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

Uncertainty of fast biological radiation dose assessment for emergency response scenarios.

Science.gov (United States)

Ainsbury, Elizabeth A; Higueras, Manuel; Puig, Pedro; Einbeck, Jochen; Samaga, Daniel; Barquinero, Joan Francesc; Barrios, Lleonard; Brzozowska, Beata; Fattibene, Paola; Gregoire, Eric; Jaworska, Alicja; Lloyd, David; Oestreicher, Ursula; Romm, Horst; Rothkamm, Kai; Roy, Laurence; Sommer, Sylwester; Terzoudi, Georgia; Thierens, Hubert; Trompier, Francois; Vral, Anne; Woda, Clemens

2017-01-01

Reliable dose estimation is an important factor in appropriate dosimetric triage categorization of exposed individuals to support radiation emergency response. Following work done under the EU FP7 MULTIBIODOSE and RENEB projects, formal methods for defining uncertainties on biological dose estimates are compared using simulated and real data from recent exercises. The results demonstrate that a Bayesian method of uncertainty assessment is the most appropriate, even in the absence of detailed prior information. The relative accuracy and relevance of techniques for calculating uncertainty and combining assay results to produce single dose and uncertainty estimates is further discussed. Finally, it is demonstrated that whatever uncertainty estimation method is employed, ignoring the uncertainty on fast dose assessments can have an important impact on rapid biodosimetric categorization.

Isobio software: biological dose distribution and biological dose volume histogram from physical dose conversion using linear-quadratic-linear model.

Science.gov (United States)

Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit; Tharavichitkul, Ekkasit

2017-02-01

To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD 2 ) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD 2 verification with pair t -test statistical analysis using IBM SPSS Statistics version 22 (64-bit). Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D 90% , 0.56% in the bladder, 1.74% in the rectum when determined by D 2cc , and less than 1% in Pinnacle. The difference in the EQD 2 between the software calculation and the manual calculation was not significantly different with 0.00% at p -values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR-CTV, bladder, and rectum, respectively. The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT.

A Paradigm Shift in Low Dose Radiation Biology

Directory of Open Access Journals (Sweden)

Z. Alatas

2015-08-01

Full Text Available When ionizing radiation traverses biological material, some energy depositions occur and ionize directly deoxyribonucleic acid (DNA molecules, the critical target. A classical paradigm in radiobiology is that the deposition of energy in the cell nucleus and the resulting damage to DNA are responsible for the detrimental biological effects of radiation. It is presumed that no radiation effect would be expected in cells that receive no direct radiation exposure through nucleus. The risks of exposure to low dose ionizing radiation are estimated by extrapolating from data obtained after exposure to high dose radiation. However, the validity of using this dose-response model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose radiation than they do to high dose radiation. Moreover, recent experimental evidences from many laboratories reveal the fact that radiation effects also occur in cells that were not exposed to radiation and in the progeny of irradiated cells at delayed times after radiation exposure where cells do not encounter direct DNA damage. Recently, the classical paradigm in radiobiology has been shifted from the nucleus, specifically the DNA, as the principal target for the biological effects of radiation to cells. The universality of target theory has been challenged by phenomena of radiation-induced genomic instability, bystander effect and adaptive response. The new radiation biology paradigm would cover both targeted and non-targeted effects of ionizing radiation. The mechanisms underlying these responses involve biochemical/molecular signals that respond to targeted and non-targeted events. These results brought in understanding that the biological response to low dose radiation at tissue or organism level is a complex process of integrated response of cellular targets as well as extra-cellular factors. Biological understanding of

Strategies for Biologic Image-Guided Dose Escalation: A Review

International Nuclear Information System (INIS)

Sovik, Aste; Malinen, Eirik; Olsen, Dag Rune

2009-01-01

There is increasing interest in how to incorporate functional and molecular information obtained by noninvasive, three-dimensional tumor imaging into radiotherapy. The key issues are to identify radioresistant regions that can be targeted for dose escalation, and to develop radiation dose prescription and delivery strategies providing optimal treatment for the individual patient. In the present work, we review the proposed strategies for biologic image-guided dose escalation with intensity-modulated radiation therapy. Biologic imaging modalities and the derived images are discussed, as are methods for target volume delineation. Different dose escalation strategies and techniques for treatment delivery and treatment plan evaluation are also addressed. Furthermore, we consider the need for response monitoring during treatment. We conclude with a summary of the current status of biologic image-based dose escalation and of areas where further work is needed for this strategy to become incorporated into clinical practice

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

Biologically based modelling and simulation of carcinogenesis at low doses

International Nuclear Information System (INIS)

Ouchi, Noriyuki B.

2003-01-01

The process of the carcinogenesis is studied by computer simulation. In general, we need a large number of experimental samples to detect mutations at low doses, but in practice it is difficult to get such a large number of data. To satisfy the requirements of the situation at low doses, it is good to study the process of carcinogenesis using biologically based mathematical model. We have mainly studied it by using as known as 'multi-stage model'; the model seems to get complicated, as we adopt the recent new findings of molecular biological experiments. Moreover, the basic idea of the multi-stage model is based on the epidemiologic data of log-log variation of cancer incidence with age, it seems to be difficult to compare with experimental data of irradiated cell culture system, which has been increasing in recent years. Taking above into consideration, we concluded that we had better make new model with following features: 1) a unit of the target system is a cell, 2) the new information of the molecular biology can be easily introduced, 3) having spatial coordinates for checking a colony formation or tumorigenesis. In this presentation, we will show the detail of the model and some simulation results about the carcinogenesis. (author)

Biological effects of low-dose ionizing radiation exposure

International Nuclear Information System (INIS)

Reinoehl-Kompa, Sabine; Baldauf, Daniela; Heller, Horst

2009-01-01

The report on the meeting of the Strahlenschutzkommission 2007 concerning biological effects of low-dose ionizing radiation exposure includes the following contributions: Adaptive response. The importance of DNA damage mechanisms for the biological efficiency of low-energy photons. Radiation effects in mammography: the relative biological radiation effects of low-energy photons. Radiation-induced cataracts. Carcinomas following prenatal radiation exposure. Intercellular apoptosis induction and low-dose irradiation: possible consequences for the oncogenesis control. Mechanistic models for the carcinogenesis with radiation-induced cell inactivation: application to all solid tumors in the Japanese atomic bomb survivors. Microarrays at low radiation doses. Mouse models for the analysis of biological effects of low-dose ionizing radiation. The bystander effect: observations, mechanisms and implications. Lung carcinoma risk of Majak workers - modeling of carcinogenesis and the bystander effect. Microbeam studies in radiation biology - an overview. Carcinogenesis models with radiation-induced genomic instability. Application to two epidemiological cohorts.

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

SU-C-202-04: Adapting Biologically Optimized Dose Escalation Based On Mid-Treatment PET/CT for Non-Small-Cell Lung Cancer

Energy Technology Data Exchange (ETDEWEB)

Zhang, P; Kuo, L; Yorke, E; Hu, Y; Lockney, N; Mageras, G; Deasy, J; Rimner, A [Memorial Sloan Kettering Cancer Center, New York, NY (United States)

2016-06-15

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after the full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical

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...

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.

Mathematical simulation of biologically equivalent doses for LDR-HDR

International Nuclear Information System (INIS)

Slosarek, K.; Zajusz, A.

1996-01-01

Based on the LQ model examples of biologically equivalent doses LDR, HDR and external beams were calculated. The biologically equivalent doses for LDR were calculated by appending to the LQ model the corrector for the time of repair of radiation sublethal damages. For radiation continuously delivered at a low dose rate the influence of sublethal damage repair time changes on biologically equivalent doses were analysed. For fractionated treatment with high dose rate the biologically equivalent doses were calculated by adding to the LQ model the formula of accelerated repopulation. For total biologically equivalent dose calculation for combine LDR-HDR-Tele irradiation examples are presented with the use of different parameters of the time of repair of sublethal damages and accelerated repopulation. The calculations performed show, that the same biologically equivalent doses can be obtained for different parameters of cell kinetics changes during radiation treatment. It also shows, that during biologically equivalent dose calculations for different radiotherapy schedules, ignorance of cell kinetics parameters can lead to relevant errors

WE-B-304-02: Treatment Planning Evaluation and Optimization Should Be Biologically and Not Dose/volume Based

International Nuclear Information System (INIS)

Deasy, J.

2015-01-01

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning by the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations

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

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

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

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)

Biological dose estimation and comet analysis of the victims in a high dose 60Co radiation accident

International Nuclear Information System (INIS)

Chen Ying; Liu Xiulin; Luo Yisheng; Li You; Yao Bo

2007-01-01

Objective: To explore the methods of chromosome preparation in human peripheral blood and bone marrow after very high dose exposure and fit the dose-response curve of dicentrics and tings in the range of high doses over 6 Gy for estimating biological dose and detecting DNA damage in the victims of '10.21' accident. Methods: The samples of peripheral blood and bone marrow in 2 victims were collected to prepare chromosome mataphases and dicentrics (multicentrics) + rings were counted. The dose-response curve and equation of human blood irradiated between 6-22 Gy in vitro were established and applied to assess biological dose of 2 victims. In addition, their DNA damages were tested by alkaline single cell gel electrophoresis. Results: The dicentric + ring numbers of 4.47 per cell in victims B's peripheral blood lymphocytes and 9.15 per cell in victim A's bone marrow who had no mitosis in peripheral blood cell. The whole body average doses of victims B and A estimated by 6-22 Gy equation arrived at 9.4 Gy and 19.5 Gy, respectively. The serious DNA damages were expressed by small head and large tail comet figures. Conclusions: The biological doses of 2 victims estimated by 6-22 Gy dose-response curve have reached the levels of extreme grave bone marrow and intestinal ARS, respectively. (authors)

WE-B-304-00: Point/Counterpoint: Biological Dose Optimization

International Nuclear Information System (INIS)

2015-01-01

The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor control probability (TCP) with an acceptable normal tissue complication probability (NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. It has been suggested that treatment planning evaluation and optimization would be more effective if they were biologically and not dose/volume based, and this is the claim debated in this month’s Point/Counterpoint. After a brief overview of biologically and DVH based treatment planning by the Moderator Colin Orton, Joseph Deasy (for biological planning) and Charles Mayo (against biological planning) will begin the debate. Some of the arguments in support of biological planning include: this will result in more effective dose distributions for many patients DVH-based measures of plan quality are known to have little predictive value there is little evidence that either D95 or D98 of the PTV is a good predictor of tumor control sufficient validated outcome prediction models are now becoming available and should be used to drive planning and optimization Some of the arguments against biological planning include: several decades of experience with DVH-based planning should not be discarded we do not know enough about the reliability and errors associated with biological models the radiotherapy community in general has little direct experience with side by side comparisons of DVH vs biological metrics and outcomes it is unlikely that a clinician would accept extremely cold regions in a CTV or hot regions in a PTV, despite having acceptable TCP values Learning Objectives: To understand dose/volume based treatment planning and its potential limitations To understand biological metrics such as EUD, TCP, and NTCP To understand biologically based treatment planning and its potential limitations

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

Biological effects in lymphocytes irradiated with {sup 99m}Tc: determination of the curve dose-response; Efeitos biologicos em linfocitos irradiados com {sup 99m}Tc: determinacao da curva dose-resposta

Energy Technology Data Exchange (ETDEWEB)

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 {sup 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 {sup 99m} Tc were used, allowing the irradiation of blood with different administered activities of {sup 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 {sup 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 {sup 99m} Tc was best fitted by the curve Y=(8,99 {+-}2,06) x 1-{sup -4} + (1,24 {+-}0,62) x 10{sup -2} D + (5,67 {+-} 0,64) x 10{sup -2} D{sup 2}. (author)

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...

Physics must join with biology in better assessing risk from low-dose irradiation

International Nuclear Information System (INIS)

Feinendegen, L. E.; Neumann, R. D.

2005-01-01

This review summarises the complex response of mammalian cells and tissues to low doses of ionising radiation. This thesis encompasses induction of DNA damage, and adaptive protection against both renewed damage and against propagation of damage from the basic level of biological organisation to the clinical expression of detriment. The induction of DNA damage at low radiation doses apparently is proportional to absorbed dose at the physical/chemical level. However, any propagation of such damage to higher levels of biological organisation inherently follows a sigmoid function. Moreover, low-dose-induced inhibition of damage propagation is not linear, but instead follows a dose-effect function typical for adaptive protection, after an initial rapid rise it disappears at doses higher than ∼0.1-0.2 Gy to cells. The particular biological response duality at low radiation doses precludes the validity of the linear-no-threshold hypothesis in the attempt to relate absorbed dose to cancer. In fact, theory and observation support not only a lower cancer incidence than expected from the linear-no-threshold hypothesis, but also a reduction of spontaneously occurring cancer, a hormetic response, in the healthy individual. (authors)

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

Biological Effects of Low-Dose Exposure

CERN Document Server

Komochkov, M M

2000-01-01

On the basis of the two-protection reaction model an analysis of stochastic radiobiological effects of low-dose exposure of different biological objects has been carried out. The stochastic effects are the results published in the last decade: epidemiological studies of human cancer mortality, the yield of thymocyte apoptosis of mice and different types of chromosomal aberrations. The results of the analysis show that as dependent upon the nature of biological object, spontanous effect, exposure conditions and radiation type one or another form dose - effect relationship is realized: downwards concave, near to linear and upwards concave with the effect of hormesis included. This result testifies to the incomplete conformity of studied effects of 1990 ICRP recomendations based on the linear no-threshold hypothesis about dose - effect relationship. Because of this the methodology of radiation risk estimation recomended by ICRP needs more precisian and such quantity as collective dose ought to be classified into...

Dose prescription complexity versus tumor control probability in biologically conformal radiotherapy

International Nuclear Information System (INIS)

South, C. P.; Evans, P. M.; Partridge, M.

2009-01-01

The technical feasibility and potential benefits of voxel-based nonuniform dose prescriptions for biologically heterogeneous tumors have been widely demonstrated. In some cases, an ''ideal'' dose prescription has been generated by individualizing the dose to every voxel within the target, but often this voxel-based prescription has been discretized into a small number of compartments. The number of dose levels utilized and the methods used for prescribing doses and assigning tumor voxels to different dose compartments have varied significantly. The authors present an investigation into the relationship between the complexity of the dose prescription and the tumor control probability (TCP) for a number of these methods. The linear quadratic model of cell killing was used in conjunction with a number of modeled tumors heterogeneous in clonogen density, oxygenation, or proliferation. Models based on simple mathematical functions, published biological data, and biological image data were investigated. Target voxels were assigned to dose compartments using (i) simple rules based on the initial biological distribution, (ii) iterative methods designed to maximize the achievable TCP, or (iii) methods based on an ideal dose prescription. The relative performance of the simple rules was found to depend on the form of heterogeneity of the tumor, while the iterative and ideal dose methods performed comparably for all models investigated. In all cases the maximum achievable TCP was approached within the first few (typically two to five) compartments. Results suggest that irrespective of the pattern of heterogeneity, the optimal dose prescription can be well approximated using only a few dose levels but only if both the compartment boundaries and prescribed dose levels are well chosen.

Calculation of integrated biological response in brachytherapy

International Nuclear Information System (INIS)

Dale, Roger G.; Coles, Ian P.; Deehan, Charles; O'Donoghue, Joseph A.

1997-01-01

Purpose: To present analytical methods for calculating or estimating the integrated biological response in brachytherapy applications, and which allow for the presence of dose gradients. Methods and Materials: The approach uses linear-quadratic (LQ) formulations to identify an equivalent biologically effective dose (BED eq ) which, if applied to a specified tissue volume, would produce the same biological effect as that achieved by a given brachytherapy application. For simple geometrical cases, BED multiplying factors have been derived which allow the equivalent BED for tumors to be estimated from a single BED value calculated at a dose reference point. For more complex brachytherapy applications a voxel-by-voxel determination of the equivalent BED will be more accurate. Equations are derived which when incorporated into brachytherapy software would facilitate such a process. Results: At both high and low dose rates, the BEDs calculated at the dose reference point are shown to be lower than the true values by an amount which depends primarily on the magnitude of the prescribed dose; the BED multiplying factors are higher for smaller prescribed doses. The multiplying factors are less dependent on the assumed radiobiological parameters. In most clinical applications involving multiple sources, particularly those in multiplanar arrays, the multiplying factors are likely to be smaller than those derived here for single sources. The overall suggestion is that the radiobiological consequences of dose gradients in well-designed brachytherapy treatments, although important, may be less significant than is sometimes supposed. The modeling exercise also demonstrates that the integrated biological effect associated with fractionated high-dose-rate (FHDR) brachytherapy will usually be different from that for an 'equivalent' continuous low-dose-rate (CLDR) regime. For practical FHDR regimes involving relatively small numbers of fractions, the integrated biological effect to

The relative biological effectiveness of out-of-field dose

International Nuclear Information System (INIS)

Balderson, Michael; Koger, Brandon; Kirkby, Charles

2016-01-01

Purpose: using simulations and models derived from existing literature, this work investigates relative biological effectiveness (RBE) for out-of-field radiation and attempts to quantify the relative magnitudes of different contributing phenomena (spectral, bystander, and low dose hypersensitivity effects). Specific attention is paid to external beam radiotherapy treatments for prostate cancer. Materials and methods: using different biological models that account for spectral, bystander, and low dose hypersensitivity effects, the RBE was calculated for different points moving radially out from isocentre for a typical single arc VMAT prostate case. The RBE was found by taking the ratio of the equivalent dose with the physical dose. Equivalent doses were calculated by determining what physical dose would be necessary to produce the same overall biological effect as that predicted using the different biological models. Results: spectral effects changed the RBE out-of-field less than 2%, whereas response models incorporating low dose hypersensitivity and bystander effects resulted in a much more profound change of the RBE for out-of-field doses. The bystander effect had the largest RBE for points located just outside the edge of the primary radiation beam in the cranial caudal (z-direction) compared to low dose hypersensitivity and spectral effects. In the coplanar direction, bystander effect played the largest role in enhancing the RBE for points up to 8.75 cm from isocentre. Conclusions: spectral, bystander, and low dose hypersensitivity effects can all increase the RBE for out-of-field radiation doses. In most cases, bystander effects seem to play the largest role followed by low dose hypersensitivity. Spectral effects were unlikely to be of any clinical significance. Bystander, low dose hypersensitivity, and spectral effect increased the RBE much more in the cranial caudal direction (z-direction) compared with the coplanar directions. (paper)

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)

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)

Biological-based and physical-based optimization for biological evaluation of prostate patient's plans

Science.gov (United States)

Sukhikh, E.; Sheino, I.; Vertinsky, A.

2017-09-01

Modern modalities of radiation treatment therapy allow irradiation of the tumor to high dose values and irradiation of organs at risk (OARs) to low dose values at the same time. In this paper we study optimal radiation treatment plans made in Monaco system. The first aim of this study was to evaluate dosimetric features of Monaco treatment planning system using biological versus dose-based cost functions for the OARs and irradiation targets (namely tumors) when the full potential of built-in biological cost functions is utilized. The second aim was to develop criteria for the evaluation of radiation dosimetry plans for patients based on the macroscopic radiobiological criteria - TCP/NTCP. In the framework of the study four dosimetric plans were created utilizing the full extent of biological and physical cost functions using dose calculation-based treatment planning for IMRT Step-and-Shoot delivery of stereotactic body radiation therapy (SBRT) in prostate case (5 fractions per 7 Gy).

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

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

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

A phenomenological biological dose model for proton therapy based on linear energy transfer spectra.

Science.gov (United States)

Rørvik, Eivind; Thörnqvist, Sara; Stokkevåg, Camilla H; Dahle, Tordis J; Fjaera, Lars Fredrik; Ytre-Hauge, Kristian S

2017-06-01

The relative biological effectiveness (RBE) of protons varies with the radiation quality, quantified by the linear energy transfer (LET). Most phenomenological models employ a linear dependency of the dose-averaged LET (LET d ) to calculate the biological dose. However, several experiments have indicated a possible non-linear trend. Our aim was to investigate if biological dose models including non-linear LET dependencies should be considered, by introducing a LET spectrum based dose model. The RBE-LET relationship was investigated by fitting of polynomials from 1st to 5th degree to a database of 85 data points from aerobic in vitro experiments. We included both unweighted and weighted regression, the latter taking into account experimental uncertainties. Statistical testing was performed to decide whether higher degree polynomials provided better fits to the data as compared to lower degrees. The newly developed models were compared to three published LET d based models for a simulated spread out Bragg peak (SOBP) scenario. The statistical analysis of the weighted regression analysis favored a non-linear RBE-LET relationship, with the quartic polynomial found to best represent the experimental data (P = 0.010). The results of the unweighted regression analysis were on the borderline of statistical significance for non-linear functions (P = 0.053), and with the current database a linear dependency could not be rejected. For the SOBP scenario, the weighted non-linear model estimated a similar mean RBE value (1.14) compared to the three established models (1.13-1.17). The unweighted model calculated a considerably higher RBE value (1.22). The analysis indicated that non-linear models could give a better representation of the RBE-LET relationship. However, this is not decisive, as inclusion of the experimental uncertainties in the regression analysis had a significant impact on the determination and ranking of the models. As differences between the models were

Biology of dose rate in brachytherapy

International Nuclear Information System (INIS)

Brenner, David J.

1995-01-01

Purpose: This course is designed for practitioners and beginners in brachytherapy. The aim is to review biological principles underlying brachytherapy, to understand why current treatment regimes are the way they are, and to discuss what the future may hold in store. Brachytherapy has a long history. It was suggested as long ago as 1903 by Alexander Graham Bell, and the optimal application of this technique has been a subject of debate ever since. 'Brachy' means 'short', and the essential features of conventional brachytherapy are: positioning of the source a short distance from, or in, the tumor, allowing good dose distributions; short overall treatment times, to counter tumor repopulation; low dose rate, enabling a good therapeutic advantage between tumor control and damage to late-responding tissue. The advantages of good dose distributions speak for themselves; in some situations, as we shall see, computer-based dose optimization can be used to improve them still further. The advantages of short overall times stem from the fact that accelerated repopulation of the tumor typically begins a few weeks after the start of a radiation treatment. If all the radiation can be crammed in before that time, the risks of tumor repopulation can be considerably reduced. In fact even external-beam radiotherapy is moving in this direction, with the use of highly accelerated protocols. The advantages of low dose rate stem from the differential response to fractionation of early- and late-responding tissues. Essentially, lowering the dose rate spares late-responding tissue more than it does early-responding tissue such as tumors. We shall also discuss some recent innovations in the context of the general principles that have been outlined. For example, High dose rate brachytherapy, particularly for the uterine cervix: Does it work? If so, when and why? Use of Ir-192 sources, with a half life of 70 days: Should corrections be made for changing biological effectiveness as the dose

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

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

The biological response of plucked human hair to low-dose radiation: a measure of individual radiosensitivity and a technique for biological dosimetry

International Nuclear Information System (INIS)

Swain, D.

1997-01-01

It is often assumed that the effects of radiation are linear with dose and that high dose effects can be extrapolated to low dose levels. However, there are a variety of mechanisms which can alter the response at low doses. The most important of these relate to induced sensitivity or induced repair mechanisms. It is therefore important that this area is studied in more depth by looking at the molecular effects and damage to cells at low doses. It is well known that there are certain rare genetic syndromes which predispose individuals to cancer, e.g. ataxia telangiectasia. It is also probable that there is a large range of sensitivity in the natural variation of individuals to the risk of radiation-induced cancer. It is proposed that radiosensitivity is studied using stimulated lymphocytes from whole blood and the technique extended to look at the effects in cell cultures established from human hair. Radiation treatment of cell cultures established from plucked human hair has been previously advocated as a non-invasive technique for non-uniform biological dosimetry and it is proposed that these techniques are adapted to the use of hair to estimate individual radiosensitivity. The aim is to establish and optimize these techniques for culturing keratinocytes from plucked human hair follicles with a view to study biological markers for the subsequent assessment of radiosensitivity. Preliminary results are promising and suggest that the technique for culturing keratinocytes from hair presents a feasible approach. Results from this primary cell culture technique and results from the comparison of the micronuclei data obtained from the cell cultures and stimulated lymphocytes will be presented. (author)

Application of biological dose concept in dose optimization for conformal radiotherapy of prostate carcinoma

International Nuclear Information System (INIS)

Li Yunhai; Liao Yuan; Zhou Lijun; Pan Ziqiang; Feng Yan

2003-01-01

Objective: On basis of physical dose optimization, LQ model was used to investigate the difference between the curves of biological effective dose and physical isodose. The influence of applying the biological dose concept on three dimensional conformal radiotherapy of prostate carcinoma was discussed. Methods: Four treatment plannings were designed for physical dose optimization: three fields, four-box fields, five fields and six fields. Target dose uniformity and protection of the critical tissue-rectum were used as the principal standard for designing the treatment planning. Biological effective dose (BED) was calculated by LQ model. The difference between the BED curve drawn in the central layer and the physical isodose curve was studied. The difference between the adjusted physical dose (APD) and the physical dose was also studied. Results: Five field planning was the best in target dose uniformity and protection of the critical tissue-rectum. The physical dose was uniform in the target, but the biological effective doses revealed great discrepancy in the biological model. Adjusted physical dose distribution also displayed larger discrepancy than the physical dose unadjusted. Conclusions: Intensified Modulated Radiotherapy (IMRT) technique with inversion planning using biological dose concept may be much more advantageous to reach a high tumor control probability and low normal tissue complication probability

Low dose irradiation and biological defense mechanisms

International Nuclear Information System (INIS)

Sugahara, Tsutomu; Sagan, L.A.; Aoyama, Takashi

1992-01-01

It has been generally accepted in the context of radiation protection that ionizing radiation has some adverse effect even at low doses. However, epidemiological studies of human populations cannot definitively show its existence or absence. Furthermore, recent studies of populations living in areas of different background radiation levels reported some decrease in adverse health effects at high background levels. Genetic studies of atomic bomb survivors failed to produce statistically significant findings on the mutagenic effects of ionizing radiation. A British study however, suggests that a father's exposure to low dose radiation on the job may increase his children's risk of leukemia. On the other hand, many experimental studies have raised the possibility that low doses of ionizing radiation may not be harmful or may even produce stimulating or adaptive responses. The term 'hormesis' has come to be used to describe these phenomena produced by low doses of ionizing radiation when they were beneficial for the organisms studied. At the end of the International Conference on Low Dose Irradiation one conclusion appeared to be justified: radiation produces an adaptive response, though it is not universally detected yet. The conference failed to obtain any consensus on risk assessment at low doses, but raised many problems to be dealt with by future studies. The editors therefore believe that the Proceedings will be useful for all scientists and people concerned with radiation protection and the biological effects of low-dose irradiation

Radiation dose response of normal lung assessed by Cone Beam CT - A potential tool for biologically adaptive radiation therapy

International Nuclear Information System (INIS)

Bertelsen, Anders; Schytte, Tine; Bentzen, Soren M.; Hansen, Olfred; Nielsen, Morten; Brink, Carsten

2011-01-01

Background: Density changes of healthy lung tissue during radiotherapy as observed by Cone Beam CT (CBCT) might be an early indicator of patient specific lung toxicity. This study investigates the time course of CBCT density changes and tests for a possible correlation with locally delivered dose. Methods: A total of 665 CBCTs in 65 lung cancer patients treated with IMRT/VMAT to 60 or 66 Gy in 2 Gy fractions were analyzed. For each patient, CBCT lung density changes during the treatment course were related to the locally delivered dose. Results: A dose response is observed for the patient population at the end of the treatment course. However, the observed dose response is highly variable among patients. Density changes at 10th and 20th fraction are clearly correlated to those observed at the end of the treatment course. Conclusions: CBCT density changes in healthy lung tissue during radiotherapy correlate with the locally delivered dose and can be detected relatively early during the treatment. If these density changes are correlated to subsequent clinical toxicity this assay could form the basis for biological adaptive radiotherapy.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

Science.gov (United States)

Delate, Thomas; Meyer, Roxanne; Jenkins, Daniel

2017-08-01

Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). Approximately 1 in 10 study patients with RA was identified as a

Clinically Applicable Monte Carlo–based Biological Dose Optimization for the Treatment of Head and Neck Cancers With Spot-Scanning Proton Therapy

Energy Technology Data Exchange (ETDEWEB)

Wan Chan Tseung, Hok Seum, E-mail: wanchantseung.hok@mayo.edu; Ma, Jiasen; Kreofsky, Cole R.; Ma, Daniel J.; Beltran, Chris

2016-08-01

Purpose: Our aim is to demonstrate the feasibility of fast Monte Carlo (MC)–based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. Methods and Materials: Recently, a fast and accurate graphics processor unit (GPU)–based MC simulation of proton transport was developed and used as the dose-calculation engine in a GPU-accelerated intensity modulated proton therapy (IMPT) optimizer. Besides dose, the MC can simultaneously score the dose-averaged linear energy transfer (LET{sub d}), which makes biological dose (BD) optimization possible. To convert from LET{sub d} to BD, a simple linear relation was assumed. By use of this novel optimizer, inverse biological planning was applied to 4 patients, including 2 small and 1 large thyroid tumor targets, as well as 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional intensity modulated radiation therapy (IMRT) and IMPT plans were also created using Eclipse (Varian Medical Systems) in each case. The same critical-structure PD constraints were used for the IMRT, IMPT, and biologically optimized plans. The BD distributions for the IMPT plans were obtained through MC recalculations. Results: Compared with standard IMPT, the biologically optimal plans for patients with small tumor targets displayed a BD escalation that was around twice the PD increase. Dose sparing to critical structures was improved compared with both IMRT and IMPT. No significant BD increase could be achieved for the large thyroid tumor case and when the presence of critical structures mitigated the contribution of additional fields. The calculation of the biologically optimized plans can be completed in a clinically viable time (<30 minutes) on a small 24-GPU system. Conclusions: By exploiting GPU acceleration, MC-based, biologically optimized plans were created for

Biological impact of high-dose and dose-rate radiation exposure

International Nuclear Information System (INIS)

Maliev, V.; Popov, D.; Jones, J.; Gonda, S.; Prasad, K.; Viliam, C.; Haase, G.; Kirchin, V.; Rachael, C.

