An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

    Science.gov (United States)

    Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

    2016-05-01

    Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with

  10. Computational systems biology and dose-response modeling in relation to new directions in toxicity testing.

    Science.gov (United States)

    Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E; Conolly, Rory B

    2010-02-01

    The new paradigm envisioned for toxicity testing in the 21st century advocates shifting from the current animal-based testing process to a combination of in vitro cell-based studies, high-throughput techniques, and in silico modeling. A strategic component of the vision is the adoption of the systems biology approach to acquire, analyze, and interpret toxicity pathway data. As key toxicity pathways are identified and their wiring details elucidated using traditional and high-throughput techniques, there is a pressing need to understand their qualitative and quantitative behaviors in response to perturbation by both physiological signals and exogenous stressors. The complexity of these molecular networks makes the task of understanding cellular responses merely by human intuition challenging, if not impossible. This process can be aided by mathematical modeling and computer simulation of the networks and their dynamic behaviors. A number of theoretical frameworks were developed in the last century for understanding dynamical systems in science and engineering disciplines. These frameworks, which include metabolic control analysis, biochemical systems theory, nonlinear dynamics, and control theory, can greatly facilitate the process of organizing, analyzing, and understanding toxicity pathways. Such analysis will require a comprehensive examination of the dynamic properties of "network motifs"--the basic building blocks of molecular circuits. Network motifs like feedback and feedforward loops appear repeatedly in various molecular circuits across cell types and enable vital cellular functions like homeostasis, all-or-none response, memory, and biological rhythm. These functional motifs and associated qualitative and quantitative properties are the predominant source of nonlinearities observed in cellular dose response data. Complex response behaviors can arise from toxicity pathways built upon combinations of network motifs. While the field of computational cell

  11. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    Directory of Open Access Journals (Sweden)

    Jan B W J Cornelissen

    Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  12. Evaluation of Different Dose-Response Models for High Hydrostatic Pressure Inactivation of Microorganisms

    Directory of Open Access Journals (Sweden)

    Sencer Buzrul

    2017-09-01

    Full Text Available Modeling of microbial inactivation by high hydrostatic pressure (HHP requires a plot of the log microbial count or survival ratio versus time data under a constant pressure and temperature. However, at low pressure and temperature values, very long holding times are needed to obtain measurable inactivation. Since the time has a significant effect on the cost of HHP processing it may be reasonable to fix the time at an appropriate value and quantify the inactivation with respect to pressure. Such a plot is called dose-response curve and it may be more beneficial than the traditional inactivation modeling since short holding times with different pressure values can be selected and used for the modeling of HHP inactivation. For this purpose, 49 dose-response curves (with at least 4 log10 reduction and ≥5 data points including the atmospheric pressure value (P = 0.1 MPa, and with holding time ≤10 min for HHP inactivation of microorganisms obtained from published studies were fitted with four different models, namely the Discrete model, Shoulder model, Fermi equation, and Weibull model, and the pressure value needed for 5 log10 (P5 inactivation was calculated for all the models above. The Shoulder model and Fermi equation produced exactly the same parameter and P5 values, while the Discrete model produced similar or sometimes the exact same parameter values as the Fermi equation. The Weibull model produced the worst fit (had the lowest adjusted determination coefficient (R2adj and highest mean square error (MSE values, while the Fermi equation had the best fit (the highest R2adj and lowest MSE values. Parameters of the models and also P5 values of each model can be useful for the further experimental design of HHP processing and also for the comparison of the pressure resistance of different microorganisms. Further experiments can be done to verify the P5 values at given conditions. The procedure given in this study can also be extended for

  13. Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment

    International Nuclear Information System (INIS)

    Al-Mayah, Adil; Moseley, Joanne; Hunter, Shannon; Brock, Kristy

    2015-01-01

    Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D). (paper)

  14. Hormesis: from marginalization to mainstream A case for hormesis as the default dose-response model in risk assessment

    International Nuclear Information System (INIS)

    Calabrese, Edward J.

    2004-01-01

    The paper provides an account of how the hormetic dose response has emerged in recent years as a serious dose-response model in toxicology and risk assessment after decades of extreme marginalization. In addition to providing the toxicological basis of this dose-response revival, the paper reexamines the concept of a default dose model in toxicology and risk assessment and makes the argument that the hormetic model satisfies criteria (e.g., generalizability, frequency, application to risk assessment endpoints, false positive/negative potential, requirements for hazard assessment, reliability of estimating risks, capacity for validation of risk estimates, public health implications of risk estimates) for such a default model better than its chief competitors, the threshold and linear at low dose models. The selection of the hormetic model as the default model in risk assessment for noncarcinogens and specifically for carcinogens would have a profound impact on the practice of risk assessment and its societal implications

  15. Using plant biomonitors and flux modelling to develop O3 dose-response relationships in Catalonia

    International Nuclear Information System (INIS)

    Filella, Iolanda; Pen-tilde uelas, Josep; Ribas, Angela

    2005-01-01

    We used tobacco Bel-W3 biomonitoring data and ozone flux modelling (WINDEP model) with the aim of developing the absorbed dose-response relationship, and comparing this approach with the most commonly used AOT40 (the sum of hourly ozone concentrations above a cut-off of 40 ppb during daylight hours, when global radiation exceeds 50 W m -2 ) in the estimation of exposure-damage curves. Leaf damage values were more related to OAD 15days,potential (potential ozone absorbed dose calculated over 15 consecutive days) than to AOT40 in all the studied stations. An OAD 15days,potential of 180 mg m -2 was found to be the threshold for damage to the most sensitive species in this region under well watered conditions. The results show the applicability of the flux approach for risk assessment at the local scale, the improvement of the ozone damage estimation when the potential absorbed dose is modelled and used instead of just the ozone exposure, and finally, the possibilities opened by the use of biomonitoring networks. - Modelling of biomonitors ozone absorbed dose improves damage estimation in comparison with exposure indices such as AOT40

  16. New flux based dose-response relationships for ozone for European forest tree species.

    Science.gov (United States)

    Büker, P; Feng, Z; Uddling, J; Briolat, A; Alonso, R; Braun, S; Elvira, S; Gerosa, G; Karlsson, P E; Le Thiec, D; Marzuoli, R; Mills, G; Oksanen, E; Wieser, G; Wilkinson, M; Emberson, L D

    2015-11-01

    To derive O3 dose-response relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  17. Three-dimensional dose-response models of risk for radiation injury carcinogenesis

    International Nuclear Information System (INIS)

    Raabe, O.G.

    1988-01-01

    The use of computer graphics in conjunction with three-dimensional models of dose-response relationships for chronic exposure to ionizing radiation dramaticly clarifies the separate and interactive roles of competing risks. The three dimensions are average dose rate, exposure time, and risk. As an example, the functionally injurious and carcinogenic responses after systemic uptake of Ra-226 by beagles, mice and people with consequent alpha particle irradiation of the bone are represented by three-dimensional dose-rate/time/response surfaces that demonstrate the contributions with the passage of time of the competing deleterious responses. These relationships are further evaluated by mathematical stripping with three-dimensional illustrations that graphically show the resultant separate contribution of each effect. Radiation bone injury predominates at high dose rates and bone cancer at intermediate dose rates. Low dose rates result in spontaneous deaths from natural aging, yielding a type of practical threshold for bone cancer induction. Risk assessment is benefited by the insights that become apparent with these three-dimensional models. The improved conceptualization afforded by them contributes to planning and evaluating epidemiological analyses and experimental studies

  18. Computational model of dose response for low-LET-induced complex chromosomal aberrations

    International Nuclear Information System (INIS)

    Eidelman, Y.A.; Andreev, S.G.

    2015-01-01

    Experiments with full-colour mFISH chromosome painting have revealed high yield of radiation-induced complex chromosomal aberrations (CAs). The ratio of complex to simple aberrations is dependent on cell type and linear energy transfer. Theoretical analysis has demonstrated that the mechanism of CA formation as a result of interaction between lesions at a surface of chromosome territories does not explain high complexes-to-simples ratio in human lymphocytes. The possible origin of high yields of γ-induced complex CAs was investigated in the present work by computer simulation. CAs were studied on the basis of chromosome structure and dynamics modelling and the hypothesis of CA formation on nuclear centres. The spatial organisation of all chromosomes in a human interphase nucleus was predicted by simulation of mitosis-to-interphase chromosome structure transition. Two scenarios of CA formation were analysed, 'static' (existing in a nucleus prior to irradiation) centres and 'dynamic' (formed in response to irradiation) centres. The modelling results reveal that under certain conditions, both scenarios explain quantitatively the dose-response relationships for both simple and complex γ-induced inter-chromosomal exchanges observed by mFISH chromosome painting in the first post-irradiation mitosis in human lymphocytes. (authors)

  19. Youth suicide attempts and the dose-response relationship to parental risk factors: a population-based study

    DEFF Research Database (Denmark)

    Christiansen, E; Goldney, R D; Beautrai, A L

    2011-01-01

    BACKGROUND: There is a lack of specific knowledge about the dose-response effect of multiple parental risk factors for suicide attempts among children and adolescents. The aim of this study was to determine the dose-response effect of multiple parental risk factors on an offspring's risk for suic......BACKGROUND: There is a lack of specific knowledge about the dose-response effect of multiple parental risk factors for suicide attempts among children and adolescents. The aim of this study was to determine the dose-response effect of multiple parental risk factors on an offspring's risk...... for suicide attempt.MethodWe designed a population-based two-generation nested case-control study and used Danish register data. A population of 403 431 individuals born between 1983 and 1989 was sampled. Among these, 3465 (0.8%) were registered as having had a suicide attempt. Twenty controls were matched...... to each case and a link to the offspring's biological parents was established. RESULTS: There was a dose-response relationship between the number of exposures and the risk of suicide attempts, with the increased risk seeming to be a multiplicative effect. Parental suicide, suicide attempt, psychiatric...

  20. Gamma- and electron dose response of the electrical conductivity of polyaniline based polymer blends

    International Nuclear Information System (INIS)

    Sevil, U.A.; Gueven, O.; Slezsak, I.

    2002-01-01

    Complete text of publication follows. Conducting polymers, also known as 'synthetic metals' have been the subject of widespread investigations over the past decade due to their very promising characteristics. Polyaniline (PANI) holds a special position among conducting polymers in that its most highly conducting doped form can be reached by protonic acid doping or oxidative doping. It was published earlier, that the electrical conductivity of some polyaniline based polymer composites increases to a significant extent when irradiated to gamma, electron or UV radiation. The aim of the present study was to measure the high frequency conductivity of blended films of PANI with poly(vinylchloride), PVC, and chlorinated poly(propylene) irradiated in air to different doses. In order to find the most suitable composition od these composites the mass percentage of PANI within the PPCl and PVC matrix was changed between 5 - 30%. These samples were then gamma irradiated and the induced electrical conductivity was measured in the 1 kHz - 1 MHz frequency range to determine the most sensitive evaluation conditions. After selecting both the most suitable measuring conditions as well as the blend compositions the dose response of the chosen samples was determined in the dose range of 10 - 250 kGy. With respect to potential dosimetry application the effect of electron irradiation, the effect of irradiation temperature and the stability of the irradiated samples have also been investigated

  1. Sludge reduction by ozone: Insights and modeling of the dose-response effects.

    Science.gov (United States)

    Fall, C; Silva-Hernández, B C; Hooijmans, C M; Lopez-Vazquez, C M; Esparza-Soto, M; Lucero-Chávez, M; van Loosdrecht, M C M

    2018-01-15

    Applying ozone to the return flow in an activated sludge (AS) process is a way for reducing the residual solids production. To be able to extend the activated sludge models to the ozone-AS process, adequate prediction of the tri-atoms effects on the particulate COD fractions is needed. In this study, the biomass inactivation, COD mineralization, and solids dissolution were quantified in batch tests and dose-response models were developed as a function of the reacted ozone doses (ROD). Three kinds of model-sludge were used. S1 was a lab-cultivated synthetic sludge with two components (heterotrophs X H and X P ). S2 was a digestate of S1 almost made by the endogenous residues, X P . S3 was from a municipal activated sludge plant. The specific ozone uptake rate (SO 3 UR, mgO 3 /gCOD.h) was determined as a tool for characterizing the reactivity of the sludges. SO 3 UR increased with the X H fraction and decreased with more X P . Biomass inactivation was exponential (e -β.ROD ) as a function of the ROD doses. The percentage of solids reduction was predictable through a linear model (C Miner  + Y sol ROD), with a fixed part due to mineralization (C Miner ) and a variable part from the solubilization process. The parameters of the models, i.e. the inactivation and the dissolution yields (β, 0.008-0.029 (mgO 3 /mgCOD ini ) -1 vs Y sol , 0.5-2.8 mg COD sol /mgO 3 ) varied in magnitude, depending on the intensity of the scavenging reactions and potentially the compactness of the flocs for each sludge. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Dose-response model of murine typhus (Rickettsia typhi: time post inoculation and host age dependency analysis

    Directory of Open Access Journals (Sweden)

    Tamrakar Sushil B

    2012-03-01

    Full Text Available Abstract Background Rickettsia typhi (R. mooseri is the causative agent of murine typhus. It is one of the most widely distributed flea-borne diseases with a relatively mild febrile initial illness with six to 14 days of incubation period. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through fleabites or via contact with infected feces. This paper develops dose-response models of different routes of exposure for typhus in rodents. Methods Data from published articles were analyzed using parametric dose-response relationship models. Dose-response relationships were fit to data using the method of maximum likelihood estimation (MLE. Results Dose-response models quantifying the effects of different ages of rats and time post inoculation in BALB/c mice were analyzed in the study. Both the adult rats (inoculated intradermally and newborn rats (inoculated subcutaneously were best fit by exponential models and both distributions could be described by a single dose-response relationship. The BALB/C mice inoculated subcutaneously were best fit by Beta-Poisson models. The time post inoculation analysis showed that there was a definite time and response relationship existed in this case. Conclusions Intradermally or subcutaneously inoculated rats (adult and newborn models suggest that less than 1 plaque-forming unit (PFU (1.33 to 0.38 in 95% confidence limits of the pathogen is enough to seroconvert 50% of the exposed population on average. For the BALB/c mouse time post inoculation model, an average dose of 0.28 plaque-forming units (PFU (0.75 to 0.11 in 95% confidence limits will seroconvert 50% of the exposed mice.

  3. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Science.gov (United States)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  4. Dose Response Model of Biological Reaction to Low Dose Rate Gamma Radiation

    International Nuclear Information System (INIS)

    Magae, J.; Furikawa, C.; Hoshi, Y.; Kawakami, Y.; Ogata, H.

    2004-01-01

    It is necessary to use reproducible and stable indicators to evaluate biological responses to long term irradiation at low dose-rate. They should be simple and quantitative enough to produce the results statistically accurate, because we have to analyze the subtle changes of biological responses around background level at low dose. For these purposes we chose micronucleus formation of U2OS, a human osteosarcoma cell line, as indicators of biological responses. Cells were exposed to gamma ray in irradiation rom bearing 50,000 Ci 60Co. After irradiation, they were cultured for 24 h in the presence of cytochalasin B to block cytokinesis, and cytoplasm and nucleus were stained with DAPI and prospidium iodide, respectively. the number of binuclear cells bearing micronuclei was counted under a fluorescence microscope. Dose rate in the irradiation room was measured with PLD. Dose response of PLD is linear between 1 mGy to 10 Gy, and standard deviation of triplicate count was several percent of mean value. We fitted statistically dose response curves to the data, and they were plotted on the coordinate of linearly scale response and dose. The results followed to the straight line passing through the origin of the coordinate axes between 0.1-5 Gy, and dose and does rate effectiveness factor (DDREF) was less than 2 when cells were irradiated for 1-10 min. Difference of the percent binuclear cells bearing micronucleus between irradiated cells and control cells was not statistically significant at the dose above 0.1 Gy when 5,000 binuclear cells were analyzed. In contrast, dose response curves never followed LNT, when cells were irradiated for 7 to 124 days. Difference of the percent binuclear cells bearing micronucleus between irradiated cells and control cells was not statistically significant at the dose below 6 Gy, when cells were continuously irradiated for 124 days. These results suggest that dose response curve of biological reaction is remarkably affected by exposure

  5. A study on dose response of NIPAM-based dosimeter used in radiotherapy

    International Nuclear Information System (INIS)

    Hsieh, B.T.; Wu, J.; Chang, Y.J.; Han, R.P.; Hsieh, L.L.; Chang, C.J.

    2011-01-01

    The newly manufactured N-isopropylacrylamide (NIPAM) polymer gel is composed of four components, i.e., gelatin, monomer (NIPAM), crosslinker (N,N'-methylenebisacrylamide, Bis), and antioxidant (tetrakis hydroxymethyl phosphonium chloride, THPC). In this study, we investigated the effects of gel composition on the dose response of NIPAM polymer gel. A statistical experiment to analyze the contribution of each composition to the linearity and sensitivity of NIPAM gel was performed. Results indicate that the amount of gelatin, NIPAM (15.17%), Bis, and THPC have dominant effects on the sensitivity of the gel, with contributions of 59.73, 15.17, 10.64, and 14.45%, respectively. The amount of gelatin and Bis mainly affected the linearity of the gel, with contributions of 44.70 and 50.99%, respectively. The linearity of most compositions of the gel was greater than 0.99 when (%C)/(%T) was lower than 8.0. Optimal (%C)/(%T) for higher sensitivity should be in the range of 4-9. The temporal stability experiment showed that the dose response curve attained stability at about 5 h after irradiation and persisted up to 3 months. (author)

  6. Dose response characteristics of polymethacrylic acid gel (PMAAG) for a polymerization-based dosimeter using NMR.

    Science.gov (United States)

    Iskandar, S M; Elias, S; Jumiah, H; Asri, M T M; Masrianis, A; Ab Rahman, M Z; Taiman, K; Abdul Rashid, M Y

    2004-05-01

    The radiation-response characteristics of polymetharylic acid gel dosimeter prepared with different concentrations of monomer and cross-linker is described in these studies. The dosimeters were prepared under the hypoxic condition in a glove box and were then irradiated with gamma-rays produced by Co-60 radionuclide that was generated at 1.25MeV energy. The irradiation took place at different doses ranged from 0Gy to 19Gy. Due to the radiation activities, chain-reaction polymerisation processes had taken place in the formation of polymethacrylic acid (PMAA) gel, which cause the dose response mechanism increased in the NMR relaxation rates of protons. It has been observed that for higher concentration of monomer and cross-linker, the polymerization rate was increased.

  7. Multistage models of carcinogenesis and their implications for dose-response models and risk projections

    International Nuclear Information System (INIS)

    Hoel, D.G.

    1992-01-01

    Multistage models are used to both describe the biological steps in developing a cancer and as a mathematical description of the relationship of exposure to tumor incidence. With the rapid development of molecular biology the stages of tumor development are becoming understood. Specifically, the effect and role of proto-oncogenes and suppressor genes are exciting developments in the field of carcinogenesis. Mathematically the field has moved from the original Armitage-Doll multistage model to the more current cell kinetic models. These latter models attempt to describe both the rate of cell mutation and the birth-death process involved in clonal expansion. This then allows modeling of both initiation and promotion or cellular proliferation. The field of radiation carcinogenesis has a considerable body of data and knowledge. Unfortunately, relatively little work has been done with the cell kinetic models as to estimation of tumor incidence. This may be due to the newness of kinetic models in general. The field holds promise and it is essential if we are to develop better human risk estimates from exposure to ionizing radiation. (author)

  8. Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

    Science.gov (United States)

    Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

    2018-01-12

    Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

  9. SU-D-16A-03: A Radiation Pneumonitis Dose-Response Model Incorporating Non- Local Radiation-Induced Bystander Effect

    International Nuclear Information System (INIS)

    Gordon, J; Snyder, K; Zhong, H; Chetty, I

    2014-01-01

    Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an

  10. SU-D-16A-03: A Radiation Pneumonitis Dose-Response Model Incorporating Non- Local Radiation-Induced Bystander Effect

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, J; Snyder, K; Zhong, H; Chetty, I [Henry Ford Health System, Dept. Radiation Oncology, Detroit, MI (United States)

    2014-06-01

    Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an

  11. Dose response from pharmacological interventions for CBF changes in a baboon model using 99Tcm-HMPAO and SPECT

    International Nuclear Information System (INIS)

    Dormehl, I.C.; Hugo, N.; Oliver, D.W.

    1993-01-01

    This study assesses the sensitivity of the baboon model under anaesthesia to determine by single photon emission computed tomography (SPECT) and 99 Tc m -hexamethylpropyleneamine oxime (HMPAO) dose responses from drugs (acetazolamide) with known regional cerebral blood flow (rCBF) effects on humans. Three dosages of acetazolamide were chosen: 250, 500 and 750 mg. The effects of these were studied by conventional SPECT 5 min after intravenous (i.v.) administration and compared to previous studies of rCBF with the baboons under anaesthesia only. An additional study concerned the effect of 500 mg acetazolamide at 15 min after administration. Haemodynamic parameters and blood gases were also monitored. No statistically significant regional effects were noted. The largest increase in CBF (39%) was observed from 500 mg acetazolamide after 5 min. This was statistically significantly different from control values only at a 10% level of confidence; then following a 27% increase above control values after 750 mg (5 min). At 15 min 500 mg yielded values lower by 10% than the high dose. No effects were observed from 250 mg acetazolamide; only pO 2 showed changes which largely confirm the CBF findings. The model did not give significant results at a 5% level of confidence but large fluctuations were observed, also in the haemodynamic and blood gas values. At a 10% level a significant dose response was confirmed for acetazolamide. (author)

  12. Pathway to a paradigm: the linear nonthreshold dose-response model in historical context. The American Academy of Health Physics 1995 Radiology Centennial Hartman Oration.

    Science.gov (United States)

    Kathren, R L

    1996-05-01

    This paper traces the evolution of the linear nonthreshold dose-response model and its acceptance as a paradigm in radiation protection practice and risk analysis. Deterministic effects such as skin burns and even deep tissue trauma were associated with excessive exposure to x rays shortly after their discovery, and carcinogenicity was observed as early as 1902. Still, it was not until 1925 that the first protective limits were suggested. For three decades these limits were based on the concept of a tolerance dose which, if not exceeded, would result in no demonstrable harm to the individual and implicitly assumed a threshold dose below which radiation effects would be absent. After World War II, largely because of genetic concerns related to atmospheric weapons testing, radiation protection dose limits were expressed in terms of a risk based maximum permissible dose which clearly implied no threshold. The 1927 discovery by Muller of x-ray induced genetic mutations in fruit flies, linear with dose and with no apparent threshold, was an important underpinning of the standards. The linear nonthreshold dose-response model was originally used to provide an upper limit estimate of the risk, with zero being the lower limit, of low level irradiation since the dose-response curve could not be determined at low dose levels. Evidence to the contrary such as hormesis and the classic studies of the radium dial painters notwithstanding, the linear nonthreshold model gained greater acceptance and in the centennial year of the discovery of x rays stands as a paradigm although serious questions are beginning to be raised regarding its general applicability. The work includes a brief digression describing the work of x-ray protection pioneer William Rollins and concludes with a recommendation for application of a de minimis dose level in radiation protection.

  13. Harnessing the theoretical foundations of the exponential and beta-Poisson dose-response models to quantify parameter uncertainty using Markov Chain Monte Carlo.

    Science.gov (United States)

    Schmidt, Philip J; Pintar, Katarina D M; Fazil, Aamir M; Topp, Edward

    2013-09-01

    Dose-response models are the essential link between exposure assessment and computed risk values in quantitative microbial risk assessment, yet the uncertainty that is inherent to computed risks because the dose-response model parameters are estimated using limited epidemiological data is rarely quantified. Second-order risk characterization approaches incorporating uncertainty in dose-response model parameters can provide more complete information to decisionmakers by separating variability and uncertainty to quantify the uncertainty in computed risks. Therefore, the objective of this work is to develop procedures to sample from posterior distributions describing uncertainty in the parameters of exponential and beta-Poisson dose-response models using Bayes's theorem and Markov Chain Monte Carlo (in OpenBUGS). The theoretical origins of the beta-Poisson dose-response model are used to identify a decomposed version of the model that enables Bayesian analysis without the need to evaluate Kummer confluent hypergeometric functions. Herein, it is also established that the beta distribution in the beta-Poisson dose-response model cannot address variation among individual pathogens, criteria to validate use of the conventional approximation to the beta-Poisson model are proposed, and simple algorithms to evaluate actual beta-Poisson probabilities of infection are investigated. The developed MCMC procedures are applied to analysis of a case study data set, and it is demonstrated that an important region of the posterior distribution of the beta-Poisson dose-response model parameters is attributable to the absence of low-dose data. This region includes beta-Poisson models for which the conventional approximation is especially invalid and in which many beta distributions have an extreme shape with questionable plausibility. © Her Majesty the Queen in Right of Canada 2013. Reproduced with the permission of the Minister of the Public Health Agency of Canada.

  14. A comparison of dose-response characteristics of four NTCP models using outcomes of radiation-induced optic neuropathy and retinopathy

    International Nuclear Information System (INIS)

    Moiseenko, Vitali; Song, William Y; Mell, Loren K; Bhandare, Niranjan

    2011-01-01

    Biological models are used to relate the outcome of radiation therapy to dose distribution. As use of biological models in treatment planning expands, uncertainties associated with the use of specific models for predicting outcomes should be understood and quantified. In particular, the question to what extent model predictions are data-driven or dependent on the choice of the model has to be explored. Four dose-response models--logistic, log-logistic, Poisson-based and probit--were tested for their ability and consistency in describing dose-response data for radiation-induced optic neuropathy (RION) and retinopathy (RIRP). Dose to the optic nerves was specified as the minimum dose, D min , received by any segment of the organ to which the damage was diagnosed by ophthalmologic evaluation. For retinopathy, the dose to the retina was specified as the highest isodose covering at least 1/3 of the retinal surface (D 33% ) that geometrically covered the observed retinal damage. Data on both complications were modeled separately for patients treated once daily and twice daily. Model parameters D 50 and γ and corresponding confidence intervals were obtained using maximum-likelihood method. Model parameters were reasonably consistent for RION data for patients treated once daily, D 50 ranging from 94.2 to 104.7 Gy and γ from 0.88 to 1.41. Similar consistency was seen for RIRP data which span a broad range of complication incidence, with D 50 from 72.2 to 75.0 Gy and γ from 1.51 to 2.16 for patients treated twice daily; 72.2-74.0 Gy and 0.84-1.20 for patients treated once daily. However, large variations were observed for RION in patients treated twice daily, D 50 from 96.3 to 125.2 Gy and γ from 0.80 to 1.56. Complication incidence in this dataset in any dose group did not exceed 20%. For the considered data sets, the log-logistic model tends to lead to larger D 50 and lower γ compared to other models for all datasets. Statements regarding normal tissue

  15. A dose-response model for the conventional phototherapy of the newborn.

    Science.gov (United States)

    Osaku, Nelson Ossamu; Lopes, Heitor Silvério

    2006-06-01

    Jaundice of the newborn is a common problem as a consequence of the rapid increment of blood bilirubin in the first days of live. In most cases, it is considered a physiological transient situation, but unmanaged hyperbilirubinemia can lead to death or serious injuries for the survivors. For decades, phototherapy has been used as the main method for prevention and treatment of hyperbilirubinaemia of the newborn. This work aims at finding a predictive model for the decrement of blood bilirubin for patients submitted to conventional phototherapy. Data from the phototherapy of 90 term newborns were collected and used in a multiple regression method. A rigorous statistical analysis was done in order to guarantee a correct and valid model. The obtained model was able to explain 78% of the variation of the dependent variable. We show that it is possible to predict the total serum bilirubin of the patient under conventional phototherapy by knowing its birth weight, bilirubin level at the beginning of treatment and the radiant energy density (dose). Besides, it is possible to infer the time necessary for a given decrement of bilirubin, under approximately constant irradiance. Statistical analysis of the obtained model shows that it is valid for several ranges of birth weight, initial bilirubin level, and radiant energy density. It is expected that the proposed model can be useful in the clinical management of hyperbilirubinemia of the newborn.

  16. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats

    NARCIS (Netherlands)

    Cornelissen, J.B.W.J.; Giessen, van der J.W.B.; Takumi, K.; Teunis, P.F.M.; Wisselink, H.J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment.

  17. The role of dose inhomogeneity in biological models of dose response

    International Nuclear Information System (INIS)

    Crawford-Brown, D.J.

    1989-01-01

    The paper focuses on the semi-empirical functions proposed by NAS (1980), ICRP (1977), in which terms for initiation and cell killing appear. The extent is not to produce a new model of carcinogenesis, or to reanalyse existing epidemiological data, but to explore whether an existing extrapolation function (proposed by the NAS) can be shown to have coherent theoretical support, while at the same time reproducing (however reasonably) the features of epidemiological data. Attention is restricted to irradiation by high LET radiations such as alpha particles, which may produce large inhomogeneities in both emission density and dose in cellular populations. Particular interest is directed towards epidemiological studies of uranium miners (Hornung and Meinhardt, 1987) and persons injected with 224 Ra (Spiess and Mays, 1970), although the results of the radium dial studies are included since they are discussed in the NAS report. Both populations are characterized by large uncertainties in dose estimation (mean organ dose) and by highly inhomogeneous patterns of irradiation within a single organ (Arnold and Jee, 1959; Diel, 1978; Singh, Bennettee and Wrenn, 1987; Rowland and Marshall, 1959). (author)

  18. Three-dimensional dose-response models of competing risks and natural life span

    International Nuclear Information System (INIS)

    Raabe, O.G.

    1987-01-01

    Three-dimensional dose-rate/time/response surfaces for chronic exposure to carcinogens, toxicants, and ionizing radiation dramatically clarify the separate and interactive roles of competing risks. The three dimensions are average dose rate, exposure time, and risk. An illustration with computer graphics shows the contributions with the passage of time of the competing risks of death from radiation pneumonitis/fibrosis, lung cancer, and natural aging consequent to the inhalation of plutonium-239 dioxide by beagles. These relationships are further evaluated by mathematical stripping with three-dimensional illustrations that graphically show the resultant separate contribution of each fatal effect. Radiation pneumonitis predominates at high dose rates and lung cancer at intermediate dose rates. Low dose rates result in spontaneous deaths from natural aging, yielding a type of practical threshold for lung cancer induction. Risk assessment is benefited by the insights that become apparent with these three-dimensional models. The improved conceptualization afforded by them contributes to the planning and evaluation of epidemiological analyses and experimental studies involving chronic exposure to toxicants

  19. A review: Development of a microdose model for analysis of adaptive response and bystander dose response behavior.

    Science.gov (United States)

    Leonard, Bobby E

    2008-02-27

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  20. The dose-response relationship between cumulative lifting load and lumbar disk degeneration based on magnetic resonance imaging findings.

    Science.gov (United States)

    Hung, Yu-Ju; Shih, Tiffany T-F; Chen, Bang-Bin; Hwang, Yaw-Huei; Ma, Li-Ping; Huang, Wen-Chuan; Liou, Saou-Hsing; Ho, Ing-Kang; Guo, Yue L

    2014-11-01

    Lumbar disk degeneration (LDD) has been related to heavy physical loading. However, the quantification of the exposure has been controversial, and the dose-response relationship with the LDD has not been established. The purpose of this study was to investigate the dose-response relationship between lifetime cumulative lifting load and LDD. This was a cross-sectional study. Every participant received assessments with a questionnaire, magnetic resonance imaging (MRI) of the lumbar spine, and estimation of lumbar disk compression load. The MRI assessments included assessment of disk dehydration, annulus tear, disk height narrowing, bulging, protrusion, extrusion, sequestration, degenerative and spondylolytic spondylolisthesis, foramina narrowing, and nerve root compression on each lumbar disk level. The compression load was predicted using a biomechanical software system. A total of 553 participants were recruited in this study and categorized into tertiles by cumulative lifting load (ie, lifting load. The best dose-response relationships were found at the L5-S1 disk level, in which high cumulative lifting load was associated with elevated odds ratios of 2.5 (95% confidence interval [95% CI]=1.5, 4.1) for dehydration and 4.1 (95% CI=1.9, 10.1) for disk height narrowing compared with low lifting load. Participants exposed to intermediate lifting load had an increased odds ratio of 2.1 (95% CI=1.3, 3.3) for bulging compared with low lifting load. The tests for trend were significant. There is no "gold standard" assessment tool for measuring the lumbar compression load. The results suggest a dose-response relationship between cumulative lifting load and LDD. © 2014 American Physical Therapy Association.

  1. Health effects of low doses at low dose rates: dose-response relationship modeling in a cohort of workers of the nuclear industry

    International Nuclear Information System (INIS)

    Metz-Flamant, Camille

    2011-01-01

    The aim of this thesis is to contribute to a better understanding of the health effects of chronic external low doses of ionising radiation. This work is based on the French cohort of CEA-AREVA NC nuclear workers. The mains stages of this thesis were (1) conducting a review of epidemiological studies on nuclear workers, (2) completing the database and performing a descriptive analysis of the cohort, (3) quantifying risk by different statistical methods and (4) modelling the exposure-time-risk relationship. The cohort includes monitored workers employed more than one year between 1950 and 1994 at CEA or AREVA NC companies. Individual annual external exposure, history of work, vital status and causes of death were reconstructed for each worker. Standardized mortality ratios using French national mortality rates as external reference were computed. Exposure-risk analysis was conducted in the cohort using the linear excess relative risk model, based on both Poisson regression and Cox model. Time dependent modifying factors were investigated by adding an interaction term in the model or by using exposure time windows. The cohort includes 36, 769 workers, followed-up until age 60 in average. During the 1968- 2004 period, 5, 443 deaths, 2, 213 cancers, 62 leukemia and 1, 314 cardiovascular diseases were recorded. Among the 57% exposed workers, the mean cumulative dose was 21.5 milli-sieverts (mSv). A strong Healthy Worker Effect is observed in the cohort. Significant elevated risks of pleura cancer and melanoma deaths were observed in the cohort but not associated with dose. No significant association was observed with solid cancers, lung cancer and cardiovascular diseases. A significant dose-response relationship was observed for leukemia excluding chronic lymphatic leukemia, mainly for doses received less than 15 years before and for yearly dose rates higher than 10 mSv. This PhD work contributes to the evaluation of risks associated to chronic external radiation

  2. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y [University of Michigan, Ann Arbor, MI (United States)

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  3. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    International Nuclear Information System (INIS)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y

    2014-01-01

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  4. Dose response models and a quantitative microbial risk assessment framework for the Mycobacterium avium complex that account for recent developments in molecular biology, taxonomy, and epidemiology.

    Science.gov (United States)

    Hamilton, Kerry A; Weir, Mark H; Haas, Charles N

    2017-02-01

    Mycobacterium avium complex (MAC) is a group of environmentally-transmitted pathogens of great public health importance. This group is known to be harbored, amplified, and selected for more human-virulent characteristics by amoeba species in aquatic biofilms. However, a quantitative microbial risk assessment (QMRA) has not been performed due to the lack of dose response models resulting from significant heterogeneity within even a single species or subspecies of MAC, as well as the range of human susceptibilities to mycobacterial disease. The primary human-relevant species and subspecies responsible for the majority of the human disease burden and present in drinking water, biofilms, and soil are M. avium subsp. hominissuis, M. intracellulare, and M. chimaera. A critical review of the published literature identified important health endpoints, exposure routes, and susceptible populations for MAC risk assessment. In addition, data sets for quantitative dose-response functions were extracted from published in vivo animal dosing experiments. As a result, seven new exponential dose response models for human-relevant species of MAC with endpoints of lung lesions, death, disseminated infection, liver infection, and lymph node lesions are proposed. Although current physical and biochemical tests used in clinical settings do not differentiate between M. avium and M. intracellulare, differentiating between environmental species and subspecies of the MAC can aid in the assessment of health risks and control of MAC sources. A framework is proposed for incorporating the proposed dose response models into susceptible population- and exposure route-specific QMRA models. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Positioning and number of nutritional levels in dose-response trials to estimate the optimal-level and the adjustment of the models

    Directory of Open Access Journals (Sweden)

    Fernando Augusto de Souza

    2014-07-01

    Full Text Available The aim of this research was to evaluate the influence of the number and position of nutrient levels used in dose-response trials in the estimation of the optimal-level (OL and the goodness of fit on the models: quadratic polynomial (QP, exponential (EXP, linear response plateau (LRP and quadratic response plateau (QRP. It was used data from dose-response trials realized in FCAV-Unesp Jaboticabal considering the homogeneity of variances and normal distribution. The fit of the models were evaluated considered the following statistics: adjusted coefficient of determination (R²adj, coefficient of variation (CV and the sum of the squares of deviations (SSD.It was verified in QP and EXP models that small changes on the placement and distribution of the levels caused great changes in the estimation of the OL. The LRP model was deeply influenced by the absence or presence of the level between the response and stabilization phases (change in the straight to plateau. The QRP needed more levels on the response phase and the last level on stabilization phase to estimate correctly the plateau. It was concluded that the OL and the adjust of the models are dependent on the positioning and the number of the levels and the specific characteristics of each model, but levels defined near to the true requirement and not so spaced are better to estimate the OL.

  6. Comparative study of nuclear magnetic resonance and UV-visible spectroscopy dose-response of polymer gel based on N-(Isobutoxymethyl) acrylamide

    Science.gov (United States)

    Lotfy, S.; Basfar, A. A.; Moftah, B.; Al-Moussa, A. A.

    2017-12-01

    A comparative study of nuclear magnetic resonance and UV-visible spectroscopy of dose-response for polymer gel dosimeters was performed. Dosimeters were prepared using N-(Isobutoxymethyl) acrylamide (NIBMA) as a new monomer via radiation induced polymerization for use in radiotherapy planning. The prepared dosimeters were irradiated with doses up to 30 Gy at a constant dose rate of 600 MU/min. Using a medical linear accelerator at irradiation energies of 6, 10 and 18 MV photon beam. The nuclear magnetic resonance (NMR), via spin-spin relaxation rate (R2) for water proton surrounding the polymer formulation and UV-Visible spectroscopy, via the optical absorbance measurements of irradiated dosimeters at selected wavelengths of 500 nm, was used to investigate the dose response of NIBMAGAT gel dosimeters. Scavenge of oxygen was done using tetrakis (hydroxymethyl) phosphonium chloride (THPC). The THPC optimum concentration in the dosimeters formulations were 5 and 10 mM for the NMR and optical absorbance measurements respectively. The quantitative investigation of the dosimeters components reveals the selective formulations based on 4% w/w gelatin, 1% w/w NIBMA, 3% w/w BisAAm, 5 or 10 mM THPC and 17% w/w glycerol which significantly increase the dosimeters dose response. The prepared dosimeters were found to be dose rate and photon beam irradiation energy independent. The stability study shows no change in the relaxation rate or in the optical absorbance of the gel dosimeters up to 8 days post-irradiation. The prepared polymer gel dosimeters at the energies of 6, 10 and 18 MV photon beam irradiation in the range of 1-30 Gy have the linearity of the dose response function in the case of R2 is better than in the case of absorbance measurements; correlation coefficient (r2) equals 0.995 and 0.991, respectively. Dose sensitivity, R2 of NIBMAGAT dosimeters (0.0775 s-1 Gy-1). The absorption band intensity increases linearly with a dose sensitivity of 0.016 cm-1 Gy-1. The

  7. Radiation dose responses for chemoradiation therapy of pancreatic cancer: an analysis of compiled clinical data using biophysical models.

    Science.gov (United States)

    Moraru, Ion C; Tai, An; Erickson, Beth; Li, X Allen

    2014-01-01

    We analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer (LAPC) in order to examine possible benefits from radiation therapy dose escalation. A modified linear quadratic model was used to fit clinical tumor response and survival data of chemoradiation treatments for LAPC reported from 20 institutions. Biophysical radiosensitivity parameters were extracted from the fits. Examination of the clinical data demonstrated an enhancement in tumor response with higher irradiation dose, an important clinical result for palliation and quality of life. Little indication of improvement in 1-year survival with increased radiation dose was observed. Possible dose escalation schemes are proposed based on calculations of the biologically effective dose required for a 50% tumor response rate. Based on the evaluation of tumor response data, the escalation of radiation dose presents potential clinical benefits which when combined with normal tissue complication analyses may result in improved treatment outcome for locally advanced pancreatic cancer patients. Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

  8. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    International Nuclear Information System (INIS)

    Cucinotta, Francis A

    2016-01-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  9. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    O' Neill, Peter [University of Oxford; Anderson, Jennifer [University of Oxford

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  10. Systems Biology Model of Interactions between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFβ and ATM Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, Francis A [Univ. of Nevada, Las Vegas, NV (United States)

    2016-09-01

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently, the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses, and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low-dose responses and cross-talk between the ATM and TGFβ pathways initiated by low- and high-LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to crosstalk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  11. Bolus dose response characteristics of single chain urokinase plasminogen activator and tissue plasminogen activator in a dog model of arterial thrombosis.

    Science.gov (United States)

    Badylak, S F; Voytik, S; Klabunde, R E; Henkin, J; Leski, M

    1988-11-15

    Tissue plasminogen activator (t-PA) and single chain urokinase-plasminogen activator (scu-PA) are relatively "fibrin-specific" thrombolytic drugs with short plasma half lives of 6-8 minutes. Most treatment regimens with these agents utilize a bolus injection followed by continuous drug infusion, usually combined with anticoagulant therapy. The purpose of this study was to establish the dose-response characteristics for scu-PA and t-PA, when given as a single intravenous bolus injection, in a dog model of arterial thrombosis. Eight groups of 6 dogs each were given one of the following doses of scu-PA (mg/kg): 0.20, 0.50, 1.00, 2.00; or t-PA: 0.05, 0.10, 0.20; or an equivalent amount of saline (control group). All doses were given as a single bolus injection 60 minutes after formation of a totally occlusive femoral artery thrombus. Thrombolysis was measured by monitoring the continuous decrement of 125I activity from a radiolabelled thrombus. Ninety minutes after drug injection, all scu-PA treated dogs showed greater thrombolysis (30%, 45%, 56%, and 67%, respectively) than the control group (15%, p less than 0.01). The 0.10 and 0.20 mg/kg t-PA treated dogs showed greater thrombolysis (35% and 49%, respectively) than the control group (15%, p less than 0.01). Both scu-PA and t-PA caused a partial and dose-dependent decrease in alpha 2-antiplasmin activity but scu-PA caused a greater depletion (72% vs. 18%, respectively, p less than 0.05) at 60 minutes after the highest dose of drug administration. Both drugs showed a longer than expected thrombolytic effect based upon the known half lives. Neither drug caused significant changes in the prothrombin time, activated partial thromboplastin time, thrombin time, hematocrit, platelet count, or fibrin degradation product concentration. Single bolus injections of scu-PA and t-PA produce safe and effective thrombolysis in this dog model of arterial thrombosis.

  12. On the significance of contaminant plume-scale and dose-response models in defining hydrogeological characterization needs

    Science.gov (United States)

    de Barros, F.; Rubin, Y.; Maxwell, R.; Bai, H.

    2007-12-01

    Defining rational and effective hydrogeological data acquisition strategies is of crucial importance since financial resources available for such efforts are always limited. Usually such strategies are developed with the goal of reducing uncertainty, but less often they are developed in the context of the impacts of uncertainty. This paper presents an approach for determining site characterization needs based on human health risk factors. The main challenge is in striking a balance between improved definition of hydrogeological, behavioral and physiological parameters. Striking this balance can provide clear guidance on setting priorities for data acquisition and for better estimating adverse health effects in humans. This paper addresses this challenge through theoretical developments and numerical testing. We will report on a wide range of factors that affect the site characterization needs including contaminant plume's dimensions, travel distances and other length scales that characterize the transport problem, as well as health risk models. We introduce a new graphical tool that allows one to investigate the relative impact of hydrogeological and physiological parameters in risk. Results show that the impact of uncertainty reduction in the risk-related parameters decreases with increasing distances from the contaminant source. Also, results indicate that human health risk becomes less sensitive to hydrogeological measurements when dealing with ergodic plumes. This indicates that under ergodic conditions, uncertainty reduction in human health risk may benefit from better understanding of the physiological component as opposed to a detailed hydrogeological characterization

  13. Coupling a continuous watershed-scale microbial fate and transport model with a stochastic dose-response model to estimate risk of illness in an urban watershed.

    Science.gov (United States)

    Liao, Hehuan; Krometis, Leigh-Anne H; Kline, Karen

    2016-05-01

    Within the United States, elevated levels of fecal indicator bacteria (FIB) remain the leading cause of surface water-quality impairments requiring formal remediation plans under the federal Clean Water Act's Total Maximum Daily Load (TMDL) program. The sufficiency of compliance with numerical FIB criteria as the targeted endpoint of TMDL remediation plans may be questionable given poor correlations between FIB and pathogenic microorganisms and varying degrees of risk associated with exposure to different fecal pollution sources (e.g. human vs animal). The present study linked a watershed-scale FIB fate and transport model with a dose-response model to continuously predict human health risks via quantitative microbial risk assessment (QMRA), for comparison to regulatory benchmarks. This process permitted comparison of risks associated with different fecal pollution sources in an impaired urban watershed in order to identify remediation priorities. Results indicate that total human illness risks were consistently higher than the regulatory benchmark of 36 illnesses/1000 people for the study watershed, even when the predicted FIB levels were in compliance with the Escherichia coli geometric mean standard of 126CFU/100mL. Sanitary sewer overflows were associated with the greatest risk of illness. This is of particular concern, given increasing indications that sewer leakage is ubiquitous in urban areas, yet not typically fully accounted for during TMDL development. Uncertainty analysis suggested the accuracy of risk estimates would be improved by more detailed knowledge of site-specific pathogen presence and densities. While previous applications of the QMRA process to impaired waterways have mostly focused on single storm events or hypothetical situations, the continuous modeling framework presented in this study could be integrated into long-term water quality management planning, especially the United States' TMDL program, providing greater clarity to watershed

  14. Calculation of the uncertainty in complication probability for various dose-response models, applied to the parotid gland

    International Nuclear Information System (INIS)

    Schilstra, C.; Meertens, H.