2006-01-01

Experimental anti-radiation vaccine is a power tool of immune - prophylaxis of the acute radiation disease. Existing principles of treatment of the acute radiation dis ease are based on a correction of developing patho-physiological and biochemical processes within the first days after irradiation. Protection from radiation is built on the general principles of immunology and has two main forms - active and passive immunization. Active immunization by the essential radiation toxins of specific radiation determinant (S.D.R.) group allows significantly reduce the lethality and increase duration of life among animals that are irradiated by lethal and sub-lethal doses of gamma radiation.The radiation toxins of S.D.R. group have antigenic properties that are specific for different forms of acute radiation disease. Development of the specific and active immune reaction after intramuscular injection of radiation toxins allows optimize a manifestation of a clinical picture and stabilize laboratory parameters of the acute radiation syndromes. Passive immunization by the anti-radiation serum or preparations of immune-globulins gives a manifestation of the radioprotection effects immediately after this kind of preparation are injected into organisms of mammals. Providing passive immunization by preparations of anti-radiations immune-globulins is possible in different periods of time after radiation. Providing active immunization by preparations of S.D.R. group is possible only to achieve a prophylaxis goal and form the protection effects that start to work in 18 - 35 days after an injection of biological active S.D.R. substance has been administrated. However active and passive immunizations by essential anti-radiation toxins and preparations of gamma-globulins extracted from a hyper-immune serum of a horse have significantly different medical prescriptions for application and depend on many factors like a type of radiation, a power of radiation, absorption doses, a time of

Biological impact of high-dose and dose-rate radiation exposure

Energy Technology Data Exchange (ETDEWEB)

Maliev, V.; Popov, D. [Russian Academy of Science, Vladicaucas (Russian Federation); Jones, J.; Gonda, S. [NASA -Johnson Space Center, Houston (United States); Prasad, K.; Viliam, C.; Haase, G. [Antioxida nt Research Institute, Premier Micronutrient Corporation, Novato (United States); Kirchin, V. [Moscow State Veterinary and Biotechnology Acade my, Moscow (Russian Federation); Rachael, C. [University Space Research Association, Colorado (United States)

2006-07-01

Experimental anti-radiation vaccine is a power tool of immune - prophylaxis of the acute radiation disease. Existing principles of treatment of the acute radiation dis ease are based on a correction of developing patho-physiological and biochemical processes within the first days after irradiation. Protection from radiation is built on the general principles of immunology and has two main forms - active and passive immunization. Active immunization by the essential radiation toxins of specific radiation determinant (S.D.R.) group allows significantly reduce the lethality and increase duration of life among animals that are irradiated by lethal and sub-lethal doses of gamma radiation.The radiation toxins of S.D.R. group have antigenic properties that are specific for different forms of acute radiation disease. Development of the specific and active immune reaction after intramuscular injection of radiation toxins allows optimize a manifestation of a clinical picture and stabilize laboratory parameters of the acute radiation syndromes. Passive immunization by the anti-radiation serum or preparations of immune-globulins gives a manifestation of the radioprotection effects immediately after this kind of preparation are injected into organisms of mammals. Providing passive immunization by preparations of anti-radiations immune-globulins is possible in different periods of time after radiation. Providing active immunization by preparations of S.D.R. group is possible only to achieve a prophylaxis goal and form the protection effects that start to work in 18 - 35 days after an injection of biological active S.D.R. substance has been administrated. However active and passive immunizations by essential anti-radiation toxins and preparations of gamma-globulins extracted from a hyper-immune serum of a horse have significantly different medical prescriptions for application and depend on many factors like a type of radiation, a power of radiation, absorption doses, a time of

Biological evidence of low ionizing radiation doses

International Nuclear Information System (INIS)

Mirsch, Johanna

2017-01-01

assessed with sub-μm resolution by utilizing the unique morphology of the retina as a model tissue. The analysis revealed a 1/r 2 dependency of the dose deposition by δ-electrons, which was hitherto only determined with physical approaches in inorganic material. Moreover, the biological measurements indicate the presence of a background dose at larger distances from primary particles, which arises as a result of additive dose contributions from several independent particles. In conclusion, this interdisciplinary project put emphasis on the transition between the physical and the biological radiation effects and provided extensive data for the biological verification of physical measurements and models. Some of these models are used for the planning of tumor treatment with charged particles. The second project built upon previously obtained data and focused on the investigation of the DSB repair efficiency of cells irradiated with low doses. For this project, radiation doses were selected that are comparable to the doses, which are routinely used during diagnostic medical examinations. While a linear induction of DSBs with the applied dose was detected in human fibroblasts, these cells fail to repair DSBs efficiently after very low doses of X-rays. However, the repair efficiency was increased in cells pre-treated with low concentrations of hydrogen peroxide, suggesting that this induces a response, which is required for the repair of radiation-induced DSBs after exposure to low radiation doses (Grudzenski et al., 2010, PNAS 107:14205-10). One interpretation of this finding is that a certain cellular radical level is required to efficiently activate the repair machinery. To test this hypothesis, we asked if the DSB repair capacity at low doses can be further diminished when cells are treated with a radical scavenger prior to irradiation. Indeed, a decreased DSB repair capacity in cells pre-treated with the radical scavenger N-Acetylcystein was observed. Appropriate in vivo

Biological effects of low-dose ionizing radiation exposure; Biologische Wirkungen niedriger Dosen ionisierender Strahlung

Energy Technology Data Exchange (ETDEWEB)

Reinoehl-Kompa, Sabine; Baldauf, Daniela; Heller, Horst (comps.)

2009-07-01

The report on the meeting of the Strahlenschutzkommission 2007 concerning biological effects of low-dose ionizing radiation exposure includes the following contributions: Adaptive response. The importance of DNA damage mechanisms for the biological efficiency of low-energy photons. Radiation effects in mammography: the relative biological radiation effects of low-energy photons. Radiation-induced cataracts. Carcinomas following prenatal radiation exposure. Intercellular apoptosis induction and low-dose irradiation: possible consequences for the oncogenesis control. Mechanistic models for the carcinogenesis with radiation-induced cell inactivation: application to all solid tumors in the Japanese atomic bomb survivors. Microarrays at low radiation doses. Mouse models for the analysis of biological effects of low-dose ionizing radiation. The bystander effect: observations, mechanisms and implications. Lung carcinoma risk of Majak workers - modeling of carcinogenesis and the bystander effect. Microbeam studies in radiation biology - an overview. Carcinogenesis models with radiation-induced genomic instability. Application to two epidemiological cohorts.

Towards biologically conformal radiation therapy (BCRT): Selective IMRT dose escalation under the guidance of spatial biology distribution

International Nuclear Information System (INIS)

Yang Yong; Xing Lei

2005-01-01

It is well known that the spatial biology distribution (e.g., clonogen density, radiosensitivity, tumor proliferation rate, functional importance) in most tumors and sensitive structures is heterogeneous. Recent progress in biological imaging is making the mapping of this distribution increasingly possible. The purpose of this work is to establish a theoretical framework to quantitatively incorporate the spatial biology data into intensity modulated radiation therapy (IMRT) inverse planning. In order to implement this, we first derive a general formula for determining the desired dose to each tumor voxel for a known biology distribution of the tumor based on a linear-quadratic model. The desired target dose distribution is then used as the prescription for inverse planning. An objective function with the voxel-dependent prescription is constructed with incorporation of the nonuniform dose prescription. The functional unit density distribution in a sensitive structure is also considered phenomenologically when constructing the objective function. Two cases with different hypothetical biology distributions are used to illustrate the new inverse planning formalism. For comparison, treatments with a few uniform dose prescriptions and a simultaneous integrated boost are also planned. The biological indices, tumor control probability (TCP) and normal tissue complication probability (NTCP), are calculated for both types of plans and the superiority of the proposed technique over the conventional dose escalation scheme is demonstrated. Our calculations revealed that it is technically feasible to produce deliberately nonuniform dose distributions with consideration of biological information. Compared with the conventional dose escalation schemes, the new technique is capable of generating biologically conformal IMRT plans that significantly improve the TCP while reducing or keeping the NTCPs at their current levels. Biologically conformal radiation therapy (BCRT

Ionizing radiation induced biological response and its public health implication

International Nuclear Information System (INIS)

Koeteles, Gy.

1994-01-01

Several sources of ionizing radiation exist in natural and artificial environment of humanity. An overview of their biological effects and the biological response of man is present. Emphasize is given to the differences caused by high and low doses. The interrelation of radiology, radiation hygiene and public health is pointed out. Especially, the physical and biological effects of radiation on cells and their responses are discussed in more detail. (R.P.)

Evaluation of a commercial biologically based IMRT treatment planning system

International Nuclear Information System (INIS)

Semenenko, Vladimir A.; Reitz, Bodo; Day, Ellen; Qi, X. Sharon; Miften, Moyed; Li, X. Allen

2008-01-01

A new inverse treatment planning system (TPS) for external beam radiation therapy with high energy photons is commercially available that utilizes both dose-volume-based cost functions and a selection of cost functions which are based on biological models. The purpose of this work is to evaluate quality of intensity-modulated radiation therapy (IMRT) plans resulting from the use of biological cost functions in comparison to plans designed using a traditional TPS employing dose-volume-based optimization. Treatment planning was performed independently at two institutions. For six cancer patients, including head and neck (one case from each institution), prostate, brain, liver, and rectal cases, segmental multileaf collimator IMRT plans were designed using biological cost functions and compared with clinically used dose-based plans for the same patients. Dose-volume histograms and dosimetric indices, such as minimum, maximum, and mean dose, were extracted and compared between the two types of treatment plans. Comparisons of the generalized equivalent uniform dose (EUD), a previously proposed plan quality index (fEUD), target conformity and heterogeneity indices, and the number of segments and monitor units were also performed. The most prominent feature of the biologically based plans was better sparing of organs at risk (OARs). When all plans from both institutions were combined, the biologically based plans resulted in smaller EUD values for 26 out of 33 OARs by an average of 5.6 Gy (range 0.24 to 15 Gy). Owing to more efficient beam segmentation and leaf sequencing tools implemented in the biologically based TPS compared to the dose-based TPS, an estimated treatment delivery time was shorter in most (five out of six) cases with some plans showing up to 50% reduction. The biologically based plans were generally characterized by a smaller conformity index, but greater heterogeneity index compared to the dose-based plans. Overall, compared to plans based on dose

Biological effects of low doses of ionizing radiation

International Nuclear Information System (INIS)

Gonzalez, A.J.

1994-01-01

Few weeks ago, when the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) submitted to the U.N. General Assembly the UNSCEAR 1994 report, the international community had at its disposal a broad view of the biological effects of low doses of ionizing radiation. The 1994 report (272 pages) specifically addressed the epidemiological studies of radiation carcinogenesis and the adaptive responses to radiation in cells and organisms. The report was aimed to supplement the UNSCEAR 1993 report to the U.N. General Assembly- an extensive document of 928 pages-which addressed the global levels of radiation exposing the world population, as well as some issues on the effects of ionizing radiation, including: mechanisms of radiation oncogenesis due to radiation exposure, influence of the level of dose and dose rate on stochastic effects of radiation, hereditary effects of radiation effects on the developing human brain, and the late deterministic effects in children. Those two UNSCEAR reports taken together provide an impressive overview of current knowledge on the biological effects of ionizing radiation. This article summarizes the essential issues of both reports, although it cannot cover all available information. (Author)

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.

Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

Energy Technology Data Exchange (ETDEWEB)

Scott, Bobby, R., Ph.D.

2003-06-27

OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer. Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on

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)

Dose rate effect models for biological reaction to ionizing radiation in human cell lines

International Nuclear Information System (INIS)

Magae, Junji; Ogata, Hiromitsu

2008-01-01

Full text: Because of biological responses to ionizing radiation are dependent on irradiation time or dose rate as well as dose, simultaneous inclusion of dose and dose rate is required to evaluate the risk of long term irradiation at low dose rates. We previously published a novel statistical model for dose rate effect, modified exponential (MOE) model, which predicts irradiation time-dependent biological response to low dose rate ionizing radiation, by analyzing micronucleus formation and growth inhibition in a human osteosarcoma cell line, exposed to wide range of doses and dose rates of gamma-rays. MOE model demonstrates that logarithm of median effective dose exponentially increases in low dose rates, and thus suggests that the risk approaches to zero at infinitely low dose rate. In this paper, we extend the analysis in various kinds of human cell lines exposed to ionizing radiation for more than a year. We measured micronucleus formation and [ 3 H]thymidine uptake in human cell lines including an osteosarcoma, a DNA-dependent protein kinase-deficient glioma, a SV40-transformed fibroblast derived from an ataxia telangiectasia patient, a normal fibroblast, and leukemia cell lines. Cells were exposed to gamma-rays in irradiation room bearing 50,000 Ci of cobalt-60. After the 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. The number of binuclear cells bearing a micronucleus was counted under a fluorescence microscope. For proliferation inhibition, cells were cultured for 48 h after the irradiation and [ 3 H] thymidine was pulsed for 4 h before harvesting. We statistically analyzed the data for quantitative evaluation of radiation risk. While dose and dose rate relationship cultured within one month followed MOE model in cell lines holding wild-type DNA repair system, dose rate effect was greatly impaired in DNA repair-deficient cell lines

Dose estimation by biological methods

International Nuclear Information System (INIS)

Guerrero C, C.; David C, L.; Serment G, J.; Brena V, M.

1997-01-01

The human being is exposed to strong artificial radiation sources, mainly of two forms: the first is referred to the occupationally exposed personnel (POE) and the second, to the persons that require radiological treatment. A third form less common is by accidents. In all these conditions it is very important to estimate the absorbed dose. The classical biological dosimetry is based in the dicentric analysis. The present work is part of researches to the process to validate the In situ Fluorescent hybridation (FISH) technique which allows to analyse the aberrations on the chromosomes. (Author)

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

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.

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

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

Interpretation of proton relative biological effectiveness using lesion induction, lesion repair, and cellular dose distribution

International Nuclear Information System (INIS)

Paganetti, H.

2005-01-01

Phenomenological biophysical models have been successfully used to estimate the relative biological effectiveness (RBE) of ions. The predictive power of these models is limited because they require measured dose-response data that are not necessarily available for all clinically relevant end points. Furthermore, input parameters often lack mechanistic interpretation. In order to link RBE to more fundamental biological parameters we combine the concepts of two well-established biophysical models, i.e., the phenomenological 'track structure' model and the more mechanistic 'lethal lesion/potentially lethal lesion' (LPL) model. We parametrize a relation between RBE, dose homogeneity in the cell nucleus and induction rates for different lesion types. The macroscopic dose-response relationship is described in the LPL model and the microscopic, subcellular, relationship is determined by the local dose deposition pattern. The formalism provides a framework for a mechanistic interpretation of RBE values

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

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.

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)

Evaluation of experimental animal biological state at exposure to low-dose ionizing radiation

International Nuclear Information System (INIS)

Rozanov, V.A.; Rejtarova, T.Je.; Chernyikov, G.B.; Timoshevs'ka, Je.V.; Kozozojeva, O.O.

1997-01-01

New approaches to quantitative evaluation of ionizing radiation absorbed dose within the low-dose range (up to 400 mGy) according to the degree of the organism biological response was developed. The purpose of the stage of the work published in Communication 1 is to evaluate the shifts in the animal behaviour and cellular composition of the blood at irradiation by the dose of 100,200 and 400 mGy. Distinct dose dependence of behaviour reactions and hematological indices within the dose range of 100-400 mGy was not noted

Biological dose assessment of 15 victims in Haerbin radiation accident

International Nuclear Information System (INIS)

Liu, Jian-xiang; Huang, Min-yan; Ruan, Jian-lei; Bai, Yu-shu; Xu, Su

2008-01-01

Full text: a) On July 5 and 8, 2005, Two patients with bone marrow suppression were successively hospitalized by the First Affiliated Hospital of Haerbin Medical University. Examination results showed that the patients seemed to get suspicious radiation disease. On July 13, 2005, a radioactive source was found in the patients' dwelling. The radiation source is Iridium-192 with 0.5 Ci(1.85 x 10 10 Bq) radioactivity. The radiation source is a metal bar which is a kind of radioactive industrial detection source for welding. The source is currently stored in the urban radioactive waste storehouse of Heilongjiang province. After finding the radioactive source on July 13, The Haerbin municipal government initiated an emergency response plan and developed medical rescue, radioactive source examination and case detection through organizing ministries involving health, environmental protection and public security. After receiving a report at 17:00 on July 14, 2005, Chinese Ministry of Health immediately sent experts to the spot for investigation, dose estimation and direction of patients' rescue. Health authority carried out physical examination twice on 113 residents within 30 meters to the source, among which 4 got radiation sickness, 5 showed abnormal hemotogram, and others showed no abnormal response. Of 4 patients with radiation sickness, one 81 year old patient has died of severe bone marrow form of sub acute radiation sickness coupled with lung infection and prostrate apparatus at 13:00 on Oct., 20. Two children have been treated in Beitaiping Road Hospital in Beijing, another patient has been treated in local hospital. b) Biological dosimetry using conventional chromosome aberration analysis in human peripheral blood lymphocytes has been shown as a reliable and useful tool in medical management of radiation accident victims. Peripheral blood lymphocytes of the victims were cultured using conventional culture medium with colchicine added at the beginning. Chromosome

A biological-based model that links genomic instability, bystander effects, and adaptive response

International Nuclear Information System (INIS)

Scott, B.R.

2004-01-01

This paper links genomic instability, bystander effects, and adaptive response in mammalian cell communities via a novel biological-based, dose-response model called NEOTRANS 3 . The model is an extension of the NEOTRANS 2 model that addressed stochastic effects (genomic instability, mutations, and neoplastic transformation) associated with brief exposure to low radiation doses. With both models, ionizing radiation produces DNA damage in cells that can be associated with varying degrees of genomic instability. Cells with persistent problematic instability (PPI) are mutants that arise via misrepair of DNA damage. Progeny of PPI cells also have PPI and can undergo spontaneous neoplastic transformation. Unlike NEOTRANS 2 , with NEOTRANS 3 newly induced mutant PPI cells and their neoplastically transformed progeny can be suppressed via our previously introduced protective apoptosis-mediated (PAM) process, which can be activated by low linear energy transfer (LET) radiation. However, with NEOTRANS 3 (which like NEOTRANS 2 involves cross-talk between nongenomically compromised [e.g., nontransformed, nonmutants] and genomically compromised [e.g., mutants, transformants, etc.] cells), it is assumed that PAM is only activated over a relatively narrow, dose-rate-dependent interval (D PAM ,D off ); where D PAM is a small stochastic activation threshold, and D off is the stochastic dose above which PAM does not occur. PAM cooperates with activated normal DNA repair and with activated normal apoptosis in guarding against genomic instability. Normal repair involves both error-free repair and misrepair components. Normal apoptosis and the error-free component of normal repair protect mammals by preventing the occurrence of mutant cells. PAM selectively removes mutant cells arising via the misrepair component of normal repair, selectively removes existing neoplastically transformed cells, and probably selectively removes other genomically compromised cells when it is activated

Review of low dose-rate epidemiological studies and biological mechanisms of dose-rate effects on radiation induced carcinogenesis

International Nuclear Information System (INIS)

Iwasaki, Toshiyasu; Otsuka, Kensuke; Yoshida, Kazuo

2015-01-01

Radiation protection system adopts the linear non-threshold model with using dose and dose-rate effectiveness factor (DDREF). The dose-rate range where DDREF is applied is below 100 mGy per hour, and it is regarded that there are no dose-rate effects at very low dose rate, less than of the order of 10 mGy per year, even from the biological risk evaluation model based on cellular and molecular level mechanisms for maintenance of genetic integrity. Among low dose-rate epidemiological studies, studies of residents in high natural background areas showed no increase of cancer risks at less than about 10 mGy per year. On the other hand, some studies include a study of the Techa River cohort suggested the increase of cancer risks to the similar degree of Atomic bomb survivor data. The difference of those results was supposed due to the difference of dose rate. In 2014, International Commission on Radiological Protection opened a draft report on stem cell biology for public consultations. The report proposed a hypothesis based on the new idea of stem cell competition as a tissue level quality control mechanism, and suggested that it could explain the dose-rate effects around a few milligray per year. To verify this hypothesis, it would be needed to clarify the existence and the lowest dose of radiation-induced stem cell competition, and to elucidate the rate of stem cell turnover and radiation effects on it. As for the turnover, replenishment of damaged stem cells would be the important biological process. It would be meaningful to collect the information to show the difference of dose rates where the competition and the replenishment would be the predominant processes. (author)

Detection of base damage in DNA in human blood exposed to ionizing radiation at biologically relevant doses

International Nuclear Information System (INIS)

Loon, A.A.W.M. van; Lohman, P.H.M.; Groenendijk, R.H.; Schans, G.P. van der; Baan, R.A.

1991-01-01

The alkaline elution technique for the detection of DNA damage has been adapted to allow application on unlabelled blood cells. Both the induction and subsequent repair have been studied of two classes of DNA damage, viz. single-strand breaks and base damage recognized by the γ-endonuclease activity in a cell-free extract of Micrococcus luteus bacteria. The high sensitivity of the assay permitted the measurement of induction and repair of base damage after in vitro exposure of full blood under aerobic conditions to biologically relevant doses of γ-rays (1.5-4.5 Gy). After a radiation dose of 3 Gy about 50% of the base damage was removed within 1.5 h of repair. Base damage could still be detected at 24h after exposure to 15 Gy. (author)

Donor-specific cell-based assays in studying sensitivity to low-dose radiation: a population-based perspective

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Dora eIl'yasova

2014-11-01

Full Text Available Currently, a linear no-threshold model is used to estimate health risks associated with exposure to low-dose radiation, a prevalent exposure in the general population, because the direct estimation from epidemiological studies suffers from uncertainty. This model has been criticized based on unique biology of low-dose radiation. Whether the departure from linearity is toward increased or decreased risk is intensely debated. We present an approach based on individual radiosensitivity testing and discuss how individual radiosensitivity can be assessed with the goal to develop a quantifiable measure of cellular response that can be conducted via high-throughput population testing.

The Biological Responses to Magnesium-Based Biodegradable Medical Devices

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Lumei Liu

2017-11-01

Full Text Available The biocompatibility of Magnesium-based materials (MBMs is critical to the safety of biodegradable medical devices. As a promising metallic biomaterial for medical devices, the issue of greatest concern is devices’ safety as degrading products are possibly interacting with local tissue during complete degradation. The aim of this review is to summarize the biological responses to MBMs at the cellular/molecular level, including cell adhesion, transportation signaling, immune response, and tissue growth during the complex degradation process. We review the influence of MBMs on gene/protein biosynthesis and expression at the site of implantation, as well as throughout the body. This paper provides a systematic review of the cellular/molecular behavior of local tissue on the response to Mg degradation, which may facilitate a better prediction of long-term degradation and the safe use of magnesium-based implants through metal innovation.

EUD-based biological optimization for carbon ion therapy

International Nuclear Information System (INIS)

Brüningk, Sarah C.; Kamp, Florian; Wilkens, Jan J.

2015-01-01

Purpose: Treatment planning for carbon ion therapy requires an accurate modeling of the biological response of each tissue to estimate the clinical outcome of a treatment. The relative biological effectiveness (RBE) accounts for this biological response on a cellular level but does not refer to the actual impact on the organ as a whole. For photon therapy, the concept of equivalent uniform dose (EUD) represents a simple model to take the organ response into account, yet so far no formulation of EUD has been reported that is suitable to carbon ion therapy. The authors introduce the concept of an equivalent uniform effect (EUE) that is directly applicable to both ion and photon therapies and exemplarily implemented it as a basis for biological treatment plan optimization for carbon ion therapy. Methods: In addition to a classical EUD concept, which calculates a generalized mean over the RBE-weighted dose distribution, the authors propose the EUE to simplify the optimization process of carbon ion therapy plans. The EUE is defined as the biologically equivalent uniform effect that yields the same probability of injury as the inhomogeneous effect distribution in an organ. Its mathematical formulation is based on the generalized mean effect using an effect-volume parameter to account for different organ architectures and is thus independent of a reference radiation. For both EUD concepts, quadratic and logistic objective functions are implemented into a research treatment planning system. A flexible implementation allows choosing for each structure between biological effect constraints per voxel and EUD constraints per structure. Exemplary treatment plans are calculated for a head-and-neck patient for multiple combinations of objective functions and optimization parameters. Results: Treatment plans optimized using an EUE-based objective function were comparable to those optimized with an RBE-weighted EUD-based approach. In agreement with previous results from photon

Metabolomics identifies a biological response to chronic low-dose natural uranium contamination in urine samples.

Science.gov (United States)

Grison, Stéphane; Favé, Gaëlle; Maillot, Matthieu; Manens, Line; Delissen, Olivia; Blanchardon, Eric; Banzet, Nathalie; Defoort, Catherine; Bott, Romain; Dublineau, Isabelle; Aigueperse, Jocelyne; Gourmelon, Patrick; Martin, Jean-Charles; Souidi, Maâmar

2013-01-01

Because uranium is a natural element present in the earth's crust, the population may be chronically exposed to low doses of it through drinking water. Additionally, the military and civil uses of uranium can also lead to environmental dispersion that can result in high or low doses of acute or chronic exposure. Recent experimental data suggest this might lead to relatively innocuous biological reactions. The aim of this study was to assess the biological changes in rats caused by ingestion of natural uranium in drinking water with a mean daily intake of 2.7 mg/kg for 9 months and to identify potential biomarkers related to such a contamination. Subsequently, we observed no pathology and standard clinical tests were unable to distinguish between treated and untreated animals. Conversely, LC-MS metabolomics identified urine as an appropriate biofluid for discriminating the experimental groups. Of the 1,376 features detected in urine, the most discriminant were metabolites involved in tryptophan, nicotinate, and nicotinamide metabolic pathways. In particular, N -methylnicotinamide, which was found at a level seven times higher in untreated than in contaminated rats, had the greatest discriminating power. These novel results establish a proof of principle for using metabolomics to address chronic low-dose uranium contamination. They open interesting perspectives for understanding the underlying biological mechanisms and designing a diagnostic test of exposure.

Low doses of ionizing radiation: Relationship between biological benefit and damage induction. A synopsis

International Nuclear Information System (INIS)

Feinendegen, L.E.

2005-01-01

Absorption of ionizing radiation in biological tissue stochastically interacts with constituent atoms and molecules and always generates energy deposition (track) events accompanied by bursts of reactive oxygen species (ROS). These ROS are quite similar to those ROS that arise abundantly and constantly by normal oxidative metabolism. ROS effects from either source need attention when assessing radiation-induced alterations in biological structure and function. Endogenous ROS alone induce about 10 6 DNA oxyadducts per cell per day compared to about 5x10 -3 total DNA damage per average cell per day from background radiation exposure (1 mGy per year). At this background level, the corresponding ratio of probabilities of endogenous versus radiogenic DNA double strand breaks (DSBs) per cell per day is about 103 with some 25-40 % of low-LET caused radiogenic DNA-DSBs being of the multi-damage-site type. Radiogenic DNA damage increases in proportion to absorbed dose over a certain dose range. By evolution, tissues possess physiological mechanisms of protection against an array of potentially toxic agents, externally from the environment and endogenously from metabolism, mainly against the abundantly and constantly produced ROS. Ad hoc protection operates at a level that is genetically determined. Following small to moderate perturbation of cell-tissue homeostasis by a toxic impact, adaptive responses develop with a delay and may last from hours to weeks, even months, and aim at protecting the system against renewed insults. Protective responses encompass defense by scavenging mechanisms, DNA repair, damage removal largely by apoptosis and immune responses, as well as changes in cell proliferation. Acute low-dose irradiation below about 0.2 Gy can not only disturb cell-tissue homeostasis but also initiate adaptived protection that appears with a delay of hours and may last from less than a day to months. The balance between damage production and adaptive protection favors

Dose-rate and humidity effects upon the gamma-radiation response of nylon-based radiachromic film dosimeters

International Nuclear Information System (INIS)

Gehringer, P.; Eschweiler, H.; Proksch, E.

1979-10-01

At dose-rates typical for 60 Co gamma irradiation sources, the radiation response of hexahydroxyethyl pararosaniline cyanide/ 50μm nylon radiachromic films is dependent upon dose-rate as well as upon the moisture content of the films, or the relative humidity of the surrounding atmosphere, respectively. Under equilibrium moisture conditions, the response measured at 606 nm 24 hours after end of irradiation shows its highest dose-rate dependence at about 32 % r.h. A decrease in dose-rate from 2.8 to 0.039 Gy.s -1 results in a decrease in response by 17%. At higher humidities, the sensitivity of the film as well as the rate dependence decreases and at 86% r.h. no discernible dose-rate effect could be found. At lower humidities than 32% a flat maximum in response follows. At nominal 0% r.h. a second absorption band at 412 nm appears which is converted completely to an additional 606 nm absorption by exposure to a humid atmosphere. After that procedure the resultant response is somewhat lower than but shows almost the same dose-rate dependence as at 32% r.h. or else to eliminate the dose-rate effect by an extrapolation procedure based on the fact that the rate dependence vanishes at zero dose. (author)

Modelling the Influence of Shielding on Physical and Biological Organ Doses

CERN Document Server

Ballarini, Francesca; Ferrari, Alfredo; Ottolenghi, Andrea; Pelliccioni, Maurizio; Scannicchio, Domenico

2002-01-01

Distributions of "physical" and "biological" dose in different organs were calculated by coupling the FLUKA MC transport code with a geometrical human phantom inserted into a shielding box of variable shape, thickness and material. While the expression "physical dose" refers to the amount of deposited energy per unit mass (in Gy), "biological dose" was modelled with "Complex Lesions" (CL), clustered DNA strand breaks calculated in a previous work based on "event-by-event" track-structure simulations. The yields of complex lesions per cell and per unit dose were calculated for different radiation types and energies, and integrated into a version of FLUKA modified for this purpose, allowing us to estimate the effects of mixed fields. As an initial test simulation, the phantom was inserted into an aluminium parallelepiped and was isotropically irradiated with 500 MeV protons. Dose distributions were calculated for different values of the shielding thickness. The results were found to be organ-dependent. In most ...

Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

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Elizabeth A Brezinski

Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

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.

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

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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.

Exposure dose response relationships of the freshwater bivalve Hyridella australis to cadmium spiked sediments

International Nuclear Information System (INIS)

Marasinghe Wadige, Chamani P.M.; Maher, William A.; Taylor, Anne M.; Krikowa, Frank

2014-01-01

organisms, which suggests that H. australis has some tolerance to cadmium. The metallothionein like protein fraction played an important role in the sequestration and detoxification of cadmium and the amount sequestered in this fraction increased with increased cadmium exposure. The highest percentage of biologically active cadmium was associated with the lysosome + microsome and mitochondrial fractions. Cadmium concentrations in these two fractions of cadmium exposed organisms were significantly higher with respect to controls. Total antioxidant capacity decreased with increased cadmium exposure and tissue dose. Lipid peroxidation increased and lysosomal membrane stability decreased significantly with increased cadmium exposure and tissue dose. Based on exposure–dose–response analysis in this study, H. australis would be a suitable organism for assessing cadmium sediment exposure and toxicity

Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation

Energy Technology Data Exchange (ETDEWEB)

Song, You, E-mail: you.song@niva.no [Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV), Centre for Environmental Radioactivity - CERAD, P.O. Box 5003, N-1432 Ås (Norway); Norwegian Institute for Water Research (NIVA), Gaustadalléen 21, N-0349 Oslo (Norway); Salbu, Brit; Teien, Hans-Christian; Heier, Lene Sørlie [Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV), Centre for Environmental Radioactivity - CERAD, P.O. Box 5003, N-1432 Ås (Norway); Rosseland, Bjørn Olav [Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV), Centre for Environmental Radioactivity - CERAD, P.O. Box 5003, N-1432 Ås (Norway); Norwegian University of Life Sciences (NMBU), Department of Ecology and Natural Resource Management, P.O. Box 5003, N-1432 Ås (Norway); Tollefsen, Knut Erik [Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV), Centre for Environmental Radioactivity - CERAD, P.O. Box 5003, N-1432 Ås (Norway); Norwegian Institute for Water Research (NIVA), Gaustadalléen 21, N-0349 Oslo (Norway)

2014-11-15

Highlights: • First study on early stress responses in salmon exposed to low-dose gamma radiation. • Dramatic dose-dependent transcriptional responses characterized. • Multiple modes of action proposed for gamma radiation. - Abstract: Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280 mGy) gamma radiation after short-term (48 h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280 mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280 mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15 mGy radiation

Responses of epithelial cells to low and very low doses of low let radiation

International Nuclear Information System (INIS)

Mothersill, Carmel; Seymour, Colin

2003-01-01

Recent advances in our knowledge of the biological effects of low doses of ionizing radiation have shown unexpected phenomena. These vary in the endpoint used to detect them and in the dose range examined but all occur as high-frequency events in cell populations. They include: 1. a 'bystander effect' which can be demonstrated at low doses as a transferable.factor(s) causing radiobiological effects in unexposed cells, 2. an assortment of delayed effects' occurring in progeny of cells exposed to low doses, 3. Low-dose Hypersensitivity (HRS) and Increased radioresistance (IRR) which can collectively be demonstrated as a change in the dose-effect relationship, occurring around 0.5-1 Gy of low LET radiation and 4. adaptive responses where cells exposed to very low doses followed by higher doses, exhibit an induced relatively resistant response to the second dose. In all cases, the effect of very low doses is greater than would be predicted by extrapolation of high dose data and is inconsistent with conventional DNA break/repair-based radiobiology. In practical risk assessment terms, the relative importance of the effects are high at low doses where they dominate the response, and small at high doses. This paper reviews these assorted phenomena and in particular seeks to explore whether related or distinct mechanisms underlie these various effects Understanding the mechanistic basis of these phenomena may suggest new approaches to controlling death or survival sectoring at low radiation doses. The key question is whether these low dose phenomena necessitate a new approach to risk assessment. (author)

Late biological effects of ionizing radiation as influenced by dose, dose rate, age at exposure, and genetic sensitivity to neoplastic transformation

International Nuclear Information System (INIS)

Spalding, J.F.; Prine, J.R.; Tietjen, G.L.

1978-01-01

A most comprehensive investigation is in progress at the Los Alamos Scientific Laboratory to study the late biological effects of whole-body exposure to gamma irradiation as they may be influenced by total dose, dose rate, age at exposure, and genetic background. Strain C57B1/6J mice of four age groups (newborn, 2, 6, and 15 months) were given five doses (20, 60, 180, 540, and 1620 rad) of gamma rays, with each dose being delivered at six dose rates (0.7, 2.1, 6.3, 18.9, 56.7 rad/day and 25 rad/min). Forty to sixty mice were used in each of the approximately 110 dose/dose-rate and age combinations. The study was done in two replications with an equal number of mice per replication. Strain RF/J mice were used in a companion study to investigate the influence of genetic background on the type and magnitude of effect. Results of the first and second replications of the 15-month-old age group and data on the influence of genetic background on biological response have been completed, and the results show no significant life shortening within the dose and dose-rate range used

A model for inverse dose-rate effects - low dose-rate hyper-sensibility in response to targeted radionuclide therapy

International Nuclear Information System (INIS)

Murray, I.; Mather, S.J.

2015-01-01

Full text of publication follows. The aim of this work was to test the hypothesis that the Linear-Quadratic (LQ) model of cell survival, developed for external beam radiotherapy (EBRT), could be extended to targeted radionuclide therapy (TRT) in order to predict dose-response relationships in a cell line exhibiting low dose hypersensitivity (LDH). Methods: aliquots of the PC-3 cancer cell line were treated with either EBRT or an in-vitro model of TRT (Irradiation of cell culture with Y-90 EDTA over 24, 48, 72 or 96 hours). Dosimetry for the TRT was calculated using radiation transport simulations with the Monte Carlo PENELOPE code. Clonogenic as well as functional biological assays were used to assess cell response. An extension of the LQ model was developed which incorporated a dose-rate threshold for activation of repair mechanisms. Results: accurate dosimetry for in-vitro exposures of cell cultures to radioactivity was established. LQ parameters of cell survival were established for the PC-3 cell line in response to EBRT. The standard LQ model did not predict survival in PC-3 cells exposed to Y 90 irradiation over periods of up to 96 hours. In fact cells were more sensitive to the same dose when irradiation was carried out over 96 hours than 24 hours. I.e. at a lower dose-rate. Deviations from the LQ predictions were most pronounced below a threshold dose-rate of 0.5 Gy/hr. These results led to an extension of the LQ model based upon a dose-rate dependent sigmoid model of single strand DNA repair. This extension to the model resulted in predicted cell survival curves that closely matched the experimental data. Conclusion: the LQ model of cell survival to radiation has been shown to be largely predictive of response to low dose-rate irradiation. However, in cells displaying LDH, further adaptation of the model was required. (authors)

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.)

Assay of micronuclei in peripheral blood lymphocytes as a biological indicator of radiation dose

International Nuclear Information System (INIS)

Sreedevi, B.; Rao, B.S.

1994-01-01

Chromosomal aberration analysis (CA) has regularly been used as a biological dosemeter to evaluate suspected overexposures to ionising radiations. Recently, the micronucleus (MN) assay has been suggested as an alternative method. An attempt has been made to explore the dose response parameters of MN assay in cytokinesis-blocked lymphocytes. Whole blood was irradiated with 60 Co gamma rays or 250 kV p X rays. A dose-dependent increase in micronuclei yield was observed. The dose response could be best described by a linear-quadratic relationship for both gamma rays and X rays. The α and β coefficients were found to be 1.9 x 10 -2 Gy -1 and 5.7 x 10 -2 Gy -2 for gamma rays and 6.3 x 10 -2 Gy -1 and 4.3 x 10 -2 Gy -2 for X rays, respectively. In the low dose region X rays were three times more efficient in inducing micronuclei. The background value derived for 25 samples from healthy individuals ranged from 6-18 micronuclei per 1000 cells, with a mean value of 12 ± 4 x 10 -3 . Biological dose estimates for individuals exposed in the range 0.1-1 Gy made by MN and CA methods yielded similar results for doses ≥ 0.5 Gy. Due to the uncertainties in the background incidence of MN, at present this technique cannot provide reliable estimates at low doses. (author)

The influence of dose fractionation and dose rate on normal tissue responses

International Nuclear Information System (INIS)

Barendsen, G.W.

1982-01-01

An analysis of responses of a variety of normal tissues in animals to fractionated irradiations has been made with the aim of developing a formalism for the prediction of tolerance doses as a function of the dose per fraction and the overall treatment time. An important feature of the formalism is that it is directly based on radiological insights and therefore provides a logical concept to account for the diversity of tissue responses. (Auth.)

Biological dosimetry of ionizing radiation: Evaluation of the dose with cytogenetic methodologies by the construction of calibration curves

Science.gov (United States)

Zafiropoulos, Demetre; Facco, E.; Sarchiapone, Lucia

2016-09-01

In case of a radiation accident, it is well known that in the absence of physical dosimetry biological dosimetry based on cytogenetic methods is a unique tool to estimate individual absorbed dose. Moreover, even when physical dosimetry indicates an overexposure, scoring chromosome aberrations (dicentrics and rings) in human peripheral blood lymphocytes (PBLs) at metaphase is presently the most widely used method to confirm dose assessment. The analysis of dicentrics and rings in PBLs after Giemsa staining of metaphase cells is considered the most valid assay for radiation injury. This work shows that applying the fluorescence in situ hybridization (FISH) technique, using telomeric/centromeric peptide nucleic acid (PNA) probes in metaphase chromosomes for radiation dosimetry, could become a fast scoring, reliable and precise method for biological dosimetry after accidental radiation exposures. In both in vitro methods described above, lymphocyte stimulation is needed, and this limits the application in radiation emergency medicine where speed is considered to be a high priority. Using premature chromosome condensation (PCC), irradiated human PBLs (non-stimulated) were fused with mitotic CHO cells, and the yield of excess PCC fragments in Giemsa stained cells was scored. To score dicentrics and rings under PCC conditions, the necessary centromere and telomere detection of the chromosomes was obtained using FISH and specific PNA probes. Of course, a prerequisite for dose assessment in all cases is a dose-effect calibration curve. This work illustrates the various methods used; dose response calibration curves, with 95% confidence limits used to estimate dose uncertainties, have been constructed for conventional metaphase analysis and FISH. We also compare the dose-response curve constructed after scoring of dicentrics and rings using PCC combined with FISH and PNA probes. Also reported are dose response curves showing scored dicentrics and rings per cell, combining

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

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)

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)

Vanguards of paradigm shift in radiation biology. Radiation-induced adaptive and bystander responses

International Nuclear Information System (INIS)

Matsumoto, Hideki; Hamada, Nobuyuki; Kobayashi, Yasuhiko; Takahashi, Akihisa; Ohnishi, Takeo

2007-01-01

The risks of exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to high dose radiation, using a linear no-threshold model (LNT model). However, the validity of using this dose-response model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than they do to high dose/high dose-rate radiation. In other words, there are accumulated findings which cannot be explained by the classical ''target theory'' of radiation biology. The radioadaptive response, radiation-induced bystander effects, low-dose radio-hypersensitivity, and genomic instability are specifically observed in response to low dose/low dose-rate radiation, and the mechanisms underlying these responses often involve biochemical/molecular signals that respond to targeted and non-targeted events. Recently, correlations between the radioadaptive and bystander responses have been increasingly reported. The present review focuses on the latter two phenomena by summarizing observations supporting their existence, and discussing the linkage between them from the aspect of production of reactive oxygen and nitrogen species. (author)

Health effects of low-dose radiation: Molecular, cellular, and biosystem response

International Nuclear Information System (INIS)

Pollycove, M.; Paperiello, C.J.

1997-01-01

Since the fifties, the prime concern of radiation protection has been protecting DNA from damage. UNSCEAR initiated a focus on biosystem response to damage with its 1994 report, ''Adaptive Responses to Radiation of Cells and Organisms''. The DNA damage-control biosystem is physiologically operative on both metabolic and radiation induced damage, both effected predominantly by free radicals. These adaptive responses are suppressed by high-dose and stimulated by low dose radiation. Increased biosystem efficiently reduces the number of mutations that accumulate during a lifetime and decrease DNA damage-control with resultant aging and malignancy. Several statistically significant epidemiologic studies have shown risk decrements of cancer mortality and mortality from all causes in populations exposed to low-dose radiation. Further biologic and epidemiologic research is needed to establish a valid threshold below which risk decrements occur. (author)

Treatment planning for heavy ion radiotherapy: calculation and optimization of biologically effective dose

International Nuclear Information System (INIS)

Kraemer, M.; Scholz, M.

2000-09-01

We describe a novel approach to treatment planning for heavy ion radiotherapy based on the local effect model (LEM) which allows to calculate the biologically effective dose not only for the target region but for the entire irradiation volume. LEM is ideally suited to be used as an integral part of treatment planning code systems for active dose shaping devices like the GSI raster scan system. Thus, it has been incorporated into our standard treatment planning system for ion therapy (TRiP). Single intensity modulated fields can be optimized with respect to homogeneous biologically effective dose. The relative biological effectiveness (RBE) is calculated separately for each voxel of the patient CT. Our radiobiologically oriented code system is in use since 1995 for the planning of irradiation experiments with cell cultures and animals such as rats and minipigs. Since 1997 it is in regular and successful use for patient treatment planning. (orig.)

Biological dosimetry: chromosomal aberration analysis for dose assessment

International Nuclear Information System (INIS)

1986-01-01

In view of the growing importance of chromosomal aberration analysis as a biological dosimeter, the present report provides a concise summary of the scientific background of the subject and a comprehensive source of information at the technical level. After a review of the basic principles of radiation dosimetry and radiation biology basic information on the biology of lymphocytes, the structure of chromosomes and the classification of chromosomal aberrations are presented. This is followed by a presentation of techniques for collecting blood, storing, transporting, culturing, making chromosomal preparations and scaring of aberrations. The physical and statistical parameters involved in dose assessment are discussed and examples of actual dose assessments taken from the scientific literature are given

Late biological effects of ionizing radiation as influenced by dose, dose rate, age at exposure and genetic sensitivity to neoplastic transformation

International Nuclear Information System (INIS)

Spalding, J.F.; Prine, J.R.; Tietjen, G.L.

1978-01-01

A most comprehensive investigation is in progress at the Los Alamos Scientific Laboratory to study the late biological effects of whole-body exposure to gamma irradiation as they may be influenced by total dose, dose rate, age at exposure and genetic background. Strain C57B1/6J mice of four age groups (newborn, 2, 6 and l5 months) were given five doses (20, 60, 180, 540, and 1620 rads) of gamma rays, with each dose being delivered at six dose rates (0.7, 2.1, 6.3, 18.9, 56.7 rads/day and 25 rads/min). Forty to sixty mice were used in each of the approximately 119 dose/dose-rate and age combinations. The study was done in two replications with an equal number of mice per replicaton. Strain RF/J mice were used in a companion study to investigate the influence of genetic background on the type and magnitude of effect. Results of the first and second replications of the l5-month-old age group and data on the influence of genetic background on biological response have been completed, and the results show no significant life shortening within the dose and dose-rate range used. It was also concluded that radiaton-induced neoplastic transformaton was significantly greater in mice with a known genetic sensitivity to neoplastic disease than in mammals which do not normally have a significant incidence of tumours. (author)

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner.

Science.gov (United States)

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR.

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

Science.gov (United States)

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID:29531508

The biological bases of the dose-effect relationship

International Nuclear Information System (INIS)

Lafuma, J.

2001-01-01

In radiation protection, the recent data in epidemiology, in animal experimentation and on the base researches are no more compatible with a linear dose-effect relationship without threshold and do not account for the radiological risks at low doses. The cancers should be accelerated by radiations as any pathology linked to the ageing and for which threshold exit. Relative to the genetic risk it is known today that the natural exposure that lasts for several generations has not lead excess of hereditary illness as it was to be feared in 1959 for several countries. Considering that for populations the exposure levels induced by human activities have already been, under these ones of average natural exposures the genetic risk can be negligible and it is the somatic risk alone, with its thresholds that has to be into account. (N.C.)

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.

Rationale for nonlinear dose response functions of power greater or less than one

International Nuclear Information System (INIS)

Baum, J.W.

1977-08-01

Risk estimates and radiation protection standards are generally made using a nonthreshold premise and linear extrapolations from existing data to estimate biological radiation effects at lower doses and at lower dose rates. This seems reasonable in light of the variety of shapes of dose-effect relations which have been observed both in animal studies and in human epidemiological studies. An unexplained observation in several studies was a response which followed a power function of dose with exponent less than one. One explanation offered for this type of response in humans was a postulated population of heterogeneous sensitivity. An alternate, though related, way of considering this question is in terms of multiple-stresses, and this postulate is discussed

Biological response modifiers

Energy Technology Data Exchange (ETDEWEB)

Weller, R.E.

1991-10-01

Much of what used to be called immunotherapy is now included in the term biological response modifiers. Biological response modifiers (BRMs) are defined as those agents or approaches that modify the relationship between the tumor and host by modifying the host's biological response to tumor cells with resultant therapeutic effects.'' Most of the early work with BRMs centered around observations of spontaneous tumor regression and the association of tumor regression with concurrent bacterial infections. The BRM can modify the host response in the following ways: Increase the host's antitumor responses through augmentation and/or restoration of effector mechanisms or mediators of the host's defense or decrease the deleterious component by the host's reaction; Increase the host's defenses by the administration of natural biologics (or the synthetic derivatives thereof) as effectors or mediators of an antitumor response; Augment the host's response to modified tumor cells or vaccines, which might stimulate a greater response by the host or increase tumor-cell sensitivity to an existing response; Decrease the transformation and/or increase differentiation (maturation) of tumor cells; or Increase the ability of the host to tolerate damage by cytotoxic modalities of cancer treatment.

The biological effects of low doses of radiation: medical, biological and ecological aspects

International Nuclear Information System (INIS)

Gun-Aajav, T.; Ajnai, L.; Manlaijav, G.

2007-01-01

Full text: The results of recent studies show that low doses of radiation make many different structural and functional changes in a cell and these changes are preserved for a long time. This phenomenon is called as effects of low doses of radiation in biophysics, radiation biology and radiation medicine. The structural and functional changes depend on doses and this dependence has non-linear and bimodal behaviour. More detail, the radiation effect goes up and reaches its maximum (Low doses maximum) in low doses region, then it goes down and takes its stationary means (there is a negative effect in a few cases). With increases in doses and with further increases it goes up. It is established that low dose's maximum depends on physiological state of a biological object, radiation quality and dose rate. During the experiments another special date was established. This specialty is that many different physical and chemical factors are mutually connected and have synergetic behaviour. At present, researches are concentrating their attention on the following three directions: 1. Direct and indirect interaction of radiation's low doses: 2. Interpretation of its molecular mechanism, regulation of the positive effects and elaboration of ways o removing negative effects: 3. Application of the objective research results into practice. In conclusion the authors mention the current concepts on interpretation of low doses effect mechanism, forward their own views and emphasize the importance of considering low doses effects in researches of environmental radiation pollution, radiation medicine and radiation protection. (author)

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)

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)

WE-AB-BRA-02: Development of Biomechanical Models to Describe Dose-Volume Response to Liver Stereotactic Body Radiation Therapy (SBRT) Patients

International Nuclear Information System (INIS)

McCulloch, M; Polan, D; Feng, M; Lawrence, T; Haken, R Ten; Brock, K

2015-01-01

Purpose: Previous studies have shown that radiotherapy treatment for liver metastases causes marked liver hypertrophy in areas receiving low dose and atrophy/fibrosis in areas receiving high dose. The purpose of this work is to develop and evaluate a biomechanical model-based dose-response model to describe these liver responses to SBRT. Methods: In this retrospective study, a biomechanical model-based deformable registration algorithm, Morfeus, was expanded to include dose-based boundary conditions. Liver and tumor volumes were contoured on the planning images and CT/MR images three months post-RT and converted to finite element models. A thermal expansion-based relationship correlating the delivered dose and volume response was generated from 22 patients previously treated. This coefficient, combined with the planned dose, was applied as an additional boundary condition to describe the volumetric response of the liver of an additional cohort of metastatic liver patients treated with SBRT. The accuracy of the model was evaluated based on overall volumetric liver comparisons and the target registration error (TRE) using the average deviations in positions of identified vascular bifurcations on each set of registered images, with a target accuracy of the 2.5mm isotropic dose grid (vector dimension 4.3mm). Results: The thermal expansion coefficient models the volumetric change of the liver to within 3%. The accuracy of Morfeus with dose-expansion boundary conditions a TRE of 5.7±2.8mm compared to 11.2±3.7mm using rigid registration and 8.9±0.28mm using Morfeus with only spatial boundary conditions. Conclusion: A biomechanical model has been developed to describe the volumetric and spatial response of the liver to SBRT. This work will enable the improvement of correlating functional imaging with delivered dose, the mapping of the delivered dose from one treatment onto the planning images for a subsequent treatment, and will further provide information to assist

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

Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization.

Directory of Open Access Journals (Sweden)

Devaraj Jayachandran

Full Text Available 6-Mercaptopurine (6-MP is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN through enzymatic reaction involving thiopurine methyltransferase (TPMT. Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.

Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization

Science.gov (United States)

Jayachandran, Devaraj; Laínez-Aguirre, José; Rundell, Ann; Vik, Terry; Hannemann, Robert; Reklaitis, Gintaras; Ramkrishna, Doraiswami

2015-01-01

6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP’s widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient’s ability to metabolize the drug instead of the traditional standard-dose-for-all approach. PMID:26226448

Dose-specific transcriptional responses in thyroid tissue in mice after 131I administration

International Nuclear Information System (INIS)

Rudqvist, Nils; Schüler, Emil; Parris, Toshima Z.; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

2015-01-01

Introduction: In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after 131 I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with 131 I exposure in normal mouse thyroid tissue and 2) propose biomarkers for 131 I exposure of the thyroid. Methods: Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of 131 I and killed 24 h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. Results: In total, 497, 546, and 90 transcripts were regulated (fold change ≥ 1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Conclusion: Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to 131 I exposure of thyroid. Advances in knowledge: During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low

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

Testing the Capacity of the National Biological Dose Response Plan (NBDRP) EX40801

Science.gov (United States)

2009-11-01

Blood Collection All donors were volunteers that willingly responded to an advertising call for participation in a research proposal approved by...Scorers from the same laboratory are shown in the same colour . In Figure 2, the dose estimates based on QuickScan are shown. Figure 3 shows the doses

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

Harderian Gland Tumorigenesis: Low-Dose and LET Response

Energy Technology Data Exchange (ETDEWEB)

Chang, Polly Y. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cucinotta, Francis A. [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Bjornstad, Kathleen A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Bakke, James [SRI International, Menlo Park, CA (United States). Biosciences Div.; Rosen, Chris J. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Du, Nicholas [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Fairchild, David G. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cacao, Eliedonna [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Blakely, Eleanor A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.

2016-04-19

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

Biological effects of low-dose radiation on human population living in high-background radiation areas of Kerala coast

International Nuclear Information System (INIS)

Das, Birajalaxmi

2016-01-01

High-level natural radiation areas (HLNRA) of Kerala coast is densely populated and known for its wide variation in background radiation dose levels due to uneven distribution of monazite in the beach sand. The background radiation dose varies from 1 to 45 mGv/y. The areas with >1.5mGy/y is considered as HLNRA. Human population inhabiting in this area are exposed to low-dose chronic radiation since generations. Hence, this population provides an ideal situation to study dose response and adaptive response, if any, due to natural chronic low-dose exposure. It has been investigated extensively to study the biological and health effects of long-term low-dose/low-dose radiation exposure. So far over 150, 000 newborns monitored from hospital-based study did not reveal any significant difference in the incidence of any of the malformations and stillbirth between HLNRA and adjacent control areas. A case-control study on cleft lip/palate and mental retardation did not show any association with background radiation dose. Cytogenetic investigation of over 27,000 newborns did not show any significant increase in the frequency of chromosome aberrations and karyotype anomalies. DNA damage endpoints, such as micronuclei, telomere length and DNA strand breaks, did not reveal any significant difference between control and exposed population. Studies on DNA damage and repair revealed efficient repair of DNA strand breaks in HLNRA individuals. Molecular studies using high throughput microarray analysis indicated a large number of genes involved in various molecular and cellular pathways. Indications of in vivo radioadaptive response due to natural chronic low-dose exposure in this population have important implications to human health. (author)

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.

Radiation research contracts: Biological effects of small radiation doses

Energy Technology Data Exchange (ETDEWEB)

Hug, O [International Atomic Energy Agency, Division of Health, Safety and Waste Disposal, Vienna (Austria)

1959-04-15

To establish the maximum permissible radiation doses for occupational and other kinds of radiation exposure, it is necessary to know those biological effects which can be produced by very small radiation doses. This particular field of radiation biology has not yet been sufficiently explored. This holds true for possible delayed damage after occupational radiation exposure over a period of many years as well as for acute reactions of the organism to single low level exposures. We know that irradiation of less than 25 Roentgen units (r) is unlikely to produce symptoms of radiation sickness. We have, however, found indications that even smaller doses may produce certain instantaneous reactions which must not be neglected

Low dose effects of ionizing radiations in in vitro and in vivo biological systems: a multi-scale approach study

International Nuclear Information System (INIS)

Antoccia, A.; Berardinelli, F.; Argazzi, E.; Balata, M.; Bedogni, R.

2011-01-01

Long-term biological effects of low-dose radiation are little known nowadays and its carcinogenic risk is estimated on the assumption that risk remains linearly proportional to the radiation dose down to low-dose levels. However in the last 20 years this hypothesis has gradually begun to seem in contrast with a huge collection of experimental evidences, which has shown the presence of plethora of non-linear phenomena (including hypersensitivity and induced radioresistance, adaptive response, and non-targeted phenomena like bystander effect and genomic instability) occurring after low-dose irradiation. These phenomena might imply a non-linear behaviour of cancer risk curves in the low-dose region and question the validity of the Linear No-Threshold (LNT) model currently used for cancer risk assessment through extrapolation from existing high-dose data. Moreover only few information is available regarding the effects induced on cryo preserved cells by multi-year background radiation exposure, which might induce a radiation-damage accumulation, due to the inhibition of cellular repair mechanisms. In this framework, the multi-year Excalibur (Exposure effects at low doses of ionizing radiation in biological culture) experiment, funded by INFN-CNS5, has undertaken a multi-scale approach investigation on the biological effects induced in in vitro and in vivo biological systems, in culture and cryo preserved conditions, as a function of radiation quality (X/γ-rays, protons, He-4 ions of various energies) and dose, with particular emphasis on the low-dose region and non-linear phenomena, in terms of different biological endpoints.

Application of Key Events Dose Response Framework to defining the upper intake level of leucine in young men.

Science.gov (United States)

Pencharz, Paul B; Russell, Robert M

2012-12-01

Leucine is sold in large doses in health food stores and is ingested by weight-training athletes. The safety of ingestion of large doses of leucine is unknown. Before designing chronic high-dose leucine supplementation experiments, we decided to determine the effect of graded doses of leucine in healthy participants. The Key Events Dose Response Framework is an organizational and analytical framework that dissects the various biologic steps (key events) that occur between exposure to a substance and an eventual adverse effect. Each biologic event is looked at for its unique dose-response characteristics. For nutrients, there are a number of biologic homeostatic mechanisms that work to keep circulating/tissue levels in a safe, nontoxic range. If a response mechanism at a particular key event is especially vulnerable and easily overwhelmed, this is known as a determining event, because this event drives the overall slope or shape of the dose-response relationship. In this paper, the Key Events Dose Framework has been applied to the problem of leucine toxicity and leucine's tolerable upper level. After analyzing the experimental data vis a vis key events for leucine leading to toxicity, it became evident that the rate of leucine oxidation was the determining event. A dose-response study has been conducted to graded intakes of leucine in healthy human adult male volunteers. All participants were started at the mean requirement level of leucine [50 mg/(kg · d)] and the highest leucine intake was 1250 mg/( kg · d), which is 25 times the mean requirement. No gut intolerance was seen. Blood glucose fell progressively but remained within normal values without any changes in plasma insulin. Maximal leucine oxidation levels occurred at an intake of 550 mg leucine/( kg · d), after which plasma leucine progressively increased and plasma ammonia also increased in response to leucine intakes >500 mg/( kg · d). Thus, the "key determining event" appears to be when the

Flattening the Energy Response of a Scintillator Based Gamma Dose Rate Meter Coupled to SiPM

International Nuclear Information System (INIS)

Knafo, Y.; Manor, A.; Ginzburg, D.; Ellenbogen, M.; Osovizky, A.; Wengrowicz, U.; Ghelman, M.; Seif, R.; Mazor, T.; Kadmon, Y.; Cohen, Y.