    2001-01-01

    Purpose: Usually, models that predict normal tissue complication probability (NTCP) are fitted to clinical data with the maximum likelihood (ML) method. This method inevitably causes a loss of information contained in the data. In this study, an alternative method is investigated that calculates the parameter probability distribution (PD), and, thus, conserves all information. The PD method also allows the calculation of the uncertainty in the NTCP, which is an (often-neglected) prerequisite for the intercomparison of both treatment plans and NTCP models. The PD and ML methods are applied to parotid gland data, and the results are compared. Methods and Materials: The drop in salivary flow due to radiotherapy was measured in 25 parotid glands of 15 patients. Together with the parotid gland dose-volume histograms (DVH), this enabled the calculation of the parameter PDs for three different NTCP models (Lyman, relative seriality, and critical volume). From these PDs, the NTCP and its uncertainty could be calculated for arbitrary parotid gland DVHs. ML parameters and resulting NTCP values were calculated also. Results: All models fitted equally well. The parameter PDs turned out to have nonnormal shapes and long tails. The NTCP predictions of the ML and PD method usually differed considerably, depending on the NTCP model and the nature of irradiation. NTCP curves and ML parameters suggested a highly parallel organization of the parotid gland. Conclusions: Considering the substantial differences between the NTCP predictions of the ML and PD method, the use of the PD method is preferred, because this is the only method that takes all information contained in the clinical data into account. Furthermore, PD method gives a true measure of the uncertainty in the NTCP

  15. Coupling a continuous watershed-scale microbial fate and transport model with a stochastic dose-response model to estimate risk of illness in an urban watershed

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Hehuan, E-mail: hehuan86@vt.edu [Department of Biological Systems Engineering, Virginia Tech, 155 Ag Quad Lane, Blacksburg, VA 24061 (United States); Krometis, Leigh-Anne H. [Department of Biological Systems Engineering, Virginia Tech, 155 Ag Quad Lane, Blacksburg, VA 24061 (United States); Kline, Karen [Department of Biological Systems Engineering, Virginia Tech, 155 Ag Quad Lane, Blacksburg, VA 24061 (United States); Center for Watershed Studies, Virginia Tech, 155 Ag Quad Lane, Blacksburg, VA 24061 (United States)

    2016-05-01

    Within the United States, elevated levels of fecal indicator bacteria (FIB) remain the leading cause of surface water-quality impairments requiring formal remediation plans under the federal Clean Water Act's Total Maximum Daily Load (TMDL) program. The sufficiency of compliance with numerical FIB criteria as the targeted endpoint of TMDL remediation plans may be questionable given poor correlations between FIB and pathogenic microorganisms and varying degrees of risk associated with exposure to different fecal pollution sources (e.g. human vs animal). The present study linked a watershed-scale FIB fate and transport model with a dose-response model to continuously predict human health risks via quantitative microbial risk assessment (QMRA), for comparison to regulatory benchmarks. This process permitted comparison of risks associated with different fecal pollution sources in an impaired urban watershed in order to identify remediation priorities. Results indicate that total human illness risks were consistently higher than the regulatory benchmark of 36 illnesses/1000 people for the study watershed, even when the predicted FIB levels were in compliance with the Escherichia coli geometric mean standard of 126 CFU/100 mL. Sanitary sewer overflows were associated with the greatest risk of illness. This is of particular concern, given increasing indications that sewer leakage is ubiquitous in urban areas, yet not typically fully accounted for during TMDL development. Uncertainty analysis suggested the accuracy of risk estimates would be improved by more detailed knowledge of site-specific pathogen presence and densities. While previous applications of the QMRA process to impaired waterways have mostly focused on single storm events or hypothetical situations, the continuous modeling framework presented in this study could be integrated into long-term water quality management planning, especially the United States' TMDL program, providing greater clarity to

  16. Coupling a continuous watershed-scale microbial fate and transport model with a stochastic dose-response model to estimate risk of illness in an urban watershed

    International Nuclear Information System (INIS)

    Liao, Hehuan; Krometis, Leigh-Anne H.; Kline, Karen

    2016-01-01

    Within the United States, elevated levels of fecal indicator bacteria (FIB) remain the leading cause of surface water-quality impairments requiring formal remediation plans under the federal Clean Water Act's Total Maximum Daily Load (TMDL) program. The sufficiency of compliance with numerical FIB criteria as the targeted endpoint of TMDL remediation plans may be questionable given poor correlations between FIB and pathogenic microorganisms and varying degrees of risk associated with exposure to different fecal pollution sources (e.g. human vs animal). The present study linked a watershed-scale FIB fate and transport model with a dose-response model to continuously predict human health risks via quantitative microbial risk assessment (QMRA), for comparison to regulatory benchmarks. This process permitted comparison of risks associated with different fecal pollution sources in an impaired urban watershed in order to identify remediation priorities. Results indicate that total human illness risks were consistently higher than the regulatory benchmark of 36 illnesses/1000 people for the study watershed, even when the predicted FIB levels were in compliance with the Escherichia coli geometric mean standard of 126 CFU/100 mL. Sanitary sewer overflows were associated with the greatest risk of illness. This is of particular concern, given increasing indications that sewer leakage is ubiquitous in urban areas, yet not typically fully accounted for during TMDL development. Uncertainty analysis suggested the accuracy of risk estimates would be improved by more detailed knowledge of site-specific pathogen presence and densities. While previous applications of the QMRA process to impaired waterways have mostly focused on single storm events or hypothetical situations, the continuous modeling framework presented in this study could be integrated into long-term water quality management planning, especially the United States' TMDL program, providing greater clarity to watershed

  17. The Key Events Dose-Response Framework: A cross-Disciplinary Mode-of-Action Based Approach to Examining Does-Response and Thresholds

    Science.gov (United States)

    the ILSI Research Foundation conveded a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categoreis of bioactive agents: food allergens, nutrients, pathogenic microorganisms, and ...

  18. SU-F-T-202: An Evaluation Method of Lifetime Attributable Risk for Comparing Between Proton Beam Therapy and Intensity Modulated X-Ray Therapy for Pediatric Cancer Patients by Averaging Four Dose-Response Models for Carcinoma Induction

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, M; Shirato, H [Department of Radiation Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido (Japan); Ito, Y [Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido (Japan); Sakurai, H; Mizumoto, M; Kamizawa, S [Proton Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki (Japan); Murayama, S; Yamashita, H [Proton Therapy Division, Shizuoka Cancer Center Hospital, Nagaizumi, Shizuoka (Japan); Takao, S; Suzuki, R [Department of Medical Physics, Hokkaido University Hospital, Sapporo, Hokkaido (Japan)

    2016-06-15

    Purpose: To examine how much lifetime attributable risk (LAR) as an in silico surrogate marker of radiation-induced secondary cancer would be lowered by using proton beam therapy (PBT) in place of intensity modulated x-ray therapy (IMXT) in pediatric patients. Methods: From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: a) brain, head, and neck, b) thoracic, c) abdominal, and d) whole craniospinal (WCNS) irradiation. IMXT was re-planned using the same computed tomography and region of interest. Using dose volume histogram (DVH) of PBT and IMXT, the LAR of Schneider et al. was calculated for the same patient. The published four dose-response models for carcinoma induction: i) full model, ii) bell-shaped model, iii) plateau model, and ix) linear model were tested for organs at risk. In the case that more than one dose-response model was available, the LAR for this patient was calculated by averaging LAR for each dose-response model. Results: Calculation of the LARs of PBT and IMXT based on DVH was feasible for all patients. The mean±standard deviation of the cumulative LAR difference between PBT and IMXT for the four categories was a) 0.77±0.44% (n=7, p=0.0037), b) 23.1±17.2%,(n=8, p=0.0067), c) 16.4±19.8% (n=8, p=0.0525), and d) 49.9±21.2% (n=3, p=0.0275, one tailed t-test), respectively. The LAR was significantly lower by PBT than IMXT for the the brain, head, and neck region, thoracic region, and whole craniospinal irradiation. Conclusion: In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. This method was suggested to be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques. This research was supported by the Translational Research Network Program, JSPS KAKENHI Grant No. 15H04768 and the Global Institution for

  19. SU-F-T-202: An Evaluation Method of Lifetime Attributable Risk for Comparing Between Proton Beam Therapy and Intensity Modulated X-Ray Therapy for Pediatric Cancer Patients by Averaging Four Dose-Response Models for Carcinoma Induction

    International Nuclear Information System (INIS)

    Tamura, M; Shirato, H; Ito, Y; Sakurai, H; Mizumoto, M; Kamizawa, S; Murayama, S; Yamashita, H; Takao, S; Suzuki, R

    2016-01-01

    Purpose: To examine how much lifetime attributable risk (LAR) as an in silico surrogate marker of radiation-induced secondary cancer would be lowered by using proton beam therapy (PBT) in place of intensity modulated x-ray therapy (IMXT) in pediatric patients. Methods: From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: a) brain, head, and neck, b) thoracic, c) abdominal, and d) whole craniospinal (WCNS) irradiation. IMXT was re-planned using the same computed tomography and region of interest. Using dose volume histogram (DVH) of PBT and IMXT, the LAR of Schneider et al. was calculated for the same patient. The published four dose-response models for carcinoma induction: i) full model, ii) bell-shaped model, iii) plateau model, and ix) linear model were tested for organs at risk. In the case that more than one dose-response model was available, the LAR for this patient was calculated by averaging LAR for each dose-response model. Results: Calculation of the LARs of PBT and IMXT based on DVH was feasible for all patients. The mean±standard deviation of the cumulative LAR difference between PBT and IMXT for the four categories was a) 0.77±0.44% (n=7, p=0.0037), b) 23.1±17.2%,(n=8, p=0.0067), c) 16.4±19.8% (n=8, p=0.0525), and d) 49.9±21.2% (n=3, p=0.0275, one tailed t-test), respectively. The LAR was significantly lower by PBT than IMXT for the the brain, head, and neck region, thoracic region, and whole craniospinal irradiation. Conclusion: In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. This method was suggested to be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques. This research was supported by the Translational Research Network Program, JSPS KAKENHI Grant No. 15H04768 and the Global Institution for

  20. Dose-response-a challenge for allelopathy?

    Science.gov (United States)

    Belz, Regina G; Hurle, Karl; Duke, Stephen O

    2005-04-01

    The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

  1. Human Dose-Response Data for Francisella tularensis and a Dose- and Time-Dependent Mathematical Model of Early-Phase Fever Associated with Tularemia After Inhalation Exposure.

    Science.gov (United States)

    McClellan, Gene; Coleman, Margaret; Crary, David; Thurman, Alec; Thran, Brandolyn

    2018-04-25

    Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose-dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early-phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis. © 2018 Society for Risk Analysis.

  2. Non-linear least squares curve fitting of a simple theoretical model to radioimmunoassay dose-response data using a mini-computer

    International Nuclear Information System (INIS)

    Wilkins, T.A.; Chadney, D.C.; Bryant, J.; Palmstroem, S.H.; Winder, R.L.

    1977-01-01

    Using the simple univalent antigen univalent-antibody equilibrium model the dose-response curve of a radioimmunoassay (RIA) may be expressed as a function of Y, X and the four physical parameters of the idealised system. A compact but powerful mini-computer program has been written in BASIC for rapid iterative non-linear least squares curve fitting and dose interpolation with this function. In its simplest form the program can be operated in an 8K byte mini-computer. The program has been extensively tested with data from 10 different assay systems (RIA and CPBA) for measurement of drugs and hormones ranging in molecular size from thyroxine to insulin. For each assay system the results have been analysed in terms of (a) curve fitting biases and (b) direct comparison with manual fitting. In all cases the quality of fitting was remarkably good in spite of the fact that the chemistry of each system departed significantly from one or more of the assumptions implicit in the model used. A mathematical analysis of departures from the model's principal assumption has provided an explanation for this somewhat unexpected observation. The essential features of this analysis are presented in this paper together with the statistical analyses of the performance of the program. From these and the results obtained to date in the routine quality control of these 10 assays, it is concluded that the method of curve fitting and dose interpolation presented in this paper is likely to be of general applicability. (orig.) [de

  3. Dose response relationship and Alara

    International Nuclear Information System (INIS)

    Hubert, P.

    1986-09-01

    In this paper, it will be shown how dose-response relationships allow to give quantitative figures for the detriment of irradiation. At this stage, the detriment is expressed directly as a certain number of health effects, whose valuation is not dealt with here. The present tools for quantifying, their weaknesses and their strenghts, and their scientific basis will be developed

  4. Adjuvant Radiation Therapy for Margin-Positive Vulvar Squamous Cell Carcinoma: Defining the Ideal Dose-Response Using the National Cancer Data Base

    International Nuclear Information System (INIS)

    Chapman, Bhavana V.; Gill, Beant S.; Viswanathan, Akila N.; Balasubramani, Goundappa K.; Sukumvanich, Paniti; Beriwal, Sushil

    2017-01-01

    Purpose: Positive surgical margins after radical vulvectomy for vulvar cancer portend a high risk for local relapse, which may be challenging to salvage. We assessed the impact of adjuvant radiation therapy (aRT) on overall survival (OS) and the dose-response relationship using the National Cancer Data Base. Methods and Materials: Patients with vulvar squamous cell carcinoma who underwent initial extirpative surgery with positive margins from 1998 to 2012 were included. Factors associated with aRT and specific dose levels were analyzed using logistic regression. Log-rank and multivariable Cox proportional hazards modeling were used for OS analysis. Results: We identified 3075 patients with a median age of 66 years (range, 22-90 years); the median follow-up time was 36.4 months (interquartile range [IQR] 15.4-71.0 months). Stage IA/B disease represented 41.2% of the cohort. Sixty-three percent underwent lymph node assessment, with a 45% positivity rate. In total, 1035 patients (35.3%) received aRT, with a median dose of 54.0 Gy (IQR 48.6-60.0 Gy). The 3-year OS improved from 58.5% to 67.4% with aRT (P<.001). On multivariable analysis, age, Charlson-Deyo score ≥1, stage ≥II, tumors ≥4 cm, no aRT, and adverse nodal characteristics led to inferior survival. Dose of aRT was positively associated with OS as a continuous variable on univariate analysis (P<.001). The unadjusted 3-year OS for dose subsets 30.0 to 45.0 Gy, 45.1 to 53.9 Gy, 54.0 to 59.9 Gy, and ≥60 Gy was 54.3%, 55.7%, 70.1%, and 65.3%, respectively (P<.001). Multivariable analysis using a 4-month conditional landmark revealed that the greatest mortality reduction occurred in cumulative doses ≥54 Gy: 45.1 to 53.9 Gy (hazard ratio [HR] 0.94, P=.373), 54.0 to 59.9 Gy (HR 0.75, P=.024), ≥60 Gy (HR 0.71, P=.015). No survival benefit was seen with ≥60 Gy compared with 54.0 to 59.9 Gy (HR 0.95, P=.779). Conclusions: Patients with vulvar squamous cell carcinoma and positive surgical

  5. Effectiveness of home- and community-based rehabilitation in a large cohort of patients disabled by cerebrovascular accident: evidence of a dose-response relationship.

    Science.gov (United States)

    Altman, Irwin M; Swick, Shannon; Malec, James F

    2013-09-01

    To (1) assess the effectiveness of home- and community-based rehabilitation (HCBR) in a large cohort of individuals with disabilities secondary to cerebrovascular accident (CVA); and (2) evaluate the responsiveness to treatment of the Mayo-Portland Adaptability Inventory (MPAI-4) to changes resulting from HCBR in this patient group. Retrospective analysis of program evaluation data for treatment completers and noncompleters. HCBR conducted in 7 geographically distinct U.S. cities. Individuals with CVA (n=738) who completed the prescribed course of rehabilitation (completed course of treatment [CCT]) compared with 150 individuals who were precipitously discharged (PD) before program completion. HCBR delivered by certified professional staff on an individualized basis. Mayo-Portland Adaptability Inventory (MPAI-4) completed by professional consensus on admission and at discharge. With the use of analysis of covariance, MPAI-4 total scores at discharge for CCT participants were compared with those of PD participants, with admission MPAI-4, age, length of stay, and time since event as covariates. CCT participants showed greater improvement than PD participants (F=99.48, PMPAI-4 indexes than those in the PD group who were discharged before completing the prescribed program. This dose-response relationship provides evidence of a causal relationship between treatment and outcome. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  6. Dose-response relationship of tryptophan with large neutral amino acids, and its impact on physiological responses in the chick model.

    Science.gov (United States)

    Bello, Alhassan Usman; Idrus, Zulkifli; Meng, Goh Yong; Narayan, Edward J; Farjam, Abdoreza Soleimani

    2018-05-01

    Tryptophan (Trp) has been associated with the regulation of several behavioral and physiological processes, through stimulation of serotonergic activity. Tryptophan utilization at the metabolic level is influenced by the competitive carrier system it shares with large neutral amino acids (LNAA). This study was carried out using meat-type chicken as a model, to investigate the dose response effects of Trp/LNAA on fear response (tonic immobility; TI) and hormonal responses, including corticosterone (CORT), serotonin (5-HT), triiodothyronine (T 3 ) and thyroxine (T 4 ). A total of 12 cages (48 birds) were assigned to each of the six experimental groups at 29-42 days of age. Experimental diets were formulated to have incremental levels of Trp/LNAA (0.025, 0.030, 0.035, 0.040, 0.045, and 0.050). The results revealed that, Trp/NAA had no significant effect on growth performance and TI of the birds. However, elevation of Trp/LNAA was concurred with a linear reduction in CORT (P < .0001, r 2  = 0.819) and linear increases in 5-HT (P < .0001, r 2  = 0.945), T 3 (P = .0003, r 2  = 0.403) and T 4 (P < .0001, r 2  = 0.937) levels. In conclusion, the results from the current study demonstrated that, although incremental levels of Trp/LNAA did not affect bird growth performance or fearfulness, it increased 5-HT, T 3 and T 4, and decreased CORT levels in a linear dose-dependent manner. Manipulation of Trp feeding levels could be applied to manage stressful conditions in birds. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Statistical and low dose response

    International Nuclear Information System (INIS)

    Thorson, M.R.; Endres, G.W.R.

    1981-01-01

    The low dose response and the lower limit of detection of the Hanford dosimeter depend upon may factors, including the energy of the radiation, whether the exposure is to be a single radiation or mixed fields, annealing cycles, environmental factors, and how well various batches of TLD materials are matched in the system. A careful statistical study and sensitivity analysis were performed to determine how these factors influence the response of the dosimeter system. Estimates have been included in this study of the standard deviation of calculated dose for various mixed field exposures from 0 to 1000 mrem

  8. Dose-response relationships and risk estimates for the induction of cancer due to low doses of low-LET radiation

    International Nuclear Information System (INIS)

    Elaguppillai, V.

    1981-01-01

    Risk estimates for radiation-induced cancer at low doses can be obtained only by extrapolation from the known effects at high doses and high dose rates, using a suitable dose-response model. The applicability of three different models, linear, sublinear and supralinear, are discussed in this paper. Several experimental studies tend to favour a sublinear dose-response model (linear-quadratic model) for low-LET radiation. However, human epidemiological studies do not exclude any of the dose-response relationships. The risk estimates based on linear and linear quadratic dose-response models are compared and it is concluded that, for low-LET radiation, the linear dose-response model would probably over-estimate the actual risk of cancer by a factor of two or more. (author)

  9. Biphasic dose responses in biology, toxicology and medicine: Accounting for their generalizability and quantitative features

    International Nuclear Information System (INIS)

    Calabrese, Edward J.

    2013-01-01

    The most common quantitative feature of the hormetic-biphasic dose response is its modest stimulatory response which at maximum is only 30–60% greater than control values, an observation that is consistently independent of biological model, level of organization (i.e., cell, organ or individual), endpoint measured, chemical/physical agent studied, or mechanism. This quantitative feature suggests an underlying “upstream” mechanism common across biological systems, therefore basic and general. Hormetic dose response relationships represent an estimate of the peak performance of integrative biological processes that are allometrically based. Hormetic responses reflect both direct stimulatory or overcompensation responses to damage induced by relatively low doses of chemical or physical agents. The integration of the hormetic dose response within an allometric framework provides, for the first time, an explanation for both the generality and the quantitative features of the hormetic dose response. -- Highlights: •The hormetic stimulation is at maximum 30–60% greater than control responses. •Hormesis is a measure of biological performance and plasticity. •The hormetic response is evolutionary based and highly generalizable. -- This paper provides a biologically based explanation for the generalizability/quantitative features of the hormetic dose response, representing a fundamental contribution to the field

  10. Soiling of window glass of building façades: a new Dose-Response Function based on the mass of deposited particles

    Science.gov (United States)

    Ionescu, Anda; Lefèvre, Roger

    2017-04-01

    Materials used in building façades are subject to different types of weathering, an important one being soiling. The material studied here is the silica-soda-lime glass, used for windows and contemporaneous façades. Glass weathering in a polluted environment, sheltered from rain, is dominated by soiling. This phenomenon can be expressed either by an optical parameter, the haze, or by the mass of Deposited and Neoformed Particles by unit of glass surface (DNPs). By contrast to the haze, which is an optical parameter requiring an expensive technology (spectrophotometry), measuring DNPs is much simpler: the glass sample is weighed before and after exposure and the result, divided by the sample surface. After the development of a previous Dose-Response Function (DRF) expressing soiling evolution through haze, this study focuses on the development of a new DRF for soiling expressed in terms of DNPs mass, sheltered from rain. The development of this DRF follows a statistical approach. The general form proposed for the DRF is: DNPs=A(dose1, dose2, …., dosen).g(t) where g(t) represents the temporal trend obtained from standardized data. Data standardization has been employed in order to obtain a general trend independent of the environmental characteristics of the monitoring site. According to previous studies and physical considerations, the analytical form of the temporal trend g(t) was expressed by a function admitting an horizontal asymptote: the saturation level of soling. Ten monitoring campaigns (performed at different European sites) were used; the longest one runs up to 2102 days and the shortest ones, up to 365 days, with 14 to 5 records, respectively. Two different models were fitted by a non-linear regression: the Hill's model and a decreasing exponential model. Both models performed well (R2 ranging from 0.73 to 0.76) and they were further tested in order to get the final form of the DRF. The amplitude function A was considered as a linear combination of

  11. Dose-response relationships for carcinogens: a review

    International Nuclear Information System (INIS)

    Zeise, L.; Wilson, R.; Crouch, E.A.C.

    1987-01-01

    The authors review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Their major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so they pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites

  12. Dose-Response Calculator for ArcGIS

    Science.gov (United States)

    Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

    2011-01-01

    The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

  13. Dose-response analysis in the joint action of two effectors. A new approach to simulation, identification and modelling of some basic interactions.

    Directory of Open Access Journals (Sweden)

    Miguel Anxo Murado García

    Full Text Available In systems with several effectors, the results of dose-response (DR experiments are usually assessed by checking them against two hypotheses: independent action (IA and concentration addition (CA. Both are useful simplifications, but do not represent the only possible responses, and avoid to a large extent the analysis of the interactions that are possible in the system. In addition, these are often applied in such a way that they produce insufficient descriptions of the problem that raises them, frequent inconclusive cases and doubtful decisions. In this work a generative approach is attempted, starting from some simple mechanisms necessarily underlying the response of an elementary biological entity to an effector agent. A set of simulations is formulated next through an equally simple system of logical rules, and several families of virtual responses are thus generated. These families include typical responses of IA and CA modes of action, other ones not less probable from a physiological point of view, and even other derived from common and expectable forms of interactions. The analysis of these responses enabled, firstly, to relate some phenomenological regularities with some general mechanistic principles, and to detect several causes by which the IA-CA dualism is necessarily ambiguous. Secondly, it allowed identifying different forms of synergy and antagonism that contribute to explain some controversial aspects of these notions. Finally, it led to propose two sets of explicit algebraic equations that describe accurately a wide diversity of possible and realistic responses.

  14. Dose-Response Analysis in the Joint Action of Two Effectors. A New Approach to Simulation, Identification and Modelling of Some Basic Interactions

    Science.gov (United States)

    Murado García, Miguel Anxo; Prieto Lage, Miguel Ángel

    2013-01-01

    In systems with several effectors, the results of dose-response (DR) experiments are usually assessed by checking them against two hypotheses: independent action (IA) and concentration addition (CA). Both are useful simplifications, but do not represent the only possible responses, and avoid to a large extent the analysis of the interactions that are possible in the system. In addition, these are often applied in such a way that they produce insufficient descriptions of the problem that raises them, frequent inconclusive cases and doubtful decisions. In this work a generative approach is attempted, starting from some simple mechanisms necessarily underlying the response of an elementary biological entity to an effector agent. A set of simulations is formulated next through an equally simple system of logical rules, and several families of virtual responses are thus generated. These families include typical responses of IA and CA modes of action, other ones not less probable from a physiological point of view, and even other derived from common and expectable forms of interactions. The analysis of these responses enabled, firstly, to relate some phenomenological regularities with some general mechanistic principles, and to detect several causes by which the IA-CA dualism is necessarily ambiguous. Secondly, it allowed identifying different forms of synergy and antagonism that contribute to explain some controversial aspects of these notions. Finally, it led to propose two sets of explicit algebraic equations that describe accurately a wide diversity of possible and realistic responses. PMID:23637825

  15. Dose/response relationships and policy formulation

    International Nuclear Information System (INIS)

    Robinson, P.D.

    1981-01-01

    The ICRP 26 cost/benefit approach to establishing operational radiation protection guidelines is discussed. The purpose is to aid the policy maker in the decision making process, using as a basis the dose-response curve

  16. Confidence bounds for nonlinear dose-response relationships

    DEFF Research Database (Denmark)

    Baayen, C; Hougaard, P

    2015-01-01

    An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve...... intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated...

  17. Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003

    Energy Technology Data Exchange (ETDEWEB)

    Schoellnberger, Helmut [Helmholtz Zentrum Muenchen, Department of Radiation Sciences, Institute of Radiation Protection, Neuherberg (Germany); Federal Office for Radiation Protection, Department of Radiation Protection and the Environment, Neuherberg (Germany); Eidemueller, Markus; Simonetto, Cristoforo; Kaiser, Jan Christian [Helmholtz Zentrum Muenchen, Department of Radiation Sciences, Institute of Radiation Protection, Neuherberg (Germany); Cullings, Harry M. [Radiation Effects Research Foundation, Department of Statistics, Hiroshima (Japan); Neff, Frauke [Staedtisches Klinikum Muenchen and Technical University of Munich, Institute of Pathology, Munich (Germany)

    2018-03-15

    The scientific community faces important discussions on the validity of the linear no-threshold (LNT) model for radiation-associated cardiovascular diseases at low and moderate doses. In the present study, mortalities from cerebrovascular diseases (CeVD) and heart diseases from the latest data on atomic bomb survivors were analyzed. The analysis was performed with several radio-biologically motivated linear and nonlinear dose-response models. For each detrimental health outcome one set of models was identified that all fitted the data about equally well. This set was used for multi-model inference (MMI), a statistical method of superposing different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. MMI provides a more accurate determination of the dose response and a more comprehensive characterization of uncertainties. It was found that for CeVD, the dose-response curve from MMI is located below the linear no-threshold model at low and medium doses (0-1.4 Gy). At higher doses MMI predicts a higher risk compared to the LNT model. A sublinear dose-response was also found for heart diseases (0-3 Gy). The analyses provide no conclusive answer to the question whether there is a radiation risk below 0.75 Gy for CeVD and 2.6 Gy for heart diseases. MMI suggests that the dose-response curves for CeVD and heart diseases in the Lifespan Study are sublinear at low and moderate doses. This has relevance for radiotherapy treatment planning and for international radiation protection practices in general. (orig.)

  18. Dose-response meta-analysis of differences in means

    Directory of Open Access Journals (Sweden)

    Alessio Crippa

    2016-08-01

    Full Text Available Abstract Background Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. Methods We proposed a two-stage approach. A flexible dose-response model is estimated within each study (first stage taking into account the covariance of the data points (mean differences, standardized mean differences. Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage to address heterogeneity across studies. Results The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic, spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS, pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30 observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. Conclusion The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate

  19. SU-E-T-256: Radiation Dose Responses for Chemoradiation Therapy of Pancreatic Cancer: An Analysis of Compiled Clinical Data Using Biophysical Models.

    Science.gov (United States)

    Moraru, I; Tai, A; Erickson, B; Li, X

    2012-06-01

    We have analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer in order to examine possible benefits from radiotherapy (RT) dose escalation as well as to propose possible dose escalated fractionation schemes. A modified linear quadratic (LQ) model was used to fit clinical tumor response data from chemoradiation treatments using different fractionations. Biophysical radiosensitivy parameters, a and α/β, tumor potential doubling time, Td, and delay time for tumor doubling during treatment, Tk, were extracted from the fits and were used to calculate feasible fractionation schemes for dose escalations. Examination of published data from 20 institutions showed no clear indication of improved survival with raised radiation dose. However, an enhancement in tumor response was observed for higher irradiation doses, an important and promising clinical Result with respect to palliation and quality of life. The radiobiological parameter estimates obtained from the analysis are: α/β = 10 ± 3 Gy, a = 0.010 ± 0.003 Gŷ-1, Td = 56 ± 5 days and Tk = 7 ± 2 days. Possible dose escalation schemes are proposed based on the calculation of the biologically equivalent dose (BED) required for a 50% tumor response rate. From the point of view of tumor response, escalation of the administered radiation dose leads to a potential clinical benefit, which when combined with normal tissue complication analyses may Result in improved treatments for certain patients with advanced pancreatic cancer. Based on this analysis, a dose escalation trial with 2.25 Gy/fraction up to 69.75 Gy is being initiated for unresectable pancreatic cancer at our institution. Partially supported by MCW Cancer Center Meinerz Foundation. © 2012 American Association of Physicists in Medicine.

  20. Effects of wildland fire smoke on a tree-roosting bat: integrating a plume model, field measurements, and mammalian dose-response relationships

    Science.gov (United States)

    M.B. Dickinson; J.C. Norris; A.S. Bova; R.L. Kremens; V. Young; M.J. Lacki

    2010-01-01

    Faunal injury and mortality in wildland fires is a concern for wildlife and fire management although little work has been done on the mechanisms by which exposures cause their effects. In this paper, we use an integral plume model, field measurements, and models of carbon monoxide and heat effects to explore risk to tree-roosting bats during prescribed fires in mixed-...

  1. Dose-response analysis using R

    DEFF Research Database (Denmark)

    Ritz, Christian; Baty, Florent; Streibig, Jens Carl

    2015-01-01

    Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides...

  2. Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig.

    Science.gov (United States)

    Gutting, Bradford W; Rukhin, Andrey; Mackie, Ryan S; Marchette, David; Thran, Brandolyn

    2015-05-01

    The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species. © 2014 Society for Risk Analysis.

  3. Biostatistical approaches for modeling U-shaped dose-response curves and study design considerations in assessing the biological effects of low doses

    International Nuclear Information System (INIS)

    Downs, T.

    1992-01-01

    The demonstration of hormetic effects is rendered difficult for a number of reasons: The spontaneous rate must be large enough for a difference to be detectable. In contrast with detrimental effects, there is a limited range of doses over which beneficial effects are likely to be found. Publication bias hampers publication of low-dose beneficial effects and discourages research in the area. Some scientists actually believe that hormetic effects are contary to reason. All these factors contribute to lessen the chances of detecting hormetic effects through synthesis of the scientific literature. The extra statistical power obtained from mathematical modeling is not available for hormetic studies when appropriate models are not available. Even a simple statistical device such as a test for linear trend does not work well for U-shaped data. The first part of this two-part chapter deals with the probabilities of determining qualitatively what kinds of health effects may result from exposures to substances, and the second part with characterizing quantitative relationships between such health effects and exposures. The health effects may be beneficial in some situations, and detrimental in others

  4. Dose-response relationship in clinical oncology

    International Nuclear Information System (INIS)

    Gehan, E.A.

    1984-01-01

    The relationship of dose (and dose rate) to response and toxicity in clinical oncology is reviewed. The concepts expressed by some authors in dose-response studies in animal and human systems are reviewed briefly. Dose rate and tactics of conducting clinical studies are reviewed for both radiotherapy and various types of chemotherapeutic treatment. Examples are given from clinical studies in Hodgkin's disease, acute leukemia, and breast cancer that may prove useful in planning future clinical studies

  5. Dose-response curves from incomplete data

    International Nuclear Information System (INIS)

    Groer, P.G.

    1978-01-01

    Frequently many different responses occur in populations (animal or human) exposed to ionizing radiation. To obtain a dose-response curve, the exposed population is first divided into sub-groups whose members received the same radiation dose. To estimate the response, the fraction of subjects in each sub-group that showed the particular response of interest is determined. These fractions are plotted against dose to give the dose-response curve. This procedure of plotting the fractions versus the radiation dose is not the correct way to estimate the time distribution for a particular response at the different dose levels. Other observed responses competed for the individuals in the exposed population and therefore prevented manifestation of the complete information on the response-time distribution for one specific response. Such data are called incomplete in the statistical literature. A procedure is described which uses the by now classical Kaplan-Meier estimator, to establish dose-response curves from incomplete data under the assumption that the different observed responses are statistically independent. It is demonstrated that there is insufficient information in the observed survival functions to estimate the time distribution for one particular response if the assumption of independence is dropped. In addition, it is not possible to determine from the data (i.e. type of response and when it occurred) whether or not the different response-time distributions are independent. However, it is possible to give sharp bounds between which the response has to lie. This implies that for incomplete data, only a 'dose-response band' can be established if independence of the competing responses cannot be assumed. Examples are given using actual data to illustrate the estimation procedures

  6. Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.

    Science.gov (United States)

    Demonty, Isabelle; Ras, Rouyanne T; van der Knaap, Henk C M; Duchateau, Guus S M J E; Meijer, Linsie; Zock, Peter L; Geleijnse, Johanna M; Trautwein, Elke A

    2009-02-01

    Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)-lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C-lowering efficacy of different phytosterol doses. Eighty-four trials including 141 trial arms were included. A nonlinear equation comprising 2 parameters (the maximal LDL-C lowering and an incremental dose step) was used to describe the dose-response curve. The overall pooled absolute (mmol/L) and relative (%) LDL-C-lowering effects of phytosterols were also assessed with a random effects model. The pooled LDL-C reduction was 0.34 mmol/L (95% CI: -0.36, -0.31) or 8.8% (95% CI: -9.4, -8.3) for a mean daily dose of 2.15 g phytosterols. The impacts of subject baseline characteristics, food formats, type of phytosterols, and study quality on the continuous dose-response curve were determined by regression or subgroup analyses. Higher baseline LDL-C concentrations resulted in greater absolute LDL-C reductions. No significant differences were found between dose-response curves established for plant sterols vs. stanols, fat-based vs. non fat-based food formats and dairy vs. nondairy foods. A larger effect was observed with solid foods than with liquid foods only at high phytosterol doses (>2 g/d). There was a strong tendency (P = 0.054) towards a slightly lower efficacy of single vs. multiple daily intakes of phytosterols. In conclusion, the dose-dependent LDL-C-lowering efficacy of phytosterols incorporated in various food formats was confirmed and equations of the continuous relationship were established to predict the effect of a given phytosterol dose. Further investigations are warranted to investigate the impact of solid vs. liquid food formats and frequency of intake on phytosterol efficacy.

  7. Dose Response of Alanine Detectors Irradiated with Carbon Ion Beams

    DEFF Research Database (Denmark)

    Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo

    2011-01-01

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type, when irradiated with ion beams. The purpose of this study is to investigate the response behaviour of the alanine detector in clinical carbon ion beams and compare the results with model predictions......-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasi mono energetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties...

  8. The Dose Response Relationship for Radiation Carcinogenesis

    Science.gov (United States)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  9. I-131 dose response for incident thyroid cancers in Ukraine related to the Chornobyl accident.

    Science.gov (United States)

    Brenner, Alina V; Tronko, Mykola D; Hatch, Maureen; Bogdanova, Tetyana I; Oliynik, Valery A; Lubin, Jay H; Zablotska, Lydia B; Tereschenko, Valery P; McConnell, Robert J; Zamotaeva, Galina A; O'Kane, Patrick; Bouville, Andre C; Chaykovskaya, Ludmila V; Greenebaum, Ellen; Paster, Ihor P; Shpak, Victor M; Ron, Elaine

    2011-07-01

    Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case-control studies, and studies of prevalent cancers. To address this limitation, we evaluated the dose-response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study. The cohort consists of individuals radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose-response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43-6.34], and the EAR per 10⁴ PY/Gy was 2.21 (95% CI, 0.04-5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. I-131-related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.

  10. Dose-response curve estimation: a semiparametric mixture approach.

    Science.gov (United States)

    Yuan, Ying; Yin, Guosheng

    2011-12-01

    In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples. © 2011, The International Biometric Society.

  11. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L.; DuFrain, R.J.

    1986-01-01

    In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  12. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok

    2001-01-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2±7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non-irradiated liver

  13. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa[γd + g(t, tau)d 2 ], where t is the time and d is dose. The coefficient of the d 2 term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  14. Maximum likelihood estimation for cytogenetic dose-response curves

    Energy Technology Data Exchange (ETDEWEB)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  15. Methods for extracting dose response curves from radiation therapy data. I. A unified approach

    International Nuclear Information System (INIS)

    Herring, D.F.

    1980-01-01

    This paper discusses an approach to fitting models to radiation therapy data in order to extract dose response curves for tumor local control and normal tissue damage. The approach is based on the method of maximum likelihood and is illustrated by several examples. A general linear logistic equation which leads to the Ellis nominal standard dose (NSD) equation is discussed; the fit of this equation to experimental data for mouse foot skin reactions produced by fractionated irradiation is described. A logistic equation based on the concept that normal tissue reactions are associated with the surviving fraction of cells is also discussed, and the fit of this equation to the same set of mouse foot skin reaction data is also described. These two examples illustrate the importance of choosing a model based on underlying mechanisms when one seeks to attach biological significance to a model's parameters

  16. Dose response curves for effects of low-level radiation

    International Nuclear Information System (INIS)

    Myers, D.K.

    1980-01-01

    The linear dose-response model used by international committees to assess the genetic and carcinogenic hazards of low-level radiation appears to be the most reasonable interpretation of the available scientific data that are relevant to this topic. There are, of course, reasons to believe that this model may overestimate radiation hazards in certain instances, a fact acknowledged in recent reports of these committees. The linear model is now also being utilized to estimate the potential carcinogenic hazards of other agents such as asbestos and polycyclic aromatic hydrocarbons. This model implies that there is no safe dose for any of these agents and that potential health hazards will increase in direct proportion to total accumulated dose. The practical implication is the recommendation that all exposures should be kept 'as low as reasonably achievable, economic and social factors being taken into account'. (auth)

  17. Health effects of low doses at low dose rates: dose-response relationship modeling in a cohort of workers of the nuclear industry; Effets sanitaires des faibles doses a faibles debits de dose: modelisation de la relation dose-reponse dans une cohorte de travailleurs du nucleaire

    Energy Technology Data Exchange (ETDEWEB)

    Metz-Flamant, Camille

    2011-09-19

    The aim of this thesis is to contribute to a better understanding of the health effects of chronic external low doses of ionising radiation. This work is based on the French cohort of CEA-AREVA NC nuclear workers. The mains stages of this thesis were (1) conducting a review of epidemiological studies on nuclear workers, (2) completing the database and performing a descriptive analysis of the cohort, (3) quantifying risk by different statistical methods and (4) modelling the exposure-time-risk relationship. The cohort includes monitored workers employed more than one year between 1950 and 1994 at CEA or AREVA NC companies. Individual annual external exposure, history of work, vital status and causes of death were reconstructed for each worker. Standardized mortality ratios using French national mortality rates as external reference were computed. Exposure-risk analysis was conducted in the cohort using the linear excess relative risk model, based on both Poisson regression and Cox model. Time dependent modifying factors were investigated by adding an interaction term in the model or by using exposure time windows. The cohort includes 36, 769 workers, followed-up until age 60 in average. During the 1968- 2004 period, 5, 443 deaths, 2, 213 cancers, 62 leukemia and 1, 314 cardiovascular diseases were recorded. Among the 57% exposed workers, the mean cumulative dose was 21.5 milli-sieverts (mSv). A strong Healthy Worker Effect is observed in the cohort. Significant elevated risks of pleura cancer and melanoma deaths were observed in the cohort but not associated with dose. No significant association was observed with solid cancers, lung cancer and cardiovascular diseases. A significant dose-response relationship was observed for leukemia excluding chronic lymphatic leukemia, mainly for doses received less than 15 years before and for yearly dose rates higher than 10 mSv. This PhD work contributes to the evaluation of risks associated to chronic external radiation

  18. Effect of Enamel Caries Lesion Baseline Severity on Fluoride Dose-Response

    Directory of Open Access Journals (Sweden)

    Frank Lippert

    2017-01-01

    Full Text Available This study aimed to investigate the effect of enamel caries lesion baseline severity on fluoride dose-response under pH cycling conditions. Early caries lesions were created in human enamel specimens at four different severities (8, 16, 24, and 36 h. Lesions were allocated to treatment groups (0, 83, and 367 ppm fluoride as sodium fluoride based on Vickers surface microhardness (VHN and pH cycled for 5 d. The cycling model comprised 3 × 1 min fluoride treatments sandwiched between 2 × 60 min demineralization challenges with specimens stored in artificial saliva in between. VHN was measured again and changes versus lesion baseline were calculated (ΔVHN. Data were analyzed using two-way ANOVA (p<0.05. Increased demineralization times led to increased surface softening. The lesion severity×fluoride concentration interaction was significant (p<0.001. Fluoride dose-response was observed in all groups. Lesions initially demineralized for 16 and 8 h showed similar overall rehardening (ΔVHN and more than 24 and 36 h lesions, which were similar. The 8 h lesions showed the greatest fluoride response differential (367 versus 0 ppm F which diminished with increasing lesion baseline severity. The extent of rehardening as a result of the 0 ppm F treatment increased with increasing lesion baseline severity, whereas it decreased for the fluoride treatments. In conclusion, lesion baseline severity impacts the extent of the fluoride dose-response.

  19. Repair and dose-response at low doses

    International Nuclear Information System (INIS)

    Totter, J.R.; Weinberg, A.M.

    1977-04-01

    The DNA of each individual is subject to formation of some 2-4 x 10 14 ion pairs during the first 30 years of life from background radiation. If a single hit is sufficient to cause cancer, as is implicit in the linear, no-threshold theories, it is unclear why all individuals do not succumb to cancer, unless repair mechanisms operate to remove the damage. We describe a simple model in which the exposed population displays a distribution of repair thresholds. The dose-response at low dose is shown to depend on the shape of the threshold distribution at low thresholds. If the probability of zero threshold is zero, the response at low dose is quadratic. The model is used to resolve a longstanding discrepancy between observed incidence of leukemia at Nagasaki and the predictions of the usual linear hypothesis

  20. A biological basis for the linear non-threshold dose-response relationship for low-level carcinogen exposure

    International Nuclear Information System (INIS)

    Albert, R.E.

    1981-01-01

    This chapter examines low-level dose-response relationships in terms of the two-stage mouse tumorigenesis model. Analyzes the feasibility of the linear non-threshold dose-response model which was first adopted for use in the assessment of cancer risks from ionizing radiation and more recently from chemical carcinogens. Finds that both the interaction of B(a)P with epidermal DNA of the mouse skin and the dose-response relationship for the initiation stage of mouse skin tumorigenesis showed a linear non-threshold dose-response relationship. Concludes that low level exposure to environmental carcinogens has a linear non-threshold dose-response relationship with the carcinogen acting as an initiator and the promoting action being supplied by the factors that are responsible for the background cancer rate in the target tissue

  1. Hierarchical Bayesian inference for ion channel screening dose-response data [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Ross H Johnstone

    2017-03-01

    Full Text Available Dose-response (or ‘concentration-effect’ relationships commonly occur in biological and pharmacological systems and are well characterised by Hill curves. These curves are described by an equation with two parameters: the inhibitory concentration 50% (IC50; and the Hill coefficient. Typically just the ‘best fit’ parameter values are reported in the literature. Here we introduce a Python-based software tool, PyHillFit , and describe the underlying Bayesian inference methods that it uses, to infer probability distributions for these parameters as well as the level of experimental observation noise. The tool also allows for hierarchical fitting, characterising the effect of inter-experiment variability. We demonstrate the use of the tool on a recently published dataset on multiple ion channel inhibition by multiple drug compounds. We compare the maximum likelihood, Bayesian and hierarchical Bayesian approaches. We then show how uncertainty in dose-response inputs can be characterised and propagated into a cardiac action potential simulation to give a probability distribution on model outputs.

  2. Alcohol and cirrhosis: dose--response or threshold effect?

    DEFF Research Database (Denmark)

    Kamper-Jørgensen, Mads; Grønbaek, Morten; Tolstrup, Janne

    2004-01-01

    BACKGROUND/AIMS: General population studies have shown a strong association between alcohol intake and death from alcoholic cirrhosis, but whether this is a dose-response or a threshold effect remains unknown, and the relation among alcohol misusers has not been studied. METHODS: A cohort of 6152...... alcohol misusing men and women aged 15-83 were interviewed about drinking pattern and social issues and followed for 84,257 person-years. Outcome was alcoholic cirrhosis mortality. Data was analyzed by means of Cox-regression models. RESULTS: In this large prospective cohort study of alcohol misusers...... there was a 27 fold increased mortality from alcoholic cirrhosis in men and a 35 fold increased mortality from alcoholic cirrhosis in women compared to the Danish population. Number of drinks per day was not significantly associated with death from alcoholic cirrhosis, since there was no additional risk of death...

  3. Dose-response relationship for breast cancer induction at radiotherapy dose

    Directory of Open Access Journals (Sweden)

    Gruber Günther

    2011-06-01

    Full Text Available Abstract Purpose Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including breast cancer. Materials and methods In this work a dose-response relationship for breast cancer is derived based on (i the analysis of breast cancer induction after Hodgkin's disease, (ii a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and (iii the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy, (iv the breast cancer induction of the A-bomb survivor data. Results The fitted model parameters for an α/β = 3 Gy were α = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data. Conclusions The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.

  4. The dose-response relationship for UV-tumorigenesis

    International Nuclear Information System (INIS)

    Gruijl, F.R. de.

    1982-01-01

    The main objective of the investigations was to extend the knowledge on experimental UV-carcinogenesis and to use the experimental results as guidelines for developing a dose-response model for UV-carcinogenesis. The animal experiments carried out were all long-term ones. It was decided that - in anticipation of the data to be obtained - a model for such an assessment should be developed using the experimental results available at the start of the present study (1977). This initial study is presented. The results of two animal experiments are presented, which show that UV radiation is capable of inducing a systemic effect that enhances the de novo formation of UV induced tumors. The results of the main experiment are presented. In this experiment groups of mice were subjected to daily exposure to a certain dose of UV radiation in order to find the dose-response relationship. The relation between the daily dose and the duration of the treatment till the appearance of tumors (for instance, as measured by the yield) was ascertained for tumors of different sizes. It appears that the growth of a tumor is dose-independent, and, therefore, only the initiation of a tumor is dose-dependent. Finally an experiment is presented in which it was measured that, if a mouse is subjected to daily UV exposure, the transmission of the epidermis in the shortwave UV region decreases continuously. This decrease is due to hyperplasia of the epidermis, i.e., thickening of the epidermis by an increase in the number of cells per unit surface area. (Auth.)

  5. Dose-response relationships for radium-induced bone sarcomas

    International Nuclear Information System (INIS)

    Rowland, R.E.; Stehney, A.F.; Lucas, H.F. Jr.

    1981-01-01

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + αD + #betta#D 2 )e/sup -#betta#D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + αD + #betta#D 2 )e/sup -#betta#D/ and I = (C + #betta#D 2 )e/sup -#betta#D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + αD) fit the data for first measurement. The function I = (C + #betta#D 2 )e/sup -#betta#D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted

  6. An adaptive two-stage dose-response design method for establishing proof of concept.

    Science.gov (United States)

    Franchetti, Yoko; Anderson, Stewart J; Sampson, Allan R

    2013-01-01

    We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics. The stage-wise test results are then combined to establish "global" PoC using a conditional error function. Our simulation studies showed good and more robust power in our design method compared to conventional and fixed designs.

  7. Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer

    DEFF Research Database (Denmark)

    Appelt, Ane L.; Bentzen, Søren M.; Jakobsen, Anders

    2015-01-01

    BACKGROUND: Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity...... based on a large, single-institution series. MATERIAL AND METHODS: In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0-5). Clinical variables...... and radiation dose to the bladder were related to graded toxicity using multivariate ordinal logistic regression. Three models were optimized, each containing all available clinical variables and one of three dose metrics: Mean dose (Dmean), equivalent uniform dose (EUD), or relative volume given x Gy or above...

  8. Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer

    International Nuclear Information System (INIS)

    Levegruen, Sabine; Jackson, Andrew; Zelefsky, Michael J.; Venkatraman, Ennapadam S.; Skwarchuk, Mark W.; Schlegel, Wolfgang; Fuks, Zvi; Leibel, Steven A.; Ling, C. Clifton

    2002-01-01

    Background and purpose: We fit phenomenological tumor control probability (TCP) models to biopsy outcome after three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer patients to quantify the local dose-response of prostate cancer. Materials and methods: We analyzed the outcome after photon beam 3D-CRT of 103 patients with stage T1c-T3 prostate cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) (prescribed target doses between 64.8 and 81 Gy) who had a prostate biopsy performed ≥2.5 years after end of treatment. A univariate logistic regression model based on D mean (mean dose in the planning target volume of each patient) was fit to the whole data set and separately to subgroups characterized by low and high values of tumor-related prognostic factors T-stage ( 6), and pre-treatment prostate-specific antigen (PSA) (≤10 ng/ml vs. >10 ng/ml). In addition, we evaluated five different classifications of the patients into three risk groups, based on all possible combinations of two or three prognostic factors, and fit bivariate logistic regression models with D mean and the risk group category to all patients. Dose-response curves were characterized by TCD 50 , the dose to control 50% of the tumors, and γ 50 , the normalized slope of the dose-response curve at TCD 50 . Results: D mean correlates significantly with biopsy outcome in all patient subgroups and larger values of TCD 50 are observed for patients with unfavorable compared to favorable prognostic factors. For example, TCD 50 for high T-stage patients is 7 Gy higher than for low T-stage patients. For all evaluated risk group definitions, D mean and the risk group category are independent predictors of biopsy outcome in bivariate analysis. The fit values of TCD 50 show a clear separation of 9-10.6 Gy between low and high risk patients. The corresponding dose-response curves are steeper (γ 50 =3.4-5.2) than those obtained when all patients are analyzed together (γ 50 =2

  9. Mass shootings: a meta-analysis of the dose-response relationship.

    Science.gov (United States)

    Wilson, Laura C

    2014-12-01

    A meta-analysis was conducted to examine the dose-response theory as it relates to posttraumatic stress symptoms (PTSSs) following mass shootings. It was hypothesized that greater exposure to a mass shooting would be associated with greater PTSSs. Trauma exposure in the current study was broadly defined as the extent to which a person experienced or learned about a mass shooting. The meta-analysis identified 11 qualifying studies that included 13 independent effect sizes from a total of 8,047 participants. The overall weighted mean effect size, based on a random effects model, was r = .19, p shooting on the relationship between exposure and PTSSs. Because so few studies satisfied the inclusion criteria, the present study also documents that this area of the literature is underresearched. Copyright © 2014 International Society for Traumatic Stress Studies.

  10. Accelerometer-measured dose-response for physical activity, sedentary time, and mortality in US adults

    DEFF Research Database (Denmark)

    Matthews, Charles E; Keadle, S. K.; Troiano, Richard P

    2016-01-01

    Background: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Objectives: Using accelerometer-based measures, we 1) described the mortality dose-response...... for sedentary time and light-and moderateto-vigorous-intensity activity using restricted cubic splines, and 2) estimated the mortality benefits associated with replacing sedentary time with physical activity, accounting for total activity. Design: US adults (n = 4840) from NHANES (2003-2006) wore...... an accelerometer for #7 d and were followed prospectively for mortality. Proportional hazards models were used to estimate adjusted HRs and 95% CIs for mortality associations with time spent sedentary and in light-and moderate-to-vigorous-intensity physical activity. Splines were used to graphically present...

  11. Assembled cross-species perchlorate dose-response data

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set contains dose-response data for perchlorate exposure in multiple species. These data were assembled from peer-reviewed studies. Species included in...

  12. Mahalanobis distance and variable selection to optimize dose response

    International Nuclear Information System (INIS)

    Moore, D.H. II; Bennett, D.E.; Wyrobek, A.J.; Kranzler, D.

    1979-01-01

    A battery of statistical techniques are combined to improve detection of low-level dose response. First, Mahalanobis distances are used to classify objects as normal or abnormal. Then the proportion classified abnormal is regressed on dose. Finally, a subset of regressor variables is selected which maximizes the slope of the dose response line. Use of the techniques is illustrated by application to mouse sperm damaged by low doses of x-rays

  13. Population variability in biological adaptive responses to DNA damage and the shapes of carcinogen dose-response curves

    International Nuclear Information System (INIS)

    Conolly, Rory B.; Gaylor, David W.; Lutz, Werner K.

    2005-01-01

    Carcinogen dose-response curves for both ionizing radiation and chemicals are typically assumed to be linear at environmentally relevant doses. This assumption is used to ensure protection of the public health in the absence of relevant dose-response data. A theoretical justification for the assumption has been provided by the argument that low dose linearity is expected when an exogenous agent adds to an ongoing endogenous process. Here, we use computational modeling to evaluate (1) how two biological adaptive processes, induction of DNA repair and cell cycle checkpoint control, may affect the shapes of dose-response curves for DNA-damaging carcinogens and (2) how the resulting dose-response behaviors may vary within a population. Each model incorporating an adaptive process was capable of generating not only monotonic dose-responses but also nonmonotonic (J-shaped) and threshold responses. Monte Carlo analysis suggested that all these dose-response behaviors could coexist within a population, as the spectrum of qualitative differences arose from quantitative changes in parameter values. While this analysis is largely theoretical, it suggests that (a) accurate prediction of the qualitative form of the dose-response requires a quantitative understanding of the mechanism (b) significant uncertainty is associated with human health risk prediction in the absence of such quantitative understanding and (c) a stronger experimental and regulatory focus on biological mechanisms and interindividual variability would allow flexibility in regulatory treatment of environmental carcinogens without compromising human health

  14. A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

    Science.gov (United States)

    Chiu, Weihsueh A; Slob, Wout

    2015-12-01

    When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

  15. SU-F-J-59: Assessment of Dose Response Distribution in Individual Human Tumor

    Energy Technology Data Exchange (ETDEWEB)

    Yan, D [William Beaumont Hospital, Royal Oak, MI (United States); Chen, S; Krauss, D; Chen, P [Beaumont Health System, Royal Oak, Michigan (United States); Wilson, G [Beaumont Health System, Royal Oak, MI (United States)

    2016-06-15

    Purpose: To fulfill precision radiotherapy via adaptive dose painting by number, voxel-by-voxel dose response or radio-sensitivity in individual human tumor needs to be determined in early treatment to guide treatment adaptation. In this study, multiple FDG PET images obtained pre- and weekly during the treatment course were utilized to determine the distribution/spectrum of dose response parameters in individual human tumors. Methods: FDG PET/CT images of 18 HN cancer patients were used in the study. Spatial parametric image of tumor metabolic ratio (dSUV) was created following voxel by voxel deformable image registration. Each voxel value in dSUV was a function of pre-treatment baseline SUV and treatment delivered dose, and used as a surrogate of tumor survival fraction (SF). Regression fitting with break points was performed using the LQ-model with tumor proliferation for the control and failure group of tumors separately. The distribution and spectrum of radiation sensitivity and growth in individual tumors were determined and evaluated. Results: Spectrum of tumor dose-sensitivity and proliferation in the controlled group was broad with α in tumor survival LQ-model from 0.17 to 0.8. It was proportional to the baseline SUV. Tlag was about 21∼25 days, and Tpot about 0.56∼1.67 days respectively. Commonly tumor voxels with high radio-sensitivity or larger α had small Tlag and Tpot. For the failure group, the radio-sensitivity α was low within 0.05 to 0.3, but did not show clear Tlag. In addition, tumor voxel radio-sensitivity could be estimated during the early treatment weeks. Conclusion: Dose response distribution with respect to radio-sensitivity and growth in individual human tumor can be determined using FDG PET imaging based tumor metabolic ratio measured in early treatment course. The discover is critical and provides a potential quantitative objective to implement tumor specific precision radiotherapy via adaptive dose painting by number.

  16. Linear dose response curves in fungi and tradescantia

    International Nuclear Information System (INIS)

    Unrau, P.

    1999-07-01

    Tradescantia Clone 02 data suggests that linear non-threshold dose responses are expected to the lowest doses and dose rates of low linear energy transfer (LET) radiation. This is likely to be true for other living organisms even though Clone 02 is radiation sensitive. It is concluded that Clone 02 is partially defective in the RAD 6 pathway for the repair of DNA interstrand cross-links (ISCL) and other loss of coding damage (LCD), based on its cross sensitivities to EMS and ionizing radiation. Tradescantia Clone 02 data showing linear non-threshold induction of somatic genetic events in part reflects the repair deficiency of this Clone. More DNA damage is repaired by recombinational mechanisms in Clone 02 than would occur in a wild-type strain. Two important classes of DNA lesions are induced by ionizing radiation in DNA - double strand breaks (DSB) which are repaired by recombination mechanisms, and loss of coding information damage (LCD), which is repaired by error prone mechanisms but may also be a substrate for recombinational repair. Based on data from yeast, there are two different repair pathways which deal with these differing lesions with different somatic genetic consequences. From yeast, yield cross sections can be derived and applied to DNA damage and repair in Tradescantia. For Clone 02, per lesion, more visible genetic events are scored than in wild-type strains. In a radiation-derived sub-clone, Clone 0106, which is more variable than Clone 02, even more events occur per lesion. This derivative clone, plus breeding experiments, indicate that Clone 02 is heterozygous, or a 'carrier' for a mutant version of a gene in the Tradescantia RAD 6 repair pathway. Clone 02 is, therefore, much like a Fanconi's anemia carrier in a human population, while the Clone 0106 derivative is much like a homozygous Fanconi's anemia patient, with respect to its response to ionizing radiation damage. Two anomalies in its dose response curves for 'pink' loss of

  17. Dose-response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jinsil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Suh, Chang Ok

    2002-01-01

    Purpose: Dose escalation using three-dimensional conformal radiotherapy (3D-CRT) is based on the hypothesis that increasing the dose can enhance tumor control. This study aimed to determine whether a dose-response relationship exists in local radiotherapy for primary hepatocellular carcinoma (HCC). Methods and Materials: One hundred fifty-eight patients were enrolled in the present study between January 1992 and March 2000. The exclusion criteria included the presence of an extrahepatic metastasis, liver cirrhosis of Child class C, tumors occupying more than two-thirds of the entire liver, and a performance status on the Eastern Cooperative Oncology Group scale of more than 3. Radiotherapy was given to the field, including the tumor, with generous margin using 6- or 10-MV X-rays. The mean radiation dose was 48.2 ± 7.9 Gy in daily 1.8-Gy fractions. The tumor response was assessed based on diagnostic radiologic examinations, including a computed tomography scan, magnetic resonance imaging, and hepatic artery angiography 4-8 weeks after the completion of treatment. Liver toxicity and gastrointestinal complications were evaluated. Results: An objective response was observed in 106 of 158 (67.1%) patients. Statistical analysis revealed that the total dose was the most significant factor associated with the tumor response. The response rates in patients treated with doses 50 Gy were 29.2%, 68.6%, and 77.1%, respectively. Survivals at 1 and 2 years after radiotherapy were 41.8% and 19.9%, respectively, with a median survival time of 10 months. The rate of liver toxicity according to the doses 50 Gy was 4.2%, 5.9%, and 8.4%, respectively, and the rate of gastrointestinal complications was 4.2%, 9.9%, and 13.2%, respectively. Conclusions: The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response. The results of this study showed that 3D

  18. The dose-response relationship between in-ear occupational noise exposure and hearing loss.

    Science.gov (United States)

    Rabinowitz, Peter M; Galusha, Deron; Dixon-Ernst, Christine; Clougherty, Jane E; Neitzel, Richard L

    2013-10-01

    Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use of hearing protection, and with limited data regarding noise exposures below 85 dBA. We report on the hearing loss experience of a unique cohort of industrial workers, with daily monitoring of noise inside of hearing protection devices. At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory programme to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high-frequency hearing loss over a 6-year period using a mixed-effects model, adjusting for potential confounders. Workers' high-frequency hearing levels at study inception averaged more than 40 dB Hearing threshold level (HTL). Most noise exposures were less than 85 dBA (mean LAVG 76 dBA, IQR 74-80 dBA). We found no statistical relationship between LAvg and high-frequency hearing loss (p=0.53). Using a metric for monthly maximum noise exposure did not improve model fit. At-ear noise exposures below 85 dBA did not show an association with risk of high-frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85 dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose-response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure.

  19. The Dose Response Relationship between In Ear Occupational Noise Exposure and Hearing Loss

    Science.gov (United States)

    Rabinowitz, Peter M.; Galusha, Deron; Dixon-Ernst, Christine; Clougherty, Jane E.; Neitzel, Richard L.

    2014-01-01

    Objectives Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use hearing protection and with limited data regarding noise exposures below 85dBA. We report on the hearing loss experience of a unique cohort of industrial workers with daily monitoring of noise inside of hearing protection devices. Methods At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory program to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high frequency hearing loss over a six year period using a mixed effects model, adjusting for potential confounders. Results Workers’ high frequency hearing levels at study inception averaged more than 40 dB hearing threshold level (HTL). Most noise exposures were less than 85dBA (mean LAVG 76 dBA, interquartile range 74 to 80 dBA). We found no statistical relationship between LAvg and high frequency hearing loss (p = 0.53). Using a metric for monthly maximum noise exposure did not improve model fit. Conclusion At-ear noise exposures below 85dBA did not show an association with risk of high frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure. PMID:23825197

  20. [Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

    Science.gov (United States)

    Fronius, M

    2016-04-01

    Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

  1. Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity

    NARCIS (Netherlands)

    Koshy, Gibby; Delpisheh, Ali; Brabin, Bernard J.

    2011-01-01

    The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental

  2. Dose escalation with 3-D CRT in prostate cancer: five year dose responses and optimal treatment

    International Nuclear Information System (INIS)

    Hanks, Gerald; Hanlon, Alexandra; Pinover, Wayne; Hunt, Margie; Movsas, Benjamin; Schultheiss, Timothy

    1997-01-01

    Purpose: To report 5 yr dose responses in prostate cancer patients treated with 3D-CRT and describe optimal treatment based on dose response. Methods: Dose escalation was studied in 233 consecutive patients treated with 3D-CRT between 3/89 and 10/92. All surviving patients have >32 mo follow-up, the median follow-up is 55 mo. Estimated logistic cumulative distribution functions (logit response models) fit to 5 yr actuarial bNED outcome are reported for 3 dose groups in each of 3 pretreatment PSA groupings (10-19.9 ng/ml and 20+ ng/ml); no dose response is observed for patients with pretreatment PSA <10 ng/ml. Logit response models fit to 5 yr actuarial late morbidity rates (grade 2 GI, grade 2 GU, grade 3,4 GI) are also reported for 4 dose groups. Patients are treated with CT planned 4-field conformal technique where the PTV encompasses the CTV by 1.0 cm in all directions including the anterior rectal wall margin. Patients are followed at 6 mo intervals with PSA and DRE, and bNED failure is defined as PSA ≥1.5 ng/ml and rising on two consecutive measures. The Fox Chase modification of the LENT morbidity scale is used for GI morbidity including any blood transfusion and/or more than 2 coagulations as a grade 3 event. GU morbidity follows the RTOG scale. Results: The logit response models based on 5 yr bNED results have slopes of 27% and 18% for pretreatment PSA grouping 10-19.9 ng/ml and 20+ ng/ml, respectively. The 50% bNED response is observed at 71 Gy and 80 Gy respectively, while the 80% bNED response is observed at 76 Gy for the 10-19.9 ng/ml group and estimated at 88 Gy for the 20+ ng/ml group. Logit dose response models for grade 2 GI and grade 2 GU morbidity show markedly different slopes, 23% versus 4%, respectively. The slope for grade 3,4 GI is 12%. The dose response model indicates grade 3,4 GI complication rates at 5 yrs are 8% at 76 Gy and 12% at 80 Gy. Conclusion: Based on 5 yr results, we can draw some conclusions about appropriate dose from these

  3. Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk From Trichloroethylene-Contaminated Ground Water Beale Air Force Base in California: Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response; TOPICAL

    International Nuclear Information System (INIS)

    Bogen, K.T.

    1999-01-01

    Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability after applying a unified probabilistic approach to the distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such an approach was applied to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA(sub g)) vs. a cytotoxic/nonlinear (MA(sub c)) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA(sub G) based on seven rodent-bioassay data sets, and under MA, based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were and lt;10(sup -6) and and lt;10(sup -4), respectively, while corresponding estimates based on traditional deterministic methods were and gt;10(sup -5) and and gt;10(sup -4), respectively. It was estimated that no TCE-related harm is likely occur due any plausible residential exposure scenario involving the site. The unified approach illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action

  4. Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy

    International Nuclear Information System (INIS)

    Alevronta, Eleftheria; Ahlberg, Alexander; Mavroidis, Panayiotis; Al-Abany, Massoud; Friesland, Signe; Tilikidis, Aris; Laurell, Goeran; Lind, Bengt K.

    2010-01-01

    Background and purpose: Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck. Material and methods: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. Results: For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D 50 = 61.5 Gy (52.9-84.9 Gy), γ = 1.4 (0.8-2.6) and s = 0.1 (0.01-0.3). Conclusions: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.

  5. A threshold in the dose-response relationship for X-ray induced somatic mutation frequency in drosophila melanogaster

    International Nuclear Information System (INIS)

    Koana, Takao; Sakai, Kazuo; Okada, M.O.

    2004-01-01

    The dose-response relationship of ionizing radiation and its stochastic effects has been thought to be linear without any thresholds for a long time. The basic data for this model was obtained from mutational assays using germ cells of male fruit fly Drosophila melanogaster. However, cancer-causing activity should be examined more appropriately in somatic cells than in germ cells. In this paper, we examined the dose-response relationship of X-ray irradiation and somatic mutation in drosophila, and found a threshold at approximately 1 Gy in the DNA repair proficient flies. In the repair deficient siblings, the threshold was smaller and the inclination of the dose-response curve was five times steeper. These results suggest that the dose-response relationship between X-ray irradiation and somatic mutation has a threshold, and that the DNA repair function contributes to its formation. (author)

  6. Linear dose response curves in fungi and tradescantia

    Energy Technology Data Exchange (ETDEWEB)

    Unrau, P. [Atomic Energy of Canada Ltd., Chalk River, Ontario (Canada)

    1999-07-15

    Tradescantia Clone 02 data suggests that linear non-threshold dose responses are expected to the lowest doses and dose rates of low linear energy transfer (LET) radiation. This is likely to be true for other living organisms even though Clone 02 is radiation sensitive. It is concluded that Clone 02 is partially defective in the RAD 6 pathway for the repair of DNA interstrand cross-links (ISCL) and other loss of coding damage (LCD), based on its cross sensitivities to EMS and ionizing radiation. Tradescantia Clone 02 data showing linear non-threshold induction of somatic genetic events in part reflects the repair deficiency of this Clone. More DNA damage is repaired by recombinational mechanisms in Clone 02 than would occur in a wild-type strain. Two important classes of DNA lesions are induced by ionizing radiation in DNA - double strand breaks (DSB) which are repaired by recombination mechanisms, and loss of coding information damage (LCD), which is repaired by error prone mechanisms but may also be a substrate for recombinational repair. Based on data from yeast, there are two different repair pathways which deal with these differing lesions with different somatic genetic consequences. From yeast, yield cross sections can be derived and applied to DNA damage and repair in Tradescantia. For Clone 02, per lesion, more visible genetic events are scored than in wild-type strains. In a radiation-derived sub-clone, Clone 0106, which is more variable than Clone 02, even more events occur per lesion. This derivative clone, plus breeding experiments, indicate that Clone 02 is heterozygous, or a 'carrier' for a mutant version of a gene in the Tradescantia RAD 6 repair pathway. Clone 02 is, therefore, much like a Fanconi's anemia carrier in a human population, while the Clone 0106 derivative is much like a homozygous Fanconi's anemia patient, with respect to its response to ionizing radiation damage. Two anomalies in its dose response curves for &apos

  7. Shared dosimetry error in epidemiological dose-response analyses

    International Nuclear Information System (INIS)

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of 'possible' dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed

  8. Dose-response of photographic emulsions under gamma irradiation

    International Nuclear Information System (INIS)

    Tran Dai Nghiep; Do Thi Nguyet Minh; Le Van Vinh

    2003-01-01

    Photographic emulsion is irradiated under gamma rays irradiation of 137 Cs in the IAEA/WHO secondary standard dosimetry laboratory. Dose-response of the film is established. The sensitivity of the film is determined. The dose-rate effect is studied. (author)

  9. Dose-response relation between physical activity and sick leave

    NARCIS (Netherlands)

    Proper, K.I.; Heuvel, S.G. van den; Vroome, E.M. de; Hildebrandt, V.H.; Beek, A.J. van der

    2006-01-01

    Objective: To investigate the dose-response relation between moderate and vigorous physical activity and sick leave in a working population. Methods: Data were used from three large Dutch databases: two continuous, cross sectional surveys among a representative sample of the Dutch population and one

  10. Dose-response relationship with radiotherapy: an evidence?

    International Nuclear Information System (INIS)

    Chauvet, B.; Rauglaudre, G. de; Mineur, L.; Alfonsi, M.; Reboul, F.

    2003-01-01

    The dose-response relationship is a fundamental basis of radiobiology. Despite many clinical data, difficulties remain to demonstrate a relation between dose and local control: relative role of treatment associated with radiation therapy (surgery, chemotherapy, hormonal therapy), tumor heterogeneity, few prospective randomized studies, uncertainty of local control assessment. Three different situations are discussed: tumors with high local control probabilities for which dose effect is demonstrated by randomized studies (breast cancer) or sound retrospective data (soft tissues sarcomas), tumors with intermediate local control probabilities for which dose effect seems to be important according to retrospective studies and ongoing or published phase III trials (prostate cancer), tumors with low local control probabilities for which dose effect appears to be modest beyond standard doses, and inferior to the benefit of concurrent chemotherapy (lung and oesophageal cancer). For head and neck tumors, the dose-response relationship has been explored through hyperfractionation and accelerated radiation therapy and a dose effect has been demonstrated but must be compared to the benefit of concurrent chemotherapy. Last but not least, the development of conformal radiotherapy allow the exploration of the dose response relationship for tumors such as hepatocellular carcinomas traditionally excluded from the field of conventional radiation therapy. In conclusion, the dose-response relationship remains a sound basis of radiation therapy for many tumors and is a parameter to take into account for further randomized studies. (author)

  11. Chronic periodontitis and smoking. Prevalence and dose-response relationship.

    Science.gov (United States)

    Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H

    2016-08-01

    To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan.   This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (greater than 5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables.  Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p less than 0.007), male gender (p less than 0.001), and lower education level (p less than 0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p less than 0.001) and severity (p less than 0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p less than 0.001). Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis.

  12. Radiation Dose-Response Relationships and Risk Assessment

    International Nuclear Information System (INIS)

    Strom, Daniel J.

    2005-01-01

    The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented

  13. Bayesian nonparametric estimation of continuous monotone functions with applications to dose-response analysis.

    Science.gov (United States)

    Bornkamp, Björn; Ickstadt, Katja

    2009-03-01

    In this article, we consider monotone nonparametric regression in a Bayesian framework. The monotone function is modeled as a mixture of shifted and scaled parametric probability distribution functions, and a general random probability measure is assumed as the prior for the mixing distribution. We investigate the choice of the underlying parametric distribution function and find that the two-sided power distribution function is well suited both from a computational and mathematical point of view. The model is motivated by traditional nonlinear models for dose-response analysis, and provides possibilities to elicitate informative prior distributions on different aspects of the curve. The method is compared with other recent approaches to monotone nonparametric regression in a simulation study and is illustrated on a data set from dose-response analysis.

  14. I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chornobyl Accident

    OpenAIRE

    Brenner, Alina V.; Tronko, Mykola D.; Hatch, Maureen; Bogdanova, Tetyana I.; Oliynik, Valery A.; Lubin, Jay H.; Zablotska, Lydia B.; Tereschenko, Valery P.; McConnell, Robert J.; Zamotaeva, Galina A.; O?Kane, Patrick; Bouville, Andre C.; Chaykovskaya, Ludmila V.; Greenebaum, Ellen; Paster, Ihor P.

    2011-01-01

    Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case?control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose?response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who ...

  15. The shape of the cancer mortality dose-response curve for atomic bomb survivors

    International Nuclear Information System (INIS)

    Pierce, D.A.; Vaeth, M.

    1989-10-01

    The shape of the cancer mortality dose-response in the atomic bomb survivor data is analyzed in the context of linear-quadratic (LQ) models. Results are given for all cancers except leukemia as a group, for leukemia, and for combined inferences assuming common curvature. Since there is substantial information aside from these data suggesting a dose-response concave from above, the emphasis here is not on estimating the best-fitting dose-response curve, but rather on assessing the maximal extent of curvature under LQ models which is consistent with the data. Such inferences are substantially affected by imprecision in the dose estimates, and methods are applied which make explicit allowances for biases due to this. The primary means used here to express the extent of curvature is the factor by which linear risk estimates should be divided to arrive at appropriate low-dose risk estimates. In the past, influential committees have recommended ranges of 2-10 and of 1.5-3 for such a factor. Results here suggest that values greater than about 2 are at least moderately inconsistent with these data, within the context of LQ models. It is emphasized, however, that there is little direct information in these data regarding low-dose risks; the inferences here depend strongly on the link between low-dose and high-dose risks provided by the assumption of an LQ model. (author)

  16. Radiation dose response of strand breaks in SINPV-DNA

    International Nuclear Information System (INIS)

    Zhang Chunxiang; Luo Daling; Li Mianfeng; Liu Xiaowei; Zeng Rong; Wang Xunzhang

    1995-01-01

    The Spodoplera litura Nuclear Polyhedrosis Viruses (SINPV) is a kind of insectile virus with a simple structure, in which a double helix DNA is encapsulated in a protein coat and there is no function of enzymatic repair. The SINPV samples in dry powdered form held in sealed plastic tube were irradiated by 1-100 kGy gamma rays. The single strand breaks (SSB) and double strand breaks (DSB) induced in SINPV after irradiation were measured by neutral and alkaline agarose gel electrophoresis. A dose-response function combining the responses of one-hit and two-hit events was used to describe the SSB and DSB dose-response curves. It is shown that the SSB are one-hit events and the DSB are the combination of both one-hit, and two-hit events, and two-hit events are predominant in the DSB process

  17. Quantifying the dose-response of walking in reducing coronary heart disease risk: meta-analysis.

    Science.gov (United States)

    Zheng, Henry; Orsini, Nicola; Amin, Janaki; Wolk, Alicja; Nguyen, Van Thi Thuy; Ehrlich, Fred

    2009-01-01

    The evidence for the efficacy of walking in reducing the risk of and preventing coronary heart disease (CHD) is not completely understood. This meta-analysis aimed to quantify the dose-response relationship between walking and CHD risk reduction for both men and women in the general population. Studies on walking and CHD primary prevention between 1954 and 2007 were identified through Medline, SportDiscus and the Cochrane Database of Systematic Reviews. Random-effect meta-regression models were used to pool the relative risks from individual studies. A total of 11 prospective cohort studies and one randomized control trial study met the inclusion criteria, with 295,177 participants free of CHD at baseline and 7,094 cases at follow-up. The meta-analysis indicated that an increment of approximately 30 min of normal walking a day for 5 days a week was associated with 19% CHD risk reduction (95% CI = 14-23%; P-heterogeneity = 0.56; I (2) = 0%). We found no evidence of heterogeneity between subgroups of studies defined by gender (P = 0.67); age of the study population (P = 0.52); or follow-up duration (P = 0.77). The meta-analysis showed that the risk for developing CHD decreases as walking dose increases. Walking should be prescribed as an evidence-based effective exercise modality for CHD prevention in the general population.

  18. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Energy Technology Data Exchange (ETDEWEB)

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  19. Human cytogenetic dosimetry: a dose-response relationship for alpha particle radiation from 241Am

    International Nuclear Information System (INIS)

    DuFrain, R.J.; Littlefield, L.G.; Joiner, E.E.; Frome, E.L.

    1979-01-01

    Cytogenetic dosimetry estimates to guide treatment of persons internally contaminated with transuranic elements have not previously been possible because appropriate in vitro dose-response curves specifically for alpha particle irradiation of human lymphocytes do not exist. Using well-controlled cytogenetic methods for human lymphocyte culture, an experimentally derived dose-response curve for 241 Am alpha particle (5.49 and 5.44 MeV) radiation of G 0 lymphocytes was generated. Cells were exposed to 43.8, 87.7, 175.3 or 350.6 nCi/ml 241 Am for 1.7 hr giving doses of 0.85, 1.71, 3.42 or 6.84 rad. Based on dicentric chromosome yield, the linear dose-response equation is Y = 4.90(+-0.42) x 10 -2 X, with Y given as dicentrics per cell and X as dose in rads. The study also shows that the two-break asymmetrical exchanges in cells damaged by alpha particle radiation are overdispersed when compared to a Poisson distribution. An example is presented to show how the derived dose-response equation can be used to estimate the radiation dose for a person internally contaminated with an actinide. An experimentally derived RBE value of 118 at 0.85 rad is calculated for the efficiency of 241 Am alpha particle induction of dicentric chromosomes in human G 0 lymphocytes as compared with the efficiency of 60 Co gamma radiation. The maximum theoretical value for the RBE for cytogenetic damage from alpha irradiation was determined to be 278 at 0.1 rad or less which is in marked contrast to previously reported RBE values of approx. 20. (author)

  20. The Radiation Dose-Response of the Human Spinal Cord

    International Nuclear Information System (INIS)

    Schultheiss, Timothy E.

    2008-01-01

    Purpose: To characterize the radiation dose-response of the human spinal cord. Methods and Materials: Because no single institution has sufficient data to establish a dose-response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and α/β ratio in a logistic dose-response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results: The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4-72.6). The α/β = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions: The estimate of α/β is smaller than usually quoted, but values this small were found in some studies. Using α/β = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation

  1. Dose response relationship in anti-stress gene regulatory networks.

    Science.gov (United States)

    Zhang, Qiang; Andersen, Melvin E

    2007-03-02

    To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on

  2. Dose response relationship in anti-stress gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    2007-03-01

    Full Text Available To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear depends on changes in the specific values of local response coefficients (gains distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear

  3. Dose-response relationships for chromosome aberrations in peripheral blood lymphocytes after whole- and partial-body irradiations. Pt. 1

    International Nuclear Information System (INIS)

    Liniecki, J.; Bajerska, A.; Wyszynska, K.

    1983-01-01

    Dose-response relationships were established for yield of dicentrics and for a fraction of damaged metaphases in lymphocytes after γ-irradiation of rabbits' whole blood in vitro. These relationships were based on the scoring of cells only in their first post-stimulation division and they served as a reference system for comparison with results of 60 Co γ-irradiation in vivo, either of the whole or of predetermined parts of an animal's body. There was a statistically acceptable agreement between dose-response data established for dicentric yield after whole-body irradiation in vivo and the reference dose-response curve derived from exposure of rabbit's blood in vitro. For partial-body (1/2) irradiations there was a satisfactory agreement between the dose-response curves in vitro for dicentric yield and fraction of metaphases damaged on the one hand and the response in vivo when the latter was related to mean doses to circulating blood. However, there was a drastic disagreement with the dose responses in vitro when measured cytogenetic quantities were plotted versus mean doses to body mass. When the latter were substituted for by comparable doses to circulating blood the in vivo-in vitro agreement was acceptable after irradiation. (orig.)

  4. Neuromuscular dose-response studies: determining sample size.

    Science.gov (United States)

    Kopman, A F; Lien, C A; Naguib, M

    2011-02-01

    Investigators planning dose-response studies of neuromuscular blockers have rarely used a priori power analysis to determine the minimal sample size their protocols require. Institutional Review Boards and peer-reviewed journals now generally ask for this information. This study outlines a proposed method for meeting these requirements. The slopes of the dose-response relationships of eight neuromuscular blocking agents were determined using regression analysis. These values were substituted for γ in the Hill equation. When this is done, the coefficient of variation (COV) around the mean value of the ED₅₀ for each drug is easily calculated. Using these values, we performed an a priori one-sample two-tailed t-test of the means to determine the required sample size when the allowable error in the ED₅₀ was varied from ±10-20%. The COV averaged 22% (range 15-27%). We used a COV value of 25% in determining the sample size. If the allowable error in finding the mean ED₅₀ is ±15%, a sample size of 24 is needed to achieve a power of 80%. Increasing 'accuracy' beyond this point requires increasing greater sample sizes (e.g. an 'n' of 37 for a ±12% error). On the basis of the results of this retrospective analysis, a total sample size of not less than 24 subjects should be adequate for determining a neuromuscular blocking drug's clinical potency with a reasonable degree of assurance.

  5. Dose-response characteristics of an amorphous silicon EPID

    International Nuclear Information System (INIS)

    Winkler, Peter; Hefner, Alfred; Georg, Dietmar

    2005-01-01

    Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output

  6. External beam radiotherapy for painful osseous metastases: pooled data dose response analysis

    International Nuclear Information System (INIS)

    Ben-Josef, Edgar; Shamsa, Falah; Youssef, Emad; Porter, Arthur T.

    1999-01-01

    Purpose: Although the effectiveness of external beam irradiation in palliation of pain from osseous metastases is well established, the optimal fractionation schedule has not been determined. Clinical studies to date have failed to demonstrate an advantage for higher doses. To further address this issue, we conducted a pooled dose response analysis using data from published Phase III clinical trials. Methods and Materials: Complete response (CR) was used as an endpoint because it was felt to be least susceptible to inconsistencies in assessment.The biological effective dose (BED) was calculated for each schedule using the linear-quadratic model and an α/β of 10. Using SAS version 6.12, the data were fitted using a weighted linear regression, a logistic model, and the spline technique. Finally, BED was categorized, and odds ratios for each level were calculated. Results: CR was assessed early and late in 383 and 1,007 patients, respectively. Linear regression on the early-response data yielded a poor fit and a nonsignificant dose coefficient. With the late-response data, there was an excellent fit (R-square = 0.842) and a highly significant dose coefficient (p = 0.0002). Fitting early CR to a logistic model, we could not establish a significant dose response relationship. However, with the late-response data there was an excellent fit and the dose coefficient was significantly different from zero (0.017 ± 0.00524; p = 0.0012). Application of the spline technique or removal of an outlier resulted in an improved fit (p 0.048 and p = 0.0001, respectively). Using BED of < 14.4 Gy as a reference level, the odds ratios for late CR were 2.29-3.32 (BED of 19.5-51.4 Gy, respectively). Conclusion: Our results demonstrate a clear dose-response for pain relief. Further testing of high intensity regiments is warranted

  7. Multifraction dose response of growing and resting phase hair follicles

    International Nuclear Information System (INIS)

    Vegesna, V.; Withers, H.R.

    1987-01-01

    It has been established in both the clinic and the laboratory that there is a differentiation response to changes in dose per fraction in early and late responding tissues. To study one possible biological reason for differences in early and late responses. The authors selected one kind of cellular entity, the hair follicle, in two different phases of mitotic activity. The follicles are usually in a resting phase (7-12 wks), but mitotic activity can be initiated by plucking the club hairs. This was done on one half of the thorax and then exposing mice to doses of radiation (cesium gamma-ray). Dose responses for epilation between growing (early) and resting (late) follicles were compared for the same mouse. The fractionated response was studied by reducing the dose down to 2.5 Gy/fx. As the literature suggests, the total dose tolerated by a resting (late) follicle increased more than that for a growing (early) follicle

  8. Dose-Response Relationships of Resistance Training in Healthy Old Adults : A Systematic Review and Meta-Analysis

    NARCIS (Netherlands)

    Borde, Ron; Hortobagyi, Tibor; Granacher, Urs

    2015-01-01

    Background Resistance training (RT) is an intervention frequently used to improve muscle strength and morphology in old age. However, evidence-based, dose-response relationships regarding specific RT variables (e.g., training period, frequency, intensity, volume) are unclear in healthy old adults.

  9. Dose-Response Relationships of Balance Training in Healthy Young Adults : A Systematic Review and Meta-Analysis

    NARCIS (Netherlands)

    Lesinski, Melanie; Hortobagyi, Tibor; Muehlbauer, Thomas; Gollhofer, Albert; Granacher, Urs

    Background Balance training (BT) has been used for the promotion of balance and sports-related skills as well as for prevention and rehabilitation of lower extremity sport injuries. However, evidence-based dose-response relationships in BT parameters have not yet been established. Objective The

  10. Introduction to methodology of dose-response meta-analysis for binary outcome: With application on software.

    Science.gov (United States)

    Zhang, Chao; Jia, Pengli; Yu, Liu; Xu, Chang

    2018-05-01

    Dose-response meta-analysis (DRMA) is widely applied to investigate the dose-specific relationship between independent and dependent variables. Such methods have been in use for over 30 years and are increasingly employed in healthcare and clinical decision-making. In this article, we give an overview of the methodology used in DRMA. We summarize the commonly used regression model and the pooled method in DRMA. We also use an example to illustrate how to employ a DRMA by these methods. Five regression models, linear regression, piecewise regression, natural polynomial regression, fractional polynomial regression, and restricted cubic spline regression, were illustrated in this article to fit the dose-response relationship. And two types of pooling approaches, that is, one-stage approach and two-stage approach are illustrated to pool the dose-response relationship across studies. The example showed similar results among these models. Several dose-response meta-analysis methods can be used for investigating the relationship between exposure level and the risk of an outcome. However the methodology of DRMA still needs to be improved. © 2018 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.

  11. Dose-response evaluation after Yttrium-90 resin microsphere radio-embolization of breast cancer liver metastases

    International Nuclear Information System (INIS)

    Gnesin, S.; Verdun, F.R.; Baechler, S.; Boubacker, A.; Adib, S.; Cherbuin, N.; Prior, J.O.; Bize, P.; Denys, A.

    2015-01-01

    Full text of publication follows. Aim: Yttrium-90 resin microsphere radio-embolization is a valuable therapeutic option in metastatic breast cancer patients with progressive disease refractory to chemotherapy. The goal of this study was to evaluate the dose-response relationship of liver metastasis based on a 3D voxelized 90 Y PET dosimetry. Materials and methods: we studied the dose-response relationship of twelve hepatic lesions in four selected patients with metastatic breast cancer who underwent 90 Y radio-embolization (Sirtex SIR-Spheres Pty Ltd.). The administered activity ranged from 1 to 1.3 GBq. Ten days before treatment, patients underwent a baseline 18 F-FDG PET/CT. The determination of the 90 Y-microsphere activity to administer for treatment was based on the BSA method refined with the partition model derived from a 99m Tc-MAA SPECT/CT performed a week prior to radio-embolization. Within 24 hours after treatment, 90 Y TOF PET/CT imaging was performed. A follow-up 18 F-FDG PET/CT was performed 1 month after the treatment to evaluate the response to radio-embolization. For each patient, 3D voxelized dose-maps were obtained from the post-treatment 90 Y TOF PET/CT. A volume of interest (VOI) was drawn for each selected hepatic lesion using the baseline 18 F-FDG PET/CT. To obtain dose-volume histogram (DVH) for each lesion, image co-registration and VOI masks were generated using the PMOD 3.4 software and then exported in Matlab for dose calculation. Furthermore, the average absorbed dose in lesions was corrected for PVE effects by multiplication for appropriate (phantom-based) recovery coefficients according to the lesion size. Early metabolic lesion response was assessed in terms of variation in the maximum standard uptake value (ΔSUVmax) between baseline and follow-up 18 F-FDG PET/CT. The average absorbed dose for each lesion was associated with the respective metabolic response. Results: for the 12 selected lesions, the average volume was 35 cm 3

  12. Critical reevaluation of the dose-response relationships for carcinogenic effects of low-level ionizing radiation

    International Nuclear Information System (INIS)

    Upton, A.C.

    2003-01-01

    In recent decades, it has been customary, for radiation protection purposes, to assume that the overall risk of radiation-induced cancer increases as a linear-nonthreshold function of the dose. The existing data do not exclude the existence of a threshold, however, and the dose-response relationship is known to vary, depending on the type of cancer in queation, the dose, dose rate, and LET of the radiation, the age, sex, and physiological state of the exposed individuals, and other variables, including the potential influence of adaptive responses and bystander effects at low doses. In light of advncing knowledge, therefore, the dose-response relationship for carcinogenic effects of low-level radiation has been reevaluated periodically by the National Council on Radiation Protection and Measurements, the International Commission of Radiological Protection, the United Nations Scientific Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences, and other organizations. The most recent such reviews have generally found the weight of evidence to suggest that lesions which are precursors to cancer (i.e., mutations and chromosome aberrations), and certain types of cancer as well, may increase in frequency linearly with the dose in the low-dose domain. On this basis, it is concluded that no alternative dose-response model for the carcinogenic effects of low-level radiation is more plausible than the linear-nonthreshold model, although other dose-response relationships cannot be excluded. (authors)

  13. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease.

    Science.gov (United States)

    Qi, Hui; Li, Shixue

    2014-04-01

    A dose-response meta-analysis was carried out between Parkinson's disease (PD) risk, and coffee, tea and caffeine consumption. A comprehensive search was carried out to identify eligible studies. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline. A total of 13 articles involving 901 764 participants for coffee, eight articles involving 344 895 participants for tea and seven articles involving 492 724 participants for caffeine were included. A non-linear relationship was found between coffee consumption and PD risk overall, and the strength of protection reached the maximum at approximately 3 cups/day (smoking-adjusted relative risk: 0.72, 95% confidence interval 0.65-0.81). A linear relationship was found between tea and caffeine consumption, and PD risk overall, and the smoking-adjusted risk of PD decreased by 26% and 17% for every two cups/day and 200 mg/day increments, respectively. The association of coffee and tea consumption with PD risk was stronger for men than that for women, and the association of caffeine consumption with PD risk was stronger for ever users of hormones than that for never users of hormones among postmenopausal women. The aforementioned associations were weaker for USA relative to Europe or Asia. A linear dose-relationship for decreased PD risk with tea and caffeine consumption was found, whereas the strength of protection reached a maximum at approximately 3 cups/day for coffee consumption overall. Further studies are required to confirm the findings. © 2013 Japan Geriatrics Society.

  14. Dose-response curves for fish MFO induction: How do we interpret different maxima and slopes?

    International Nuclear Information System (INIS)

    Parrott, J.L.

    1995-01-01

    Induction of hepatic mixed function oxygenase (MFO) activity has been useful for screening effluents from pulp mills and oil refineries. Effluents and pure compounds can be assessed by direct fish exposure or by concentration with semipermeable membrane devices (SPMDs) and by measuring MFO in fish liver cell lines exposed to SPMD extracts. In these experiments, both fish and fish cells showed differences in slopes of dose-response curves, and in the maximal ethoxyresorufin-O-deethylase (EROD) activity. For example, TCDD elicits an EROD maxima of over 500 pmol/mg/min in PLHC-1 (Poeciliopsis lucida hepatocellular carcinoma cell line), while pulp mill and oil refinery effluent extracts showed maxima of 40 to 200 pmol/mg/min. Substituted phenanthrenes caused induction maxima of 100 pmol/mg/min. Similarly, in rainbow trout in vivo, TCDD and other chlorinated dioxins and furans induced up to 500 pmol/mg/min, whereas pulp mill and refinery effluents and substituted phenanthrenes produced EROD maxima of up to 100 pmol/mg/min. Differences in the slopes of dose-response curves were also common. In the current assessment of potencies, these diverse response curves are boiled-down to one number, the EC50 or other threshold-type of concentration. Comparisons of EC50s cannot express these differences and instead, ignore them. However, the authors realize there must be a better approach that takes into account these large differences in dose-response curve shape, slope and maxima. Interaction and discussions with modelers in the session will allow them to discuss various approaches to expressing the potencies of MFO inducers in fish

  15. Flow characterization and patch clamp dose responses using jet microfluidics in a tubeless microfluidic device.

    Science.gov (United States)

    Resto, Pedro J; Bhat, Abhishek; Stava, Eric; Lor, Chong; Merriam, Elliot; Diaz-Rivera, Ruben E; Pearce, Robert; Blick, Robert; Williams, Justin C

    2017-11-01

    Surface tension passive pumping is a way to actuate flow without the need for pumps, tubing or valves by using the pressure inside small drop to move liquid via a microfluidic channel. These types of tubeless devices have typically been used in cell biology. Herein we present the use of tubeless devices as a fluid exchange platform for patch clamp electrophysiology. Inertia from high-speed droplets and jets is used to create flow and perform on-the-fly mixing of solutions. These are then flowed over GABA transfected HEK cells under patch in order to perform a dose response analysis. TIRF imaging and electrical recordings are used to study the fluid exchange properties of the microfluidic device, resulting in 0-90% fluid exchange times of hundreds of milliseconds. COMSOL is used to model flow and fluid exchange within the device. Patch-clamping experiments show the ability to use high-speed passive pumping and its derivatives for studying peak dose responses, but not for studying ion channel kinetics. Our system results in fluid exchange times slower than when using a standard 12-barrel application system and is not as stable as traditional methods, but it offers a new platform with added functionality. Surface tension passive pumping and tubeless devices can be used in a limited fashion for electrophysiology. Users may obtain peak dose responses but the system, in its current form, is not capable of fluid exchange fast enough to study the kinetics of most ion channels. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Dose response of bone-targeted enzyme replacement for murine hypophosphatasia.

    Science.gov (United States)

    Yadav, Manisha C; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L; Whyte, Michael P; Crine, Philippe; Millán, José Luis

    2011-08-01

    Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Determination of tolerance dose uncertainties and optimal design of dose response experiments with small animal numbers

    International Nuclear Information System (INIS)

    Karger, C.P.; Hartmann, G.H.