2014-01-01

Among the newest emerging technologies that are used in the design of personal gamma radiation detection instruments, the silicon photomultiplier (SiPM) light sensor is playing an important role. This type of photo sensor is characterized by low power consumption, small dimensions and high gain. These special characteristics present applicable alternatives for the replacement of traditional gamma sensors based on scintillator coupled to Photomultiplier tubes (PMT) or on Geiger-Muller(G.M.) sensors. For health physics applications, flat energy response is required for a wide range of radio-nuclides emitting gamma rays of different energies. Scintillation based radiation instrumentation provides count rate and amplitude of the measured pulses. These pulses can be split in different bins corresponding to the energy of the measured isotopes and their intensity. The count rate and the energy of the measured events are related to the dose rate. The conversion algorithm applys a different calibration factor for each energy bin in order to provide an accurate dose rate response for a wide range of gamma energies. This work describes the utilization of an innovative approach for dose rate conversion by using the abilities of newest 32-bit microcontroller based ARM core architecture

Biological effective doses in the intracavitary high dose rate brachytherapy of cervical cancer

Directory of Open Access Journals (Sweden)

Y. Sobita Devi

2011-12-01

Full Text Available Purpose: The aim of this study is to evaluate the decrease of biological equivalent dose and its correlation withlocal/loco-regional control of tumour in the treatment of cervical cancer when the strength of the Ir-192 high dose rate(HDR brachytherapy (BT source is reduced to single, double and triple half life in relation to original strength of10 Ci (~ 4.081 cGy x m2 x h–1. Material and methods: A retrospective study was carried out on 52 cervical cancer patients with stage II and IIItreated with fractionated HDR-BT following external beam radiation therapy (EBRT. International Commission onRadiation Units and Measurement (ICRU points were defined according to ICRU Report 38, using two orthogonal radiographimages taken by Simulator (Simulix HQ. Biologically effective dose (BED was calculated at point A for diffe -rent Ir-192 source strength and its possible correlation with local/loco-regional tumour control was discussed. Result: The increase of treatment time per fraction of dose due to the fall of dose rate especially in HDR-BT of cervicalcancer results in reduction in BED of 2.59%, 7.02% and 13.68% with single, double and triple half life reduction ofsource strength, respectively. The probabilities of disease recurrence (local/loco-regional within 26 months are expectedas 0.12, 0.12, 0.16, 0.39 and 0.80 for source strength of 4.081, 2.041, 1.020, 0.510 and 0.347 cGy x m2 x h–1, respectively.The percentages of dose increase required to maintain the same BED with respect to initial BED were estimated as1.71, 5.00, 11.00 and 15.86 for the dose rate of 24.7, 12.4, 6.2 and 4.2 Gy/hr at point A, respectively. Conclusions: This retrospective study of cervical cancer patients treated with HDR-BT at different Ir-192 sourcestrength shows reduction in disease free survival according to the increase in treatment time duration per fraction.The probable result could be associated with the decrease of biological equivalent dose to point A. Clinical

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

The biological bases of the dose-effect relationship; Les bases biologiques de la relation dose-effet

Energy Technology Data Exchange (ETDEWEB)

Lafuma, J

2001-06-01

In radiation protection, the recent data in epidemiology, in animal experimentation and on the base researches are no more compatible with a linear dose-effect relationship without threshold and do not account for the radiological risks at low doses. The cancers should be accelerated by radiations as any pathology linked to the ageing and for which threshold exit. Relative to the genetic risk it is known today that the natural exposure that lasts for several generations has not lead excess of hereditary illness as it was to be feared in 1959 for several countries. Considering that for populations the exposure levels induced by human activities have already been, under these ones of average natural exposures the genetic risk can be negligible and it is the somatic risk alone, with its thresholds that has to be into account. (N.C.)

Biological influence from low dose and low-dose rate radiation

International Nuclear Information System (INIS)

Magae, Junji

2007-01-01

Although living organisms have defense mechanisms for radioadaptive response, the influence is considered to vary qualitatively and quantitatively for low dose and high dose, as well as for low-dose rate and high-dose rate. This article describes the bioresponse to low dose and low-dose rate. Among various biomolecules, DNA is the most sensitive to radiation, and accurate replication of DNA is an essential requirement for the survival of living organisms. Also, the influence of active enzymes resulted from the effect of radiation on enzymes in the body is larger than the direct influence of radiation on the body. After this, the article describes the carcinogenic risk by low-dose radiation, and then so-called Hormesis effect to create cancer inhibition effect by stimulating active physiology. (S.K.)

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...

Biological dose estimation for accidental supra-high dose gamma-ray exposure

International Nuclear Information System (INIS)

Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

2011-01-01

To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

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)

A single low dose of Fe ions can cause long-term biological responses in NL20 human bronchial epithelial cells

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Cao, Qianlin; Wang, Jingdong; Cao, Jianping; Yang, Hongying [Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou, Jiangsu (China); Liu, Wei [Soochow University, Department of Radiotherapy and Oncology, Second Affiliated Hospital, Suzhou, Jiangsu (China)

2018-03-15

Space radiation cancer risk may be a potential obstacle for long-duration spaceflight. Among all types of cancer space radiation may induce, lung cancer has been estimated to be the largest potential risk. Although previous animal study has shown that Fe ions, the most important contributor to the total dose equivalent of space radiation, induced a higher incidence of lung tumorigenesis per dose than X-rays, the underlying mechanisms at cellular level remained unclear. Therefore, in the present study, we investigated long-term biological changes in NL20 human bronchial epithelial cells after exposure to Fe ion or X-ray irradiation. We found that compared with sham control, the progeny of NL20 cells irradiated with 0.1 Gy of Fe ions showed slightly increased micronucleus formation, significantly decreased cell proliferation, disturbed cell cycle distribution, and obviously elevated intracellular ROS levels accompanied by reduced SOD1 and SOD2 expression, but the progeny of NL20 cells irradiated with 0.9 Gy of X-rays did not show any significant changes. More importantly, Fe ion exposure caused much greater soft-agar colony formation than X-rays did in the progeny of irradiated NL20 cells, clearly suggesting higher cell transformation potential of Fe ions compared with X-rays. These data may shed the light on the potential lung tumorigenesis risk from Fe ion exposure. In addition, ATM inhibition by Ku55933 reversed some of the changes in the progeny of Fe ion-irradiated cells but not others such as soft-agar colony formation, suggesting complex processes from DNA damage to carcinogenesis. These data indicate that even a single low dose of Fe ions can induce long-term biological responses such as cell transformation, etc., suggesting unignorable health risk from space radiation to astronauts. (orig.)

Brachytherapy optimization using radiobiological-based planning for high dose rate and permanent implants for prostate cancer treatment

Science.gov (United States)

Seeley, Kaelyn; Cunha, J. Adam; Hong, Tae Min

2017-01-01

We discuss an improvement in brachytherapy--a prostate cancer treatment method that directly places radioactive seeds inside target cancerous regions--by optimizing the current standard for delivering dose. Currently, the seeds' spatiotemporal placement is determined by optimizing the dose based on a set of physical, user-defined constraints. One particular approach is the ``inverse planning'' algorithms that allow for tightly fit isodose lines around the target volumes in order to reduce dose to the patient's organs at risk. However, these dose distributions are typically computed assuming the same biological response to radiation for different types of tissues. In our work, we consider radiobiological parameters to account for the differences in the individual sensitivities and responses to radiation for tissues surrounding the target. Among the benefits are a more accurate toxicity rate and more coverage to target regions for planning high-dose-rate treatments as well as permanent implants.

Developing point of care and high-throughput biological assays for determining absorbed radiation dose

International Nuclear Information System (INIS)

Joiner, Michael C.; Thomas, Robert A.; Grever, William E.; Smolinski, Joseph M.; Divine, George W.; Konski, Andre A.; Auner, Gregory W.; Tucker, James D.

2011-01-01

Background and purpose: Systems are being developed to assess radiation exposure based on leukocyte mRNA levels obtained by finger-stick sampling. The goal is to provide accurate detection of dose exposures up to 10 Gy for up to 1 week following exposure. We previously showed that specific mRNA sequences increase expression within an hour of exposure, and some genes continue to show elevated expression for at least 24 h. Full duration and dose-dependence of this persistence remain to be determined. In the present study, real-time quantitative PCR (qPCR) was used to determine changes in gene expression. qPCR can rapidly analyze small blood samples and could be adopted into a field-portable instrument that provides a radiation dose readout within 30 min. Materials and methods: From previous microarray analysis of 21,000 genes expressed in human lymphoblastoid cells 4 h post-irradiation (0–4 Gy), 118 genes were selected for evaluation by qPCR of gene expression in the leukocytes of human blood irradiated in vitro with doses of 0–10 Gy from a Co-60 gamma source at a dose rate of 30 cGy/min. Results: Blood from 20 normal healthy human donors yielded many mRNA sequences that could be used for radiation dosimetry. We observed four genes with large and persistent responses following exposure: ASTN2, CDKN1A, GADD45A, and GDF15. Five genes were identified as reliably non-responsive and were suitable for use as endogenous controls: DPM1, ITFG1, MAP4, PGK1, and SLC25A36; of these, ITFG1 was used for the analyses presented here. A significant dose-responsive increase in expression occurred for CDKN1A that was >16-fold at 10 Gy and 3-fold at 0.5 Gy compared to pre-irradiation values. Conclusions: These data show large, selective increases in mRNA transcript levels that persist for at least 48 h after single exposures between 0.5 and 10 Gy. Stable, non-responsive mRNA sequences for use as endogenous controls were also identified. These results indicate that following further

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

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.

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

Effect of edema, relative biological effectiveness, and dose heterogeneity on prostate brachytherapy

International Nuclear Information System (INIS)

Wang, Jian Z.; Mayr, Nina A.; Nag, Subir; Montebello, Joseph; Gupta, Nilendu; Samsami, Nina; Kanellitsas, Christos

2006-01-01

Many factors influence response in low-dose-rate (LDR) brachytherapy of prostate cancer. Among them, edema, relative biological effectiveness (RBE), and dose heterogeneity have not been fully modeled previously. In this work, the generalized linear-quadratic (LQ) model, extended to account for the effects of edema, RBE, and dose heterogeneity, was used to assess these factors and their combination effect. Published clinical data have shown that prostate edema after seed implant has a magnitude (ratio of post- to preimplant volume) of 1.3-2.0 and resolves exponentially with a half-life of 4-25 days over the duration of the implant dose delivery. Based on these parameters and a representative dose-volume histogram (DVH), we investigated the influence of edema on the implant dose distribution. The LQ parameters (α=0.15 Gy -1 and α/β=3.1 Gy) determined in earlier studies were used to calculate the equivalent uniform dose in 2 Gy fractions (EUD 2 ) with respect to three effects: edema, RBE, and dose heterogeneity for 125 I and 103 Pd implants. The EUD 2 analysis shows a negative effect of edema and dose heterogeneity on tumor cell killing because the prostate edema degrades the dose coverage to tumor target. For the representative DVH, the V 100 (volume covered by 100% of prescription dose) decreases from 93% to 91% and 86%, and the D 90 (dose covering 90% of target volume) decrease from 107% to 102% and 94% of prescription dose for 125 I and 103 Pd implants, respectively. Conversely, the RBE effect of LDR brachytherapy [versus external-beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy] enhances dose effect on tumor cell kill. In order to balance the negative effects of edema and dose heterogeneity, the RBE of prostate brachytherapy was determined to be approximately 1.2-1.4 for 125 I and 1.3-1.6 for 103 Pd implants. These RBE values are consistent with the RBE data published in the literature. These results may explain why in earlier modeling studies

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)

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)

Biological indicators for radiation absorbed dose: a review

International Nuclear Information System (INIS)

Paul, S.F.D.; Venkatachalam, P.; Jeevanram, R.K.

1996-01-01

Biological dosimetry has an important role to play in assessing the cumulative radiation exposure of persons working with radiation and also in estimating the true dose received during accidents involving external and internal exposure. Various biodosimetric methods have been tried to estimate radiation dose for the above purposes. Biodosimetric methods include cytogenetic, immunological and mutational assays. Each technique has certain advantages and disadvantages. We present here a review of each technique, the actual method used for detection of dose, the sensitivity of detection and its use in long term studies. (author)

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.

Radiation biology. Chapter 20

Energy Technology Data Exchange (ETDEWEB)

Wondergem, J. [International Atomic Energy Agency, Vienna (Austria)

2014-09-15

Radiation biology (radiobiology) is the study of the action of ionizing radiations on living matter. This chapter gives an overview of the biological effects of ionizing radiation and discusses the physical, chemical and biological variables that affect dose response at the cellular, tissue and whole body levels at doses and dose rates relevant to diagnostic radiology.

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.

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

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

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

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.

In situ biological dose mapping estimates the radiation burden delivered to 'spared' tissue between synchrotron X-ray microbeam radiotherapy tracks.

Directory of Open Access Journals (Sweden)

Kai Rothkamm

Full Text Available Microbeam radiation therapy (MRT using high doses of synchrotron X-rays can destroy tumours in animal models whilst causing little damage to normal tissues. Determining the spatial distribution of radiation doses delivered during MRT at a microscopic scale is a major challenge. Film and semiconductor dosimetry as well as Monte Carlo methods struggle to provide accurate estimates of dose profiles and peak-to-valley dose ratios at the position of the targeted and traversed tissues whose biological responses determine treatment outcome. The purpose of this study was to utilise γ-H2AX immunostaining as a biodosimetric tool that enables in situ biological dose mapping within an irradiated tissue to provide direct biological evidence for the scale of the radiation burden to 'spared' tissue regions between MRT tracks. Γ-H2AX analysis allowed microbeams to be traced and DNA damage foci to be quantified in valleys between beams following MRT treatment of fibroblast cultures and murine skin where foci yields per unit dose were approximately five-fold lower than in fibroblast cultures. Foci levels in cells located in valleys were compared with calibration curves using known broadbeam synchrotron X-ray doses to generate spatial dose profiles and calculate peak-to-valley dose ratios of 30-40 for cell cultures and approximately 60 for murine skin, consistent with the range obtained with conventional dosimetry methods. This biological dose mapping approach could find several applications both in optimising MRT or other radiotherapeutic treatments and in estimating localised doses following accidental radiation exposure using skin punch biopsies.

A new method for dosing uranium in biological media

International Nuclear Information System (INIS)

Henry, Ph.; Kobisch, Ch.

1964-01-01

This report describes a new method for dosing uranium in biological media based on measurement of alpha activity. After treatment of the sample with a mineral acid, the uranium is reduced to the valency four by trivalent titanium and is precipitated as phosphate in acid solution. The uranium is then separated from the titanium by precipitation as UF 4 with lanthanum as carrier. A slight modification, unnecessary in the case of routine analyses, makes it possible to eliminate other possible alpha emitters (thorium and transuranic elements). (authors) [fr

Oligodendroglial response to ionizing radiation: Dose and dose-rate response

International Nuclear Information System (INIS)

Levy, R.P.

1991-01-01

An in vitro system using neuroglia from neonatal rat brain was developed to examining the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute γ-radiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. It was concluded that oligodendrocytes in irradiated cultures had significantly lower functional capacity than did unirradiated controls. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. At DIC 14, the group irradiated in a single fraction had significantly lower oligodendrocyte counts than any group given split doses; all irradiated cultures had marked depression of MBP synthesis, but to significant differences referable to time interval between doses. At DIC 21, cultures irradiated at intervals of 0 h to 2 h had similar oligodendrocyte counts to one another, but these counts were significantly lower than in cultures irradiated at intervals of 4 h to 6 h; MBP levels remained depressed at DIC 21 for all irradiated cultures. The oligodendrocyte response to dose rate (0.03 to 1.97 Gy/min) was evaluated at DIC 14 and DIC 21. Exposure at 0.03 Gy/min suppressed oligodendrocyte counts at DIC 21 less than did higher dose rates in 5-Gy irradiated cultures

Biological UV-doses and the effect on an ozone layer depletion

International Nuclear Information System (INIS)

Dahlback, A.; Henriksen, T.

1988-08-01

Effective UV-doses were calculated based on the integrated product of the biological action spectrum and the solar radiation. The calculations included absorption and scattering of UV-radiation in the atmosphere, both for normal ozone conditions as well as for a depleted ozone layer. The effective annual UV-dose increases by approximately 4% per degree of latitude towards the equator. An ozone depletion of 1% increases the annual UV-dose by approximately 1% at 60 o N. A large depletion of 50% over Scandinavia (60 o N) would give this region an effective UV-dose similar to that obtained, with normal ozone conditions, at a latitude of 40 o N (California or the Mediterranean countries). The Antarctic ozone hole increases the annual UV-dose by 20 to 25% which is a similar increase as that attained by moving 5 to 6 degrees of latitude nearer the equator. The annual UV-dose on higher latitudes is mainly determined by the summer values of ozone. Both the ozone values and the effective UV-doses vary from one year to another (within ±4%). No positive or negative trend is observed for Scandinavia from 1978 to 1988

The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent

International Nuclear Information System (INIS)

Naciff, Jorge M.; Khambatta, Zubin S.; Reichling, Timothy D.; Carr, Gregory J.; Tiesman, Jay P.; Singleton, David W.; Khan, Sohaib A.; Daston, George P.

2010-01-01

A reliable in vitro model to determine the potential estrogenic activity of chemicals of interest is still unavailable. To further investigate the usefulness of a human-derived cell line, we determined the transcriptional changes induced by bisphenol A (BPA) in Ishikawa cells at various doses (1 nM, 100 nM, 10 μM, and 100 μM) and time points (8, 24 and 48 h) by comparing the response of approximately 38,500 human genes and ESTs between treatment groups and controls (vehicle-treated). By trend analysis, we determined that the expression of 2794 genes was modified by BPA in a dose- and time-dependent manner (p ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest doses of BPA evaluated (10-100 μM), while the genomic response of the cells exposed to low doses of BPA was essentially negligible. By comparing the Ishikawa cells' response to BPA vs.17α-ethynyl estradiol we determined that the change in the expression of 307 genes was identical in the direction of the change, although the magnitude of the change for some genes was different. Further, the response of Ishikawa cells to high doses of BPA shared similarities to the estrogenic response of the rat uterus, specifically, 362 genes were regulated in a similar manner in vivo as well as in vitro. Gene ontology analysis indicated that BPA results in changes to multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response after exposure to chemicals with varied estrogenic activity, and offer an in vitro model to assess this mode of action.

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.

Time and dose in carcinogenesis

International Nuclear Information System (INIS)

Mayneord, W.V.; Clarke, R.H.

1978-05-01

Previous work on the implications of different forms of dose response relationships is extended to include time as a variable, not only in time of irradiation but also in the time of appearance of effects following irradiation. The forms of relationships for time distribution of tumours revealed experimentally for both radiation and chemical carcinogens are first considered. It appears that much data may be correlated in terms of a log-normal distribution of tumour yield following the insult. Further, it is noted, that there is evidence that the median time of tumour appearance may be a function of total dose received or even of dose rate for protracted exposure. Using numerical values of these parameters derived from the biological literature speculative studies have been made of the effects on dose response relationships of using a time distribution of tumour yield, considering both uniform irradiation and point sources. In addition the effects of using dose rate rather than dose to define the log-normal distribution to tumour appearance have been investigated. It is assumed that biological response is directly proportional to dose but that effect is distributed in time. From this linear assumption the appearance of non-linear dose response relationships and apparent thresholds are continually seen. Finally, both the importance of attempting analyses of biological data in terms of stochastic concepts and the need for biological data to test our hypotheses is emphasised. (author)

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

Biological evidence of low ionizing radiation doses; Biologischer Nachweis niedriger Dosen ionisierender Strahlung

Energy Technology Data Exchange (ETDEWEB)

Mirsch, Johanna

2017-03-17

assessed with sub-μm resolution by utilizing the unique morphology of the retina as a model tissue. The analysis revealed a 1/r{sup 2} dependency of the dose deposition by δ-electrons, which was hitherto only determined with physical approaches in inorganic material. Moreover, the biological measurements indicate the presence of a background dose at larger distances from primary particles, which arises as a result of additive dose contributions from several independent particles. In conclusion, this interdisciplinary project put emphasis on the transition between the physical and the biological radiation effects and provided extensive data for the biological verification of physical measurements and models. Some of these models are used for the planning of tumor treatment with charged particles. The second project built upon previously obtained data and focused on the investigation of the DSB repair efficiency of cells irradiated with low doses. For this project, radiation doses were selected that are comparable to the doses, which are routinely used during diagnostic medical examinations. While a linear induction of DSBs with the applied dose was detected in human fibroblasts, these cells fail to repair DSBs efficiently after very low doses of X-rays. However, the repair efficiency was increased in cells pre-treated with low concentrations of hydrogen peroxide, suggesting that this induces a response, which is required for the repair of radiation-induced DSBs after exposure to low radiation doses (Grudzenski et al., 2010, PNAS 107:14205-10). One interpretation of this finding is that a certain cellular radical level is required to efficiently activate the repair machinery. To test this hypothesis, we asked if the DSB repair capacity at low doses can be further diminished when cells are treated with a radical scavenger prior to irradiation. Indeed, a decreased DSB repair capacity in cells pre-treated with the radical scavenger N-Acetylcystein was observed. Appropriate in

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

Imprecision in estimates of dose from ingested 137Cs due to variability in human biological characteristics

International Nuclear Information System (INIS)

Schwarz, G.; Dunning, D.E. Jr.

1982-01-01

An attempt has been made to quantify the variability in human biological parameters determining dose to man from ingestion of a unit activity of soluble 137 Cs and the resulting imprecision in the predicted total-body dose commitment. The analysis is based on an extensive review of the literature along with the application of statistical methods to determine parameter variability, correlations between parameters, and predictive imprecision. The variability in the principal biological parameters (biological half-time and total-body mass) involved can be described by a geometric standard deviation of 1.2-1.5 for adults and 1.6-1.9 for children/ adolescents of age 0.1-18 yr. The estimated predictive imprecision (using a Monte Carlo technique) in the total-body dose commitment from ingested 137 Cs can be described by a geometric standard deviation on the order of 1.3-1.4, meaning that the 99th percentile of the predicted distribution of dose is within approximately 2.1 times the mean value. The mean dose estimate is 0.009 Sv/MBq (34 mrem/μ Ci) for children/adolescents and 0.01 Sv/MBq (38 mrem/μ Ci) for adults. Little evidence of age dependence in the total-body dose from ingested 137 Cs is observed. (author)

Cytogenetic biological dosimetry. Dose estimative in accidental exposure

International Nuclear Information System (INIS)

Santos, O.R. dos; Campos, I.M.A. de.

1988-01-01

The methodology of cytogenetic biological dosimetry is studied. The application in estimation of dose in five cases of accidental exposure is reported. An hematological study and culture of lymphocytes is presented. (M.A.C.) [pt

Dose estimate of exposure to radioisotopes in molecular and cellular biology

International Nuclear Information System (INIS)

Onado, C.; Faretta, M.; Ubezio, P.

1999-01-01

A method for prospectively evaluating the annual equivalent doses and effective dose to biomedical researchers working with unsealed radioisotopes, and their classification, is presented here. Simplified formulae relate occupational data to a reasonable overestimate of the annual effective dose, and the equivalent doses to the hands and to the skin. The procedure, up to the classification of personnel and laboratories, can be made fully automatic, using a common spreadsheet on a personal computer. The method is based on occupational data, accounting for the amounts of each radioisotope used by a researcher, the time of exposure and the overall amounts employed in the laboratories where experiments are performed. The former data serve to forecast a contribution to the dose arising from a researcher's own work, the latter to a forecast of an 'environmental' contribution deriving simply from the presence in a laboratory where other people are working with radioisotopes. The estimates of the doses due to one's own radioisotope handling and to 'environment' were corrected for accidental exposure, considered as a linear function of the manipulated activity or of the time spent in the laboratories respectively, and summed up to give the effective dose. The effective dose associated with some common experiments in molecular and cellular biology is pre-evaluated by this method. (author)

TLD estimation of absorbed dose for 131I on the surface of biological organs of REMCAL phantom

International Nuclear Information System (INIS)

Tandon, Pankaj; Gaur, P.K.; Bhatt, B.C.; Soni, P.S.

2001-01-01

In nuclear medicine, the accuracy of absorbed dose of an internally distributed radiopharmaceuticals estimated by the MIRD (medical internal radiation dose) method depends on the cumulated activity of the source organs and their mass. The usual method for obtaining the cumulated activities are: 1) direct measurements by a) positron emission tomography (PET) and b) single photon emission computed tomography (SPECT) 2) extrapolation from animal data and 3) calculations based on the mathematical biokinetic model. Among these methods, extrapolation of animal data to humans includes inevitable inaccuracy due to large interspecies metabolic differences with regard to the administered radiochemical. Biokinetic modeling requires adequate knowledge of various kinetic parameters, which is based on some biological assumptions. Direct measurements can provide cumulated distributions with fewer biological assumptions. But direct measurements of PET/SPECT are difficult to perform routinely. A method has been developed to obtain the surface dose of different biological organs by using TLDs. Here, a number of TLDs are placed just above the surface of the biological organs of the REMCAL Alderson human phantom filled with water. Firstly, investigation of the accuracy of this method by calibration studies using the said phantom, which is having the entire biological organ intact and simulate the organs as human body is done. These organs are filled with the known activity of the radioisotope. In the present study, estimation of radiation dose received by fifteen different target organs, when the known activity was filled in the three major organs of interest was carried out

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

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

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.

Predicted allowable doses to normal organs for biologically targeted radiotherapy

International Nuclear Information System (INIS)

O'Donoghue, J.A.; Wheldon, T.E.; Western Regional Hospital Board, Glasgow

1988-01-01

The authors have used Dale's extension to the ''linear quadratic'' (LQ) model (Dale, 1985) to evaluate ''equivalent doses'' in cases involving exponentially decaying dose rates. This analysis indicates that the dose-rate effect will be a significant determinant of allowable doses to organs such as liver, kidney and lung. These organ tolerance doses constitute independent constraints on the therapeutic intensity of biologically targeted radiotherapy in exactly the same way as for conventional external beam radiotherapy. In the context of marrow rescue they will in all likelihood constitute the dose-limiting side-effects and thus be especially important. (author)

Study on the radiation-induced biological responses based on the analysis of metabolites

International Nuclear Information System (INIS)

Jo, Sungkee; Jung, Uhee; Park, Haeran; Roh, Changhyun; Shin, Heejune; Ryu, Dongkyoung

2013-01-01

1. Objectives □ Establishment of basis of biological radiation response study by metabolite analysis 2. Project results □ Establishment of analytical basis of radiation-responsive metabolites in biological samples - Large scale collection of tissue samples from irradiated animal for radiation metabolomics research - Establishment of mass spectromety (GC MS, LC MS-MS) analysis methods of biological samples - 3 Standard Operation Protocols (SOP) for ultra high resolution mass spectrometry (FT-ICR MS, Q-TOF MS) analysis of metabolites from biological samples - Establishment of database for radiation metabolites □ Basic research on radiation-responsive metabolites and the interpretation of their functions - Validation of spermidine as a candidate biomarker of acute radiation response in mouse blood - Verification of 5 radiation-responsive steroid hormones and alteration of their metabolic enzyme activities in mouse blood - Verification of 13 radiation-responsive amino acids (related to oxidative stress, neurotransmission, energy metabolism) in regional mouse brain -Verification of 10 radiation-responsive amino acids (related to oxidative stress, neurotransmission, energy metabolism) in regional mouse brain - Verification of 74 radiation-responsive metabolites in whole rat brain by ultra high resolution FT-ICR MS and Q-TOF MS analysis 3. Expected benefits and plan of application □ Establishment of research basis of radiation metabolomics in Korea □ Provision of core technology in radiation bioscience and safety field by application of radiation metabolomics results to the technology development in radiation biodosimetry, and radiation response evaluation and modulation

Study on the radiation-induced biological responses based on the analysis of metabolites

Energy Technology Data Exchange (ETDEWEB)

Jo, Sungkee; Jung, Uhee; Park, Haeran; Roh, Changhyun; Shin, Heejune; Ryu, Dongkyoung

2013-01-15

1. Objectives □ Establishment of basis of biological radiation response study by metabolite analysis 2. Project results □ Establishment of analytical basis of radiation-responsive metabolites in biological samples - Large scale collection of tissue samples from irradiated animal for radiation metabolomics research - Establishment of mass spectromety (GC MS, LC MS-MS) analysis methods of biological samples - 3 Standard Operation Protocols (SOP) for ultra high resolution mass spectrometry (FT-ICR MS, Q-TOF MS) analysis of metabolites from biological samples - Establishment of database for radiation metabolites □ Basic research on radiation-responsive metabolites and the interpretation of their functions - Validation of spermidine as a candidate biomarker of acute radiation response in mouse blood - Verification of 5 radiation-responsive steroid hormones and alteration of their metabolic enzyme activities in mouse blood - Verification of 13 radiation-responsive amino acids (related to oxidative stress, neurotransmission, energy metabolism) in regional mouse brain -Verification of 10 radiation-responsive amino acids (related to oxidative stress, neurotransmission, energy metabolism) in regional mouse brain - Verification of 74 radiation-responsive metabolites in whole rat brain by ultra high resolution FT-ICR MS and Q-TOF MS analysis 3. Expected benefits and plan of application □ Establishment of research basis of radiation metabolomics in Korea □ Provision of core technology in radiation bioscience and safety field by application of radiation metabolomics results to the technology development in radiation biodosimetry, and radiation response evaluation and modulation.

Epistemological problems in assessing cancer risks at low radiation doses

International Nuclear Information System (INIS)

Walinder, G.

1987-01-01

Historically, biology has not been subjected to any epistemological analysis as has been the case with mathematics and physics. Our knowledge of the effects in biological systems of various stimuli proves to be dualistic in a complementary (although not mutually exclusive) way, which bears resemblance to the knowledge of phenomena in quantum physics. The dualistic limbs of biological knowledge are the action of stimuli and the response of the exposed, biological system. With regard to radiogenic cancer, this corresponds to the action of the ionizations and the response of the exposed mammal to that action, respectively. The following conclusions can be drawn from the present analysis: Predictions as to radiogenic cancer seem often if not always to have neglected the response variability (variations in radiosensitivity) in individuals or among individuals in populations, i.e. the predictions have been based exclusively on radiation doses and exposure conditions. The exposed individual or population, however, must be considered an open statistical system, i.e. a system in which predictions as to the effect of an agent are only conditionally possible. The knowledge is inverse to the size of the dose or concentration of the active agent. On epistemological grounds, we can not gain knowledge about the carcinogenic capacity of very low (non-dominant) radiation doses. Based on the same principle, we can not predict cancer risks at very low (non-dominant) radiation doses merely on the basis of models, or otherwise interpolated or extrapolated high-dose effects, observed under special exposure conditions

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd→Be) for normal tissues. Pt. 3

International Nuclear Information System (INIS)

Rezvani, M.; Hopewell, J.W.; Robbins, M.E.C.; Hamlet, R.; Barnes, D.W.H.; Sansom, J.M.; Adams, P.J.V.

1990-01-01

The effect of single and fractionated doses of fast neutrons (42 MeV d→Bc ) on the early and late radiation responses of the pig lung have been assessed by the measurement of changes in lung function using a 133 Xe washout technique. The results obtained for irradiation schedules with fast neutrons have been compared with those after photon irradiation. There was no statistically significant difference between the values for the relative biological effectiveness (RBE) for the early and late radiation response of the lung. The RBE of the neutron beam increased with decreasing size of dose/fraction with an upper limit value of 4.39 ± 0.94 for infinitely small X-ray doses per fraction. (author)

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.

Comparative transcriptome analysis of rice seedlings induced by different doses of heavy ion radiation

Science.gov (United States)

Zhao, Qian; Sun, Yeqing; Wang, Wei

2016-07-01

Highly ionizing radiation (HZE) in space is considered as a main factor causing biological effects on plant seeds. To investigate the different effects on genome-wide gene expression of low-dose and high-dose ion radiation, we carried out ground-base carbon particle HZE experiments with different cumulative doses (0Gy, 0.2Gy, 2Gy) to rice seeds and then performed comparative transcriptome analysis of the rice seedlings. We identified a total of 2551 and 1464 differentially expressed genes (DEGs) in low-dose and high-dose radiation groups, respectively. Gene ontology analyses indicated that low-dose and high-dose ion radiation both led to multiple physiological and biochemical activities changes in rice. By Gene Ontology analyses, the results showed that only one process-oxidation reduction process was enriched in the biological process category after high-dose ion radiation, while more processes such as response to biotic stimulus, heme binding, tetrapyrrole binding, oxidoreductase activity, catalytic activity and oxidoreductase activity were significantly enriched after low-dose ion radiation. The results indicated that the rice plants only focused on the process of oxidation reduction to response to high-dose ion radiation, whereas it was a coordination of multiple biological processes to response to low-dose ion radiation. To elucidate the transcriptional regulation of radiation stress-responsive genes, we identified several DEGs-encoding TFs. AP2/EREBP, bHLH, C2H2, MYB and WRKY TF families were altered significantly in response to ion radiation. Mapman analysis speculated that the biological effects on rice seedlings caused by the radiation stress might share similar mechanisms with the biotic stress. Our findings highlight important alterations in the expression of radiation response genes, metabolic pathways, and TF-encoding genes in rice seedlings exposed to low-dose and high-dose ion radiation.

Dose response relationship in anti-stress gene regulatory networks.

Science.gov (United States)

Zhang, Qiang; Andersen, Melvin E

2007-03-02

the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

Dose response relationship in anti-stress gene regulatory networks.

Directory of Open Access Journals (Sweden)

Qiang Zhang

2007-03-01

, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

Biological stress responses induced by alpha radiation exposure in Lemna minor

Energy Technology Data Exchange (ETDEWEB)

Van Hoeck, A.; Horemans, N.; Van Hees, M.; Nauts, R. [Belgian Nuclear Research Centre SCK-CEN (Belgium); Knapen, D.; Blust, R. [University of Antwerp (Belgium)

2014-07-01

To enhance the robustness of radiation protection criteria for biota, additional information on the biological impact of radionuclides on non-human biota is needed. In particular the effects of alpha emitting isotopes have been poorly studied within a radioecological contextual though they exhibit a high linear energy transfer which can cause significant biological damage when taken up by organisms. Therefore, it is not only essential to measure alpha radiation toxicity, but also try to understand the underlying mechanisms of this stressor. The current study aimed to contribute to a better knowledge of the fundamental processes regulating alpha radiation stress response mechanisms in higher plants. {sup 241}Am was primarily selected as it is an almost pure alpha emitter and, as a daughter nuclide of {sup 241}Pu, it will become one of the dominant pollutants in plutonium affected areas. The aquatic macrophyte Lemna minor has proven its value in eco-toxicological research as representative of higher aquatic plants (OECD guideline nr. 221) and will be used to analyze alpha radiation stress in plant systems. An individual growth inhibition test was set up by means of single dose-response curve in order to identify the Effective Dose Rates (EDR-values) for frond size and biomass. As the mean path length is small for alpha particles, the accumulation of the radionuclide inside species represents almost exclusively the dosimetry. Therefore, quantification of {sup 241}Am uptake and {sup 241}Am distribution were evaluated separately for roots and fronds taking the activity concentrations of growth medium into account. Taken together with the respective dose conversion coefficients from the ERICA tool, this allowed to construct an accurate dosimetric model to determine internal and external dose rates. Different standard media were tested on growth rate and biomass to analyse the amount of {sup 241}Am taken up by the plants exposed from 2.5 to 100 kBq/L. From these

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

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.

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.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

Energy Technology Data Exchange (ETDEWEB)

Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 (United States)

2013-05-15

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

International Nuclear Information System (INIS)

Zeng Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

Science.gov (United States)

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

2013-05-01

Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability

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.)

Cancer risk of low dose/low dose rate radiation: a meta-analysis of cancer data of mammals exposed to low doses of radiation

International Nuclear Information System (INIS)

Ogata, Hiromitsu; Magae, Junji

2008-01-01

Full text: Linear No Threshold (LNT) model is a basic theory for radioprotection, but the adaptability of this hypothesis to biological responses at low doses or at low dose rates is not sufficiently investigated. Simultaneous consideration of the cumulative dose and the dose rate is necessary for evaluating the risk of long-term exposure to ionizing radiation at low dose. This study intends to examine several numerical relationships between doses and dose rates in biological responses to gamma radiation. Collected datasets on the relationship between dose and the incidence of cancer in mammals exposed to low doses of radiation were analysed using meta-regression models and modified exponential (MOE) model, which we previously published, that predicts irradiation time-dependent biological response at low dose rate ionizing radiation. Minimum doses of observable risk and effective doses with a variety of dose rates were calculated using parameters estimated by fitting meta-regression models to the data and compared them with other statistical models that find values corresponding to 'threshold limits'. By fitting a weighted regression model (fixed-effects meta-regression model) to the data on risk of all cancers, it was found that the log relative risk [log(RR)] increased as the total exposure dose increased. The intersection of this regression line with the x-axis denotes the minimum dose of observable risk. These estimated minimum doses and effective doses increased with decrease of dose rate. The goodness of fits of MOE-model depended on cancer types, but the total cancer risk is reduced when dose rates are very low. The results suggest that dose response curve for cancer risk is remarkably affected by dose rate and that dose rate effect changes as a function of dose rate. For scientific discussion on the low dose exposure risk and its uncertainty, the term 'threshold' should be statistically defined, and dose rate effects should be included in the risk

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.

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

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)

A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

Energy Technology Data Exchange (ETDEWEB)

Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A., E-mail: marcelazoo@yahoo.com.br [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Departamento de Energia Nuclear

2015-10-15

Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. (author)

A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

Science.gov (United States)

Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

2015-10-01

Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

Global DNA methylation responses to low dose radiation exposure

International Nuclear Information System (INIS)

Newman, M.R.; Ormsby, R.J.; Blyth, B.J.; Sykes, P.J.; Bezak, E.

2011-01-01

Full text: High radiation doses cause breaks in the DNA which are considered the critical lesions in initiation of radiation-induced cancer. However, at very low radiation doses relevant for the general public, the induction of such breaks will be rare, and other changes to the DNA such as DNA methylation which affects gene expression may playa role in radiation responses. We are studying global DNA methylation after low dose radiation exposure to determine if low dose radiation has short- and/or long-term effects on chromatin structure. We developed a sensitive high resolution melt assay to measure the levels of DNA methylation across the mouse genome by analysing a stretch of DNA sequence within Long Interspersed Nuclear Elements-I (LINE I) that comprise a very large proportion of the mouse and human genomes. Our initial results suggest no significant short-term or longterm) changes in global NA methylation after low dose whole-body X-radiation of 10 J1Gyor 10 mGy, with a significant transient increase in NA methylation observed I day after a high dose of I Gy. If the low radiation doses tested are inducing changes in bal DNA methylation, these would appear to be smaller than the variation observed between the sexes and following the general stress of the sham-irradiation procedure itself. This research was funded by the Low Dose Radiation Research Program, Biological and Environmental Research, US DOE, Grant DE-FG02-05ER64104 and MN is the recipient of the FMCF/BHP Dose Radiation Research Scholarship.

Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

International Nuclear Information System (INIS)

Baechler, Sebastien; Hobbs, Robert F.; Prideaux, Andrew R.; Wahl, Richard L.; Sgouros, George

2008-01-01

In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high α/β), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial

Biological responses of a tropical coastal ecosystem to releases from electro-nuclear installations

International Nuclear Information System (INIS)

Patel, B.; Patel, S.; Balani, M.C.

1979-01-01

The implications of low-level radioactive waste discharges from electronuclear installations on the biological responses of the arcid clam Anadara granosa have been studied. The rate of feeding, measured in terms of clearance of dye suspension, was not affected by exposure to acute doses of up to 5 R. Exposure to higher doses (up to 40 R) increased the rate by 70%. On further irradiation (100-700 R), however, it dropped significantly. The changes in the feeding rates following bioaccumulation of the fission product nuclides have also been studied. The effect of ionizing radiations at the cellular level was evaluated by studying the electrophoretic mobility of clam erythrocytes. The electrokinetic behaviour of erythrocytes was not affected following irradiation at low doses (0.1 kR), but on exposure to higher doses (1-8 kR) the EPM showed oscillatory behaviour. The paper also discusses the biological half-life of caesium-137, its localization in subcellular fractions of various tissues of A. granosa and the effects of low-level discharges on the intertidal ecosystem. (author)

Genome Wide Evaluation of Normal Human Tissue in Response to Controlled, In vivo Low-Dose Low LET Ionizing Radiation Exposure: Pathways and Mechanisms Final Report, September 2013

Energy Technology Data Exchange (ETDEWEB)

Rocke, David M. [University of California Davis

2013-09-09

During course of this project, we have worked in several areas relevant to low-dose ionizing radiation. Using gene expression to measure biological response, we have examined the response of human skin exposed in-vivo to radation, human skin exposed ex-vivo to radiation, and a human-skin model exposed to radiation. We have learned a great deal about the biological response of human skin to low-dose ionizing radiation.

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

The biologically equivalent dose BED - Is the approach for calculation of this factor really a reliable basis?

International Nuclear Information System (INIS)

Jensen, J.M.; Zimmermann, J.

2000-01-01

To predict the effect on tumours in radiotherapy, especially relating to irreversible effects, but also to realize the retrospective assessment the so called L-Q-model is relied on at present. Internal specific organ parameters, such as α, β, γ, T p , T k , and ρ, as well as external parameters, so as D, d, n, V, and V ref , were used for determination of the biologically equivalent dose BED. While the external parameters are determinable with small deviations, the internal parameters depend on biological varieties and dispersons: In some cases the lowest value is assumed to be Δ=±25%. This margin of error goes on to the biologically equivalent dose by means of the principle of superposition of errors. In some selected cases (lung, kidney, skin, rectum) these margins of error were calculated exemplarily. The input errors especially of the internal parameters cause a mean error Δ on the biologically equivalent dose and a dispersion of the single fraction dose d dependent on the organ taking into consideration, of approximately 8-30%. Hence it follows only a very critical and cautious application of those L-Q-algorithms in expert proceedings, and in radiotherapy more experienced based decisions are recommended, instead of acting only upon simple two-dimensional mechanistic ideas. (orig.) [de

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

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)

Exposures at low doses and biological effects of ionizing radiations

International Nuclear Information System (INIS)

Masse, R.

2000-01-01

Everyone is exposed to radiation from natural, man-made and medical sources, and world-wide average annual exposure can be set at about 3.5 mSv. Exposure to natural sources is characterised by very large fluctuations, not excluding a range covering two orders of magnitude. Millions of inhabitants are continuously exposed to external doses as high as 10 mSv per year, delivered at low dose rates, very few workers are exposed above the legal limit of 50 mSv/year, and referring to accidental exposures, only 5% of the 116 000 people evacuated following the Chernobyl disaster encountered doses above 100 mSv. Epidemiological survey of accidentally, occupationally or medically exposed groups have revealed radio-induced cancers, mostly following high dose-rate exposure levels, only above 100 mSv. Risk coefficients were derived from these studies and projected into linear models of risk (linear non-threshold hypothesis: LNT), for the purpose of risk management following exposures at low doses and low dose-rates. The legitimacy of this approach has been questioned, by the Academy of sciences and the Academy of medicine in France, arguing: that LNT was not supported by Hiroshima and Nagasaki studies when neutron dose was revisited; that linear modelling failed to explain why so many site-related cancers were obviously nonlinearly related to the dose, and especially when theory predicted they ought to be; that no evidence could be found of radio-induced cancers related to natural exposures or to low exposures at the work place; and that no evidence of genetic disease could be shown from any of the exposed groups. Arguments were provided from cellular and molecular biology helping to solve this issue, all resulting in dismissing the LNT hypothesis. These arguments included: different mechanisms of DNA repair at high and low dose rate; influence of inducible stress responses modifying mutagenesis and lethality; bystander effects allowing it to be considered that individual

Dose painting based on tumor uptake of Cu-ATSM and FDG

DEFF Research Database (Denmark)

Clausen, Malene Martini; Hansen, Anders Elias; Lundemann, Michael

2014-01-01

definitions based on FDG, 64Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that 64Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting...

Major cost savings associated with biologic dose reduction in patients with inflammatory arthritis.

LENUS (Irish Health Repository)

Murphy, C L

2015-01-01

The purpose of this study was to explore whether patients with Inflammatory Arthritis (IA) (Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) or Ankylosing Spondylitis (AS)) would remain in remission following a reduction in biologic dosing frequency and to calculate the cost savings associated with dose reduction. This prospective non-blinded non-randomised study commenced in 2010. Patients with Inflammatory Arthritis being treated with a biologic agent were screened for disease activity. A cohort of those in remission according to standardized disease activity indices (DAS28 < 2.6, BASDAI < 4) was offered a reduction in dosing frequency of two commonly used biologic therapies (etanercept 50 mg once per fortnight instead of weekly, adalimumab 40 mg once per month instead of fortnightly). Patients were assessed for disease activity at 3, 6, 12, 18 and 24 months following reduction in dosing frequency. Cost saving was calculated. 79 patients with inflammatory arthritis in remission were recruited. 57% had rheumatoid arthritis (n = 45), 13% psoriatic arthritis (n = 10) and 30% ankylosing spondylitis (n = 24). 57% (n = 45) were taking etanercept and 43% (n = 34) adalimumab. The percentage of patients in remission at 24 months was 56% (n = 44). This resulted in an actual saving to the state of approximately 600,000 euro over two years. This study demonstrates the reduction in biologic dosing frequency is feasible in Inflammatory Arthritis. There was a considerable cost saving at two years. The potential for major cost savings in biologic usage should be pursued further.

Biological monitoring to determine worker dose in a butadiene processing plant

Energy Technology Data Exchange (ETDEWEB)

Bechtold, W.E.; Hayes, R.B. [National Cancer Inst., Bethesda, MD (United States)

1995-12-01

Butadiene (BD) is a reactive gas used extensively in the rubber industry and is also found in combustion products. Although BD is genotoxic and acts as an animal carcinogen, the evidence for carcinogenicity in humans is limited. Extrapolation from animal studies on BD carcinogenicity to risk in humans has been controversial because of uncertainties regarding relative biologic exposure and related effects in humans vs. experimental animals. To reduce this uncertainty, a study was designed to characterize exposure to BD at a polymer production facility and to relate this exposure to mutational and cytogenetic effects. Biological monitoring was used to better assess the internal dose of BD received by the workers. Measurement of 1,2-dihydroxy-4-(N-acetylcysteinyl) butane (M1) in urine served as the biomarker in this study. M1 has been shown to correlate with area monitoring in previous studies. Most studies that relate exposure to a toxic chemical with its biological effects rely on exposure concentration as the dose metric; however, exposure concentration may or may not reflect the actual internal dose of the chemical.

Laser-based irradiation apparatus and method to measure the functional dose-rate response of semiconductor devices

Science.gov (United States)

Horn, Kevin M [Albuquerque, NM

2008-05-20

A broad-beam laser irradiation apparatus can measure the parametric or functional response of a semiconductor device to exposure to dose-rate equivalent infrared laser light. Comparisons of dose-rate response from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems can determine if aging has affected the device's overall functionality. The dependence of these changes on equivalent dose-rate pulse intensity and/or duration can be measured with the apparatus. The synchronized introduction of external electrical transients into the device under test can be used to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure while exposing the device to dose-rate equivalent infrared laser light.

Switching From Age-Based Stimulus Dosing to Dose Titration Protocols in Electroconvulsive Therapy: Empirical Evidence for Better Patient Outcomes With Lower Peak and Cumulative Energy Doses.

Science.gov (United States)

O'Neill-Kerr, Alex; Yassin, Anhar; Rogers, Stephen; Cornish, Janie

2017-09-01

The aim of this study was to test the proposition that adoption of a dose titration protocol may be associated with better patient outcomes, at lower treatment dose, and with comparable cumulative dose to that in patients treated using an age-based stimulus dosing protocol. This was an analysis of data assembled from archived records and based on cohorts of patients treated respectively on an age-based stimulus dosing protocol and on a dose titration protocol in the National Health Service in England. We demonstrated a significantly better response in the patient cohort treated with dose titration than with age-based stimulus dosing. Peak doses were less and the total cumulative dose was less in the dose titration group than in the age-based stimulus dosing group. Our findings are consistent with superior outcomes in patients treated using a dose titration protocol when compared with age-based stimulus dosing in a similar cohort of patients.

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

Energy Technology Data Exchange (ETDEWEB)

Munira A Kadhim

2010-03-05

To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

Animal study on biological responses by radon inhalation making use of waste rock which contains feeble activity of uranium (Joint research)

International Nuclear Information System (INIS)

Ishimori, Yuu; Sakoda, Akihiro; Tanaka, Hiroshi; Mitsunobu, Fumihiro; Yamaoka, Kiyonori; Kataoka, Takahiro; Yamato, Keiko; Nishiyama, Yuichi

2013-06-01

Okayama University and the Japan Atomic Energy Agency (JAEA) have carried out the collaborative study of physiological effects of inhaled radon for the low-dose range. Main assignments were as follows. Based on the clinical knowledge, Misasa Medical Center (Okayama University Hospital) clarified the issues that should be addressed. Graduate School of Health Sciences (Okayama University) supervised the research and studied the biological responses. The JAEA made the development and control of a facility for radon inhalation experiments and the investigation of biokinetics and absorbed doses of radon. From 2007 to 2011, the following results were obtained. (1) Literature on effects of radon for the low-dose range was surveyed to determine the present tasks. (2) The first Japanese large-scale facility was developed for radon inhalation experiments with small animals. (3) Relationships between radon concentration and inhalation time were widely examined to understand the change in antioxidative functions due to radon, which are the most basic parameters. (4) Inhibitory effects of radon on oxidative damages were observed using model mice with reactive oxygen- or free radical-related diseases like alcohol-induced oxidative damages and type I diabetes. (5) In order to discuss biological responses quantitatively following radon inhalation, the biokinetics of inhaled radon was examined and the model for calculation of absorbed doses for organs and tissues was obtained. (author)

MONTEC, an interactive fortran program to simulate radiation dose and dose-rate responses of populations

International Nuclear Information System (INIS)

Perry, K.A.; Szekely, J.G.

1983-09-01

The computer program MONTEC was written to simulate the distribution of responses in a population whose members are exposed to multiple radiation doses at variable dose rates. These doses and dose rates are randomly selected from lognormal distributions. The individual radiation responses are calculated from three equations, which include dose and dose-rate terms. Other response-dose/rate relationships or distributions can be incorporated by the user as the need arises. The purpose of this documentation is to provide a complete operating manual for the program. This version is written in FORTRAN-10 for the DEC system PDP-10

Validation of dose-response curve of CRCN-NE - Regional Center for Nuclear Sciences from Northeast Brazil for 60Co: preliminary results

International Nuclear Information System (INIS)

Mendonca, Julyanne C.G.; Mendes, Mariana E.; Hwang, Suy F.; Lima, Fabiana F.; Santos, Neide

2014-01-01

The cytogenetic study has the chromosomal alterations as biomarkers in absorbed dose estimation by the body of individuals involved in exposure to ionizing radiation by interpreting a dose response calibration curve. Since the development of the technique to the analysis of data, you can see protocol characteristics, leading the International Atomic Energy Agency indicate that any laboratory with intention to carry out biological dosimetry establish their own calibration curves. The Biological Dosimetry Laboratory of the Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN), Brazil, recently established the calibration curve related to gamma radiation ( 60 Co). Thus, this work aimed to start the validation of this calibration curve from samples of three different blood donors which were irradiated with an absorbed known single dose of 1 Gy. Samples were exposed to 60 Co source (Glaucoma 220) located in the Department of Nuclear Energy (DEN/UFPE). After fixation with methanol and acetic acid and 5% Giemsa staining, the frequency of chromosomal alterations (dicentric chromosomes, acentric rings and fragments) were established from reading of 500 metaphases per sample and doses were estimated using Dose Estimate program. The results showed that, using the dose-response curve calibration for dicentrics, the dose absorbed estimated for the three individuals ranged from 0.891 - 1,089Gy, taking into account the range of confidence of 95%. By using the dose-response curve for dicentrics added to rings and for the same interval of confidence the doses ranged from 0,849 - 1,081Gy. Thus, the estimative encompassed known absorbed dose the three individuals in confidence interval of 95%. These preliminary results seems to demonstrate that dicentric dose-response curves and dicentrics plus rings established by CRCN-NE / CNEN are valid for dose estimation in exposed individuals. This validation will continue with samples from different individuals at different doses

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

Specification of carbon ion dose at the National Institute of Radiological Sciences (NIRS)

International Nuclear Information System (INIS)

Matsufuji, Naruhiro; Nakai, Tatsuaki; Kanematsu, Nobuyuki

2007-01-01

The clinical dose distributions of therapeutic carbon beams, currently used at National Institute of Radiological Sciences (NIRS) Heavy Ion Medical Accelerator in Chiba (HIMAC), are based on in-vitro Human Salivary Gland (HSG) cell survival response and clinical experience from fast neutron radiotherapy. Moderate radiosensitivity of HSG cells is expected to be a typical response of tumours to carbon beams. At first, the biological dose distribution is designed so as to cause a flat biological effect on HSG cells in the spread-out Bragg peak (SOBP) region. Then, the entire biological dose distribution is evenly raised in order to attain a RBE (relative biological effectiveness)=3.0 at a depth where dose-averaged LET (linear energy transfer) is 80 keV/μm. At that point, biological experiments have shown that carbon ions can be expected to have a biological effect identical to fast neutrons, which showed a clinical RBE of 3.0 for fast neutron radiotherapy at NIRS. The resulting clinical dose distribution in this approximation is not dependent on dose level, tumour type or fractionation scheme and thus reduces the unknown parameters in the analysis of the clinical results. The width SOBP and the clinical/physical dose at the center of SOBP specify the dose distribution. The clinical results analyzed in terms of tumor control probability (TCP) were found to show good agreement with the expected RBE value at higher TCP levels. The TCP analysis method was applied for the prospective dose estimation of hypofractionation. (author)

Use of normalized total dose to represent the biological effect of fractionated radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Flickinger, J C; Kalend, A [Pittsburgh University School of Medicine (USA). Department of Radiation Oncology Pittsburg Cancer Institute (USA)

1990-03-01

There are currently a number of radiobiological models to account for the effects of dose fractionation and time. Normalized total dose (NTD) is not another new model but is a previously reported, clinically useful form in which to represent the biological effect, determined by any specific radiobiological dose-fractionation model, of a course of radiation using a single set of standardized, easily understood terminology. The generalized form of NTD reviewed in this paper describes the effect of a course of radiotherapy administered with nonstandard fractionation as the total dose of radiation in Gy that could be administered with a given reference fractionation such as 2 Gy per fraction, 5 fractions per week that would produce an equivalent biological effect (probability of complications or tumor control) as predicted by a given dose-fractionation formula. The use of normalized total dose with several different exponential and linear-quadratic dose-fraction formulas is presented. (author). 51 refs.; 1 fig.; 1 tab.

Use of normalized total dose to represent the biological effect of fractionated radiotherapy

International Nuclear Information System (INIS)

Flickinger, J.C.; Kalend, A.

1990-01-01

There are currently a number of radiobiological models to account for the effects of dose fractionation and time. Normalized total dose (NTD) is not another new model but is a previously reported, clinically useful form in which to represent the biological effect, determined by any specific radiobiological dose-fractionation model, of a course of radiation using a single set of standardized, easily understood terminology. The generalized form of NTD reviewed in this paper describes the effect of a course of radiotherapy administered with nonstandard fractionation as the total dose of radiation in Gy that could be administered with a given reference fractionation such as 2 Gy per fraction, 5 fractions per week that would produce an equivalent biological effect (probability of complications or tumor control) as predicted by a given dose-fractionation formula. The use of normalized total dose with several different exponential and linear-quadratic dose-fraction formulas is presented. (author). 51 refs.; 1 fig.; 1 tab

Biological dose estimation for charged-particle therapy using an improved PHITS code coupled with a microdosimetric kinetic model

International Nuclear Information System (INIS)

Sato, Tatsuhiko; Watanabe, Ritsuko; Kase, Yuki; Niita, Koji; Sihver, Lembit

2009-01-01

High-energy heavy ions (HZE particles) have become widely used for radiotherapy of tumors owing to their high biological effectiveness. In the treatment planning of such charged-particle therapy, it is necessary to estimate not only physical but also biological dose, which is the product of physical dose and relative biological effectiveness (RBE). In the Heavy-ion Medical Accelerator in Chiba (HIMAC), the biological dose is estimated by a method proposed by Kanai et al., which is based on the linear-quadratic (LQ) model with its parameters α and β determined by the dose distribution in terms of the unrestricted linear energy transfer (LET). Thus, RBE is simply expressed as a function of LET in their model. However, RBE of HZE particles cannot be uniquely determined from their LET because of their large cross sections for high-energy δ-ray production. Hence, development of a biological dose estimation model that can explicitly consider the track structure of δ-rays around the trajectory of HZE particles is urgently needed. Microdosimetric quantities such as lineal energy y are better indexes for representing RBE of HZE particles in comparison to LET, since they can express the decrease of ionization densities around their trajectories due to the production of δ-rays. The difference of the concept between LET and y is illustrated in Figure 1. However, the use of microdosimetric quantities in computational dosimetry was severely limited because of the difficulty in calculating their probability densities (PDs) in macroscopic matter. We therefore improved the 3-dimensional particle transport simulation code PHITS, providing it with the capability of estimating the microdosimetric PDs in a macroscopic framework by incorporating a mathematical function that can instantaneously calculate the PDs around the trajectory of HZE particles with precision equivalent to a microscopic track-structure simulation. A new method for estimating biological dose from charged

The researches on the effects of low doses irradiation

International Nuclear Information System (INIS)

2009-02-01

All research conducted as part of 'Risc-Rad' and those conducted by actors in international programs on low doses allow progress in understanding mechanisms of carcinogenesis associated with irradiation. The data do not question the use in radiation protection, risk estimation models based on a linear increase of the risk with the dose of radiation. Nevertheless, they show that the nature of biological responses induced by low doses of radiation has differences with the responses induced by high doses of radiation. They also show the diversity of effects/dose relationships as the mechanism observed and the importance of genetic predisposition in the individual sensitivity to low doses of radiation. It is therefore essential to continue to bring new data to better understand the complex biological effects and their impact on the establishment of radiation protection standards. In addition, the results have often been at the cellular level. The diversity of responses induced by radiations is also a function of cell types observed, the aging of cells and tissue organization. It is essential to strengthen researches at the tissue and body level, involving in vitro and in vivo approaches while testing the hypothesis in epidemiology with a global approach to systems biology. Over the past four years, the collaboration between partners of 'Risc-Rad' using experimental biology approaches and those using mathematical modeling techniques aimed at developing a new model describing the carcinogenesis induced by low radiation doses. On an other hand, The High level expert group on European low dose risk research (H.L.E.G.) develop programmes in the area of low dose irradiation (Germany, Finland, France, Italy and United Kingdom). It proposed a structure of trans national government called M.E.L.O.D.I. ( multidisciplinary european low dose initiative). Its objective is to structure and integrate European research by gathering around a common programme of multidisciplinary

Dose estimation by biological methods; Estimacion de dosis por metodos biologicos

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Guerrero C, C; David C, L; Serment G, J; Brena V, M [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

1997-07-01

The human being is exposed to strong artificial radiation sources, mainly of two forms: the first is referred to the occupationally exposed personnel (POE) and the second, to the persons that require radiological treatment. A third form less common is by accidents. In all these conditions it is very important to estimate the absorbed dose. The classical biological dosimetry is based in the dicentric analysis. The present work is part of researches to the process to validate the In situ Fluorescent hybridation (FISH) technique which allows to analyse the aberrations on the chromosomes. (Author)

Definition of the dose(tempo)-distribution in the biological irradiation-facility of the RIVM

International Nuclear Information System (INIS)

Bader, F.J.M.