    2001-01-01

    Background: Dose response experiments aim to determine the complication probability as a function of dose. Adjusting the parameters of the frequently used dose response model P(D)=1/[1+(D 50 /D) k ] to the experimental data, 2 intuitive quantities are obtained: The tolerance dose D 50 and the slope parameter k. For mathematical reasons, however, standard statistic software uses a different set of parameters. Therefore, the resulting fit parameters of the statistic software as well as their standard errors have to be transformed to obtain D 50 and k as well as their standard errors. Material and Methods: The influence of the number of dose levels on the uncertainty of the fit parameters is studied by a simulation for a fixed number of animals. For experiments with small animal numbers, statistical artifacts may prevent the determination of the standard errors of the fit parameters. Consequences on the design of dose response experiments are investigated. Results: Explicit formulas are presented, which allow to calculate the parameters D 50 and k as well as their standard errors from the output of standard statistic software. The simulation shows, that the standard errors of the resulting parameters are independent of the number of dose levels, as long as the total number of animals involved in the experiment, remains constant. Conclusion: Statistical artifacts in experiments containing small animal numbers may be prevented by an adequate design of the experiment. For this, it is suggested to select a higher number of dose levels, rather than using a higher number of animals per dose level. (orig.) [de

  18. Low-Active Male Adolescents: A Dose Response to High-Intensity Interval Training.

    Science.gov (United States)

    Logan, Greig Robert Melrose; Harris, Nigel; Duncan, Scott; Plank, Lindsay D; Merien, Fabrice; Schofield, Grant

    2016-03-01

    High-intensity interval training (HIIT) is a potential alternative to traditionally recommended steady state exercise for providing health benefits in adolescents, yet its dose-response relationship in this cohort remains unclear, as does its translatability to real-world, nonclinical settings. The present study adopts a novel dose-response design to investigate the effects of undertaking 8 wk of HIIT on the cardiometabolic health of low-active male adolescents. Twenty-six male adolescents (age 16 ± 1 yr), identified as low active by nonparticipation in structured sport and physical education classes, were randomly assigned to one of five treatment groups. Corresponding with their group numbers (1-5), participants completed a number of HIIT "sets," which consisted of 4 repeated bouts of 20-s near-maximal exertion interspersed with 10-s passive recovery. Participants performed two HIIT sessions and one resistance training session each week for 8 wk. Baseline and follow-up health measures consisted of peak oxygen uptake (V˙O2peak) with an incremental ramp test to volitional exhaustion; body composition (including visceral fat mass, body fat, and lean tissue mass) with dual-energy x-ray absorptiometry; and lipid profile, glucose, insulin, and interleukin-6 from blood analysis. All health outcomes were analyzed as percentage changes, and data were modeled using a quadratic function to explore dose-response relationships. Significant improvements were observed for V˙O2peak (∼6%), body fat percentage (∼4%), visceral fat mass (∼10%), and waist circumference-to-height ratio (∼3%), but there was no clear effect of dose across groups. Low-active adolescent males performing a single HIIT set twice weekly, in addition to one resistance training session, gained meaningful improvements in fitness and body composition. Performing additional HIIT sets provided no additional improvements to those of the lowest dose in this study.

  19. Dose response on the 110 °C thermoluminescence peak of un-heated, synthetic Merck quartz

    Energy Technology Data Exchange (ETDEWEB)

    Kaya Keleş, Şule, E-mail: sule.kaya@ankara.edu.tr; Meriç, Niyazi; Polymeris, George S.

    2016-07-15

    Studies on 110 °C TL peak have been carried out using natural quartz from different origins and synthetic quartz produced by different suppliers. The interest in quartz is due to its usage in dating and retrospective dosimetry as a main material; both synthetic and natural types of quartz yield the 110 °C TL peak in their glow curve. In most studies to understand the physical mechanism behind the TL system, synthetic quartz samples are used and there are many investigations about dose response, in both low and high radiation dose region. In these studies generally synthetic quartz samples produced by Sawyer Research Products are used and the studies showed that both heated and un-heated synthetic quartz samples have intense supra-linear responses. Supra-linearity was enhanced by applying a pre-irradiation while several models have been developed towards an explanation to these supra-linearity effects. In this study commercially available synthetic Merck quartz was used. Different combinations of optical filters were used to obtain dose response curves upto 266 Gy and the effect of pre-dose to these dose response curves was studied. Un-pre-dosed Merck quartz samples dose supra-linearity index is below 1 independently on the optical filters; so Merck quartz showed linear or sub-linear dose response.

  20. Establishment and verification of dose-response curve of chromosomal aberrations after exposure to very high dose γ-ray

    International Nuclear Information System (INIS)

    Chen Ying; Luo Yisheng; Cao Zhenshan; Liu Xiulin

    2006-01-01

    To estimate accurately biological dose of the victims exposed to high dose, the dose-response curves of chromosome aberration induced by 6-22 Gy 60 Co γ-ray were established. Human peripheral blood in vitro was irradiated, then lymphocytes were concentrated, cultured 52h, 68h and 72h and harvested. The frequencies of dicentrics (multi-centrics) and rings were counted and compared between different culture times. The dose-response curves and equations were established, as well as verified with high dose exposure accidents. The experiment showed that the culture time should be prolonged properly after high dose exposure, and no significant differences were observed between 52-72h culture. The dose-response curve of 6-22 Gy fitted to linear-square model Y=-2.269 + 0.776D - 7.868 x 10 -3 D 2 and is reliable through verification of the accident dose estimations. In this study, the dose-response curve and equation of chromosome dic + r after 6-22 Gy high dose irradiation were established firstly, and exact dose estimation can be achieved according to it. (authors)

  1. A Threshold Exists in the Dose-response Relationship for Somatic Mutation Frequency Inducted by X-ray Irradiation of Drosophia

    International Nuclear Information System (INIS)

    Koana, T.; Takashima, Y.; Okada, M. O.; Ikehata, M.; Miyakoshi, J.; Sakai, K.

    2004-01-01

    The dose-response relationship of ionizing radiation and its stochastic effects has been thought to be linear without any thresholds. The basic data for this model was obtained from mutational assays in the male germ cells of fruits fly Drosophila melanogaster. However, carcinogenic activity should be examined more appropriately in somatic cells than in germ cells. Here, the dose-response relationship of X- ray irradiation and somatic mutation is examined in Drosophila. A threshold at approximately 1Gy was observed in the DNA repair proficient flies. In the repair deficient siblings, the threshold was smaller and the inclination of the dose-response curve was much steeper. These results suggest that the dose-response relationship between X-ray irradiation and somatic mutation has a threshold, and that the DNA repair function contributes to its formation. (Author) 35 refs

  2. Biophysical Monitoring and dose response characteristics of irradiated hemoglobin

    International Nuclear Information System (INIS)

    Elshemey, W.M; Selim, N.S.; Desouky, O.

    2003-01-01

    The present work aims to move a step forward towards a deeper understanding of the scattering of x-ray, from lyophilized biological samples. Comparative study has been performed using LAXS and UV-visible spectrophotometry for monitoring the dose response characteristics of the hemoglobin molecule of irradiated blood. Blood samples were irradiated at doses ranging from 5 up to 100 Gy. Diluted hemoglobin solution was scanned in the UV- visible range (200-700 nm), and lyophilized hemoglobin was prepared for LAXS measurement. The radiation-induced changes in the hemoglobin structure have been evaluated. The LAXS profile of hemoglobin molecule is characterized by the presence of two peaks in the forward direction of scattering. These peaks were found to be sensitive to the variations in the molecular structure of a given sample. The obtained results suggest that the 1 s t peak, recorded at 4.65 o , is sensitive to the tertiary and quaternary structure of the globin part, while the major peak, recorded at 10.5 o , appeared to be related to its primary and secondary structure

  3. Optimal dose-response relationships in voice therapy.

    Science.gov (United States)

    Roy, Nelson

    2012-10-01

    Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding "effective" concentrations of specific voice therapies vs "toxic" concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible "overdosing".

  4. Dose - Response Curves for Dicentrics and PCC Rings: Preparedness for Radiological Emergency in Thailand

    International Nuclear Information System (INIS)

    Rungsimaphorn, B.; Rerkamnuaychoke, B.; Sudprasert, W.

    2014-01-01

    Establishing in-vitro dose calibration curves is important for reconstruction of radiation dose in the exposed individuals. The aim of this pioneering work in Thailand was to generate dose-response curves using conventional biological dosimetry: dicentric chromosome assay (DCA) and premature chromosome condensation (PCC) assay. The peripheral blood lymphocytes were irradiated with 137 Cs at a dose rate of 0.652 Gy/min to doses of 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4 and 5 Gy for DCA technique, and 5, 10, 15, 20 and 25 Gy for PCC technique. The blood samples were cultured and processed following the standard procedure given by the IAEA with slight modifications. At least 500-1,000 metaphases or 100 dicentrics/ PCC rings were analyzed using an automated metaphase finder system. The yield of dicentrics with dose was fitted to a linear quadratic model using Chromosome Aberration Calculation Software (CABAS, version 2.0), whereas the dose-response curve of PCC rings was fitted to a linear relationship. These curves will be useful for in-vitro dose reconstruction and can support the preparedness for radiological emergency in the country.

  5. Dose-response relationship for elective neck irradiation of head and neck cancer - facts and controversies

    International Nuclear Information System (INIS)

    Suwinski, R.; Maciejewski, B.; Withers, H.R.

    1998-01-01

    The aim of this study is to assign dose-response relationship for subclinical neck metastases of squamous cell head and neck cancer based on extensive survey of 24 data sets collected from the literature. Neck relapse rates (NRR) without and after elective (ENI) or preoperative irradiation were estimated for each site and stage of primary tumor and the reduction in neck relapse rate was calculated. An average NRR without ENI was 22% (12-35% ) and only 2.5% (0-1 0%) after the ENI with total dose of 46- 50 Gy which gives high reduction rate in the risk of neck recurrences being on the average 89% and 42% (0-46%) after preoperative irradiation using 22-30 Gy. Dose response curve for elective and preoperative irradiation have shown that 50 Gy in 2 Gy fraction reduces the incidence of neck relapses in the NO patients by more than 90% and only by less than 50% after total doses lower than 30 Gy. No correlation between the risk of neck metastases without ENI and the reduction in neck relapses after ENI was found. (authors)

  6. Dose Response Association between Physical Activity and Biological, Demographic, and Perceptions of Health Variables

    Directory of Open Access Journals (Sweden)

    Paul D. Loprinzi

    2013-08-01

    Full Text Available Background: Few population-based studies have examined the association between physical activity (PA and cardiovascular disease risk factors, demographic variables, and perceptions of health status, and we do not have a clear understanding of the dose-response relationship among these variables. Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey was used to examine the dose-response relationship between objectively measured PA and metabolic syndrome (and its individual cardiovascular disease risk factors, demographic variables, and perceptions of health. After exclusions, 5,538 participants 18 years or older were included in the present study, with 2,538 participants providing fasting glucose and 2,527 providing fasting triglyceride data. PA was categorized into deciles. Results: Overall, the health benefits showed a general pattern of increase with each increasing levels of PA. Of the ten PA classifications examined, participants in the highest moderate-to-vigorous physical activity (MVPA category (at least 71 min/day had the lowest odds of developing metabolic syndrome. Conclusion: At a minimum, sedentary adults should strive to meet current PA guidelines (i.e., 150 min/week of MVPA, with additional positive benefits associated with engaging in three times this level of PA.

  7. Biological dosimetry in radiation accidents. Dose-response curve by chromosomal aberrations analysis

    International Nuclear Information System (INIS)

    Hadjidekova, V.; Hristova, R.; Atanasova, P.; Popova, L.; Stainova, A.; Bulanova, M.; Georgieva, I.; Vukov, M.

    2005-01-01

    The aim of this paper is to obtain a dose-response relationship for chromosomal aberrations induced in human lymphocytes after in vitro irradiation. Peripheral blood samples of 7 different donors were used. The blood irradiation was done with Cs137 gamma-rays at different doses: 0.0, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0 and 3.0 Gy. Lymphocyte cultures were established and maintain for 48 hours at 37 0 C in CO 2 incubator for chromosomal aberration analysis. The dose response relationship has been established based on dysenteric and ring chromosomes yield. The relationship can be described by the following equation: Y = 0.0274D + 0.0251 D 2 , where (Y) = dysenteric and ring chromosomes yield, (D) = radiation dose obtained. EXCEL software was established for calculation of the received dose by using this equation, as a whole body equivalent dose acute irradiation

  8. Dose-response relationship in the treatment of gastrointestinal disorders.

    Science.gov (United States)

    Weihrauch, T R; Demol, P

    1989-08-01

    Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

  9. Dose-response relationship between cigarette smoking and site-specific cancer risk: protocol for a systematic review with an original design combining umbrella and traditional reviews.

    Science.gov (United States)

    Lugo, Alessandra; Bosetti, Cristina; Peveri, Giulia; Rota, Matteo; Bagnardi, Vincenzo; Gallus, Silvano

    2017-11-01

    Only a limited number of meta-analyses providing risk curve functions of dose-response relationships between various smoking-related variables and cancer-specific risk are available. To identify all relevant original publications on the issue, we will conduct a series of comprehensive systematic reviews based on three subsequent literature searches: (1) an umbrella review, to identify meta-analyses, pooled analyses and systematic reviews published before 28 April 2017 on the association between cigarette smoking and the risk of 28 (namely all) malignant neoplasms; (2) for each cancer site, an updated review of original publications on the association between cigarette smoking and cancer risk, starting from the last available comprehensive review identified through the umbrella review; and (3) a review of all original articles on the association between cigarette smoking and site-specific cancer risk included in the publications identified through the umbrella review and the updated reviews. The primary outcomes of interest will be (1) the excess incidence/mortality of various cancers for smokers compared with never smokers; and (2) the dose-response curves describing the association between smoking intensity, duration and time since stopping and incidence/mortality for various cancers. For each cancer site, we will perform a meta-analysis by pooling study-specific estimates for smoking status. We will also estimate the dose-response curves for other smoking-related variables through random-effects meta-regression models based on a non-linear dose-response relationship framework. Ethics approval is not required for this study. Main results will be published in peer-reviewed journals and will also be included in a publicly available website. We will provide therefore the most complete and updated estimates on the association between various measures of cigarette smoking and site-specific cancer risk. This will allow us to obtain precise estimates on the cancer burden

  10. Prevalence of Hyperthyroidism Following Exposure During Childhood or Adolescence to Radioiodines from the Chornobyl Nuclear Accident: Dose-Response Results from the Ukrainian-American Cohort Study

    Science.gov (United States)

    Hatch, M.; Furukawa, K.; Brenner, A.; Olinjyk, V.; Ron, E.; Zablotska, L.; Terekhova, G.; McConnell, R.; Markov, V.; Shpak, V.; Ostroumova, E.; Bouville, A.; Tronko, M.

    2013-01-01

    Relatively few data are available on the prevalence of hyperthyroidism (TSH concentrations of hyperthyroidism among 11,853 individuals exposed as children or adolescents in Ukraine who underwent an in-depth, standardized thyroid gland screening examination 12–14 years later. Radioactivity measurements taken shortly after the accident were available for all subjects and were used to estimate individual thyroid doses. We identified 76 cases of hyperthyroidism (11 overt, 65 subclinical). Using logistic regression, we tested a variety of continuous risk models and conducted categorical analyses for all subjects combined and for females (53 cases, n=5,767) and males (23 cases, n=6,086) separately, but found no convincing evidence of a dose response relationship between I-131 and hyperthyroidism. There was some suggestion of elevated risk among females in an analysis based on a dichotomous dose model with a threshold of 0.5 Gy chosen empirically (OR=1.86, P=0.06), but the statistical significance level was reduced (P=0.13) in a formal analysis with an estimated threshold. In summary, after a thorough exploration of the data, we found no statistically significant dose response relationship between individual I-131 thyroid doses and prevalent hyperthyroidism. PMID:21128800

  11. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure

    Science.gov (United States)

    Johnston, Sara C.; Lin, Kenny L.; Twenhafel, Nancy A.; Raymond, Jo Lynne W.; Shamblin, Joshua D.; Wollen, Suzanne E.; Wlazlowski, Carly B.; Wilkinson, Eric R.; Botto, Miriam A.; Goff, Arthur J.

    2015-01-01

    Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies. PMID:26413900

  12. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure.

    Directory of Open Access Journals (Sweden)

    Sara C Johnston

    Full Text Available Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies.

  13. Pleural mesothelioma: dose-response relation at low levels of asbestos exposure in a french population-based case-control study; Mesotheliome pleural: relation dose-reponse a faibles niveaux d'exposition a l'amiante dans une etude cas-temoins au sein d'une polulation francaise

    Energy Technology Data Exchange (ETDEWEB)

    Iwatsubo, Y.; Pairo, J.C.; Boutin, C.; Menard, O.; Massin, N.; Caillaud, D.; Orlowski, E.; Galateau-Salle, F.; Bignon, J.; Brochard, P.

    1998-03-01

    The objectives of this study were to study the dose-response relationship between professional exposure to asbestos and the supervening of the pleural mesothelioma in general population. This work notes an excess of death by pulmonary cancer among the asbestos-cement workers but one can regret the weakness of the exposure estimation (only one source of exposure is considered) and that some others risk factors have not been taken into account (tobacco, for example). (N.C.)

  14. Comparison of the dose-response relationships for chromosome aberration frequencies between the T65D and DS86 dosimetries

    International Nuclear Information System (INIS)

    Preston, D.L.; McConney, M.E.; Awa, A.A.; Ohtaki, Kazuo; Itoh, Masahiro; Honda, Takeo.

    1989-05-01

    Cytogenetic data, derived from cultured lymphocytes of atomic bomb survivors and controls in the ABCC-RERF Adult Health Study cohort, have been analyzed to determine differences in the dose-response relationships for chromosome aberrations between the T65D and DS86 dose estimates and to assess differences between Hiroshima and Nagasaki. For a linear dose-response model, the average percentage of cells with at least one chromosome aberration increases less rapidly with dose in Nagasaki than in Hiroshima. The magnitude of the intercity difference in the percentage of cells with aberrations per gray is less for DS86 than for T65D, though the difference is statistically significant for both kerma and bone marrow dose with either dosimetry. The percentage of cells with aberrations per gray for DS86 kerma estimates is about 60 % greater than the corresponding T65D slope. Analyses to test nonlinearity in the dose-response function indicate significant departures (p<.001) from linearity, using both dosimetries for both kerma and marrow dose. Therefore, comparative results are presented for a range of RBE relationships under various linear (L) and linearquadratic linear (LQ-L) models. As an illustrative result, if one assumes an LQ-L model similar to models reported in the cytogenetic literature, with a limiting RBE of 20 at zero dose, the DS86 slope (the percentage of cells with aberrations per sievert) is 120 % greater than the corresponding T65D value. (J.P.N.)

  15. SU-F-J-147: Magnetic Field Dose Response Considerations for a Linac Monitor Chamber

    Energy Technology Data Exchange (ETDEWEB)

    Reynolds, M; Fallone, B [Cross Cancer Institute, Edmonton, AB (Canada)

    2016-06-15

    Purpose: The impact of magnetic fields on the readings of a linac monitor chamber have not yet been investigated. Herein we examine the total dose response as well as any deviations in the beam parameters of flatness and symmetry when a Varian monitor chamber is irradiated within an applied magnetic field. This work has direct application to the development of Linac-MR systems worldwide. Methods: A Varian monitor chamber was modeled in the Monte Carlo code PENELOPE and irradiated in the presence of a magnetic field with a phase space generated from a model of a Linac-MR prototype system. The magnetic field strength was stepped from 0 to 3.0T in both parallel and perpendicular directions with respect to the normal surface of the phase space. Dose to each of the four regions in the monitor chamber were scored separately for every magnetic field adaptation to evaluate the effect of the magnetic field on flatness and symmetry. Results: When the magnetic field is perpendicular to the phase space normal we see a change in dose response with a maximal deviation (10–25% depending on the chamber region) near 0.75T. In the direction of electron deflection we expectedly see opposite responses in chamber regions leading to a measured asymmetry. With a magnetic field parallel to the phase space normal we see no measured asymmetries, however there is a monotonic rise in dose response leveling off at about +12% near 2.5T. Conclusion: Attention must be given to correct for the strength and direction of the magnetic field at the location of the linac monitor chamber in hybrid Linac-MR devices. Elsewise the dose sampled by these chambers may not represent the actual dose expected at isocentre; additionally there may be a need to correct for the symmetry of the beam recorded by the monitor chamber. Fallone is a co-founder and CEO of MagnetTx Oncology Solutions (under discussions to license Alberta bi-planar linac MR for commercialization).

  16. A method to adjust radiation dose-response relationships for clinical risk factors

    DEFF Research Database (Denmark)

    Appelt, Ane Lindegaard; Vogelius, Ivan R

    2012-01-01

    Several clinical risk factors for radiation induced toxicity have been identified in the literature. Here, we present a method to quantify the effect of clinical risk factors on radiation dose-response curves and apply the method to adjust the dose-response for radiation pneumonitis for patients...

  17. Dose-response relationships and threshold levels in skin and respiratory allergy

    NARCIS (Netherlands)

    Arts, J.H.E.; Mommers, C.; Heer, C.de

    2006-01-01

    A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well

  18. Dose-response regressions for algal growth and similar continuous endpoints: Calculation of effective concentrations

    DEFF Research Database (Denmark)

    Christensen, Erik R.; Kusk, Kresten Ole; Nyholm, Niels

    2009-01-01

    We derive equations for the effective concentration giving 10% inhibition (EC10) with 95% confidence limits for probit (log-normal), Weibull, and logistic dose -responsemodels on the basis of experimentally derived median effective concentrations (EC50s) and the curve slope at the central point (50......% inhibition). For illustration, data from closed, freshwater algal assays are analyzed using the green alga Pseudokirchneriella subcapitata with growth rate as the response parameter. Dose-response regressions for four test chemicals (tetraethylammonium bromide, musculamine, benzonitrile, and 4...... regression program with variance weighting and proper inverse estimation. The Weibull model provides the best fit to the data for all four chemicals. Predicted EC10s (95% confidence limits) from our derived equations are quite accurate; for example, with 4-4-(trifluoromethyl)phenoxy-phenol and the probit...

  19. SO/sub 2/ dose-response sensitivity classification data for crops and natural vegetation species

    Energy Technology Data Exchange (ETDEWEB)

    Irving, P.M.; Ballou, S.W.

    1980-09-01

    Over the past several years studies have been made on the interaction of sulfur dioxide (SO/sub 2/) and vegetation by performing field research and by developing analytical procedures for applying field observation data to energy impact assessments. As a result of this work, numerous reports have been prepared on crop-pollutant interactions, such as dose-response data; on the applications of such data to screening approaches for identifying crops at risk; and on models that predict crop yield reductions from point source emissions of SO/sub 2/. Data that were used for these studies, such as the crop-at-risk screening procedure, are presented in this report. Maps are also presented that show the national distribution of SO/sub 2/-sensitive crops and natural vegetation.

  20. SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

    Science.gov (United States)

    Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

    2017-08-01

    Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi. © The Author(s) 2017. Published by Oxford University Press.

  1. Dose-Response Association Between Physical Activity and Incident Hypertension: A Systematic Review and Meta-Analysis of Cohort Studies.

    Science.gov (United States)

    Liu, Xuejiao; Zhang, Dongdong; Liu, Yu; Sun, Xizhuo; Han, Chengyi; Wang, Bingyuan; Ren, Yongcheng; Zhou, Junmei; Zhao, Yang; Shi, Yuanyuan; Hu, Dongsheng; Zhang, Ming

    2017-05-01

    Despite the inverse association between physical activity (PA) and incident hypertension, a comprehensive assessment of the quantitative dose-response association between PA and hypertension has not been reported. We performed a meta-analysis, including dose-response analysis, to quantitatively evaluate this association. We searched PubMed and Embase databases for articles published up to November 1, 2016. Random effects generalized least squares regression models were used to assess the quantitative association between PA and hypertension risk across studies. Restricted cubic splines were used to model the dose-response association. We identified 22 articles (29 studies) investigating the risk of hypertension with leisure-time PA or total PA, including 330 222 individuals and 67 698 incident cases of hypertension. The risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.96) with each 10 metabolic equivalent of task h/wk increment of leisure-time PA. We found no evidence of a nonlinear dose-response association of PA and hypertension ( P nonlinearity =0.094 for leisure-time PA and 0.771 for total PA). With the linear cubic spline model, when compared with inactive individuals, for those who met the guidelines recommended minimum level of moderate PA (10 metabolic equivalent of task h/wk), the risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.97). This meta-analysis suggests that additional benefits for hypertension prevention occur as the amount of PA increases. © 2017 American Heart Association, Inc.

  2. Statistical issues in radiation dose-response analysis of employees of the nuclear industry in Oak Ridge, Tennessee

    International Nuclear Information System (INIS)

    Frome, E.L.; Watkins, J.P.

    1997-01-01

    Poisson regression methods are used to describe dose-response relations for cancer mortality for a subcohort of 28,347 white male radiation workers. Age specific baseline rates are described using both internal and external (US white male) rates. Regression analyses are based on an analytic data structure (ADS) that consists of a table of observed deaths, expected deaths, and person-years at risk for each combination of levels of seven risk factors. The factors are socioeconomic status, length of employment, birth cohort, age at risk, facility, internal exposure, and external exposure. Each observation in the ADS consists of the index value of each of the stratifying factors, the observed deaths, the expected deaths, the person-years, and the ten year lagged average cumulative dose. Regression diagnostics show that a linear exponential relative risk model is not appropriate for these data. Results are presented using a main effects model for factors other than external radiation, and an excess relative risk term for cumulative external radiation dose

  3. Advancing Dose-Response Assessment Methods for Environmental Regulatory Impact Analysis: A Bayesian Belief Network Approach Applied to Inorganic Arsenic.

    Science.gov (United States)

    Zabinski, Joseph W; Garcia-Vargas, Gonzalo; Rubio-Andrade, Marisela; Fry, Rebecca C; Gibson, Jacqueline MacDonald

    2016-05-10

    Dose-response functions used in regulatory risk assessment are based on studies of whole organisms and fail to incorporate genetic and metabolomic data. Bayesian belief networks (BBNs) could provide a powerful framework for incorporating such data, but no prior research has examined this possibility. To address this gap, we develop a BBN-based model predicting birthweight at gestational age from arsenic exposure via drinking water and maternal metabolic indicators using a cohort of 200 pregnant women from an arsenic-endemic region of Mexico. We compare BBN predictions to those of prevailing slope-factor and reference-dose approaches. The BBN outperforms prevailing approaches in balancing false-positive and false-negative rates. Whereas the slope-factor approach had 2% sensitivity and 99% specificity and the reference-dose approach had 100% sensitivity and 0% specificity, the BBN's sensitivity and specificity were 71% and 30%, respectively. BBNs offer a promising opportunity to advance health risk assessment by incorporating modern genetic and metabolomic data.

  4. Application of Dempster–Shafer theory in dose response outcome analysis

    International Nuclear Information System (INIS)

    Chen Wenzhou; Cui Yunfeng; Yu Yan; Galvin, James; Xiao Ying; He Yanyan; Hussaini, Yousuff M

    2012-01-01

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster–Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster–Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman–Kutcher–Burman (LKB) model to fit these values and a belief–plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose–volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief–plausibility range we calculated by the Dempster–Shafer theory. (paper)

  5. Application of Dempster-Shafer theory in dose response outcome analysis

    Science.gov (United States)

    Chen, Wenzhou; Cui, Yunfeng; He, Yanyan; Yu, Yan; Galvin, James; Hussaini, Yousuff M.; Xiao, Ying

    2012-09-01

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster-Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster-Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman-Kutcher-Burman (LKB) model to fit these values and a belief-plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose-volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief-plausibility range we calculated by the Dempster-Shafer theory.

  6. Biological dosimetry in radiological protection: dose response curves elaboration for 60Co and 137Cs

    International Nuclear Information System (INIS)

    Silva, Marcia Augusta da

    1997-01-01

    Ionizing radiation sources for pacific uses are being extensively utilized by modern society and the applications of these sources have raised the probability of the occurrence of accidents. The accidental exposition to radiation creates a necessity of the development of methods to evaluate dose quantity. This data could be obtained by the measurement of damage caused by radiation in the exposed person. The radiation dose can be estimated in exposed persons through physical methods (physical dosimetry) but the biological methods can't be dispensed, and among them, the cytogenetic one that makes use of chromosome aberrations (dicentric and centric ring) formed in peripheral blood lymphocytes (PBL) exposed to ionizing radiation. This method correlates the frequency of radioinduced aberrations with the estimated absorbed dose, as in vitro as in vivo, which is called cytogenetic dosimetry. By the introduction of improved new techniques in culture, in the interpretation of aberrations in the different analysers of slides and by the adoption of different statistical programs to analyse the data, significant differences are observed among laboratories in dose-response curves (calibration curves). The estimation of absorbed dose utilizing other laboratory calibration curves may introduce some uncertainties, so the International Atomic Energy Agency (IAEA) advises that each laboratory elaborates your own dose-response curve for cytogenetic dosimetry. The results were obtained from peripheral blood lymphocytes of the healthy and no-smoking donors exposed to 60 Co and 137 Cs radiation, with dose rate of 5 cGy.min. -1 . Six points of dose were determined 20,50,100,200,300,400 cGy and the control not irradiated. The analysed aberrations were of chromosomic type, dicentric and centric ring. The dose response curve for dicentrics were obtained by frequencies weighted in liner-quadratic mathematic model and the equation resulted were for 60 Co: Y = (3 46 +- 2.14)10 -4 cGy -1 + (3

  7. Effect of processing time delay on the dose response of Kodak EDR2 film.

    Science.gov (United States)

    Childress, Nathan L; Rosen, Isaac I

    2004-08-01

    Kodak EDR2 film is a widely used two-dimensional dosimeter for intensity modulated radiotherapy (IMRT) measurements. Our clinical use of EDR2 film for IMRT verifications revealed variations and uncertainties in dose response that were larger than expected, given that we perform film calibrations for every experimental measurement. We found that the length of time between film exposure and processing can affect the absolute dose response of EDR2 film by as much as 4%-6%. EDR2 films were exposed to 300 cGy using 6 and 18 MV 10 x 10 cm2 fields and then processed after time delays ranging from 2 min to 24 h. An ion chamber measured the relative dose for these film exposures. The ratio of optical density (OD) to dose stabilized after 3 h. Compared to its stable value, the film response was 4%-6% lower at 2 min and 1% lower at 1 h. The results of the 4 min and 1 h processing time delays were verified with a total of four different EDR2 film batches. The OD/dose response for XV2 films was consistent for time periods of 4 min and 1 h between exposure and processing. To investigate possible interactions of the processing time delay effect with dose, single EDR2 films were irradiated to eight different dose levels between 45 and 330 cGy using smaller 3 x 3 cm2 areas. These films were processed after time delays of 1, 3, and 6 h, using 6 and 18 MV photon qualities. The results at all dose levels were consistent, indicating that there is no change in the processing time delay effect for different doses. The difference in the time delay effect between the 6 and 18 MV measurements was negligible for all experiments. To rule out bias in selecting film regions for OD measurement, we compared the use of a specialized algorithm that systematically determines regions of interest inside the 10 x 10 cm2 exposure areas to manually selected regions of interest. There was a maximum difference of only 0.07% between the manually and automatically selected regions, indicating that the use of

  8. Quantitative assessment of the dose-response of alkylating agents in DNA repair proficient and deficient ames tester strains.

    Science.gov (United States)

    Tang, Leilei; Guérard, Melanie; Zeller, Andreas

    2014-01-01

    Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even "thresholded" dose-response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium: the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada-), YG7104 (Ogt-/Ada+) and YG7108 (Ogt-/Ada-). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose-response curves were statistically fitted by the PROAST benchmark dose model and the Lutz-Lutz "hockeystick" model. These dose-response curves suggest efficient DNA-repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl-transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds. Copyright © 2013 Wiley Periodicals, Inc.

  9. Critical reevaluation of the dose-response relationships for carcinogenic effects of low-level ionizing radiation

    International Nuclear Information System (INIS)

    Upton, Arthur C.

    2002-01-01

    In recent decades, it has been customary, for radiation protection purposes, to assume that the overall risk of radiation- included cancer increases as a linear-nonthreshold function of the dose. The existing data do not exclude the existence of a threshold, however, and the dose-response relationship is known to vary depending on the type of cancer in question, the dose, dose rate and LET of the radiation, the age, sex and physiological state of the exposed individuals, and other variables, including the potential influence of adaptive responses and bystander effects at low doses. In light of advancing knowledge, therefore, the dose-response relationship for carcinogenic effects of low-level radiation has been reevaluated periodically by the National Council on Radiation Protection and Measurements, the International Commission of Radiological Protection, the United Nations Scientific Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences, and other organizations. The most recent such reviews have generally found the weight of evidence to suggest that lesions which are precursors to cancer (i.e., mutations and chromosome aberrations), and certain types of cancer as well, may increase in frequency linearly aberrations), and certain types of cancer as well, may increase in frequency linearly with the dose in the low-dose domain. On this basis, it is concluded that no alternative dose-response model for the carcinogenic effects of low-level radiation is ore plausible than the linear-nonthreshold model, although other dose-response relationships cannot be excluded. (author)

  10. Assessing dose-response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity.

    Science.gov (United States)

    Zoeller, R Thomas; Vandenberg, Laura N

    2015-05-15

    The fundamental principle in regulatory toxicology is that all chemicals are toxic and that the severity of effect is proportional to the exposure level. An ancillary assumption is that there are no effects at exposures below the lowest observed adverse effect level (LOAEL), either because no effects exist or because they are not statistically resolvable, implying that they would not be adverse. Chemicals that interfere with hormones violate these principles in two important ways: dose-response relationships can be non-monotonic, which have been reported in hundreds of studies of endocrine disrupting chemicals (EDCs); and effects are often observed below the LOAEL, including all environmental epidemiological studies examining EDCs. In recognition of the importance of this issue, Lagarde et al. have published the first proposal to qualitatively assess non-monotonic dose response (NMDR) relationships for use in risk assessments. Their proposal represents a significant step forward in the evaluation of complex datasets for use in risk assessments. Here, we comment on three elements of the Lagarde proposal that we feel need to be assessed more critically and present our arguments: 1) the use of Klimisch scores to evaluate study quality, 2) the concept of evaluating study quality without topical experts' knowledge and opinions, and 3) the requirement of establishing the biological plausibility of an NMDR before consideration for use in risk assessment. We present evidence-based logical arguments that 1) the use of the Klimisch score should be abandoned for assessing study quality; 2) evaluating study quality requires experts in the specific field; and 3) an understanding of mechanisms should not be required to accept observable, statistically valid phenomena. It is our hope to contribute to the important and ongoing debate about the impact of NMDRs on risk assessment with positive suggestions.

  11. Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: Evidence of a radiation and chemotherapy dose response

    International Nuclear Information System (INIS)

    Geh, J. Ian; Bond, Simon J.; Bentzen, Soren M.; Glynne-Jones, Robert

    2006-01-01

    Background and purpose: Numerous trials have shown that pathological complete response (pCR) following preoperative chemoradiotherapy (CRT) and surgery for oesophageal cancer is associated with improved survival. However, different radiotherapy doses and fractionations and chemotherapy drugs, doses and scheduling were used, which may account for the differences in observed pCR and survival rates. A dose-response relationship may exist between radiotherapy and chemotherapy dose and pCR. Patients and methods: Trials using a single radiotherapy and chemotherapy regimen (5FU, cisplatin or mitomycin C-based) and providing information on patient numbers, age, resection and pCR rates were eligible. The endpoint used was pCR and the covariates analysed were prescribed radiotherapy dose, radiotherapy dosexdose per fraction, radiotherapy treatment time, prescribed chemotherapy (5FU, cisplatin and mitomycin C) dose and median age of patients within the trial. The model used was a multivariate logistic regression. Results: Twenty-six trials were included (1335 patients) in which 311 patients (24%) achieved pCR. The probability of pCR improved with increasing dose of radiotherapy (P=0.006), 5FU (P=0.003) and cisplatin (P=0.018). Increasing radiotherapy treatment time (P=0.035) and increasing median age (P=0.019) reduced the probability of pCR. The estimated α/β ratio of oesophageal cancer was 4.9 Gy (95% confidence interval (CI) 1.5-17 Gy) and the estimated radiotherapy dose lost per day was 0.59 Gy (95% CI 0.18-0.99 Gy). One gram per square metre of 5FU was estimated to be equivalent to 1.9 Gy (95% CI 0.8-5.2 Gy) of radiation and 100 mg/m 2 of cisplatin was estimated to be equivalent to 7.2 Gy (95% CI 2.1-28 Gy). Mitomycin C dose did not appear to influence pCR rates (P=0.60). Conclusions: There was evidence of a dose-response relationship between increasing protocol prescribed radiotherapy, 5FU and cisplatin dose and pCR. Additional significant factors were radiotherapy

  12. A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer.

    Science.gov (United States)

    Wang, F; Yeung, K L; Chan, W C; Kwok, C C H; Leung, S L; Wu, C; Chan, E Y Y; Yu, I T S; Yang, X R; Tse, L A

    2013-11-01

    This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; Pheterogeneity night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; Pheterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.

  13. Depressive disorder, coronary heart disease, and stroke: dose-response and reverse causation effects in the Whitehall II cohort study.

    Science.gov (United States)

    Brunner, Eric J; Shipley, Martin J; Britton, Annie R; Stansfeld, Stephen A; Heuschmann, Peter U; Rudd, Anthony G; Wolfe, Charles D A; Singh-Manoux, Archana; Kivimaki, Mika

    2014-03-01

    Systematic reviews examining associations of depressive disorder with coronary heart disease and stroke produce mixed results. Failure to consider reverse causation and dose-response patterns may have caused inconsistencies in evidence. This prospective cohort study on depressive disorder, coronary heart disease, and stroke analysed reverse causation and dose-response effects using four 5-year and three 10-year observation cycles (total follow up 24 years) based on multiple repeat measures of exposure. Participants in the Whitehall II study (n = 10,036, 31,395 person-observations, age at start 44.4 years) provided up to six repeat measures of depressive symptoms via the 30-item General Health Questionnaire (GHQ-30) and one measure via Center for Epidemiologic Studies Depression Scale (CES-D). The cohort was followed up for major coronary events (coronary death/nonfatal myocardial infarction) and stroke (stroke death/morbidity) through the national mortality register Hospital Episode Statistics, ECG-screening, medical records, and self-report questionnaires. GHQ-30 caseness predicted stroke over 0-5 years (age-, sex- and ethnicity-adjusted HR 1.60, 95% CI 1.1-2.3) but not over 5-10 years (HR 0.94, 95% CI 0.6-1.4). Using the last 5-year observation cycle, cumulative GHQ-30 caseness was associated with incident coronary heart disease in a dose-response manner (1-2 times a case: HR 1.12, 95% CI 0.7-1.7; 3-4 times: HR 2.06, 95% CI 1.2-3.7), and CES-D caseness predicted coronary heart disease (HR 1.81, 95% CI 1.1-3.1). There was evidence of a dose-response effect of depressive symptoms on risk of coronary heart disease. In contrast, prospective associations of depressive symptoms with stroke appeared to arise wholly or partly through reverse causation.

  14. Dose-response relationship analysis for cancer and circulatory system disease mortality risks among uranium miners

    International Nuclear Information System (INIS)

    Drubay, Damien

    2015-01-01

    probability during the follow-up (e.g. SHRWismut-radon /100 WLM=1.012 [0.983; 1.042]). CSD mortality risk analyses in the French cohort showed a significant increase of the risks of mortality from CSD (n=442, CSHR/100 WLM=1.11 [1.01; 1.22]) and from Cerebrovascular Disease (MCeV, n=105, CSHR/100 WLM=1.25 [1.09; 1.43]) with radon exposure. A case-control study nested in the French cohort was set up to collect the information related to CSD risk factors (overweight, hypertension, diabetes...) from the medical records of 313 miners (76 deaths from CSD (including 26 from Ischemic Heart Disease (IHD) and 16 from MCeV) and 237 controls). For the three radiological exposures, the exposure-risk relation was analyzed in a pseudo-cohort (n=1,644 pseudo-individuals, obtained from the weighting of the observations by their inverse selection probability) with the Cox model, adjusted for the CSD risk factors. The association between the radiological exposure and the risk of mortality from CSD, IHD or MCeV was not significant (e.g. CSHRCSD-radon/100 WLM=1.43 [0.71; 2.87]). The adjustment for CSD risk factors did not substantially change the exposure-risk relation. The lack of a significant dose-response relation suggests that the excess of kidney cancer mortality among the French uranium miners may be induced by other risk factors, unavailable for this study. The small change of the coefficients observed after adjustment for CSD risk factors in the nested case-control study supports the assumption of the existence of the MCeV mortality risk increase associated with radon exposure in the French cohort of uranium miners. Future analyses based on further follow-up updates should allow to confirm or not these results. (author)

  15. The alanine detector in BNCT dosimetry: dose response in thermal and epithermal neutron fields.

    Science.gov (United States)

    Schmitz, T; Bassler, N; Blaickner, M; Ziegner, M; Hsiao, M C; Liu, Y H; Koivunoro, H; Auterinen, I; Serén, T; Kotiluoto, P; Palmans, H; Sharpe, P; Langguth, P; Hampel, G

    2015-01-01

    The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a (60)Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model. The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. The alanine detector can be used without

  16. Dose response and factors related to interstitial pneumonitis after bone marrow transplant

    International Nuclear Information System (INIS)

    Sampath, Sagus; Schultheiss, Timothy E.; Wong, Jeffrey

    2005-01-01

    Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The α/β value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D 50 , for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D 50 is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding. Shielding the lung

  17. Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer

    Science.gov (United States)

    Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S. E.; Høyer, M.; Apte, A.; Deasy, J. O.

    2014-07-01

    When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3 mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and generalized equivalent uniform dose (gEUD) values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness

  18. Equivalent dose determination in foraminifera: analytical description of the CO2--signal dose-response curve

    International Nuclear Information System (INIS)

    Hoffmann, D.; Woda, C.; Mangini, A.

    2003-01-01

    The dose-response of the CO 2 - signal (g=2.0006) in foraminifera with ages between 19 and 300 ka is investigated. The sum of two exponential saturation functions is an adequate function to describe the dose-response curve up to an additional dose of 8000 Gy. It yields excellent dating results but requires an artificial doses of at least 5000 Gy. For small additional doses of about 500 Gy the single exponential saturation function can be used to calculate a reliable equivalent dose D E , although it does not describ the dose-response for higher doses. The CO 2 - -signal dose-response indicates that the signal has two components of which one is less stable than the other

  19. Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

    OpenAIRE

    Lagarde, Fabien; Beausoleil, Claire; Belcher, Scott M; Belzunces, Luc P; Emond, Claude; Guerbet, Michel; Rousselle, Christophe

    2015-01-01

    International audience; Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that repor...

  20. Dose response of alanine and methyl alanine towards gamma and in-situ alpha irradiation

    International Nuclear Information System (INIS)

    Mohapatra, M.; Rajeswari, B.; Bhide, M.K.; Rane, Vinayak; Kadam, R.M.

    2017-01-01

    In situ alpha and external gamma dose response of two ESR (electron spin resonance) dosimetric materials namely alanine and methyl alanine were investigated. It was observed that alanine dosimeter had a better dose response in comparison to methyl alanine for the in-situ alpha irradiation by using 239 Pu powder. On the other hand, in case of gamma radiation, methyl alanine was found to have the sensitivity as twice that of alanine. (author)

  1. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    Energy Technology Data Exchange (ETDEWEB)

    Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Gilbert, Ethel; Curtis, Rochelle; Inskip, Peter; Kleinerman, Ruth; Morton, Lindsay; Rajaraman, Preetha; Little, Mark P. [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

    2013-06-01

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.

  2. Cytogenetic dose-response and adaptive response in cells of ungulate species exposed to ionizing radiation

    International Nuclear Information System (INIS)

    Ulsh, B.A.; Miller, S.M.; Mallory, F.F.; Mitchel, R.E.J.; Morrison, D.P.; Boreham, D.R.

    2004-01-01

    In the studies reported here, the micronucleus assay, a common cytogenetic technique, was used to examine the dose-responses in fibroblasts from three ungulate species (white-tailed deer, woodland caribou, and Indian muntjac) exposed to high doses of ionizing radiation (1-4 Gy of 60 Co gamma radiation). This assay was also used to examine the effects of exposure to low doses (1-100 mGy) typical of what these species experience in a year from natural and anthropogenic environmental sources. An adaptive response, defined as the induction of resistance to a stressor by a prior exposure to a small 'adapting' stress, was observed after exposure to low doses. This work indicates that very small doses are protective for the endpoint examined. The same level of protection was seen at all adapting doses, including 1 radiation track per cell, the lowest possible cellular dose. These results are consistent with other studies in a wide variety of organisms that demonstrate a protective effect of low doses at both cellular and whole-organism levels. This implies that environmental regulations predicated on the idea that even the smallest dose of radiation carries a quantifiable risk of direct adverse consequences to the exposed organism require further examination. Cytogenetic assays provide affordable and feasible biological effects-based alternatives that are more biologically relevant than traditional contaminant concentration-based radioecological risk assessment

  3. Habitual Chocolate Consumption May Increase Body Weight in a Dose-Response Manner

    Science.gov (United States)

    Greenberg, James A.; Buijsse, Brian

    2013-01-01

    Objective Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. Methods We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987–98), and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (∼28 g) serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. Results Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1–4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2) of 0.26 (95% CI 0.08, 0.44) and 0.39 (0.23, 0.55), respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. Conclusions Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with lower body

  4. Habitual chocolate consumption may increase body weight in a dose-response manner.

    Science.gov (United States)

    Greenberg, James A; Buijsse, Brian

    2013-01-01

    Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987-98), and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (~28 g) serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1-4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2) of 0.26 (95% CI 0.08, 0.44) and 0.39 (0.23, 0.55), respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with lower body weight did not apply to participants without

  5. Habitual chocolate consumption may increase body weight in a dose-response manner.

    Directory of Open Access Journals (Sweden)

    James A Greenberg

    Full Text Available OBJECTIVE: Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. METHODS: We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987-98, and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (~28 g serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. RESULTS: Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1-4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2 of 0.26 (95% CI 0.08, 0.44 and 0.39 (0.23, 0.55, respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. CONCLUSIONS: Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with

  6. Dose-response effects in an outbreak of Salmonella enteritidis.

    OpenAIRE

    Mintz, E. D.; Cartter, M. L.; Hadler, J. L.; Wassell, J. T.; Zingeser, J. A.; Tauxe, R. V.

    1994-01-01

    The effects of ingested Salmonella enteritidis (SE) dose on incubation period and on the severity and duration of illness were estimated in a cohort of 169 persons who developed gastroenteritis after eating hollandaise sauce made from grade-A shell eggs. The cohort was divided into three groups based on self-reported dose of sauce ingested. As dose increased, median incubation period decreased (37 h in the low exposure group v. 21 h in the medium exposure group v. 17.5 h in the high exposure ...

  7. Dose-response and operational thresholds/NOAELs for in vitro mutagenic effects from DNA-reactive mutagens, MMS and MNU.