1990-02-01

The RIVM biological irradiation facility (BBF) for the irradiation of biological samples and small animals is a self shielded device and can be safely operated in an existing laboratory environment. There are two 137 Cs sources (15TBq) in a bilateral geometry to give maximum dose uniformity. The easily accessible irradiation chamber is housed in a rotating lead shielding. The dosimetry of BBF was performed by the Dosimetry Section of the RIVM. Experiments were made to determine the absorbed dose in plastic tubes filled with water and the dose distribution over the tube-holder. Separate experiments were made to determine the absorbed dose during the rotation of the irradiation chamber and to check the irradiation timer. For the experiments LiF:Mg,Ti (TLD-100) extruded ribbons were used. The TLDs were calibrated in a collimated beam of 137 Cs gamma rays. The determination of the absorbed dose in water was based on a users biological irradiation set up. The TLDs were individually sealed in thin plastic foil and put in plastic tubes filled for 1/3 with water. The tubes were vertically placed in the tube-holder and placed in the centre of the irradiation chamber. The results show that the absorbed dose in water (determined on January 1, 1990) is equal to 0.97 Gy/timer-unit, with a total uncertainty of 7 percent (1σ). During the rotation of the irradiation chamber the absorbed dose (determined on January 1, 1990) is equal to 0.38 Gy, with a total uncertainty of 15 percent (1σ). The variation of the dose distribution was determined at 15 different measurement points distributed over the tube-holder. The dosis in the measurement point in the centre of the tube-holder was taken as reference value. The maximum observed deviation over the other 14 measurement points amounts to -16 percent of it. The BBF-timer was checked against a special timer. The results indicate that within a range from 2-11 'timer-units' no differences are present. (author). 6 refs.; 6 figs.; 3 fotos

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

Biological dosimetry of X-rays by micronuclei study

International Nuclear Information System (INIS)

Gomez, E.; Silva, A.; Navlet, J.

1991-01-01

Biological dosimetry consists of estimating absorbed doses for people exposed to radiation by mean biological methods. Several indicators used are based in hematological, biochemical an cytogenetics data, although nowadays without doubt, the cytogenetic method is considered to be the most reliable, in this case, the study of micronuclei in peripheral blood lymphocytes cytokinetic blocked can be related to absorbed dose through an experimental calibration curve. An experimental dose-response curve, using micronuclei assay for X-rays at 250 kVp, 43,79 rads/min and temperature 37 degree celsius has been produced. Experimental data is fitted to model Y=c+ α D+β D 2 where. Y is the number micronuclei per cell and D the dose. the curve is compared with those produced elsewhere

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

The influence of tube voltage and phantom size in computed tomography on the dose-response relationship of dicentrics in human blood samples

International Nuclear Information System (INIS)

Jost, G; Pietsch, H; Lengsfeld, P; Voth, M; Schmid, E

2010-01-01

The aim of this study was to investigate the dose response relationship of dicentrics in human lymphocytes after CT scans at tube voltages of 80 and 140 kV. Blood samples from a healthy donor placed in tissue equivalent abdomen phantoms of standard, pediatric and adipose sizes were exposed at dose levels up to 0.1 Gy using a 64-slice CT scanner. It was found that both the tube voltage and the phantom size significantly influenced the CT scan-induced linear dose-response relationship of dicentrics in human lymphocytes. Using the same phantom (standard abdomen), 80 kV CT x-rays were biologically more effective than 140 kV CT x-rays. However, it could also be determined that the applied phantom size had much more influence on the biological effectiveness. Obviously, the increasing slopes of the CT scan-induced dose response relationships of dicentrics in human lymphocytes obtained in a pediatric, a standard and an adipose abdomen have been induced by scattering effects of photons, which strongly increase with increasing phantom size.

The influence of tube voltage and phantom size in computed tomography on the dose-response relationship of dicentrics in human blood samples

Energy Technology Data Exchange (ETDEWEB)

Jost, G; Pietsch, H [TRG Diagnostic Imaging, Bayer Schering Pharma AG, Berlin (Germany); Lengsfeld, P; Voth, M [Global Medical Affairs Diagnostic Imaging, Bayer Schering Pharma AG, Berlin (Germany); Schmid, E, E-mail: Ernst.Schmid@lrz.uni-muenchen.d [Institute for Cell Biology, Center for Integrated Protein Science, University of Munich (Germany)

2010-06-07

The aim of this study was to investigate the dose response relationship of dicentrics in human lymphocytes after CT scans at tube voltages of 80 and 140 kV. Blood samples from a healthy donor placed in tissue equivalent abdomen phantoms of standard, pediatric and adipose sizes were exposed at dose levels up to 0.1 Gy using a 64-slice CT scanner. It was found that both the tube voltage and the phantom size significantly influenced the CT scan-induced linear dose-response relationship of dicentrics in human lymphocytes. Using the same phantom (standard abdomen), 80 kV CT x-rays were biologically more effective than 140 kV CT x-rays. However, it could also be determined that the applied phantom size had much more influence on the biological effectiveness. Obviously, the increasing slopes of the CT scan-induced dose response relationships of dicentrics in human lymphocytes obtained in a pediatric, a standard and an adipose abdomen have been induced by scattering effects of photons, which strongly increase with increasing phantom size.

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.

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)

Introducing Biological Microdosimetry for Ionising Radiation

International Nuclear Information System (INIS)

Scott, B.R.; Schoellnberger, H.

2000-01-01

Microdosimetry is important for radiation protection, for understanding mechanisms of radiation action, and for radiation risk assessment. This article introduces a generic, Monte Carlo based approach to biological microdosimetry for ionising radiation. Our Monte Carlo analyses are carried out with a widely used Crystal Ball software. The approach to biological microdosimetry presented relates to quantal biological effects data (e.g. cell survival, mutagenesis, neoplastic transformation) for which there is an initial linear segment to the dose-response curve. The macroscopic dose data considered were selected such that is could be presumed that the vast majority of cells at risk have radiation dose delivered to their critical target. For cell killing, neoplastic transformation, and mutagenesis, the critical biological target for radiation is presumed to be DNA. Our approach to biological microdosimetry does not require detailed information about the mass, volume, and shape of the critical biological target. Further, one does not have to know what formal distribution function applies to the microdose distribution. However, formal distributions are required for the biological data used to derive the non-parametric microdose distributions. Here, we use the binomial distribution to characterise the variability in the number of cells affected by a fixed macroscopic dose. Assuming this variability to arise from variability in the microscopic dose to the critical biological target, a non-parametric microdose distribution is generated by the standard Monte Carlo method. The non-parametric distribution is then fitted using a set of formal distributions (beta, exponential, extreme value, gamma, logistic, log-normal, normal, Pareto, triangular, uniform, and Weibull). The best fit is then evaluated based on statistical criteria (chi-square test). To demonstrate the application of biological microdosimetry, the standard Monte Carlo method is used with radiobiological data for

Introducing Biological Microdosimetry for Ionising Radiation

Energy Technology Data Exchange (ETDEWEB)

Scott, B.R.; Schoellnberger, H

2000-07-01

Microdosimetry is important for radiation protection, for understanding mechanisms of radiation action, and for radiation risk assessment. This article introduces a generic, Monte Carlo based approach to biological microdosimetry for ionising radiation. Our Monte Carlo analyses are carried out with a widely used Crystal Ball software. The approach to biological microdosimetry presented relates to quantal biological effects data (e.g. cell survival, mutagenesis, neoplastic transformation) for which there is an initial linear segment to the dose-response curve. The macroscopic dose data considered were selected such that is could be presumed that the vast majority of cells at risk have radiation dose delivered to their critical target. For cell killing, neoplastic transformation, and mutagenesis, the critical biological target for radiation is presumed to be DNA. Our approach to biological microdosimetry does not require detailed information about the mass, volume, and shape of the critical biological target. Further, one does not have to know what formal distribution function applies to the microdose distribution. However, formal distributions are required for the biological data used to derive the non-parametric microdose distributions. Here, we use the binomial distribution to characterise the variability in the number of cells affected by a fixed macroscopic dose. Assuming this variability to arise from variability in the microscopic dose to the critical biological target, a non-parametric microdose distribution is generated by the standard Monte Carlo method. The non-parametric distribution is then fitted using a set of formal distributions (beta, exponential, extreme value, gamma, logistic, log-normal, normal, Pareto, triangular, uniform, and Weibull). The best fit is then evaluated based on statistical criteria (chi-square test). To demonstrate the application of biological microdosimetry, the standard Monte Carlo method is used with radiobiological data for

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.

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

Excessive biologic response to IFNβ is associated with poor treatment response in patients with multiple sclerosis.

Directory of Open Access Journals (Sweden)

Richard A Rudick

Full Text Available BACKGROUND: Interferon-beta (IFNβ is used to inhibit disease activity in multiple sclerosis (MS, but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified. METHODS: The relationship between the molecular response to IFNβ and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70 or poor response (n = 15. Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs. RESULTS: The molecular response to IFNβ differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual 'IFN response fingerprint'. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNβ injections. CONCLUSION: MS patients exhibit individually unique but temporally stable biological responses to IFNβ. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNβ for individual MS patients.

Characterizing dose response relationships: Chronic gamma radiation in Lemna minor induces oxidative stress and altered polyploidy level

International Nuclear Information System (INIS)

Van Hoeck, Arne; Horemans, Nele; Van Hees, May; Nauts, Robin; Knapen, Dries; Vandenhove, Hildegarde; Blust, Ronny

2015-01-01

The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h"−"1 up to 1.5 Gy h"−"1. Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h"−"1. A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR_1_0) was estimated at 95 ± 7 mGy h"−"1, followed by 153 ± 13 mGy h"−"1 and 169 ± 12 mGy h"−"1 on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h"−"1, antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h"−"1 which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic

Dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro

International Nuclear Information System (INIS)

Liu Shuchun; Lu Zhe; Li Yanbo; Kang Shunai; Gong Shouliang; Zhao Wenju

2008-01-01

Objective: To observe the dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro in order to reveal the possible mechanism of biological effect and adaptive response induced by low dose radiation. Methods: The experiment was divided into D2 (challenging dose), D1 (inductive dose) + D2 and sham-irradiation groups. EL-4 lymphoma cells were irradiated with D1 (75 mGy, 6.25-200.00 mGy·mm -1 ) and D2(1.5 Gy, 287 mGy·min -1 ), the time interval between D1 and D2 was 6 h. The percentage of apoptosis and each cell cycle phase were measured with flow cytometry. Results: When the dose rates of D1 were 6.25-50.00 mGy·min -1 , the percentages of apoptosis in the D1 + D2 group were significantly lower than those in the D2 group (P 0 /G 1 phase cells decreased significantly (P -1 , D2 is 1.5 Gy (287 mGy·min -1 ), and the time interval between D1 and D2 is 6 h, the adaptive response of apoptosis and cell cycle progression in EL-4 lymphoma cells in vitro could be induced. (authors)

Comparison study of in vivo dose response to laser-driven versus conventional electron beam.

Science.gov (United States)

Oppelt, Melanie; Baumann, Michael; Bergmann, Ralf; Beyreuther, Elke; Brüchner, Kerstin; Hartmann, Josefin; Karsch, Leonhard; Krause, Mechthild; Laschinsky, Lydia; Leßmann, Elisabeth; Nicolai, Maria; Reuter, Maria; Richter, Christian; Sävert, Alexander; Schnell, Michael; Schürer, Michael; Woithe, Julia; Kaluza, Malte; Pawelke, Jörg

2015-05-01

The long-term goal to integrate laser-based particle accelerators into radiotherapy clinics not only requires technological development of high-intensity lasers and new techniques for beam detection and dose delivery, but also characterization of the biological consequences of this new particle beam quality, i.e. ultra-short, ultra-intense pulses. In the present work, we describe successful in vivo experiments with laser-driven electron pulses by utilization of a small tumour model on the mouse ear for the human squamous cell carcinoma model FaDu. The already established in vitro irradiation technology at the laser system JETI was further enhanced for 3D tumour irradiation in vivo in terms of beam transport, beam monitoring, dose delivery and dosimetry in order to precisely apply a prescribed dose to each tumour in full-scale radiobiological experiments. Tumour growth delay was determined after irradiation with doses of 3 and 6 Gy by laser-accelerated electrons. Reference irradiation was performed with continuous electron beams at a clinical linear accelerator in order to both validate the dedicated dosimetry employed for laser-accelerated JETI electrons and above all review the biological results. No significant difference in radiation-induced tumour growth delay was revealed for the two investigated electron beams. These data provide evidence that the ultra-high dose rate generated by laser acceleration does not impact the biological effectiveness of the particles.

Validation of dose-response curve of CRCN-NE - Regional Center for Nuclear Sciences from Northeast Brazil for {sup 60}Co: preliminary results; Validacao da curva dose-resposta do CRCN-NE para {sup 60}Co: resultados preliminares

Energy Technology Data Exchange (ETDEWEB)

Mendonca, Julyanne C.G.; Mendes, Mariana E.; Hwang, Suy F.; Lima, Fabiana F. [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Santos, Neide, E-mail: july_cgm@yahoo.com.br [Universidade Federal de Pernambuco (CCB/UFPE), Recife, PE (Brazil). Departamento de Genetica

2014-07-01

The cytogenetic study has the chromosomal alterations as biomarkers in absorbed dose estimation by the body of individuals involved in exposure to ionizing radiation by interpreting a dose response calibration curve. Since the development of the technique to the analysis of data, you can see protocol characteristics, leading the International Atomic Energy Agency indicate that any laboratory with intention to carry out biological dosimetry establish their own calibration curves. The Biological Dosimetry Laboratory of the Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN), Brazil, recently established the calibration curve related to gamma radiation ({sup 60}Co). Thus, this work aimed to start the validation of this calibration curve from samples of three different blood donors which were irradiated with an absorbed known single dose of 1 Gy. Samples were exposed to {sup 60}Co source (Glaucoma 220) located in the Department of Nuclear Energy (DEN/UFPE). After fixation with methanol and acetic acid and 5% Giemsa staining, the frequency of chromosomal alterations (dicentric chromosomes, acentric rings and fragments) were established from reading of 500 metaphases per sample and doses were estimated using Dose Estimate program. The results showed that, using the dose-response curve calibration for dicentrics, the dose absorbed estimated for the three individuals ranged from 0.891 - 1,089Gy, taking into account the range of confidence of 95%. By using the dose-response curve for dicentrics added to rings and for the same interval of confidence the doses ranged from 0,849 - 1,081Gy. Thus, the estimative encompassed known absorbed dose the three individuals in confidence interval of 95%. These preliminary results seems to demonstrate that dicentric dose-response curves and dicentrics plus rings established by CRCN-NE / CNEN are valid for dose estimation in exposed individuals. This validation will continue with samples from different individuals at different doses.

Biological-based optimization and volumetric modulated arc therapy delivery for stereotactic body radiation therapy

International Nuclear Information System (INIS)

Diot, Quentin; Kavanagh, Brian; Timmerman, Robert; Miften, Moyed

2012-01-01

Purpose: To describe biological-based optimization and Monte Carlo (MC) dose calculation-based treatment planning for volumetric modulated arc therapy (VMAT) delivery of stereotactic body radiation therapy (SBRT) in lung, liver, and prostate patients. Methods: Optimization strategies and VMAT planning parameters using a biological-based optimization MC planning system were analyzed for 24 SBRT patients. Patients received a median dose of 45 Gy [range, 34-54 Gy] for lung tumors in 1-5 fxs and a median dose of 52 Gy [range, 48-60 Gy] for liver tumors in 3-6 fxs. Prostate patients received a fractional dose of 10 Gy in 5 fxs. Biological-cost functions were used for plan optimization, and its dosimetric quality was evaluated using the conformity index (CI), the conformation number (CN), the ratio of the volume receiving 50% of the prescription dose over the planning target volume (Rx/PTV50). The quality and efficiency of the delivery were assessed according to measured quality assurance (QA) passing rates and delivery times. For each disease site, one patient was replanned using physical cost function and compared to the corresponding biological plan. Results: Median CI, CN, and Rx/PTV50 for all 24 patients were 1.13 (1.02-1.28), 0.79 (0.70-0.88), and 5.3 (3.1-10.8), respectively. The median delivery rate for all patients was 410 MU/min with a maximum possible rate of 480 MU/min (85%). Median QA passing rate was 96.7%, and it did not significantly vary with the tumor site. Conclusions: VMAT delivery of SBRT plans optimized using biological-motivated cost-functions result in highly conformal dose distributions. Plans offer shorter treatment-time benefits and provide efficient dose delivery without compromising the plan conformity for tumors in the prostate, lung, and liver, thereby improving patient comfort and clinical throughput. The short delivery times minimize the risk of patient setup and intrafraction motion errors often associated with long SBRT treatment

The use of biologically based cancer risk models in radiation epidemiology

International Nuclear Information System (INIS)

Krewski, D.; Zielinski, J.M.; Hazelton, W.D.; Garner, M.J.; Moolgavkar, S.H.

2003-01-01

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article, biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiologic datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada. (author)

A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger?

Directory of Open Access Journals (Sweden)

Raffaella Marconi

Full Text Available Preclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR. In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects.We reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED. To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells.Our results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated.Our study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice.

Isoeffective dose: a concept for biological weighting of absorbed dose in proton and heavier-ion therapies

CERN Document Server

Wambersie, A; Menzel, H G; Gahbauer, R; DeLuca, P M; Hendry, J H; Jones, D T L

2011-01-01

When reporting radiation therapy procedures, International Commission on Radiation Units and Measurements (ICRU) recommends specifying absorbed dose at/in all clinically relevant points and/or volumes. In addition, treatment conditions should be reported as completely as possible in order to allow full understanding and interpretation of the treatment prescription. However, the clinical outcome does not only depend on absorbed dose but also on a number of other factors such as dose per fraction, overall treatment time and radiation quality radiation biology effectiveness (RBE). Therefore, weighting factors have to be applied when different types of treatments are to be compared or to be combined. This had led to the concept of `isoeffective absorbed dose', introduced by ICRU and International Atomic Energy Agency (IAEA). The isoeffective dose D(IsoE) is the dose of a treatment carried out under reference conditions producing the same clinical effects on the target volume as those of the actual treatment. It i...

Animal study on biological responses by radon inhalation making use of waste rock which contains feeble activity of uranium (2) (Joint research)

International Nuclear Information System (INIS)

Ishimori, Yuu; Sakoda, Akihiro; Tanaka, Hiroshi; Mitsunobu, Fumihiro; Yamaoka, Kiyonori; Kataoka, Takahiro; Etani, Reo

2016-03-01

Okayama University and the Japan Atomic Energy Agency (JAEA) have carried out the collaborative study of physiological effects of inhaled radon for the low-dose range. Main assignments were as follows. Based on the clinical knowledge, Misasa Medical Center (Okayama University Hospital) clarified the issues that should be addressed. Graduate School of Health Sciences (Okayama University) supervised the research and studied the biological responses. The JAEA made the development and control of a facility for radon inhalation experiments and the investigation of biokinetics and exposure doses of radon. From 2009 to 2013, the following results were obtained. (1) Literature on drinking effects of radon hot spring water was surveyed to determine the present tasks. (2) Under the present experimental conditions, drinking of hot spring water into which radon was intentionally introduced using the equipment in the facility did not have significant effects on mice. (3) Inhibitory effects of antioxidant pre-supplements (Vitamins C and E) and radon pre-inhalation on hepatic or renal oxidative damage were examined to make the comparison. (4) In order to discuss biological responses quantitatively following radon inhalation, the biokinetics of inhaled radon were studied. (5) Some exposure routes due to inhalation of radon or its progeny were modeled to calculate organ doses in mice. (author)

TH-A-BRD-01: Radiation Biology for Radiation Therapy Physicists

International Nuclear Information System (INIS)

Orton, C; Borras, C; Carlson, D

2014-01-01

Mechanisms by which radiation kills cells and ways cell damage can be repaired will be reviewed. The radiobiological parameters of dose, fractionation, delivery time, dose rate, and LET will be discussed. The linear-quadratic model for cell survival for high and low dose rate treatments and the effect of repopulation will be presented and discussed. The rationale for various radiotherapy techniques such as conventional fractionation, hyperfractionation, hypofractionation, and low and high dose rate brachytherapy, including permanent implants, will be presented. The radiobiological principles underlying radiation protection guidelines and the different radiation dosimetry terms used in radiation biology and in radiation protection will be reviewed. Human data on radiation induced cancer, including increases in the risk of second cancers following radiation therapy, as well as data on radiation induced tissue reactions, such as cardiovascular effects, for follow up times up to 20–40 years, published by ICRP, NCRP and BEIR Committees, will be examined. The latest risk estimates per unit dose will be presented. Their adoption in recent radiation protection standards and guidelines and their impact on patient and workers safety in radiotherapy will be discussed. Biologically-guided radiotherapy (BGRT) provides a systematic method to derive prescription doses that integrate patient-specific information about tumor and normal tissue biology. Treatment individualization based on patient-specific biology requires the identification of biological objective functions to facilitate the design and comparison of competing treatment modalities. Biological objectives provide a more direct approach to plan optimization instead of relying solely on dose-based surrogates and can incorporate factors that alter radiation response, such as DNA repair, tumor hypoxia, and relative biological effectiveness. We review concepts motivating biological objectives and provide examples of how

TH-A-BRD-01: Radiation Biology for Radiation Therapy Physicists

Energy Technology Data Exchange (ETDEWEB)

Orton, C [Wayne State University, Grosse Pointe, MI (United States); Borras, C [Radiological Physics and Health Services, Washington, DC (United States); Carlson, D [Yale University School of Medicine, New Haven, CT (United States)

2014-06-15

Mechanisms by which radiation kills cells and ways cell damage can be repaired will be reviewed. The radiobiological parameters of dose, fractionation, delivery time, dose rate, and LET will be discussed. The linear-quadratic model for cell survival for high and low dose rate treatments and the effect of repopulation will be presented and discussed. The rationale for various radiotherapy techniques such as conventional fractionation, hyperfractionation, hypofractionation, and low and high dose rate brachytherapy, including permanent implants, will be presented. The radiobiological principles underlying radiation protection guidelines and the different radiation dosimetry terms used in radiation biology and in radiation protection will be reviewed. Human data on radiation induced cancer, including increases in the risk of second cancers following radiation therapy, as well as data on radiation induced tissue reactions, such as cardiovascular effects, for follow up times up to 20–40 years, published by ICRP, NCRP and BEIR Committees, will be examined. The latest risk estimates per unit dose will be presented. Their adoption in recent radiation protection standards and guidelines and their impact on patient and workers safety in radiotherapy will be discussed. Biologically-guided radiotherapy (BGRT) provides a systematic method to derive prescription doses that integrate patient-specific information about tumor and normal tissue biology. Treatment individualization based on patient-specific biology requires the identification of biological objective functions to facilitate the design and comparison of competing treatment modalities. Biological objectives provide a more direct approach to plan optimization instead of relying solely on dose-based surrogates and can incorporate factors that alter radiation response, such as DNA repair, tumor hypoxia, and relative biological effectiveness. We review concepts motivating biological objectives and provide examples of how

γ irradiation with different dose rates induces different DNA damage responses in Petunia x hybrida cells.

Science.gov (United States)

Donà, Mattia; Ventura, Lorenzo; Macovei, Anca; Confalonieri, Massimo; Savio, Monica; Giovannini, Annalisa; Carbonera, Daniela; Balestrazzi, Alma

2013-05-15

In plants, there is evidence that different dose rate exposures to gamma (γ) rays can cause different biological effects. The dynamics of DNA damage accumulation and molecular mechanisms that regulate recovery from radiation injury as a function of dose rate are poorly explored. To highlight dose-rate dependent differences in DNA damage, single cell gel electrophoresis was carried out on regenerating Petunia x hybrida leaf discs exposed to LDR (total dose 50 Gy, delivered at 0.33 Gy min(-1)) and HDR (total doses 50 and 100 Gy, delivered at 5.15 Gy min(-1)) γ-ray in the 0-24h time period after treatments. Significant fluctuations of double strand breaks and different repair capacities were observed between treatments in the 0-4h time period following irradiation. Dose-rate-dependent changes in the expression of the PhMT2 and PhAPX genes encoding a type 2 metallothionein and the cytosolic isoform of ascorbate peroxidase, respectively, were detected by Quantitative RealTime-Polymerase Chain Reaction. The PhMT2 and PhAPX genes were significantly up-regulated (3.0- and 0.7-fold) in response to HDR. The results are discussed in light of the potential practical applications of LDR-based treatments in mutation breeding. Copyright © 2013 Elsevier GmbH. All rights reserved.

In search of a dose-response relationship with radiotherapy in the management of recurrent rectal carcinoma in the pelvis: a systematic review

International Nuclear Information System (INIS)

Wong, Rebecca; Thomas, Gillian; Cummings, Bernard; Froud, Peter; Shelley, Wendy; Withers, Rodney; Williams, Jack

1998-01-01

Purpose: A systematic review of the literature was undertaken to address the question: ''What is the most effective dose fractionation schedule for the relief of symptoms in patients with pelvic recurrence from rectal or colorectal carcinoma?'' Methods and Materials: Cancerlit/Medline-computerized databases were searched between the years 1966-1996. Studies that explored the response to radiotherapy in patients with pelvic recurrence from rectal/rectosigmoid carcinoma were included. Factors that may contribute to differences in results were postulated in advance and the variations encountered between articles were presented. Articles with data applicable to recurrent disease only were included in the primary analysis. The effect of including articles that reported outcomes of recurrences with unresectable primaries and residual disease was presented as a sensitivity analysis. Results: Only retrospective series (level V evidence) were available. The many sources of potential bias inherent in retrospective analyses make the data suitable for hypothesis generation only. Comparison of response was made between 'lower' vs. 'higher' doses, using 45-50 Gy as the dividing dose, base on the primary analysis. There were no significant differences observable in terms of initial response and the proportion maintaining a response at 6 months, within the range of doses employed. When data from articles that reported outcomes of recurrent disease with primary untreated cancers and postoperative residual disease were included, there was a suggestion for a more favorable response with higher doses. This requires cautious interpretation within the methodological limitations of the data. Conclusion: The optimal dose fractionation schedule for the palliation of pelvic recurrence from rectal carcinoma remains undefined. Well-designed randomized studies, with study arms that are sufficiently diverse biologically to allow the detection of a dose-response relationship if one existed

Dose/dose-rate responses of shrimp larvae to UV-B radiation

International Nuclear Information System (INIS)

Damkaer, D.M.

1981-01-01

Previous work indicated dose-rate thresholds in the effects of UV-B on the near-surface larvae of three shrimp species. Additional observations suggest that the total dose response varies with dose-rate. Below 0.002 Wm -2 sub([DNA]) irradiance no significant effect is noted in activity, development, or survival. Beyond that dose-rate threshold, shrimp larvae are significantly affected if the total dose exceeds about 85 Jm -2 sub([DNA]). Predictions cannot be made without both the dose-rate and the dose. These dose/dose-rate thresholds are compared to four-year mean dose/dose-rate solar UV-B irradiances at the experimental site, measured at the surface and calculated for 1 m depth. The probability that the shrimp larvae would receive lethal irradiance is low for the first half of the season of surface occurrence, even with a 44% increase in damaging UV radiation. (orig.)

Dose/dose-rate responses of shrimp larvae to UV-B radiation

Energy Technology Data Exchange (ETDEWEB)

Damkaer, D.M.; Dey, D.B.; Heron, G.A.

1981-01-01

Previous work indicated dose-rate thresholds in the effects of UV-B on the near-surface larvae of three shrimp species. Additional observations suggest that the total dose response varies with dose-rate. Below 0.002 Wm/sup -2/sub((DNA)) irradiance no significant effect is noted in activity, development, or survival. Beyond that dose-rate threshold, shrimp larvae are significantly affected if the total dose exceeds about 85 Jm/sup -2/sub((DNA)). Predictions cannot be made without both the dose-rate and the dose. These dose/dose-rate thresholds are compared to four-year mean dose/dose-rate solar UV-B irradiances at the experimental site, measured at the surface and calculated for 1 m depth. The probability that the shrimp larvae would receive lethal irradiance is low for the first half of the season of surface occurrence, even with a 44% increase in damaging UV radiation.