    Science.gov (United States)

    Pottenger, Lynn H; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Fontaine, Donald D; McFadden, Lisa G; Bhaskar Gollapudi, B

    2009-08-01

    The dose-response relationships for in vitro mutagenicity induced by methylmethanesulfonate (MMS) or methylnitrosourea (MNU) in L5178Y mouse lymphoma (ML) cells were examined. DNA adducts (N7-methylguanine, N7MeG and O(6)-methylguanine, O(6)MeG) were quantified as biomarkers of exposure. Both endpoints were assessed using 5replicates/dose (4-h treatment) with MMS or MNU (0.0069-50muM), or vehicle (1% DMSO). Mutant frequency (MF) (thymidine kinase (TK) locus) was determined using the soft agar cloning methodology and a 2-day expression period; in addition, microwell and Sequester-Express-Select (SES) methods were used for MMS. Isolated DNA was acid-hydrolyzed, and adducts quantified by LC/ESI-MS/MS, using authentic and internal standards. MF dose-responses were analyzed using several statistical approaches, all of which confirmed that a threshold dose-response model provided the best fit. NOAELs for MF were 10muM MMS and 0.69muM MNU, based on ANOVA and Dunnett's test (p/=10muM MMS or 3.45muM MNU. O(6)MeG levels were only quantifiable at >/=10muM MNU; O(6)MeG was not quantifiable in control or MMS-treated cells at current detection limits. Thus, (1) cells treated with MMS did not demonstrate increases in TK(-) MF, but did demonstrate quantifiable levels of N7MeG adducts; and (2) the levels of N7MeG adducts did not correlate with induced MF, as MNU-treated cells had fewer N7MeG adducts but higher MF compared with MMS-treated cells, for quasi-equimolar doses. Taken together, these results demonstrate operational thresholds, defined as the highest dose for which the response is not significantly (statistically or biologically) distinguishable from the control/background values, for induction of mutations and N7MeG adducts in ML cells treated with MMS or MNU, and a lack of correlation between induced MF and levels of N7MeG adducts.

  8. Patch test dose-response study of p-phenylenediamine

    DEFF Research Database (Denmark)

    Sosted, Heidi; Menné, Torkil; Johansen, Jeanne Duus

    2006-01-01

    The elicitation response in allergic contact dermatitis for the hair dye substance p-phenylenediamine (PPD) is dose dependent, but threshold concentrations have not previously been investigated. 15 PPD-sensitive patients participated in a serial dilution 48-hr patch test with PPD using 8...... concentrations of PPD ranging from 1 to 10 000 on the upper back. Petrolatum was applied as control. Three concentrations (50, 100 and 500 p.p.m. PPD) were also applied to the retroauricular area and on the lateral aspects of the upper arms. 14 of the 15 participants reacted to one or more of the test samples....... The threshold value for 10% of the tested persons (ED10) based on+or stronger reactions for PPD on the back was 38 p.p.m. (CI: 4.3-100). There were no statistically significant differences in the sensitivity of the three anatomical regions. The upper back is a suitable region for patch testing patients...

  9. Fruit and vegetables consumption and incident hypertension: dose-response meta-analysis of prospective cohort studies.

    Science.gov (United States)

    Wu, L; Sun, D; He, Y

    2016-10-01

    The role of dietary factors on chronic diseases seems essential in the potentially adverse or preventive effects. However, no evidence of dose-response meta-analysis of prospective cohort studies has verified the association between the intake of fruit and/or vegetables and the risk of developing hypertension. The PubMed and Embase were searched for prospective cohort studies. A generic inverse-variance method with random effects model was used to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs). Generalized least squares trend estimation model was used to calculate the study-specific slopes for the dose-response analyses. Seven articles comprised nine cohorts involving 185 676 participants were assessed. The highest intake of fruit or vegetables separately, and total fruit and vegetables were inversely associated with the incident risk of hypertension compared with the lowest level, and the pooled RRs and 95% CIs were 0.87 (0.79, 0.95), 0.88 (0.79, 0.99) and 0.90 (0.84, 0.98), respectively. We also found an inverse dose-response relation between the risk of developing hypertension and fruit intake, and total fruit and vegetables consumption. The incident risk of hypertension was decreased by 1.9% for each serving per day of fruit consumption, and decreased by 1.2% for each serving per day of total fruit and vegetables consumption. Our results support the recommendation to increase the consumption of fruit and vegetables with respect to preventing the risk of developing hypertension. However, further large prospective studies and long-term high-quality randomized controlled trials are still needed to confirm the observed association.

  10. The feasibility of 10 keV X-ray as radiation source in total dose response radiation test

    International Nuclear Information System (INIS)

    Li Ruoyu; Li Bin; Luo Hongwei; Shi Qian

    2005-01-01

    The standard radiation source utilized in traditional total dose response radiation test is 60 Co, which is environment-threatening. X-rays, as a new radiation source, has the advantages such as safety, precise control of dose rate, strong intensity, possibility of wafer-level test or even on-line test, which greatly reduce cost for package, test and transportation. This paper discussed the feasibility of X-rays replacing 60 Co as the radiation source, based on the radiation mechanism and the effects of radiation on gate oxide. (authors)

  11. Dose - response relationship between noise exposure and the risk of occupational injury

    Directory of Open Access Journals (Sweden)

    Jin-Ha Yoon

    2015-01-01

    Full Text Available Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers′ Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively. Workplace dust exposure was classified as 90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals derived from a logistic regression model were 1.68 (1.27-2.24 and 3.42 (2.26-5.17 at 80-89 dB and ≥90 dB versus <80 dB. These associations remained significant when in a separate analysis according to high or low dust exposure level. Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.

  12. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners.

    Science.gov (United States)

    Manzi, Vincenzo; Castagna, Carlo; Padua, Elvira; Lombardo, Mauro; D'Ottavio, Stefano; Massaro, Michele; Volterrani, Maurizio; Iellamo, Ferdinando

    2009-06-01

    In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMP(i)) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMP(i) steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.90 to 0.99; P marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population.

  13. Dose-response effects in an outbreak of Salmonella enteritidis.

    Science.gov (United States)

    Mintz, E D; Cartter, M L; Hadler, J L; Wassell, J T; Zingeser, J A; Tauxe, R V

    1994-02-01

    The effects of ingested Salmonella enteritidis (SE) dose on incubation period and on the severity and duration of illness were estimated in a cohort of 169 persons who developed gastroenteritis after eating hollandaise sauce made from grade-A shell eggs. The cohort was divided into three groups based on self-reported dose of sauce ingested. As dose increased, median incubation period decreased (37 h in the low exposure group v. 21 h in the medium exposure group v. 17.5 h in the high exposure group, P = 0.006) and greater proportions reported body aches (71 v. 85 v. 94%, P = 0.0009) and vomiting (21 v. 56 v. 57%, P = 0.002). Among 118 case-persons who completed a follow-up questionnaire, increased dose was associated with increases in median weight loss in kilograms (3.2 v. 4.5 v. 5.0, P = 0.0001), maximum daily number of stools (12.5 v. 15.0 v. 20.0, P = 0.02), subjective rating of illness severity (P = 0.0007), and the number of days of confinement to bed (3.0 v. 6.5 v. 6.5, P = 0.04). In this outbreak, ingested dose was an important determinant of the incubation period, symptoms and severity of acute salmonellosis.

  14. Investigation of vacuum pumping on the dose response of the MAGAS normoxic polymer gel dosimeter

    International Nuclear Information System (INIS)

    Venning, AJ.; Canberra Hospital, Canberra; University of Sydney, Sydney; Mather, ML.; Baldock, C.

    2005-01-01

    The effect of vacuum pumping on the dose response of the MAGAS polymer gel dosimeter has been investigated. A delay of several days post-manufacture before irradiation was previously necessary due to the slow oxygen scavenging of ascorbic acid. The MAGAS polymer gel dosimeter was vacuum pumped before gelation to remove dissolved oxygen. The MAGAS polymer gel dosimeter was poured into glass screw-top vials, which were irradiated at various times, post-manufacture to a range of doses. Magnetic resonance imaging techniques were used to determine the R2-dose response and /?2-dose sensitivity of the MAGAS polymer gel. The results were compared with a control batch of MAGAS polymer gel that was not vacuum pumped. It was shown that vacuum pumping on the MAGAS polymer gel solution immediately prior to sealing in glass screw-top vials initially increases the R2-dose response and R2-dose sensitivity of the dosimeter. An increase in the .R2-dose response and i?2-dose sensitivity was observed with increasing time between manufacture and irradiation. Over the range of post-manufacture irradiation times investigated, the greatest i?2-dose response and if 2 -dose sensitivity occurred at 96 hours

  15. The dose-response relationship of balance training in physically active older adults.

    Science.gov (United States)

    Maughan, Kristen K; Lowry, Kristin A; Franke, Warren D; Smiley-Oyen, Ann L

    2012-10-01

    A 6-wk group balance-training program was conducted with physically active older adults (based on American College of Sports Medicine requirements) to investigate the effect of dose-related static and dynamic balance-specific training. All participants, age 60-87 yr, continued their regular exercise program while adding balance training in 1 of 3 doses: three 20-min sessions/wk (n = 20), one 20-min session/wk (n = 21), or no balance training (n = 19). Static balance (single-leg-stance, tandem), dynamic balance (alternate stepping, limits of stability), and balance confidence (ABC) were assessed pre- and posttraining. Significant interactions were observed for time in single-leg stance, excursion in limits of stability, and balance confidence, with the greatest increase observed in the group that completed 3 training sessions/wk. The results demonstrate a dose-response relationship indicating that those who are already physically active can improve balance performance with the addition of balance-specific training.

  16. Dose responses in a normoxic polymethacrylic acid gel dosimeter using optimal CT scanning parameters

    Energy Technology Data Exchange (ETDEWEB)

    Cho, K.H. [Department of Radiation Oncology, College of Medicine, Soonchunhyang University, Bucheon 420-767 (Korea, Republic of); Department of Medical Physics, Kyonggi University, Suwon 443-760 (Korea, Republic of); Cho, S.J. [Department of Radiation Oncology, College of Medicine, Eulji University, Seongnam 461-713 (Korea, Republic of); Lee, S. [Department of Radiation Oncology, College of Medicine, Korea University, Seoul 130-701 (Korea, Republic of); Lee, S.H. [Cheil General Hospital and Women' s Healthcare Center, Kwandong University College of Medicine, Seoul 100-380 (Korea, Republic of); Min, C.K.; Kim, Y.H.; Moon, S.K.; Kim, E.S.; Chang, A.R. [Department of Radiation Oncology, College of Medicine, Soonchunhyang University, Bucheon 420-767 (Korea, Republic of); Kwon, S.I., E-mail: sikwon@kyonggi.ac.kr [Department of Medical Physics, Kyonggi University, Suwon 443-760 (Korea, Republic of)

    2012-05-21

    The dosimetric characteristics of normoxic polymethacrylic acid gels are investigated using optimal CT scanning parameters and the possibility of their clinical application is also considered. The effects of CT scanning parameters (tube voltage, tube current, scan time, slick thickness, field of view, and reconstruction algorithm) are experimentally investigated to determine the optimal parameters for minimizing the amount of noise in images obtained using normoxic polymethacrylic acid gel. In addition, the dose sensitivity, dose response, accuracy, and reproducibility of the normoxic polymethacrylic acid gel are evaluated. CT images are obtained using a head phantom that is fabricated for clinical applications. In addition, IMRT treatment planning is performed using a Tomotherapy radiation treatment planning system. A program for analyzing the results is produced using Visual C. A comparison between the treatment planning and the CT images of irradiated gels is performed. The dose sensitivity is found to be 2.41{+-}0.04 HGy{sup -1}. The accuracies of dose evaluation at doses of 2 Gy and 4 Gy are 3.0% and 2.6%, respectively, and their reproducibilities are 2.0% and 2.1%, respectively. In the comparison of gel and Tomotherpay planning, the pass rate of the {gamma}-index, based on the reference values of a dose error of 3% and a DTA of 3 mm, is 93.7%.

  17. Dose responses in a normoxic polymethacrylic acid gel dosimeter using optimal CT scanning parameters

    Science.gov (United States)

    Cho, K. H.; Cho, S. J.; Lee, S.; Lee, S. H.; Min, C. K.; Kim, Y. H.; Moon, S. K.; Kim, E. S.; Chang, A. R.; Kwon, S. I.

    2012-05-01

    The dosimetric characteristics of normoxic polymethacrylic acid gels are investigated using optimal CT scanning parameters and the possibility of their clinical application is also considered. The effects of CT scanning parameters (tube voltage, tube current, scan time, slick thickness, field of view, and reconstruction algorithm) are experimentally investigated to determine the optimal parameters for minimizing the amount of noise in images obtained using normoxic polymethacrylic acid gel. In addition, the dose sensitivity, dose response, accuracy, and reproducibility of the normoxic polymethacrylic acid gel are evaluated. CT images are obtained using a head phantom that is fabricated for clinical applications. In addition, IMRT treatment planning is performed using a Tomotherapy radiation treatment planning system. A program for analyzing the results is produced using Visual C. A comparison between the treatment planning and the CT images of irradiated gels is performed. The dose sensitivity is found to be 2.41±0.04 HGy-1. The accuracies of dose evaluation at doses of 2 Gy and 4 Gy are 3.0% and 2.6%, respectively, and their reproducibilities are 2.0% and 2.1%, respectively. In the comparison of gel and Tomotherpay planning, the pass rate of the γ-index, based on the reference values of a dose error of 3% and a DTA of 3 mm, is 93.7%.

  18. The use of dose-response data in a margin of exposure approach to carcinogenic risk assessment for genotoxic chemicals in food.

    Science.gov (United States)

    Benford, Diane J

    2016-05-01

    Genotoxic substances are generally not permitted for deliberate use in food production. However, an appreciable number of known or suspected genotoxic substances occur unavoidably in food, e.g. from natural occurrence, environmental contamination and generation during cooking and processing. Over the past decade a margin of exposure (MOE) approach has increasingly been used in assessing the exposure to substances in food that are genotoxic and carcinogenic. The MOE is defined as a reference point on the dose-response curve (e.g. a benchmark dose lower confidences limit derived from a rodent carcinogenicity study) divided by the estimated human intake. A small MOE indicates a higher concern than a very large MOE. Whilst the MOE cannot be directly equated to risk, it supports prioritisation of substances for further research or for possible regulatory action, and provides a basis for communicating to the public. So far, the MOE approach has been confined to substances for which carcinogenicity data are available. In the absence of carcinogenicity data, evidence of genotoxicity is used only in hazard identification. The challenge to the genetic toxicology community is to develop approaches for characterising risk to human health based on data from genotoxicity studies. In order to achieve wide acceptance, it would be important to further address the issues that have been discussed in the context of dose-response modelling of carcinogenicity data in order to assign levels of concern to particular MOE values, and also whether it is possible to make generic conclusions on how potency in genotoxicity assays relates to carcinogenic potency. © Crown copyright 2015.

  19. A dose-response relationship for marketable yield reduction of two lettuce (Lactuca sativa L.) cultivars exposed to tropospheric ozone in Southern Europe.

    Science.gov (United States)

    Marzuoli, Riccardo; Finco, Angelo; Chiesa, Maria; Gerosa, Giacomo

    2017-12-01

    The present study investigated the response to ozone (O 3 ) of two cultivars (cv.'Romana' and cv. 'Canasta') of irrigated lettuce grown in an open-top chamber (OTC) experiment in Mediterranean conditions. Two different levels of O 3 were applied, ambient O 3 in non-filtered OTCs (NF-OTCs) and -40% of ambient O 3 in charcoal-filtered OTCs (CF-OTCs), during four consecutive growing cycles. At the end of each growing cycle, the marketable yield (fresh biomass) was assessed while during the growing periods, measurements of the stomatal conductance at leaf level were performed and used to define a stomatal conductance model for calculation of the phytotoxic ozone dose (POD) absorbed by the plants.Results showed that O 3 caused statistically significant yield reductions in the first and in the last growing cycle. In general, the marketable yield of the NF-OTC plants was always lower than the CF-OTC plants for both cultivars, with mean reductions of -18.5 and -14.5% for 'Romana' and 'Canasta', respectively. On the contrary, there was no statistically significant difference in marketable yield due to the cultivar factor or to the interaction between O 3 and cultivar in any of the growing cycle performed.Dose-response relationships for the marketable relative yield based on the POD values were calculated according to different flux threshold values (Y). The best regression fit was obtained using an instantaneous flux threshold of 6 nmol O 3 m -2  s -1 (POD 6 ); the same value was obtained also for other crops. According to the generic lettuce dose-response relationship, an O 3 critical level of 1 mmol O 3 m -2 of POD 6 for a 15% of marketable yield loss was found.

  20. Validation of dose-response calibration curve for X-Ray field of CRCN-NE/CNEN: preliminary results

    International Nuclear Information System (INIS)

    Silva, Laís Melo; Mendonç, Julyanne Conceição de Goes; Andrade, Aida Mayra Guedes de; Hwang, Suy F.; Mendes, Mariana Esposito; Lima, Fabiana F.; Melo, Ana Maria M.A.

    2017-01-01

    It is very important in accident investigations that accurate estimating of absorbed dose takes place, so that it contributes to medical decisions and overall assessment of long-term health consequences. Analysis of chromosome aberrations is the most developed method for biological monitoring, and frequencies of dicentric chromosomes are related to absorbed dose of human peripheral blood lymphocytes using calibration curves. International Atomic Energy Agency (IAEA) recommends that each biodosimetry laboratory sets its own calibration curves, given that there are intrinsic differences in protocols and dose interpretations when using calibration curves produced in other laboratories, which could add further uncertainties to dose estimations. The Laboratory for Biological Dosimetry CRCN-NE recently completed dose-response calibration curves for X ray field. Curves of chromosomes dicentrics and dicentrics plus rings were made using Dose Estimate. This study aimed to validate the calibration curves dose-response for X ray with three irradiated samples. Blood was obtained by venipuncture from healthy volunteer and three samples were irradiated by x-rays of 250 kVp with different absorbed doses (0,5Gy, 1Gy and 2Gy). The irradiation was performed at the CRCN-NE/CNEN Metrology Service with PANTAK X-ray equipment, model HF 320. The frequency of dicentric and centric rings chromosomes were determined in 500 metaphases per sample after cultivation of lymphocytes, and staining with Giemsa 5%. Results showed that the estimated absorbed doses are included in the confidence interval of 95% of real absorbed dose. These Dose-response calibration curves (dicentrics and dicentrics plus rings) seems valid, therefore other tests will be done with different volunteers. (author)

  1. Internal and external generalizability of temporal dose-response relationships for xerostomia following IMRT for head and neck cancer.

    Science.gov (United States)

    Thor, Maria; Owosho, Adepitan A; Clark, Haley D; Oh, Jung Hun; Riaz, Nadeem; Hovan, Allan; Tsai, Jillian; Thomas, Steven D; Yom, Sae Hee K; Wu, Jonn S; Huryn, Joseph M; Moiseenko, Vitali; Lee, Nancy Y; Estilo, Cherry L; Deasy, Joseph O

    2017-02-01

    To study internal and external generalizability of temporal dose-response relationships for xerostomia after intensity-modulated radiotherapy (IMRT) for head and neck cancer, and to investigate potential amendments of the QUANTEC guidelines. Objective xerostomia was assessed in 121 patients (n Cohort1 =55; n Cohort2 =66) treated to 70Gy@2Gy in 2006-2015. Univariate and multivariate analyses (UVA, MVA with 1000 bootstrap populations) were conducted in Cohort1, and generalizability of the best-performing MVA model was investigated in Cohort2 (performance: AUC, p-values, and Hosmer-Lemeshow p-values (p HL )). Ultimately and for clinical guidance, minimum mean dose thresholds to the contralateral and the ipsilateral parotid glands (Dmean contra , Dmean ipsi ) were estimated from the generated dose-response curves. The observed xerostomia rate was 38%/47% (3months) and 19%/23% (11-12months) in Cohort1/Cohort2. Risk of xerostomia at 3months increased for higher Dmean contra and Dmean ipsi (Cohort1: 0.17·Dmean contra +0.11·Dmean ipsi -8.13; AUC=0.90±0.05; p=0.0002±0.002; p HL =0.22±0.23; Cohort2: AUC=0.81; pxerostomia following IMRT. Our results also suggest decreasing Dmean contra to below 20Gy, while keeping Dmean ipsi to around 25Gy. Long-term xerostomia was less frequent, and no dose-response relationship was established for this follow-up time. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Validation of dose-response calibration curve for X-Ray field of CRCN-NE/CNEN: preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Laís Melo; Mendonç, Julyanne Conceição de Goes; Andrade, Aida Mayra Guedes de; Hwang, Suy F.; Mendes, Mariana Esposito; Lima, Fabiana F., E-mail: falima@cnen.gov.br, E-mail: mendes_sb@hotmail.com [Centro Regional de Ciências Nucleares, (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Melo, Ana Maria M.A., E-mail: july_cgm@yahoo.com.br [Universidade Federal de Pernambuco (UFPE), Vitória de Santo Antão, PE (Brazil). Centro Acadêmico de Vitória

    2017-07-01

    It is very important in accident investigations that accurate estimating of absorbed dose takes place, so that it contributes to medical decisions and overall assessment of long-term health consequences. Analysis of chromosome aberrations is the most developed method for biological monitoring, and frequencies of dicentric chromosomes are related to absorbed dose of human peripheral blood lymphocytes using calibration curves. International Atomic Energy Agency (IAEA) recommends that each biodosimetry laboratory sets its own calibration curves, given that there are intrinsic differences in protocols and dose interpretations when using calibration curves produced in other laboratories, which could add further uncertainties to dose estimations. The Laboratory for Biological Dosimetry CRCN-NE recently completed dose-response calibration curves for X ray field. Curves of chromosomes dicentrics and dicentrics plus rings were made using Dose Estimate. This study aimed to validate the calibration curves dose-response for X ray with three irradiated samples. Blood was obtained by venipuncture from healthy volunteer and three samples were irradiated by x-rays of 250 kVp with different absorbed doses (0,5Gy, 1Gy and 2Gy). The irradiation was performed at the CRCN-NE/CNEN Metrology Service with PANTAK X-ray equipment, model HF 320. The frequency of dicentric and centric rings chromosomes were determined in 500 metaphases per sample after cultivation of lymphocytes, and staining with Giemsa 5%. Results showed that the estimated absorbed doses are included in the confidence interval of 95% of real absorbed dose. These Dose-response calibration curves (dicentrics and dicentrics plus rings) seems valid, therefore other tests will be done with different volunteers. (author)

  3. Association between tea consumption and risk of cognitive disorders: A dose-response meta-analysis of observational studies.

    Science.gov (United States)

    Liu, Xueying; Du, Xiaoyuan; Han, Guanying; Gao, Wenyuan

    2017-06-27

    The epidemiological evidence for a dose-response relationship between tea consumption and risk of cognitive disorders is sparse. The aim of the study was to summarize the evidence for the association of tea consumption with risk of cognitive disorders and assess the dose-response relationship. We searched electronic databases of Pubmed, Embase, and Cochrane Library (from 1965 to Jan 19, 2017) for eligible studies that published in the international journals. A random-effects model was used to pool the most adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Seventeen studies involving 48,435 participants were included in our study. The meta-analysis showed that a higher tea consumption was associated with a significant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82). When considering the specific types of tea consumption, the significantly inverse association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response meta-analysis indicated that tea consumption is linearly associated with a reduced risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower risk of cognitive disorders. Tea consumption is inversely and linearly related to the risk of cognitive disorders. More studies are needed to further confirm our findings.

  4. Radiation dose-response relationship of micronucleus occurrence in pollen mother cells of tradescantia

    International Nuclear Information System (INIS)

    Kim, Jin Kyu; Kim, Yeon Ku; Song, Hi Sup

    1999-01-01

    This study was carried out to investigate the radiation dose-response of micronucleus frequencies in Tradescantia pollen mother cells. The number of micronuclei increased in the tetrads as a result of chromosome deletion after irradiation. The maximal frequency of micronucleus showed a good dose-response relationship in the range of dose 0∼50 cGy. On the basis of the relationship, a dose of 1 cGy resulted in two additional micronuclei in 100 tetrads. The radiation dose-response relationship of micronucleus occurrence is prerequisite to biological monitoring of radiation and can be modified for biological risk assessment of toxicants, and to safety test of water or soil integrity

  5. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review

    International Nuclear Information System (INIS)

    Yoshida, Takahiko; Yamauchi, Hiroshi; Sun Guifan

    2004-01-01

    Chronic arsenic (As) poisoning has become a worldwide public health issue. Most human As exposure occurs from consumption of drinking water containing high amounts of inorganic As (iAs). In this paper, epidemiological studies conducted on the dose-response relationships between iAs exposure via the drinking water and related adverse health effects are reviewed. Before the review, the methods for evaluation of the individual As exposure are summarized and classified into two types, that is, the methods depending on As concentration of the drinking water and the methods depending on biological monitoring for As exposure; certain methods may be applied as optimum As exposure indexes to study dose-response relationship based on various As exposure situation. Chronic effects of iAs exposure via drinking water include skin lesions, neurological effects, hypertension, peripheral vascular disease, cardiovascular disease, respiratory disease, diabetes mellitus, and malignancies including skin cancer. The skin is quite sensitive to arsenic, and skin lesions are some of the most common and earliest nonmalignant effects related to chronic As exposure. The increase of prevalence in the skin lesions has been observed even at the exposure levels in the range of 0.005-0.01 mg/l As in drinking waters. Skin, lung, bladder, kidney, liver, and uterus are considered as sites As-induced malignancies, and the skin is though to be perhaps the most sensitive site. Prospective studies in large area of endemic As poisoning, like Bangladesh or China, where the rate of malignancies is expected to increase within the next several decades, will help to clarify the dose-response relationship between As exposure levels and adverse health effects with enhanced accuracy

  6. Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy

    International Nuclear Information System (INIS)

    Cheung, Rex; Tucker, Susan L.; Lee, Andrew K.; Crevoisier, Renaud de; Dong Lei; Kamat, Ashish; Pisters, Louis; Kuban, Deborah

    2005-01-01

    Purpose: In this era of dose escalation, the benefit of higher radiation doses for low-risk prostate cancer remains controversial. For intermediate-risk patients, the data suggest a benefit from higher doses. However, the quantitative characterization of the benefit for these patients is scarce. We investigated the radiation dose-response relation of tumor control probability in low-risk and intermediate-risk prostate cancer patients treated with radiotherapy alone. We also investigated the differences in the dose-response characteristics using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition vs. an alternative biochemical failure definition. Methods and materials: This study included 235 low-risk and 387 intermediate-risk prostate cancer patients treated with external beam radiotherapy without hormonal treatment between 1987 and 1998. The low-risk patients had 1992 American Joint Committee on Cancer Stage T2a or less disease as determined by digital rectal examination, prostate-specific antigen (PSA) levels of ≤10 ng/mL, and biopsy Gleason scores of ≤6. The intermediate-risk patients had one or more of the following: Stage T2b-c, PSA level of ≤20 ng/mL but >10 ng/mL, and/or Gleason score of 7, without any of the following high-risk features: Stage T3 or greater, PSA >20 ng/mL, or Gleason score ≥8. The logistic models were fitted to the data at varying points after treatment, and the dose-response parameters were estimated. We used two biochemical failure definitions. The ASTRO PSA failure was defined as three consecutive PSA rises, with the time to failure backdated to the mid-point between the nadir and the first rise. The second biochemical failure definition used was a PSA rise of ≥2 ng/mL above the current PSA nadir (CN + 2). The failure date was defined as the time at which the event occurred. Local, nodal, and distant relapses and the use of salvage hormonal therapy were also failures. Results: On the basis of the

  7. Base Station Performance Model

    OpenAIRE

    Walsh, Barbara; Farrell, Ronan

    2005-01-01

    At present the testing of power amplifiers within base station transmitters is limited to testing at component level as opposed to testing at the system level. While the detection of catastrophic failure is possible, that of performance degradation is not. This paper proposes a base station model with respect to transmitter output power with the aim of introducing system level monitoring of the power amplifier behaviour within the base station. Our model reflects the expe...

  8. Dose-response relationship of leukemia incidence among atomic bomb survivors and their controls by absorbed marrow dose and two types of leukemia Hiroshima and Nagasaki, October 1950 - December 1978

    International Nuclear Information System (INIS)

    Ishimaru, Toranosuke; Otake, Masanori; Ichimaru, Michito; Mikami, Motoko.

    1982-07-01

    Analysis of the relationship of the incidence of leukemia to gamma and neutron dose among atomic bomb survivors until 1971 has been reported previously by RERF. The present inquiry was prompted by the extension of case finding to 1978 and by the recent availability of new dose estimates for this fixed cohort. It is focused on the relationship of absorbed marrow dose of gamma rays and neutrons to the incidence of two types of leukemia in the fixed cohort of A-bomb survivors and their controls, the Life Span Study extended sample, in the period October 1950-December 1978. Three dose-response models have been fitted to the data on acute leukemia and chronic granulocytic leukemia. The relationship of the incidence of acute leukemia to gamma and neutron dose again suggests that the ''best'' fitting model involves a dependence on the square of the gamma dose and a linear dependence on neutrons. The estimated relative biological effectiveness (RBE) of neutrons in the induction of acute leukemia is approximately 44/√Dn(Dn = neutron dose) under this model. Based on the 95% confidence limits of the estimated RBE, the risk of this disease is estimated as 0.0026 - 0.0072 cases per million person-years per rem 2 of marrow dose. This analysis has failed, however, to produce a significant dose-response function for the incidence of chronic granulocytic leukemia in relation to the two kinds of radiation. (author)

  9. A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer.

    Science.gov (United States)

    Wang, Xiao; Ji, Alin; Zhu, Yi; Liang, Zhen; Wu, Jian; Li, Shiqi; Meng, Shuai; Zheng, Xiangyi; Xie, Liping

    2015-09-22

    A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121-1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03-1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.

  10. Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.

    Science.gov (United States)

    Crippa, Alessio; Discacciati, Andrea; Larsson, Susanna C; Wolk, Alicja; Orsini, Nicola

    2014-10-15

    Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Dose-response association between leisure time physical activity and work ability: Cross-sectional study among 3000 workers.

    Science.gov (United States)

    Calatayud, Joaquin; Jakobsen, Markus D; Sundstrup, Emil; Casaña, Jose; Andersen, Lars L

    2015-12-01

    Regular physical activity is important for longevity and health, but knowledge about the optimal dose of physical activity for maintaining good work ability is unknown. This study investigates the association between intensity and duration of physical activity during leisure time and work ability in relation to physical demands of the job. From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners with physically demanding work (n = 2952) replied to questions about work, lifestyle and health. Excellent (100 points), very good (75 points), good (50 points), fair (25 points) and poor (0 points) work ability in relation to the physical demands of the job was experienced by 18%, 40%, 30%, 10% and 2% of the respondents, respectively. General linear models that controlled for gender, age, physical and psychosocial work factors, lifestyle and chronic disease showed that the duration of high-intensity physical activity during leisure was positively associated with work ability, in a dose-response fashion (p performing ⩾ 5 hours of high-intensity physical activity per week had on average 8 points higher work ability than those not performing such activities. The duration of low-intensity leisure-time physical activity was not associated with work ability (p = 0.5668). The duration of high-intensity physical activity during leisure time is associated in a dose-response fashion with work ability, in workers with physically demanding jobs. © 2015 the Nordic Societies of Public Health.

  12. Cytogenetics dosimetry: dose-response curve for low doses of X-ray

    International Nuclear Information System (INIS)

    Lara, Virginia E. Noval; Pineda Bolivar, William R.; Riano, Victor M. Pabon; Ureana, Cecilia Crane

    2013-01-01

    The purpose of this study was to conduct a preliminary study for the standardization in the future, the dose-response curve for low doses of X-rays, through the analysis of in vitro cultures of peripheral blood samples of 3 men and 3 women occupationally not exposed to artificial sources of ionizing radiation, age 18-40 years, where possible nonsmokers

  13. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Torekov, Signe Sørensen; Kipnes, M S; Harley, R E

    2011-01-01

    To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles....

  14. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  15. IsoGeneGUI : Multiple approaches for dose-response analysis of microarray data using R

    NARCIS (Netherlands)

    Otava, Martin; Sengupta, Rudradev; Shkedy, Ziv; Lin, Dan; Pramana, Setia; Verbeke, Tobias; Haldermans, Philippe; Hothorn, Ludwig A.; Gerhard, Daniel; Kuiper, Rebecca M.; Klinglmueller, Florian; Kasim, Adetayo

    2017-01-01

    The analysis of transcriptomic experiments with ordered covariates, such as dose-response data, has become a central topic in bioinformatics, in particular in omics studies. Consequently, multiple R packages on CRAN and Bioconductor are designed to analyse microarray data from various perspectives

  16. QUANTITATION OF MOLECULAR ENDPOINTS FOR THE DOSE-RESPONSE COMPONENT OF CANCER RISK ASSESSMENT

    Science.gov (United States)

    Cancer risk assessment involves the steps of hazard identification, dose-response assessment, exposure assessment and risk characterization. The rapid advances in the use of molecular biology approaches has had an impact on all four components, but the greatest overall current...

  17. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    Science.gov (United States)

    Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

    2012-01-01

    Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

  18. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms

    DEFF Research Database (Denmark)

    Urbain, Paul; Jakobsen, Jette

    2015-01-01

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour...

  19. Implementation of the New Approach for the Dose-Response Functions Development for the Case of Athens and Greece

    Science.gov (United States)

    Christodoulakis, J.; Tzanis, C. G.; Varotsos, C. A.; Kouremadas, G.

    2016-08-01

    Dose-response functions (DRFs) are functions used for estimating corrosion and/or soiling levels of materials used in constructions and cultural monuments. In order to achieve this, DRFs lean on ground-based measurements of specific air pollution and climatic parameters like nitrogen oxides, ozone, temperature and others. In DRAGON 3 2015 Symposium we presented a new approach which proposed a technique for using satellite-based data for the necessary parameters instead of ground-based expanding in this way: a) the usage of DRFs in cases/areas where there is no availability of in situ measurements, b) the applicability of satellite-based data. In this work we present mapping results of deterioration levels (corrosion and soiling) for the case of Athens, Greece but also for the whole Greece country.

  20. Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts.

    Science.gov (United States)

    Yun, K L; Fann, J I; Sokoloff, M H; Fong, L G; Sarris, G E; Billingham, M E; Miller, D C

    1991-01-01

    With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7

  1. Web Based VRML Modelling

    NARCIS (Netherlands)

    Kiss, S.; Sarfraz, M.

    2004-01-01

    Presents a method to connect VRML (Virtual Reality Modeling Language) and Java components in a Web page using EAI (External Authoring Interface), which makes it possible to interactively generate and edit VRML meshes. The meshes used are based on regular grids, to provide an interaction and modeling

  2. Intracoronary irradiation: dose response for the prevention of restenosis in swine

    International Nuclear Information System (INIS)

    Weinberger, Judah; Amols, Howard; Ennis, Ronald D.; Schwartz, Allan; Wiedermann, Joseph G.; Marboe, Charles

    1996-01-01

    Purpose: Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192 Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect. Methods and Materials: Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192 Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 ± 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry. Results: Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both). Conclusions: Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall

  3. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos

    Directory of Open Access Journals (Sweden)

    Candy Yuen Ping Ng

    2017-02-01

    Full Text Available Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf revealed through acridine orange (AO staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy and alpha-particle (4.4 mGy exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis.

  4. Teratogenic radiation effects: Phenomena, dose-response relationships and risk levels

    International Nuclear Information System (INIS)

    Konermann, G.

    1991-01-01

    The report in hand informs about a study performed within the framework of the research project 'Animal experiments with albino mice for establishing a model for the detection and assessment of radiation-induced, developmental risks in man due to low-dose irradiation'. The subjects investigated in this study are: (1) Dose-response relationships for postnatal developmental disturbances of the brain as a result of prenatal X-ray treatment. (2) Biokinetics, distribution patterns and effects of inorganically and organically bonded radioiodine (I-125) during the phase of development of the brain. For investigation of the first-mentioned subject, computerized microphotograph analysis was applied for detecting and assessing disturbances of the alignment of axons, as well as deviations from normal cross-sectional data of the Cortex layer, and cerebral commissures as final locations of neurogenetic damage. With all parameters studied, the slope of the relevant curves was found to decrease as a function of age of the fetus at the time of exposure. In addition, time factor effects were investigated. For the parameter cross-sectional area of the Cortex, a clear decrease of effect was found, but for all other parameters, reactions were ambiguous. The study into the second subject was done with cell cultures, showing that the I-125 bonded to the cell nucleus has a much stronger radiotoxic effect than I-125 bonded to the cytoplasma. This difference in effect was studied in mice after incorporation of equal doses administered by way of (I-125)-sodium iodide or (I-125)-iododesoxyuridine. Long-term effects on Cortex cross-sectional areas, cerebral commissures or the texture of axons were quantified by microphotograph analysis. Acute cell death and initial disturbances of the neuronal cell growth were evident after incorporation of (I-125)-IdUR, but not detectable after administration of (I-125)-NaI. (orig./MG) [de

  5. Parity and pancreatic cancer risk: a dose-response meta-analysis of epidemiologic studies.

    Directory of Open Access Journals (Sweden)

    Hong-Bo Guan

    Full Text Available BACKGROUND: Previous epidemiologic studies have reported inconsistent results between parity and pancreatic cancer (PC risk. To our knowledge, a comprehensive and quantitative assessment of this association has not been conducted. METHODS: Relevant published studies of parity and PC were identified using MEDLINE (PubMed and Web of Science databases until November 2013. Two authors (H-BG and LW independently assessed eligibility and extracted data. Eleven prospective and 11 case-control studies reported relative risk (RR estimates and 95% confidence intervals (CIs of PC associated with parity. Fixed- and random-effects models were used to estimate the summary RR depending on the heterogeneity of effects. RESULTS: The summary RR for PC comparing the highest versus lowest parity was 0.86 (95% CI: 0.73-1.02; Q = 50.49, P<0.001, I2 = 58.4%. Significant inverse associations were also observed in the studies that adjusted for cigarette smoking (RR = 0.81; 95% CI: 0.68-0.98, Type 2 diabetes mellitus (RR = 0.83; 95% CI: 0.75-0.93, and those that included all confounders or important risk factors (RR = 0.85; 95% CI: 0.76-0.96. Additionally, in the dose-response analysis, the summary RR for per one live birth was 0.97 (95% CI: 0.94-1.01; Q = 62.83, P<0.001, I2 = 69.8%, which also indicated a borderline statistically significant inverse effect of parity on PC risk. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. CONCLUSION: In summary, these findings suggest that higher parity is associated with a decreased risk of PC. Future large consortia or pooled studies are warranted to fully adjust for potential confounders to confirm this association.

  6. Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

    Science.gov (United States)

    Nielsen, Jace C; Hutmacher, Matthew M; Wesche, David L; Tolbert, Dwain; Patel, Mahlaqa; Kowalski, Kenneth G

    2015-01-01

    Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively. © 2014, The American College of Clinical Pharmacology.

  7. Energy crop (Sida hermaphrodita) fertilization using digestate under marginal soil conditions: A dose-response experiment

    Science.gov (United States)

    Nabel, Moritz; Bueno Piaz Barbosa, Daniela; Horsch, David; Jablonowski, Nicolai David

    2014-05-01

    The global demand for energy security and the mitigation of climate change are the main drivers pushing energy-plant production in Germany. However, the cultivation of these plants can cause land use conflicts since agricultural soil is mostly used for plant production. A sustainable alternative to the conventional cultivation of food-based energy-crops is the cultivation of special adopted energy-plants on marginal lands. To further increase the sustainability of energy-plant cultivation systems the dependency on synthetic fertilizers needs to be reduced via closed nutrient loops. In the presented study the energy-plant Sida hermaphrodita (Malvaceae) will be used to evaluate the potential to grow this high potential energy-crop on a marginal sandy soil in combination with fertilization via digestate from biogas production. With this dose-response experiment we will further identify an optimum dose, which will be compared to equivalent doses of NPK-fertilizer. Further, lethal doses and deficiency doses will be observed. Two weeks old Sida seedlings were transplanted to 1L pots and fertilized with six doses of digestate (equivalent to a field application of 5, 10, 20, 40, 80, 160t/ha) and three equivalent doses of NPK-fertilizer. Control plants were left untreated. Sida plants will grow for 45 days under greenhouse conditions. We hypothesize that the nutrient status of the marginal soil can be increased and maintained by defined digestate applications, compared to control plants suffering of nutrient deficiency due to the low nutrient status in the marginal substrate. The dose of 40t/ha is expected to give a maximum biomass yield without causing toxicity symptoms. Results shall be used as basis for further experiments on the field scale in a field trial that was set up to investigate sustainable production systems for energy crop production under marginal soil conditions.

  8. Defining a dose-response relationship with radiotherapy for prostate cancer: is more really better?

    International Nuclear Information System (INIS)

    Vicini, Frank A.; Abner, Anthony; Baglan, Kathy L.; Kestin, Larry L.; Martinez, Alvaro A.

    2001-01-01

    Purpose: Data were reviewed addressing the association between radiation therapy (RT) dose and treatment outcome for localized prostate cancer to help clarify the existence of a potential dose-response relationship. Methods and Materials: Articles were identified through the MEDLINE database, CancerLit database, and reference lists of relevant articles. Studies were categorized into four groups based upon the endpoint analyzed, including biochemical control (BC), local control (LC), pathologic control (PC), and cause-specific survival (CSS). The impact of increasing RT dose with each endpoint was recorded. Results: Twenty-two trials involving a total of 11,297 patients were identified. Of the 11 trials addressing the association of RT dose with LC, 9 showed statistically significant improvements. Of the 12 trials that reported BC with RT dose, all showed statistically significant improvements. Two out of 4 studies analyzing PC with increasing dose showed a positive correlation. Finally, 3 out of 9 studies addressing RT dose with CSS showed statistically significant improvements. Despite inconclusive results, patients with poor risk features (e.g., prostate-specific antigen [PSA] ≥10, Gleason score [GS] ≥7, or tumor stage ≥T2b) were most likely to benefit from increasing dose with respect to each endpoint. However, the optimal RT dose and the magnitude of benefit of dose escalation could not be identified. Conclusions: Although RT dose appears to correlate with various measures of treatment outcome, objective, high-quality data addressing this critical issue are still lacking. At the present time, the absolute improvement in outcome due to dose escalation, the subset of patients benefiting most, and the optimal dose remain to be defined

  9. Dose-response relationships of propranolol in Chinese subjects with different CYP2D6 genotypes.

    Science.gov (United States)

    Huang, Chin-Wei; Lai, Ming-Liang; Lin, Min-Shung; Lee, Hwei-Ling; Huang, Jin-Ding

    2003-01-01

    For clinical treatment, a smaller dosage of propranolol is often used among Chinese people. Propranolol is metabolized by polymorphic CYP2D6. We postulate that the lower propranolol dosage in Chinese is due to a slower CYP2D6 metabolism. A majority of the Chinese population has the nucleotide T188 in the CYP2D6 gene (CYP2D6*10) instead of C188 (CYP2D6*1), which most white subjects have. Chinese subjects of different CYP2D6*1/CYP2D6*10 genotypes have been shown to have different propranolol pharmacokinetic characteristics. In this study, we compared the beta-blockade effects of propranolol in Chinese subjects of the two different CYP2D6 genotypes. Based on the nucleotide 188 genotypes, two groups of 10 healthy subjects each were selected. Each subject was given a 10-, 20-, or 40-mg rac-propranolol tablet three times a day for 3 days in 3 different phases. Heart rate and blood pressure were measured in both supine and upright positions. The heart rate was also determined during treadmill exercise test. Plasma concentration of S-propranolol at 2 hrs after the last-dose administration was measured. Despite therebeing higher S-propranolol plasma concentration in CYP2D6*10 subjects than in CYP2D6*1 subjects at 10- and 20-mg dosage, the dose-response relationship was not significantly different in these subjects. Our results do not support the hypothesis that CYP2D6*1/CYP2D6*10 polymorphism may affect the beta-blockade effect of propranolol in Chinese subjects.

  10. Non-Linear Dose Response Relationships in Biology, Toxicology, and Medicine (June 8-10, 2004). Final Report

    International Nuclear Information System (INIS)

    Calabrese, Edward J.

    2004-01-01

    The conference attracts approximately 500 scientists researching in the area of non-linear low dose effects. These scientists represent a wide range of biological/medical fields and technical disciplines. Observations that biphasic dose responses are frequently reported in each of these areas but that the recognition of similar dose response relationships across disciplines is very rarely appreciated and exploited. By bringing scientist of such diverse backgrounds together who are working on the common area of non-linear dose response relationships this will enhance our understanding of the occurrence, origin, mechanism, significance and practical applications of such dose response relationships

  11. Dose response in prostate cancer with 8-12 years' follow-up

    International Nuclear Information System (INIS)

    Hanks, Gerald E.; Hanlon, Alexandra L.; Epstein, Barry; Horwitz, Eric M.

    2002-01-01

    ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels 9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure

  12. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.

    Science.gov (United States)

    Arem, Hannah; Moore, Steven C; Patel, Alpa; Hartge, Patricia; Berrington de Gonzalez, Amy; Visvanathan, Kala; Campbell, Peter T; Freedman, Michal; Weiderpass, Elisabete; Adami, Hans Olov; Linet, Martha S; Lee, I-Min; Matthews, Charles E

    2015-06-01

    The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. Leisure time moderate- to vigorous-intensity physical activity. The upper limit of mortality benefit from high levels of leisure time physical activity. Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR

  13. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Science.gov (United States)

    Wang, Yan; Xu, Chang; Du, Li Qing; Cao, Jia; Liu, Jian Xiang; Su, Xu; Zhao, Hui; Fan, Fei-Yue; Wang, Bing; Katsube, Takanori; Fan, Sai Jun; Liu, Qiang

    2013-01-01

    Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001). A time-response relationship was also found within 72 h after irradiation (p < 0.001). The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined. PMID:24240807

  14. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Directory of Open Access Journals (Sweden)

    Qiang Liu

    2013-11-01

    Full Text Available Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001. A time-response relationship was also found within 72 h after irradiation (p < 0.001. The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined.

  15. Model Based Temporal Reasoning

    Science.gov (United States)

    Rabin, Marla J.; Spinrad, Paul R.; Fall, Thomas C.

    1988-03-01

    Systems that assess the real world must cope with evidence that is uncertain, ambiguous, and spread over time. Typically, the most important function of an assessment system is to identify when activities are occurring that are unusual or unanticipated. Model based temporal reasoning addresses both of these requirements. The differences among temporal reasoning schemes lies in the methods used to avoid computational intractability. If we had n pieces of data and we wanted to examine how they were related, the worst case would be where we had to examine every subset of these points to see if that subset satisfied the relations. This would be 2n, which is intractable. Models compress this; if several data points are all compatible with a model, then that model represents all those data points. Data points are then considered related if they lie within the same model or if they lie in models that are related. Models thus address the intractability problem. They also address the problem of determining unusual activities if the data do not agree with models that are indicated by earlier data then something out of the norm is taking place. The models can summarize what we know up to that time, so when they are not predicting correctly, either something unusual is happening or we need to revise our models. The model based reasoner developed at Advanced Decision Systems is thus both intuitive and powerful. It is currently being used on one operational system and several prototype systems. It has enough power to be used in domains spanning the spectrum from manufacturing engineering and project management to low-intensity conflict and strategic assessment.

  16. Linear dose-response of acentric chromosome fragments down to 1 R of x-rays in grasshopper neuroblasts, a potential mutagen-test system

    International Nuclear Information System (INIS)

    Gaulden, M.E.; Read, C.B.

    1978-01-01

    Grasshopper-embryo neuroblasts have no spontaneous chromosome breakage; therefore they permit easy detection of agents that break chromosomes. An X-ray exposure of 1 R induces in them a detectable number of chromosome fragments. The dose-response of acentric fragment frequency fits a linear model between 0 and 128 R. Thus another cell type is added to those previously demonstrated to have no threshold dose for the induction of chromosome or gene mutations

  17. Dose response of micronuclei induced by combination radiation of α-particles and γ-rays in human lymphoblast cells

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Ruiping; He, Mingyuan; Dong, Chen; Xie, Yuexia; Ye, Shuang; Yuan, Dexiao [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China); Shao, Chunlin, E-mail: clshao@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China)

    2013-01-15

    Highlights: ► α-Particle induced MN had a biphasic dose–response followed by a bystander model. ► MN dose–response of α- and γ-combination IR was similar to that of α-particle. ► α-Particles followed by γ-rays yielded a synergistic effect on MN induction. ► Low dose γ-rays triggered antagonistic and adaptive responses against α-particle. - Abstract: Combination radiation is a real situation of both nuclear accident exposure and space radiation environment, but its biological dosimetry is still not established. This study investigated the dose–response of micronuclei (MN) induction in lymphocyte by irradiating HMy2.CIR lymphoblast cells with α-particles, γ-rays, and their combinations. Results showed that the dose–response of MN induced by γ-rays was well-fitted with the linear-quadratic model. But for α-particle irradiation, the MN induction had a biphasic phenomenon containing a low dose hypersensitivity characteristic and its dose response could be well-stimulated with a state vector model where radiation-induced bystander effect (RIBE) was involved. For the combination exposure, the dose response of MN was similar to that of α-irradiation. However, the yield of MN was closely related to the sequence of irradiations. When the cells were irradiated with α-particles at first and then γ-rays, a synergistic effect of MN induction was observed. But when the cells were irradiated with γ-rays followed by α-particles, an antagonistic effect of MN was observed in the low dose range although this combination radiation also yielded a synergistic effect at high doses. When the interval between two irradiations was extended to 4 h, a cross-adaptive response against the other irradiation was induced by a low dose of γ-rays but not α-particles.

  18. Childhood adversity specificity and dose-response effect in non-affective first-episode psychosis

    DEFF Research Database (Denmark)

    Trauelsen, Anne Marie; Bendall, Sarah; Jansen, Jens Einar

    2015-01-01

    BACKGROUND: Reviews conclude that childhood and adolescence sexual, physical, emotional abuse and emotional and physical neglect are all risk factors for psychosis. However, studies suggest only some adversities are associated with psychosis. Dose-response effects of several adversities on risk......% of the control group. Childhood and adolescent sexual, physical, emotional abuse, and physical and emotional neglect, separation and institutionalization were about four to 17 times higher for the FEP group (all p... of psychosis have not been consistently found. The current study aimed to explore adversity specificity and dose-response effects of adversities on risk of psychosis. METHOD: Participants were 101 persons with first-episode psychosis (FEP) diagnosed with ICD-10 F20 - F29 (except F21) and 101 non-clinical...

  19. Aspartame tablets-gamma dose response and usability for routine radiation processing dosimetry using spectrophotometry

    Energy Technology Data Exchange (ETDEWEB)

    Shinde, S.H. [Radiation Safety Systems Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India)]. E-mail: shs_barc@yahoo.com; Mukherjee, T. [Radiation Safety Systems Division, Chemistry Group, Bhabha Atomic Research Centre, Mumbai 400 085 (India)

    2007-02-15

    Aspartame tablets were studied for gamma dose response, using spectrophotometric read-out method. The optimum concentration for ferrous ions was 2x10{sup -4}moldm{sup -3} and xylenol orange with 2.5x10{sup -1}moldm{sup -3} of sulphuric acid for the optimum acidity in FX solution. Wavelength of maximum absorbance is 548nm. Post-irradiation stability is appreciable i.e. for not less than one month. Dose response is non-linear with third order polynomial fit, in the dose range of 1000-10000Gy. This system of aspartame was further used for carrying out relative percentage dose profile measurement in Gamma Cell-220. Results obtained were inter-compared with that of a glutamine dosimeter, which showed that maximum difference between the values of aspartame and glutamine systems is within +/-10%.

  20. Dose response of artificial irradiation of fluvial sediment sample for ESR dating

    International Nuclear Information System (INIS)

    Liu Chunru; Yin Gongming; Gao Lu; Li Jianping; Han Fei; Lin Min

    2011-01-01

    ESR dating samples need be irradiated to obtain dose response curve and the equivalent dose. The artificial dose rate is about 1 x 10 -1 -1 x 10 2 Gy/min, whereas the natural dose rate is about 3 Gy/ka. Therefore, one must be sure whether the much higher artificial dose rate is suitable for the ESR dating study. In this paper, we use different artificial dose rate to irradiate the same fluvial sample and measure the quartz Al centre ESR signal under the same conditions. The dose response curves are compared, in an attempt to gain a preliminary knowledge on that problem and build a good foundation for our ESR dating studies on fluvial samples. (authors)

  1. Epidemiological methods for assessing dose-response and dose-effect relationships

    DEFF Research Database (Denmark)

    Kjellström, Tord; Grandjean, Philippe

    2007-01-01

    Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity General Considerations of Dose-Effect and Dose-Response Relationships Interactions in Metal Toxicology Epidemiological Methods for Assessing Dose-Response and Dose-Effect Relationships Essential Metals: Assessing Risks from Deficiency......Description Handbook of the Toxicology of Metals is the standard reference work for physicians, toxicologists and engineers in the field of environmental and occupational health. This new edition is a comprehensive review of the effects on biological systems from metallic elements...... access to a broad range of basic toxicological data and also gives a general introduction to the toxicology of metallic compounds. Audience Toxicologists, physicians, and engineers in the fields of environmental and occupational health as well as libraries in these disciplines. Will also be a useful...

  2. Aspartame tablets-gamma dose response and usability for routine radiation processing dosimetry using spectrophotometry

    International Nuclear Information System (INIS)

    Shinde, S.H.; Mukherjee, T.

    2007-01-01

    Aspartame tablets were studied for gamma dose response, using spectrophotometric read-out method. The optimum concentration for ferrous ions was 2x10 -4 moldm -3 and xylenol orange with 2.5x10 -1 moldm -3 of sulphuric acid for the optimum acidity in FX solution. Wavelength of maximum absorbance is 548nm. Post-irradiation stability is appreciable i.e. for not less than one month. Dose response is non-linear with third order polynomial fit, in the dose range of 1000-10000Gy. This system of aspartame was further used for carrying out relative percentage dose profile measurement in Gamma Cell-220. Results obtained were inter-compared with that of a glutamine dosimeter, which showed that maximum difference between the values of aspartame and glutamine systems is within +/-10%

  3. Single-dose-response curves of murine gastrointestinal crypt stem cells

    International Nuclear Information System (INIS)

    Masuda, K.; Withers, H.R.; Mason, K.A.; Chen, K.Y.

    1977-01-01

    Dose-response curves for the reproductive capacity of crypt stem cells of murine colonic, jejunal, and gastric mucosae exposed in situ to multifractionated gamma ray exposures were analyzed and single-dose-survival curves of these cells were constructed. The following conclusions were drawn: (1) The single-dose-response curves bend downward over a dose range of approximately 200 to 1500 rad; (2) cell death seems to be due to nonrepairable damage at doses less than 250 rad for colon, and 220 rad for jejunum; (3) there are 21, 110, and 140 stem cells per crypt of gastric, colonic, and jejunal mucosa, respectively; and (4) jejunal stem cells are the most radiosensitive and gastric mucosal stem cells are the most resistant

  4. Dose response of tracheal epithelial cells to ionizing radiation in air-liquid interface cultures

    International Nuclear Information System (INIS)

    Fukutsu, K.; Yamada, Y.; Shimo, M.

    2002-01-01

    The dose-response relationships of tracheal epithelial cells to ionizing radiation was examined in air-liquid interface cultures, which were developed for the purpose of simulating in vivo conditions. The cultures investigated in this study were expected to be advantageous for the performance of irradiation experiments using short-range α rays. The level of dose response of air-liquid interface cultures to ionizing radiation proved to be the same as that for in vivo conditions. This result indicates that air-liquid interface cultures will prove most useful, to facilitate future studies for the investigation of the biological effects induced in tracheal epithelial cells by ionizing radiation, especially by α-rays. (orig.)

  5. Dose-response association between leisure time physical activity and work ability

    DEFF Research Database (Denmark)

    Calatayud, Joaquin; Jakobsen, Markus D.; Sundstrup, Emil

    2015-01-01

    INTRODUCTION: Regular physical activity is important for longevity and health, but knowledge about the optimal dose of physical activity for maintaining good work ability is unknown. This study investigates the association between intensity and duration of physical activity during leisure time......, lifestyle and chronic disease showed that the duration of high-intensity physical activity during leisure was positively associated with work ability, in a dose-response fashion (p physical activity per week had on average 8 points higher work ability...... than those not performing such activities. The duration of low-intensity leisure-time physical activity was not associated with work ability (p = 0.5668). CONCLUSIONS: The duration of high-intensity physical activity during leisure time is associated in a dose-response fashion with work ability...

  6. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics

    NARCIS (Netherlands)

    Nesse, Willem; Linde, Annemiek; Abbas, Frank; Spijkervet, Frederik Karst Lucien; Dijkstra, Pieter Ubele; de Brabander, Eric Carl; Gerstenbluth, Izzy; Vissink, Arjan

    Nesse W, Linde A, Abbas F, Spijkervet FKL, Dijkstra PU, de Brabander EC, Gerstenbluth I, Vissink A. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 diabetics. J Clin Periodontol 2009; 36: 295-300. doi: 10.1111/j.1600-051X.2009.01377.x. A dose-response

  7. A new method for synthesizing radiation dose-response data from multiple trials applied to prostate cancer

    DEFF Research Database (Denmark)

    Diez, Patricia; Vogelius, Ivan S; Bentzen, Søren M

    2010-01-01

    A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high).......A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high)....

  8. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Yuece, Ulkue Rabia, E-mail: ulkuyuce@hotmail.co [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Meric, Niyazi, E-mail: meric@ankara.edu.t [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Atakol, Orhan, E-mail: atakol@science.ankara.edu.t [Ankara University, Science Faculty, Department of Chemistry, 06100, Tandogan - Ankara (Turkey); Yasar, Fusun, E-mail: ab121310@adalet.gov.t [Council of Forensic Medicine, Ankara Branch, Ankara (Turkey)

    2010-08-15

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  9. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    International Nuclear Information System (INIS)

    Yuece, Ulkue Rabia; Meric, Niyazi; Atakol, Orhan; Yasar, Fusun

    2010-01-01

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  10. Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

    Energy Technology Data Exchange (ETDEWEB)

    Little, Mark P., E-mail: mark.little@nih.gov [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Kleinerman, Ruth A. [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Stovall, Marilyn; Smith, Susan A. [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mabuchi, Kiyohiko [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States)

    2012-12-01

    Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  11. Gustatory tissue injury in man: radiation dose response relationships and mechanisms of taste loss

    International Nuclear Information System (INIS)

    Mossman, K.L.

    1986-01-01

    In this report dose response data for gustatory tissue damage in patients given total radiation doses ranging from 3000 to 6000 cGy are presented. In order to evaluate direct radiation injury to gustatory tissues as a mechanism of taste loss, measurements of damage to specific taste structures in bovine and murine systems following radiation exposure in the clinical range are correlated to taste impairment observed in radiotherapy patients. (author)

  12. Dose-Response of Sodium Bicarbonate Ingestion Highlights Individuality in Time Course of Blood Analyte Responses.

    Science.gov (United States)

    Jones, Rebecca Louise; Stellingwerff, Trent; Artioli, Guilherme Giannini; Saunders, Bryan; Cooper, Simon; Sale, Craig

    2016-10-01

    To defend against hydrogen cation accumulation and muscle fatigue during exercise, sodium bicarbonate (NaHCO 3 ) ingestion is commonplace. The individualized dose-response relationship between NaHCO 3 ingestion and blood biochemistry is unclear. The present study investigated the bicarbonate, pH, base excess and sodium responses to NaHCO 3 ingestion. Sixteen healthy males (23 ± 2 years; 78.6 ± 15.1 kg) attended three randomized order-balanced, nonblinded sessions, ingesting a single dose of either 0.1, 0.2 or 0.3 g·kg -1 BM of NaHCO 3 (Intralabs, UK). Fingertip capillary blood was obtained at baseline and every 10 min for 1 hr, then every 15 min for a further 2 hr. There was a significant main effect of both time and condition for all assessed blood analytes (p ≤ .001). Blood analyte responses were significantly lower following 0.1 g·kg -1 BM compared with 0.2 g·kg -1 BM; bicarbonate concentrations and base excess were highest following ingestion of 0.3 g·kg -1 BM (p ≤ .01). Bicarbonate concentrations and pH significantly increased from baseline following all doses; the higher the dose the greater the increase. Large interindividual variability was shown in the magnitude of the increase in bicarbonate concentrations following each dose (+2.0-5; +5.1-8.1; and +6.0-12.3 mmol·L -1 for 0.1, 0.2 and 0.3 g·kg -1 BM) and in the range of time to peak concentrations (30-150; 40-165; and 75-180 min for 0.1, 0.2 and 0.3 g·kg -1 BM). The variability in bicarbonate responses was not affected by normalization to body mass. These results challenge current practices relating to NaHCO 3 supplementation and clearly show the need for athletes to individualize their ingestion protocol and trial varying dosages before competition.

  13. Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response

    Directory of Open Access Journals (Sweden)

    Hemantkumar Chavan

    2017-01-01

    Full Text Available Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis.

  14. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults.

    Science.gov (United States)

    Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong

    2011-08-01

    It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.

  15. Human evidence on the shape of the dose-response curves for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Burkart, W.

    1981-09-01

    The carcinogenic effects of high levels of ionizing radiation are better understood than those of any other environmental agent. However, the somatic risk from low doses is highly disputed. The uncertainties stem from the fact that a direct estimation of small risks requires impracticably large samples. Therefore, risk estimates for low doses have to be derived indirectly by extrapolation from high exposure data and are heavily dependent on assumptions about the form of the dose-response curve. Although radiobiological theories tested on in vitro systems predict a quadratic term in the dose-response equation which should, at least for sparsely ionizing radiation, dominate the shape of the curve, the epidemiological data available cannot exclude the possibility of a pure linear relationship. In some cases, apparent thresholds may result from latent periods inversely related to dose. Besides depending on the quality of the radiation, the shape seems also to differ with the type of cancer induced. Studies on uranium miners, atomic bomb survivors and on irradiated patients are reviewed with emphasis on the shape of the dose-response. The credibility of the most publicized reports claiming a large cancer risk from low levels of radiation is assessed. The feasibility of a new study in an area of high natural background is explored. Finally, the influence of the uncertainties concerning the effect of low level radiation on future exposure limits set by regulatory bodies is discussed. (Auth.)

  16. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

    Science.gov (United States)

    Blumberg, Jeffrey B.; Vita, Joseph A.; Chen, C. -Y. Oliver

    2015-01-01

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

  17. Respiratory dysfunction in swine production facility workers: dose-response relationships of environmental exposures and pulmonary function.

    Science.gov (United States)

    Donham, K J; Reynolds, S J; Whitten, P; Merchant, J A; Burmeister, L; Popendorf, W J

    1995-03-01

    Human respiratory health hazards for people working in livestock confinement buildings have been recognized since 1974. However, before comprehensive control programs can be implemented, more knowledge is needed of specific hazardous substances present in the air of these buildings, and at what concentrations they are harmful. Therefore, a medical epidemiological and exposure-response study was conducted on 207 swine producers using intensive housing systems (108 farms). Dose-response relationships between pulmonary function and exposures are reported here. Positive correlations were seen between change in pulmonary function over a work period and exposure to total dust, respirable dust, ammonia, respirable endotoxin, and the interactions of age-of-producer and dust exposure and years-of-working-in-the-facility and dust exposure. Relationships between baseline pulmonary function and exposures were not strong and therefore, not pursued in this study. The correlations between exposure and response were stronger after 6 years of exposure. Multiple regression models were used to identify total dust and ammonia as the two primary environmental predictors of pulmonary function decrements over a work period. The regression models were then used to determine exposure concentrations related to pulmonary function decrements suggestive of a health hazard. Total dust concentrations > or = 2.8 mg/m3 were predictive of a work period decrement of > or = 10% in FEV1. Ammonia concentrations of > or = 7.5 ppm were predictive of a > or = 3% work period decrement in FEV1. These predictive concentrations were similar to a previous dose-response study, which suggested 2.5 mg/m3 of total dust and 7 ppm of NH3 were associated with significant work period decrements. Therefore, dust > or = 2.8 mg/m3 and ammonia > or = 7.5 ppm should be considered reasonable evidence for guidelines regarding hazardous exposure concentrations in this work environment.

  18. Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies.

    Science.gov (United States)

    Schwingshackl, Lukas; Schwedhelm, Carolina; Hoffmann, Georg; Knüppel, Sven; Iqbal, Khalid; Andriolo, Violetta; Bechthold, Angela; Schlesinger, Sabrina; Boeing, Heiner

    2017-11-01

    The aim of this systematic review and meta-analysis was to summarize the evidence on the relation of the intakes of 12 major food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSBs) with the risk of hypertension. PubMed, Scopus, and Web of Science were searched systematically until June 2017 for prospective studies having quantitatively investigated the above-mentioned foods. We conducted meta-analysis on the highest compared with the lowest intake categories and linear and nonlinear dose-response meta-analyses to analyze the association. Summary RRs and 95% CIs were estimated by using a random-effects model. Overall, 28 reports were included in the meta-analysis. An inverse association for the risk of hypertension was observed for 30 g whole grains/d (RR: 0.92; 95% CI: 0.87, 0.98), 100 g fruits/d (RR: 0.97; 95% CI: 0.96, 0.99), 28 g nuts/d (RR: 0.70; 95% CI: 0.45, 1.08), and 200 g dairy/d (RR: 0.95; 95% CI: 0.94, 0.97), whereas a positive association for 100 g red meat/d (RR: 1.14; 95% CI: 1.02, 1.28), 50 g processed meat/d (RR: 1.12; 95% CI: 1.00, 1.26), and 250 mL SSB/d (RR: 1.07; 95% CI: 1.04, 1.10) was seen in the linear dose-response meta-analysis. Indication for nonlinear relations of the intakes of whole grains, fruits, fish, and processed meats with the risk of hypertension was detected. In summary, this comprehensive dose-response meta-analysis of 28 reports identified optimal intakes of whole grains, fruits, nuts, legumes, dairy, red and processed meats, and SSBs related to the risk of hypertension. These findings need to be seen under the light of very-low to low quality of meta-evidence. However, the findings support the current dietary guidelines in the prevention of hypertension. © 2017 American Society for Nutrition.

  19. Nationwide Study of Humidifier Disinfectant Lung Injury in South Korea, 1994-2011. Incidence and Dose-Response Relationships.

    Science.gov (United States)

    Paek, Domyung; Koh, Younsuck; Park, Dong-Uk; Cheong, Hae-Kwan; Do, Kyung-Hyun; Lim, Chae-Man; Hong, Soo-Jong; Kim, Yong-Hwa; Leem, Jong-Han; Chung, Kyu Hyuck; Choi, Ye-Yong; Lee, Jong-Hyeon; Lim, Sin-Ye; Chung, Eun-Hee; Cho, Young Ah; Chae, Eun Jin; Joh, Joon-Sung; Yoon, Yup; Lee, Kyu-Hong; Choi, Bo Youl; Gwack, Jin

    2015-12-01

    Humidifier disinfectant lung injury is an acute lung disease attributed to recurrent inhalation of certain disinfectant aerosols emitted from room humidifiers. An outbreak of this toxic lung injury occurred in South Korea from 1995 until all humidifier disinfectant products were recalled from the consumer market by the government in 2011. A nationwide study was conducted to ascertain and classify all potential cases of humidifier disinfectant lung injury in Korea and to assess dose-response relationships. By several mechanisms, clinicians and the general public were invited to report all suspected cases of humidifier disinfectant lung injury to public health officials in South Korea. A committee was convened to define diagnostic criteria based on pathologic, radiologic, and clinical findings for index cases, combined with assessment of environmental exposure to humidifier disinfectants. Clinical review and environmental assessments were performed and later combined to determine overall likelihood of disease for each study participant, classified as definite, probable, possible, or unlikely. Survival time from exposure to onset of symptoms was analyzed to assess dose-response relationships. Three broad categories of risk factors were examined: (1) biological susceptibility, (2) temporal cycle of exposure and recovery, and (3) spatial conditions and density of disinfectant. Of 374 possible cases identified and reviewed, 329 were unanimously classified by the diagnostic committee, as follows: 117 definite, 34 probable, 38 possible and 140 unlikely cases. A total of 62 individuals with definite or probable disease died. Risk factors examined for polyhexamethyleneguanidine phosphate exposure that were found to be significant in shortening survival included age 4 years or younger at onset, use of disinfectant for 7 days per week, airborne density of 800 μg/m(3) or more of disinfectant, and daily exposure 11 or more hours in duration. Dose-response analysis indicated

  20. SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

    International Nuclear Information System (INIS)

    Dean, J; Welsh, L; Gulliford, S; Harrington, K; Nutting, C

    2014-01-01

    Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receiving radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% – 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in

  1. Systematic review and meta-analysis of reduction in all-cause mortality from walking and cycling and shape of dose response relationship.

    Science.gov (United States)

    Kelly, Paul; Kahlmeier, Sonja; Götschi, Thomas; Orsini, Nicola; Richards, Justin; Roberts, Nia; Scarborough, Peter; Foster, Charlie

    2014-10-24

    Walking and cycling have shown beneficial effects on population risk of all-cause mortality (ACM). This paper aims to review the evidence and quantify these effects, adjusted for other physical activity (PA). We conducted a systematic review to identify relevant studies. Searches were conducted in November 2013 using the following health databases of publications: Embase (OvidSP); Medline (OvidSP); Web of Knowledge; CINAHL; SCOPUS; SPORTDiscus. We also searched reference lists of relevant texts and reviews. Eligible studies were prospective cohort design and reporting walking or cycling exposure and mortality as an outcome. Only cohorts of individuals healthy at baseline were considered eligible. Extracted data included study population and location, sample size, population characteristics (age and sex), follow-up in years, walking or cycling exposure, mortality outcome, and adjustment for other co-variables. We used random-effects meta-analyses to investigate the beneficial effects of regular walking and cycling. Walking (18 results from 14 studies) and cycling (8 results from 7 studies) were shown to reduce the risk of all-cause mortality, adjusted for other PA. For a standardised dose of 11.25 MET.hours per week (or 675 MET.minutes per week), the reduction in risk for ACM was 11% (95% CI = 4 to 17%) for walking and 10% (95% CI = 6 to 13%) for cycling. The estimates for walking are based on 280,000 participants and 2.6 million person-years and for cycling they are based on 187,000 individuals and 2.1 million person-years. The shape of the dose-response relationship was modelled through meta-analysis of pooled relative risks within three exposure intervals. The dose-response analysis showed that walking or cycling had the greatest effect on risk for ACM in the first (lowest) exposure interval. The analysis shows that walking and cycling have population-level health benefits even after adjustment for other PA. Public health approaches would have the biggest impact

  2. Skull base tumor model.

    Science.gov (United States)

    Gragnaniello, Cristian; Nader, Remi; van Doormaal, Tristan; Kamel, Mahmoud; Voormolen, Eduard H J; Lasio, Giovanni; Aboud, Emad; Regli, Luca; Tulleken, Cornelius A F; Al-Mefty, Ossama

    2010-11-01

    Resident duty-hours restrictions have now been instituted in many countries worldwide. Shortened training times and increased public scrutiny of surgical competency have led to a move away from the traditional apprenticeship model of training. The development of educational models for brain anatomy is a fascinating innovation allowing neurosurgeons to train without the need to practice on real patients and it may be a solution to achieve competency within a shortened training period. The authors describe the use of Stratathane resin ST-504 polymer (SRSP), which is inserted at different intracranial locations to closely mimic meningiomas and other pathological entities of the skull base, in a cadaveric model, for use in neurosurgical training. Silicone-injected and pressurized cadaveric heads were used for studying the SRSP model. The SRSP presents unique intrinsic metamorphic characteristics: liquid at first, it expands and foams when injected into the desired area of the brain, forming a solid tumorlike structure. The authors injected SRSP via different passages that did not influence routes used for the surgical approach for resection of the simulated lesion. For example, SRSP injection routes included endonasal transsphenoidal or transoral approaches if lesions were to be removed through standard skull base approach, or, alternatively, SRSP was injected via a cranial approach if the removal was planned to be via the transsphenoidal or transoral route. The model was set in place in 3 countries (US, Italy, and The Netherlands), and a pool of 13 physicians from 4 different institutions (all surgeons and surgeons in training) participated in evaluating it and provided feedback. All 13 evaluating physicians had overall positive impressions of the model. The overall score on 9 components evaluated--including comparison between the tumor model and real tumor cases, perioperative requirements, general impression, and applicability--was 88% (100% being the best possible

  3. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    Science.gov (United States)

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2) = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, p(linearity) = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer. © 2015 UICC.

  4. Dairy products consumption and risk of type 2 diabetes: systematic review and dose-response meta-analysis.

    Directory of Open Access Journals (Sweden)

    Dengfeng Gao

    Full Text Available BACKGROUND: The consumption of dairy products may influence the risk of type 2 diabetes mellitus (T2DM, but inconsistent findings have been reported. Moreover, large variation in the types of dairy intake has not yet been fully explored. METHODS AND RESULTS: We conducted a systematic review and meta-analysis to clarify the dose-response association of dairy products intake and T2DM risk. We searched PubMed, EMBASE and Scopus for studies of dairy products intake and T2DM risk published up to the end of October 2012. Random-effects models were used to estimate summary relative risk (RR statistics. Dose-response relations were evaluated using data from different dairy products in each study. We included 14 articles of cohort studies that reported RR estimates and 95% confidence intervals (95% CIs of T2DM with dairy products intake. We found an inverse linear association of consumption of total dairy products (13 studies, low-fat dairy products (8 studies, cheese (7 studies and yogurt (7 studies and risk of T2DM. The pooled RRs were 0.94 (95% CI 0.91-0.97 and 0.88 (0.84-0.93 for 200 g/day total and low-fat dairy consumption, respectively. The pooled RRs were 0.80 (0.69-0.93 and 0.91 (0.82-1.00 for 30 g/d cheese and 50 g/d yogurt consumption, respectively. We also found a nonlinear association of total and low-fat dairy intake and T2DM risk, and the inverse association appeared to be strongest within 200 g/d intake. CONCLUSION: A modest increase in daily intake of dairy products such as low fat dairy, cheese and yogurt may contribute to the prevention of T2DM, which needs confirmation in randomized controlled trials.

  5. Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

    Science.gov (United States)

    Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

    2017-08-15

    The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

  6. Soy food intake and risk of gastric cancer: A dose-response meta-analysis of prospective studies.

    Science.gov (United States)

    Weng, Ke-Gui; Yuan, Ya-Ling

    2017-08-01

    Epidemiological studies were inconsistent on the association between soy food intake and risk of gastric cancer (GC). This study aimed to determine the role of soy food intake in the development of GC.A systematic search was conducted in PubMed and Web of Science to identify all relevant studies. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model, and the dose-response relationship between soy food intake and GC risk was also assessed.Thirteen prospective studies were identified with a total of 517,106 participants and 5800 cases. Among 11 types of soy food, high intake of total soy food (the highest vs the lowest category: RR: 0.78, 95% CI: 0.62-0.98) and nonfermented soy food (RR: 0.63, 95% CI: 0.50-0.79) were inversely associated with GC risk, while high intake of miso soup was associated with the risk in male (RR: 1.17, 95% CI: 1.02-1.36). In dose-response meta-analysis, total soy food intake (0-150 g/day) showed no significant association with GC risk, while high intake of nonfermented soy food was inversely related, especially an intake of more than 100 g/day. In male, miso soup intake (1-5 cups/day) was significantly associated with GC risk.High intake of nonfermented soy food might reduce the risk of GC, while miso soup intake might increase the risk in male.

  7. Dose-response curve for blood exposed to gamma-neutron mixed field by conventional cytogenetic method

    International Nuclear Information System (INIS)

    Brandao, Jose Odinilson de C.; Souza, Priscilla L.G.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F.; Calixto, Merilane S.; Santos, Neide

    2009-01-01

    There is increasing concern about airline crew members (about one million worldwide) are exposed to measurable neutrons doses. Historically, cytogenetic biodosimetry assays have been based on quantifying asymmetrical chromosome alterations (dicentrics, centric rings and acentric fragments) in mytogen-stimulated T-lymphocytes in their first mitosis after radiation exposure. Increased levels of chromosome damage in peripheral blood lymphocytes are a sensitive indicator of radiation exposure and they are routinely exploited for assessing radiation absorbed dose after accidental or occupational exposure. Since radiological accidents are not common, not all nations feel that it is economically justified to maintain biodosimetry competence. However, dependable access to biological dosimetry capabilities is completely critical in event of an accident. In this paper the dose-response curve was measured for the induction of chromosomal alterations in peripheral blood lymphocytes after chronic exposure in vitro to neutron-gamma mixes field. Blood was obtained from one healthy donor and exposed to two neutron-gamma mixed field from sources 241 AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The evaluated absorbed doses were 0.2 Gy; 1.0 Gy and 2.5 Gy. The dicentric chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphase figures were analyzed for the presence of dicentrics by two experienced scorers after painted by giemsa 5%. Our preliminary results showed a linear dependence between radiations absorbed dose and dicentric chromosomes frequencies. Dose-response curve described in this paper will contribute to the construction of calibration curve that will be used in our laboratory for biological dosimetry. (author)

  8. On the existence of a threshold in the dose-response relationship from the epidemiological data of atomic bomb survivors

    International Nuclear Information System (INIS)

    Matsuura, Tatsuo; Sugahara, Tsutomu

    2002-01-01

    Whether or not there is a threshold dose in the dose-response relationship for cancer incidence due to radiation is one of the most important but controversial issues in radiation protection and nuclear policy making. The epidemiological studies on the Life Span Study (LSS) group of atomic bomb survivors in Hiroshima and Nagasaki, conducted by Radiation Effects Research Foundation (RERF) have been regarded to be most authentic, and they keep the view that there is no evidence to deny the linear non-threshold (LNT) hypotheses. The authors have claimed the necessity of reassessment of exposure doses of survivors, by considering the contribution of chronic dose, which comes from fall-out, induced radioactivity, and early entrance near the center of the city. The authors also have stressed the importance of the cases of if 'not-in-city' survivors, frequently reported to be fatal by the heavy chronic exposure. Recently we have noticed that the appearance of acute radiation symptoms is an important index for estimating total dose. In this paper, based on Obos statistical data (in 1957) for the acute symptoms observed for various category of survivors, we present an estimation of the average chronic dose of survivors, which should be added to the instantaneous dose for the directly exposed groups. By assuming the threshold for the appearance of the acute symptom such as epilation as 0.5 Sv, average chronic dose of 0.32 Sv was estimated for all survivors. Then the present dose-response relationship for cancer incidence should be shifted to the right hand side by this amount, and the value of about 0.32 Sv or more is suggested as the threshold for cancer incidence in low radiation level region

  9. Dose-response curve for blood exposed to gamma-neutron mixed field by conventional cytogenetic method

    Energy Technology Data Exchange (ETDEWEB)

    Brandao, Jose Odinilson de C.; Souza, Priscilla L.G.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F., E-mail: jodinilson@cnen.gov.b, E-mail: fflima@cnen.gov.b, E-mail: jasantos@cnen.gov.b [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Calixto, Merilane S.; Santos, Neide, E-mail: santos_neide@yahoo.com.b [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Genetica

    2009-07-01

    There is increasing concern about airline crew members (about one million worldwide) are exposed to measurable neutrons doses. Historically, cytogenetic biodosimetry assays have been based on quantifying asymmetrical chromosome alterations (dicentrics, centric rings and acentric fragments) in mytogen-stimulated T-lymphocytes in their first mitosis after radiation exposure. Increased levels of chromosome damage in peripheral blood lymphocytes are a sensitive indicator of radiation exposure and they are routinely exploited for assessing radiation absorbed dose after accidental or occupational exposure. Since radiological accidents are not common, not all nations feel that it is economically justified to maintain biodosimetry competence. However, dependable access to biological dosimetry capabilities is completely critical in event of an accident. In this paper the dose-response curve was measured for the induction of chromosomal alterations in peripheral blood lymphocytes after chronic exposure in vitro to neutron-gamma mixes field. Blood was obtained from one healthy donor and exposed to two neutron-gamma mixed field from sources {sup 241}AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The evaluated absorbed doses were 0.2 Gy; 1.0 Gy and 2.5 Gy. The dicentric chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphase figures were analyzed for the presence of dicentrics by two experienced scorers after painted by giemsa 5%. Our preliminary results showed a linear dependence between radiations absorbed dose and dicentric chromosomes frequencies. Dose-response curve described in this paper will contribute to the construction of calibration curve that will be used in our laboratory for biological dosimetry. (author)

  10. Reproductive factors, menopausal hormone therapies and primary liver cancer risk: a systematic review and dose-response meta-analysis of observational studies.

    Science.gov (United States)

    Zhong, Guo-Chao; Liu, Yan; Chen, Nan; Hao, Fa-Bao; Wang, Kang; Cheng, Jia-Hao; Gong, Jian-Ping; Ding, Xiong

    2016-12-01

    A striking gender disparity in the incidence and outcome of primary liver cancer (PLC) has been well recognized. Mounting evidence from basic research suggests that hormonal factors may be involved in the gender disparity of PLC. Whether hormonal exposures in human subjects are associated with PLC risk is largely unknown. Whether reproductive factors and use of menopausal hormone therapies (MHTs) in women are associated with PLC risk remains controversial. We conducted this study to clarify this issue. PubMed and EMBASE were searched to July, 2016 for studies published in English or Chinese. Observational studies (cohort, nested case-control and case-control) that provided risk estimates of reproductive factors, MHTs and PLC risk were eligible. The quality of included studies was determined based on the Newcastle-Ottawa quality assessment scale. Summary risk ratios (RRs) were calculated using a random-effects model. Dose-response analysis was conducted where possible. Fifteen peer-reviewed studies, involving 1795 PLC cases and 2 256 686 women, were included. Overall meta-analyses on parity and PLC risk did not find any significant associations; however, when restricting to studies with PLC cases ≥100, increasing parity was found to be significantly associated with a decreased risk of PLC [RR for the highest versus lowest parity 0.67, 95% CI 0.52, 0.88; RR for parous versus nulliparous 0.71, 95% CI 0.53, 0.94; RR per one live birth increase 0.93, 95% CI 0.88, 0.99]. A J-shaped relationship between parity and PLC risk was identified (P non-linearity  Parity is associated with PLC risk in a J-shaped dose-response pattern. Late age at menarche and ever use of MHT are associated with a reduced risk of PLC, whereas there is no association of ever use of ET and EPT, age at first birth, or spontaneous and induced abortion with PLC risk. Compared to women with no history of oophorectomy, those with a history of oophorectomy are at an increased risk of PLC. Our findings

  11. Systematic review using meta-analyses to estimate dose-response relationships between iodine intake and biomarkers of iodine status in different population groups.

    Science.gov (United States)

    Ristić-Medić, Danijela; Dullemeijer, Carla; Tepsić, Jasna; Petrović-Oggiano, Gordana; Popović, Tamara; Arsić, Aleksandra; Glibetić, Marija; Souverein, Olga W; Collings, Rachel; Cavelaars, Adriënne; de Groot, Lisette; van't Veer, Pieter; Gurinović, Mirjana

    2014-03-01

    The objective of this systematic review was to identify studies investigating iodine intake and biomarkers of iodine status, to assess the data of the selected studies, and to estimate dose-response relationships using meta-analysis. All randomized controlled trials, prospective cohort studies, nested case-control studies, and cross-sectional studies that supplied or measured dietary iodine and measured iodine biomarkers were included. The overall pooled regression coefficient (β) and the standard error of β were calculated by random-effects meta-analysis on a double-log scale, using the calculated intake-status regression coefficient (β) for each individual study. The results of pooled randomized controlled trials indicated that the doubling of dietary iodine intake increased urinary iodine concentrations by 14% in children and adolescents, by 57% in adults and the elderly, and by 81% in pregnant women. The dose-response relationship between iodine intake and biomarkers of iodine status indicated a 12% decrease in thyroid-stimulating hormone and a 31% decrease in thyroglobulin in pregnant women. The model of dose-response quantification used to describe the relationship between iodine intake and biomarkers of iodine status may be useful for providing complementary evidence to support recommendations for iodine intake in different population groups.

  12. Application of Physiologically Based Pharmacokinetic Models in Chemical Risk Assessment

    Directory of Open Access Journals (Sweden)

    Moiz Mumtaz

    2012-01-01

    Full Text Available Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting “in silico” tools such as physiologically based pharmacokinetic (PBPK models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application—health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The “human PBPK model toolkit” is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures.

  13. Effect of heterogeneity of human population in cell radiosensitivity on the extrapolation of dose-response relationships to low doses

    International Nuclear Information System (INIS)

    Filyushkin, I.V.; Bragin, Yu.N.; Khandogina, E.K.

    1989-01-01

    Presented are the results of an investigation of the dose-response relationship for the yield of chromosome aberrations in peripheral blood lymphocytes of persons with some hereditary diseases which represent the high risk group with respect to the increased incidence of malignant tumors and decreased life span. Despite substantially different absolute radiosensitivities of chromosomes, the variations of the alpha/beta ratio determining the extrapolation of experimental dose-response relationships to low doses did not prove to be too high, the mean deviation from the control being 15%. This points to the possible practical use of the dose-response relationships averaged over the human population as a whole

  14. Regulation of operant oral ethanol self-administration: a dose-response curve study in rats.

    Science.gov (United States)

    Carnicella, Sebastien; Yowell, Quinn V; Ron, Dorit

    2011-01-01

    Oral ethanol self-administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self-administration of a 20, 40, and 60% ethanol solution. Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U-shaped dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders. Copyright © 2010 by the Research Society on Alcoholism.

  15. Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment of Amblyopia Study (MOTAS).

    Science.gov (United States)

    Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

    2004-09-01

    Amblyopia is the commonest visual disorder of childhood. Yet the contributions of the two principal treatments (spectacle wear and occlusion) to outcome are unknown. This study was undertaken to investigate the dose-response relationship of amblyopia therapy. The study comprised three distinct phases: baseline, in which repeat measures of visual function were undertaken to confirm the initial visual deficit; refractive adaptation: an 18-week period of spectacle wear with six weekly measurements of logarithm of the minimum angle of resolution (logMAR) visual acuity; occlusion: in which participants were prescribed 6 hours of "patching" per day. In the latter phase, occlusion was objectively monitored and logMAR visual acuity recorded at 2-week intervals until any observed gains had ceased. Data were obtained from 94 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 34), anisometropia (n = 23), and both anisometropia and strabismus (n = 37). Eighty-six underwent refractive adaptation. Average concordance with patching was 48%. The relationship between logMAR visual acuity gain and total occlusion dose was monotonic and linear. Increasing dose rate beyond 2 h/d hastened the response but did not improve outcome. More than 80% of the improvement during occlusion occurred within 6 weeks. Treatment outcome was significantly better for children younger than 4 years (n = 17) than in those older than 6 years (n = 24; P = 0.0014). Continuous objective monitoring of the amount of patching therapy received has provided insight into the dose-response relationship of occlusion therapy for amblyopia. Patching is most effective within the first few weeks of treatment, even for those in receipt of a relatively small dose. Further studies are needed to elucidate the neural basis for the dose-response functions. Copyright Association for Research in Vision and Ophthalmology

  16. Dose-response functions and corrosion mapping for a small geographical area

    International Nuclear Information System (INIS)

    Haagenrud, S.E.; Henriksen, J.F.; Gram, F.

    1985-01-01

    Detailed corrosion and environmental measurements have been used to develop dose response (D/R) functions for carbon steel, zinc, copper, and aluminum for a 26 x 31 km urban/rural area with approximately homogeneous climate. The D/R functions, expressed in terms of SO 2 and time of wetness, were of the same type for all four metals. The SO 2 contribution to the total corrosion dominates in the centers of towns and around an industrial plant. Corrosion maps for the whole area were established

  17. Similarity criterion analysis of dose-response curves in biological assay and radioimmunoassay of hormones

    International Nuclear Information System (INIS)

    Cristakou, H.D.

    1983-01-01

    The difficulties involved in the control of biological and radioimmunological assay systems, and in the maintenance of standard, as well as, the usual heterogeneity of assayed samples require some evidence of similarity between the dose-response curves obtained with the standard and the sample. Nowadays the parallelism test is used to provide such evidence. However, some indications of non-normal errors distribution, such as the presence of out layers, render the parallelism test both conceptually implausible and statistically inefficient. In such a manner we suggest the non-parametric 'frequencial' test as a more sounding option. (author)

  18. Non-linear dose response of a few plant taxa to acute gamma radiation

    International Nuclear Information System (INIS)

    George, J.T.; Patel, B.B.; Pius, J.; Narula, B.; Shankhadarwar, S.; Rane, V.A.; Venu-Babu, P.; Eapen, S.; Singhal, R.K.

    2014-01-01

    Micronuclei induction serves as an essential biomarker of radiation stress in a living system, and the simplicity of its detection technique has made it a widely used indicator of radiation damage. The present study was conducted to reveal the cytological dose-response of a few plant taxa, viz., Allium cepa var. aggregatum Linn., Allium sativum Linn., Chlorophytum comosum (Thunb.) Jacques and Eichhornia crassipes (Mart.) Solms, to low LET gamma radiation with special emphasis on the pattern of micronuclei induced across low and high dose regimes. A tri-phasic non-linear dose-response pattern was observed in the four taxa studied, characterized by a low dose linear segment, a plateau and a high dose linear segment. Despite a similar response trend, the critical doses where the phase transitions occurred varied amongst the plant taxa, giving an indication to their relative radiosensitivities. E. crassipes and A. sativum, with their lower critical doses for slope modifications of phase transitions, were concluded as being more radiosensitive as compared to C. comosum and A. cepa, which had relatively higher critical doses. (author)

  19. The dose-response analysis between BMI and common chronic diseases in northeast China.

    Science.gov (United States)

    Yu, Jianxing; Tao, Yuchun; Dou, Jing; Ye, Junsen; Yu, Yaqin; Jin, Lina

    2018-03-09

    High body mass index (BMI) predisposes to several chronic diseases, but a large-scale systematic and detailed study of dose-response relationship between BMI and chronic diseases has not been reported previously. In this study, we aimed to investigate the relationship between BMI and 3 chronic diseases (hypertension, dyslipidemia and MetS) in northeast China. A sample of 16412 participants aged 18~79 years old were included in Jilin province in 2012. The lambda-mu-sigma (LMS) method was applied to examine the trend of BMI by age, and the restricted cubic splines were used to investigate the non-linear associations (dose-response curve) between BMI and chronic diseases. It was pointed out that BMI increased rapidly when young, then kept steady in middle age, and finally declined slowly in old age, and accordingly age was divided into 3 segments, which were different by gender. The odds ratios (ORs) of BMI for the chronic diseases increased relatively slowly when young, then increased dramatically in middle-age and old population, especially for men. Further, the ORs of BMI among non-smokers were lower than those among smokers, and the same trend was shown to be more apparent among drinkers and non-drinkers. The risk of BMI for common chronic diseases increased dramatically in middle-aged, especially for men with drinking and smoking habits.

  20. Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

    Directory of Open Access Journals (Sweden)

    Rui-Ru Ji

    2009-09-01

    Full Text Available The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901 across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.

  1. Dose response evaluation of a low-density normoxic polymer gel dosimeter using MRI

    Energy Technology Data Exchange (ETDEWEB)

    Haraldsson, P [Medical Radiation Physics, Department of Clinical Sciences, Lund University, Malmoe University Hospital, SE-205 02 Malmoe (Sweden); Department of Radiation Physics, Finsen Centre, Copenhagen University Hospital, DK-2100 Copenhagen (Denmark); Karlsson, A [Medical Radiation Physics, Department of Clinical Sciences, Lund University, Malmoe University Hospital, SE-205 02 Malmoe (Sweden); Wieslander, E [Medical Radiation Physics, Department of Clinical Sciences, Lund University Hospital, SE-221 85 Lund (Sweden); Gustavsson, H [Medical Radiation Physics, Department of Clinical Sciences, Lund University, Malmoe University Hospital, SE-205 02 Malmoe (Sweden); Baeck, S A J [Medical Radiation Physics, Department of Clinical Sciences, Lund University, Malmoe University Hospital, SE-205 02 Malmoe (Sweden)

    2006-02-21

    A low-density ({approx}0.6 g cm{sup -3}) normoxic polymer gel, containing the antioxidant tetrakis (hydroxymethyl) phosponium (THP), has been investigated with respect to basic absorbed dose response characteristics. The low density was obtained by mixing the gel with expanded polystyrene spheres. The depth dose data for 6 and 18 MV photons were compared with Monte Carlo calculations. A large volume phantom was irradiated in order to study the 3D dose distribution from a 6 MV field. Evaluation of the gel was carried out using magnetic resonance imaging. An approximately linear response was obtained for 1/T2 versus dose in the dose range of 2 to 8 Gy. A small decrease in the dose response was observed for increasing concentrations of THP. A good agreement between measured and Monte Carlo calculated data was obained, both for test tubes and the larger 3D phantom. It was shown that a normoxic polymer gel with a reduced density could be obtained by adding expanded polystyrene spheres. In order to get reliable results, it is very important to have a uniform distribution of the gel and expanded polystyrene spheres in the phantom volume.

  2. Dose response evaluation of a low-density normoxic polymer gel dosimeter using MRI

    Science.gov (United States)

    Haraldsson, P.; Karlsson, A.; Wieslander, E.; Gustavsson, H.; Bäck, S. Å. J.

    2006-02-01

    A low-density (~0.6 g cm-3) normoxic polymer gel, containing the antioxidant tetrakis (hydroxymethyl) phosponium (THP), has been investigated with respect to basic absorbed dose response characteristics. The low density was obtained by mixing the gel with expanded polystyrene spheres. The depth dose data for 6 and 18 MV photons were compared with Monte Carlo calculations. A large volume phantom was irradiated in order to study the 3D dose distribution from a 6 MV field. Evaluation of the gel was carried out using magnetic resonance imaging. An approximately linear response was obtained for 1/T2 versus dose in the dose range of 2 to 8 Gy. A small decrease in the dose response was observed for increasing concentrations of THP. A good agreement between measured and Monte Carlo calculated data was obained, both for test tubes and the larger 3D phantom. It was shown that a normoxic polymer gel with a reduced density could be obtained by adding expanded polystyrene spheres. In order to get reliable results, it is very important to have a uniform distribution of the gel and expanded polystyrene spheres in the phantom volume.