Biologically based analysis of lung cancer incidence in a large Canadian occupational cohort with low-LET low-dose radiation exposure, and comparison with Japanese atomic bomb survivors

International Nuclear Information System (INIS)

Hazelton, W.D.; Curtis, S.B.; Moolgavkar, S.H.; Hutchinson, F.; Krewski, D.

2003-01-01

Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using several types of multistage models. The primary analysis utilizes the two-stage clonal expansion model (TSCE), with sensitivity analyses using extensions of this model incorporating additional stages. Characteristic and distinct temporal patterns of risk are found for dose-response affecting early, middle, or late stages of carcinogenesis, e.g. initiation with one or more stages, clonal expansion, or malignant conversion. Fixed lag or lag distributions are used to model time from first malignant cell to incidence. Background rates are analyzed by gender, job classification and birth cohort. Lacking individual smoking data, surrogate doses based on US annual per capita cigarette consumption appear to account for much of the birth cohort effect. Males, with mean cumulative exposure for gamma and tritium of 11.5 mSv and 322 incident lung cancer cases have a significant dose-response with 33 cases attributable to radiation. Female dose-response, with mean cumulative exposure of 1.7 mSv and 78 incident cases, appears similar but is not statistically significant. Findings for males include an inverse-dose-rate effect (increased risk with protraction of a given dose) and dose-response effects on initiation, promotion and malignant conversion, although the effect on initiation is not statistically significant. The excess relative risk (ERR) and excess absolute risk (EAR) depend on age at exposure, duration, dose, and age at follow-up. The ERR increases with dose, tapering off at higher doses, making a plot of ERR against dose concave-downward, similar to apparent low-dose results seen below 1 Sv for solid tumor mortality of atomic bomb survivors. The concave-downward trend of ERR and the inverse-dose-rate effect are both counter to prevailing beliefs about effects of low

The RBE of tritium-beta exposure for the induction of the adaptive response and apoptosis; cellular defense mechanisms against the biological effects of ionizing radiation

International Nuclear Information System (INIS)

Boreham, D.R.; Bahen, M.E.; Dolling, J-A.

1997-01-01

Adaption to radiation is one of a few biological responses that has been demonstrated to occur in mammalian cells exposed to doses of ionizing radiation in the occupational exposure range. The adaptive response has been well characterized in the yeast Saccharomyces cerevisiae, although the doses required to induce the response are higher than in mammalian cells. When yeast cells are primed with sublethal doses of gamma-radiation, they subsequently undergo an adaptive response and develop resistance to radiation, heat the chemical mutagens in a time and dose dependent manner. We have used this model system to assess the relative ability of tritium-beta radiation to induce the adaptive response the examined tritium-induced radiation resistance, thermal tolerance and suppression of mutation. The results show that sublethal priming doses of tritium caused yeast cells to develop resistance to radiation, heat, and a chemical mutagen MNNG. The magnitude and kinetics of the response, per unit dose, were the same for tritium and gamma-radiation. Therefore, the relative biological effectiveness (RBE) of tritium induction of the adaptive response was about 1.0. Apoptosis is a genetically programmed cell death or cell suicide. Cells damaged by radiation can be selectively removed from the population by apoptosis and therefore eliminated as a potential cancer risk to the organism. Since we have previously shown that apoptosis is a sensitive indicator of radiation damage in human lymphocytes exposed to low doses, we have used this endpoint to investigate the potency of tritium-beta radiation. Initially, tritium was compared to X-rays for relative effectiveness at inducing apoptosis. The results showed the lymphocytes irradiated in vitro with X-rays or tritium had similar levels of apoptosis per unit dose. Therefore the relative biology effectiveness of tritium for induction of apoptosis in human lymphocytes was also about 1. In the work presented here, we have demonstrated that

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.

Biological effects of low doses of radiation at low dose rate

International Nuclear Information System (INIS)

1996-05-01

The purpose of this report was to examine available scientific data and models relevant to the hypothesis that induction of genetic changes and cancers by low doses of ionizing radiation at low dose rate is a stochastic process with no threshold or apparent threshold. Assessment of the effects of higher doses of radiation is based on a wealth of data from both humans and other organisms. 234 refs., 26 figs., 14 tabs

On the sensitivity of IMRT dose optimization to the mathematical form of a biological imaging-based prescription function

International Nuclear Information System (INIS)

Bowen, Stephen R; Bentzen, Soeren M; Jeraj, Robert; Flynn, Ryan T

2009-01-01

Voxel-based prescriptions of deliberately non-uniform dose distributions based on molecular imaging, so-called dose painting or theragnostic radiation therapy, require specification of a transformation that maps the image data intensities to prescribed doses. However, the functional form of this transformation is currently unknown. An investigation into the sensitivity of optimized dose distributions resulting from several possible prescription functions was conducted. Transformations between the radiotracer activity concentrations from Cu-ATSM PET images, as a surrogate of tumour hypoxia, and dose prescriptions were implemented to yield weighted distributions of prescribed dose boosts in high uptake regions. Dose escalation was constrained to reflect clinically realistic whole tumour doses and constant normal tissue doses. Optimized heterogeneous dose distributions were found by minimizing a voxel-by-voxel quadratic objective function in which all tumour voxels were given equal weight. Prescriptions based on a polynomial mapping function were found to be least constraining on their optimized plans, while prescriptions based on a sigmoid mapping function were the most demanding to deliver. A prescription formalism that fixed integral dose was less sensitive to errors in the choice of the mapping function than one that boosted integral dose. Integral doses to normal tissue and critical structures were insensitive to the shape of the prescription function. Planned target dose conformity improved with smaller beamlet dimensions until the inherent spatial resolution of the functional image was matched. Clinical implementation of dose painting depends on advances in absolute quantification of functional images and improvements in delivery techniques over smaller spatial scales.

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

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

A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients.

Directory of Open Access Journals (Sweden)

S C Nair

Full Text Available Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA. We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents.Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice.The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39, differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78, and also increased with higher DAS28 at baseline (OR = 1.28. Rheumatoid factor positivity, functional disability (a higher HAQ, and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation.Prediction of response using MRP8/14 levels along with clinical predictors has

Comparative studies of the dose-response relationship of radiation-induced chromosomal aberrations in human lymphocytes induced by low radiation doses, using Feulgen orcein glacial acetic acid and FPG staining

International Nuclear Information System (INIS)

Wagner, R.

1982-01-01

Peripheral lymphocytes were exposed in vitro to 220 kV X-radiation, with doses of 0.05, 0.1, 0.2, 0.4, and 0.5 Gy, their culture and preparation was made under standardized conditions. The slides were stained using two different methods, namely FPG staining (fluorescence plus giemsa), and the conventional Feulgen orcein glacial acetic acid method. Compared to the conventional method, FPG staining achieved absolute yields of acentric fragments three times higher, and of dicentric chromosomes twice as high. A linear dose-response relationship in acentric fragments was found by the two staining methods alike, which agrees with the theory. Both staining methods revealed a linear-square dose-response relationship in dicentric chromosomes. Using FPG staining, preparing only M 1 cells for evaluation, the linear component was found to be dominant over the whole dose range applied. The conventional method, analysing M 1 and M 2 cells, revealed the square component to be the most important one. The dose-response relationships determined after FPG staining can be used for biological dosimetry. Calibration can be improved by increasing the number of cells analysed at doses [de

Biological Dosimetry of X-rays by micronuclei study

International Nuclear Information System (INIS)

Gomez, E.; Silva, A.; Navlet, J.

1991-01-01

Biological dosimetry consists of estimating absorbed doses for people exposed to radiation by mean biological methods. Several indicators used are based in haematological, biochemical an cytogenetics data, although nowadays without doubt, the cytogenetic method is considered to be the most reliable, in this case, the study of micronuclei in peripheral blood lymphocytes citokinetics blocked can be related to absorbed dose through an experimental calibration curve. An experimental dose-response curve, using micronuclei assay for X-rays at 250 kVp, 43,79 rads/min and temperature 37 degree centigree has been produced. Experimental data is fitted to model Y=C+ αD+BD''2 where Y is the number of micronuclei per cell and D the dose. The curve is compared with those produced elsewhere. (Author) 24 refs

Risk-based approach to appraise valve closure in the clam Corbicula fluminea in response to waterborne metals

International Nuclear Information System (INIS)

Liao, C.-M.; Jou, L.-J.; Chen, B.-C.

2005-01-01

We developed a risk-based approach to assess how the valve closure behavior of Asiatic clam Corbicula fluminea responds to waterborne copper (Cu) and cadmium (Cd). We reanalyzed the valve closure response data from published literature to reconstruct the response time-dependent dose-response profiles based on an empirical three-parameter Hill equation model. We integrated probabilistic exposure profiles of measured environmental Cu and Cd concentrations in the western coastal areas of Taiwan with the reconstructed dose-response relationships at different integration times of response to quantitatively estimate the valve response risk. The risk assessment results implicate exposure to waterborne Cu and Cd may pose no significant risk to clam valve activity in the short-time response periods (e.g., <30 min), yet a relative high risk for valve closure response to waterborne Cu at response times greater than 120 min is alarming. We successfully linked reconstructed dose-response profiles and EC50-time relationships associated with the fitted daily valve opening/closing rhythm characterized by a three-parameter lognormal function to predict the time-varying bivalve closure rhythm response to waterborne metals. We parameterized the proposed predictive model that should encourage a risk-management framework for discussion of future design of biological monitoring systems. - A model was developed to link valve closure in clams to concentrations of metals in water

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...

Gamma-irradiated onions as a biological indicator of radiation dose

International Nuclear Information System (INIS)

Vaijapurkar, S.G.; Agarwal, Deepshikha; Chaudhuri, S.K.; Ram Senwar, Kana; Bhatnagar, P.K.

2001-01-01

Post-irradiation identification and dose estimation are required to assess the radiation-induced effects on living things in any nuclear emergency. In this study, radiation-induced morphological/cytological changes i.e., number of root formation and its length, shooting length, reduction in mitotic index, micronuclei formation and chromosomal aberrations in the root tip cells of gamma-irradiated onions at lower doses (50-2000 cGy) are reported. The capabilities of this biological species to store the radiation-induced information are also studied

TU-AB-BRC-02: Accuracy Evaluation of GPU-Based OpenCL Carbon Monte Carlo Package (goCMC) in Biological Dose and Microdosimetry in Comparison to FLUKA Simulations

Energy Technology Data Exchange (ETDEWEB)

Taleei, R; Peeler, C; Qin, N; Jiang, S; Jia, X [UT Southwestern Medical Center, Dallas, TX (United States)

2016-06-15

Purpose: One of the most accurate methods for radiation transport is Monte Carlo (MC) simulation. Long computation time prevents its wide applications in clinic. We have recently developed a fast MC code for carbon ion therapy called GPU-based OpenCL Carbon Monte Carlo (goCMC) and its accuracy in physical dose has been established. Since radiobiology is an indispensible aspect of carbon ion therapy, this study evaluates accuracy of goCMC in biological dose and microdosimetry by benchmarking it with FLUKA. Methods: We performed simulations of a carbon pencil beam with 150, 300 and 450 MeV/u in a homogeneous water phantom using goCMC and FLUKA. Dose and energy spectra for primary and secondary ions on the central beam axis were recorded. Repair-misrepair-fixation model was employed to calculate Relative Biological Effectiveness (RBE). Monte Carlo Damage Simulation (MCDS) tool was used to calculate microdosimetry parameters. Results: Physical dose differences on the central axis were <1.6% of the maximum value. Before the Bragg peak, differences in RBE and RBE-weighted dose were <2% and <1%. At the Bragg peak, the differences were 12.5% caused by small range discrepancy and sensitivity of RBE to beam spectra. Consequently, RBE-weighted dose difference was 11%. Beyond the peak, RBE differences were <20% and primarily caused by differences in the Helium-4 spectrum. However, the RBE-weighted dose agreed within 1% due to the low physical dose. Differences in microdosimetric quantities were small except at the Bragg peak. The simulation time per source particle with FLUKA was 0.08 sec, while goCMC was approximately 1000 times faster. Conclusion: Physical doses computed by FLUKA and goCMC were in good agreement. Although relatively large RBE differences were observed at and beyond the Bragg peak, the RBE-weighted dose differences were considered to be acceptable.

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

Biological clearance and committed dose equivalent in pulmonary region from inhaled radioaerosols for lung scanning

Energy Technology Data Exchange (ETDEWEB)

Soni, P.S.; Sharma, S.M.; Raghunath, B.; Somasundaram, S.

1987-01-01

Biological clearance half-lives (Tsub(b)) of different /sup 99/Tcsup(m)-labelled compounds from each lung have been determined, after administering the radioaerosol to normal subjects using the BARC dry aerosol generation and inhalation system. Based on these experimental clearance half-lives, the committed dose equivalent to the lungs has been computed using both the ICRP lung model and MIRD-11 values.

Biological clearance and committed dose equivalent in pulmonary region from inhaled radioaerosols for lung scanning

International Nuclear Information System (INIS)

Soni, P.S.; Sharma, S.M.; Raghunath, B.; Somasundaram, S.

1987-01-01

Biological clearance half-lives (Tsub(b)) of different 99 Tcsup(m)-labelled compounds from each lung have been determined, after administering the radioaerosol to normal subjects using the BARC dry aerosol generation and inhalation system. Based on these experimental clearance half-lives, the committed dose equivalent to the lungs has been computed using both the ICRP lung model and MIRD-11 values. (author)

Angular dependence of dose equivalent response of an albedo neutron dosimeter

International Nuclear Information System (INIS)

Torres, B.A.; Boswell, E.; Schwartz, R.B.

1994-01-01

The ANSI provides procedures for testing the performance of dosimetry services. Although neutron dose equivalent angular response studies are not now mandated, future standards may well require that such studies be performed. Current studies with an albedo dosimeter will yield information regarding the angular dependence of dose equivalent response for this type of personnel dosimeter. Preliminary data for bare 252 Cf fluences show a marked decrease in dosimeter reading with increasing angle. The response decreased by an approximate factor of four. For the horizontal orientation, the same response was noted from both positive and negative angles. However, for the vertical orientation, the response was unexplainably assymetric. We are also examining the response of the personnel badge in moderated 252 Cf fluences. Responses from the moderated and unmoderated 252 Cf fields and theoretical calculations of the neutron angular response will be compared. This information will assist in building a data base for future comparisons of neutron angular responses with other neutron albedo dosimeters and phantoms

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

TU-AB-BRC-09: Fast Dose-Averaged LET and Biological Dose Calculations for Proton Therapy Using Graphics Cards

International Nuclear Information System (INIS)

Wan, H; Tseung, Chan; Beltran, C

2016-01-01

Purpose: To demonstrate fast and accurate Monte Carlo (MC) calculations of proton dose-averaged linear energy transfer (LETd) and biological dose (BD) on a Graphics Processing Unit (GPU) card. Methods: A previously validated GPU-based MC simulation of proton transport was used to rapidly generate LETd distributions for proton treatment plans. Since this MC handles proton-nuclei interactions on an event-by-event using a Bertini intranuclear cascade-evaporation model, secondary protons were taken into account. The smaller contributions of secondary neutrons and recoil nuclei were ignored. Recent work has shown that LETd values are sensitive to the scoring method. The GPU-based LETd calculations were verified by comparing with a TOPAS custom scorer that uses tabulated stopping powers, following recommendations by other authors. Comparisons were made for prostate and head-and-neck patients. A python script is used to convert the MC-generated LETd distributions to BD using a variety of published linear quadratic models, and to export the BD in DICOM format for subsequent evaluation. Results: Very good agreement is obtained between TOPAS and our GPU MC. Given a complex head-and-neck plan with 1 mm voxel spacing, the physical dose, LETd and BD calculations for 10"8 proton histories can be completed in ∼5 minutes using a NVIDIA Titan X card. The rapid turnover means that MC feedback can be obtained on dosimetric plan accuracy as well as BD hotspot locations, particularly in regards to their proximity to critical structures. In our institution the GPU MC-generated dose, LETd and BD maps are used to assess plan quality for all patients undergoing treatment. Conclusion: Fast and accurate MC-based LETd calculations can be performed on the GPU. The resulting BD maps provide valuable feedback during treatment plan review. Partially funded by Varian Medical Systems.

TU-AB-BRC-09: Fast Dose-Averaged LET and Biological Dose Calculations for Proton Therapy Using Graphics Cards

Energy Technology Data Exchange (ETDEWEB)

Wan, H; Tseung, Chan; Beltran, C [Mayo Clinic, Rochester, MN (United States)

2016-06-15

Purpose: To demonstrate fast and accurate Monte Carlo (MC) calculations of proton dose-averaged linear energy transfer (LETd) and biological dose (BD) on a Graphics Processing Unit (GPU) card. Methods: A previously validated GPU-based MC simulation of proton transport was used to rapidly generate LETd distributions for proton treatment plans. Since this MC handles proton-nuclei interactions on an event-by-event using a Bertini intranuclear cascade-evaporation model, secondary protons were taken into account. The smaller contributions of secondary neutrons and recoil nuclei were ignored. Recent work has shown that LETd values are sensitive to the scoring method. The GPU-based LETd calculations were verified by comparing with a TOPAS custom scorer that uses tabulated stopping powers, following recommendations by other authors. Comparisons were made for prostate and head-and-neck patients. A python script is used to convert the MC-generated LETd distributions to BD using a variety of published linear quadratic models, and to export the BD in DICOM format for subsequent evaluation. Results: Very good agreement is obtained between TOPAS and our GPU MC. Given a complex head-and-neck plan with 1 mm voxel spacing, the physical dose, LETd and BD calculations for 10{sup 8} proton histories can be completed in ∼5 minutes using a NVIDIA Titan X card. The rapid turnover means that MC feedback can be obtained on dosimetric plan accuracy as well as BD hotspot locations, particularly in regards to their proximity to critical structures. In our institution the GPU MC-generated dose, LETd and BD maps are used to assess plan quality for all patients undergoing treatment. Conclusion: Fast and accurate MC-based LETd calculations can be performed on the GPU. The resulting BD maps provide valuable feedback during treatment plan review. Partially funded by Varian Medical Systems.

Characterizing dose response relationships: Chronic gamma radiation in Lemna minor induces oxidative stress and altered polyploidy level.

Science.gov (United States)

Van Hoeck, Arne; Horemans, Nele; Van Hees, May; Nauts, Robin; Knapen, Dries; Vandenhove, Hildegarde; Blust, Ronny

2015-12-01

The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h(-1) up to 1.5 Gy h(-1). Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h(-1). A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR10) was estimated at 95 ± 7 mGy h(-1), followed by 153 ± 13 mGy h(-1) and 169 ± 12 mGy h(-1) on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h(-1), antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h(-1) which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic stress conditions

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.

Choline PET based dose-painting in prostate cancer - Modelling of dose effects

International Nuclear Information System (INIS)

Niyazi, Maximilian; Bartenstein, Peter; Belka, Claus; Ganswindt, Ute

2010-01-01

Several randomized trials have documented the value of radiation dose escalation in patients with prostate cancer, especially in patients with intermediate risk profile. Up to now dose escalation is usually applied to the whole prostate. IMRT and related techniques currently allow for dose escalation in sub-volumes of the organ. However, the sensitivity of the imaging modality and the fact that small islands of cancer are often dispersed within the whole organ may limit these approaches with regard to a clear clinical benefit. In order to assess potential effects of a dose escalation in certain sub-volumes based on choline PET imaging a mathematical dose-response model was developed. Based on different assumptions for α/β, γ50, sensitivity and specificity of choline PET, the influence of the whole prostate and simultaneous integrated boost (SIB) dose on tumor control probability (TCP) was calculated. Based on the given heterogeneity of all potential variables certain representative permutations of the parameters were chosen and, subsequently, the influence on TCP was assessed. Using schedules with 74 Gy within the whole prostate and a SIB dose of 90 Gy the TCP increase ranged from 23.1% (high detection rate of choline PET, low whole prostate dose, high γ50/ASTRO definition for tumor control) to 1.4% TCP gain (low sensitivity of PET, high whole prostate dose, CN + 2 definition for tumor control) or even 0% in selected cases. The corresponding initial TCP values without integrated boost ranged from 67.3% to 100%. According to a large data set of intermediate-risk prostate cancer patients the resulting TCP gains ranged from 22.2% to 10.1% (ASTRO definition) or from 13.2% to 6.0% (CN + 2 definition). Although a simplified mathematical model was employed, the presented model allows for an estimation in how far given schedules are relevant for clinical practice. However, the benefit of a SIB based on choline PET seems less than intuitively expected. Only under the

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

Clinical oncology based upon radiation biology

International Nuclear Information System (INIS)

Hirata, Hideki

2016-01-01

This paper discussed the biological effects of radiation as physical energy, especially those of X-ray as electromagnetic radiation, by associating the position of clinical oncology with classical radiation cell biology as well as recent molecular biology. First, it described the physical and biological effects of radiation, cell death due to radiation and recovery, radiation effects at tissue level, and location information and dosage information in the radiotherapy of cancer. It also described the territories unresolved through radiation biology, such as low-dose high-sensitivity, bystander effects, etc. (A.O.)

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

Dose-response relationship of dicentric chromosomes in human lymphocytes obtained for the fission neutron therapy facility MEDAPP at the research reactor FRM II.

Science.gov (United States)

Schmid, E; Wagner, F M; Romm, H; Walsh, L; Roos, H

2009-02-01

The biological effectiveness of neutrons from the neutron therapy facility MEDAPP (mean neutron energy 1.9 MeV) at the new research reactor FRM II at Garching, Germany, has been analyzed, at different depths in a polyethylene phantom. Whole blood samples were exposed to the MEDAPP beam in special irradiation chambers to total doses of 0.14-3.52 Gy at 2-cm depth, and 0.18-3.04 Gy at 6-cm depth of the phantom. The neutron and gamma-ray absorbed dose rates were measured to be 0.55 Gy min(-1) and 0.27 Gy min(-1) at 2-cm depth, while they were 0.28 and 0.25 Gy min(-1) at 6-cm depth. Although the irradiation conditions at the MEDAPP beam and the RENT beam of the former FRM I research reactor were not identical, neutrons from both facilities gave a similar linear-quadratic dose-response relationship for dicentric chromosomes at a depth of 2 cm. Different dose-response curves for dicentrics were obtained for the MEDAPP beam at 2 and 6 cm depth, suggesting a significantly lower biological effectiveness of the radiation with increasing depth. No obvious differences in the dose-response curves for dicentric chromosomes estimated under interactive or additive prediction between neutrons or gamma-rays and the experimentally obtained dose-response curves could be determined. Relative to (60)Co gamma-rays, the values for the relative biological effectiveness at the MEDAPP beam decrease from 5.9 at 0.14 Gy to 1.6 at 3.52 Gy at 2-cm depth, and from 4.1 at 0.18 Gy to 1.5 at 3.04 Gy at 6-cm depth. Using the best possible conditions of consistency, i.e., using blood samples from the same donor and the same measurement techniques for about two decades, avoiding the inter-individual variations in sensitivity or the differences in methodology usually associated with inter-laboratory comparisons, a linear-quadratic dose-response relationship for the mixed neutron and gamma-ray MEDAPP field as well as for its fission neutron part was obtained. Therefore, the debate on whether the fission

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.

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

Low doses of ionizing radiation: Biological effects and regulatory control. Invited papers and discussions. Proceedings of an international conference

International Nuclear Information System (INIS)

1998-01-01

The levels and biological effects resulting from exposure to ionizing radiation are continuously reviewed by the United Nations Committee on the Effects of Atomic Radiation (UNSCEAR). Since its creation in 1928, the International Commission on Radiological Protection (ICRP) has issued recommendations on protection against ionizing radiation. The UNSCEAR estimates and the ICRP recommendations have served as the basis for national and international safety standards on radiation safety, including those developed by the International Atomic Energy Agency (IAEA) and the World Health Organization (WHO). Concerning health effects of low doses of ionizing radiation, the international standards are based on the plausible assumption that, above the unavoidable background radiation dose, the probability of effects increases linearly with dose, i.e. on a 'linear, no threshold' (LNT) assumption. However, in recent years the biological estimates of health effects of low doses of ionizing radiation and the regulatory approach to the control of low level radiation exposure have been much debated. To foster information exchange on the relevant issues, an International Conference on Low Doses of Ionizing Radiation: Biological Effects and Regulatory Control, jointly sponsored by the IAEA and WHO in co-operation with UNSCEAR, was held from 17-21 November 1997 at Seville, Spain. These Proceedings contain the invited special reports, keynote papers, summaries of discussions, session summaries and addresses presented at the opening and closing of the Conference

Biological dosimetry of ionizing radiation by chromosomal aberration analysis

International Nuclear Information System (INIS)

Gonzalez-Castano, S.; Silva, A.; Navlet, J.

1990-01-01

Biological dosimetry consists of estimating absorbed doses for people exposed to radiation by mean biological methods. Several indicators used are based in haematological, biochemical, and cytogenetic data, although nowadays without doubt, the cytogenetic method is considered to be the most reliable. In this case, the study ol chromosomal aberrations, normally dicentric chromosomes, in peripheral lymphocytes can be related to absorbed dose through an experimental calibration curve. An experimental dose-response curve, using dicentric chromosomes analysis, X-rays at 300 kVp, 114 rad/min and temperature 37 degree celsius has been produced. Experimental data is fitted to model Y =α + β 1 D + β 2 D 2 , where Y is the number of dicentrics per cell and D the dose. The curve is compared with those produced elsewhere. (Author) 14 refs

Biological dosimetry of ionizing radiation by chromosomal aberration analysis

International Nuclear Information System (INIS)

Navlet Armenta, J.M.; Gonzalez, S.; Silva, A.

1990-01-01

Biological dosimetry consists of estimating absorbed doses for people exposed to radiation by mean biological methods. Several indicators used are based in haemathological, biochemical, and cytogenetic data, although nowadays without doubt, the cytogenetic method is considered to be the most reliable. In this case, the study of chromosomal aberrations, normally dicentric chromosomes, in peripheral lymphocytes can be related to absorbed dose through an experimental calibration curve. An experimental dose-response curve using dicentric chromosomes analysis, X-rays at 300 kVp, 114 rad/min and temperature 37 o C has been produced. Experimental data is fitted to model Y = α+β 1 D+β 2 D 2 , where Y is the number of dicentrics per cell and D the dose. The curve is compared with those produced elsewhere. (Author)

Statistical issues in biological radiation dosimetry for risk assessment using stable chromosome aberrations

International Nuclear Information System (INIS)

Cologne, J.B.; Preston, D.L.

1998-01-01

Biological dosimeters are useful for epidemiologic risk assessment in populations exposed to catastrophic nuclear events and as a means of validating physical dosimetry in radiation workers. Application requires knowledge of the magnitude of uncertainty in the biological dose estimates and an understanding of potential statistical pitfalls arising from their use. This paper describes the statistical aspects of biological dosimetry in general and presents a detailed analysis in the specific case of dosimetry for risk assessment using stable chromosome aberration frequency. Biological dose estimates may be obtained from a dose-response curve, but negative estimates can result and adjustment must be made for regression bias due to imprecise estimation when the estimates are used in regression analyses. Posterior-mean estimates, derived as the mean of the distribution of true doses compatible with a given value of the biological endpoint, have several desirable properties: they are nonnegative, less sensitive to extreme skewness in the true dose distribution, and implicitly adjusted to avoid regression bias. The methods necessitate approximating the true-dose distribution in the population in which biological dosimetry is being applied, which calls for careful consideration of this distribution through other information. An important question addressed here is to what extent the methods are robust to misspecification of this distribution, because in many applications of biological dosimetry it cannot be characterized well. The findings suggest that dosimetry based solely on stable chromosome aberration frequency may be useful for population-based risk assessment

The choice of a biological model in assessing internal dose equivalent

International Nuclear Information System (INIS)

Parodo, A.; Erre, N.

1977-01-01

Many are the biological models related to kinetic behavior of radioactive materials within the organism, or in an organ. This is true particularly for the metabolic kinetics of bone-seekers radionuclides described differently by various authors: as a consequence, different forms of the retention function have been used in calculating internal dose equivalent. In our opinion, the retention functions expressed as linear combinations of exponential terms with negative exponents are preferable. In fact, they can be obtained by coherent compartmental analysis and allow a mathematical formalism fairly well definite and easily adaptable to computers. Moreover, it is possible to make use of graphs and monograms already published. The role of the biological model in internal dosimetry, referred to the reliability of the quantitative informations on the kinetic behavior of the radionuclides in the organism and, therefrom, to the accuracy of the doses calculated, is discussed. By comparing the results obtained with different biological models, one finds that the choice of a model is less important than the choice of the value of the appropriate parameters

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

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.

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

Long-term biological effects induced by ionizing radiation--implications for dose mediated risk.

Science.gov (United States)

Miron, S D; Astărăstoae, V

2014-01-01

Ionizing radiations are considered to be risk agents that are responsible for the effects on interaction with living matter. The occurring biological effects are due to various factors such as: dose, type of radiation, exposure time, type of biological tissue, health condition and the age of the person exposed. The mechanisms involved in the direct modifications of nuclear DNA and mitochondrial DNA are reviewed. Classical target theory of energy deposition in the nucleus that causes DNA damages, in particular DNA double-strand breaks and that explanation of the biological consequences of ionizing radiation exposure is a paradigm in radiobiology. Recent experimental evidences have demonstrated the existence of a molecular mechanism that explains the non-targeted effects of ionizing radiation exposure. Among these novel data, genomic instability and a variety of bystander effects are discussed here. Those bystander effects of ionizing radiation are fulfilled by cellular communication systems that give rise to non-targeted effects in the neighboring non irradiated cells. This paper provides also a commentary on the synergistic effects induced by the co-exposures to ionizing radiation and various physical agents such as electromagnetic fields and the co-exposures to ionizing radiation and chemical environmental contaminants such as metals. The biological effects of multiple stressors on genomic instability and bystander effects are also discussed. Moreover, a brief presentation of the methods used to characterize cyto- and genotoxic damages is offered.

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

Synthetic biology, metaphors and responsibility.

Science.gov (United States)

McLeod, Carmen; Nerlich, Brigitte

2017-08-29

Metaphors are not just decorative rhetorical devices that make speech pretty. They are fundamental tools for thinking about the world and acting on the world. The language we use to make a better world matters; words matter; metaphors matter. Words have consequences - ethical, social and legal ones, as well as political and economic ones. They need to be used 'responsibly'. They also need to be studied carefully - this is what we want to do through this editorial and the related thematic collection. In the context of synthetic biology, natural and social scientists have become increasingly interested in metaphors, a wave of interest that we want to exploit and amplify. We want to build on emerging articles and books on synthetic biology, metaphors of life and the ethical and moral implications of such metaphors. This editorial provides a brief introduction to synthetic biology and responsible innovation, as well as a comprehensive review of literature on the social, cultural and ethical impacts of metaphor use in genomics and synthetic biology. Our aim is to stimulate an interdisciplinary and international discussion on the impact that metaphors can have on science, policy and publics in the context of synthetic biology.

Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

Science.gov (United States)

Jones, Hannah M; Mayawala, Kapil; Poulin, Patrick

2013-04-01

Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

Biological bases of radiological protection criteria for superficial, low penetrating radiation exposure

Energy Technology Data Exchange (ETDEWEB)

Charles, M W

1986-01-01

When the body is exposed to low penetrating radiation such as beta or low energy X-rays, the skin, eyes and sometimes testes may be the most highly irradiated organs of the body. In order to assess the biological response following such exposures it is necessary to understand the radiobiology of the specific organs and, in particular, the identity and depth of the most radiosensitive cells. This information is also directly relevant to the needs of those responsible for calculating and measuring doses to personnel. Up to date information on the identification and depth of cells at risk, and the biological response following non-uniform exposures will be reviewed. The limitations in this knowledge which are creating problems for dosimetric applications are identified so that radiobiology programmes can then be evaluated and tailored to meet these practical needs.

Laser-based irradiation apparatus and methods for monitoring the dose-rate response of semiconductor devices

Science.gov (United States)

Horn, Kevin M [Albuquerque, NM

2006-03-28

A scanned, pulsed, focused laser irradiation apparatus can measure and image the photocurrent collection resulting from a dose-rate equivalent exposure to infrared laser light across an entire silicon die. Comparisons of dose-rate response images or time-delay images from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems allows precise identification of those specific age-affected circuit structures within a device that merit further quantitative analysis with targeted materials or electrical testing techniques. Another embodiment of the invention comprises a broad-beam, dose rate-equivalent exposure apparatus. The broad-beam laser irradiation apparatus can determine if aging has affected the device's overall functionality. This embodiment can be combined with the synchronized introduction of external electrical transients into a device under test to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure.

Studies on adaptive response of lymphocyte transformation induced by low-dose irradiation

International Nuclear Information System (INIS)

Du Zeji; Su Liaoyuan; Tian Hailin; Zou Huawei

1995-10-01

Human peripheral blood lymphocytes stimulated by mitogen in vitro for 24 h were exposed to low-dose γ-ray irradiation (0.5∼4.0 cGy, adaptive dose). They showed an adaptive response to the inhibition of 3 H-TdR incorporation by subsequent higher acute doses of γ-ray (challenge dose). At the interval of 24 h between adaptive dose and challenge dose, the strongest adaptive response induced by low-dose irradiation was found. It is also found that the response induced by 1.0 cGy of adaptive dose was more obvious than that by other doses and that 3.0 Gy of challenge dose produced the strongest adaptive response. As the challenge doses increased, the adaptive response reduced. (2 figs., 2 tabs.)

Space radiation-induced bystander effect: kinetics of biologic responses, mechanisms, and significance of secondary radiations

International Nuclear Information System (INIS)

Gonon, Geraldine

2011-01-01

more cells than expected based on the fraction of cells traversed through the nucleus by an iron or silicon ion. The effect was expressed as early as 15 min after exposure, peaked at 1 h and decreased by 24 h. A similar tendency occurred after exposure to a mean absorbed dose of 0.2 cGy of 3.7 MeV a particles, but not after 0.2 cGy of 290 MeV/u carbon ions.Analyses in dishes that incorporate a CR-39 solid state nuclear track detector bottom identified the cells irradiated with iron or silicon ions and further supported the participation of bystander cells in the stress response. Mechanistic studies indicated that gap junction intercellular communication, DNA repair, and oxidative metabolism participate in the propagation of the induced effects. We also considered the possible contribution of secondary particles produced along the primary particle tracks to the biological responses. Simulations with the FLUKA multi-particle transport code revealed that fragmentation products, other than electrons, in cells cultures exposed to HZE particles comprise ≤1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 μm. Thus, the latter are unlikely to significantly contribute to the stressful effects in cells not targeted by primary HZE particles. (author)

Tumor and normal tissue responses to fractioned non-uniform dose delivery

Energy Technology Data Exchange (ETDEWEB)

Kaellman, P; Aegren, A; Brahme, A [Karolinska Inst., Stockholm (Sweden). Dept. of Radiation Physics

1996-08-01

The volume dependence of the radiation response of a tumor is straight forward to quantify because it depends primarily on the eradication of all its clonogenic cells. A tumor therefore has a parallel organization as any surviving clonogen in principle can repopulate the tumor. The difficulty with the response of the tumor is instead to know the density and sensitivity distribution of the most resistant clonogenic cells. The increase in the 50% tumor control dose and the decrease in the maximum normalized slope of the dose response relation, {gamma}, in presence of small compartments of resistant tumor cells have therefore been quantified to describe their influence on the dose response relation. Injury to normal tissue is a much more complex and gradual process. It depends on earlier effects induced long before depletion of the differentiated and clonogenic cells that in addition may have a complex structural and functional organization. The volume dependence of the dose response relation of normal tissues is therefore described here by the relative seriality, s, of the infrastructure of the organ. The model can also be generalized to describe the response of heterogeneous tissues to non uniform dose distributions. The new model is compared with clinical and experimental data on normal tissue response, and shows good agreement both with regard to the shape of dose response relation and the volume dependence of the isoeffect dose. The response of tumors and normal tissues are quantified for arbitrary dose fractionations using the linear quadratic cell survival parameters {alpha} and {beta}. The parameters of the dose response relation are derived both for a constant dose per fraction and a constant number of dose fractions, thus in the latter case accounting also for non uniform dose delivery. (author). 26 refs, 4 figs.

Calibration curve to establish the exposure dose at Co60 gamma radiation

International Nuclear Information System (INIS)

Guerrero C, C.; Brena V, M.

2000-01-01

The biological dosimetry is an adequate method for the dose determination in cases of overexposure to ionizing radiation or doubt of the dose obtained by physical methods. It is based in the aberrations analysis produced in the chromosomes. The behavior of leisure in chromosomes is of dose-response type and it has been generated curves in distinct laboratories. Next is presented the curve for gamma radiation produced in the National Institute of Nuclear Research (ININ) laboratory. (Author)

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)

Radiotherapy Dose Fractionation under Parameter Uncertainty

International Nuclear Information System (INIS)

Davison, Matt; Kim, Daero; Keller, Harald

2011-01-01

In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.

Estimation of low-dose radiation-responsive proteins in the absence of genomic instability in normal human fibroblast cells.

Science.gov (United States)

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Nam, Seon Young; Kim, Cha Soon

2017-11-01

Low-dose radiation has various biological effects such as adaptive responses, low-dose hypersensitivity, as well as beneficial effects. However, little is known about the particular proteins involved in these effects. Here, we sought to identify low-dose radiation-responsive phosphoproteins in normal fibroblast cells. We assessed genomic instability and proliferation of fibroblast cells after γ-irradiation by γ-H2AX foci and micronucleus formation analyses and BrdU incorporation assay, respectively. We screened fibroblast cells 8 h after low-dose (0.05 Gy) γ-irradiation using Phospho Explorer Antibody Microarray and validated two differentially expressed phosphoproteins using Western blotting. Cell proliferation proceeded normally in the absence of genomic instability after low-dose γ-irradiation. Phospho antibody microarray analysis and Western blotting revealed increased expression of two phosphoproteins, phospho-NFκB (Ser536) and phospho-P70S6K (Ser418), 8 h after low-dose radiation. Our findings suggest that low-dose radiation of normal fibroblast cells activates the expression of phospho-NFκB (Ser536) and phospho-P70S6K (Ser418) in the absence of genomic instability. Therefore, these proteins may be involved in DNA damage repair processes.

Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid.

Science.gov (United States)

Weterings, Peter J J M; Loftus, Christine; Lewandowski, Thomas A

2016-08-22

Potential adverse effects of chemical substances on thyroid function are usually examined by measuring serum levels of thyroid-related hormones. Instead, recent risk assessments for thyroid-active chemicals have focussed on iodine uptake inhibition, an upstream event that by itself is not necessarily adverse. Establishing the extent of uptake inhibition that can be considered de minimis, the chosen benchmark response (BMR), is therefore critical. The BMR values selected by two international advisory bodies were 5% and 50%, a difference that had correspondingly large impacts on the estimated risks and health-based guidance values that were established. Potential treatment-related inhibition of thyroidal iodine uptake is usually determined by comparing thyroidal uptake of radioactive iodine (RAIU) during treatment with a single pre-treatment RAIU value. In the present study it is demonstrated that the physiological intra-individual variation in iodine uptake is much larger than 5%. Consequently, in-treatment RAIU values, expressed as a percentage of the pre-treatment value, have an inherent variation, that needs to be considered when conducting dose-response analyses. Based on statistical and biological considerations, a BMR of 20% is proposed for benchmark dose analysis of human thyroidal iodine uptake data, to take the inherent variation in relative RAIU data into account. Implications for the tolerated daily intakes for perchlorate and chlorate, recently established by the European Food Safety Authority (EFSA), are discussed. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

Cellular response to ionizing radiations: a study of the roles of physics and biology

International Nuclear Information System (INIS)

DeWyngaert, J.K.

1982-01-01

A study of the complementary roles of physics and biology in determining the response of cellular systems to ionizing radiations has been conducted. Upon exposure to radiation, a cell responds in a binary (yes/no) manner in terms of its proliferative ability (survival). The relationship between the survival probability and absorbed dose may then be examined in terms of relevant physical and biological parameters. The approach to these studies was to vary the physics and biology independently and observe separately their influences upon the measured effect. Unique to these studies was the use of heterogeneous tumor systems. These are solid tumors found to consist of genetically related but identifiably distinct populations of cells. The two heterogeneous systems studied, a murine system consisting of four subpopulations and a human tumor system with two subpopulations, were exposed to graded doses of 14 MeV neutrons or x-rays and their effectiveness in inducing cell lethality compared. A further examination of the radiation effect involved a study at the chemical level, measuring the ability of oxygen to potentiate the damage produced by photon irradiation. To summarize, the physics, biology and the environment have all been varied, and the systematics of the responses studied. The data were analyzed within the formalisms of the dual theory of radiation action, the repair-misrepair model, and the repair saturation model of cell killing. The change in survival curve shape and the increased effectiveness in cell killing for higher Linear Energy Transfer (LET) radiations (neutrons vs. x-rays) are discussed in relation to explanations in terms of either physical or biochemical processes

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

Dicentric chromosomes and γ-H2AX foci formation in lymphocytes of human blood samples exposed to a CT scanner: A direct comparison of dose response relationships

International Nuclear Information System (INIS)

Golfier, S.; Jost, G.; Pietsch, H.; Lengsfeld, P.; Eckardt-Schupp, F.; Schmid, E.; Voth, M.

2009-01-01

Experiments using the induction of dicentric chromosomes (dicentrics) as well as the γ-H2AX foci formation in lymphocytes of blood samples from a healthy donor were performed to directly evaluate the radiation sensitivity of both biological endpoints. For computed tomography scans at dose levels from 0.025 to 1 Gy, a linear-quadratic dose - response relationship for dicentrics and a linear dose - response relationship for γ-H2AX foci were obtained. The coefficients of the dose - response relationship for dicentrics are α = (3.76 ± 0.29) x 10 -2 Gy -1 and β = (5.54 ± 0.45) x 10 -2 Gy -2 , the linear coefficient for γ-H2AX foci is (7.38 ± 0.11) Gy -1 . The findings indicate that scoring of dicentrics as well as microscopic analysis of γ-H2AX foci are sensitive methods to quantify a radiation-induced biological damage at low doses. However, since γ-H2AX foci can be partially repaired within a few hours, biological damages present for days or even months, which constitute the clinically relevant endpoints, can only be quantified reliably by scoring of chromosome aberrations. Thus currently the quantification of dicentrics or reciprocal translocations remains the recommended method for estimating the effect of exposures to low dose levels of radiation ('biological dosimetry'). However, owing to the high radiation sensitivity of the γ-H2AX foci assay observed in the present study, further investigations on the effectiveness of low-linear energy transfer radiation qualities in producing γ-H2AX foci in lymphocytes from healthy donors should be performed. (authors)

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

The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

International Nuclear Information System (INIS)

Clark, Brenda G.; Souhami, Luis; Pla, Conrado; Al-Amro, Abdullah S.; Bahary, Jean-Paul; Villemure, Jean-Guy; Caron, Jean-Louis; Olivier, Andre; Podgorsak, Ervin B.

1998-01-01

Purpose: The aim of this work was to develop a parameter for use during fractionated stereotactic radiotherapy treatment planning to aid in the determination of the appropriate treatment volume and fractionation regimen that will minimize risk of late damage to normal tissue. Materials and Methods: We have used the linear quadratic model to assess the biologically effective dose at the periphery of stereotactic radiotherapy treatment volumes that impinge on the brain stem. This paper reports a retrospective study of 77 patients with malignant and benign intracranial lesions, treated between 1987 and 1995, with the dynamic rotation technique in 6 fractions over a period of 2 weeks, to a total dose of 42 Gy prescribed at the 90% isodose surface. From differential dose-volume histograms, we evaluated biologically effective dose-volume histograms and obtained an integral biologically-effective dose (IBED) in each case. Results: Of the 77 patients in the study, 36 had target volumes positioned so that the brain stem received more than 1% of the prescribed dose, and 4 of these, all treated for meningioma, developed serious late damage involving the brain stem. Other than type of lesion, the only significant variable was the volume of brain stem exposed. An analysis of the IBEDs received by these 36 patients shows evidence of a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiotherapy. Conclusions: We have introduced a new parameter, the IBED, that may be used to represent the fractional effective dose to structures such as the brain stem that are partially irradiated with stereotactic dose distributions. The IBED is easily calculated prior to treatment and may be used to determine appropriate treatment volumes and fractionation regimens minimizing possible toxicity to normal tissue

Photo-Responsive Graphene and Carbon Nanotubes to Control and Tackle Biological Systems

Science.gov (United States)

Cardano, Francesca; Frasconi, Marco; Giordani, Silvia

2018-01-01

Photo-responsive multifunctional nanomaterials are receiving considerable attention for biological applications because of their unique properties. The functionalization of the surface of carbon nanotubes (CNTs) and graphene, among other carbon based nanomaterials, with molecular switches that exhibit reversible transformations between two or more isomers in response to different kind of external stimuli, such as electromagnetic radiation, temperature and pH, has allowed the control of the optical and electrical properties of the nanomaterial. Light-controlled molecular switches, such as azobenzene and spiropyran, have attracted a lot of attention for nanomaterial's functionalization because of the remote modulation of their physicochemical properties using light stimulus. The enhanced properties of the hybrid materials obtained from the coupling of carbon based nanomaterials with light-responsive switches has enabled the fabrication of smart devices for various biological applications, including drug delivery, bioimaging and nanobiosensors. In this review, we highlight the properties of photo-responsive carbon nanomaterials obtained by the conjugation of CNTs and graphene with azobenzenes and spiropyrans molecules to investigate biological systems, devising possible future directions in the field. PMID:29707534

Photo-Responsive Graphene and Carbon Nanotubes to Control and Tackle Biological Systems

Science.gov (United States)

Cardano, Francesca; Frasconi, Marco; Giordani, Silvia

2018-04-01

Photo-responsive multifunctional nanomaterials are receiving considerable attention for biological applications because of their unique properties. The functionalization of the surface of carbon nanotubes (CNTs) and graphene, among other carbon based nanomaterials, with molecular switches that exhibit reversible transformations between two or more isomers in response to different kind of external stimuli, such as electromagnetic radiation, temperature and pH, has allowed the control of the optical and electrical properties of the nanomaterial. Light-controlled molecular switches, such as azobenzene and spiropyran, have attracted a lot of attention for nanomaterial’s functionalization because of the remote modulation of their physicochemical properties using light stimulus. The enhanced properties of the hybrid materials obtained from the coupling of carbon based nanomaterials with light-responsive switches has enabled the fabrication of smart devices for various biological applications, including drug delivery, bioimaging and nanobiosensors. In this review, we highlight the properties of photo-responsive carbon nanomaterials obtained by the conjugation of CNTs and graphene with azobenzenes and spiropyrans molecules to investigate biological systems, devising possible future directions in the field.

Biological effect of low-dose application beta-radiation on the gingival mucosa of dogs

International Nuclear Information System (INIS)

Ippolitov, Yu.A.; Kovtun, N.N.; Timofeev, L.V.

1999-01-01

Biological effect of low-dose application beta-radiation on the gingival mucosa of dogs is studied. Obtained data illustrate the interactions between tissues in local exposure of live tissue to beta-radiation and determine the threshold total dose as 400 sGy. Higher doses lead to secondary changes in the gingival mucosa after which the tissue barrier does not recover [ru

A tiered approach for integrating exposure and dosimetry with in vitro dose-response data in the modern risk assessment paradigm

Science.gov (United States)

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biolog...

Application of biological effective dose (BED) to estimate the duration of symptomatic relief and repopulation dose equivalent in palliative radiotherapy and chemotherapy

International Nuclear Information System (INIS)

Jones, Bleddyn; Cominos, Matilda; Dale, Roger G.

2003-01-01

Purpose: To investigate the potential for mathematic modeling in the assessment of symptom relief in palliative radiotherapy and cytotoxic chemotherapy. Methods: The linear quadratic model of radiation effect with the overall treatment time and the daily dose equivalent of repopulation is modified to include the regrowth time after completion of therapy. Results: The predicted times to restore the original tumor volumes after treatment are dependent on the biological effective dose (BED) delivered and the repopulation parameter (K); it is also possible to estimate K values from analysis of palliative treatment response durations. Hypofractionated radiotherapy given at a low total dose may produce long symptom relief in slow-growing tumors because of their low α/β ratios (which confer high fraction sensitivity) and their slow regrowth rates. Cancers that have high α/β ratios (which confer low fraction sensitivity), and that are expected to repopulate rapidly during therapy, are predicted to have short durations of symptom control. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same duration of symptom relief as palliative chemotherapy. Conclusion: Relatively simple radiobiologic modeling can be used to guide decision-making regarding the choice of the most appropriate palliative schedules and has important implications in the design of radiotherapy or chemotherapy clinical trials. The methods described provide a rationalization for treatment selection in a wide variety of tumors

Random Forest Segregation of Drug Responses May define Regions of Biological Significance

Directory of Open Access Journals (Sweden)

Qasim eBukhari

2016-03-01

Full Text Available The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF method to detect differences in the pharmacological MRI (phMRI response in rats to treatment with an analgesic drug (buprenorphine as compared to control (saline. Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD and high dose (HD, and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow an unsupervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies.

The evolutionary reserve cell concept and model of cellular response induced by low doses of radiation

International Nuclear Information System (INIS)

Spitkovsky, D.M.; Talyzina, T.A.

1995-01-01

The model is based on the concept of programmed initiation of genetic damage in sub-populations of specific evolutionary reserve cells (ERC). The model quantitatively predicts a dose response of genetic lesions at low dose range and furnishes an explanation of the minimum observed in the dose-response curve at doses corresponding to one (on the average) event of energy deposition per ERC. The complex shape of the dose-response curve is demonstrated to result from superposition of processes in different sub-populations within the exposed cell population (at low doses mainly in ERC). Programmed initiation of genetic lesions in ERC requires two hits to cell membrane and probably, at the same time, to the cell nucleus. The equation for dicentric yield in human lymphocytes as a function of dose describes the experimental observations rather well. (Author)

Tritium biological effects and perspective of the biological study

International Nuclear Information System (INIS)

Komatsu, Kenshi

1998-01-01

Since tritium is an emitter of weak β-rays (5.7keV) and is able to bind to DNA, i.e., the most important genome component, the biological effects should be expected to be more profound than that of X-rays and γ-rays. When carcinogenesis, genetical effects and the detriments for fetus and embryo were used as a biological endpoint, most of tritium RBE (relative biological effectiveness) ranged from 1 to 2. The tritium risk in man could be calculated from these RBEs and γ-ray risk for human exposure, which are obtained mainly from the data on Atomic Bomb survivors. However, the exposure modality from environmental tritium should be a chronic irradiation with ultra low dose rate or a fractionated irradiation. We must estimate the tritium effect in man based on biological experiments alone, due to lack of such epidemiological data. Low dose rate experiment should be always accompanied by the statistical problem of data, since their biological effects are fairy low, and they should involve a possible repair system, such as adaptive response (or hormesis effect) and 'Kada effect' observed in bacteria. Here we discuss future works for the tritium assessment in man, such as (1) developing a high radiation sensitive assay system with rodent hybrid cells containing a single human chromosome and also (2) study on mammal DNA repair at molecular levels using a radiosensitive hereditary disease, Nijmegen Breakage Syndrome. (author)

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

The effect of low dose rate on metabolomic response to radiation in mice

International Nuclear Information System (INIS)

Goudarzi, Maryam; Mak, Tytus D.; Chen, Congju; Smilenov, Lubomir B.; Brenner, David J.; Fornace, Albert J.

2014-01-01

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual's exposure in a radiobiological event and thus would have utility for both triage and injury assessment. (orig.)

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 ...

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...

Low Dose Radiation Response Curves, Networks and Pathways in Human Lymphoblastoid Cells Exposed from 1 to 10 cGy of Acute Gamma Radiation

Energy Technology Data Exchange (ETDEWEB)

Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.; Furtado, M. R.; Bhattacharya, M. S.; Marchetti, F.; Coleman, M.A.

2011-04-18

We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

RADIOIODINE TREATMENT OF GRAVES’ DISEASE – DOSE/RESPONSE ANALYSIS

Directory of Open Access Journals (Sweden)

Jitka Čepková

2014-01-01

Full Text Available The clinical outcome of 153 Graves’ disease patients treated with a wide dose range of radioactive iodine-131 (RAI was analyzed retrospectively. Six to nine months after the first dose of RAI 60 patients (39% were hypothyroid (or rather thyroxine-substituted and 26 (17% were euthyroid, while 67 patients (44% did not respond properly: in 32 (21% their antithyroid drug (ATD dose could be reduced but not withdrawn (partial response and 35 (23% remained hyperthyroid or the same dose of ATD was necessary (no response. The outcome did not correspond significantly to the administered activity of RAI (medians 259, 259, 222, and 259 MBq for hypothyroid, euthyroid, partial, and no response subgroups, respectively, or the activity retained in the gland at 24 h (medians 127, 105, 143, and 152 MBq. The effect was, however, clearly, and in a stepwise pattern, dependent on initial thyroid volume (17, 26, 33 and 35 ml, P  6 MBq/g, cure rate 80% and lower (≤ 6 MBq/g, cure rate 46% doses gave highly significant difference (P < 0.001. With our dosing range we found a dose-dependent clinical outcome that suggests an optimum delivered dose near 6.5 MBq/g, resulting in successful treatment of ca 80% patients.

Dose inhomogeneities at various levels of biological organization

International Nuclear Information System (INIS)

Bond, V.P.

1988-01-01

Dose inhomogeneities in both tumor and normal tissue, inherent to the application of boron neutron capture therapy (BNCT), can be the result not only of ununiform distribution of 10 B at various levels of biological organization, but also of the distribution of the thermal neutrons and of the energy depositions from more energetic neutrons and other radiations comprising the externally-applied beams. The severity of the problems resulting from such inhomogeneities, and approaches to evaluating them, are illustrated by three examples, at the macro, micro and intermediate levels

Modified Exponential (MOE) Models: statistical Models for Risk Estimation of Low dose Rate Radiation

International Nuclear Information System (INIS)

Ogata, H.; Furukawa, C.; Kawakami, Y.; Magae, J.

2004-01-01

Simultaneous inclusion of dose and dose-rate is required to evaluate the risk of long term irradiation at low dose-rates, since biological responses to radiation are complex processes that depend both on irradiation time and total dose. Consequently, it is necessary to consider a model including cumulative dose,dose-rate and irradiation time to estimate quantitative dose-response relationship on the biological response to radiation. In this study, we measured micronucleus formation and (3H) thymidine uptake in U2OS, human osteosarcoma cell line, as indicators of biological response to gamma radiation. Cells were exposed to gamma ray in irradiation room bearing 50,000 Ci 60Co. After irradiation, they were cultured for 24h in the presence of cytochalasin B to block cytokinesis, and cytoplasm and nucleus were stained with DAPI and propidium iodide. The number of binuclear cells bearing a micronucleus was counted under a florescence microscope. For proliferation inhibition, cells were cultured for 48 h after the irradiation and (3h) thymidine was pulsed for 4h before harvesting. We statistically analyzed the data for quantitative evaluation of radiation risk at low dose/dose-rate. (Author)

Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

Energy Technology Data Exchange (ETDEWEB)

Gillmann, Clarissa, E-mail: clarissa.gillmann@med.uni-heidelberg.de [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Jäkel, Oliver [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Heidelberg Ion Beam Therapy Center (HIT), Heidelberg (Germany); Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Schlampp, Ingmar [Department of Radiation Oncology and Radiation Therapy, Heidelberg University Hospital, Heidelberg (Germany); Karger, Christian P. [Department of Medical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg (Germany)

2014-04-01

Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a

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.

Recommendations for the validation of cell-based assays used for the detection of neutralizing antibody immune responses elicited against biological therapeutics.

Science.gov (United States)

Gupta, Shalini; Devanarayan, Viswanath; Finco, Deborah; Gunn, George R; Kirshner, Susan; Richards, Susan; Rup, Bonita; Song, An; Subramanyam, Meena

2011-07-15

The administration of biological therapeutics may result in the development of anti-drug antibodies (ADAs) in treated subjects. In some cases, ADA responses may result in the loss of therapeutic efficacy due to the formation of neutralizing ADAs (NAbs). An important characteristic of anti-drug NAbs is their direct inhibitory effect on the pharmacological activity of the therapeutic. Neutralizing antibody responses are of particular concern for biologic products with an endogenous homolog whose activity can be potentially dampened or completely inhibited by the NAbs leading to an autoimmune-type deficiency syndrome. Therefore, it is important that ADAs are detected and characterized appropriately using sensitive and reliable methods. The design, development and optimization of cell-based assays used for detection of NAbs have been published previously by Gupta et al. 2007 [1]. This paper provides recommendations on best practices for the validation of cell-based NAb assay and suggested validation parameters based on the experience of the authors. Copyright © 2011 Elsevier B.V. All rights reserved.

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

Science.gov (United States)

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

OEDIPE, a software for personalized Monte Carlo dosimetry and treatment planning optimization in nuclear medicine: absorbed dose and biologically effective dose considerations

International Nuclear Information System (INIS)

Petitguillaume, A.; Broggio, D.; Franck, D.; Desbree, A.; Bernardini, M.; Labriolle Vaylet, C. de

2014-01-01

For targeted radionuclide therapies, treatment planning usually consists of the administration of standard activities without accounting for the patient-specific activity distribution, pharmacokinetics and dosimetry to organs at risk. The OEDIPE software is a user-friendly interface which has an automation level suitable for performing personalized Monte Carlo 3D dosimetry for diagnostic and therapeutic radionuclide administrations. Mean absorbed doses to regions of interest (ROIs), isodose curves superimposed on a personalized anatomical model of the patient and dose-volume histograms can be extracted from the absorbed dose 3D distribution. Moreover, to account for the differences in radiosensitivity between tumoral and healthy tissues, additional functionalities have been implemented to calculate the 3D distribution of the biologically effective dose (BED), mean BEDs to ROIs, isoBED curves and BED-volume histograms along with the Equivalent Uniform Biologically Effective Dose (EUD) to ROIs. Finally, optimization tools are available for treatment planning optimization using either the absorbed dose or BED distributions. These tools enable one to calculate the maximal injectable activity which meets tolerance criteria to organs at risk for a chosen fractionation protocol. This paper describes the functionalities available in the latest version of the OEDIPE software to perform personalized Monte Carlo dosimetry and treatment planning optimization in targeted radionuclide therapies. (authors)

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.

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)