  3. Application of the International Life Sciences Institute Key Events Dose-Response Framework to food contaminants.

    Science.gov (United States)

    Fenner-Crisp, Penelope A

    2012-12-01

    Contaminants are undesirable constituents in food. They may be formed during production of a processed food, present as a component in a source material, deliberately added to substitute for the proper substance, or the consequence of poor food-handling practices. Contaminants may be chemicals or pathogens. Chemicals generally degrade over time and become of less concern as a health threat. Pathogens have the ability to multiply, potentially resulting in an increased threat level. Formal structures have been lacking for systematically generating and evaluating hazard and exposure data for bioactive agents when problem situations arise. We need to know what the potential risk may be to determine whether intervention to reduce or eliminate contact with the contaminant is warranted. We need tools to aid us in assembling and assessing all available relevant information in an expeditious and scientifically sound manner. One such tool is the International Life Sciences Institute (ILSI) Key Events Dose-Response Framework (KEDRF). Developed as an extension of the WHO's International Program on Chemical Safety/ILSI mode of action/human relevance framework, it allows risk assessors to understand not only how a contaminant exerts its toxicity but also the dose response(s) for each key event and the ultimate outcome, including whether a threshold exists. This presentation will illustrate use of the KEDRF with case studies included in its development (chloroform and Listeriaonocytogenes) after its publication in the peer-reviewed scientific literature (chromium VI) and in a work in progress (3-monochloro-1, 2-propanediol).

  4. Does a dose-response relation exist between spinal pain and temporomandibular disorders?

    Directory of Open Access Journals (Sweden)

    Englund Erling

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to test whether a reciprocal dose-response relation exists between frequency/severity of spinal pain and temporomandibular disorders (TMD. Methods A total of 616 subjects with varying severity of spinal pain or no spinal pain completed a questionnaire focusing on symptoms in the jaw, head and spinal region. A subset of the population (n = 266 were sampled regardless of presence or absence of spinal pain. We used two different designs, one with frequency/severity of spinal pain, and the other, with frequency/severity of TMD symptoms as independent variable. All 616 participants were allocated to four groups, one control group without spinal pain and three spinal pain groups. The subjects in the subset were allocated to one control group without TMD symptoms and three TMD groups. Odds ratios (ORs were calculated for presence of frequent TMD symptoms in the separate spinal pain groups as well as for frequent spinal pain in the separate TMD groups. Results The analysis showed increasing ORs for TMD with increasing frequency/severity of spinal pain. We also found increasing ORs for spinal pain with increasing frequency/severity of TMD symptoms. Conclusion This study shows a reciprocal dose-response-like relationship between spinal pain and TMD. The results indicate that these two conditions may share common risk factors or that they may influence each other. Studies on the temporal sequence between spinal pain and TMD are warranted.

  5. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

  6. Thermoluminescence dose response of quartz as a function of irradiation temperature

    International Nuclear Information System (INIS)

    Kitis, G.; Kaldoudi, E.; Charalambous, S.

    1990-01-01

    The thermoluminescence (TL) response of pure Norwegian quartz as a function of irradiation temperature (T irr ) and dose has been investigated. The TL response of the (150-230 o C) and (230-350 o C) glow curve intervals shows a strong dependence on T irr between 77 and 373 K in the dose range from 54 to 8.4 x 10 4 Gy. Both glow curve intervals also show temperature dependent dose response properties. The 150-230 o C interval is supralinear from the lowest dose (54 Gy). Its maximum supralinearity factor appears at T irr = 293 K. The 230-350 o C interval shows sublinear behaviour below T irr = + 193 K, while at T irr ≥ 273 K it shows the well known dose response curves. Its maximum supralinearity factor appears at T irr = 323 K. The linear response is extended up to 460 Gy at T irr = 273 K and falls to 80 Gy at T irr = 373 K. (author)

  7. Radiation dose response of N channel MOSFET submitted to filtered X-ray photon beam

    Science.gov (United States)

    Gonçalves Filho, Luiz C.; Monte, David S.; Barros, Fabio R.; Santos, Luiz A. P.

    2018-01-01

    MOSFET can operate as a radiation detector mainly in high-energy photon beams, which are normally used in cancer treatments. In general, such an electronic device can work as a dosimeter from threshold voltage shift measurements. The purpose of this article is to show a new way for measuring the dose-response of MOSFETs when they are under X-ray beams generated from 100kV potential range, which is normally used in diagnostic radiology. Basically, the method consists of measuring the MOSFET drain current as a function of the radiation dose. For this the type of device, it has to be biased with a high value resistor aiming to see a substantial change in the drain current after it has been irradiated with an amount of radiation dose. Two types of N channel device were used in the experiment: a signal transistor and a power transistor. The delivered dose to the device was varied and the electrical curves were plotted. Also, a sensitivity analysis of the power MOSFET response was made, by varying the tube potential of about 20%. The results show that both types of devices have responses very similar, the shift in the electrical curve is proportional to the radiation dose. Unlike the power MOSFET, the signal transistor does not provide a linear function between the dose rate and its drain current. We also have observed that the variation in the tube potential of the X-ray equipment produces a very similar dose-response.

  8. The scientific basis for the establishment of threshold levels and dose response relationships of carcinogenesis

    International Nuclear Information System (INIS)

    1975-01-01

    The International Atomic Energy Agency hosted a two day Symposium from 2-3 December 1974 at its Headquarters, organized by the 'International Academy for Environmental Safety and the Forum fur Wissenschaft, Wirtschaft und Politik' on the subject 'Scientific Basis for the Establishment of Threshold. Levels and Dose Response Relationships of Carcinogenesis'. Following an introductory paper by the Radiation Biology Section of the Agency on 'Radiation Carcinogenesis - Dose Response Relationship, Threshold and Risk Estimates', a series of papers dealt with this problem in chemical carcinogenesis.It was suggested that more experiments should be done using non-human primates for tests of carcinogens, especially chemicals. Preliminary experiments using monkeys with a potent carcinogen - nitrosoamine - indicate that there could possibly be a dose where no effect can be observed during the 5 year period of study. It was also pointed out that the overall cost/benefit and risk/ benefit relationships should be taken into consideration in determining limits for chemicals which are potentially carcinogenic but are used routinely by the public and industries; these considerations have been weighed in setting exposure limits for radiation

  9. Radiation effects on cancer mortality among A-bomb survivors, 1950-72. Comparison of some statistical models and analysis based on the additive logit model

    Energy Technology Data Exchange (ETDEWEB)

    Otake, M [Hiroshima Univ. (Japan). Faculty of Science

    1976-12-01

    Various statistical models designed to determine the effects of radiation dose on mortality of atomic bomb survivors in Hiroshima and Nagasaki from specific cancers were evaluated on the basis of a basic k(age) x c(dose) x 2 contingency table. From the aspects of application and fits of different models, analysis based on the additive logit model was applied to the mortality experience of this population during the 22year period from 1 Oct. 1950 to 31 Dec. 1972. The advantages and disadvantages of the additive logit model were demonstrated. Leukemia mortality showed a sharp rise with an increase in dose. The dose response relationship suggests a possible curvature or a log linear model, particularly if the dose estimated to be more than 600 rad were set arbitrarily at 600 rad, since the average dose in the 200+ rad group would then change from 434 to 350 rad. In the 22year period from 1950 to 1972, a high mortality risk due to radiation was observed in survivors with doses of 200 rad and over for all cancers except leukemia. On the other hand, during the latest period from 1965 to 1972 a significant risk was noted also for stomach and breast cancers. Survivors who were 9 year old or less at the time of the bomb and who were exposed to high doses of 200+ rad appeared to show a high mortality risk for all cancers except leukemia, although the number of observed deaths is yet small. A number of interesting areas are discussed from the statistical and epidemiological standpoints, i.e., the numerical comparison of risks in various models, the general evaluation of cancer mortality by the additive logit model, the dose response relationship, the relative risk in the high dose group, the time period of radiation induced cancer mortality, the difference of dose response between Hiroshima and Nagasaki and the relative biological effectiveness of neutrons.

  10. X-ray dose response of calcite—A comprehensive analysis for optimal application in TL dosimetry

    International Nuclear Information System (INIS)

    Kalita, J.M.; Wary, G.

    2016-01-01

    Highlights: • Effect of annealing temperature on TL signal of calcite has been studied. • Specific annealing treatment for optimal dose response has been evaluated. • The dose response of natural calcite has been analyzed quantitatively. - Abstract: The effect of various annealing treatments on dosimetric characteristics of orange calcite (CaCO_3) mineral has been studied in detail. Quantitative analysis on the dose response shows that the 573 K annealed sample showed sublinear dose response from 10 mGy to 1 Gy. The fading and reproducibility of this sample are also good enough for dosimetric application. However, a specific annealing treatment after irradiation shows some significant improvements in the dosimetric characteristics of the sample. The 773 K pre-annealed sample, after X-ray irradiation post-annealing at 340 K for 6 min provides linear dose response from 10 mGy to 3.60 Gy, very less fading and good reproducibility. Moreover, this sample after post-annealing at 380 K for 6 min shows linear dose response from 10 mGy to 5.40 Gy when analyzed from the ∼408 K thermoluminescence (TL) glow peak. Analysis of TL glow curves confirmed that the 1.30 eV trap center in calcite crystal is the most effective trapping site for dosimetric application.

  11. X-ray dose response of calcite—A comprehensive analysis for optimal application in TL dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Kalita, J.M., E-mail: jitukalita09@gmail.com; Wary, G.

    2016-09-15

    Highlights: • Effect of annealing temperature on TL signal of calcite has been studied. • Specific annealing treatment for optimal dose response has been evaluated. • The dose response of natural calcite has been analyzed quantitatively. - Abstract: The effect of various annealing treatments on dosimetric characteristics of orange calcite (CaCO{sub 3}) mineral has been studied in detail. Quantitative analysis on the dose response shows that the 573 K annealed sample showed sublinear dose response from 10 mGy to 1 Gy. The fading and reproducibility of this sample are also good enough for dosimetric application. However, a specific annealing treatment after irradiation shows some significant improvements in the dosimetric characteristics of the sample. The 773 K pre-annealed sample, after X-ray irradiation post-annealing at 340 K for 6 min provides linear dose response from 10 mGy to 3.60 Gy, very less fading and good reproducibility. Moreover, this sample after post-annealing at 380 K for 6 min shows linear dose response from 10 mGy to 5.40 Gy when analyzed from the ∼408 K thermoluminescence (TL) glow peak. Analysis of TL glow curves confirmed that the 1.30 eV trap center in calcite crystal is the most effective trapping site for dosimetric application.

  12. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    Science.gov (United States)

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  13. SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, J; Liang, J; Chen, S; Qin, A; Yan, D [Beaumont Health Systeml, Royal Oak, MI (United States)

    2016-06-15

    Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition was used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal organ

  14. Aspirin as a potential modality for the chemoprevention of breast cancer: A dose-response meta-analysis of cohort studies from 857,831 participants.

    Science.gov (United States)

    Lu, Liming; Shi, Leiyu; Zeng, Jingchun; Wen, Zehuai

    2017-06-20

    Previous meta-analyses on the relationship between aspirin use and breast cancer risk have drawn inconsistent results. In addition, the threshold effect of different doses, frequencies and durations of aspirin use in preventing breast cancer have yet to be established. The search yielded 13 prospective cohort studies (N=857,831 participants) that reported an average of 7.6 cases/1,000 person-years of breast cancer during a follow-up period of from 4.4 to 14 years. With a random effects model, a borderline significant inverse association was observed between overall aspirin use and breast cancer risk, with a summarized RR = 0.94 (P = 0.051, 95% CI 0.87-1.01). The linear regression model was a better fit for the dose-response relationship, which displayed a potential relationship between the frequency of aspirin use and breast cancer risk (RR = 0.97, 0.95 and 0.90 for 5, 10 and 20 times/week aspirin use, respectively). It was also a better fit for the duration of aspirin use and breast cancer risk (RR = 0.86, 0.73 and 0.54 for 5, 10 and 20 years of aspirin use). We searched MEDLINE, EMBASE and CENTRAL databases through early October 2016 for relevant prospective cohort studies of aspirin use and breast cancer risk. Meta-analysis of relative risks (RR) estimates associated with aspirin intake were presented by fixed or random effects models. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Our study confirmed a dose-response relationship between aspirin use and breast cancer risk. For clinical prevention, long term (>5 years) consistent use (2-7 times/week) of aspirin appears to be more effective in achieving a protective effect against breast cancer.

  15. Dose response effect of cement dust on respiratory muscles competence in cement mill workers.

    Science.gov (United States)

    Meo, Sultan A; Azeem, Muhammad A; Qureshi, Aijaz A; Ghori, G Moinudin; Al-Drees, Abdul Majeed; Feisal Subhan, Mirza Muhammad

    2006-12-01

    Electromyography (EMG) of respiratory muscles is a reliable method of assessing the ventilatory muscle function, but still its use has not been fully utilized to determine the occupational and environmental hazards on respiratory muscles. Therefore, EMG of intercostal muscles was performed to determine the dose response effect of cement dust on respiratory muscles competence. Matched cross-sectional study of EMG in 50 non-smoking cement mill workers with an age range of 20 - 60 years, who worked without the benefit of cement dust control ventilation or respiratory protective devices. EMG was performed by using surface electrodes and chart recorder. Significant reduction was observed in number of peaks (p competence and stratification of results shows a dose-effect of years of exposure in cement mill.

  16. Summary of dosimetry, pathology, and dose response for bone sarcomas in beagles injected with radium-226

    International Nuclear Information System (INIS)

    Wrenn, M.E.; Taylor, G.N.; Stevens, W.

    1986-01-01

    In the completed 226 Ra portion of a 30-year-long experiment to determine the relative radiotoxicity of injected 226 Ra and 239 Pu, 42 of 116 animals injected with 226 Ra developed 63 bone sarcomas; none were observed in 44 controls. Average alpha plus beta dose to the skeleton to death was calculated on the basis of mathematical functions developed from sequential measurements of radium and radon retention in each dog. Bone sarcomas were identified radiographically or clinically, with subsequent histopathological confirmation and classification. Most primary bone tumors were classified as osteosarcomas if osteoid arose from a malignant stroma. The dose-response curve over the six lowest injected dose levels fits well to a linear, no-threshold, least squares fit, through a control incidence of 0.8%, and with a slope of 0.042% incidence per rad. 19 refs., 5 figs., 2 tabs

  17. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

    International Nuclear Information System (INIS)

    Sheehan, Daniel M.

    2006-01-01

    We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from ∼1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate

  18. Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

    Science.gov (United States)

    Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

    2011-01-01

    This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

  19. Dose response of xylitol and sorbitol for epr retrospective dosimetry with applications to chewing gum

    International Nuclear Information System (INIS)

    Israelsson, A.; Gustafsson, H.; Lund, E.

    2013-01-01

    The purpose of this investigation was to study the radiation-induced electron paramagnetic resonance signal in sweeteners xylitol and sorbitol for use in retrospective dosimetry. For both sweeteners and chewing gum, the signal changed at an interval of 1-84 d after irradiation with minimal changes after 4-8 d. A dependence on storage conditions was noticed and the exposure of the samples to light and humidity was therefore minimised. Both the xylitol and sorbitol signals showed linearity with dose in the measured dose interval, 0-20 Gy. The dose-response measurements for the chewing gum resulted in a decision threshold of 0.38 Gy and a detection limit of 0.78 Gy. A blind test illustrated the possibility of using chewing gums as a retrospective dosemeter with an uncertainty in the dose determination of 0.17 Gy (1 SD). (authors)

  20. Relative radiation sensitivity of the integumentary system: Dose response of the epidermal, microvascular, and dermal populations

    International Nuclear Information System (INIS)

    Archambeau, J.O.

    1987-01-01

    This presentation lists gross and histologic changes produced by irradiation of the skin that have been quantified. It examines available cell kinetic radiobiological and morphological variables to identify interactions that occur between component populations. The dose response data of the hair and epidermal, fibrocytic, and endothelial cell populations are examined and a rank ordering is attempted. The contribution of the radiosensitivity of these populations to defining the dose tolerance of the skin is discussed. Future clinical needs are considered. The intent is to quantify or define tissue population changes in the irradiated skin so that the data may serve as guidelines to aid the radiation therapist to select therapy schedules that preserve skin function while improving cancer control

  1. The influence of parameters of A-type carbonated apatites synthesis on radiation dose response

    International Nuclear Information System (INIS)

    Oliveira, Liana Macedo de; Lopes, Ricardo Tadeu

    2000-01-01

    The aim of this work is the investigation of dose response of A-type carbonated apatites prepared in different conditions. Irradiated samples prepared with carbonate content of 1.45 to 4.84% are studied by using electron paramagnetic resonance (EPR). The EPR spectra are mainly constituted of lines associated to axial CO 2 - species (g perp = 2.0028 and g // = 1.9973) and CO 3 - species (g 1 = 2,0170, g 2 = 2,0090 e g 3 = 2,0041). The production of CO 2 - species on gamma irradiation depends on the carbonate concentration and the hydroxyapatite stoichiometry. The lowest dose detection limit was achieved with stoichiometric samples and carbonate content around of 3.7%. (author)

  2. Radiation dose response correlation between thermoluminescence and optically stimulated luminescence in quartz

    International Nuclear Information System (INIS)

    Oniya, E.O.; Polymeris, G.S.; Tsirliganis, N.C.; Kitis, G.

    2012-01-01

    The fast, linearly modulated optically stimulated luminescence (LM-OSL) component in quartz is the main dosimetric signal used for the dating applications of this material. Since the blue light stimulation (470 nm, 40 mW cm −2 ) time needed to obtain the fast LM-OSL component is less than 50 s the electron trapping levels responsible for it are still highly populated. In this way an active radiation history is created which could play an important role in the dosimetric characteristics of the fast OSL signal. In the present work the dose response behavior of the fast OSL signal is investigated in quartz samples with an annealed radiation history and quartz samples possessing an artificial radiation history. A computerized curve de-convolution analysis of the LM-OSL curves for 50 s stimulation time showed that it consists of three individual OSL components. The faster component C 1 with peak maximum time around 5 s has a linear dose response in virgin samples, which turns to a slight superlinearity as a function of the artificial radiation history. On the other hand the component C 2 with peak maximum time at 12 s is slightly superlinear which turns into strong superlinearity as a function of artificial radiation history. Finally, component C 3 with peak maximum time at about 45 s is strongly superlinear for both virgin samples and as a function of artificial radiation history. The implications to practical application are discussed. - Highlights: ► The fast OSL component consists of three components. ► The linearity of first fast component does not depend on radiation history. ► The linearity of second and third components depend on radiation history. ► The TL between 180 and 300 °C is the major source of OSL.

  3. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response

    International Nuclear Information System (INIS)

    Skwarchuk, Mark W.; Jackson, Andrew; Zelefsky, Michael J.; Venkatraman, Ennapadam S.; Cowen, Didier M.; Levegruen, Sabine; Burman, Chandra M.; Fuks, Zvi; Leibel, Steven A.; Ling, C. Clifton

    2000-01-01

    Purpose: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. Methods and Materials: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy--13 patients, 75.6 Gy--36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy--39 patients, 75.6 Gy--83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. Results: A dose response for ≥ Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with ≥ Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p max (p max

  4. Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

    International Nuclear Information System (INIS)

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H.

    1990-01-01

    Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time

  5. Childhood adversity specificity and dose-response effect in non-affective first-episode psychosis.

    Science.gov (United States)

    Trauelsen, Anne Marie; Bendall, Sarah; Jansen, Jens Einar; Nielsen, Hanne-Grethe Lyse; Pedersen, Marlene Buch; Trier, Christopher Høier; Haahr, Ulrik H; Simonsen, Erik

    2015-06-01

    Reviews conclude that childhood and adolescence sexual, physical, emotional abuse and emotional and physical neglect are all risk factors for psychosis. However, studies suggest only some adversities are associated with psychosis. Dose-response effects of several adversities on risk of psychosis have not been consistently found. The current study aimed to explore adversity specificity and dose-response effects of adversities on risk of psychosis. Participants were 101 persons with first-episode psychosis (FEP) diagnosed with ICD-10 F20 - F29 (except F21) and 101 non-clinical control persons matched by gender, age and parents' socio-economic status. Assessment included the Childhood Trauma Questionnaire and parts of the Childhood Experience of Care and Abuse Questionnaire. Eighty-nine percent of the FEP group reported one or more adversities compared to 37% of the control group. Childhood and adolescent sexual, physical, emotional abuse, and physical and emotional neglect, separation and institutionalization were about four to 17 times higher for the FEP group (all p<0.01). The risk of psychosis increased two and a half times for each additional adversity. All associations between specific adversities and psychosis decreased when they were adjusted for other adversities. Our findings suggest that there is a large shared effect of adversities on the risk of psychosis. Contrary to the call for further research into specific adversities, we suggest a search for mechanisms in the shared effects of traumatization. Clinical implications are thorough assessment of adversities and their possible effects. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    Science.gov (United States)

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P open field test.

  7. Use of three-dimensional lognormal dose-response surfaces in lifetime studies of radiation-induced cancer

    International Nuclear Information System (INIS)

    Raabe, O.G.

    1986-01-01

    The three-dimensional lognormal cumulative probability power function was used to provide a unifying dose-response description of the lifetime cancer risk for chronic exposure of experimental animals and people, for risk evaluation, and for scaling between species. Bone tumor fatilities, primarily from alpha irradiation of the skeleton in lifetime studies of beagles injected with 226 Ra, were shown to be well described by this function. This function described cancer risk in lifetime studies as a curved smooth surface depending on radiation exposure rate and elapsed time, such that the principal risk at low dose rates occurred near the end of the normal life span without significant life shortening. Essentially identical functions with the median value of the power function displaced with respect to appropriate RBE values were shown to describe bone-cancer induction primarily from alpha irradiation of the skeleton in lifetime beagle studies with injected 226 Ra, 228 Th, 239 Pu and 241 Am, and with inhaled 238 Pu. Application of this model to human exposures to 226 Ra yielded a response ratio of 3.6; that is, the time required for development of bone cancer in people was 3.6 times longer than for beagles at the same average skeletal dose rate. It was suggested that similar techniques were appropriate to other carcinogens and other critical organs. 20 refs., 8 figs., 3 tabs

  8. Dose-response analysis of phthalate effects on gene expression in rat whole embryo culture

    NARCIS (Netherlands)

    Robinson, J.F.; Verhoef, A.; van Beelen, V.A.; Pennings, J.L.A.; Piersma, A.H.|info:eu-repo/dai/nl/071276947

    2012-01-01

    The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to

  9. Model-Based Reasoning

    Science.gov (United States)

    Ifenthaler, Dirk; Seel, Norbert M.

    2013-01-01

    In this paper, there will be a particular focus on mental models and their application to inductive reasoning within the realm of instruction. A basic assumption of this study is the observation that the construction of mental models and related reasoning is a slowly developing capability of cognitive systems that emerges effectively with proper…

  10. Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

    Science.gov (United States)

    Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

    2017-07-01

    Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

    Science.gov (United States)

    Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

    2011-10-01

    For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

  12. Generation of dose-response relationships to assess the effects of acidity in precipitation on growth and productivity of vegetation

    International Nuclear Information System (INIS)

    Evans, L.S.

    1981-01-01

    Experiments were performed with several plant species in natural environments as well in a greenhouse and/or tissue culture facilities to establish dose-response functions of plant responses to simulated acidic rain in order to determine environmental risk assessments to ambient levels of acidic rain. Response functions of foliar injury, biomass of leaves and seed of soybean and pinto beans, root yields of radishes and garden beets, and reproduction of bracken fern are considered. The dose-response function of soybean seed yields with the hydrogen ion concentration of simulated acidic rainfalls was expressed by the equation y = 21.06-1.01 log x where y = seed yield in grams per plant and x = the hydrogen concentration if μeq l -1 . The correlation coefficient of this relationship was -0.90. A similar dose-response function was generated for percent fertilization of ferns in a forest understory. When percent fertilization is plotted on logarithmic scale with hydrogen ion concentration of the simulated rain solution, the Y intercept is 51.18, slope -0.041 with a correlation coefficient of -0.98. Other dose-response functions were generated that assist in a general knowledge as to which plant species and which physiological processes are most impacted by acidic precipitation. Some responses did not produce convenient dose-response relationships. In such cases the responses may be altered by other environmental factors or there may be no differences among treatment means

  13. Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens.

    Science.gov (United States)

    Fahrer, Jörg; Kaina, Bernd

    2017-08-01

    Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, which is causally linked to dietary habits, notably the intake of processed and red meat. Processed and red meat contain dietary carcinogens, including heterocyclic aromatic amines (HCAs) and N-nitroso compounds (NOC). NOC are agents that induce various N-methylated DNA adducts and O 6 -methylguanine (O 6 -MeG), which are removed by base excision repair (BER) and O 6 -methylguanine-DNA methyltransferase (MGMT), respectively. HCAs such as the highly mutagenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) cause bulky DNA adducts, which are removed from DNA by nucleotide excision repair (NER). Both O 6 -MeG and HCA-induced DNA adducts are linked to the occurrence of KRAS and APC mutations in colorectal tumors of rodents and humans, thereby driving CRC initiation and progression. In this review, we focus on DNA repair pathways removing DNA lesions induced by NOC and HCA and assess their role in protecting against mutagenicity and carcinogenicity in the large intestine. We further discuss the impact of DNA repair on the dose-response relationship in colorectal carcinogenesis in view of recent studies, demonstrating the existence of 'no effect' point of departures (PoDs), i.e. thresholds for genotoxicity and carcinogenicity. The available data support the threshold concept for NOC with DNA repair being causally involved. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Study of the dose response of the system ferrous ammonium sulfate–sucrose–xylenol orange in acid aqueous solution

    International Nuclear Information System (INIS)

    Juarez-Calderon, J.M.; Negron-Mendoza, A.; Ramos-Bernal, S.

    2014-01-01

    An aqueous solution of ammonium ferrous sulfate–sucrose–xylenol orange in sulfuric acid (FSX) is proposed as a dosimetric system for the processes of gamma irradiation in a range between 0.3 and 6 Gy. This system is based on the indirect oxidation of ferrous ion by an organic compound (sucrose) to ferric ion and on the formation of a color complex of Fe 3+ in an acidic medium with xylenol orange (a dye). After gamma radiation, an observable change occurs in the color of the system. Irradiation was executed at three different temperatures (13 °C, 22 °C, and 40 °C). A spectrometric readout method at 585 nm was employed to evaluate the system's dose response. In all of the cases analyzed, the responses had a linear behavior, and a slight effect of irradiation temperature was observed. Post-irradiation response was also evaluated and showed the stability of the solutions 24 h after the irradiation. The results obtained suggest that FSX might be used as a dosimeter for low doses of gamma irradiation because it provides a stable signal, good reproducibility, and an accessible technique for analysis. - Highlights: • The system ferrous-sucrose-xylenol is reproducibility with less than 5% error. • The dosimeter has low cost and easy readout using UV-vis spectrometry, and the response is stable for several days. • The system proposed is suitable for low irradiation doses

  15. A novel method of estimating dose responses for polymer gels using texture analysis of scanning electron microscopy images.

    Directory of Open Access Journals (Sweden)

    Cheng-Ting Shih

    Full Text Available Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM images. The modified N-isopropyl-acrylamide (NIPAM gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM. The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2 value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection.

  16. A randomized phase II dose-response exercise trial among colon cancer survivors: Purpose, study design, methods, and recruitment results.

    Science.gov (United States)

    Brown, Justin C; Troxel, Andrea B; Ky, Bonnie; Damjanov, Nevena; Zemel, Babette S; Rickels, Michael R; Rhim, Andrew D; Rustgi, Anil K; Courneya, Kerry S; Schmitz, Kathryn H

    2016-03-01

    Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the courage trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. The primary objective of the courage trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min·week(-1)) and high-dose (300 min·week(-1)) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (Pclinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Marginal Iodide Deficiency and Thyroid Function: Dose-response analysis for quantitative pharmacokinetic modeling

    Science.gov (United States)

    Severe iodine deficiency is known to cause adverse health outcomes and remains a benchmark for understanding the effects of hypothyroidism. However, the implications of marginal iodine deficiency on function of the thyroid axis remain less well known. The current study examined t...

  18. Human dose response models for Q fever: estimation of Coxiella burnetii exposure and disease burden

    NARCIS (Netherlands)

    Brooke, RJ

    2016-01-01

    The largest Q fever outbreak in the world occurred in the Netherlands between 2007 and 2009 with 4,500 reported acute symptomatic Q fever cases. Interventions were required to stop the release of aerosolized Coxiella burnetii from infected goat farms and the outbreak developed into a major public

  19. Whole grain and refined grain consumption and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies.

    Science.gov (United States)

    Aune, Dagfinn; Norat, Teresa; Romundstad, Pål; Vatten, Lars J

    2013-11-01

    Several studies have suggested a protective effect of intake of whole grains, but not refined grains on type 2 diabetes risk, but the dose-response relationship between different types of grains and type 2 diabetes has not been established. We conducted a systematic review and meta-analysis of prospective studies of grain intake and type 2 diabetes. We searched the PubMed database for studies of grain intake and risk of type 2 diabetes, up to June 5th, 2013. Summary relative risks were calculated using a random effects model. Sixteen cohort studies were included in the analyses. The summary relative risk per 3 servings per day was 0.68 (95% CI 0.58-0.81, I(2) = 82%, n = 10) for whole grains and 0.95 (95% CI 0.88-1.04, I(2) = 53%, n = 6) for refined grains. A nonlinear association was observed for whole grains, p nonlinearity cereals, wheat bran and brown rice, but these results were based on few studies, while white rice was associated with increased risk. Our meta-analysis suggests that a high whole grain intake, but not refined grains, is associated with reduced type 2 diabetes risk. However, a positive association with intake of white rice and inverse associations between several specific types of whole grains and type 2 diabetes warrant further investigations. Our results support public health recommendations to replace refined grains with whole grains and suggest that at least two servings of whole grains per day should be consumed to reduce type 2 diabetes risk.

  20. Model-based Software Engineering

    DEFF Research Database (Denmark)

    Kindler, Ekkart

    2010-01-01

    The vision of model-based software engineering is to make models the main focus of software development and to automatically generate software from these models. Part of that idea works already today. But, there are still difficulties when it comes to behaviour. Actually, there is no lack in models...

  1. Principles of models based engineering

    Energy Technology Data Exchange (ETDEWEB)

    Dolin, R.M.; Hefele, J.

    1996-11-01

    This report describes a Models Based Engineering (MBE) philosophy and implementation strategy that has been developed at Los Alamos National Laboratory`s Center for Advanced Engineering Technology. A major theme in this discussion is that models based engineering is an information management technology enabling the development of information driven engineering. Unlike other information management technologies, models based engineering encompasses the breadth of engineering information, from design intent through product definition to consumer application.

  2. Dose-response for X-ray induction of myeloid leukaemia in male CBA/H mice

    Energy Technology Data Exchange (ETDEWEB)

    Mole, R H; Papworth, D G; Corp, M J [Medical Research Council, Harwell (UK). Radiobiological Research Unit

    1983-02-01

    The form of the dose-response for induction of malignant diseases in vivo by ionizing radiation is not yet established in spite of its scientific interest and its practical importance. Considerably extended observations have confirmed that the dose-response for acute myeloid leukaemia induced in male CBA/H mice by X-ray exposure is highly curvilinear. The dose-response was well fitted by the expression aD/sup 2/esup(-..gamma..D) (D = dose) in agreement with induction at the cellular level in proportion to D/sup 2/ over the whole dose range 0.25-6.0 Gy. The factor esup(-..gamma..D) accounts for the inescapable concomitant inactivating action of the inducing irradiation. The quantitative aspects of induction of myeloid leukaemia by ionizing radiation are unlike the induction of genetic mutation or cell inactivation and suggest that interaction of two adjoining cells is an essential element in radiation leukaemogenesis.

  3. Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

    Science.gov (United States)

    Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

    2015-01-01

    We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

  4. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

    International Nuclear Information System (INIS)

    Calabrese, Edward J.; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M. George; Chiueh, Chuang C.; Clarkson, Thomas W.; Cook, Ralph R.; Diamond, David M.; Doolittle, David J.; Dorato, Michael A.; Duke, Stephen O.; Feinendegen, Ludwig; Gardner, Donald E.; Hart, Ronald W.; Hastings, Kenneth L.; Hayes, A. Wallace; Hoffmann, George R.; Ives, John A.; Jaworowski, Zbigniew; Johnson, Thomas E.; Jonas, Wayne B.; Kaminski, Norbert E.; Keller, John G.; Klaunig, James E.; Knudsen, Thomas B.; Kozumbo, Walter J.; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I.; Masoro, Edward J.; McClellan, Roger O.; Mehendale, Harihara M.; Mothersill, Carmel; Newlin, David B.; Nigg, Herbert N.; Oehme, Frederick W.; Phalen, Robert F.; Philbert, Martin A.; Rattan, Suresh I.S.; Riviere, Jim E.; Rodricks, Joseph; Sapolsky, Robert M.; Scott, Bobby R.; Seymour, Colin; Sinclair, David A.; Smith-Sonneborn, Joan; Snow, Elizabeth T.; Spear, Linda; Stevenson, Donald E.; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M.; Mattson, Mark P.

    2007-01-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines

  5. Maximum likelihood estimation of dose-response parameters for therapeutic operating characteristic (TOC) analysis of carcinoma of the nasopharynx

    International Nuclear Information System (INIS)

    Metz, C.E.; Tokars, R.P.; Kronman, H.B.; Griem, M.L.

    1982-01-01

    A Therapeutic Operating Characteristic (TOC) curve for radiation therapy plots, for all possible treatment doses, the probability of tumor ablation as a function of the probability of radiation-induced complication. Application of this analysis to actual therapeutic situation requires that dose-response curves for ablation and for complication be estimated from clinical data. We describe an approach in which ''maximum likelihood estimates'' of these dose-response curves are made, and we apply this approach to data collected on responses to radiotherapy for carcinoma of the nasopharynx. TOC curves constructed from the estimated dose-response curves are subject to moderately large uncertainties because of the limitations of available data.These TOC curves suggest, however, that treatment doses greater than 1800 rem may substantially increase the probability of tumor ablation with little increase in the risk of radiation-induced cervical myelopathy, especially for T1 and T2 tumors

  6. Risk based modelling

    International Nuclear Information System (INIS)

    Chapman, O.J.V.; Baker, A.E.

    1993-01-01

    Risk based analysis is a tool becoming available to both engineers and managers to aid decision making concerning plant matters such as In-Service Inspection (ISI). In order to develop a risk based method, some form of Structural Reliability Risk Assessment (SRRA) needs to be performed to provide a probability of failure ranking for all sites around the plant. A Probabilistic Risk Assessment (PRA) can then be carried out to combine these possible events with the capability of plant safety systems and procedures, to establish the consequences of failure for the sites. In this way the probability of failures are converted into a risk based ranking which can be used to assist the process of deciding which sites should be included in an ISI programme. This paper reviews the technique and typical results of a risk based ranking assessment carried out for nuclear power plant pipework. (author)

  7. The crooked shall be made straight: dose response relationships for carcinogenesis

    International Nuclear Information System (INIS)

    Hall, E.J.

    2003-01-01

    Estimates of radiation-induced malignancies come principally from the A-bomb survivors and from medically exposed individuals, including second cancers in radiotherapy patients. The A-bomb survivors show an excess incidence of carcinomas which is linear with dose from about 10 cGy to 2.5 Gy. Above and below this dose range, there is considerable uncertainty concerning the shape of the dose response relationship. These two dose ranges will be discussed separately. Low dose extrapolations ICRP and NCRP suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. This is labeled a 'prudent and conservative' assumption but is a subject of considerable controversy. Two factors, the existence of radiosensitive subgroups in the human population (such as AT heterozygotes), and the demonstration of a Bystander effect both exaggerate the consequences of small doses of radiation and imply that a linear extrapolation from high doses would underestimate low dose risks. High dose extrapolations In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. The question is, what is the dose response for carcinogenesis in the range 10 to 70 Gy? At one extreme, it might be expected that the risk of inducing cancer would fall off rapidly at higher does due to cell killing. The other extreme possibility is that the risk of solid tumors levels off by about 10 Gy, but does not decline thereafter. For a few cancers, data are available from 2 Gy in A-bomb survivors to 70 Gy in radiotherapy patients, and it appears that the relative risk does not vary with dose. This implies that the volume of tissue irradiated is more important than the maximum dose. This result has far reaching implications for new technologies such as IMRT, which

  8. Model-based consensus

    NARCIS (Netherlands)

    Boumans, M.; Martini, C.; Boumans, M.

    2014-01-01

    The aim of the rational-consensus method is to produce "rational consensus", that is, "mathematical aggregation", by weighing the performance of each expert on the basis of his or her knowledge and ability to judge relevant uncertainties. The measurement of the performance of the experts is based on

  9. Model-based consensus

    NARCIS (Netherlands)

    Boumans, Marcel

    2014-01-01

    The aim of the rational-consensus method is to produce “rational consensus”, that is, “mathematical aggregation”, by weighing the performance of each expert on the basis of his or her knowledge and ability to judge relevant uncertainties. The measurement of the performance of the experts is based on

  10. Dose-response relationship of neutrons and γ rays to leukemia incidence among atomic bomb survivors in Hiroshima and Nagasaki by type of leukemia, 1950--1971

    International Nuclear Information System (INIS)

    Ishimaru, T.; Otake, M.; Ichimaru, M.

    1979-01-01

    The incidence of leukemia during 1950 to 1971 in a fixed mortality sample of atomic bomb survivors in Hiroshima and Nagasaki was analyzed as a function of neutron and γ kerma and marrow doses. Two dose-response models were tested for acute leukemia, chronic granulocytic leukemia, and all types of leukemia, respectively. Each model postulates that the leukemia incidence depends upon the sum of separate risks imposed by γ and neutron doses. In Model I the risk from both types of radiation is assumed to be directly proportional to the respective doses, while Model II assumes that whereas the risk from neutrons is directly proportional to the dose, the risk from γ rays is proportional to dose-squared. The analysis demonstrated that the dose-response of the two types of leukemia differed by type of radiation. The data suggested that the response of acute leukemia was best explained by Model II, while the response of chronic granulocytic leukemia depended almost linearly upon neutron dose alone, because the regression coefficients associated with γ radiation for both Models I and II were not significant. The relative biological effectiveness (RBE) of neutrons in relation to γ rays for incidence of acute leukemia was estimated to be approximately 30/(Dn)/sup 1/2/ [95% confidence limits; 17/(Dn)/sup 1/2/ approx. 54/(Dn)/sup 1/2/] for kerma and 32/(Dn)/sup 1/2/ [95% confidence limits; 18/(Dn)/sup 1/2/ approx. 58/(Dn)/sup 1/2/] for marrow dose (Dn = neutron dose). If acute and chronic granulocytic leukemias are considered together as all types of leukemia, Model II appears to fit the data slightly better than Model I, but neither model is statistically rejected by the data

  11. Activity-based DEVS modeling

    DEFF Research Database (Denmark)

    Alshareef, Abdurrahman; Sarjoughian, Hessam S.; Zarrin, Bahram

    2018-01-01

    architecture and the UML concepts. In this paper, we further this work by grounding Activity-based DEVS modeling and developing a fully-fledged modeling engine to demonstrate applicability. We also detail the relevant aspects of the created metamodel in terms of modeling and simulation. A significant number......Use of model-driven approaches has been increasing to significantly benefit the process of building complex systems. Recently, an approach for specifying model behavior using UML activities has been devised to support the creation of DEVS models in a disciplined manner based on the model driven...... of the artifacts of the UML 2.5 activities and actions, from the vantage point of DEVS behavioral modeling, is covered in details. Their semantics are discussed to the extent of time-accurate requirements for simulation. We characterize them in correspondence with the specification of the atomic model behavior. We...

  12. Dose Response for Monokaryon mycelium of Pleurotus pulmonarius After Acute Gamma Radiation

    International Nuclear Information System (INIS)

    Wan Safina Wan Abdul Razak; Azhar Mohamad; Nie, H.J.

    2016-01-01

    Pleurotus pulmonarius is locally known as Grey oyster. The species is popular and widely cultivated throughout the world mostly in Asia Europe as their simple and low cost production technology and higher biological efficiency. Mutation induction is an alternative ways for improving available commercial strain for better quality traits. Dose response is important in evaluating effects of mutagenesis via acute gamma radiation. Monokaryon mycelium of Pleurotus pulmonarius was exposed to acute gamma radiation ranged from 0 Gy, 0.1 kGy, 0.2 kGy, 0.3 kGy, 0.4 kGy, 0.5 kGy, 0.6 kGy, 0.7 kGy, 0.8 kGy, 0.9 kGy, 1.0 kGy, 1.5 Gy, 2.0 kGy, 3.0 kGy and 4.0 kGy at dose rate 0.013 kGy/ min. growth performance was measured at 2 days interval to get the LD_5_0. Increasing of the irradiation dose found to decrease the growth performance of the monokaryon mycelium. LD_5_0 was revealed at 1.56 kGy for mono karyon mycelium. Discoveries of the works are important for the improvement of Pleurotus species via acute gamma radiation and benefiting to growers and mushroom industries. (author)

  13. Digitoxin medication and cancer; case control and internal dose-response studies

    International Nuclear Information System (INIS)

    Haux, Johan; Klepp, Olbjørn; Spigset, Olav; Tretli, Steinar

    2001-01-01

    Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents

  14. A dose-response analysis for classical Kaposi's sarcoma management by radiotherapy

    International Nuclear Information System (INIS)

    Oysul, K.; Beyzadeoglu, M.; Surenkok, S.; Ozyigit, G.; Dirican, B.

    2008-01-01

    Objective was to evaluate the dose-response relationship in classical Kaposi's sarcoma CKS patients treated with external beam radiotherapy. Between 1993 and 2004, patients with CKS treated at the Department of Radiation Oncology, Gulhane Military Medical School, Ankara, Turkey were evaluated in this retrospective study. The median age at initial presentation was 60 years. First we analyzed the overall response rates for normalized total dose2Gy NTD2Gy of 20Gy. Secondly we searched for whether better response rates could be obtained with the NTD2Gy of >/=20Gy compared to the NTD2Gy of /20Gy and 64% and 24%for NDT2Gyof 20< Gy and these were statistically different p=0.001. Late side effects of radiation therapy were acceptable in all but 4 patients with fibrosis and edema. This retrospective analysis showed that radiotherapy schedules with an NDT2Gy of 20 Gy and above by using local irradiation fields are effective in terms of complete response rates in the management of CKS compared to NDT2Gy of < 20 Gy. (author)

  15. Dose-response analysis of parotid gland function: what is the best measure of xerostomia?

    Science.gov (United States)

    Miah, Aisha B; Gulliford, Sarah L; Clark, Catharine H; Bhide, Shreerang A; Zaidi, Shane H; Newbold, Kate L; Harrington, Kevin J; Nutting, Christopher M

    2013-03-01

    To describe the dose-response relationships for the different measures of salivary gland recovery following radical radiotherapy for locally advanced head and neck squamous cell cancers (LA-HNSCC). Dosimetric analysis of data from the PARSPORT trial, a Phase III study of conventional RT (RT) and intensity modulated radiotherapy (IMRT) for LA-HNSCC was undertaken to determine the relationship between parotid gland mean dose and toxicity endpoints: high-grade subjective and objective xerostomia and xerostomia-related quality of life scores. LKB-NTCP parameters (TD50, m and n) were generated and tolerance doses (D50) reported using non-linear logistic regression analysis. Data were available on 63 patients from the PARSPORT trial. Parotid saliva flow rate provided the strongest association between mean dose and recovery, D50=23.4 Gy (20.6-26.2) and k=3.2 (1.9-4.5), R(2)=0.85. Corresponding LKB parameters were TD50=26.3 Gy (95% CI: 24.0-30.1), m=0.25 (0.18-1.0 and n=1). LENTSOMA subjective xerostomia also demonstrated a strong association D50=33.3 Gy (26.7-39.8), k=2.8 (91.4-4.4), R(2)=0.77). We recommend using the LENT SOMA subjective xerostomia score to predict recovery of salivation due to its strong association with dosimetry and ease of recording. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. Dose-response relationships for female radium dial workers: A new look

    International Nuclear Information System (INIS)

    Rowland, R.E.

    1994-01-01

    The values of initial systemic intake and of skeletal dose for all of the U.S. radium cases have recently been revised. This revision was required following the demonstrations by Rundo and by Keane that humans who were exposed to radium as adults lost radium at a rate that depended on the quantity of radium originally deposited within their bodies. These new values have been used to define new dose-response relationships for both the bone sarcomas and the carcinomas arising in the paranasal sinuses and mastoid air cells induced by internally deposited radium. The population examined was employed in the U.S. dial painting industry prior to 1950 and consisted of 1530 female dial workers for whom radium body burden measurements were available. By the end of 1990, 46 cases of bone sarcomas and 19 cases of head carcinomas had been diagnosed in this cohort. The head carcinoma incidence can be adequately fitted by a simple linear function, as was found in previous analyses. The bone sarcoma cases were previously fitted by a dose-squared-exponential function. With the revised values of systemic intake, the sarcoma results could not be satisfactorily fitted with this expression. When the exponent on D was increased to larger values, excellent fits were obtained

  17. Dose-Response of High-Intensity Training (HIT) on Atheroprotective miRNA-126 Levels

    Science.gov (United States)

    Schmitz, Boris; Schelleckes, Katrin; Nedele, Johanna; Thorwesten, Lothar; Klose, Andreas; Lenders, Malte; Krüger, Michael; Brand, Eva; Brand, Stefan-Martin

    2017-01-01

    Aim: MicroRNA-126 (miR-126) exerts beneficial effects on vascular integrity, angiogenesis, and atherosclerotic plaque stability. The purpose of this investigation was to analyze the dose-response relationship of high-intensity interval training (HIIT) on miR-126-3p and -5p levels. Methods: Sixty-one moderately trained individuals (females = 31 [50.8%]; 22.0 ± 1.84 years) were consecutively recruited and allocated into three matched groups using exercise capacity. During a 4-week intervention a HIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out), a progressive HIIT (proHIIT) group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out) with one extra session every week (up to 7 × 30 s) and a low-intensity training (LIT) control group performed three exercise sessions/week for 25 min HIIT groups (after 4 min of high-intensity running). After the intervention, the LIT group presented an increase in miR-126-3p, while in the HIIT group, miR-126-3p levels were still reduced (all p HIIT (−1.05 ± 2.6 units). Conclusions: LIT and proHIIT may be performed to increase individual miR-126 levels. HIIT without progression was less effective in increasing miR-126. PMID:28611681

  18. High-LET dose-response characteristics by track structure theory of heavy charged particles

    International Nuclear Information System (INIS)

    Hansen, J.W.; Olsen, K.J.

    1981-09-01

    The track structure theory developed by Katz and co-workers ascribes the effect of high-LET radiation to the highly inhomogeneous dose distribution due to low energy Δ-rays ejected from the particle track. The theory predicts the effectiveness of high-LET radiation by using the ion parameters zsub(eff') effective charge of the ion, and β = v/c, the relative ion velocity, together with the characteristic dose D 37 derived from low-LET dose-response characteristic of the detector and the approximate size asub(0) of the sensitive element of the detector. 60 Co gamma-irradiation is used as a reference low-LET radiation, while high-LET radiation ranging from 16 MeV protons to 4 MeV/amu 16 0-ions covering an initial LET range of 30-5500 MeVcm 2 /g is obtained from a tandem Van de Graaff accelerator. A thin film (5mg/cm 2 ) radiochromic dye cyanide plastic dosemeter was used as detector with the characteristic dose of 16.8 Mrad and a sensitive element size of 10 -7 cm. Theoretical and experimental effectiveness, RBE, agreed within 10 to 25% depending on LET. (author)

  19. Mutiple simultaneous event model for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Baum, J.W.

    1979-01-01

    Theoretical Radiobiology and Risk Estimates includes reports on: Multiple Simultaneous Event Model for Radiation Carcinogenesis; Cancer Risk Estimates and Neutron RBE Based on Human Exposures; A Rationale for Nonlinear Dose Response Functions of Power Greater or Less Than One; and Rationale for One Double Event in Model for Radiation Carcinogenesis

  20. Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

    Science.gov (United States)

    Godos, Justyna; Micek, Agnieszka; Marranzano, Marina; Salomone, Federico; Rio, Daniele Del; Ray, Sumantra

    2017-08-28

    A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.

  1. Low back pain in drivers exposed to whole body vibration: analysis of a dose-response pattern

    NARCIS (Netherlands)

    Tiemessen, I. J. H.; Hulshof, C. T. J.; Frings-Dresen, M. H. W.

    2008-01-01

    Analysis of a dose-response pattern between exposure to whole body vibration (WBV) and low back pain (LBP) in a group of drivers. This study assessed individual factors, work-related risk factors, various LBP outcome measures and LBP disability in a group of drivers (n = 571) approached at baseline

  2. Continuous Dose-Response Response Relationship of the LDL-Cholesterol-Lowering Effect of Phytosterol Intake 1,2

    NARCIS (Netherlands)

    Demonty, I.; Ras, R.T.; Knaap, van der H.C.M.; Duchateau, G.S.M.J.E.; Meijer, L.; Zock, P.L.; Geleijnse, J.M.; Trautwein, E.A.

    2009-01-01

    Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)¿lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C¿lowering efficacy of different

  3. Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

    NARCIS (Netherlands)

    Grabowski, Gregory A.; Kacena, Katherine; Cole, J. Alexander; Hollak, Carla E. M.; Zhang, Lin; Yee, John; Mistry, Pramod K.; Zimran, Ari; Charrow, Joel; vom Dahl, Stephan

    2009-01-01

    Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme

  4. Dose-response and concentration-response relation of rocuronium infusion during propofol nitrous oxide and isoflurane nitrous oxide anaesthesia

    NARCIS (Netherlands)

    Kansanaho, M; Olkkola, KT; Wierda, JMKH

    The dose-response and concentration-response relation of rocuronium infusion was studied in 20 adult surgical patients during proporfol-nitrous oxide and isoflurane (1 MAC) -nitrous oxide anaesthesia. Neuromuscular block was kept constant, initially at 90% and then at 50% with a closed-loop feedback

  5. Dairy consumption is inversely associated with type 2 diabetes: dose-response meta-analysis of prospective cohort studies

    NARCIS (Netherlands)

    Gijsbers, L.; Geleijnse, J.M.; Soedamah-Muthu, S.S.

    2011-01-01

    Observational studies suggest an inverse association between dairy intake and incident type 2 diabetes, but the quantity of dairy is not known. Previous meta-analyses did not take into account the type of dairy product. Therefore, we examined dose-response associations between the intake of total

  6. Low dose effects and non-monotonic dose responses for endocrine active chemicals: Science to practice workshop: Workshop summary

    DEFF Research Database (Denmark)

    Beausoleil, Claire; Ormsby, Jean-Nicolas; Gies, Andreas

    2013-01-01

    A workshop was held in Berlin September 12–14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses (“low dose hypothesis”) for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of lectu...

  7. European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'

    DEFF Research Database (Denmark)

    Calderón, M A; Larenas, D; Kleine-Tebbe, J

    2011-01-01

    For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen prod...

  8. Dose-response of seeds of the parasitic weeds Striga and Orobanche toward the synthetic germination stimulants GR24.

    NARCIS (Netherlands)

    Wigchert, S.C.M.; Kuiper, E.; Boelhouwer, G.J.; Nefkens, G.H.L.; Verkley, J.A.C.; Zwanenburg, B.

    1999-01-01

    Striga and Orobanche seeds germinate in response to a host-derived germination stimulant. Dose-response curves of the synthetic strigolactone analogues GR 24 and Nijmegen 1 were determined, and their activities were compared to that of the naturally occurring stimulant sorgolactone. Typical

  9. Pancreatic beta cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

    DEFF Research Database (Denmark)

    Malin, Steven K; Solomon, Thomas; Blaszczak, Alecia

    2013-01-01

    While some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older, obese adults with prediabetes underwent a progressive 12-week supervised exercise...

  10. Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-Fixed Paraffin-Embedded (FFPE) Samples.

    Science.gov (United States)

    Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...

  11. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    International Nuclear Information System (INIS)

    Mossman, K.L.

    1983-01-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated with 60 Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response

  12. Quantitative radiation dose-response relationships for normal tissues in man - I. Gustatory tissues response during photon and neutron radiotherapy

    International Nuclear Information System (INIS)

    Mossman, K.L.

    1982-01-01

    Quantitative radiation dose-response curves for normal gustatory tissue in man were studied. Taste function, expressed as taste loss, was evaluated in 84 patients who were given either photon or neutron radiotherapy for tumors in the head and neck region. Patients were treated to average tumor doses of 6600 cGy (photon) or 2200 cGy intervals for photon patients and 320-cGy intervals for neutron patients during radiotherapy. The dose-response curves for photons and neutrons were analyzed by fitting a four-parameter logistic equation to the data. Photon and neutron curves differed principally in their relative position along the dose axis. Comparison of the dose-response curves were made by determination of RBE. At 320 cGy, the lowest neutron dose at which taste measurements were made, RBE = 5.7. If this RBE is correct, then the therapeutic gain factor may be equal to or less than 1, indicating no biological advantage in using neutrons over photons for this normal tissue. These studies suggest measurements of taste function and evaluation of dose-response relationships may also be useful in quantitatively evaluating the efficacy of chemical modifiers of radiation response such as hypoxic cell radiosensitizers and radioprotectors

  13. Event-Based Conceptual Modeling

    DEFF Research Database (Denmark)

    Bækgaard, Lars

    The paper demonstrates that a wide variety of event-based modeling approaches are based on special cases of the same general event concept, and that the general event concept can be used to unify the otherwise unrelated fields of information modeling and process modeling. A set of event......-based modeling approaches are analyzed and the results are used to formulate a general event concept that can be used for unifying the seemingly unrelated event concepts. Events are characterized as short-duration processes that have participants, consequences, and properties, and that may be modeled in terms...... of information structures. The general event concept can be used to guide systems analysis and design and to improve modeling approaches....

  14. Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy—A Multi-Institutional Observational Study

    Energy Technology Data Exchange (ETDEWEB)

    Pisansky, Thomas M., E-mail: pisansky.thomas@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Agrawal, Shree [Case Western Reserve University School of Medicine, Cleveland, Ohio (United States); Hamstra, Daniel A. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Koontz, Bridget F. [Department of Radiation Oncology, Duke Cancer Institute, Durham, North Carolina (United States); Liauw, Stanley L. [Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois (United States); Efstathiou, Jason A. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Michalski, Jeff M. [Department of Radiation Oncology, Washington University, St. Louis, Missouri (United States); Feng, Felix Y. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Abramowitz, Matthew C.; Pollack, Alan [Department of Radiation Oncology, University of Miami, Miami, Florida (United States); Anscher, Mitchell S. [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia (United States); Moghanaki, Drew [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia (United States); Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia (United States); Den, Robert B. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Stephans, Kevin L. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Zietman, Anthony L. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Lee, W. Robert [Department of Radiation Oncology, Duke Cancer Institute, Durham, North Carolina (United States); Kattan, Michael W. [Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio (United States); and others

    2016-12-01

    Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

  15. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

    International Nuclear Information System (INIS)

    Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E.; De Flora, Silvio

    2011-01-01

    Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m 3 of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were measured by 32 P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

  16. A dose-response relationship between long working hours and unmet need for access to hospital facilities.

    Science.gov (United States)

    Soek, Hongdeok; Won, Jong-Uk; Lee, Tae Il; Kim, Yeong-Kwang; Lee, Wanhyung; Lee, June-Hee; Roh, Jaehoon; Yoon, Jin-Ha

    2016-03-01

    Lack of access to hospital facilities, indicating unmet healthcare need, plays an important role in health inequity in the workplace. We aimed to investigate the association between long working hours and unmet healthcare need. We used data from the Korea National Health and Nutrition Examination Surveys collected during 2007-2012, which included 8369 participants (4765 males, 3604 females) aged 20-54 years, who were paid workers. We used a logistic regression model with gender stratification to investigate the association between working hours and unmet healthcare need. Of the 8369 participants, 855 males (17.94%) and 981 females (27.22%) experienced unmet healthcare need. After adjusting for covariates, and compared to 30-39 working hours per week, the odds ratios (OR) of unmet healthcare need were 1.07 [(95% confidence interval (95% CI) 0.76-1.51], 1.46 (95% CI 1.03-2.07), and 1.57 (95% CI 1.11-2.23) in males, and 1.13 (95% CI 0.92-1.40), 1.30 (95% CI 0.99-1.69), and 1.60 (95% CI 1.21-2.10) in females, for 40-49, 50-59, and ≥ 60 work hours per week, respectively. There was a dose-response relationship between working hours per week and unmet healthcare need in both genders. Those who work long hours are more likely to have unmet healthcare needs, the cause of which seems to be lack of time.

  17. Biological effects in lymphocytes irradiated with 99mTc: determination of the curve dose-response

    International Nuclear Information System (INIS)

    Oliveira, Romero Marcilio Barros Matias de

    2002-08-01

    Biological dosimetry estimates the absorbed dose taking into account changes in biological parameters. The most used biological indicator of an exposition to ionizing radiation is the quantification of chromosomal aberrations of lymphocytes from irradiated individuals. The curves of dose versus induced biological effects, obtained through bionalyses, are used in used in retrospective evaluations of the dose, mainly in the case of accidents. In this research, a simple model for electrons and photons transports was idealized to simulate the irradiation of lymphocytes with 99m Tc, representing a system used for irradiation of blood cells. The objective of the work was to establish a curve of dose versus frequencies of chromosomal aberrations in lymphocytes of human blood. For the irradiation of blood samples micro spheres of human serum of albumin (HSAM) market with 99m Tc were used, allowing the irradiation of blood with different administered activities of 99m Tc, making possible the study the cytogenetical effects as a function of such activities. The conditions of irradiation in vivo using HSAM spheres marked with 99m Tc were simulated with MCNP 4C (Monte Carlo N-Particle) code to obtain the dose-response curve. Soft tissue composition was employed to simulate blood tissue and the analyses of the curve of dose versus biological effect showed a linear quadratic response of the unstable chromosomal aberrations. As a result, the response of dose versus chromosomal aberrations of blood irradiation with 99m Tc was best fitted by the curve Y=(8,99 ±2,06) x 1- -4 + (1,24 ±0,62) x 10 -2 D + (5,67 ± 0,64) x 10 -2 D 2 . (author)

  18. Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy—A Multi-Institutional Observational Study

    International Nuclear Information System (INIS)

    Pisansky, Thomas M.; Agrawal, Shree; Hamstra, Daniel A.; Koontz, Bridget F.; Liauw, Stanley L.; Efstathiou, Jason A.; Michalski, Jeff M.; Feng, Felix Y.; Abramowitz, Matthew C.; Pollack, Alan; Anscher, Mitchell S.; Moghanaki, Drew; Den, Robert B.; Stephans, Kevin L.; Zietman, Anthony L.; Lee, W. Robert; Kattan, Michael W.

    2016-01-01

    Purpose: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. Methods and Materials: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. Results: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. Conclusions: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

  19. HMM-based Trust Model

    DEFF Research Database (Denmark)

    ElSalamouny, Ehab; Nielsen, Mogens; Sassone, Vladimiro

    2010-01-01

    Probabilistic trust has been adopted as an approach to taking security sensitive decisions in modern global computing environments. Existing probabilistic trust frameworks either assume fixed behaviour for the principals or incorporate the notion of ‘decay' as an ad hoc approach to cope...... with their dynamic behaviour. Using Hidden Markov Models (HMMs) for both modelling and approximating the behaviours of principals, we introduce the HMM-based trust model as a new approach to evaluating trust in systems exhibiting dynamic behaviour. This model avoids the fixed behaviour assumption which is considered...... the major limitation of existing Beta trust model. We show the consistency of the HMM-based trust model and contrast it against the well known Beta trust model with the decay principle in terms of the estimation precision....

  20. Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

    Science.gov (United States)

    Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

    2015-02-01

    Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population

  1. Dose-response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women.

    Science.gov (United States)

    Yang, Yang; Gao, Jing; Li, Hong-Lan; Zheng, Wei; Yang, Gong; Zhang, Wei; Ma, Xiao; Tan, Yu-Ting; Rothman, Nathaniel; Gao, Yu-Tang; Chow, Wong-Ho; Shu, Xiao-Ou; Xiang, Yong-Bing

    2016-07-15

    We aimed at evaluating the risk of liver cancer in different levels of HBsAg among Chinese men and women. We carried out a nested case-control study including 363 cases and 3,511 controls in two population-based cohorts in Shanghai. Plasma samples collected at enrollment were quantified for HBsAg levels using the Architect QT assay. Conditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for liver cancer, with adjustment for potential confounders. HBsAg was detected in 6.29% of control subjects overall (7.02% in men and 4.98% in women). HBsAg levels were positively associated with liver cancer risk in a dose-response manner (ptrend  women. In men, the adjusted ORs increased from 7.27 (95% CI: 3.49-15.15) at the lowest detectable level of HBsAg (5-9 IU/ml) to 7.16 (95% CI: 3.21-15.96), 34.30 (95% CI: 16.94-69.44), and 47.33 (95% CI: 23.50-95.34) at the highest level of HBsAg (≥1,000 IU/ml) compared to those negative for HBsAg. The corresponding ORs were much lower for women, from 1.37 (95% CI: 0.25-7.47), 3.81 (95% CI: 1.09-13.28), 7.36 (95% CI: 2.41-22.46) and 16.86 (95% CI: 7.24-39.27), respectively. HBsAg quantification has potential to distinguish individuals at different risks of liver cancer. Men with the lowest detectable level of HBsAg should still pay attention to their liver cancer risks, but those with a higher level may be given a higher priority in future liver cancer surveillance program. © 2016 UICC.

  2. Somatic cell genetics of uranium miners and plutonium workers. A biological dose-response indicator

    International Nuclear Information System (INIS)

    Brandom, W.F.; Bloom, A.D.; Bistline, R.W.; Saccomanno, G.

    1978-01-01

    Two populations of underground uranium miners and plutonium workers work in the state of Colorado, United States of America. We have explored the prevalence of structural chromosome aberrations in peripheral blood lymphocytes as a possible biological indicator of absorbed radiation late-effects in these populations. The uranium miners are divided into four exposure groups expressed in Working Level Months (WLM), the plutonium workers into six groups with estimated 239 Pu burdens expressed in nCi. Comparison of chromosome aberration frequency data between controls, miners, and plutonium workers demonstrate: (1) a cytogenetic response to occupational ionizing radiation at low estimated doses; and (2) an increasing monotonic dose-response in the prevalence of complex (all exchange) or total aberrations in all exposure groups in these populations. We also compared trends in the prevalence of aberrations per exposure unit (WLM and nCi) in each exposure subgroup for each population. In the uranium miners, the effects per WLM seem to decrease monotonically with increasing dose, whereas in the Pu workers the change per nCi appears abrupt, with all exposure groups over 1.3 nCi (minimum detectable level) having essentially similar rates. The calculations of aberrations per respective current maximum permissible dose (120 WLM and 40 nCi) for the two populations yield 4.8 X 10 -2 /100 cells for uranium miners and 90.6 X 10 -2 /100 cells for Pu workers. Factors which may have influenced this apparent 20-fold increase in the effectiveness of plutonium in the production of complex aberrations (9-fold increase in total aberrations) are discussed. (author)

  3. Digitoxin medication and cancer; case control and internal dose-response studies

    Directory of Open Access Journals (Sweden)

    Spigset Olav

    2001-08-01

    Full Text Available Abstract Background Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Methods Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. Results The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.

  4. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

    Science.gov (United States)

    Salerno, Francesco; Navickis, Roberta J; Wilkes, Mahlon M

    2015-11-25

    Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of

  5. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study.

    Science.gov (United States)

    Ilfeld, Brian M; Malhotra, Nisha; Furnish, Timothy J; Donohue, Michael C; Madison, Sarah J

    2013-11-01

    Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. There were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04-0.14, P = 0.002) and tolerance to cutaneous current (-0.03 mA/mg, SE = 0.01, 95% CI, -0.04 to -0.02, P 40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%-100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%-100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, -0.27 to 0.39, P = 0.707). The results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.

  6. Dose-response relationship of octylphenol and radiation evaluated by tradescantia-micronucleus assay

    International Nuclear Information System (INIS)

    Kim, J. K.; Cheon, K. J.; Lee, B. H.; Shin, H. S.; Lee, J. H.

    2002-01-01

    Many kinds of synthetic chemicals have been being used for various purposes. Some of them are called 'Endocrine Disruptor's because they can disturb the endocrine system of organisms. Presently no technique is established for the quantitative assessment of biological risk of the environmental hormones. The pollen mother cells (PMC) of Tradescantia are very sensitive to chemical toxicants or ionizing radiation, and thus can be used as a biological end-point assessing their effect. Micronucleus frequencies in PMC showed a good dose- and concentration-response relationship for radiation, bisphenol A and octylphenol. A parallel series of experiment using five increasing doses of gamma-ray at 10, 20, 30, 40 and 50 cGy was conducted. The MCN frequencies of 12.0, 25.2, 41.7, 76 and 83 MCN/100 tetrads were observed from each of the increasing gamma-ray dosage groups, respectively. Lenear regression analysis of the gamma-ray data MCN frequencies yielded a correlation coefficient of 0.95. the MCN frequencies in pollen mother cells treated with bisphenol a and octylphenol showed dose-response relationship in a concentration of 0, 1, 2, 4 μM and 0, 4, 10, 20 μM. the MCN frequency for the bisphenol a and octylphenol group yields 2.33, 8.06, 12.7 and 19.6 MCN/100 tetrads for the bisphenol a and 2.33, 2.33, 11.47, 17.6 MCN/100 tetrads for the octylphenol. The MCN frequency of the control was 2.33 MCN/100 tetrads. It is known from the result that Trad-MCN assay can be an excellent tool for detection of biological risk due to environmental toxicants or synthetic chemicals

  7. Dose response and efficacy of a live, attenuated human rotavirus vaccine in Mexican infants.

    Science.gov (United States)

    Ruiz-Palacios, Guillermo M; Guerrero, M Lourdes; Bautista-Márquez, Aurora; Ortega-Gallegos, Hilda; Tuz-Dzib, Fernando; Reyes-González, Leticia; Rosales-Pedraza, Gustavo; Martínez-López, Julia; Castañón-Acosta, Erika; Cervantes, Yolanda; Costa-Clemens, SueAnn; DeVos, Beatrice

    2007-08-01

    Immunization against rotavirus has been proposed as the most cost-effective intervention to reduce the disease burden associated with this infection worldwide. The objective of this study was to determine the dose response, immunogenicity, and efficacy of 2 doses of an oral, attenuated monovalent G1[P8] human rotavirus vaccine in children from the same setting in Mexico, where the natural protection against rotavirus infection was studied. From June 2001 through May 2003, 405 healthy infants were randomly assigned to 1 of 3 vaccine groups (virus concentrations 10(4.7), 10(5.2), and 10(5.8) infectious units) and to a placebo group and were monitored to the age of 2 years. The vaccine/placebo was administered concurrently with diphtheria-tetanus toxoid-pertussis/hepatitis B/Haemophilus influenzae type b vaccine at 2 and 4 months of age. After the administration of the first vaccine/placebo dose, weekly home visits to collect information regarding infant health were conducted. Stool samples were collected during each gastroenteritis episode and tested for rotavirus antigen and serotype. The vaccine was well tolerated and induced a greater rate of seroconversion than observed in infants who received placebo. For the pooled vaccine groups, efficacy after 2 oral doses was 80% and 95% against any and severe rotavirus gastroenteritis, respectively. Efficacy was 100% against severe rotavirus gastroenteritis and 70% against severe gastroenteritis of any cause with the vaccine at the highest virus concentration (10(5.8) infectious units). The predominant infecting rotavirus serotype in this cohort was wild-type G1 (85%). Adverse events, including fever, irritability, loss of appetite, cough, diarrhea, and vomiting, were similar among vaccinees and placebo recipients. This new oral, live, attenuated human rotavirus vaccine was safe, immunogenic, and highly efficacious in preventing any and, more importantly, severe rotavirus gastroenteritis in healthy infants. This vaccine

  8. Influence of Exercise Intensity for Improving Depressed Mood in Depression: A Dose-Response Study.

    Science.gov (United States)

    Meyer, Jacob D; Koltyn, Kelli F; Stegner, Aaron J; Kim, Jee-Seon; Cook, Dane B

    2016-07-01

    Exercise effectively improves mood in major depressive disorder (MDD), but the optimal exercise stimulus to improve depressed mood is unknown. To determine the dose-response relationship of acute exercise intensity with depressed mood responses to exercise in MDD. We hypothesized that the acute response to exercise would differ between light, moderate, and hard intensity exercise with higher intensities yielding more beneficial responses. Once weekly, 24 women (age: 38.6±14.0) diagnosed with MDD underwent a 30-minute session at one of three steady-state exercise intensities (light, moderate, hard; rating of perceived exertion 11, 13 or 15) or quiet rest on a stationary bicycle. Depressed mood was evaluated with the Profile of Mood States before, 10 and 30 minutes post-exercise. Exercise reduced depressed mood 10 and 30 minutes following exercise, but this effect was not influenced by exercise intensity. Participants not currently taking antidepressants (n=10) had higher baseline depression scores, but did not demonstrate a different antidepressant response to exercise compared to those taking antidepressants. To acutely improve depressed mood, exercise of any intensity significantly improved feelings of depression with no differential effect following light, moderate, or hard exercise. Pharmacological antidepressant usage did not limit the mood-enhancing effect of acute exercise. Acute exercise should be used as a symptom management tool to improve mood in depression, with even light exercise an effective recommendation. These results need to be replicated and extended to other components of exercise prescription (e.g., duration, frequency, mode) to optimize exercise guidelines for improving depression. Copyright © 2016. Published by Elsevier Ltd.

  9. Exercise volume and intensity: a dose-response relationship with health benefits.

    Science.gov (United States)

    Foulds, Heather J A; Bredin, Shannon S D; Charlesworth, Sarah A; Ivey, Adam C; Warburton, Darren E R

    2014-08-01

    The health benefits of exercise are well established. However, the relationship between exercise volume and intensity and health benefits remains unclear, particularly the benefits of low-volume and intensity exercise. The primary purpose of this investigation was, therefore, to examine the dose-response relationship between exercise volume and intensity with derived health benefits including volumes and intensity of activity well below international recommendations. Generally healthy, active participants (n = 72; age = 44 ± 13 years) were assigned randomly to control (n = 10) or one of five 13-week exercise programs: (1) 10-min brisk walking 1×/week (n = 10), (2) 10-min brisk walking 3×/week (n = 10), (3) 30-min brisk walking 3×/week (n = 18), (4) 60-min brisk walking 3×/week (n = 10), and (5) 30-min running 3×/week (n = 14), in addition to their regular physical activity. Health measures evaluated pre- and post-training including blood pressure, body composition, fasting lipids and glucose, and maximal aerobic power (VO2max). Health improvements were observed among programs at least 30 min in duration, including body composition and VO2max: 30-min walking 28.8-34.5 mL kg(-1) min(-1), 60-min walking 25.1-28.9 mL kg(-1) min(-1), and 30-min running 32.4-36.4 mL kg(-1) min(-1). The greater intensity running program also demonstrated improvements in triglycerides. In healthy active individuals, a physical activity program of at least 30 min in duration for three sessions/per week is associated with consistent improvements in health status.

  10. Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme

    International Nuclear Information System (INIS)

    Sneed, Penny K.; Lamborn, Kathleen R.; Larson, David A.; Prados, Michael D.; Malec, Mary K.; McDermott, Michael W.; Weaver, Keith A.; Phillips, Theodore L.; Wara, William M.; Gutin, Philip H.

    1996-01-01

    Purpose: To evaluate brachytherapy dose-response relationships in adults with glioblastoma undergoing temporary 125 I implant boost after external beam radiotherapy. Methods and Materials: Since June 1987, orthogonal radiographs using a fiducial marker box have been used to verify brain implant source positions and generate dose-volume histograms at the University of California, San Francisco. For adults who underwent brachytherapy boost for glioblastoma from June 1987 through December 1992, tumor volumes were reoutlined to ensure consistency and dose-volume histograms were recalculated. Univariate and multivariate analyses of various patient and treatment parameters were performed evaluating for influence of dose on freedom from local failure (FFLF) and actuarial survival. Results: Of 102 implant boosts, 5 were excluded because computer plans were unavailable. For the remaining 97 patients, analyses with adjustment for known prognostic factors (age, KPS, extent of initial surgical resection) and prognostic factors identified on univariate testing (adjuvant chemotherapy) showed that higher minimum brachytherapy tumor dose was strongly associated with improved FFLF (p = 0.001). A quadratic relationship was found between total biological effective dose and survival, with a trend toward optimal survival probability at 47 Gy minimum brachytherapy tumor dose (corresponding to about 65 Gy to 95% of the tumor volume); survival decreased with lower or higher doses. Two patients expired and one requires hospice care because of brain necrosis after brachytherapy doses > 63 Gy to 95% of the tumor volume with 60 Gy to > 18 cm 3 of normal brain. Conclusion: Although higher minimum brachytherapy tumor dose was strongly associated with better local control, a brachytherapy boost dose > 50-60 Gy may result in life-threatening necrosis. We recommend careful conformation of the prescription isodose line to the contrast enhancing tumor volume, delivery of a minimum brachytherapy

  11. Modeling Guru: Knowledge Base for NASA Modelers

    Science.gov (United States)

    Seablom, M. S.; Wojcik, G. S.; van Aartsen, B. H.

    2009-05-01

    Modeling Guru is an on-line knowledge-sharing resource for anyone involved with or interested in NASA's scientific models or High End Computing (HEC) systems. Developed and maintained by the NASA's Software Integration and Visualization Office (SIVO) and the NASA Center for Computational Sciences (NCCS), Modeling Guru's combined forums and knowledge base for research and collaboration is becoming a repository for the accumulated expertise of NASA's scientific modeling and HEC communities. All NASA modelers and associates are encouraged to participate and provide knowledge about the models and systems so that other users may benefit from their experience. Modeling Guru is divided into a hierarchy of communities, each with its own set forums and knowledge base documents. Current modeling communities include those for space science, land and atmospheric dynamics, atmospheric chemistry, and oceanography. In addition, there are communities focused on NCCS systems, HEC tools and libraries, and programming and scripting languages. Anyone may view most of the content on Modeling Guru (available at http://modelingguru.nasa.gov/), but you must log in to post messages and subscribe to community postings. The site offers a full range of "Web 2.0" features, including discussion forums, "wiki" document generation, document uploading, RSS feeds, search tools, blogs, email notification, and "breadcrumb" links. A discussion (a.k.a. forum "thread") is used to post comments, solicit feedback, or ask questions. If marked as a question, SIVO will monitor the thread, and normally respond within a day. Discussions can include embedded images, tables, and formatting through the use of the Rich Text Editor. Also, the user can add "Tags" to their thread to facilitate later searches. The "knowledge base" is comprised of documents that are used to capture and share expertise with others. The default "wiki" document lets users edit within the browser so others can easily collaborate on the

  12. Structure-Based Turbulence Model

    National Research Council Canada - National Science Library

    Reynolds, W

    2000-01-01

    .... Maire carried out this work as part of his Phi) research. During the award period we began to explore ways to simplify the structure-based modeling so that it could be used in repetitive engineering calculations...

  13. Event-Based Conceptual Modeling

    DEFF Research Database (Denmark)

    Bækgaard, Lars

    2009-01-01

    The purpose of the paper is to obtain insight into and provide practical advice for event-based conceptual modeling. We analyze a set of event concepts and use the results to formulate a conceptual event model that is used to identify guidelines for creation of dynamic process models and static...... information models. We characterize events as short-duration processes that have participants, consequences, and properties, and that may be modeled in terms of information structures. The conceptual event model is used to characterize a variety of event concepts and it is used to illustrate how events can...... be used to integrate dynamic modeling of processes and static modeling of information structures. The results are unique in the sense that no other general event concept has been used to unify a similar broad variety of seemingly incompatible event concepts. The general event concept can be used...

  14. Computer Based Modelling and Simulation

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 6; Issue 3. Computer Based Modelling and Simulation - Modelling Deterministic Systems. N K Srinivasan. General Article Volume 6 Issue 3 March 2001 pp 46-54. Fulltext. Click here to view fulltext PDF. Permanent link:

  15. New Insights to Compare and Choose TKTD Models for Survival Based on an Interlaboratory Study for Lymnaea stagnalis Exposed to Cd.

    Science.gov (United States)

    Baudrot, Virgile; Preux, Sara; Ducrot, Virginie; Pave, Alain; Charles, Sandrine

    2018-02-06

    Toxicokinetic-toxicodynamic (TKTD) models, as the General Unified Threshold model of Survival (GUTS), provide a consistent process-based framework compared to classical dose-response models to analyze both time and concentration-dependent data sets. However, the extent to which GUTS models (Stochastic Death (SD) and Individual Tolerance (IT)) lead to a better fitting than classical dose-response model at a given target time (TT) has poorly been investigated. Our paper highlights that GUTS estimates are generally more conservative and have a reduced uncertainty through smaller credible intervals for the studied data sets than classical TT approaches. Also, GUTS models enable estimating any x% lethal concentration at any time (LC x,t ), and provide biological information on the internal processes occurring during the experiments. While both GUTS-SD and GUTS-IT models outcompete classical TT approaches, choosing one preferentially to the other is still challenging. Indeed, the estimates of survival rate over time and LC x,t are very close between both models, but our study also points out that the joint posterior distributions of SD model parameters are sometimes bimodal, while two parameters of the IT model seems strongly correlated. Therefore, the selection between these two models has to be supported by the experimental design and the biological objectives, and this paper provides some insights to drive this choice.

  16. Model-based machine learning.

    Science.gov (United States)

    Bishop, Christopher M

    2013-02-13

    Several decades of research in the field of machine learning have resulted in a multitude of different algorithms for solving a broad range of problems. To tackle a new application, a researcher typically tries to map their problem onto one of these existing methods, often influenced by their familiarity with specific algorithms and by the availability of corresponding software implementations. In this study, we describe an alternative methodology for applying machine learning, in which a bespoke solution is formulated for each new application. The solution is expressed through a compact modelling language, and the corresponding custom machine learning code is then generated automatically. This model-based approach offers several major advantages, including the opportunity to create highly tailored models for specific scenarios, as well as rapid prototyping and comparison of a range of alternative models. Furthermore, newcomers to the field of machine learning do not have to learn about the huge range of traditional methods, but instead can focus their attention on understanding a single modelling environment. In this study, we show how probabilistic graphical models, coupled with efficient inference algorithms, provide a very flexible foundation for model-based machine learning, and we outline a large-scale commercial application of this framework involving tens of millions of users. We also describe the concept of probabilistic programming as a powerful software environment for model-based machine learning, and we discuss a specific probabilistic programming language called Infer.NET, which has been widely used in practical applications.

  17. Dose-response study of thimerosal-induced murine systemic autoimmunity

    International Nuclear Information System (INIS)

    Havarinasab, S.; Lambertsson, L.; Qvarnstroem, J.; Hultman, P.

    2004-01-01

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury. A.SW mice were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose-response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury

  18. Lipid metabolic dose response to dietary alpha-linolenic acid in monk parrot (Myiopsitta monachus).

    Science.gov (United States)

    Petzinger, Christina; Heatley, J J; Bailey, Christopher A; Bauer, John E

    2014-03-01

    Monk parrots (Myiopsitta monachus) are susceptible to atherosclerosis, a progressive disease characterized by the formation of plaques in the arteries accompanied by underlying chronic inflammation. The family of n-3 fatty acids, especially eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), have consistently been shown to reduce atherosclerotic risk factors in humans and other mammals. Some avian species have been observed to convert α-linolenic acid (18:3n-3, ALA) to EPA and DHA (Htin et al. in Arch Geflugelk 71:258-266, 2007; Petzinger et al. in J Anim Physiol Anim Nutr, 2013). Therefore, the metabolic effects of including flaxseed oil, as a source of ALA, in the diet at three different levels (low, medium, and high) on the lipid metabolism of Monk parrots was evaluated through measuring plasma total cholesterol (TC), free cholesterol (FC), triacylglycerols (TAG), and phospholipid fatty acids. Feed intake, body weight, and body condition score were also assessed. Thus the dose and possible saturation response of increasing dietary ALA at constant linoleic acid (18:2n-6, LNA) concentration on lipid metabolism in Monk parrots (M. monachus) was evaluated. Calculated esterified cholesterol in addition to plasma TC, FC, and TAG were unaltered by increasing dietary ALA. The high ALA group had elevated levels of plasma phospholipid ALA, EPA, and docosapentaenoic acid (DPAn-3, 22:5n-3). The medium and high ALA groups had suppressed plasma phospholipid 20:2n-6 and adrenic acid (22:4n-6, ADA) compared to the low ALA group. When the present data were combined with data from a previous study (Petzinger et al. in J Anim Physiol Anim Nutr, 2013) a dose response to dietary ALA was observed when LNA was constant. Plasma phospholipid ALA, EPA, DPAn-3, DHA, and total n-3 were positively correlated while 20:2n-6, di-homo-gamma-linoleic acid (20:3n-6Δ7), arachidonic acid (20:4n-6), ADA, and total n-6 were inversely correlated with dietary en% ALA.

  19. Dose-Response of High-Intensity Training (HIT on Atheroprotective miRNA-126 Levels

    Directory of Open Access Journals (Sweden)

    Boris Schmitz

    2017-05-01

    Full Text Available Aim: MicroRNA-126 (miR-126 exerts beneficial effects on vascular integrity, angiogenesis, and atherosclerotic plaque stability. The purpose of this investigation was to analyze the dose-response relationship of high-intensity interval training (HIIT on miR-126-3p and -5p levels.Methods: Sixty-one moderately trained individuals (females = 31 [50.8%]; 22.0 ± 1.84 years were consecutively recruited and allocated into three matched groups using exercise capacity. During a 4-week intervention a HIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out, a progressive HIIT (proHIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out with one extra session every week (up to 7 × 30 s and a low-intensity training (LIT control group performed three exercise sessions/week for 25 min <75% of maximum heart rate. Exercise miR-126-3p/-5p plasma levels were determined using capillary blood from earlobes.Results: No exercise-induced increase in miR-126 levels was detected at baseline, neither in the LIT (after 25 min low-intensity running nor the HIIT groups (after 4 min of high-intensity running. After the intervention, the LIT group presented an increase in miR-126-3p, while in the HIIT group, miR-126-3p levels were still reduced (all p < 0.05. An increase for both, miR-126-3p and -5p levels (all p < 0.05, pre- vs. during and post-exercise was detected in the proHIIT group. Between group analysis revealed that miR-126-3p levels after LIT and proHIIT increased by 2.12 ± 2.55 and 1.24 ± 2.46 units (all p < 0.01, respectively, compared to HIIT (−1.05 ± 2.6 units.Conclusions: LIT and proHIIT may be performed to increase individual miR-126 levels. HIIT without progression was less effective in increasing miR-126.

  20. [Dose-response relationship of ropivacaine for epidural block in early herpes zoster guided by CT].

    Science.gov (United States)

    Xie, K Y; Ma, J B; Xu, Q; Huang, B; Yao, M; Ni, H D; Deng, J J; Chen, G D

    2017-12-26

    Objective: To determine the dose-response relationship of ropivacaine for epidural block in early herpes zoster by CT guided. Methods: From January 2015 to February 2017, according to the principle of completely random digital table, 80 patients with early herpes zoster who were prepared for epidural block were divided into 4 groups(each group 20 patients): in group A the concentration of ropivacaine was 0.08%, in group B was 0.10%, in group C was 0.12% and in group D was 0.14%.Under CT guidance, epidural puncture was performed in the relevant section, mixing liquid 5.0 ml (with 10% iodohydrin)were injected into epidural gap.CT scan showed that the mixing liquid covered the relevant spinal nerve segmental.The numeric rating scale(NRS) values before treatment and at 30 minutes, the incidence of adverse reactions were recorded, and the treatment were evaluated. The response to ropivacaine for epidural block in early herpes zoster was defined as positive when the NRS values was less than or equal to one.The ED(50), ED(95) and 95% confidence interval ( CI ) of ropivacaine for epidural block in early herpes zoster guided by CT were calculated by probit analysis. Results: The NRS values before treatment were 5.00(4.00, 6.00), 5.00(4.25, 6.00), 5.50(5.00, 6.00) and 5.00(4.00, 6.00), the difference was no significant( Z =2.576, P =0.462). The NRS values at 30 minutes decreased and the effective rate of the treatment increased(χ(2)=8.371, P =0.004), following ropivacaine dose gradient increasing, they were 1.50(1.00, 2.00), 1.00(1.00, 2.00), 0.50(0.00, 1.00) and 0.00(0.00, 1.00), the difference was statistically significant ( Z =17.421, P =0.001). There was one case in group C and four cases in group D were hypoesthesia, others were no significant adverse reactions occurred. The ED(50) and ED(95) (95% CI ) of ropivacaine for epidural block in early herpes zoster guided by CT were 0.078%(0.015%-0.095%)and 0.157%(0.133%-0.271%), respectively. Conclusion: Ropivacaine for

  1. Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eugene [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Corbett, James R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Moran, Jean M. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Griffith, Kent A. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Ficaro, Edward C. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Pierce, Lori J., E-mail: ljpierce@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-03-15

    Purpose: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. Methods and Materials: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. Results: The mean difference in pre- and post-RT PD was −0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. Conclusions: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

  2. A direct method for estimating the alpha/beta ratio from quantitative dose-response data

    International Nuclear Information System (INIS)

    Stuschke, M.

    1989-01-01

    A one-step optimization method based on a least squares fit of the linear quadratic model to quantitative tissue response data after fractionated irradiation is proposed. Suitable end-points that can be analysed by this method are growth delay, host survival and quantitative biochemical or clinical laboratory data. The functional dependence between the transformed dose and the measured response is approximated by a polynomial. The method allows for the estimation of the alpha/beta ratio and its confidence limits from all observed responses of the different fractionation schedules. Censored data can be included in the analysis. A method to test the appropriateness of the fit is presented. A computer simulation illustrates the method and its accuracy as examplified by the growth delay end point. A comparison with a fit of the linear quadratic model to interpolated isoeffect doses shows the advantages of the direct method. (orig./HP) [de

  3. Consumption of fruit and vegetables and risk of frailty: a dose-response analysis of 3 prospective cohorts of community-dwelling older adults.

    Science.gov (United States)

    García-Esquinas, Esther; Rahi, Berna; Peres, Karine; Colpo, Marco; Dartigues, Jean-François; Bandinelli, Stefania; Feart, Catherine; Rodríguez-Artalejo, Fernando

    2016-07-01

    Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation. We sought to examine the dose-response association between FV consumption and the risk of frailty in older adults. Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model. During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss. Among community-dwelling older adults, FV consumption was associated with a lower short-term risk of frailty in a dose-response manner, and the strongest association was obtained with 3 portions of fruit/d and 2 portions of vegetables/d. © 2016 American Society for Nutrition.

  4. Cluster Based Text Classification Model

    DEFF Research Database (Denmark)

    Nizamani, Sarwat; Memon, Nasrullah; Wiil, Uffe Kock

    2011-01-01

    We propose a cluster based classification model for suspicious email detection and other text classification tasks. The text classification tasks comprise many training examples that require a complex classification model. Using clusters for classification makes the model simpler and increases...... the accuracy at the same time. The test example is classified using simpler and smaller model. The training examples in a particular cluster share the common vocabulary. At the time of clustering, we do not take into account the labels of the training examples. After the clusters have been created......, the classifier is trained on each cluster having reduced dimensionality and less number of examples. The experimental results show that the proposed model outperforms the existing classification models for the task of suspicious email detection and topic categorization on the Reuters-21578 and 20 Newsgroups...

  5. Low-dose dose-response for reduced cell viability after exposure of human keratinocyte (HEK001 cells to arsenite

    Directory of Open Access Journals (Sweden)

    Kenneth T. Bogen

    Full Text Available The in vitro arsenite (AsIII cytotoxicity dose-response (DR of human keratinocytes (HEK001 was examined at greater statistical resolution than ever previously reported using the MTT assay to determine cell viability. Fifty-four 96-well plates were treated with AsIII concentrations of 0.25, 0.5, 1, 2, 3, 4, 5, 7, 10, 15, 20, 25, or 30 μM. Because of unexpected variation in viability response patterns, a two-stage DR analysis was used in which data on plate-specific viability (%, estimated as 100% times the ratio of measured viability in exposed to unexposed cells, were fit initially to a generalized lognormal response function positing that HEK001 cells studied consisted of: a proportion P of relatively highly sensitive (HS cells, a proportion Po of relatively resistant cells, and a remaining (1–P–Po fraction of typical-sensitivity (TS cells exhibiting the intermediate level of AsIII sensitivity characteristic of most cells in each assay. The estimated fractions P and Po were used to adjust data from all 54 plates (and from the 28 plates yielding the best fits to reflect the condition that P = Po = 0 to provide detailed DR analysis specifically for TS cells. Four DR models fit to the combined adjusted data were each very predictive (R2 > 0.97 overall but were inconsistent with at least one of the data set examined (p  0.30 and exceeded 100% significance (p ≤ 10−6. A low-dose hormetic model provided the best fit to the combined adjusted data for TS cells (R2 = 0.995. Marked variability in estimates of P (the proportion of apparent HS cells was unexpected, not readily explained, and warrants further study using additional cell lines and assay methods, and in vivo. Keywords: Arsenic, Arsenate, Cell culture, Cell death, Cytotoxicity, HEK001 cells

  6. Dose response of commercially available optically stimulated luminescent detector, Al2O3:C for megavoltage photons and electrons.

    Science.gov (United States)

    Kim, Dong Wook; Chung, Weon Kuu; Shin, Dong Oh; Yoon, Myonggeun; Hwang, Ui-Jung; Rah, Jeong-Eun; Jeong, Hojin; Lee, Sang Yeob; Shin, Dongho; Lee, Se Byeong; Park, Sung Yong

    2012-04-01

    This study examined the dose response of an optically stimulated luminescence dosemeter (OSLD) to megavoltage photon and electron beams. A nanoDot™ dosemeter was used to measure the dose response of the OSLD. Photons of 6-15 MV and electrons of 9-20 MeV were delivered by a Varian 21iX machine (Varian Medical System, Inc. Milpitas, CA, USA). The energy dependency was dose was linear until 200 cGy. The superficial dose measurements revealed photon irradiation to have an angular dependency. The nanoDot™ dosemeter has potential use as an in vivo dosimetric tool that is independent of the energy, has dose linearity and a rapid response compared with normal in vivo dosimetric tools, such as thermoluminescence detectors. However, the OSLD must be treated very carefully due to the high angular dependency of the photon beam.

  7. Critical dose threshold for TL dose response non-linearity: Dependence on the method of analysis: It’s not only the data

    International Nuclear Information System (INIS)

    Datz, H.; Horowitz, Y.S.; Oster, L.; Margaliot, M.

    2011-01-01

    It is demonstrated that the method of data analysis, i.e., the method of the phenomenological/theoretical interpretation of dose response data, can greatly influence the estimation of the onset of deviation from dose response linearity of the high temperature thermoluminescence in LiF:Mg,Ti (TLD-100).

  8. Developing guidelines for economic evaluation of environmental impacts in EIAs. Part II: Case studies and dose-response literature

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    This Part II of the report contains full versions of the case studies for air, water and land (Chapters 2-4), which were only summarised in Part I. In addition, during the work the research team has collected a large amount of literature and information on dose response relationships for air and water pollution relevant to China. This information is included as Chapters 5 and 6.

  9. Developing guidelines for economic evaluation of environmental impacts in EIAs. Part II: Case studies and dose-response literature

    International Nuclear Information System (INIS)

    2005-01-01

    This Part II of the report contains full versions of the case studies for air, water and land (Chapters 2-4), which were only summarised in Part I. In addition, during the work the research team has collected a large amount of literature and information on dose response relationships for air and water pollution relevant to China. This information is included as Chapters 5 and 6

  10. Linear and Non-Linear Dose-Response Functions Reveal a Hormetic Relationship Between Stress and Learning

    OpenAIRE

    Zoladz, Phillip R.; Diamond, David M.

    2008-01-01

    Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as ...

  11. Dose-response relationship for chromosomal aberrations induced in human lymphocytes by 18 MeV electron beam irradiation

    International Nuclear Information System (INIS)

    Lashin, E.A.; Elaasar, E.M.; Moustafa, H.F.; Bakir, Y.Y.; Al Zenki, S.D.

    1990-01-01

    Dose response curves for lymphocyte chromosome aberration frequencies using X- and gamma radiation became an important and reliable indicator as biological dosimeter especially in radiation accidents and occupational over exposures. Nowadays electron beam therapy is frequently used for their advantages in cases of tumours under or near to the body surface. Dose-response curves for these electron beams are rarely published. Human peripheral blood lymphocytes were in vitro irradiated with various low and high doses (0.1 Gy to 4.9 Gy) of 18 MeV electron beams to utilize such a dose-response curve using chromosomal aberration frequencies as a biological indicator. Then we compared the biological curve with physically obtained curves normally used in planning for radiotherapy treatment. It is interesting to find a significant difference between both of them. The biological curve is generally higher in value and the aberrations induced by 93% of a dose is significantly higher and deeper in site than those aberrations induced by the 100% dose calculated physically. If the above observation is confirmed by detailed studies, it would be of importance to the radiotherapist to plan for isodose curves according to biological determinations. (author)

  12. Linear and non-linear dose-response functions reveal a hormetic relationship between stress and learning.

    Science.gov (United States)

    Zoladz, Phillip R; Diamond, David M

    2008-10-16

    Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as well as the excitatory effects of several neuromodulators, including corticosteroids, norepinephrine, corticotropin-releasing hormone, acetylcholine and dopamine. We propose that this rapid activation of the amygdala-hippocampus brain memory system results in a linear dose-response relation between emotional strength and memory formation. More prolonged stress, however, leads to an inhibition of hippocampal function, which can be attributed to compensatory cellular responses that protect hippocampal neurons from excitotoxicity. This inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear dose-response relationship between arousal and memory. Our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce a hormetic relationship between stress and learning.

  13. A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects.

    Directory of Open Access Journals (Sweden)

    Luciana Cadore Stefani

    Full Text Available Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation.The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure a