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Sample records for repeated-dose toxicology studies

  1. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine.

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    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha

    2012-12-01

    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  2. Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test.

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    McKee, Richard H; Steup, David; Schreiner, Ceinwen; Podhasky, Paula; Malley, Linda A; Roberts, Linda

    2014-01-01

    Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

  3. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... strains of young healthy adult animals should be employed. The females should be nulliparous and...

  4. Construction of the Database of Rat Repeated-dose Toxicity Tests of Pesticides for the Toxicological Characterization of Hepatocyte Hypertrophy.

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    Masuda, Akane; Masuda, Miyabi; Kawano, Takuya; Kitsunai, Yoko; Nakayama, Haruka; Nakajima, Hiroyuki; Kojima, Hiroyuki; Kitamura, Shigeyuki; Uramaru, Naoto; Hosaka, Takuomi; Sasaki, Takamitsu; Yoshinari, Kouichi

    2017-01-01

     Liver and hepatocyte hypertrophy can be induced by exposure to chemical compounds, but the mechanisms and toxicological characteristics of these phenomena have not yet been investigated extensively. In particular, it remains unclear whether the hepatocyte hypertrophy induced by chemical compounds should be judged as an adaptive response or an adverse effect. Thus, understanding of the toxicological characteristics of hepatocyte hypertrophy is of great importance to the safety evaluation of pesticides and other chemical compounds. To this end, we have constructed a database of potentially toxic pesticides. Using risk assessment reports of pesticides that are publicly available from the Food Safety Commission of Japan, we extracted all observations/findings that were based on 90-day subacute toxicity tests and 2-year chronic toxicity and carcinogenicity tests in rats. Analysis of the database revealed that hepatocyte hypertrophy was observed for 37-47% of the pesticides investigated (varying depending on sex and testing period), and that centrilobular hepatocyte hypertrophy was the most frequent among the various types of hepatocyte hypertrophy in both the 90-day and 2-year studies. The database constructed in this study enables us to investigate the relationships between hepatocyte hypertrophy and other toxicological observations/findings, and thus will be useful for characterizing hepatocyte hypertrophy.

  5. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

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    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  6. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations.

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    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  7. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

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    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  8. Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

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    Jae-Seuk Park

    2010-12-01

    Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

  9. Investigation of the toxicity of some organophosphorus pesticides in a repeated dose study in rats.

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    Baconi, Daniela Luiza; Bârcă, Maria; Manda, Gina; Ciobanu, Anne Marie; Bălălău, C

    2013-01-01

    The study aimed to the investigation of the toxicity of organophosphorus pesticides malathion (MLT) and diazinon (DZN) in Wistar rats in a repeated dose study for 35 days. MLT and DZN in corn oil vehicle were oral administered. Body and organs weights, plasma and brain cholinesterase activities, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathological changes in liver and kidney, and some parameters of the immune function, such as leukocyte formula, spleen weight and cellularity, spleen lymphocytes proliferation in response to concanavalin A (Con A) were investigated; the potential oxidative stress (malondialdehyde in plasma and brain, and blood catalase activity) was also evaluated. No clinical toxicity signs attributed to pesticides were noted; no significant changes in the organ weights have been found. Body weight tends slightly to increase, predominantly in DZN treated rats. The results suggest that plasma cholinesterase is more susceptible than brain cholinesterase to the inhibitory effect of DZN and MLT. Other serum biochemical parameters showed no significant difference. DZN produced a marked increase of the number of spleen lymphocytes without a significant gain of the relative spleen weight. The both pesticides produced an increase of the number of mononuclear cells÷weight spleen. The splenic lymphocyte proliferation has not been influenced by MLT or DZN treatment. Histopathological observations identified some changes (vasodilatation, microvacuoles, and granular dystrophy) in the liver, with MLT, inducing macrovacuolar steatosis. The study indicates that repeated exposure, at subclinical doses, to organophosphorus MLT and DZN causes some biochemical, histopathological and immune alterations in rats.

  10. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

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    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

    2014-01-01

    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  11. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae in Swiss Mice

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    Germana Freire Rocha Caldas

    2013-01-01

    Full Text Available Hyptis martiusii Benth. (Lamiaceae is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM. Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

  12. The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.

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    Molyneux, Gemma; Gibson, Frances M; Chen, Christabelle M; Marway, Harpal K; McKeag, Sean; Mifsud, Charles V J; Pilling, Andrew M; Whayman, Matthew J; Turton, John A

    2008-04-01

    Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

  13. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats.

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    Institóris, L; Siroki, O; Undeger, U; Basaran, N; Banerjee, B D; Dési, I

    2001-06-21

    In the present study, an immunotoxicity test system, containing general toxicological (body weight gain, organ weights), haematological (WBC,RBC, Ht, mean cell volume of the RBCs, cell content of the femoral bone marrow), and immune function (PFC assay, DTH reaction) investigations, was used for detection the effects of a 4 weeks repeated low dose combined oral exposure of male Wistar rats with propoxur and the heavy metals arsenic or mercury. Two doses of the compounds were used: a higher one (the lowest dose which resulted in significant change of at least one parameter examined in previous dose-effect experiments), and a lower one (the highest dose which proved to be non-effective). The applied doses were: 8.51 and 0.851 mg kg(-1) of propoxur, 13.3 and 3.33 mg kg(-1) of NaAsO(2), and 3.20 and 0.40 mg kg(-1) of HgCl(2). In the combination treatment, the high dose of propoxur was combined with the low dose of arsenic or mercury, and the high doses of each heavy metals were combined with the low dose of propoxur. The main finding of this study was that some of the combinations significantly altered the relative weight of liver, adrenals and kidneys, related to both the untreated and the high dose internal control. Among the immune functions examined, only the PFC content of the spleen showed a trend of changes in certain combinations versus the corresponding high dose control. According to the present results, combined exposure with propoxur and the heavy metals examined can modify the detection limit of the single compounds and/or may alter their toxic effects.

  14. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

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    Ryu HJ

    2014-12-01

    Full Text Available Hwa Jung Ryu,1,* Mu Yeb Seo,2,* Sung Kyu Jung,1 Eun Ho Maeng,2 Seung-Young Lee,2 Dong-Hyouk Jang,2 Taek-Jin Lee,2 Ki-Yeon Jo,2 Yu-Ri Kim,3 Kyu-Bong Cho,4 Meyoung-Kon Kim,3 Beom Jun Lee,5 Sang Wook Son1 1Department of Dermatology, Korea University College of Medicine, Seoul, 2Korea Testing and Research Institute, Gyunggido, 3Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 4Department of Clinical Laboratory Science, Shinheung College, Uijeongbu, 5College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea *These authors contributed equally to this work and both should be considered first authors Abstract: Zinc oxide (ZnO works as a long-lasting, broad-spectrum physical sunblock, and can prevent skin cancer, sunburn, and photoaging. Nanosized ZnO particles are used often in sunscreens due to consumer preference over larger sizes, which appear opaque when dermally applied. Although the US Food and Drug Administration approved the use of nanoparticles (NPs in sunscreens in 1999, there are ongoing safety concerns. The aim of this study was to evaluate the subchronic toxicity of ZnO NPs after dermal application according to the Organization for Economic Cooperation and Development Test Guidelines 411 using Good Laboratory Practice. Sprague Dawley rats were randomly divided into eight (one control, one vehicle control, three experimental, and three recovery groups. Different concentrations of ZnO NPs were dermally applied to the rats in the experimental groups for 90 days. Clinical observations as well as weight and food consumption were measured and recorded daily. Hematology and biochemistry parameters were determined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. Analyses of tissue were undertaken to determine target organ tissue distribution. There was no increased mortality in the experimental group. Although there

  15. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

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    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  16. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

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    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  17. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

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    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  18. Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats.

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    Tamura, Toru; Yokoi, Ryohei; Okuhara, Yuji; Harada, Chiho; Terashima, Yukari; Hayashi, Morimichi; Nagasawa, Tatsuya; Onozato, Tomoya; Kobayashi, Kazuo; Kuroda, Junji; Kusama, Hiroshi

    2009-01-01

    In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20 mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.

  19. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.

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    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane W; Palyada, Kiran; Shrewsbury, Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.

  20. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

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    Ishii, Shun-ichiro; Ube, Masayuki; Okada, Miyoko; Adachi, Tamiko; Sugimoto, Jiro; Inoue, Yoshimi; Uno, Yoshifumi; Mutai, Mamoru

    2009-01-01

    To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

  1. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

  2. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    Science.gov (United States)

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  3. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

    Directory of Open Access Journals (Sweden)

    Balaji Ramachandran

    2016-01-01

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  4. (1)H NMR-based metabolomics study on repeat dose toxicity of fine particulate matter in rats after intratracheal instillation.

    Science.gov (United States)

    Zhang, Yannan; Hu, Hejing; Shi, Yanfeng; Yang, Xiaozhe; Cao, Lige; Wu, Jing; Asweto, Collins Otieno; Feng, Lin; Duan, Junchao; Sun, Zhiwei

    2017-07-01

    Systemic metabolic effects and toxicity mechanisms of ambient fine particulate matter (PM2.5) remain uncertain. In order to investigate the mechanisms in PM2.5 toxicity, we explored the endogenous metabolic changes and possible influenced metabolic pathways in rats after intratracheal instillation of PM2.5 by using a (1)H nuclear magnetic resonance (NMR)-based metabolomics approach. Liver and kidney histopathology examinations were also performed. Chemical characterization demonstrated that PM2.5 was a complex mixture of elements. Histopathology showed cellular edema in liver and glomerulus atrophy of the PM2.5 treated rats. We systematically analyzed the metabolites changes of serum and urine in rats using (1)H NMR techniques in combination with multivariate statistical analysis. Significantly reduced levels of lactate, alanine, dimethylglycine, creatine, glycine and histidine in serum, together with increased levels of citrate, arginine, hippurate, allantoin and decreased levels of allthreonine, lactate, alanine, acetate, succinate, trimethylamine, formate in urine were observed of PM2.5 treated rats. The mainly affected metabolic pathways by PM2.5 were glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, citrate cycle (TCA cycle), nitrogen metabolism and methane metabolism. Our study provided important information on assessing the toxicity of PM2.5 and demonstrated that metabolomics approach can be employed as a tool to understand the toxicity mechanism of complicated environmental pollutants. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    Science.gov (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  6. Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats.

    Science.gov (United States)

    Kobayashi, Katsumi; Sakuratani, Yuki; Abe, Takemaru; Yamazaki, Kazuko; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto

    2011-01-01

    In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment-related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level.

  7. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  8. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

    Science.gov (United States)

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

    2009-01-01

    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  9. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Science.gov (United States)

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

    2000-10-01

    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  10. Toxicological study of NTO

    Energy Technology Data Exchange (ETDEWEB)

    London, J.E.; Smith, D.M.

    1985-09-01

    The acute oral LD/sub 50/ values for NTO for mice and rats are greater than 5 g/kg. According to classical guidelines, the test material would be considered only slightly toxic or practically non-toxic in both species. Skin application studies in the rabbit with NTO demonstrated that it was mildly irritating cutaneously. With the scoring scheme, the rabbit eye test was considered negative; however, transient conjunctival and corneal irritation did result from the NTO application in several animals and one developed a chronic anterior uveitis. The material did not induce sensitization in the intradermal guinea pig assay. 6 refs., 1 tab.

  11. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    Science.gov (United States)

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

  12. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).

    Science.gov (United States)

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E

    2013-11-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  13. Discussion on Improvement of Toxicological Pathology Study

    Institute of Scientific and Technical Information of China (English)

    RenJin

    2003-01-01

    Toxicological pathology plays a key role in drug safety assessment. To enhance the research level of toxicological pathology, the following stud-ies should be carried out urgently: setting up a standard operation procedure (SOP) for toxico-logical pathology assessment; emphasizing on immunotoxicology evaluation; adopting a new ex-periment model of replacement, featuring high speed and reliability; introducing new techniques and new models in toxicological mechanism re-search; and establishing a new appraisal system to screen innovative drug and rapid and high pre-cision methods for early security assessment, de-tection and measurement.

  14. Toxicologic Study of Monochloroacetic Acid

    Institute of Scientific and Technical Information of China (English)

    Lu Bo; Zhan Ping

    2006-01-01

    @@ Monochloroacetic Acid (MCA) is a chlorinated analog of acetic acids. MCA and its sodium salt (SMCA) are widely used as a chemical intermediate (primarily in the manufacture of chlorophenoxy herbicides,carboxymethylcelluose, glycine and indigoid dyes).Moreover, MCA has been found as a common by-product of the chlorination of drinking water. Chloroacetates are ubiquitous in the environment, and MCA is the most abundant among chloroacetates. A background level of 0.1 - 1μg/L is expected to occur in precipitation[1]. Total world wide annual production of MCA reported was about 400 000 tons[2]. Many studies have showed that MCA not only caused acute or chronic damage to the skin , liver, kidney, heart, brain and other organs, but also caused acute death systemically under high concentration[2,3]. So this article will discuss the toxic effect of Monochloroacetic Acid in Toxicology.

  15. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko

    2011-01-01

    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  16. Phytochemical, Toxicological and Pharmacological Studies of ...

    African Journals Online (AJOL)

    Phytochemical, Toxicological and Pharmacological Studies of Asiasari Radix et ... three species of the genus Asarum: A. heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag., ..... third-instar larvae of Culex pipiens pallens. Coquillett ...

  17. A 28-day repeat dose toxicity study of steroidal glycoalkaloids a-solanine and a-chaconine in the Syrian Golden Hamster

    NARCIS (Netherlands)

    Langkilde, S.; Mandimika, T.; Schroder, M.; Meyer, O.; Slob, W.; Peijnenburg, A.A.C.M.; Poulsen, M.

    2009-01-01

    Glycoalkaloids ¿-solanine and ¿-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of ¿-solanine to ¿-chaconine m

  18. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354 in subjects with asthma

    Directory of Open Access Journals (Sweden)

    Roskos Lorin

    2010-01-01

    Full Text Available Abstract Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354 in adults with asthma. Methods This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] ≥ 80% predicted. Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. Results Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted received ≥ 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg and volume of distribution (44-57 mL/kg were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. Trial registration NCT00974675.

  19. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster

    DEFF Research Database (Denmark)

    Langkilde, Søren; Mandimika, T.; Schrøder, Malene

    2009-01-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine...... to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity...... of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios...

  20. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    Science.gov (United States)

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  1. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

    Science.gov (United States)

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-04-01

    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  2. Reproductive toxicological study on epristeride

    Institute of Scientific and Technical Information of China (English)

    SunZY; ZhuY

    2002-01-01

    Benign protate hyperplasia (BPH) is a common disease in older men.Epristeride is an uncompetitive inhibitor of steroid 5α-reductase,the enzyme that converts testosterone to dihydrotestosterone (DHT),and has been shown to retard the growth of hyperplastic prostates.The study included the toxicological effects of epristeride on prostate,vas deferens and sperm.The results were listed below.(1)The 180 days toxicity of epristeride (100mg·kg-1) on interstitial cells of Beagle dog tests and DNA in prostatic epithelial cells couldn't reverse during 60 days vonvalescence,and that the DHT and prostate specific antigen (PSA) level in the gland,the volume of the grland,glandular epithelial cell height and acinar luminal area could reverse to normal during the same convalescence.(2)It was demonstrated that an apoptosis of vas deferens epithelial cell of SD rat was observed at the concentration of 0.3 and 1.0nmol·L-1 epristeride in vitro.The results of PCR showed the exkpression of bcl-2 on vas deferens epithelial cells treated or untreated with epristeride,but the sequence of bcl-2 did not altered.(3)Motility and motile rate of sperm of rat,dog and human in vitro were videotaped and analyzed with computer-assisted sperm anaysis(CASA) system after 1h and 2h incubation.MOT(the percentage of motile sperm) of Beagle dog sperm were significantly reduced after treated with 0.6,6 and 60μmol·L-1 epristeride,respectively,but no significant change occurred in SD rat and human at the same concertations of epristeride.Is a word,epristeride is a better drug against BPH though there are much reproductive toxicity.

  3. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

    NARCIS (Netherlands)

    Tluczkiewicz, I.; Batke, M.; Kroese, D.; Buist, H.; Aldenberg, T.; Pauné, E.; Grimm, H.; Kühne, R.; Schüürmann, G.; Mangelsdorf, I.; Escher, S.E.

    2013-01-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evalua

  4. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

    Science.gov (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  5. Toxicological studies of aqueous extract of Acacia nilotica root

    Directory of Open Access Journals (Sweden)

    Alli Lukman Adewale

    2015-03-01

    Full Text Available Acacia nilotica is a widely used plant in traditional medical practice in Northern Nigeria and many African countries. The aim of this study was to determine the toxicological effects of a single dose (acute and of repeated doses (sub-acute administration of aqueous extract of A. nilotica root in rodents, following our earlier study on antiplasmodial activity. In the acute toxicity test, three groups of Swiss albino mice were orally administered aqueous extract of A. nilotica (50, 300 and 2000 mg/kg body weight and signs of toxicity were observed daily for 14 days. In the sub-acute toxicity study, four groups of 12 rats (6 male and 6 female were used. Group 1 received 10 ml/kg b.w distilled water (control, while groups 2, 3 and 4 received 125, 250 and 500 mg/kg b.w of the extract, respectively, for 28 consecutive days by oral gavage. Signs of toxicity/mortality, food and water intake and body weight changes were observed. Biochemical parameters were analysed in both plasma and liver homogenate. In the acute and sub-acute toxicity studies, the extract did not cause mortality. A significant reduction in the activity of lactate dehydrogenase was observed at 250 and 500 mg/kg b.w, while alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities were significantly higher than control values at 500 mg/kg b.w. The aqueous extract of A. nilotica was found to be safe in single dose administration in mice but repeated administration of doses higher than 250 mg/kg b.w of the extract for 28 days in rats may cause hepatotoxicity.

  6. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  7. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  8. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    Science.gov (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  9. Repeated dose pharmacokinetics of pancopride in human volunteers.

    Science.gov (United States)

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats.

    Science.gov (United States)

    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  11. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

    Science.gov (United States)

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  12. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  13. Toxicological studies on Stryphnodendron adstringens.

    Science.gov (United States)

    Rebecca, Marcelo Alessandro; Ishii-Iwamoto, Emy Luiza; Grespan, Renata; Cuman, Roberto Kenji Nakamura; Caparroz-Assef, Silvana Martins; Mello, João Carlos Palazzo de; Bersani-Amado, Ciomar Aparecida

    2002-11-01

    This study was carried out to determine the acute toxicity of total barbatimão extract (LD(50)) after oral administration to mice, and its effect on certain biochemical parameters in plasma of rats after 30 days of administration. The LD(50) value of the extract was 2699 mg/kg. A daily oral administration of extracts at 800 and 1600 mg/kg doses for 30 days caused a decrease in body weight, thymic involution, and an increase of plasma glucose and aspartate aminotransferase levels in the animals. The results showed that the extract administered in a prolonged period produced toxic effects in the experimental animals.

  14. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

    Science.gov (United States)

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

    2012-03-01

    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  15. Statistical studies in genetic toxicology: a perspective from the U.S. National Toxicology Program.

    OpenAIRE

    Margolin, B H

    1985-01-01

    This paper surveys recent, as yet unpublished, statistical studies arising from research in genetic toxicology within the U.S. National Toxicology Program (NTP). These studies all involve analyses of data from Ames Salmonella/microsome mutagenicity tests, but the statistical methodologies are broadly applicable. Three issues are addressed: First, what is a tenable sampling model for Ames test data, and how does one best test the adequacy of the Poisson sampling assumption? Second, given that ...

  16. Pharmacokinetics of metadoxine for injection after repeated doses in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    L(U) Yuan; KANG Zi-sheng; LIU Yan; LI Tian-yun; XIAO Yong-hong

    2007-01-01

    @@ Alcohol-induced liver disease is one of the main epidemic problems nowadays. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, help restore the functional structure of the liver and relieve neuro-psychological disorders associated with alcohol intoxication.1-3 The purpose of the study was to assay the pharmacokinetics of domestic metadoxine after repeated doses.

  17. Production, composition and toxicology studies of Enzogenol® Pinus radiata bark extract.

    Science.gov (United States)

    Frevel, Mathias A E; Pipingas, Andrew; Grigsby, Warren J; Frampton, Chris M; Gilchrist, Nigel L

    2012-12-01

    Enzogenol® pine bark extract is a dietary supplement and food ingredient produced by water extraction of Pinus radiata. We present production method, composition, and safety data from rat and dog toxicological and human clinical studies. The dry powder contains proanthocyanidins (>80%), taxifolin (1-2%), other flavonoids and phenolic acids (up to 8%), and carbohydrates (5-10%). Reverse mutation assays showed lack of mutagenic activity. Single and 14-day repeat dosing in rats and dogs had no influence on body weight, feed consumption, blood chemistry, and haematology at any dose level. There were no treatment related findings on gross and detailed necroscopy, organ weights, organ weight ratios and histology. The only adverse events were emesis and diarrhoea in dogs occurring mainly in un-fed condition and at the highest dose level in a total of 18% of applications. The MTD and NOAEL in the present rat and dog studies were 2500 and 750 mg/kg/day, respectively. Consumption of 480 mg/day for 6 months and 960 mg/day for 5 weeks in two human studies showed Enzogenol® had no adverse influence on liver and kidney function, haematology, and did not cause any adverse events. Our studies indicate lack of toxicity of Enzogenol® and support safe use as a food ingredient.

  18. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    NARCIS (Netherlands)

    Kienhuis, A.S.; Bessems, J.G.M.; Pennings, J.L.A.; Driessen, M.; Luijten, M.; Delft, van J.H.M.; Ven, van der L.T.M.

    2011-01-01

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employ

  19. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  20. Gaps in aquatic toxicological studies of microplastics.

    Science.gov (United States)

    Karami, Ali

    2017-10-01

    The contamination of aquatic environments with microplastics (MPs) has spurred an unprecedented interest among scientific communities to investigate their impacts on biota. Despite the rapid growth in the number of studies on the aquatic toxicology of MPs, controversy over the fate and biological impacts of MPs is increasingly growing mainly due to the absence of standardized laboratory bioassays. Given the complex features of MPs, such as the diversity of constituent polymers, additives, shapes and sizes, as well as continuous changes in the particle buoyancy as a result of fouling and defouling processes, it is necessary to modify conventional bioassay protocols before employing them for MP toxicity testings. Moreover, several considerations including quantification of chemicals on/in the MP particles, choice of test organisms, approaches for renewing the test solution, aggregation prevention, stock solution preparation, and units used to report MP concentration in the test solution should be taken into account. This critical review suggests some important strategies to help conduct environmentally-relevant MP bioassays. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Role of chronic toxicology studies in revealing new toxicities.

    Science.gov (United States)

    Galijatovic-Idrizbegovic, Alema; Miller, Judith E; Cornell, Wendy D; Butler, James A; Wollenberg, Gordon K; Sistare, Frank D; DeGeorge, Joseph J

    2016-12-01

    Chronic (>3 months) preclinical toxicology studies are conducted to support the safe conduct of clinical trials exceeding 3 months in duration. We have conducted a review of 32 chronic toxicology studies in non-rodents (22 studies in dogs and 10 in non-human primates) and 27 chronic toxicology studies in rats dosed with Merck compounds to determine the frequency at which additional target organ toxicities are observed in chronic toxicology studies as compared to subchronic studies of 3 months in duration. Our review shows that majority of the findings are observed in the subchronic studies since additional target organs were not observed in 24 chronic non rodent studies and in 21 chronic rodent studies. However, 6 studies in non rodents and 6 studies in rodents yielded new findings that were not seen in studies of 3-month or shorter duration. For 3 compounds the new safety findings did contribute to termination of clinical development plans. Although the incidence of compound termination associated with chronic toxicology study observations is low (∼10%), the observations made in these studies can be important for evaluating human safety risk.

  2. Statistical studies in genetic toxicology: a perspective from the U.S. National Toxicology Program.

    Science.gov (United States)

    Margolin, B H

    1985-11-01

    This paper surveys recent, as yet unpublished, statistical studies arising from research in genetic toxicology within the U.S. National Toxicology Program (NTP). These studies all involve analyses of data from Ames Salmonella/microsome mutagenicity tests, but the statistical methodologies are broadly applicable. Three issues are addressed: First, what is a tenable sampling model for Ames test data, and how does one best test the adequacy of the Poisson sampling assumption? Second, given that nonmonotone dose-response curves are fairly common in the Salmonella assay, what new statistical techniques or modifications of existing ones seem appropriate to accommodate to this reality? Finally, an intriguing question: How can the extensive NTP Ames test data base be used to assess the characteristics of any mutagen-nonmutagen decision rule? The last issue is illustrated with the commonly used "two-times background" rule.

  3. Toxicology of metals and metalloids: Promising issues for future studies in environmental health and toxicology.

    Science.gov (United States)

    Barbosa, Fernando

    2017-01-01

    The function and behavior of chemical elements in ecosystems and in human health probably comprise one of the most studied issues and a theme of great interest and fascination in science. Hot topics are emerging on an annual basis in this field. Bearing this in mind, some promising themes to explore in the field of metals and metalloids in the environment and in toxicology are highlighted and briefly discussed herein.

  4. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats].

    Science.gov (United States)

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M

    1995-01-01

    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study.

  5. Effect of repeated doses of mercuric chloride on the kinetics of iron in rats

    Energy Technology Data Exchange (ETDEWEB)

    Grosicki, A.; Kossakowski, S. [National Veterinary Research Institute, Pulawy (Poland)

    1994-12-31

    The effect of repeated doses of 0.5 and 1.0 mg HgCl{sub 2}/kg b.w. given intragastrically for 30 days on the absorption and distribution of intragastrically trace dose of {sup 59}FeCl{sub 3} was studied in male Wistar rats. Both doses of mercury distributed the absorption of Fe-59 from the gastrointestinal track. Furthermore, the results revealed a dose-dependent influence of mercury on the content of Fe-59 in the organs and the AUC values. (author). 14 refs, 2 figs, 1 tab.

  6. Repeated doses of melatonin protects against focal cerebral ischemia in the rat

    OpenAIRE

    Pei, Z; Pang, SF; Cheung, RTF

    2000-01-01

    We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. ...

  7. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-02-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  8. Incorporating exposure into aquatic toxicological studies: an imperative.

    Science.gov (United States)

    Wang, Wen-Xiong

    2011-10-01

    The field of aquatic toxicology has been expanding rapidly in recent years. The ecotoxicological study of environmental toxicants encompasses three basic frameworks: environmental behavior/transport, bioavailability/bioaccumulation (exposure), and toxicity at different biological levels. Environmental risk assessments are then based on this knowledge to provide sound advice for environmental management and policies. In this article I will highlight the need to further understand the exposure to toxicants and its direct relationship with toxicological responses at different levels. Exposure considerations generally include the route, species, concentration and duration of exposure, among which the importance of the exposure route has been little considered. A typical aquatic toxicological study simply exposes the organisms to toxicants in the water for a certain period of time under different concentrations. This approach may not be environmentally relevant. Future studies should attempt to understand the toxicology under different exposure regimes. Incorporating exposure will allow aquatic toxicology to be placed in a context of environmental relevance and enhance our understanding of the impacts of toxicants on our living environments. 2011 Elsevier B.V. All rights reserved.

  9. The added value of proteomics for toxicological studies.

    Science.gov (United States)

    Miller, I; Serchi, T; Murk, A J; Gutleb, A C

    2014-01-01

    Proteomics has the potential to elucidate complex patterns of toxic action attributed to its unique holistic a posteriori approach. In the case of toxic compounds for which the mechanism of action is not completely understood, a proteomic approach may provide valuable mechanistic insight. This review provides an overview of currently available proteomic techniques, including examples of their application in toxicological in vivo and in vitro studies. Future perspectives for a wider application of state-of-the-art proteomic techniques in the field of toxicology are discussed. The examples concern experiments with dioxins, polychlorinated biphenyls, and polybrominated diphenyl ethers as model compounds, as they exhibit a plethora of sublethal effects, of which some mechanisms were revealed via successful proteomic studies. Generally, this review shows the added value of including proteomics in a modern tool box for toxicological studies.

  10. Pharmacology of ayahuasca administered in two repeated doses.

    Science.gov (United States)

    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

    2012-02-01

    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

  11. Statistical approaches to the design of toxicology studies.

    Science.gov (United States)

    Gad, S C

    2001-01-01

    Application of statistics to toxicological studies involves hypothesis testing, model fitting, and reduction of dimensionality. This unit reviews statistical approaches to data (i.e., descriptive statistics, experimental design, outliers and rounding of numbers, and specific applications) and includes a set of decision trees to assist in choosing the appropriate methods.

  12. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

    Science.gov (United States)

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

    2013-01-01

    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    Science.gov (United States)

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  14. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    Science.gov (United States)

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  15. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    Science.gov (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  16. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Scala, R.A.; Bevan, C.; Beyer, B.K. (Exxon Biomedical Sciences, Inc., East Millstone, NJ (United States))

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  17. Toxicology studies with recombinant staphylokinase and with SY 161-P5, a polyethylene glycol-derivatized cysteine-substitution mutant.

    Science.gov (United States)

    Moons, L; Vanlinthout, I; Roelants, I; Moreadith, R; Collen, D; Rapold, H J

    2001-01-01

    SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex (APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans.

  18. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    Science.gov (United States)

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  19. A toxicological study of gadolinium nitrate

    Energy Technology Data Exchange (ETDEWEB)

    London, J.E.

    1988-05-01

    The sensitization study in the guinea pig did not show gadolinium nitrate to have potential sensitizing properties. Skin application studies in the rabbit demonstrated that it was cutaneously a severe irritant. This material was considered an irritant in the rabbit eye application studies. 3 refs., 1 tab.

  20. Preliminary toxicological study of Irganox 1010

    Energy Technology Data Exchange (ETDEWEB)

    Drake, G.A.; London, J.E.; Smith, D.M.; Thomas, R.G.

    1979-10-01

    Acute oral LD/sub 50/30/ values for mice and rats receiving Irganox 1010 were found to be greater than 5 g/kg. According to classical guidelines, this material would be considered slightly toxic or practically nontoxic in both species. Skin applicaton studies in rabbits showed the material to be nonirritating. Eye irritation studies, also in the rabbit, showed that Irganox 1010 was a mild but transitory irritant. The sensitizaton study in guinea pigs did not show the material to be deleterious.

  1. Preliminary toxicological study of Silastic 386 catalyst

    Energy Technology Data Exchange (ETDEWEB)

    Smith, D.M.; Drake, G.A.; Holland, L.M.; Jackson, D.E.; London, J.E.; Prine, J.R.; Thomas, R.G.

    1978-06-01

    The calculated acute oral LD/sub 50//sup 30/ values for Silastic 386 catalyst were 1225 mg/kg in mice and 4350 mg/kg in rats. According to classical guidelines, the compound would be slightly to moderately toxic in both species. Skin application studies in the rabbit demonstrated the compound to be mildly irritating. The eye irritation study disclosed the compound to be a severe irritant causing conjunctivitis, photophobia, corneal edema, corneal ulceration, anterior uveitis, and keratitis. The sensitization study in the guinea pig did not show Silastic 386 catalyst to be deleterious in this regard.

  2. 啮齿类动物28天重复剂量经口毒性改良试验简介与进展%Introduction and progress on the enhancement of repeated dose 28-day oral toxicity study in rodents

    Institute of Scientific and Technical Information of China (English)

    王恒娟; 刘兆平

    2012-01-01

    Repeated dose 28-day oral toxicity study in rodents ( OECD Test Guidelines 407) is widely used to evaluate the general toxicity of chemicals. In 1998, the Organization for Economic Co-operation and Development (OECD) enhanced existing TG 407 to develop new Test Guidelines for screening and testing potential endocrine disruptors. This procedure has been verified by an extensive international validation program. To provide reference for developing endocrine disruptor evaluation system in China, the enhanced TG 407, its progress and its advantages and disadvantages were summarized in this paper.%经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)推荐的啮齿类动物28天重复剂量经口毒性试验( OECD TG 407)是一种广泛用于评价化学物一般毒性的毒理学试验方案.OECD在1998年对其进行改良后,建立TG 407改良试验并经世界多国实验室验证,用于检测化学物的内分泌干扰作用.本文简要介绍了OECD TG 407改良试验指南,并对其进展情况以及优缺点进行综述,以期为我国的内分泌干扰物的评价体系提供参考.

  3. Pharmacology and toxicology of sensitizers: mechanism studies

    Energy Technology Data Exchange (ETDEWEB)

    Rauth, A.M.

    1984-08-01

    Nitroimidazoles are being studied extensively as hypoxic cell radiosensitizers. Besides their ability to selectively sensitize hypoxic cells to radiation, which depends on the parent compound, nitroimidazoles have a variety of other effects in vitro, in vivo and clinically which appear to require reductive metabolism. As a first step to suggesting possible mechanisms for these other biological effects, a summary has been made of the known oxidative and reductive products of the two most widely studied radiosensitizers, metronidazole and misonidazole. As a second step to suggesting possible mechanisms for these biological effects, it is important to view the problem in terms of the in vivo situation where distribution and sites of metabolism of the drug and its reduction products will be important factors. Combining basic information about the reduction chemistry of nitroimidazoles with knowledge about the pharmacology of drugs and their reduced products should allow a better assessment of mechanism of action as well as a better implementation of these drugs clinically.

  4. [Felines: an alternative in genetic toxicology studies?].

    Science.gov (United States)

    Zamora-Perez, Ana; Gómez-Meda, Belinda C; Ramos-Ibarra, Maria L; Batista-González, Cecilia M; Luna-Aguirre, Jaime; González-Rodríguez, Andrés; Rodríguez-Avila, José L; Zúñiga-González, Guillermo M

    2008-06-01

    The micronuclei (MN) test carry out in peripheral blood is fast, simple, economic and it is used to detect genotoxic environmental agents. MN are fragments of chromosomes or complete chromosomes remaining in the cytoplasm after cell division, which increase when organisms are exposed to genotoxic agents. Therefore, species with the highest values of spontaneous micronucleated erythrocytes (MNE) are the most suitable to be potentials biomonitor of micronucleogenic agents, using a drop of blood. Nine species of Felines that present spontaneous MNE in peripheral blood are shown. From these species, the cat has been previously proven, with positive results and also lion (Panthera leo), yaguaroundi (Felis yagoaroundi), lynx (Lynx ruffus), jaguar (Panthera onca), puma (Puma concolor), tiger (Panthera tigris), ocelote (Felis padalis) and leopard (Panthera pardus) display spontaneous MNE, and with this characteristic this Family can be propose like a potential group to be used in toxicogenetic studies.

  5. Behaviour-toxicological studies in rats exposed to cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Wurms, F.

    1979-01-01

    Studies were carried out on a behaviour-toxicological animal model in order to find out whether Cd may induce a minimal cerebral dysfunction and whether this effect outlasts prenatal and neonatal exposure. For this purpose, pregnant Wistar rats were given daily s.c. injections of 0.15 mg Cd/kg for a period of 50 d until weaning of the young rats at the age of 4 weeks. The male offspring were either given no Cd until the age of 100 d when the tests were started (A-group), or they were given daily s.c. injections of the above dose (B-group). The third group consisted of NaCl-injected control animals of the same age. The behaviour-toxicological tests were carried out in a Lashley test bench, a swimming labyrinth, and an open field test under blind conditions. Cd concentrations measured in the brain, liver and kidneys at different times during the investigation showed that the placenta-brain barrier or blood-brain barrier was not fully efficient under the experimental conditions. Cd concentrations in neonates were 2.5 times higher in the brain and 5 times higher in the liver and kidneys than in control animals. In both Cd groups, visual discrimination was impaired. In the swimming labyrinth and open field test, significant changes were observed only in B-group rats. Impaired visual differentiation was observed in both groups. However, it is impossible at the present stage of investigation to decide whether the direct Cd lesions are the only cause of these behaviour-toxicological effects.

  6. Repeated dose of ketamine effect to the rat hippocampus tissue

    Directory of Open Access Journals (Sweden)

    Mehtap Okyay Karaca

    2015-01-01

    Full Text Available Aim: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. Materials and Methods: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5 th day while the ones in Group III on 21 st day. Cornu ammonis (CA and gyrus dentatus (GD regions in hippocampus tissue of rats were studied using optic fractionation method. Findings: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. Conclusion: Repeated ketamine doses caused neurotoxicity in rat hippocampus.

  7. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-10-01

    Full Text Available Rhabdomyosarcoma (RMS, a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV, are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS and alveolar rhabdomyosarcoma (ARMS cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  8. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide.

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  9. Toxicological Studies of Mycotoxins Using Enzymatic and Histochemical Methods

    Energy Technology Data Exchange (ETDEWEB)

    Badea, Mihaela, E-mail: badeamihaela@yahoo.com; Taus, Nicoleta [Transilvania University of Brasov, Faculty of Medicine (Romania); Potrovita, Monica [Sanitary-Veterinary and Food Safety Direction of Brasov (Romania); Moarcas, Monica [Transilvania University of Brasov, Faculty of Medicine (Romania)

    2009-08-15

    Studies concerning mycotoxins involve activities of relevant potential for furthering knowledge in the fields of toxicology and environmental analysis. Using bioanalytical methods (biosensors, histochemistry), the conducted research aims at contributing to raising the awareness of local, national, and international media in relation to the safety of obtaining and processing vegetal and animal foods, by analyzing the possible effects of aflatoxins and ochratoxins, promoting animal health, food hygiene, in view of ensuring animal and human health. The study using laboratory animals (mice) while being part of one of the current national research directions, also holds international priority, by its contribution to a better understanding of several fundamental mechanisms of life at molecular level and to the characterization of certain biological processes that appear in mycotoxicosis.

  10. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

    NARCIS (Netherlands)

    aan het Rot, Marije; Collins, Katherine A.; Murrough, James W.; Perez, Andrew M.; Reich, David L.; Charney, Dennis S.; Mathew, Sanjay J.

    2010-01-01

    Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days)

  11. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  12. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  13. Processing of toxicological studies results in the statistical program R

    Directory of Open Access Journals (Sweden)

    Fedoseeva Elena Vasilyevna

    2015-09-01

    Full Text Available The presented article is devoted to the analysis of the experimental values and the applicability of the toxicological studies results in the statistical environment R. This freely distributed program has great functional potential and well-designed algorithm, these make it "...the undisputed leader among the freely distributed systems for statistical analysis..." As the data, the experimental results to assess the toxicity of a highly- mineralized sample in the industrial production wastes were used. We evaluated two test-functions: the change in the population increase of cells and the fluorescence level of laboratory culture of the marine diatom algae Phaeodactylum tricornutum. The detailed algorithm of the analysis, namely: data initialization, evaluation of selective parameters of descriptive statistics, toxicity assessment, single-factor analysis of variance (ANOVA, Tukey and Dunnett multiple comparison tests, evaluation of correlation between the observed variable (Spearman and Pearson correlation coefficients are presented in the article. The complete list of scripts in the program R allows to reproduce a similar analysis.

  14. Toxicological assessment of Ricinus communis Linn root extracts.

    Science.gov (United States)

    Ilavarasan, Raju; Mallika, Moni; Venkataraman, Subramanian

    2011-03-01

    Ricinus communis Linn (Euphorbiaceae) plant parts are claimed to be used as carminative, asthma, bronchitis, leprosy, anti-inflammatory, cathartic, and aphrodisiac. The toxicological study was carried out in the root part of the plant. The collected root was extracted with methanol and water. The extracts were vacuum-dried to yield the respective aqueous (AE) and methanol (ME) extracts. Toxicological assessment sought to determine the safety of Ricinus communis root extracts. The extracts were evaluated in the acute toxicity study (OECD-423 guidelines) and 90 days repeated dose toxicological assessment in Wistar albino rats. The acute oral toxicity of the aqueous (AE) and methanol (ME) extracts did not produce any toxic symptoms or mortality at the dose level of 2000 mg/kg in rats. In the 90 days (sub-chronic toxicity) repeated dose toxicity study the extracts (AE and ME) were administered 1000 mg/kg daily through oral route. The sub-chronic toxicity study demonstrated no significant changes in body weight, food, and water intake. Hematology parameters RBC, WBC, DLC, Hb, blood clotting time, and the biochemical parameters glucose, blood urea nitrogen, creatinine, total cholesterol, total protein, total bilirubin AST, ALT, and ALP were estimated. Histopathology observation of the major vital organs (liver, kidney, heart, spleen, lungs, ovary, testis, and brain) were tested. The hematology, biochemical and histopathology evaluations did not show any adverse effects in any of the organs tested. These results demonstrate the non-toxic nature of the root extracts AE and ME can be used for long-term usage in clinical practice.

  15. Manpower Development in Toxicology. EURO Reports and Studies, No. 9.

    Science.gov (United States)

    World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

    This report addresses the widely held view that currently available literature in toxicology is inadequate in that there is a need to identify manpower deficiencies in this field and to suggest means to correct these deficiencies. It contains a list of specific recommendations including the organization of a working group, sponsored by the World…

  16. A Review of Liver Perfusion Method in Toxicology Studies

    Directory of Open Access Journals (Sweden)

    M karami

    2014-06-01

    Full Text Available Introduction: The isolated perfused rat liver is an accepted method in toxicology studies. The isolated perfused rat liver (IPRL is a useful experimental system for evaluating hepatic function without the influence of other organ systems, undefined plasma constituents, and neural-hormonal effects. Methods: The untreated male rats (180-220gr body weight were anesthetised with ether and then surgery with proper method. The abdomen was opened through a midline and one transversal incision and the bile duct was cannulated. Heparin sodium solution (0.5 ml; 500 U/ml in 0.9% NaCl was injected via the abdominal vena cava to prevent blood clotting. The liver inferior venacava was cannulated with PE-10 tubing and secured. The portal vein was immediately cannulated with an 23gr catheter which was secured and then liver was perfused in situ by Krebs- Henseleit buffer (pH 7.4; saturated with 95% O2 and 5% CO2; 37°C at a flow rate of 20 ml/min for 3hr. Temperature, perfusion pressure, flow rate and perfusion fluid pH were closely monitored during the perfusion. Results: Transferase enzymes (ALT, AST alterations can be widely used as a measure of biochemical alterations in order to assess liver damage due to use of drugs such as isoniazid (INH and animal and plant toxins. Accumulated material in gallbladder are valuable samples to assess the level of Glutathione (GSH. Sections of perfused liver tissue can also be effectively analyzed for pathological aspects such as necrosis, fibrosis, cellularity. Conclusion: The isolated perfused rat liver (IPRL is a useful and Sutible experimental system for evaluating hepatic function. In this system, the effects of adjacent organs, on the liver is minimized

  17. National Toxicology Program

    Science.gov (United States)

    ... to Main Navigation Skip to Site Sidebar National Toxicology Program http://ntp.niehs.nih.gov Home Testing ... NTP Cell Phone Radiofrequency Radiation Studies The National Toxicology Program (NTP) has been conducting experiments in rats ...

  18. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.

    Science.gov (United States)

    Johnston, C C; Stremler, R; Horton, L; Friedman, A

    1999-03-01

    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  19. Considerations for conducting imaging studies in support of developmental toxicology studies for regulatory submission.

    Science.gov (United States)

    Johnson, Colena A; Winkelmann, Christopher T; Wise, L David

    2014-09-01

    Preclinical imaging technologies are increasingly being applied to developmental toxicology studies in drug development to determine potential compound toxicity. Although most of these studies are conducted in a non-regulatory setting, there is interest in performing these imaging studies under applicable regulations, for example Good Laboratory Practices (GLP), to support regulatory decisions concerning drug safety. This manuscript will describe regulations and processes to consider when bringing an imaging technology into GLP compliance.

  20. Assessing the scientific research productivity of a leading toxicology journal: A case study of Human & Experimental Toxicology from 2003 to 2012.

    Science.gov (United States)

    Zyoud, Sa'ed H; Al-Jabi, Samah W; Sweileh, Waleed M; Awang, Rahmat

    2014-01-01

    Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were 'Human', 'Experimental' and 'Toxicology' as 'Source Title'. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (1-9) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.7-12.7) for France, followed by 7.5 (2-22.5) for Iran and 6 (3-13.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. The documents in Human & Experimental Toxicology focus principally on original data, with very few review articles. Review articles tend to have higher citation rates

  1. Toxicological study of plant extracts on termite and laboratory animals.

    Science.gov (United States)

    Rahman, I; Gogoi, Inee; Dolui, A K; Handique, Ruma

    2005-04-01

    Toxic activity of leaf extracts of Polygonum hydropiper L. and Pogostemon parviflorus Benth. were tested in the laboratory against tea termite, Odontotermes assamensis Holm. Both the tested extracts caused mortality of the termite. The highest toxic activity (100%) was found in the 2.0% chloroform extracts of P. hydropiper. The chloroform extract of P. hydropiper was explored for possible mammalian toxicological effects. The LD50 was 758.58 mg/kg in male albino mice. Subcutaneous injection of sub-lethal dose of extract into male mice once a week for 6 weeks failed to express any significant influence on WBC, RBC count and blood cholesterol.

  2. Nanomaterial synthesis and characterization for toxicological studies: TiO2 case study

    Science.gov (United States)

    Valsami-Jones, E.; Berhanu, D.; Dybowska, A.; Misra, S.; Boccaccini, A.R.; Tetley, T.D.; Luoma, S.N.; Plant, J.A.

    2008-01-01

    In recent years it has become apparent that the novel properties of nanomaterials may predispose them to a hitherto unknown potential for toxicity. A number of recent toxicological studies of nanomaterials exist, but these appear to be fragmented and often contradictory. Such discrepancies may be, at least in part, due to poor description of the nanomaterial or incomplete characterization, including failure to recognise impurities, surface modifications or other important physicochemical aspects of the nanomaterial. Here we make a case for the importance of good quality, well-characterized nanomaterials for future toxicological studies, combined with reliable synthesis protocols, and we present our efforts to generate such materials. The model system for which we present results is TiO2 nanoparticles, currently used in a variety of commercial products. ?? 2008 The Mineralogical Society.

  3. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals.

    Science.gov (United States)

    Adkins, B; O'Connor, R W; Dement, J M

    1987-06-01

    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  4. Characterisation of nanoparticle size and concentration for toxicological studies.

    Science.gov (United States)

    Bendre, V; Gautam, M; Carr, R; Smith, J; Malloy, A

    2011-02-01

    The assessment of the complete distribution of nanoparticle sizes within a suspension is notoriously difficult to carry out. We demonstrate the Nanoparticle Tracking Analysis (NTA) technique that sizes nanoparticles in suspension, based on their Brownian motion. This technique has found significant use in the field of nano- and eco-toxicology, in several research groups showing of the technique to assess a range of engineered nanoparticles including gold, SiO2, TiO2 and polystyrene. This capability shares many features in common with conventional flow cytometry but is unique in this deeply sub-micron size range. NTA is a direct and fast technique by which nanoparticles in their natural solvated state in a liquid can be rapidly detected, sized and counted. The technique can be used to complement existing techniques for the sizing of nanoparticles (e.g., DLS, PCS) allowing data obtained from these methods to be validated by direct microscopical observation of the sample.

  5. Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

    Science.gov (United States)

    Samuel, Gbeminiyi O; Hoffmann, Sebastian; Wright, Robert A; Lalu, Manoj Mathew; Patlewicz, Grace; Becker, Richard A; DeGeorge, George L; Fergusson, Dean; Hartung, Thomas; Lewis, R Jeffrey; Stephens, Martin L

    2016-01-01

    Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work.

  6. Size Distributions and Characterization of Native and Ground Samples for Toxicology Studies

    Science.gov (United States)

    McKay, David S.; Cooper, Bonnie L.; Taylor, Larry A.

    2010-01-01

    This slide presentation shows charts and graphs that review the particle size distribution and characterization of natural and ground samples for toxicology studies. There are graphs which show the volume distribution versus the number distribution for natural occurring dust, jet mill ground dust, and ball mill ground dust.

  7. Relevance of animal studies in regulatory toxicology : current approaches and future opportunities

    NARCIS (Netherlands)

    Sandt, J.J.M. van de; Feron, V.J.

    1996-01-01

    With rapidly increasing knowledge of toxicological processes, the scientific value and relevance of toxicity studies for risk assessment must be re-evaluated. In this paper, it is proposed that the rigid risk evaluation currently required should be replaced by a more flexible, case-by-case approach,

  8. Investigation of repeated dose (90 day oral toxicity, reproductive/developmental toxicity and mutagenic potential of ‘Calebin A’

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed

    2015-01-01

    Full Text Available The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as “No Observed Adverse Effect Level (NOAEL” under the test conditions.

  9. Contaminant and nutrient concentrations of natural ingredient rat and mouse diet used in chemical toxicology studies.

    Science.gov (United States)

    Rao, G N; Knapka, J J

    1987-08-01

    The NIH-07 open formula natural ingredient rat and mouse ration is the standard diet for chemical toxicity and carcinogenicity studies conducted for the National Toxicology Program (NTP). Contaminant and nutrient concentrations were determined in 2 to 94 lots of this diet used in the NTP toxicology studies. All nutrient concentrations were equivalent to or greater than the requirements for rats and mice as set forth by the National Research Council. Aflatoxins, Hg, chlorinated hydrocarbons except methoxychlor, organophosphates except malathion, estrogenic activity, and Salmonella sp. were not present at the detectable levels. Fluorine, As, Cd, Pb, Se, N-nitrosodimethylamine, N-nitrosopyrrolidine, N-nitrosomorpholine, nitrate, nitrite, butylated hydroxyanisole, butylated hydroxytoluene, ethylene dibromide, methoxychlor, malathion, and trypsin inhibitor activity were present at or above the detectable levels. Five lots of diet had nitrosamine content of 100 to 273 ppb and 7 lots had 2.08 to 3.37 ppm of Pb. All other lots of NIH-07 diet used for NTP toxicology studies contained low levels of the contaminants. After determination of the contaminant concentrations in the 94 lots of diet and the contaminant concentrations in natural ingredients used in formulating NIH-07 diet, maximum allowable levels of contaminants were established and a flexible scoring system for acceptability of each lot of diet for chemical toxicology studies was developed. By prescreening ingredients such as fish meal for heavy metals and nitrosamines, and applying the flexible scoring system proposed, more than 95% of the lots of NIH-07 diet produced during the last 3 years had scores of greater than or equal to 95 out of 100 points and were considered acceptable for toxicology studies.

  10. Regulatory forum opinion piece: blind reading of histopathology slides in general toxicology studies.

    Science.gov (United States)

    Neef, Natasha; Nikula, Kristen J; Francke-Carroll, Sabine; Boone, Laura

    2012-06-01

    With the intention of reducing bias, a recent European Food Safety Authority draft guidance document included a recommendation for blinded evaluation of histopathology slides in general toxicology studies (EFSA 2011). Although blinding as to treatment status reduces bias in many types of scientific experiment and is sometimes also appropriate in toxicologic pathology (Holland and Holland 2011), it is most unlikely to help achieve the overall goal of improved human safety when used for routine histopathology evaluation of tissues in general toxicology studies. This is the case because (1) blinding is not applicable to the inductive reasoning process used to identify test article effects in the tissues and would dramatically reduce the chances of these being successfully identified; and (2) in any case, the bias that would be reduced by blinding is actually a bias favoring diagnosis of a toxicological hazard and a conservative safety evaluation, which is appropriate in this context. Other unintended consequences of blinding histopathology evaluation include reductions in sensitivity for a variety of additional reasons and increased subjectivity of the pathology data.

  11. Chemical constituents and toxicological studies of leaves from Mimosa caesalpiniifolia Benth., a Brazilian honey plant

    Science.gov (United States)

    Monção, Nayana Bruna Nery; Costa, Luciana Muratori; Arcanjo, Daniel Dias Rufino; Araújo, Bruno Quirino; Lustosa, Maria do Carmo Gomes; Rodrigues, Klinger Antônio da França; Carvalho, Fernando Aécio de Amorim; Costa, Amilton Paulo Raposo; Lopes Citó, Antônia Maria das Graças

    2014-01-01

    Background: Mimosa caesalpiniifolia Benth. (Leguminosae) is widely found in the Brazilian Northeast region and markedly contributes to production of pollen and honey, being considered an important honey plant in this region. Objective: To investigate the chemical composition of the ethanol extract of leaves from M. caesalpiniifolia by GC-MS after derivatization (silylation), as well as to evaluate the in vitro and in vivo toxicological effects and androgenic activity in rats. Materials and Methods: The ethanol extract of leaves from Mimosa caesalpiniifolia was submitted to derivatization by silylation and analyzed by gas chromatography-mass spectrometry (GC-MS) to identification of chemical constituents. In vitro toxicological evaluation was performed by MTT assay in murine macrophages and by Artemia salina lethality assay, and the in vivo acute oral toxicity and androgenic evaluation in rats. Results: Totally, 32 components were detected: Phytol-TMS (11.66%), lactic acid-2TMS (9.16%), α-tocopherol-TMS (7.34%) and β-sitosterol-TMS (6.80%) were the major constituents. At the concentrations analyzed, the ethanol extract showed low cytotoxicity against brine shrimp (Artemia salina) and murine macrophages. In addition, the extract did not exhibit any toxicological effect or androgenic activity in rats. Conclusions: The derivatization by silylation allowed a rapid identification of chemical compounds from the M. caesalpiniifolia leaves extract. Besides, this species presents a good safety profile as observed in toxicological studies, and possess a great potential in the production of herbal medicines or as for food consumption. PMID:25298660

  12. Genetic toxicology: web resources.

    Science.gov (United States)

    Young, Robert R

    2002-04-25

    Genetic toxicology is the scientific discipline dealing with the effects of chemical, physical and biological agents on the heredity of living organisms. The Internet offers a wide range of online digital resources for the field of Genetic Toxicology. The history of genetic toxicology and electronic data collections are reviewed. Web-based resources at US National Library of Medicine (NLM), including MEDLINE, PUBMED, Gateway, Entrez, and TOXNET, are discussed. Search strategies and Medical Subject Headings (MeSH) are reviewed in the context of genetic toxicology. The TOXNET group of databases are discussed with emphasis on those databases with genetic toxicology content including GENE-TOX, TOXLINE, Hazardous Substances Data Bank, Integrated Risk Information System, and Chemical Carcinogenesis Research Information System. Location of chemical information including chemical structure and linkage to health and regulatory information using CHEMIDPLUS at NLM and other databases is reviewed. Various government agencies have active genetic toxicology research programs or use genetic toxicology data to assist fulfilling the agency's mission. Online resources at the US Food and Drug Administration (FDA), the US Environmental Protection Agency (EPA), the National Institutes of Environmental Health Sciences, and the National Toxicology Program (NTP) are outlined. Much of the genetic toxicology for pharmaceuticals, industrial chemicals and pesticides that is performed in the world is regulatory-driven. Regulatory web resources are presented for the laws mandating testing, guidelines on study design, Good Laboratory Practice (GLP) regulations, and requirements for electronic data collection and reporting. The Internet provides a range of other supporting resources to the field of genetic toxicology. The web links for key professional societies and journals in genetic toxicology are listed. Distance education, educational media resources, and job placement services are also

  13. Toxicology: then and now.

    Science.gov (United States)

    Langman, Loralie J; Kapur, Bhushan M

    2006-05-01

    Toxicology is "the science of poisons"; more specifically the chemical and physical properties of poisons, their physiological or behavioral effects on living organisms, qualitative, and quantitative methods for their analysis and the development of procedures for the treatment of poisoning. Although the history of poisons dates to the earliest times, the study and the science of toxicology can be traced to Paracelsus (1493-1541) and Orfila (1757-1853). Modern toxicology is characterized by sophisticated scientific investigation and evaluation of toxic exposures. The 20th century is marked by an advanced level of understanding of toxicology. DNA and various biochemicals that maintain cellular functions were discovered. Our level of knowledge of toxic effects on organs and cells is now being revealed at the molecular level. This paper will review the historical progress of clinical and forensic toxicology by exploring analytical techniques in drug analysis, differing biological matrices, clinical toxicology, therapeutic drug management, workplace drug testing, and pharmacodynamic monitoring and pharmacogenetics.

  14. Influence of Food on the Bioavailability of an Enteric-Coated Tablet Formulation of Omeprazole 20 mg Under Repeated Dose Conditions

    Directory of Open Access Journals (Sweden)

    ABR Thomson

    1997-01-01

    Full Text Available The objective of this study was to investigate the influence of food on the bioavailability of omeprazole (20 mg given as an enteric-coated tablet under repeated dose conditions. This open randomized crossover study consisted of three seven-day treatment periods, each separated by a drug-free period. During each treatment period an enteric-coated tablet of omeprazole was taken once daily either under fasting conditions, or immediately before or after a standardized breakfast. On the last day of each treatment period, blood samples for the determination of plasma omeprazole concentrations were collected at baseline and at predetermined intervals over the 24 h period following drug administration. Fifty-seven male and female subjects, aged 18 to 52 years, completed the study according to the protocol. No statistically significant differences were found when comparing either the before breakfast or after breakfast treatment regimens with the fasting regimen for the estimated mean area under the plasma concentration-time curve (AUC. The maximum plasma concentration was not found to differ significantly among any of the treatment regimens. However, the lower limit of the CI for the comparison of fasting/before breakfast was not contained within the limits of bioequivalence. The time to reach maximum plasma concentration was significantly different when fasting and after breakfast regimens were compared. Thus, under repeated dose conditions, food has no influence on the bioavailability (expressed as AUC of omeprazole given as the enteric-coated tablet formulation.

  15. Applications of radiotracer techniques for the pharmacology and toxicology studies of nanomaterials

    Institute of Scientific and Technical Information of China (English)

    ZHANG ZhiYong; ZHAO YuLiang; CHAI ZhiFang

    2009-01-01

    With the rapid development of nanosciences and nanotechnology, a wide variety of manufactured nanomaterials are now used in commodities, pharmaceutics, cosmetics, biomedical products, and in-dustries. While nanomaterials possess more novel and unique physicochemical properties than bulk materials, they also have an unpredictable impact on human health. In the pharmacology and toxicol-ogy studies of nanomaterials, it is essential to know the basic behavior in vivo, i.e. absorption, distri-bution, metabolism, and excretion (ADME) of these newly designed materials. Radiotracer techniques are especially well suited to such studies and have got the chance to demonstrate their enchantment.In this paper, radiolabeling methods for carbon nanomaterials, metallic and metal oxide nanoparticles,etc. are summarized and the applications of the radiolabeled nanomaterials in pharmacology and toxicology studies are outlined.

  16. Two-Stage Experimental Design for Dose–Response Modeling in Toxicology Studies

    OpenAIRE

    Wang, Kai; Yang, Feng; Porter, Dale W; Wu, Nianqiang

    2013-01-01

    The efficient design of experiments (i.e., selection of experimental doses and allocation of animals) is important to establishing dose–response relationships in toxicology studies. The proposed procedure for design of experiments is distinct from those in the literature because it is able to adequately accommodate the special features of the dose–response data, which include non-normality, variance heterogeneity, possibly nonlinearity of the dose–response curve, and data scarcity. The design...

  17. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    Science.gov (United States)

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  18. Developmental toxicology: new directions workshop: refining testing strategies and study designs.

    Science.gov (United States)

    Brannen, Kimberly C; Fenton, Suzanne E; Hansen, Deborah K; Harrouk, Wafa; Kim, James H; Shuey, Dana

    2011-10-01

    In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration. © 2011 Wiley Periodicals, Inc.

  19. [A retrospective study of animal poisoning reports to the Swiss Toxicological Information Centre (1997 - 2006)].

    Science.gov (United States)

    Curti, R; Kupper, J; Kupferschmidt, H; Naegeli, H

    2009-06-01

    The purpose of this retrospective study was to analyse the etiology, frequency and outcome of toxicological cases recorded by the consultation service of the Swiss Toxicological Information Centre (STIC) hotline over a 10-year period, from 1997 to 2006. A detailed analysis of this database indicates that common human drugs not intended for use in animals, as well as pesticides and toxic plants represent the most prominent hazards involved in the reported cases of animal poisonings. The comparison with a previous survey from the years 1976 - 1985 revealed new toxic risks due to the accidental uptake of cannabis products, castor seeds or chocolate by dogs. In addition, there is a striking increase of serious poisonings with pyrethroids in cats. The follow-up reports delivered by veterinarians also reflect novel pharmacological and technological trends in the management of poisonings.

  20. Preliminary toxicological study of Sylgard 184 curing agent

    Energy Technology Data Exchange (ETDEWEB)

    Smith, D.M.; London, J.E.; Drake, G.A.; Thomas, R.G.

    1978-06-01

    The acute oral LD/sub 50//sup 30/ values for mice and rats receiving Sylgard 184 curing agent were greater than 5 g/kg. According to classical guidelines, the compound would be considered slightly toxic or practically nontoxic in both species. Skin application studies in the rabbit demonstrated the compound to be mildly irritating. Eye irritation studies, also in the rabbit, showed that Sylgard 184 curing agent was a mild but transitory irritant. The sensitization study in guinea pigs did not show the resin to be deleterious.

  1. Preliminary toxicological study of Sylgard 184 encapsulating resin

    Energy Technology Data Exchange (ETDEWEB)

    Smith, D.M.; Drake, G.A.; London, J.E.; Thomas, R.G.

    1978-06-01

    The acute oral LD/sub 50//sup 30/ values for Sylgard 184 encapsulating resin in mice and rats were greater than 5 g/kg. According to classical guidelines, the compound would be considered slightly toxic or practically nontoxic in both species. Skin application studies in the rabbit demonstrated this material to be mildly irritating. Eye irritation studies, also in the rabbit, showed that Sylgard 184 encapsulating resin was a mild but transitory irritant. The sensitization study in guinea pigs did not show the resin to be deleterious in this regard.

  2. Preliminary toxicological study of Sylgard 184 encapsulating resin: curing agent

    Energy Technology Data Exchange (ETDEWEB)

    Smith, D.M.; Drake, G.A.; London, J.E.; Thomas, R.G.

    1978-06-01

    The acute oral LD/sub 50//sup 30/ values for Sylgard 184 (100 parts encapsulating resin plus 10 parts curing agent) were greater than 5 g/kg in rats and mice. According to classical guidelines, the mixture would be considered slightly toxic or practically nontoxic in both species. Skin application studies in the rabbit demonstrated the mixture to be mildly irritating. Eye irritation tests, also in the rabbit, showed the Sylgard 184 mixture to be a mild but transitory irritant. The sensitization study in the guinea pig demonstrated the mixture to be a very mild sensitizer in two of six animals.

  3. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.

    Science.gov (United States)

    McFadden, Lisa G; Bartels, Michael J; Rick, David L; Price, Paul S; Fontaine, Donald D; Saghir, Shakil A

    2012-07-01

    Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (αmodel was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.

  4. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Yanxin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Guo, Huanhuan [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Changchun Brother Biotech Co., Ltd., Changchun, 130000 (China); Hu, Ningning; He, Dongyun [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Zhang, Shi [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); School of Clinical Medicine, Jilin University, Changchun 130001 (China); Chu, Yunjie [Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021 (China); Huang, Yubin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Li, Xiao, E-mail: lixiao06@mails.jlu.edu.cn [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Sun, LiLi, E-mail: linjiaxiaoya@163.com [Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun 130012 (China); Jin, Ningyi, E-mail: ningyij@126.com [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China)

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

  5. Inhalation developmental toxicology studies: Gallium arsenide in mice and rats

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Greenspan, B.J.; Dill, J.A.; Stoney, K.H.; Evanoff, J.J.; Rommereim, R.L.

    1990-12-01

    Gallium arsenide is a crystalline compound used extensively in the semiconductor industry. Workers preparing solar cells and gallium arsenide ingots and wafers are potentially at risk from the inhalation of gallium arsenide dust. The potential for gallium arsenide to cause developmental toxicity was assessed in Sprague- Dawley rats and CD-1 (Swiss) mice exposed to 0, 10, 37, or 75 mg/m{sup 3} gallium arsenide, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and {approx}30 positively mated rats or {approx}24 positively mated mice. Mice were exposed on 4--17 days of gestation (dg), and rats on 4--19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Gallium and arsenic concentrations were determined in the maternal blood and uterine contents of the rats (3/group) at 7, 14, and 20 dg. 37 refs., 11 figs., 30 tabs.

  6. In vitro toxicological nanoparticle studies under flow exposure

    Energy Technology Data Exchange (ETDEWEB)

    Sambale, Franziska, E-mail: sambale@iftc.uni-hannover.de; Stahl, Frank; Bahnemann, Detlef; Scheper, Thomas [Gottfried Wilhelm Leibniz University Hanover, Institute for Technical Chemistry (Germany)

    2015-07-15

    The use of nanoparticles is becoming increasingly common in industry and everyday objects. Thus, extensive risk management concerning the potential health risk of nanoparticles is important. Currently, in vitro nanoparticle testing is mainly performed under static culture conditions without any shear stress. However, shear stress is an important biomechanical parameter. Therefore, in this study, a defined physiological flow to different mammalian cell lines such as A549 cells and NIH-3T3 cells has been applied. The effects of zinc oxide and titanium dioxide nanoparticles (TiO{sub 2}-NP), respectively, were investigated under both static and dynamic conditions. Cell viability, cell morphology, and adhesion were proven and compared to the static cell culture. Flow exposure had an impact on the cellular morphology of the cells. NIH-3T3 cells were elongated in the direction of flow and A549 cells exhibited vesicles inside the cells. Zinc oxide nanoparticles reduced the cell viability in the static and in the dynamic culture; however, the dynamic cultures were more sensitive. In the static culture and in the dynamic culture, TiO{sub 2}-NP did not affect cell viability. In conclusion, dynamic culture conditions are important for further in vitro investigations and provide more relevant results than static culture conditions.

  7. Toxicological study of lufironil in rats and dogs

    Institute of Scientific and Technical Information of China (English)

    ZhouYP; ChenSY

    2002-01-01

    The aim of this study is to verify the toxicity of lufironil(LF),a competitive inhibitor of prolyl hydroxylase by long term administration in animals.SD rats and Beagle dogs were administered orally with LF for 6 months.The daily dose were 0.05,0.35,2.5mg·kg-1 and 0.05,0.15,0.45mg·kg-1,respectively.The recovery after stopping treatments were observed for 1 month.Hydroxyproline(Hyp) assay in serum and tissues,such as liver,kidney,lung and skin were made besides routine examinations of growth rates,food consumption,hematology,clinical chemistry and histology.The results showed that LF reduced total protein and Alb in serum,increased BUN and the weight indexes of liver,kidney and lung in the rats at the highest dose.Hykp decreased only in serum and liver.No other significant changes were seen.All the tested parameters remained normal in the dogs.It is concluded that LF is a safe drug with high selectivity on prolyl hydroxylase and its toxicity occurs only at extremely high dosage and is reversible.

  8. Ethical implications of using the minipig in regulatory toxicology studies.

    Science.gov (United States)

    Webster, John; Bollen, Peter; Grimm, Herwig; Jennings, Maggy

    2010-01-01

    Two key questions are addressed in this article. What are the potential harms to minipigs relative to the harms for dogs and non-human primates and can these harms be reduced more easily in minipigs than in other species? Are there potential benefits resulting from the use of minipigs relative to dogs and non-human primates? In considering the answers to these questions, we present an ethical framework which was developed taking into account the viewpoint of all concerned parties. This ethical matrix provides a framework upon which to identify and explore issues raised by the moral imperative to seek a fair compromise between the differing needs of different interest groups, which includes both the moral agents and the moral patients. The moral agents are the different groups of human stakeholders including society at large, regulatory bodies, industrialists and animal care staff. The moral patients are the laboratory animals, both breeding stock held by the animal supplier, and experimental animals in laboratories. In considering these animals it cannot be assumed that dogs, monkeys and minipigs differ with regard to the pain and suffering that they may experience and undergo when treated in studies designed for safety assessment. On this basis we rejected the argument that minipigs are more acceptable experimental animals than dogs or monkeys despite the fact that their use may prove less offensive to some groups within society at large. Species selection must be made on a case-by-case basis where the benefits are assessed by weighing the scientific evidence relating to the predictivity of the animal model, against the harm that may accrue to the animals both from the test procedures and their lifetime experience within the laboratory environment.

  9. Influence of Study Design on Developmental and Reproductive Toxicology Study Outcomes.

    Science.gov (United States)

    Foster, Paul M D

    2017-01-01

    Regulatory studies of developmental and reproductive toxicity (DART) studies have remained largely unchanged for decades, with exposures occurring at various phases of the reproductive cycle and toxicity evaluations at different ages/times depending on the study purpose. The National Toxicology Program has conducted studies examining the power to detect adverse effects where there is a prenatal exposure, but evaluations occur postnatally. In these studies, examination is required of only 1 male and female pup from each litter beyond weaning. This provides poor resolving power to detect rare events (e.g., reproductive tract malformations). If an adverse effect is detected, there is little confidence in the shape of the dose-response curve (and the Benchmark Dose or No Observed Adverse Effect Level [NOAEL]). We have developed a new protocol to evaluate DART, the modified one generation study, with exposure commencing with pregnant animals and retention of 4 males and females from each litter beyond weaning to improve statistical power. These animals can be allocated to specific cohorts that examine subchronic toxicity, teratology, littering, and neurobehavioral toxicity in the same study. This approach also results in a reduction in animal numbers used, compared with individual stand-alone studies, and offers increased numbers of end points evaluated compared with recent Organization for Economic Cooperation and Development proposals.

  10. Evaluation of nutritional and sub-acute toxicological study of plant based supplement of Achyranthes aspera.

    Science.gov (United States)

    Fatima, Nudrat; Dar, Nabeela G; Imran, Hina; Sohail, Tehmina; Asghar, Uzma; Yaqeen, Zahra; Syed, Shazia; Jamil, Khalid

    2014-09-01

    The present study was conducted for the nutritional, microbiological and toxicological evaluation of test compound having main ingredient Achyranthes aspera. Nutritional value assessment, microbiological analysis and toxicological studies were conducted according to the standard reported methods which exhibited that A. aspera contains moisture 4.05%, proteins 20.54%, fats 0.903%, ash 20.25%, carbohydrates 54,26% and energy 294 Kcal. Vitamin profile was found to be B(1) 0.27mg/100g, B(2) 0.28mg/100g, B(3) 0.58mg/100g, B(6) 0.27mg/100g and B(9) 39μg/100g. The content of sodium, calcium, magnesium, potassium, chloride and phosphorus was found to be 1119.67, 5385.23, 5446.08, 1343.6, 675880.73 and 1447.5mg/kg respectively and trace metals i.e. iron, copper, zinc, manganese and aluminum were detected as 283.05, 8.062, 48.37, 16.12 and 9.853 mg/kg respectively. The microbiological result indicated that the compound qualifies the international standards of microbial limit and was found free from Salmonella species. The toxicological study was conducted to find safe use of Achyranthes aspera compound in human as a nutritive supplement in blood disorders. The toxicity studies exhibited that the test compound has a good effect on general health as an increase in body weights of animals of test group was noticed as compared to that of control group. Blood parameters before and after the study were monitored which confirms our hypothesis by showing an increase in hemoglobin from 9.133 to 10.96, RBC count from 3.11 to 3.6, WBC count from 5.68 to 5.73 and platelets from 245 to 319.

  11. Inhalation developmental toxicology studies: Teratology study of tetrahydrofuran in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1988-08-01

    Tetrahydrofuran (THF), a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran (THF) vapors, 6 h/day, 7 dy/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.33 positively mated rats or mice. Positively mated mice were exposed on days 6--17 of gestation (dg), and rats on 6--19 dg. The day of plug or sperm detection was designated as O dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 27 refs., 6 figs., 23 tabs.

  12. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

    Science.gov (United States)

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS

    2009-01-01

    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  13. Analysis of volatile combustion products and a study of their toxicological effects.

    Science.gov (United States)

    Seader, J. D.; Einhorn, I. N.; Drake, W. O.; Mihlfeith, C. M.

    1972-01-01

    An experimental program was conducted to study the thermochemical, flammability and toxicological characteristics of uncoated and coated polyisocyanurate foams. The coatings used were fluorinated copolymer and an intumescent material. Combustion and pyrolysis gases were analyzed by gas chromatography and mass spectrometry. The LD-50 and LD-100 tests were performed on Sprague-Dawley rats housed in an environmental chamber. The isocyanurate foam, fluorinated-copolymer-coated foam, and the intumescent-coated foam were found to have excellent flammability and insulation characteristics, although smoke development was substantial.

  14. Green toxicology.

    Science.gov (United States)

    Maertens, Alexandra; Anastas, Nicholas; Spencer, Pamela J; Stephens, Martin; Goldberg, Alan; Hartung, Thomas

    2014-01-01

    Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, in vitro, and less demanding animal tests at earlier stages of product development to identify and anticipate undesirable toxicological effects and optimize product development. The Green Chemistry movement embraces similar ideas for development of less toxic products, safer processes, and less waste and exposure. Further, the concept of benign design suggests ways to consider possible toxicities before the actual synthesis and to apply some structure/activity rules (SAR) and in silico methods. This requires not only scientific development but also a change in corporate culture in which synthetic chemists work with toxicologists. An emerging discipline called Green Toxicology (Anastas, 2012) provides a framework for integrating the principles of toxicology into the enterprise of designing safer chemicals, thereby minimizing potential toxicity as early in production as possible. Green Toxicology`s novel utility lies in driving innovation by moving safety considerations to the earliest stage in a chemical`s lifecycle, i.e., to molecular design. In principle, this field is no different than other subdisciplines of toxicology that endeavor to focus on a specific area - for example, clinical, environmental or forensic toxicology. We use the same principles and tools to evaluate an existing substance or to design a new one. The unique emphasis is in using 21st century toxicology tools as a preventative strategy to "design out" undesired human health and environmental effects, thereby increasing the likelihood of launching a successful, sustainable product. Starting with the formation of a steering group and a series of workshops

  15. Acute and chronic toxicological studies of Ajuga iva in experimental animals.

    Science.gov (United States)

    El Hilaly, Jaouad; Israili, Zafar H; Lyoussi, Badiâa

    2004-03-01

    Ajuga iva (L.) Schreber (AI), is widely used in the Moroccan pharmacopoeia as a panacea (cure-all), and specifically for gastrointestinal disorders and diabetes, and as an anthelmintic. No toxicological investigations have been carried out on this plant. We have previously observed that single oral doses (2-14 g/kg) of a lyophilised aqueous extract of AI (AI-extract) in mice or daily oral administration of 10 mg/kg of AI-extract in rats for 2 weeks did not result in any adverse effects. We have now evaluated AI-extract for its behavioural and pharmaco-toxicological effects after acute and chronic administration by the oral and intraperitoneal routes in rats and mice. No toxicity was observed in mice after single oral doses of as high as 14 g/kg of the AI-extract. However, single intraperitoneal injections of the AI-extract (1500-5500 mg/kg BW) produced a dose-dependent increase in adverse effects in the general behaviour and the mortality rate; the LD50 of acute intraperitoneal dose was 3.6 g/kg. In chronic toxicological studies in rats, the AI-extract (administered orally at daily doses of 100, 300 and 600 mg/kg for 3 months), did not cause any changes in haematological and biochemical parameters, with the exception of a transient rise in platelet counts and a short-term decrease in serum glucose levels. Histopathological examination of the brain, liver and the kidneys at the end of the study (3 months) showed normal architecture suggesting no morphological disturbances.

  16. Hepatoprotective and toxicological studies of Salvia bucharica methanolic extract in rabbits.

    Science.gov (United States)

    Ahmad, Mansoor; Muhammed, Shafi; Mehjabeen, -; Jahan, Noor

    2014-11-01

    Most of the species of genus Salvia are famous for having medicinal properties due to their chemical constituents. Salvia bucharica (Lamiacea) is found in Balochistan near Quetta in Hannaurak and Kalat. It is used in traditional system of medicine and claims to cure liver ailments. In current study crude methanolic extract (CME) of Salvia bucharica was obtained from the leaves and tested for hepatoprotective activity and possible toxicity in rabbits. Liver toxicity was induced in rabbits by administration of carbon tetra chloride (CCl4) and evaluated by biochemical tests and histopathology of tissues. In this study rabbits were divided in to 3 groups (5 rabbit in each group). Rabbits of group I (control) were administered only vehicle (0.9% sodium chloride) orally. Rabbits of group II were given CCl4 and group III were treated with CCl4 and S. bucharica CME orally. For hepatoprotective effect serum enzyme level and total protein level were calculated. Histopathology of liver sections of rabbits was also carried out to observe protective effect. Biochemical, hematological and histoptahological parameters were studied on rabbits for toxicological studies. S. bucharica CME showed significant liver protection with reduction in total bilirubin, direct bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), gamma glutamyl transpeptidase (γ-GT). And decrease in Albumin and globulin. In toxicological studies, biochemical and histoptahological parameters showed no significant toxicity in liver, heart and kidneys. It is concluded that S. bucharica CME showed hepatoprotective effects with nontoxic profile.

  17. Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions

    Directory of Open Access Journals (Sweden)

    Victoria Ríos

    2014-03-01

    Full Text Available The cyanobacterial toxin Cylindrospermopsin (CYN, a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days. In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR of the antioxidant enzymes glutathione peroxidase (GPx and soluble glutathione-S-transferases (sGST, and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance or 7 days (GPx gene expression, sGST activity. These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects.

  18. Toxicological study on the safety of DTPA as a drug, (1). Teratological study in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Fukuda, Satoshi; Iida, Haruzo (National Inst. of Radiological Sciences, Chiba (Japan))

    1983-03-01

    In order to clarify the safety of Ca-DTPA and Zn-DTPA recommended to use as drugs in the therapeutic removal of incorporated radionuclides from the human body, the teratological study on these two agents was carried out in rats as one of a series of the toxicological tests. The teratological effects of DTPA were observed because the fetus is highly susceptible to any drug. The pregnant females of Wistar rat were injected subcutaneously daily on days 9-13 of gestation with 1, 6, 12, 24 and 36 H.D. (H.D. = human dose, 1 H.D. = 30..mu..mol/kg body weight) of Ca-DTPA or Zn-DTPA, respectively. In the dams, no toxic effects were observed. In the fetuses, the decrease of the survival rate was observed in only the group injected daily with 36 H.D. of Ca-DTPA. Some cases of gross defects of fetuses: the exencephaly, microphthalmia, anophthalmia and fusion of ribs were observed in the groups injected daily with 12, 24 and 36 H.D. of Ca-DTPA. The results obtained show that Ca-DTPA should not be given to a pregnant woman. However, no toxic effects of either Ca-DTPA or Zn-DTPA observed in the dams or of Zn-DTPA even in the fetuses indicate that these agents can be used by a radiation worker who usually is an adult man.

  19. Toxicological study of the hepatotherapeutic herbal formula, Chunggan extract, in beagle dogs

    Institute of Scientific and Technical Information of China (English)

    Woo-Jin Choi; Hwa-Seung Yoo; Yeon-Weol Lee; Chang-Gue Son; Jang-Woo Shin; Jin-Young Son; Dong-Seok Seo; Hark-Soo Park; Seung-Hyun Han; Ha-Jung Sung; Jung-Hyo Cho; Chong-Kwan Cho

    2006-01-01

    AIM: To evaluate the pharmaceutical safety of a Chinese herbal formula, Chunggan extract (CGX), traditionally prescribed as a hepatotherapeutic drug via systemic acute and subacute toxicological study.METHODS: Twenty male dogs and 20 female dogs were fed doses 50 times and 4 times greater than the clinically-recommended drug dosages in an acute and a subacute toxicological study, respectively. Adverse effects were examined by comparing the differences between normal and drug-administered groups using clinical signs, necropsies, histopathologic findings, haematology,urinalysis, and biochemical analysis.RESULTS: In the acute study no change in the body weight, diarrhoea, apetite, mortality rate and histopathology of major organs was observed in male or female dogs with a single administration of CGX at 5 g/kg. No drug-induced abnormalities at analysis of histopathology,haematology, urinalysis, and biochemistry were found with any dose of this drug.CONCLUSION: CGX is supposed to be very safe when used in a clinical application with a wide therapeutic index.

  20. An integrated study on Gammarus elvirae (Crustacea, Amphipoda): perspectives for toxicology of arsenic-contaminated freshwater.

    Science.gov (United States)

    Davolos, Domenico; Chimenti, Claudio; Ronci, Lucilla; Setini, Andrea; Iannilli, Valentina; Pietrangeli, Biancamaria; De Matthaeis, Elvira

    2015-10-01

    The Italian region Latium is characterized by extensive quaternary volcanic systems that contribute greatly to arsenic (As) contamination of freshwater, including drinking water supplies. However, knowledge of the possible toxic effects in these aquatic environments is, despite being highly relevant to public health, still limited. In this paper, we approach this issue using Gammarus elvirae, an amphipod species that inhabits rivers and streams in central Italy, including Latium. We explored the possibility of using G. elvirae in the toxicology of freshwater by addressing the most relevant issues. First, we tested the usefulness of hemocytes from G. elvirae in determining non-specific DNA damage by means of the Comet assay after exposure (24 h and 7 days) to different river water samples in Latium; second, we provided an interpretative overview of the usefulness of hepatopancreatic epithelial cells of G. elvirae as a means of assessing toxicity after long-term exposure to As and other pollutants; third, the LC (50-240 h) value for G. elvirae was estimated for arsenate, which is usually the dominant arsenic species in surface waters. Our study sheds light on G. elvirae at different levels, providing a background for future toxicological research of freshwater.

  1. Toxicology screen

    Science.gov (United States)

    Toxicology screening is most often done using a blood or urine sample. However, it may be done soon after the person swallowed the medication, using stomach contents taken through gastric lavage (stomach pumping) or after vomiting.

  2. Spaceflight Toxicology

    Science.gov (United States)

    Meyers, Valerie

    2008-01-01

    This viewgraph presentation provides a review of NASA Johnson Space Center's Toxicology program. The mission of this program is to protect crews from toxic exposures during spaceflight. The presentation reviews some of the health hazards. A toxicological hazard level chart is presented that reviews the rating of hazard level, irritancy, systemic effects and containability. The program also participates in the Lunar Airborne Dust Toxicity Advisory Group.

  3. Genetic susceptibility to environmental toxicants: the interface between human and experimental studies in the development of new toxicological concepts.

    Science.gov (United States)

    Thier, Ricarda; Golka, Klaus; Brüning, Thomas; Ko, Yon; Bolt, Hermann M

    2002-02-28

    The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

  4. Uses of available record systems in epidemiologic studies of reproductive toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Polednak, A.P.; Janerich, D.T.

    1983-01-01

    The uses of available record systems in epidemiologic studies of reproductive toxicology are described with reference to New York State. The available record systems (and relevant reproductive end points) described include: a newborn screening program for metabolic diseases and hemoglobinopathies (relevant to point mutations); chromosome registries and prenatal cytogenetics (for chromosome anomalies); live birth certificates (for birth defects, birthweight, sex ratio, etc); fetal death certificates (for spontaneous fetal deaths); and a statewide cancer registry (for childhood cancers and transplacental carcinogenesis). The uses and limitations of these record systems are discussed, along with examples of their use in descriptive and analytic epidemiologic studies. Descriptive studies outlined include investigations of temporal and geographic trends in birth defects, birth weight, and fetal deaths, with reference to environmental questions (eg, Love Canal, nuclear power plants). Analytic studies described concern parental occupation in relation to specific birth defects (neural tube defects and Down syndrome) and maternal use of contraceptive drugs.

  5. Implications of the stability behavior of zinc oxide nanoparticles for toxicological studies

    Science.gov (United States)

    Meißner, Tobias; Oelschlägel, Kathrin; Potthoff, Annegret

    2014-08-01

    The increasing use of zinc oxide (ZnO) nanoparticles in sunscreens and other cosmetic products demands a risk assessment that has to be done in toxicological studies. Such investigations require profound knowledge of the behavior of ZnO in cell culture media. The current study was performed to get well-dispersed suspensions of a hydrophilic (ZnO-hydro) and a lipophilic coated (ZnO-lipo) ZnO nanomaterial for use in in vitro tests. Therefore, systematic tests were carried out with common dispersants (phosphate, lecithin, proteins) to elucidate chemical and physical changes of ZnO nanoparticles in water and physiological solutions (PBS, DMEM). Non-physiological stock suspensions were prepared using ultrasonication. Time-dependent changes of pH, conductivity, zeta potential, particle size and dissolution were recorded. Secondly, the stock suspensions were added to physiological media with or without albumin (BSA) or serum (FBS), to examine characteristics such as agglomeration and dissolution. Stable stock suspensions were obtained using phosphate as natural and physiological electrostatic stabilizing agent. Lecithin proved to be an effective wetting agent for ZnO-lipo. Although the particle size remained constant, the suspension changed over time. The pH increased as a result of ZnO dissolution and formation of zinc phosphate complexes. The behavior of ZnO in physiological media was found to depend strongly on the additives used. Applying only phosphate as additive, ZnO-hydro agglomerated within minutes. In the presence of lecithin or BSA/serum, agglomeration was inhibited. ZnO dissolution was higher under physiological conditions than in the stock suspension. Serum especially promoted this process. Using body-related dispersants (phosphate, lecithin) non-agglomerating stock suspensions of hydrophilic and lipophilic ZnO were prepared as a prerequisite to perform meaningful toxicological investigation. Both nanomaterials showed a non-negligible dissolution behavior

  6. Physiochemical and toxicological studies of the medicinal plant Cyperus rotundus L (Cyperaceae

    Directory of Open Access Journals (Sweden)

    D Jebasingh

    2012-12-01

    Full Text Available Summary: The herb Cyperus rotundus L (Cyperaceae is used by the traditional medicine practitioners of ayurvedic medicine in India for CNS disorders like loss of memory, depression and epilepsy. Though some of these properties have been evaluated, stream lined scientific evaluation is lacking to support the possible association between CNS disorders and C. rotundus. The present study was carried out to identify and characterize the phytochemical constituents and metal contents of the medicinal plant C. rotundus and to determine its toxicity. Qualitative chemical analysis confirmed the presence of phenols, tannins, glycoside and flavonoids. Physiochemical analysis revealed that the herb C. rotundus has low ash value and moderate water and alcohol solubility. Metal analysis revealed the presence of metal contents copper, lead, nickel and cadmium. Characterization of constituents using TLC technique exhibited 6 fractions and HPTLC analysis exhibited 13 peaks. Acute toxicological studies showed no mortality or morbidity up to 2000mg/kg body weight in Wistar rats. Sub chronic toxicity study revealed that, food, water consumption and body weight of animals didn’t vary significantly. But the hematological parameters showed an increase in WBC count and Hemoglobin level. The kidney function and liver function didn’t change even after long term exposure. Industrial relevance: The herb Cyprus rotundus L (Cyperaceae is used by the traditional medicine practitioners of ayurvedic medicine in India for CNS disorders like loss of memory, depression and epilepsy. The present study scientifically evaluated the physiochemical and toxicological effects of C. rotundus. The results obtained will help in identification and isolation of bioactive constituents for new therapeutic targets Keywords: Cyperus rotundus; HPLC; thin layer chromatography; physicochemical analysis; Sub chronic toxicity study.

  7. Diluted isoflurane as a suitable alternative for diethyl ether for rat anaesthesia in regular toxicology studies.

    Science.gov (United States)

    Nagate, Toshiaki; Chino, Tomonobu; Nishiyama, Chizuru; Okuhara, Daisuke; Tahara, Toru; Maruyama, Yoshimasa; Kasahara, Hiroko; Takashima, Kayoko; Kobayashi, Sayaka; Motokawa, Yoshiyuki; Muto, Shin-ichi; Kuroda, Junji

    2007-11-01

    Despite its explosive properties and toxicity to both animals and humans, diethyl ether is an agent long used in Japan in the anaesthesia jar method of rat anaesthetises. However, in response to a recent report from the Science Council of Japan condemning diethyl ether as acceptable practice, we searched for an alternative rat anaesthesia method that provided data continuous with pre-existing regular toxicology studies already conducted under diethyl ether anaesthesia. For this, we examined two candidates; 30% isoflurane diluted with propylene glycol and pentobarbitone. Whereas isoflurane is considered to be one of the representatives of modern volatile anaesthetics, the method of propylene glycol-diluted 30% isoflurane used in this study was our modification of a recently reported method revealed to have several advantages as an inhalation anaesthesia. Intraperitoneal pentobarbitone has long been accepted as a humane method in laboratory animal anaesthesiology. These 2 modalities were scrutinized in terms of consistency of haematology and blood chemistry with previous results using ether. We found that pentobarbitone required a much longer induction time than diethyl ether, which is suspected to be the cause of fluctuations in several haematological and blood chemical results. Conversely, only calcium ion concentration showed a slight difference from traditional results in the case of 30% isoflurane. Additionally, serum prolactin and corticosterone levels indicated that 30% isoflurane induced less stress than ether, confirming that 30% isoflurane can both provide results consistent with diethyl ether, while at the same time remove its disadvantages. As such 30% isoflurane appears to be a strong alternative anaesthetic agent for future regular toxicology studies in Japan.

  8. Evaluation of toxicological properties and photodynamic activity of Photolon ointment: an experimental study

    Science.gov (United States)

    Shliakhtsin, Siarhei V.; Trukhachova, Tatsiana V.; Istomin, Yuriy P.; Dunetz, Ludmila N.; Kuvshinov, Andrey V.; Naumovich, Semen A.

    2009-06-01

    The purpose of the present study was to evaluate toxicological properties and photodynamic activity of a new ready form of the photosensitizer Photolon (Fotolon) - an ointment for topical use. The data obtained show the use of topicaly applied photosensitizer provides sufficient penetration and accumulation of the active compound in tumor tissue as well as in affected periodontal tissues for the effective PDT. There are several advantages of PDT with topical application of the photosensitizer such as absence of systemic toxic and photosensitive reactions, relatively low cost of the treatment and etc. We have shown that PDT of affected periodontal tissues with local application of Photolon/Fotolon ointment provides an ability of local destruction of microbial cell, located as on the gum surface as in the spatium intercellulare what is extremely important for successful treatment of acute and chronic periodontitis.

  9. Toxicological studies on Thermomyces lanuginosus xylanase expressed by Fusarium venenatum, intended for use in food.

    Science.gov (United States)

    Pedersen, P B; Broadmeadow, A

    2000-09-01

    The xylanase used in this study was produced by a submerged fermentation of Fusarium venenatum and contained a gene code originating from Thermomyces lanuginosus. The enzyme was subject to a 13-week toxicological test in rats and in vitro tests to document its safety in use. The enzyme is to be applied as a processing aid in the baking industry to improve handling and stability of dough. The enzyme was not found to be mutagenic in the Salmonella typhimurium reverse mutation assay, nor did it cause chromosomal aberrations in cultured human lymphocytes. Oral administration to rats of up to 10.0 ml/kg bw/day (equivalent to a Total Organic Solids dosage of 1.12 g/kg bw/day or a xylanase dosage of 89422 FXU (W)/kg bw/day) for 13 weeks did not cause any adverse effect.

  10. Toxicologic Laboratory Findings in Cases Reported with Hanging Death: a Two-Year Retrospective Study in Northeast Iran

    Directory of Open Access Journals (Sweden)

    Mohammad Ranjbar

    2013-09-01

    How to cite this article: Ranjbar R, Liaghat AR, Ranjbar A, Mohabbati H. Toxicologic Laboratory Findings in Cases Reported with Hanging Death: a Two-Year Retrospective Study in Northeast Iran. Asia Pac J Med Toxicol 2013;2:92-5.

  11. UNUSUAL FINDINGS IN ZEBRAFISH, DANIO RERIO, FROM TOXICOLOGICAL STUDIES AND THE ZEBRAFISH INTERNATIONAL RESOURCE CENTER DIAGNOSTIC SERVICE

    Science.gov (United States)

    A number of interesting and unusual lesions have been diagnosed in zebrafish that have been evaluated from toxicological studies or submitted as cases to the Diagnostic Service at Oregon State University. Lesions were observed in various wild-type and mutant lines of zebrafish an...

  12. A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

    Directory of Open Access Journals (Sweden)

    Josinete B. Vieira

    2014-07-01

    Full Text Available The Density Functional Theory (DFT method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA and hierarchical cluster analysis (HCA were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS and principal component regression (PCR models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R2 = ±0.0106, R2ajust = ±0.0125, s = ±0.0234, F(4,11 = ±12.7802, Q2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and SPRESS = ±0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA, cellular permeability (PCaCO2, cell permeability Maden Darby Canine Kidney (PMDCK, skin permeability (PSkin, plasma protein binding (PPB and penetration of the blood-brain barrier (CBrain/Blood, and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.

  13. Recent studies in the behavioral toxicology of ELF electric and magnetic fields

    Energy Technology Data Exchange (ETDEWEB)

    Lovely, R.H.

    1988-01-01

    Behavioral responses to ELF electric and magnetic fields are reviewed starting with the simple sensory awareness or detection by an animal and moving on through more-complicated behavioral responses such as behavior that averts exposure. The literature selected in this review is taken primarily from the area of behavioral toxicology. As such, it does not review work on specialized response systems to ELF fields. The most notable of these omitted specialized response systems are electroreception, which occurs in a number of fish species, and homing/navigation and communication of the location of food that occurs in several species of birds and in honeybees, respectively. The toxicologic orientation of most researches that evaluate the effects of exposure to ELF electric and magnetic fields has been influenced primarily by the missions of DOE and the power industry programs to determine the health effects of power frequency (50- and 60-Hz) electric and magnetic fields. Because of these large programmatic efforts, most of the recent research has in fact been done at 50 or 60 Hz. In the context of the above limitations, remarkably few robust behavioral effects have been reported. Those that have been reported probably relate to an animal's perception of the electric field, although there are some exceptions to this generalization. The apparent lack of deleterious effects in animals is consistent with recent studies on humans that have been conducted in the UK. With this in mind, it is tempting to conclude that exposure to an ELF field is a rather innocuous event and, other than possible mini-shocks, is without hazard. 43 references.

  14. Clinical and anatomic pathology effects of serial blood sampling in rat toxicology studies, using conventional or microsampling methods.

    Science.gov (United States)

    Caron, Alexis; Lelong, Christine; Bartels, T; Dorchies, O; Gury, T; Chalier, Catherine; Benning, Véronique

    2015-08-01

    As a general practice in rodent toxicology studies, satellite animals are used for toxicokinetic determinations, because of the potential impact of serial blood sampling on toxicological endpoints. Besides toxicological and toxicokinetic determinations, blood samples obtained longitudinally from a same animal may be used for the assessment of additional parameters (e.g., metabolism, pharmacodynamics, safety biomarkers) to maximize information that can be deduced from rodents. We investigated whether removal of up to 6 × 200 μL of blood over 24h can be applied in GLP rat toxicology studies without affecting the scientific outcome. 8 week-old female rats (200-300 g) were dosed for up to 1 month with a standard vehicle and subjected or not (controls) to serial blood sampling for sham toxicokinetic/ancillary determinations, using miniaturized methods allowing collection of 6 × 50, 100 or 200 μL over 24h. In-life endpoints, clinical pathology parameters and histopathology of organs sensitive to blood volume reduction were evaluated at several time points after completion of sampling. In sampled rats, minimal and reversible changes in red blood cell mass (maximally 15%) and subtle variations in liver enzymes, fibrinogen and neutrophils were not associated with any organ/tissue macroscopic or microscopic correlate. Serial blood sampling (up to 6 × 200 μL over 24h) is compatible with the assessment of standard toxicity endpoints in adult rats. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Efficacy of repeated doses of levamisole, morantel, fenbendazole, and ivermectin against gastrointestinal nematodes in ewes.

    Science.gov (United States)

    Hembry, F G; Miller, J E; Sims, D; Rodriguez, S; Stagg, L C

    1986-08-01

    Levamisole, morantel, fenbendazole, or ivermectin was administered at 2-week intervals from May 1 through Sept 14, 1985, to breeding ewes (20 ewes/drug) infected with various gastrointestinal nematodes. All ewes had fewer gastrointestinal nematode eggs per gram of feces (epg) after 2 treatments, compared with pretreatment epg counts. Ewes administered ivermectin continued to have a low mean epg (0 to 3) throughout the study. The mean epg counts of ewes treated with levamisole increased from 3 to 483 during the study. This increase was similar to that of ewes treated with morantel (7 to 485 epg). The mean epg count of fenbendazole-treated ewes increased from 4 to 192 during the study. By the end of the study, the mean epg counts when expressed as a percentage of the pretreatment epg counts were 4% (ivermectin), 249% (fenbendazole), 627% (levamisole), and 630% (morantel). With the exception of the ivermectin-treated ewes, the epg count increased almost linearly in the ewes after the 2nd anthelmintic treatment. These data indicate that the gastrointestinal nematodes (including Haemonchus contortus) may have developed more resistance to levamisole and morantel than to fenbendazole. On the basis of the epg counts, resistance to ivermectin did not develop during the 4.5-month treatment period. The percentage of ewes shedding eggs after 2, 4, and 6 anthelmintic treatments was lowest for ewes treated with ivermectin (20%) and was similar (40%) for ewes treated with 1 of the other 3 anthelmintics. At the conclusion of the study, most of the ewes (90%) were shedding at least a small number of eggs, regardless of the anthelmintic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Safety of Repeated-Dose Intratympanic Injections with AM-101 in Acute Inner Ear Tinnitus.

    Science.gov (United States)

    Staecker, Hinrich; Morelock, Michael; Kramer, Timothy; Chrbolka, Pavel; Ahn, Joong Ho; Meyer, Thomas

    2017-09-01

    Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

  17. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  18. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach.

    Science.gov (United States)

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie

    2014-10-01

    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  19. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  20. Animal-free toxicology

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E

    2013-01-01

    Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk...... assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure......-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data....

  1. Animal-free toxicology

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E

    2013-01-01

    Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk...... assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure......-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data....

  2. Hazard identification by methods of animal-based toxicology.

    Science.gov (United States)

    Barlow, S M; Greig, J B; Bridges, J W; Carere, A; Carpy, A J M; Galli, C L; Kleiner, J; Knudsen, I; Koëter, H B W M; Levy, L S; Madsen, C; Mayer, S; Narbonne, J-F; Pfannkuch, F; Prodanchuk, M G; Smith, M R; Steinberg, P

    2002-01-01

    This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.

  3. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

    Science.gov (United States)

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M

    2009-01-01

    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  4. Aerospace Toxicology and Microbiology

    Science.gov (United States)

    James, John T.; Parmet, A. J.; Pierson, Duane L.

    2007-01-01

    Toxicology dates to the very earliest history of humanity with various poisons and venom being recognized as a method of hunting or waging war with the earliest documentation in the Evers papyrus (circa 1500 BCE). The Greeks identified specific poisons such as hemlock, a method of state execution, and the Greek word toxos (arrow) became the root of our modern science. The first scientific approach to the understanding of poisons and toxicology was the work during the late middle ages of Paracelsus. He formulated what were then revolutionary views that a specific toxic agent or "toxicon" caused specific dose-related effects. His principles have established the basis of modern pharmacology and toxicology. In 1700, Bernardo Ramazzini published the book De Morbis Artificum Diatriba (The Diseases of Workers) describing specific illnesses associated with certain labor, particularly metal workers exposed to mercury, lead, arsenic, and rock dust. Modern toxicology dates from development of the modern industrial chemical processes, the earliest involving an analytical method for arsenic by Marsh in 1836. Industrial organic chemicals were synthesized in the late 1800 s along with anesthetics and disinfectants. In 1908, Hamilton began the long study of occupational toxicology issues, and by WW I the scientific use of toxicants saw Haber creating war gases and defining time-dosage relationships that are used even today.

  5. Toxicological study of pesticides in air and precipitations of Paris by means of a bioluminescence method.

    Science.gov (United States)

    Trajkovska, S; Mbaye, M; Gaye Seye, M D; Aaron, J J; Chevreuil, M; Blanchoud, H

    2009-06-01

    A detailed toxicological study on several pesticides, including chlorothalonil, cyprodynil, dichlobénil, pendimethaline, trifluraline, and alpha-endosulfan, present at trace levels in air and total atmospheric precipitations of Paris is presented. The pesticides contained in the atmospheric samples, collected during sampling campaigns in February-March 2007, are identified and quantified by a high-performance liquid chromatographic (HPLC)-UV detection method. The toxicity measurements are performed by means of the Microtox bioluminescence method, based on the evaluation of the bioluminescence inhibition of the Vibrio fischeri marine bacteria at two exposure times to the pesticide solutions. The specific toxicity, corresponding to the particular toxicity of the compound under study and represented by the EC(50) parameter, is determined for these pesticides. Also, the global toxicity, which is the toxicity of all micro-pollutants present in the sample under study, is estimated for the extracts of air and atmospheric precipitation (rainwater) samples. The specific toxicities strongly vary with the nature of the pesticide, the EC(50) parameter values being comprised between 0.17 and 0.83 mg/mL and 0.15 and 0.66 mg/mL, respectively, for exposure times of 5 and 15 min. The importance of the atmospheric samples' global toxicity and the respective contribution of the toxic potency of the various pesticides contained in these samples are discussed.

  6. Graphical display of histopathology data from toxicology studies for drug discovery and development: An industry perspective.

    Science.gov (United States)

    Brown, Alan P; Drew, Philip; Knight, Brian; Marc, Philippe; Troth, Sean; Wuersch, Kuno; Zandee, Joyce

    2016-12-01

    Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, and tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses. A subgroup of the FDA-PhUSE Nonclinical Working Group conducted intra-industry surveys regarding the use of graphical displays of histopathology data. Visual cues, use-cases, the value of cross-domain and cross-study visualizations, and limitations were topics for discussion in the context of the surveys. The subgroup came to the following conclusions. Graphical displays appear advantageous as a communication tool to both pathologists and non-pathologists, and provide an efficient means for communicating pathology findings to project teams. Graphics can support hypothesis-generation which could include cross-domain interactive visualizations and/-or aggregating large datasets from multiple studies to observe and/or display patterns and trends. Incorporation of the SEND standard will provide a platform by which visualization tools will be able to aggregate, select and display information from complex and disparate datasets.

  7. Forced degradation studies of ivabradine and in silico toxicology predictions for its new designated impurities

    Directory of Open Access Journals (Sweden)

    Piotr ePikul

    2016-05-01

    Full Text Available All activities aim to eliminate genotoxic impurities or/and protect the medicinal compounds against degradation. There is a need to monitor impurities from all classification groups, so that ivabradine forced degradation studies were performed. Ivabradine proved to be a quite durable active substance, but still new and not known particularly. Increasing temperature, acid, base, oxidation reagent and light cause its degradation. Thirteen degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Six of them, which the most probable structures managed to establish, were selected to ADME/Tox calculations for prediction studies of their pharmacological and toxicological properties. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment of selected degradation products. Pharmacological activity of photodegradation product (UV4 that is known as active metabolite was qualified and identified. Two other degradation compounds (Ox1 and N1 which were formed during degradation process were found to be pharmacologically active with high probability.

  8. Sauropus androgynus (L. Merr. Induced Bronchiolitis Obliterans: From Botanical Studies to Toxicology

    Directory of Open Access Journals (Sweden)

    Hamidun Bunawan

    2015-01-01

    Full Text Available Sauropus androgynus L. Merr. is one of the most popular herbs in South Asia, Southeast Asia, and China where it was known as a slimming agent until two outbreaks of pulmonary dysfunction were reported in Taiwan and Japan in 1995 and 2005, respectively. Several studies described that the excessive consumption of Sauropus androgynus could cause drowsiness, constipation, and bronchiolitis obliterans and may lead to respiratory failure. Interestingly, this herb has been used in Malaysia and Indonesia in cooking and is commonly called the “multigreen” or “multivitamin” plant due to its high nutritive value and inexpensive source of dietary protein. The plant is widely used in traditional medicine for wound healing, inducing lactation, relief of urinary disorders, as an antidiabetic cure and also fever reduction. Besides these medicinal uses, the plant can also be used as colouring agent in food. This review will explore and compile the fragmented knowledge available on the botany, ethnobotany, chemical constitutes, pharmacological properties, and toxicological aspects of this plant. This comprehensive review will give readers the fundamental, comprehensive, and current knowledge regarding Sauropus androgynus L. Merr.

  9. Optimal designs for discriminating between dose-response models in toxicology studies

    CERN Document Server

    Dette, Holger; Shpilev, Piter; Wong, Weng Kee; 10.3150/10-BEJ257

    2010-01-01

    We consider design issues for toxicology studies when we have a continuous response and the true mean response is only known to be a member of a class of nested models. This class of non-linear models was proposed by toxicologists who were concerned only with estimation problems. We develop robust and efficient designs for model discrimination and for estimating parameters in the selected model at the same time. In particular, we propose designs that maximize the minimum of $D$- or $D_1$-efficiencies over all models in the given class. We show that our optimal designs are efficient for determining an appropriate model from the postulated class, quite efficient for estimating model parameters in the identified model and also robust with respect to model misspecification. To facilitate the use of optimal design ideas in practice, we have also constructed a website that freely enables practitioners to generate a variety of optimal designs for a range of models and also enables them to evaluate the efficiency of ...

  10. Sauropus androgynus (L.) Merr. Induced Bronchiolitis Obliterans: From Botanical Studies to Toxicology

    Science.gov (United States)

    Bunawan, Hamidun; Bunawan, Siti Noraini; Baharum, Syarul Nataqain; Noor, Normah Mohd.

    2015-01-01

    Sauropus androgynus L. Merr. is one of the most popular herbs in South Asia, Southeast Asia, and China where it was known as a slimming agent until two outbreaks of pulmonary dysfunction were reported in Taiwan and Japan in 1995 and 2005, respectively. Several studies described that the excessive consumption of Sauropus androgynus could cause drowsiness, constipation, and bronchiolitis obliterans and may lead to respiratory failure. Interestingly, this herb has been used in Malaysia and Indonesia in cooking and is commonly called the “multigreen” or “multivitamin” plant due to its high nutritive value and inexpensive source of dietary protein. The plant is widely used in traditional medicine for wound healing, inducing lactation, relief of urinary disorders, as an antidiabetic cure and also fever reduction. Besides these medicinal uses, the plant can also be used as colouring agent in food. This review will explore and compile the fragmented knowledge available on the botany, ethnobotany, chemical constitutes, pharmacological properties, and toxicological aspects of this plant. This comprehensive review will give readers the fundamental, comprehensive, and current knowledge regarding Sauropus androgynus L. Merr. PMID:26413127

  11. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies.

    Science.gov (United States)

    Magnuson, B A; Burdock, G A; Doull, J; Kroes, R M; Marsh, G M; Pariza, M W; Spencer, P S; Waddell, W J; Walker, R; Williams, G M

    2007-01-01

    Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive

  12. A New Stochastic Kriging Method for Modeling Multi-Source Exposure–Response Data in Toxicology Studies

    OpenAIRE

    Wang, Kai; Chen, Xi; Yang, Feng; Porter, Dale W; Wu, Nianqiang

    2014-01-01

    One of the most fundamental steps in risk assessment is to quantify the exposure–response relationship for the material/chemical of interest. This work develops a new statistical method, referred to as SKQ (stochastic kriging with qualitative factors), to synergistically model exposure–response data, which often arise from multiple sources (e.g., laboratories, animal providers, and shapes of nanomaterials) in toxicology studies. Compared to the existing methods, SKQ has several distinct featu...

  13. A critique of biomarkers in environmental toxicology: A case study in birds

    Energy Technology Data Exchange (ETDEWEB)

    Bellward, G.D. [Univ. of British Columbia, Vancouver, British Columbia (Canada)

    1995-12-31

    The authors have been testing the hypothesis that exposure to elevated levels of 2,3,7,8-TCDD and similarly-acting compounds derived from pulp mill effluent adversely affects the reproductive capacity of colonies of great blue herons and double crested cormorants in the local area. Their objectives included developing quantitative TCDD dose-response curves for various toxicologically relevant endpoints in birds, with the goal of finding an appropriate environmental biomarker of dioxin exposure and toxicity. Potential biomarkers studied included ethoxyresorufin O-deethylase (EROD) as a measure of cytochrome P-450 1-A activity, and various hormonally-relevant end-points as measures of dioxin toxicity. The animal model used was the newly hatched chick, after in ovo exposure either in the laboratory or from the environment. Because the TEQ approach is based to a large extent on the use of in vitro and in vivo biomarkers, this study provides a useful example of one of the simplest in vivo models. The authors were able to construct hepatic EROD dose-response curves from the environmentally exposed heron and cormorant chicks, and from TCDD egg injections both early and late in the incubation period. Domestic chicken and pigeons were used as control species. The EROD induction data from the late injection pigeon study was very helpful for predicting appropriate doses for use in the early injection experiments, and for the wild avian species. However, the data was too limited to use for accurately predicting such endpoints as mortality, or effects at the lower end of the dose-response curves. Using various toxic equivalency factors, TEQs for the environmental data were calculated, and compared to the laboratory derived dose-response curves for TCDD. Using specific examples from this environmental case study, the strengths and weaknesses of the use of biomarkers and the TEQ approach will be discussed.

  14. Clinical, cytogenetic and toxicological studies in rural workers exposed to pesticides in Botucatu, São Paulo, Brazil

    Directory of Open Access Journals (Sweden)

    Salete Marcia Bréga

    1998-01-01

    Full Text Available Pesticides can cause gene mutations and chromosomal aberrations in exposed individuals. We have investigated 24 workers exposed to pesticides. Clinical examinations and cytogenetic and toxicological tests were performed. Ten non-exposed individuals were used as controls. Toxicological dosages of copper, zinc and manganese (metals found in some pesticides, hepatic enzyme dosage (GOT, GPT, AR and acetylcholinesterase activity were performed in 16 workers and 8 controls. In the exposed workers, the most relevant clinical symptoms were poor digestion with fullness sensation after meals, irritated eyes, headache and fasciculations. The exposed group showed significantly lower manganese dosage and acetylcholinesterase activity, and significantly higher levels of alkaline phosphatase. Cytogenetic studies showed significantly higher chromosomal aberrations in the exposed group compared to the control group. Although the workers used protection against the pesticide's fog, the results revealed that the workers were contaminated with the pesticides. Therefore, the cytogenetic, toxicological studies with clinical examination are necessary for monitoring workers who are exposed to pesticides in any situation.

  15. Retrospective Mining of Toxicology Data to Discover Multispecies Effects: Anemia as a Case Study (SOT)

    Science.gov (United States)

    In vivo toxicology data is subject to multiple sources of uncertainty: observer severity bias (a pathologist may record only more severe effects and ignore less severe ones); dose spacing issues (this can lead to missing data, e.g. if a severe effect has a less severe precursor, ...

  16. Docking-based classification models for exploratory toxicology studies on high-quality estrogenic experimental data

    Science.gov (United States)

    Background: Exploratory toxicology is a new emerging research area whose ultimate mission is that of protecting human health and environment from risks posed by chemicals. In this regard, the ethical and practical limitation of animal testing has encouraged the promotion of compu...

  17. Indoor and outdoor airborne particles : an in vitro study on mutagenic potential and toxicological implications

    NARCIS (Netherlands)

    Houdt, van J.J.

    1988-01-01

    Introduction

    Air pollution components are present as gases and as particulate matter. As particle deposition takes place in various parts of the respiratory system particulate matter may have other toxicological implications than gaseous pollutants, which all may

  18. Indoor and outdoor airborne particles. An in vitro study on mutagenic potential and toxicological implications.

    NARCIS (Netherlands)

    Houdt, van J.J.

    1988-01-01

    IntroductionAir pollution components are present as gases and as particulate matter. As particle deposition takes place in various parts of the respiratory system particulate matter may have other toxicological implications than gaseous pollutants, which all may penetrate in the low

  19. Inhalation developmental toxicology studies: Teratology study of 1,3-butadiene in mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1987-11-01

    Maternal toxicity, reproductive performance and developmental toxicology were evaluated in CD-1 mice following whole-body, inhalation exposures to 0, 40, 200 and 1000 ppM of 1,3-butadiene. The female mice, which had mated with unexposed males were exposed to the chemical for 6 hours/day on 6 through 15 dg and sacrificed on 18 dg. Maternal animals were weighed prior to mating and on 0, 6, 11 and 18 dg; the mice were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. Significant concentration-related decreases were detected in a number of maternal body weight measures. There was a significant concentration-related depression of fetal body weights and placental weights. Body weights of male fetuses of all exposed groups were significantly lower than values for control fetuses; weights of female fetuses were significantly depressed in the mice exposed to 200 and 1000 ppM. In the 200- and 1000-ppM exposure groups, weights of placentas of male fetuses were significantly decreased, but placental weights of female fetuses were significantly affected only in litters exposed to the highest 1,3-butadiene concentration. This exposure regimen produced significant signs of maternal toxicity at concentrations of 200 and 1000 ppM 1,3-butadiene.

  20. Environmental Toxicology Research Facility

    Data.gov (United States)

    Federal Laboratory Consortium — Fully-equipped facilities for environmental toxicology research The Environmental Toxicology Research Facility (ETRF) located in Vicksburg, MS provides over 8,200 ft...

  1. Development of the dietary fiber functional food and studies on its toxicological and physiologic properties.

    Science.gov (United States)

    Hong, Yan; Zi-Jun, Wang; Jian, Xiong; Ying-jie, Dai; Fang, Ma

    2012-09-01

    Dietary fiber (DF) obtained from wheat bran by microbial fermentation was used as a food additive to cookies. The cookies were evaluated sensorally through an orthogonal test to gain the optimized production conditions as follows: the suitable DF content 8%, leavening agent 1.5%, standing time 5 min, and baking time of the cookies is 8 min. A series of toxicological and physiological functions of the cookies were studied using KM mice as the experimental animal in this paper. No deaths or abnormal behaviors of mice occurred either in acute toxicity tests or in short-term feeding tests. Besides, the weight gains, food utilization ratios, blood and serum biochemical parameters, organ coefficients and the results of organ histopathology tests of all doses groups exhibited no significant differences with the control group. This reveals that the dietary fiber functional cookies made by this formula have no acute or sub-chronic toxicity. In terms of physiological function, compared with the control group, the total cholesterol (TC) and triglycerides (TG) were 17.0-21.7% and 18.7-35.0% lower in mice serum of all DF cookie doses groups, respectively, but this difference was not significant (P>0.05). Compared with positive control group, the Cd(2+) and Pb(2+) excretion ratios of DF group were 27.4% and 25.2% higher, respectively. Thus, a conclusion has been drawn that dietary fiber functional cookies made by this formula have no toxic or harmful actions on animals or humans, and the DF food was able to decrease TC and TG concentrations to some extent in serum and increase excretion of Cd(2+) and Pb(2+) in Feces. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  2. The underlying toxicological mechanism of chemical mixtures: A case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Dayong [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Department of Chemical and Environmental Engineering, Anyang Institute of Technology, Anyang 455000 (China); Lin, Zhifen, E-mail: lzhifen@tongji.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Zhou, Xianghong [Department of Public Management, Tongji University, Shanghai 200092 (China); Yin, Daqiang [Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China)

    2013-10-15

    Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptors of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. - Highlights: • Joint effects of nitriles and aldehydes at non-equitoxic ratios were determined. • A novel descriptor, ligand–receptor interaction energy (E{sub binding}), was employed. • Quantitative relationships for mixtures were developed based on a novel descriptor. • The underlying toxic mechanism was revealed based on quantitative relationships. • Two

  3. Toxicological properties of closantel.

    Science.gov (United States)

    Van Cauteren, H; Vandenberghe, J; Hérin, V; Vanparys, P; Marsboom, R

    1985-01-01

    The acute, subacute and chronic toxicity studies in laboratory animals showed that closantel is a well tolerated substance. At multiples of the clinical dose, overdosing might result in central nervous system effects and death. Repeated oral dosing was without effects up to 40 mg/kg in rats and dogs except for focal swelling of the epididymis in male rats at 40 mg/kg due to formation of spermatic granulomas. In sheep repeated dosing at 10 and 40 mg/kg orally and at 5 and 20 mg/kg intramuscularly every four weeks during 40 weeks demonstrated an acceptable safety margin in this target species. Reproduction studies including a three-generation study in rats showed that fertility was not affected except slightly in male rats at 40 mg/kg whereas an embryotoxic or teratogenic potential in rats and rabbits was absent. Peri- and postnatal parameters in rats were not affected. In target animals, reproduction was extensively studied in bulls, rams and ewes showing no risk of closantel for reproduction parameters. A mutagenic potential was found to be absent in a Salmonella Ames test, a sex-linked recessive lethal test in Drosophila melanogaster and a dominant lethal test in male and female mice. In 400 mice and 400 rats closantel was shown not to be carcinogenic. Tolerance studies in sheep and cattle demonstrated that oral and parenteral clinical doses were very well tolerated and devoid of serious side-effects.

  4. Mass Spectrometry Applications for Toxicology

    Science.gov (United States)

    Mbughuni, Michael M.; Jannetto, Paul J.

    2016-01-01

    Toxicology is a multidisciplinary study of poisons, aimed to correlate the quantitative and qualitative relationships between poisons and their physiological and behavioural effects in living systems. Other key aspects of toxicology focus on elucidation of the mechanisms of action of poisons and development of remedies and treatment plans for associated toxic effects. In these endeavours, Mass spectrometry (MS) has become a powerful analytical technique with a wide range of application used in the Toxicological analysis of drugs, poisons, and metabolites of both. To date, MS applications have permeated all fields of toxicology which include; environmental, clinical, and forensic toxicology. While many different analytical applications are used in these fields, MS and its hyphenated applications such as; gas chromatography MS (GC-MS), liquid chromatography MS (LC-MS), inductively coupled plasma ionization MS (ICP-MS), tandem mass spectrometry (MS/MS and MSn) have emerged as powerful tools used in toxicology laboratories. This review will focus on these hyphenated MS technologies and their applications for toxicology.

  5. Mass Spectrometry Applications for Toxicology.

    Science.gov (United States)

    Mbughuni, Michael M; Jannetto, Paul J; Langman, Loralie J

    2016-12-01

    Toxicology is a multidisciplinary study of poisons, aimed to correlate the quantitative and qualitative relationships between poisons and their physiological and behavioural effects in living systems. Other key aspects of toxicology focus on elucidation of the mechanisms of action of poisons and development of remedies and treatment plans for associated toxic effects. In these endeavours, Mass spectrometry (MS) has become a powerful analytical technique with a wide range of application used in the Toxicological analysis of drugs, poisons, and metabolites of both. To date, MS applications have permeated all fields of toxicology which include; environmental, clinical, and forensic toxicology. While many different analytical applications are used in these fields, MS and its hyphenated applications such as; gas chromatography MS (GC-MS), liquid chromatography MS (LC-MS), inductively coupled plasma ionization MS (ICP-MS), tandem mass spectrometry (MS/MS and MS(n)) have emerged as powerful tools used in toxicology laboratories. This review will focus on these hyphenated MS technologies and their applications for toxicology.

  6. Toxicologic and Analytical Studies with T-2 and Related Trichothecene Mycotoxins

    Science.gov (United States)

    1985-08-20

    Bodey, G. P., Freireich, E. J. (1978). Phase I clinical evaluation of anguidine. Cancer Treatment Reports. 62(10):1497-1502. 17. Nie, N. H., Hull...aorta, pulmon - ary artery and left atrium and cardiac output using the dye dilution techniqbe, 3) cardiac output and organ blood flow using the...toxin, a trichothecene metabolite of Fusarium. Cancer Res. 39:2179-2189, 1979. 6. Tatsuno, T. Toxicologic research on substances from Fusarium nivale

  7. Space Toxicology

    Science.gov (United States)

    James, John T.

    2011-01-01

    Safe breathing air for space faring crews is essential whether they are inside an Extravehicular Mobility Suit (EMU), a small capsule such as Soyuz, or the expansive International Space Station (ISS). Sources of air pollution can include entry of propellants, excess offgassing from polymeric materials, leakage of systems compounds, escape of payload compounds, over-use of utility compounds, microbial metabolism, and human metabolism. The toxicological risk posed by a compound is comprised of the probability of escaping to cause air pollution and the magnitude of adverse effects on human health if escape occurs. The risk from highly toxic compounds is controlled by requiring multiple levels of containment to greatly reduce the probability of escape; whereas compounds that are virtually non-toxic may require little or no containment. The potential for toxicity is determined by the inherent toxicity of the compound and the amount that could potentially escape into the breathing air.

  8. Toxicology of Biodiesel Combustion products

    Science.gov (United States)

    1. Introduction The toxicology of combusted biodiesel is an emerging field. Much of the current knowledge about biological responses and health effects stems from studies of exposures to other fuel sources (typically petroleum diesel, gasoline, and wood) incompletely combusted. ...

  9. Toxicological evaluation of u-hEGF.

    Science.gov (United States)

    Maraschin, R; Bussi, R; Conz, A; Orlando, L; Pirovano, R; Nyska, A

    1995-01-01

    The toxicological evaluation of urinary human epidermal growth factor (u-hEGF) included mutagenicity, single and repeated dose general toxicity, and teratogenicity studies in various animal species. The mutagenic potential of u-hEGF was tested in vitro (Ames test, chromosome aberration in human lymphocytes, unscheduled DNA synthesis in HeLa cells) and in vivo (chromosome aberration in Chinese hamster bone marrow and micronucleus test in rat bone marrow). No mutagenic or clastogenic effects were found. The acute toxicity of u-hEGF was evaluated in mice and rats, using single subcutaneous (sc) or intravenous (i.v.) injection of 15 mg/kg. No toxic effects were observed Four-week i.v. daily administration of u-hEGF at the doses of 0.3, o.9, and 3 mg/kg in the SD rat followed by 2 wk of compound withdrawal induced pronounced and generally dose-related effects (i.e., epithelial hyperplasia) in a wide range of tissues and organs, at all doses. However, these effects were not apparently detrimental to the general health of the rats. The repeated sc administration of u-hEGF to cynomolgus monkeys for 4 wk at the same doses as used in the rat study resulted in lethality after about 7 days of treatment in the 2 higher dose groups or after 14 days at the lowest dose. The main clinical signs observed were gastrointestinal effects, respiratory distress, sedation, marked loss of body weight, and cutaneous desquamation. At histology, hyperplasia of most epithelia was seen in all groups. In addition, atrophy of the ovarian follicles and necrosis of the uterine endometrium were noted. Changes considered secondary to physical distress were atrophy of the hemopoietic and lymphatic system and hepatic steatosis. The embryofetal toxicity and teratogenicity of u-hEGF was tested, using the i.v. route in the SD rat and the i.v. and sc routes in the New Zealand White rabbit. In both species, the compound was administered at the doses of 0, 0.3, 0.9, and 3 mg/kg/day, from day 6 to 15 of

  10. Comprehensive investigation of hydroxypropyl methylcellulose, propylene glycol, polysorbate 80, and hydroxypropyl-beta-cyclodextrin for use in general toxicology studies.

    Science.gov (United States)

    Thackaberry, Evan A; Kopytek, Stephen; Sherratt, Phillip; Trouba, Kevin; McIntyre, Barry

    2010-10-01

    This study was conducted to assess the safety and tolerability of the alternative formulation vehicles polysorbate 80 (PS80), propylene glycol (PG), and hydroxypropyl-beta-cyclodextrin (HPβCD) in general toxicology studies in the mouse, rat, dog, and monkey. Twenty (20) mg/kg of hydroxypropyl methylcellulose (MC, control), 10 mg/kg PS80, 1000 mg/kg PG, 500 mg/kg HPβCD, or 1000 mg/kg HPβCD were administered by oral gavage to mice, rats, dogs, and cynomolgus monkeys for approximately 90 days. The effects of these formulations on clinical observations, body weight and food consumption parameters, clinical pathology, and histopathology were evaluated across all species. The suitability of formulations containing up to 20 mg/kg MC, 10 mg/kg PS80, and 1000 mg/kg PG for use in preclinical safety studies was confirmed by a lack of effects on all parameters examined. However, formulations containing HPβCD produced elevated transaminase (aspartate and alanine aminotransferase) levels in rats and mice and fecal changes (loose and soft stool) in large animals. Although the etiology and toxicological significance of the transaminase elevations in rats and mice is uncertain, this finding could represent a significant liability for a preclinical formulation because of the critical importance of these biomarkers in the risk assessment of novel therapeutic agents. Based on these data, PS80 and PG are considered to be practical alternatives to MC in preclinical toxicology studies. However, formulations containing HPβCD should be used with caution because of the elevations in rodent transaminase levels.

  11. Analysis of Statistical Methods Currently used in Toxicology Journals

    OpenAIRE

    Na, Jihye; Yang, Hyeri; Bae, SeungJin; Lim, Kyung-Min

    2014-01-01

    Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and in...

  12. Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data.

    Science.gov (United States)

    Munro, I C; Berndt, W O; Borzelleca, J F; Flamm, G; Lynch, B S; Kennepohl, E; Bär, E A; Modderman, J; Bernt, W O

    1998-12-01

    A critical and comprehensive review of the safety information on erythritol was undertaken. Numerous toxicity and metabolic studies have been conducted on erythritol in rats, mice and dogs. The toxicity studies consist of long-term feeding studies conducted to determine carcinogenic potential, intravenous and oral teratogenicity studies to determine the potential for effects on the foetus, oral studies in which erythritol was administered over one or two generations to determine the potential for reproductive effects, and studies in bacterial and mammalian systems to determine mutagenic potential. The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%. The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine. The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects. The clinical program for erythritol involved a series of single-dose and repeat-dose, short-duration studies which have been used to investigate the human correlates to the physiological responses seen in the preclinical studies. The clinical studies showed erythritol to be well tolerated and not to cause any toxicologically relevant effects, even following high-dose exposure. Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change. At high oral doses, urinary excretion accounted for approximately 90% of the administered dose with minimal amounts appearing in the faeces. A comparison of the human and animal data indicated a high degree of similarity in the metabolism of erythritol and this finding supports the use of the animal species used to evaluate the safety of erythritol for human consumption. It can be concluded, based on the available studies

  13. Toxicologic evaluation of ofloxacin.

    Science.gov (United States)

    Davis, G J; McKenzie, B E

    1989-12-29

    Results of studies conducted to characterize local, systemic, reproductive, and mutagenic effects indicate that ofloxacin is well tolerated within reasonable multiples of the intended clinical dose. Quinolone-associated arthropathic effects characterized by blister, erosion, and increased synovial fluid occurred in rats and dogs and appeared to be both age- and dose-related. Maternal toxicity and embryotoxicity were noted, but there was no teratogenicity in rats or rabbits. There was no impairment of fertility, and no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of offspring occurred. Target-organ studies revealed no evidence of ocular toxicity in rats, nephrotoxicity in rabbits, or antigenicity or ototoxicity in guinea pigs. Overall, the toxicologic evaluation of ofloxacin has shown this compound to be a drug with a low toxicologic potential.

  14. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995).

    Science.gov (United States)

    Shaw, D; Leon, C; Kolev, S; Murray, V

    1997-11-01

    Since 1991, the Medical Toxicology Unit (MTU) at Guys' Hospital, London, has been assessing the toxicological problems associated with the use of traditional and herbal remedies and dietary supplements. This assessment was carried out by evaluating reports to the National Poisons Information Service (London) [NPIS(L)] which provides emergency information to medical professionals. Relevant telephone enquiries to NPIS(L) were identified. Further case details were obtained by follow-up questionnaire, clinical consultation, toxicological analysis of samples from patients and/or products and botanical identification of plant material. Of 1297 symptomatic enquiries evaluated there was a possible/confirmed association in 785 cases. Case series have been identified which substantiate previous reports, including liver problems following the use of Chinese herbal medicine for skin disorders, allergic reactions to royal jelly and propolis and heavy metal poisoning caused by remedies from the Indian subcontinent. Although the overall risk to public health appears to be low, certain groups of traditional remedies have been associated with a number of potentially serious adverse effects. Considering the extent of use of herbal remedies and food supplements a comprehensive surveillance system for monitoring the adverse health effects of these products is essential. Surveillance of a large population is needed for the complex task of identifying the uncommon and unpredictable adverse effects which are potentially serious. In the UK, the Medicines Control Agency responded to the MTU report by recognising the need for vigilance and by incorporating adverse reactions reporting on unlicensed herbal remedies into their drug reaction monitoring function. As a further step to safeguard the patients/consumers an effective single regulatory system is required which would ensure the safety and quality of all herbal remedies and food supplements available in the UK.

  15. Forensic toxicology.

    Science.gov (United States)

    Drummer, Olaf H

    2010-01-01

    Forensic toxicology has developed as a forensic science in recent years and is now widely used to assist in death investigations, in civil and criminal matters involving drug use, in drugs of abuse testing in correctional settings and custodial medicine, in road and workplace safety, in matters involving environmental pollution, as well as in sports doping. Drugs most commonly targeted include amphetamines, benzodiazepines, cannabis, cocaine and the opiates, but can be any other illicit substance or almost any over-the-counter or prescribed drug, as well as poisons available to the community. The discipline requires high level skills in analytical techniques with a solid knowledge of pharmacology and pharmacokinetics. Modern techniques rely heavily on immunoassay screening analyses and mass spectrometry (MS) for confirmatory analyses using either high-performance liquid chromatography or gas chromatography as the separation technique. Tandem MS has become more and more popular compared to single-stage MS. It is essential that analytical systems are fully validated and fit for the purpose and the assay batches are monitored with quality controls. External proficiency programs monitor both the assay and the personnel performing the work. For a laboratory to perform optimally, it is vital that the circumstances and context of the case are known and the laboratory understands the limitations of the analytical systems used, including drug stability. Drugs and poisons can change concentration postmortem due to poor or unequal quality of blood and other specimens, anaerobic metabolism and redistribution. The latter provides the largest handicap in the interpretation of postmortem results.

  16. In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies.

    Directory of Open Access Journals (Sweden)

    Anna Nilsson

    Full Text Available Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.

  17. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  18. NMR-based metabolomic studies on the toxicological effects of cadmium and copper on green mussels Perna viridis

    Energy Technology Data Exchange (ETDEWEB)

    Wu Huifeng [Section of Marine Ecology and Biotechnology, Division of Life Science, Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Kowloon (Hong Kong); Wang Wenxiong, E-mail: wwang@ust.hk [Section of Marine Ecology and Biotechnology, Division of Life Science, Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Kowloon (Hong Kong)

    2010-11-15

    Traditional toxicology studies have focused on selected biomarkers to characterize the biological stress induced by metals in marine organisms. In this study, a system biology tool, metabolomics, was applied to the marine mussel Perna viridis to investigate changes in the metabolic profiles of soft tissue as a response to copper (Cu) and cadmium (Cd), both as single metal and as a mixture. The major metabolite changes corresponding to metal exposure are related to amino acids, osmolytes, and energy metabolites. Following metal exposure for 1 week, there was a significant increase in the levels of branched chain amino acids, histidine, glutamate, glutamine, hypotaurine, dimethylglycine, arginine and ATP/ADP. For the Cu + Cd co-exposed mussels, the levels of lactate, branched chain amino acid, succinate, and NAD increased, whereas the levels of glucose, glycogen, and ATP/ADP decreased, indicating a different metabolic profile for the single metal exposure groups. After 2 weeks of exposure, the mussels showed acclimatization to Cd exposure based on the recovery of some metabolites. However, the metabolic profile induced by the metal mixture was very similar to that from Cu exposure, suggesting that Cu dominantly induced the metabolic disturbances. Both Cu and Cd may lead to neurotoxicity, disturbances in energy metabolism, and osmoregulation changes. These results demonstrate the high applicability and reliability of NMR-based metabolomics in interpreting the toxicological mechanisms of metals using global metabolic biomarkers.

  19. NMR-based metabolomic studies on the toxicological effects of cadmium and copper on green mussels Perna viridis.

    Science.gov (United States)

    Wu, Huifeng; Wang, Wen-Xiong

    2010-11-15

    Traditional toxicology studies have focused on selected biomarkers to characterize the biological stress induced by metals in marine organisms. In this study, a system biology tool, metabolomics, was applied to the marine mussel Perna viridis to investigate changes in the metabolic profiles of soft tissue as a response to copper (Cu) and cadmium (Cd), both as single metal and as a mixture. The major metabolite changes corresponding to metal exposure are related to amino acids, osmolytes, and energy metabolites. Following metal exposure for 1 week, there was a significant increase in the levels of branched chain amino acids, histidine, glutamate, glutamine, hypotaurine, dimethylglycine, arginine and ATP/ADP. For the Cu+Cd co-exposed mussels, the levels of lactate, branched chain amino acid, succinate, and NAD increased, whereas the levels of glucose, glycogen, and ATP/ADP decreased, indicating a different metabolic profile for the single metal exposure groups. After 2 weeks of exposure, the mussels showed acclimatization to Cd exposure based on the recovery of some metabolites. However, the metabolic profile induced by the metal mixture was very similar to that from Cu exposure, suggesting that Cu dominantly induced the metabolic disturbances. Both Cu and Cd may lead to neurotoxicity, disturbances in energy metabolism, and osmoregulation changes. These results demonstrate the high applicability and reliability of NMR-based metabolomics in interpreting the toxicological mechanisms of metals using global metabolic biomarkers. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

    Science.gov (United States)

    Solomon, Howard M; Makris, Susan L; Alsaid, Hasan; Bermudez, Oscar; Beyer, Bruce K; Chen, Antong; Chen, Connie L; Chen, Zhou; Chmielewski, Gary; DeLise, Anthony M; de Schaepdrijver, Luc; Dogdas, Belma; French, Julian; Harrouk, Wafa; Helfgott, Jonathan; Henkelman, R Mark; Hesterman, Jacob; Hew, Kok-Wah; Hoberman, Alan; Lo, Cecilia W; McDougal, Andrew; Minck, Daniel R; Scott, Lelia; Stewart, Jane; Sutherland, Vicki; Tatiparthi, Arun K; Winkelmann, Christopher T; Wise, L David; Wood, Sandra L; Ying, Xiaoyou

    2016-06-01

    During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology. Published by Elsevier Inc.

  1. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Science.gov (United States)

    2010-07-01

    ... performance such as gonadal function, mating behavior, conception, development of the conceptus, and... not be limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and... recommended 1 . Investigations of plasma or serum must include sodium, potassium, glucose, total cholesterol...

  2. Animal-free toxicology: the use of human tissue to replace the use of animals - examples from human biomonitoring and human placental transport studies.

    Science.gov (United States)

    Knudsen, Lisbeth E

    2013-12-01

    Human data on exposure and adverse effects are the most appropriate for human risk assessment, and modern toxicology focuses on human pathway analysis and the development of human biomarkers. Human biomonitoring and human placental transport studies provide necessary information for human risk assessment, in accordance with the legislation on chemical, medicine and food safety. Toxicology studies based on human mechanistic and exposure information can replace animal studies. These animal-free approaches can be further supplemented by new in silico methods and chemical structure-activity relationships. The inclusion of replacement expertise in the international Three Rs centres, the ongoing exploration of alternatives to animal research, and the improvement of conditions for research animals, all imply the beginning of a paradigm shift in toxicology research toward the use of human data.

  3. Occupational toxicology in Mexico: current status and the potential use of molecular studies to evaluate chemical exposure.

    Science.gov (United States)

    Muñoz, Balam; Albores, Arnulfo

    2011-11-01

    Occupational toxicology is of considerable concern for several world organizations including the International Labour Organization, the World Health Organization and the International Commission for Occupational Health and, in Latin America, the Pan American Health Organization. The countries of this Region, including Mexico, own manufacturing, chemical, and petrochemical industries that employ thousands workers who are continually exposed to hazardous chemicals such as solvents, particles and exhaust fumes, many of which are very complex mixtures. Traditionally, physicians have used biochemical analyses to assess the damage caused by chronic chemical exposure. Presently, recent advances in molecular biology may offer tools to perform more thorough and precise evaluations on worker health damage, risk and current health status. In this review, we present a perspective of occupational toxicology in Mexico, as an example for Latin America and developing countries. Moreover, we summarize current reports about occupational disease associated with chemical exposure, and we present an array of molecular studies proposed for the analysis and diagnosis of workers related with industry and the relevance of including molecular biology testing to complement traditional occupational medical assays in order to improve occupational health. We conclude that developing countries, e.g., Mexico, should improve work environment standards by using new technical approaches that will result in more reliable and precise data to design better health policy strategies.

  4. Toxicological Assessment of the Cochleate Derived from Neisseria meningitidis Proteoliposome in Sprague Dawley Rats

    Science.gov (United States)

    Infante-Bourzac, Juan Francisco; Sifontes-Rodríguez, Sergio; Arencibia-Arrebola, Daniel Francisco; Hernández-Salazar, Tamara; Fariñas-Medina, Mildrey; Pérez, Oliver

    2012-01-01

    Background: The AFCo1 cochleate is a potential novel adjuvant derived from Neisseria meningitidis B proteoliposome. Aim: The aim was to assessing the safety of AFCo1 by single and repeated doses in Sprague Dawley rats. Materials and Methods: Rats were grouped for treatment with AFCo1, placebo formulation or control. The first study was a single intranasal dose of 100 μl and monitoring body weight, water, and food intakes as well as clinical symptoms. Fourteen days later the rats were killed and anatomopathological studies were conducted. In a second study, four similar doses of the test substance were instilled every 5 days. Clinical observations were carried out as for the single dose study and a number of rats from each group were killed 3 and 14 days after the last dose in order to conduct hematological, hemochemical, and anatomopathological studies. Results: No variable showed differences of toxicological relevance; the histological changes found were mild and similarly frequently in the three groups. According to the irritability index calculated form histology of the nasal region, AFCo1 was also classified as nonirritating. Conclusion: AFCo1 is potentially safe for human use by nasal route as evidenced by the absence of local and systemic signs of toxicity in Sprague Dawley rats. PMID:22454827

  5. Handbook of systems toxicology

    National Research Council Canada - National Science Library

    Casciano, Daniel A; Sahu, Saura C

    2011-01-01

    "In the first handbook to comprehensively cover the emerging area of systems toxicology, the Handbook of Systems Toxicology provides an authoritative compilation of up-to-date developments presented...

  6. National Toxicology Program

    Science.gov (United States)

    ... for modern toxicology and molecular biology. A world leader in toxicology research, NTP has evaluated more than 2800 environmental substances for potential human health effects. Learn More About NTP Director Meet NTP's director Linda Birnbaum, Ph.D. Learn ...

  7. Environmental Toxicology Research Facility

    Data.gov (United States)

    Federal Laboratory Consortium — Fully-equipped facilities for environmental toxicology researchThe Environmental Toxicology Research Facility (ETRF) located in Vicksburg, MS provides over 8,200 ft...

  8. Toxicology Education Foundation

    Science.gov (United States)

    ... bodies and our world. Welcome to the Toxicology Education Foundation! Our mission is to enhance public understanding ... In with us, follow our Tweets, choose Toxicology Education Foundation as your preferred charity through Smile.Amazon. ...

  9. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    Science.gov (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  10. Toxicological Study of Ocimum sanctum Linn Leaves: Hematological, Biochemical, and Histopathological Studies

    Directory of Open Access Journals (Sweden)

    M. K. Gautam

    2014-01-01

    Full Text Available The present study was aimed to study the acute and subacute toxicity studies with orally administered 50% ethanolic leaves extract of Ocimum sanctum Linn (OSE. In acute toxicity tests, four groups of mice (n=6/group/sex were orally treated with doses of 200, 600, and 2000 mg/kg, and general behavior, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received OSE by gavage at the doses of 200, 400, and 800 mg/kg/day (n=6/group/sex for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney, spleen, heart, and testis/ovary were determined. OSE did not produce any hazardous symptoms or death and CNS and ANS toxicities in the acute toxicity test. Subacute treatment with OSE did not show any change in body weight, food and water consumption, and hematological and biochemical profiles. In addition, no change was observed both in macroscopic and microscopic aspects of vital organs in rats. Our result showed that Ocimum sanctum extract could be safe for human use.

  11. Consideraciones prácticas acerca de la calidad del semen de conejos aplicado en estudios de toxicología de la fertilidad (Practice considerations about the semen quality of rabbits for applied in fertility toxicology study.

    Directory of Open Access Journals (Sweden)

    Arencibia Arrebola Daniel Francisco

    2009-08-01

    Full Text Available ResumenEl conejo doméstico es un descendiente del conejo salvaje que habitaba en el oeste de Europa y en el noroeste de África. En los estudios de toxicología experimental se destaca su uso en la determinación de toxicidad por irritación dérmica, ocular, toxicología de vacunas, además de ser básico como modelo animal para determinar compuestos teratogénicos, los cuales influyen tanto en la fertilidad de la hembra como en la del macho. Los métodos para la valoración de la calidad del semen, tanto para la inseminación artificial como en la investigación, están sufriendo un constante desarrollo para intentar estimar con mayor precisión la fertilidadde los machos. Desafortunadamente, las valoraciones de laboratorio nopredicen con exactitud la fertilidad y tampoco se obtiene una repetitividad de unos análisis a otros, debido a la subjetividad de muchas de dichas valoraciones. El objetivo de este trabajo es la confección de una guía teórico-práctica que permita realizar estudios del semen en conejos de la raza Nueva Zelanda Blanca, aplicado a la temática de toxicología de la fertilidad. Trataremos los temas de inducción del celo en las hembras, condiciones y método para la extracción del semen, pruebas macroscópicas y microscópicas del semen, valoración del peso de órganos y examen anatomopatológico. Todas las pruebas descritas aportan datos que nosindicarán una disminución de la calidad del semen, pero debemos realizar valoraciones que nos aporten sencillez, rapidez y que sean económicamente viables; para ello cada investigador debe utilizar aquellas que mejor se adapten a sus condiciones de trabajo.SummaryThe domestic rabbit is descendend from the wilds rabbits was to inhabited of western Europe and Northwestern Africa. The rabbits is very usefull in the experimental Toxicology study, in dermal irritation, ocular irritation and the vaccines Toxicology, beside is a basic animal models in teratogenicity evaluation of

  12. Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties

    Science.gov (United States)

    Batke, Monika; Gütlein, Martin; Partosch, Falko; Gundert-Remy, Ursula; Helma, Christoph; Kramer, Stefan; Maunz, Andreas; Seeland, Madeleine; Bitsch, Annette

    2016-01-01

    Interest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g., the European Union's Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the project presented in this publication was to develop substance categories for a read-across with complex endpoints of toxicity based on existing databases. The basic conceptual approach was to combine structural similarity with shared mechanisms of action. Substances with similar chemical structure and toxicological profile form candidate categories suitable for read-across. We combined two databases on repeated dose toxicity, RepDose database, and ELINCS database to form a common database for the identification of categories. The resulting database contained physicochemical, structural, and toxicological data, which were refined and curated for cluster analyses. We applied the Predictive Clustering Tree (PCT) approach for clustering chemicals based on structural and on toxicological information to detect groups of chemicals with similar toxic profiles and pathways/mechanisms of toxicity. As many of the experimental toxicity values were not available, this data was imputed by predicting them with a multi-label classification method, prior to clustering. The clustering results were evaluated by assessing chemical and toxicological similarities with the aim of identifying clusters with a concordance between structural information and toxicity profiles/mechanisms. From these chosen clusters, seven were selected for a quantitative read-across, based on a small ratio of NOAEL of the members with the highest and the lowest NOAEL in the cluster (cluster and to use this information for a

  13. Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Rommereim, R.L.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.

    1988-11-01

    Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.

  14. Inhalation developmental toxicology studies: Teratology study of n-hexane in rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.

    1987-12-01

    The straight chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent used in industrial, academic, and smaller commercial environments. The significant opportunity for women of child-bearing age to be exposed to this chemical prompted the undertaking of a study to assess the developmental toxicity of n-hexane in an animal model. Timed-pregnant (30 animals per group) and virgin (10 animals per group) Sprague-Dawley rats were exposed to 0 (filtered air), 200, 1000, and 5000 ppM n-hexane (99.9% purity) vapor in inhalation chambers for 20 h/day for a period of 14 consecutive days. Sperm-positive females were exposed for 6 to 19 days of gestation (dg) and virgins were exposed concurrently for 14 consecutive days. The day of sperm detection was designated as 0 dg for mated females. Adult female body weights were monitored prior to, throughout the exposure period, and at sacrifice. Uterine, placental, and fetal body weights were obtained for gravid females at sacrifice. Implants were enumerated and their status recorded as live fetus, early or late resorption, or dead. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 16 refs., 3 figs., 7 tabs.

  15. Inhalation developmental toxicology studies: Teratology study of methyl ethyl ketone in mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Dill, J.A.; Evanoff, J.J.; Rommereim, R.L.; Weigel, R.J.; Westerberg, R.B.

    1989-02-01

    Methyl ethyl ketone (MEK) is a widely used industrial solvent which results in considerable human exposure. In order to assess the potential for MEK to cause developmental toxicity in rodents, four groups of Swiss (CD-1) mice were exposed to 0, 400, 1000 or 3000 ppM MEK vapors, 7 h/day, 7 dy/wk. Ten virgin females and approx.30 plug-positive females per group were exposed concurrently for 10 consecutive days (6--15 dg for mated mice). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 18 dg. Uterine implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Exposure of pregnant mice to these concentrations of MEK did not result in apparent maternal toxicity, although there was a slight, treatment-correlated increase in liver to body weight ratios which was significant for the 3000-ppM group. Mild developmental toxicity was evident at 3000-ppM as a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes. 17 refs., 4 figs., 10 tabs.

  16. Inhalation developmental toxicology studies: Teratology study of isoprene in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1989-01-01

    Isoprene, a reactive, branched diene, is used in large quantities in the manufacture of polyisoprene and as a copolymer in the synthesis of butyl rubber. The potential for isoprene to cause developmental toxicity was assessed in rodents, by exposing four groups each of Sprague-Dawley rats and Swiss (CD-1) mice to 0, 280, 1400, or 7000 ppM isoprene vapors, 6 h/day, 7 day/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.30 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 31 refs., 6 figs., 19 tabs.

  17. Regionally contaminated aquifers--toxicological relevance and remediation options (Bitterfeld case study).

    Science.gov (United States)

    Heidrich, Susanne; Schirmer, Mario; Weiss, Holger; Wycisk, Peter; Grossmann, Jochen; Kaschl, Arno

    2004-12-15

    Large-scale contaminated megasites like Bitterfeld in eastern Germany are characterized by a regional contamination of soil, surface water and groundwater as a result of a long and varied history of chemical production. While the contaminants in soils and sediments mostly represent a localized problem, pollutants in groundwater may spread to uncontaminated areas and endanger receptors like surface water and drinking water wells according to the site-specific hydrologic regime. From the toxicological point of view, the contaminants at the Bitterfeld megasite represent a dangerous cocktail of various harmful substances coming from a multitude of sources. Appropriate remediation techniques must be able to remedy the specific problems arising from hot spot areas within the megasite in addition to preventing a further extension of the contaminated zone towards uncontaminated compartments. Therefore, a combination of specifically designed remediation technologies based on the pump and treat-principle with in situ technologies, such as reactive walls and monitored/enhanced natural attenuation, is necessary to efficiently address the miscellaneous challenges at this megasite. In this paper, the currently known contaminant distribution, the associated problems for human health and the environment and possible remediation strategies are presented for the Bitterfeld megasite.

  18. Identification of Prenatal Amphetamines Exposure by Maternal Interview and Meconium Toxicology in the Infant Development, Environment and Lifestyle (IDEAL) Study

    Science.gov (United States)

    Gray, Teresa R.; LaGasse, Linda L.; Smith, Lynne M.; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia M.; Della Grotta, Sheri A.; Strauss, Arthur; Haning, William F.; Lester, Barry M.; Huestis, Marilyn A.

    2009-01-01

    The Infant Development Environment and Lifestyle (IDEAL) study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Materials and Methods Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry (GCMS). Results The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by GCMS. Tobacco exposure was equally detected by immunoassay cotinine screen and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use, frequency or route of MAMP use. Discussion Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women ceased MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Conclusion Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers. PMID:19935364

  19. Identification of prenatal amphetamines exposure by maternal interview and meconium toxicology in the Infant Development, Environment and Lifestyle (IDEAL) study.

    Science.gov (United States)

    Gray, Teresa R; LaGasse, Linda L; Smith, Lynne M; Derauf, Chris; Grant, Penny; Shah, Rizwan; Arria, Amelia M; Della Grotta, Sheri A; Strauss, Arthur; Haning, William F; Lester, Barry M; Huestis, Marilyn A

    2009-12-01

    The Infant Development Environment and Lifestyle study is investigating the effects of prenatal methamphetamine (MAMP) exposure on infant and child development; potential concurrent exposure to cannabis and tobacco also are evaluated. Maternal self-reported drug use and/or meconium toxicology results defined drug exposure status. It is unclear how the frequency, duration, and magnitude of maternal MAMP exposure affect qualitative and quantitative meconium results. Interviews regarding maternal drug use were collected shortly after birth; meconium specimens were screened for amphetamines, cannabis, and cotinine by immunoassay and confirmed by gas chromatography mass spectrometry. The majority of MAMP- and cannabis-exposed infants were identified by maternal interview alone. Meconium tests were more likely to be positive if the mother reported MAMP and cannabis use, particularly in the third trimester. Less than half of immunoassay-positive amphetamines (31.0%) and cannabis (17.9%) meconium results were confirmed by gas chromatography mass spectrometry. Tobacco exposure was equally detected by immunoassay cotinine screening and maternal report. Meconium concentrations did not correlate with maternal self-report status or trimester of use or frequency or route of MAMP use. Maternal self-report was more sensitive than meconium testing for identifying MAMP and cannabis-exposed neonates; however, the timing of drug exposure may influence meconium toxicology results. Most women stopped MAMP and cannabis use before the third trimester. In the first trimester, meconium has not yet formed, and based on our recent results for opiates and cocaine, drug use in the second trimester appears to be poorly reflected in meconium. Low confirmation rates in meconium reinforce the need for confirmatory testing following positive screening results and additional research to identify alternative biomarkers.

  20. History of wildlife toxicology.

    Science.gov (United States)

    Rattner, Barnett A

    2009-10-01

    The field of wildlife toxicology can be traced to the late nineteenth and early twentieth centuries. Initial reports included unintentional poisoning of birds from ingestion of spent lead shot and predator control agents, alkali poisoning of waterbirds, and die-offs from maritime oil spills. With the advent of synthetic pesticides in the 1930s and 1940s, effects of DDT and other pesticides were investigated in free-ranging and captive wildlife. In response to research findings in the US and UK, and the publication of Silent Spring in 1962, public debate on the hazards of pollutants arose and national contaminant monitoring programs were initiated. Shortly thereafter, population-level effects of DDT on raptorial and fish-eating birds were documented, and effects on other species (e.g., bats) were suspected. Realization of the global nature of organochlorine pesticide contamination, and the discovery of PCBs in environmental samples, launched long-range studies in birds and mammals. With the birth of ecotoxicology in 1969 and the establishment of the Society of Environmental Toxicology and Chemistry in 1979, an international infrastructure began to emerge. In the 1980s, heavy metal pollution related to mining and smelting, agrichemical practices and non-target effects, selenium toxicosis, and disasters such as Chernobyl and the Exxon Valdez dominated the field. Biomarker development, endocrine disruption, population modeling, and studies with amphibians and reptiles were major issues of the 1990s. With the turn of the century, there was interest in new and emerging compounds (pharmaceuticals, flame retardants, surfactants), and potential population-level effects of some compounds. Based upon its history, wildlife toxicology is driven by chemical use and misuse, ecological disasters, and pollution-related events affecting humans. Current challenges include the need to more thoroughly estimate and predict exposure and effects of chemical-related anthropogenic

  1. Ion channels in toxicology.

    Science.gov (United States)

    Restrepo-Angulo, Iván; De Vizcaya-Ruiz, Andrea; Camacho, Javier

    2010-08-01

    Ion channels play essential roles in human physiology and toxicology. Cardiac contraction, neural transmission, temperature sensing, insulin release, regulation of apoptosis, cellular pH and oxidative stress, as well as detection of active compounds from chilli, are some of the processes in which ion channels have an important role. Regulation of ion channels by several chemicals including those found in air, water and soil represents an interesting potential link between environmental pollution and human diseases; for instance, de novo expression of ion channels in response to exposure to carcinogens is being considered as a potential tool for cancer diagnosis and therapy. Non-specific binding of several drugs to ion channels is responsible for a huge number of undesirable side-effects, and testing guidelines for several drugs now require ion channel screening for pharmaceutical safety. Animal toxins targeting human ion channels have serious effects on the population and have also provided a remarkable tool to study the molecular structure and function of ion channels. In this review, we will summarize the participation of ion channels in biological processes extensively used in toxicological studies, including cardiac function, apoptosis and cell proliferation. Major findings on the adverse effects of drugs on ion channels as well as the regulation of these proteins by different chemicals, including some pesticides, are also reviewed. Association of ion channels and toxicology in several biological processes strongly suggests these proteins to be excellent candidates to follow the toxic effects of xenobiotics, and as potential early indicators of life-threatening situations including chronic degenerative diseases.

  2. DATA MINING POTENCY ESTIMATORS FROM TOXICOLOGICAL DATABASES

    OpenAIRE

    Piegorsch, Walter W.; Simmons, Susan J.; Zeiger, Errol

    2004-01-01

    We discuss use of data mining techniques to study estimators of toxic potency (activity) in toxicological databases. The methods are slight variations on the standard data mining motif, but fit fully within the larger context of knowledge discovery in databases. An example illustrates the general theme of the approach, using results from a U.S. National Toxicology Program Salmonella mutagenicity database.

  3. Inhalation developmental toxicology studies of 1,3-butadiene in the rat: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1987-11-01

    Maternal toxicity, reproductive performance and developmental toxicology were evaluated in Sprague-Dawley-derived rats during and following 6 hours/day, whole-body, inhalation exposures to 0, 40, 200, and 1000 ppM of 1,3-butadiene. The female rats (Ns = 24 to 28), which had mated with unexposed males, were exposed to the chemical from 6 through 15 dg and sacrificed on 20 dg. Maternal animals were weighed prior to mating and on 0, 6, 11, 16 and 20 dg; the rats were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. There were no significant differences among treatment groups in maternal body weights or extragestational weights of rats exposed to 1,3-butadiene concentrations of 40 or 200 ppM, but, in animals exposed to 1000 ppM, significantly depressed body weight gains were observed during the first 5 days of exposure and extragestational weight gains tended to be lower than control values. These results, and the absence of clinical signs of toxicity, were considered to indicate that there was no maternal toxicity at exposure levels of 200 ppM or lower. The percentage of pregnant animals and the number of litters with live fetuses were unaffected by treatment. Under the conditions of this exposure regimen, there was no evidence for a teratogenic response to 1,3-butadiene exposure.

  4. 氟氯氰菊酯亚急性吸入毒性实验研究%Inhalation toxicity of cyfluthrin for 28-day repeated dose in rats

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民

    2012-01-01

    Objective To determine the inhalation toxicity and find the non -observed adverse effect level (NOAEL) of cyfluthrin for a 28-day repeated dose in rats. Methods Clean-grade SD rats were randomly divided into 5 groups with 5 females and 5 males in each. The animals inhaled DMSO or cyfluthrin at the concentration of 0, 7. 81 , 9. 05 and 18. 98 mg/m for 4 weeks (6 h/d, 5 d/w). At the end of inhalation , all the animals were kindly sacrificed. Their organs were collected for histopathological examination . Blood samples were collected for analysis of complete blood count , biochemistry and coagulation. Results The animals in 18. 98 mg/m3 group were found scratching repeatedly around the mouth, listless, fidgeting, trembling, discharging blood around the mouth and nose . However, symptoms in females were less serious than in males. Furthermore , the body mass , feed efficiency , weight of kidney of animals in this dose male group were found decreased compared with the control group . Biochemistry detection revealed that serum AST was elevated markedly in both genders of 18. 98 mg/m3 group and in males of 9. 05 mg/m3 group. No obvious abnormity was found in 7.81 mg/m3 group or control group. Conclusion Based on the results above, the non-observed adverse effect level (NOAEL) of cyfluthrin in SD rats is 7. 81 mg/m3 for 28 d repeated inhalation in this study.%目的 观察氟氯氰菊酯染毒大鼠亚急性吸入毒性.方法 7周龄清洁级SD大鼠随机分成5组,每组雌雄各5只,分别吸入氟氯氰菊酯0,7.81,9.05,18.98 mg/m3及溶剂二甲亚砜,每天6 h,每周5 d,共28 d.实验结束时取血液做常规生化指标、血细胞指标、血凝学指标检测.取心、肝、脾等8种主要脏器称重并做病理组织学检查.结果 18.98 mg/m3组动物在染毒中呈现反复抓挠口周、烦躁不安、鼻有血性分泌物、颤抖,染毒结束后呈现萎靡、蜂腰、四肢无力的体征.雌性动物的毒性表现较雄性低.与溶剂对照组相

  5. Occupational medicine and toxicology

    OpenAIRE

    2006-01-01

    Abstract This editorial is to announce the Journal of Occupational Medicine and Toxicology, a new Open Access, peer-reviewed, online journal published by BioMed Central. Occupational medicine and toxicology belong to the most wide ranging disciplines of all medical specialties. The field is devoted to the diagnosis, prevention, management and scientific analysis of diseases from the fields of occupational and environmental medicine and toxicology. It also covers the promotion of occupational ...

  6. Reproductive and developmental toxicology

    National Research Council Canada - National Science Library

    Gupta, Ramesh C

    2011-01-01

    .... Reproductive and Developmental Toxicology is a comprehensive and authoritative resource providing the latest literature enriched with relevant references describing every aspect of this area of science...

  7. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    Science.gov (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  8. Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies

    Directory of Open Access Journals (Sweden)

    Eleonore Fröhlich

    2014-03-01

    Full Text Available The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs depends on their hazard (negative action on cells and organism and on exposure (concentration in the inhaled air and pattern of deposition in the lung. With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs.

  9. Toxicological evaluation of chemical mixtures

    NARCIS (Netherlands)

    Feron, V.J.; Groten, J.P.

    2002-01-01

    This paper addresses major developments in the safety evaluation of chemical mixtures during the past 15 years, reviews today's state of the art of mixture toxicology, and discusses challenges ahead. Well-thought-out tailor-made mechanistic and empirical designs for studying the toxicity of mixtures

  10. [Application of operant conditioning techniques to forensic toxicology: experimental studies on alcohol and abusable drugs].

    Science.gov (United States)

    Hishida, S

    1996-10-01

    This paper describes some experiments that apply the operant conditioning techniques to forensic toxicological research. These techniques may be useful in investigating the mechanisms of action, toxic symptoms, legal competence and drug metabolism associated with substance abuse such as abuse of alcohol, psychotropic drugs, narcotics, stimulants, and organic solvents. 1) Genetic research on alcohol preference in rats. We applied operant conditioning to investigate alcohol preference in rats and constructed an apparatus for the measurement of discriminated operate responses for water or alcohol reinforcement in rat. This apparatus is a modified Skinner box with a one-lever two-liquid system. Fixed ratio-10 (FR-10) schedules of reinforcement are used to increase the work of the rat before it obtains the reinforcement. The voluntary choice of water or 10% ethanol by the rat can be assessed quantitatively by measuring the lever-pushing responses. It is an extremely useful method for measuring the real alcohol preference of rats. A rat was kept in a Skinner box overnight. The numbers of responses and reinforcement for water and ethanol and the volumes of the two liquids consumed were recorded. The ratio of ethanol reinforcement was defined as the number of ethanol reinforcement to the total number of ethanol and water reinforcement. The ratio of ethanol intake was defined as the volume of ethanol consumed to the volume of water and ethanol consumed. Ethanol consumption per g body weight was calculated from the volume of ethanol consumed by the rat. We used this apparatus to investigate alcohol preference of more than 300 Wistar Albino Rats, and divided them into a high alcohol preference (HAP) group and a low alcohol preference (LAP) group. Inbreeding between littermates was conducted in each of the HAP and LAP groups. The liver tissue of each offspring was obtained and the cytosol fraction was collected and subjected to isoelectric focusing using polyacrylamide gel

  11. Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

    Science.gov (United States)

    Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

    2016-01-01

    To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

  12. A New Stochastic Kriging Method for Modeling Multi-Source Exposure–Response Data in Toxicology Studies

    Science.gov (United States)

    2015-01-01

    One of the most fundamental steps in risk assessment is to quantify the exposure–response relationship for the material/chemical of interest. This work develops a new statistical method, referred to as SKQ (stochastic kriging with qualitative factors), to synergistically model exposure–response data, which often arise from multiple sources (e.g., laboratories, animal providers, and shapes of nanomaterials) in toxicology studies. Compared to the existing methods, SKQ has several distinct features. First, SKQ integrates data across multiple sources and allows for the derivation of more accurate information from limited data. Second, SKQ is highly flexible and able to model practically any continuous response surfaces (e.g., dose–time–response surface). Third, SKQ is able to accommodate variance heterogeneity across experimental conditions and to provide valid statistical inference (i.e., quantify uncertainties of the model estimates). Through empirical studies, we have demonstrated SKQ’s ability to efficiently model exposure–response surfaces by pooling information across multiple data sources. SKQ fits into the mosaic of efficient decision-making methods for assessing the risk of a tremendously large variety of nanomaterials and helps to alleviate safety concerns regarding the enormous amount of new nanomaterials. PMID:25068094

  13. A New Stochastic Kriging Method for Modeling Multi-Source Exposure-Response Data in Toxicology Studies.

    Science.gov (United States)

    Wang, Kai; Chen, Xi; Yang, Feng; Porter, Dale W; Wu, Nianqiang

    2014-07-07

    One of the most fundamental steps in risk assessment is to quantify the exposure-response relationship for the material/chemical of interest. This work develops a new statistical method, referred to as SKQ (stochastic kriging with qualitative factors), to synergistically model exposure-response data, which often arise from multiple sources (e.g., laboratories, animal providers, and shapes of nanomaterials) in toxicology studies. Compared to the existing methods, SKQ has several distinct features. First, SKQ integrates data across multiple sources and allows for the derivation of more accurate information from limited data. Second, SKQ is highly flexible and able to model practically any continuous response surfaces (e.g., dose-time-response surface). Third, SKQ is able to accommodate variance heterogeneity across experimental conditions and to provide valid statistical inference (i.e., quantify uncertainties of the model estimates). Through empirical studies, we have demonstrated SKQ's ability to efficiently model exposure-response surfaces by pooling information across multiple data sources. SKQ fits into the mosaic of efficient decision-making methods for assessing the risk of a tremendously large variety of nanomaterials and helps to alleviate safety concerns regarding the enormous amount of new nanomaterials.

  14. Prediction of the carcinogenic potential of human pharmaceuticals using repeated dose toxicity data and their pharmacological properties

    Directory of Open Access Journals (Sweden)

    Jan Willem Van Der Laan

    2016-10-01

    Full Text Available In an exercise designed to reduce animal use, we analysed the results of rat sub-chronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumour outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred and forty-three of the 239 compounds not inducing putative preneoplastic lesions in the sub-chronic study did not induce tumours in the carcinogenicity study (True Negatives - TN, whereas 96 compounds were categorised as False Negatives (FN, because tumours were observed in the carcinogenicity study. For the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumours in the carcinogenicity study (True positives - TP, and 19 only showed preneoplastic lesions in subchronic studies but no tumours in the carcinogenicity study (False positives - FP. In addition, we then re-assessed the prediction of the tumour outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN. For 67 compounds the presence of cellular hyperplasia as evidence for proliferative action could be found (TP. Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92 % and the ability to detect carcinogens at 98 %. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorised as FN. 1 as FP, thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological

  15. Toxicology ontology perspectives.

    Science.gov (United States)

    Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae

    2012-01-01

    The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework.

  16. Green Toxicology – Application of predictive toxicology

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Wedebye, Eva Bay; Taxvig, Camilla

    2014-01-01

    Humans are constantly challenged by exposure to a cocktail of chemicals that can have negative health effects, and fetuses and young children are particularly vulnerable. Therefore, we need safer chemicals in order to reduce any potential environmental and human hazards. A solid framework to design...... safer chemicals and to identify problematic compounds already in use such as industrial compounds, drugs, pesticides and cosmetics, is required. Green toxicology is the application of predictive toxicology to the production of chemicals with the specific intent of improving their design for hazard...

  17. Processing nanoparticles with A4F-SAXS for toxicological studies: Iron oxide in cell-based assays.

    Science.gov (United States)

    Knappe, Patrick; Boehmert, Linda; Bienert, Ralf; Kamutzki, Silvana; Karmutzki, Silvana; Niemann, Birgit; Lampen, Alfonso; Thünemann, Andreas F

    2011-07-01

    Nanoparticles are not typically ready-to-use for in vitro cell culture assays. Prior to their use in assays, powder samples containing nanoparticles must be dispersed, de-agglomerated, fractionated by size, and characterized with respect to size and size distribution. For this purpose we report exemplarily on polyphosphate-stabilized iron oxide nanoparticles in aqueous suspension. Fractionation and online particle size analysis was performed in a time-saving procedure lasting 50 min by combining asymmetrical flow field-flow fractionation (A4F) and small-angle X-ray scattering (SAXS). Narrowly distributed nanoparticle fractions with radii of gyration (R(g)) from 7 to 21 nm were obtained from polydisperse samples. The A4F-SAXS combination is introduced for the preparation of well-characterized sample fractions originating from a highly polydisperse system as typically found in engineered nanoparticles. A4F-SAXS processed particles are ready-to-use for toxicological studies. The results of preliminary tests of the effects of fractionated iron oxide nanoparticles with a R(g) of 15 nm on a human colon model cell line are reported.

  18. In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

    Directory of Open Access Journals (Sweden)

    Christiane Broichhausen

    2014-01-01

    Full Text Available A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

  19. Experimental water toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Andrushaytis, G.P. (ed.)

    1984-01-01

    The problem of water toxicology and marine ectoxicology, particularly in the Baltic Sea and the Gulf of Riga, are discussed. Emphasis is placed on the problem of creating artificial controlled marine ecosystems for the purpose of utilizing them in ecotoxicological studies and for solving problems in the intensification of bioproduction processes and predicting the functional state of water ecosystems under conditions of water pollution by toxic substances. Investigations were conducted on the effects of pesticides, phenols, and heavy metal ions on planktonic crustacea and fish. Studies were also concerned with the effect of gonadotoxic substances, including detergents, on the gametogenesis process in fish. Morphological changes in the ovicells of fish can lead to a reduction in the sensitivity of the receptor zones of the follicular casings to hormonal substances, as well as infertility.

  20. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    Science.gov (United States)

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  1. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

    Science.gov (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2017-09-01

    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Staack, Roland F; Maurer, Hans H

    2004-05-25

    Qualitative studies are described on the metabolism and the toxicological analysis of the nootropic fipexide (FIP) in rat urine using gas chromatography-mass spectrometry (GC-MS). FIP was extensively metabolized to 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), 4-chlorophenoxyacetic acid, 1-[2-(4-chlorophenoxy)acetyl]piperazine, N-(4-hydroxy-3-methoxy-benzyl)piperazine, piperazine, N-(3,4-methylenedioxybenzyl)ethylenediamine, and N-[2-(4-chlorophenoxy)acetyl]ethylenediamine. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis of one urine aliquot, liquid-liquid extraction and acetylation allowed the detection of FIP via its metabolites in rat urine after administration of a common FIP dose. Therefore, this qualitative procedure should also be suitable for detection of a FIP intake in human urine. Differentiation of an intake of FIP from that of other drugs which form common metabolites is discussed.

  3. Transcriptome–metabolome wide association study (TMWAS of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism

    Directory of Open Access Journals (Sweden)

    James R. Roede

    2014-01-01

    Full Text Available A combination of the herbicide paraquat (PQ and fungicide maneb (MB has been linked to Parkinson's disease. Previous studies show that this involves an additive toxicity with at least two different mechanisms. However, detailed understanding of mixtures is often difficult to elucidate because of the multiple ways by which toxic agents can interact. In the present study, we used a combination of transcriptomics and metabolomics to investigate mechanisms of toxicity of PQ and MB in a neuroblastoma cell line. Conditions were studied with concentrations of PQ and MB that each individually caused 20% cell death and together caused 50% cell death. Transcriptomic and metabolomic samples were collected at time points prior to significant cell death. Statistical and bioinformatic methods were applied to the resulting 30,869 transcripts and 1358 metabolites. Results showed that MB significantly changed more transcripts and metabolites than PQ, and combined PQ + MB impacted more than MB alone. Transcriptome–metabolome-wide association study (TMWAS showed that significantly changed transcripts and metabolites mapped to two network substructures, one associating with significant effects of MB and the other included features significantly associated with PQ + MB. The latter contained 4 clusters of genes and associated metabolites, with one containing genes for two cation transporters and a cation transporter regulatory protein also recognized as a pro-apoptotic protein. Other clusters included stress response genes and transporters linked to cytoprotective mechanisms. MB also had a significant network structure linked to cell proliferation. Together, the results show that the toxicologic mechanism of the combined neurotoxicity of PQ and MB involves network level interactions and that TMWAS provides an effective approach to investigate such complex mechanisms.

  4. GENOMIC ADAPTATION OF THE EMBRYONIC STEM CELL TEST (EST) FOR A TOXICOLOGICAL STUDY OF DRINKING WATER DISINFECTION BY-PRODUCTS

    Science.gov (United States)

    Among the many promised and potential applications of embryonic stem cells, in vitro toxicology is one area in which ES cells have already proven their utility. In 2003, the Embryonic Stem Cell Test (EST) protocol was validated in Europe as an in vitro alternative to live animal...

  5. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R

    1998-07-01

    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  6. Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180 in adult rats.

    Directory of Open Access Journals (Sweden)

    Matti Viluksela

    Full Text Available PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares

  7. Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.

    Science.gov (United States)

    Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T M; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

    2014-01-01

    PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological

  8. Toxicology research for precautionary decision-making and the role of Human & Experimental Toxicology

    DEFF Research Database (Denmark)

    Grandjean, P

    2015-01-01

    existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology......A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other...... being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published...

  9. The male peripubertal phase as a developmental window for reproductive toxicology studies.

    Science.gov (United States)

    Perobelli, Juliana Elaine

    2014-01-01

    The normal development of the male reproductive system can be divided into five phases: fetal, neonatal, childhood, puberty and adulthood. Childhood/peripuberty has yet been relatively little studied. Chemical insults during the peripubertal phase may result in adverse consequences that may be already visible during puberty as well as during later adult life. This occurs because endocrine disruptors often interfere in the developmental programming. The most important is to note that children are not just little adults and should be particularly investigated. The aim of this review is to discuss the recent literature (2000-2013) on male reproductive aspects in prepubertal toxicity assays, focusing on experimental in vivo studies, establishing a comparative analysis between the design, endpoints, results and consequent conclusion. The studies discussed in the present review were selected based on the period of exposure. Only studies with post-lactational exposures were included. 33 papers were included using rats, mice, rabbits or pigs as experimental model. There is a relative scarcity of studies investigating animals in development and thus an urgent need for further studies in order to evaluate the possible persistent effects on fertility and other reproductive parameters at adulthood. Another point is the lack of studies with chemical mixtures, an imminent problem in modern society. It is vital to consider the refinement of alternative methods and the experimental designs and endpoints to improve the scientific knowledge in this area.

  10. ToxEvaluator: an integrated computational platform to aid the interpretation of toxicology study-related findings.

    Science.gov (United States)

    Pelletier, D; Wiegers, T C; Enayetallah, A; Kibbey, C; Gosink, M; Koza-Taylor, P; Mattingly, C J; Lawton, M

    2016-01-01

    Attempts are frequently made to investigate adverse findings from preclinical toxicology studies in order to better understand underlying toxicity mechanisms. These efforts often begin with limited information, including a description of the adverse finding, knowledge of the structure of the chemical associated with its cause and the intended pharmacological target. ToxEvaluator was developed jointly by Pfizer and the Comparative Toxicogenomics Database (http://ctdbase.org) team at North Carolina State University as an in silico platform to facilitate interpretation of toxicity findings in light of prior knowledge. Through the integration of a diverse set of in silico tools that leverage a number of public and proprietary databases, ToxEvaluator streamlines the process of aggregating and interrogating diverse sources of information. The user enters compound and target identifiers, and selects adverse event descriptors from a safety lexicon and mapped MeSH disease terms. ToxEvaluator provides a summary report with multiple distinct areas organized according to what target or structural aspects have been linked to the adverse finding, including primary pharmacology, structurally similar proprietary compounds, structurally similar public domain compounds, predicted secondary (i.e. off-target) pharmacology and known secondary pharmacology. Similar proprietary compounds and their associated in vivo toxicity findings are reported, along with a link to relevant supporting documents. For similar public domain compounds and interacting targets, ToxEvaluator integrates relationships curated in Comparative Toxicogenomics Database, returning all direct and inferred linkages between them. As an example of its utility, we demonstrate how ToxEvaluator rapidly identified direct (primary pharmacology) and indirect (secondary pharmacology) linkages between cerivastatin and myopathy.

  11. Techniques for Investigating Molecular Toxicology of Nanomaterials.

    Science.gov (United States)

    Wang, Yanli; Li, Chenchen; Yao, Chenjie; Ding, Lin; Lei, Zhendong; Wu, Minghong

    2016-06-01

    Nanotechnology has been a rapidly developing field in the past few decades, resulting in the more and more exposure of nanomaterials to human. The increased applications of nanomaterials for industrial, commercial and life purposes, such as fillers, catalysts, semiconductors, paints, cosmetic additives and drug carriers, have caused both obvious and potential impacts on human health and environment. Nanotoxicology is used to study the safety of nanomaterials and has grown at the historic moment. Molecular toxicology is a new subdiscipline to study the interactions and impacts of materials at the molecular level. To better understand the relationship between the molecular toxicology and nanomaterials, this review summarizes the typical techniques and methods in molecular toxicology which are applied when investigating the toxicology of nanomaterials and include six categories: namely; genetic mutation detection, gene expression analysis, DNA damage detection, chromosomal aberration analysis, proteomics, and metabolomics. Each category involves several experimental techniques and methods.

  12. TOXNET: Toxicology Data Network

    Science.gov (United States)

    ... for over 600 chemicals from authoritative groups worldwide Animal Testing Alternatives ALTBIB Resources on Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing Archived, No Longer Updated ... cancer tests (1980-2011) GENE-TOX Genetic Toxicology ...

  13. Occupational medicine and toxicology

    Directory of Open Access Journals (Sweden)

    Fischer Axel

    2006-02-01

    Full Text Available Abstract This editorial is to announce the Journal of Occupational Medicine and Toxicology, a new Open Access, peer-reviewed, online journal published by BioMed Central. Occupational medicine and toxicology belong to the most wide ranging disciplines of all medical specialties. The field is devoted to the diagnosis, prevention, management and scientific analysis of diseases from the fields of occupational and environmental medicine and toxicology. It also covers the promotion of occupational and environmental health. The complexity of modern industrial processes has dramatically changed over the past years and today's areas include effects of atmospheric pollution, carcinogenesis, biological monitoring, ergonomics, epidemiology, product safety and health promotion. We hope that the launch of the Journal of Occupational Medicine and Toxicology will aid in the advance of these important areas of research bringing together multi-disciplinary research findings.

  14. Ethical implications of using the minipig in regulatory toxicology studies

    DEFF Research Database (Denmark)

    Webster, John; Bollen, Peter; Grimm, Herwig

    2010-01-01

    in studies designed for safety assessment. On this basis we rejected the argument that minipigs are more acceptable experimental animals than dogs or monkeys despite the fact that their use may prove less offensive to some groups within society at large. Species selection must be made on a case-by-case basis...

  15. The rodent estrous cycle: Characterization of vaginal cytology and its utility in toxicological studies

    Science.gov (United States)

    An evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic-pituitary-ovarian reproductive axis. It can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are disincluded from a study prior t...

  16. Inhalation developmental toxicology studies: Developmental toxicity of chloroprene vapors in New Zealand white rabbits. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1994-04-01

    Chloroprene, 2-chloro-1,3-butadiene, is a colorless liquid with a pungent ethereal odor that is primarily used as an intermediate in the manufacture of neoprene rubber, and has been used as such since about 1930. This study addressed the potential for chloroprene to cause developmental toxicity in New Zealand white rabbits following gestational exposure to 0, 10, 40, or 175 ppm chloroprene vapors, 6h/dy, 7dy/wk. Each treatment group consisted of 15 artificially inseminated females exposed on 6 through 28 days of gestation (dg). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 29 dg. Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. There were no overt signs of maternal toxicity and the change in maternal body weight over the course of the study was not affected. Exposure of pregnant rabbits to chloroprene vapors on 6-28 dg had no effect on the number of implantation, the mean percent of live pups per litter, or on the incidence of resorptions per litter. The incidence of fetal malformations was not increased by exposure to chloroprene. Results of this study indicate that gestational exposure of New Zealand white rabbits to 10, 40, or 175 ppm chloroprene did not result in observable toxicity to either the dam or the offspring.

  17. Preclinical toxicology studies with the new dopamine agonist pergolide. Acute, subchronic, and chronic evaluations.

    Science.gov (United States)

    Francis, P C; Carlson, K H; Owen, N V; Adams, E R

    1994-03-01

    Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treatment of Parkinson's disease, was evaluated for toxicity in acute, subchronic, and chronic studies. Acute toxicity tests using oral, intravenous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in rabbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for ICR mice. The predominant signs of toxicity in the acute studies included hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs were administered pergolide either by gavage or in the diet for up to 1 year. Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-related effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clinical signs in rats and dogs, weight loss or decreased weight gain, emesis in dogs, and inhibition of lysis of corpora lutea with a corresponding increase in the weight of the uterus and ovaries. Pergolide treatment was not associated with any specific target organ toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Health environmental risks surveillance systems: toxicological surveillance

    OpenAIRE

    Ana Ferrer Dufol; Santiago Nogué Xarau; Francisco Vargas Marcos; Olivia Castillo Soria; Pilar Gascó Alberich; Ana de la Torre Reoyo; Eduardo de la Peña de Torres

    2004-01-01

    A study of the Clinical Toxicological Section, about the Epidemiological Surveillance in Emergency Services, in relation to chemical products intoxications during the 1999-2003 period, is presented. This work is a result of an agreement between the Spanish Toxicological Association (AETOX) and the Spanish Ministry of Health and Consumption, and was presented in the National Congress of Environment (CONAMA) within the “Health Environmental Risks Surveillance Systems” working group.

  19. Response to the society of toxicology task force re-examination of the ED01 study.

    Science.gov (United States)

    Kodell, R L; Gaylor, D W; Greenman, D L; Littlefield, N A; Farmer, J H

    1983-01-01

    This communication has re-examined and justified certain of the NCTR's analyses and recommendations from the ED01 Study, which were either misunderstood or misinterpreted by the SOT Task Force. In addition, we have shown that some of the Task Force's own analyses and interpretations are subject to review on scientific grounds. The Task Force's rejection of the linear extrapolation method recommended by the NCTR was stated because of a suspected force-fitting of a linear model to data, an approach that is not part of the NCTR procedure. In suspecting a protective effect of 2-AAF against bladder tumors, the Task Force used an inappropriate model that overpredicted the background bladder tumor rate in control mice. Contrary to the Task Force's belief, a failure to account adequately for time to tumor response was more characteristic of analyses performed by the Task Force rather than those performed by the NCTR. The Task Force's questioning of the multistage model for risk assessment was based on its use of inappropriate, crude tumor data rather than upon NCTR's use of the multistage model with time-adjusted tumor data. The Hartley-Sielken model did not fit the ED01 tumor data as well as the Task Force had presumed. In a risk extrapolation comparison by the Task Force, a coarse time partition of the ED01 data that had been questioned by the Task Force actually produced more stable results than a finer partition proposed by the Task Force. Another problem in the Task Force report concerns the change of protocol. Instead of resulting in a loss of strength as anticipated by the Task Force, the change of protocol during the ED01 Study resulted in an increase in information as alluded to by the Task Force. If the Task Force's proposal for restricting the length of feeding studies had been followed in the ED01 Study, most of the dose related tumor information would not have been obtained. Also, the Task Force's belief that low doses of 2-AAF had some effect on the

  20. Toxicology Study of Single-walled Carbon Nanotubes and Reduced Graphene Oxide in Human Sperm

    OpenAIRE

    2016-01-01

    Carbon-based nanomaterials such as single-walled carbon nanotubes and reduced graphene oxide are currently being evaluated for biomedical applications including in vivo drug delivery and tumor imaging. Several reports have studied the toxicity of carbon nanomaterials, but their effects on human male reproduction have not been fully examined. Additionally, it is not clear whether the nanomaterial exposure has any effect on sperm sorting procedures used in clinical settings. Here, we show that ...

  1. Sauropus androgynus (L.) Merr. Induced Bronchiolitis Obliterans: From Botanical Studies to Toxicology

    OpenAIRE

    Hamidun Bunawan; Siti Noraini Bunawan; Syarul Nataqain Baharum; Normah Mohd Noor

    2015-01-01

    Sauropus androgynus L. Merr. is one of the most popular herbs in South Asia, Southeast Asia, and China where it was known as a slimming agent until two outbreaks of pulmonary dysfunction were reported in Taiwan and Japan in 1995 and 2005, respectively. Several studies described that the excessive consumption of Sauropus androgynus could cause drowsiness, constipation, and bronchiolitis obliterans and may lead to respiratory failure. Interestingly, this herb has been used in Malaysia and Indon...

  2. Mammalian Toxicology Testing: Problem Definition Study, AMTR Protocol/Pricing Report.

    Science.gov (United States)

    1981-04-01

    and water must be provided ad used in the reproductive study. Strains cesarean section approximately I day libitum. Pregnant females must be with low...justification for not providing such specific stain tested must be submitted. be sacrificed at time of cesarean section material must be submitted...This approach allows for comparisons of costs between various performance alternatives and uses a standardized pricing approach that can be updated

  3. Biochemical and toxicological studies of aqueous extract of Syzigium aromaticum (L.) Merr. & Perry (Myrtaceae) in rodents.

    Science.gov (United States)

    Agbaje, E O; Adeneye, A A; Daramola, A O

    2009-05-07

    The effects of long-term administration of boiled aqueous extract of Syzigium aromaticum (SYZ), commonly known as clove (which has been locally employed for treating gastrointestinal tract diseases and also used as food spices), on some biochemical indices, such as body weight, liver functions and blood parameters were studied in adult albino rats of both sexes. Selected doses of 300 and 700 mg kg(-1) were given orally through cannular to groups of animals for a period of 90 days, while the control group received distilled water throughout the duration of study via the same route. Blood samples collected after therapy and assayed for activities of some liver enzymes recorded a significant (p<0.05) and prominent effect on ALP and AST. Measurement of haematological parameters also revealed significant effects (p<0.05; p<0.001) on Hb, RBC (p<0.05), PCV (p<0.001), platelets (p<0.001) and granulocytes (p<0.001). An insignificant reduction was recorded for total WBC. The histopathological study conducted was in consonance with the results of the biochemical investigations that the aqueous extract of SYZ even at moderate doses, significantly affects body organs, their enzymes as well as the various functions. LD(50) for both intraperitoneal and oral routes of SYZ were 263 and 2500 mg kg(-1) respectively. The present work has revealed the toxicity of sub chronic administration of SYZ, which suggests that its prolonged usage must be avoided.

  4. Toxicological studies on the purified protoberberine alkaloidal fraction of Enantia chlorantha Oliv (ANNONACEAE).

    Science.gov (United States)

    Moody, J O; Ogundipe, O D; Akang, E U U; Agbedana, E O

    2007-12-01

    We have examined the cumulative effects of the protoberberine alkaloidal fraction (AF) of the stein bark ethanolic extracts of Enantia chlorantha on some body tissues and organs as well as on certain biochemical and metabolic parameters in mice. Acute and sub-chronic toxicity studies of the alkaloidal fractions of Enantia chlorantha were carried out in 120 mice using oral and intraperitoneal administrations. Fatality was not recorded in mice injected intraperitonealy with 100 mg kg(-1) and 150 mg kg(-1) dose level but larger doses resulted in death and the mean lethal dose (LD50) toxicity studies showed neither behavioural/untoward reactions nor death in any of the animals. The histopathological examination of the test animals when compared with the control revealed that, the sub-chronic use of the alkaloidal fractions does not have any pathological effects (lesion) on the organs examined (the stomach, the kidney, the oesophagus and the liver) except the lungs which showed mild and moderate oedema. The biochemical and metabolic analysis of the mice plasma did not show any significant difference when the corresponding values for the test mice were compared with the control mice (P > 0.05) at the end of the 14 days treatment using both 20 mg kg(-1) and 2 mg kg(-1) dose levels. The results obtained in this study suggest the relative safety of short-term use of preparations containing E. chlorantha, a very popular antimalarial herbal remedy in Southern Nigeria.

  5. Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

    Science.gov (United States)

    Rajendran, Narayanan; Hu, Shu-Chieh; Sullivan, Dennis; Muzzio, Miguel; Detrisac, Carol J; Venezia, Carmen

    2012-12-01

    The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

  6. Toxicological impact studies based on Escherichia coli bacteria in ultrafine ZnO nanoparticles colloidal medium.

    Science.gov (United States)

    Brayner, Roberta; Ferrari-Iliou, Roselyne; Brivois, Nicolas; Djediat, Shakib; Benedetti, Marc F; Fiévet, Fernand

    2006-04-01

    We report here preliminary studies of biocidal effects and cellular internalization of ZnO nanoparticles on Escherichia coli bacteria. ZnO nanoparticles were synthesized in di(ethylene glycol) (DEG) medium by forced hydrolysis of ionic Zn2+ salts. Particle size and shape were controlled by addition of small molecules and macromolecules such as tri-n-octylphosphine oxide, sodium dodecyl sulfate, polyoxyethylene stearyl ether, and bovine serum albumin. Transmission electron microscopy (TEM) and X-ray diffraction analyses were used to characterize particle structure, size, and morphology. Bactericidal tests were performed in Luria-Bertani medium on solid agar plates and in liquid systems with different concentrations of small and macromolecules and also with ZnO nanoparticles. TEM analyses of bacteria thin sections were used to study biocidal action of ZnO materials. The results confirmed that E. coli cells after contact with DEG and ZnO were damaged showing a Gram-negative triple membrane disorganization. This behavior causes the increase of membrane permeability leading to accumulation of ZnO nanoparticles in the bacterial membrane and also cellular internalization of these nanoparticles.

  7. Status of study on biological and toxicological effects of nanoscale materials

    Institute of Scientific and Technical Information of China (English)

    WANG; Bing; FENG; Weiyue; ZHAO; Yuliang; XING; Gengmei; CH

    2005-01-01

    Because the physical and chemical properties of nanosized materials mostly differ from the existing microsized materials, their potential impacts on human health and the environment will be topics under the serious discussions in press and in a number of international scientific journals. We analyze and summarize the existing data of the experimental study on the biological activities and adverse effects of nanoscale materials/particles including single wall carbon nanotubes, multi wall carbon nanotubes, titanium oxide and iron powders. Though some biological behaviors of nanoscale materials observed cannot be understood on the basis of the current knowledge, as the existing data are mostly preliminary, it is too early to make some exclusive conclusions on biological activities (or the toxicity) of any of nanoscale materials. The experimental techniques, the current topics, and the future research directions for this new research field are also discussed.

  8. TOXICOLOGICAL STUDIES AND CYTOTOXIC ACTIVITY OF ETHANOL AND ETHYL ACETATE EXTRACTS OF TECOMARIA CAPENSIS LEAVES

    Directory of Open Access Journals (Sweden)

    E. Tamil Jothi

    2013-06-01

    Full Text Available In the present study ethyl acetate and ethanol extracts of leaves of Tecomaria capensis was screened for cytotoxic activity. The cytotoxic activity was performed by two models. One was short term cytotoxicity and another was long term cytotoxicity. In short term cytotoxicity assay Dalton’s lymphoma ascites (DLA and Ehrlich ascites carcinoma (EAC cell lines were used and for long term L929 cell lines (Lungs fibroblast were used. In both methods ethyl acetate and ethanol extracts showed protective action against the cell lines. Comparing both extracts, ethanol extract has shown better cytotoxic activity than the ethyl acetate extract and in comparison of standard both extracts have moderate cytotoxic activity.

  9. Toxicology Study of Single-walled Carbon Nanotubes and Reduced Graphene Oxide in Human Sperm

    Science.gov (United States)

    Asghar, Waseem; Shafiee, Hadi; Velasco, Vanessa; Sah, Vasu R.; Guo, Shirui; El Assal, Rami; Inci, Fatih; Rajagopalan, Adhithi; Jahangir, Muntasir; Anchan, Raymond M.; Mutter, George L.; Ozkan, Mihrimah; Ozkan, Cengiz S.; Demirci, Utkan

    2016-08-01

    Carbon-based nanomaterials such as single-walled carbon nanotubes and reduced graphene oxide are currently being evaluated for biomedical applications including in vivo drug delivery and tumor imaging. Several reports have studied the toxicity of carbon nanomaterials, but their effects on human male reproduction have not been fully examined. Additionally, it is not clear whether the nanomaterial exposure has any effect on sperm sorting procedures used in clinical settings. Here, we show that the presence of functionalized single walled carbon nanotubes (SWCNT-COOH) and reduced graphene oxide at concentrations of 1–25 μg/mL do not affect sperm viability. However, SWCNT-COOH generate significant reactive superoxide species at a higher concentration (25 μg/mL), while reduced graphene oxide does not initiate reactive species in human sperm. Further, we demonstrate that exposure to these nanomaterials does not hinder the sperm sorting process, and microfluidic sorting systems can select the sperm that show low oxidative stress post-exposure.

  10. TOXICOLOGICAL STUDIES OF THE AQUEOUS EXTRACT FROM BRILLANTAISIA VOGELIANA (NÉES BENTH. (ACANTHACEAE

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    Aimé Valère SOH OUMBE

    2012-08-01

    Full Text Available Brillantaisia vogeliana (Acanthaceae is used in folk medicine in the West region of Cameroon to manage obesity. In this study, we investigated the toxic effect of the aqueous extract of B.v. in rats. Three doses of aqueous extract (250, 500, 1000 mg/kg were administrated orally once per 2 days during a period of 28 days and different hematology, biochemistry and histopatology parameters were determined. The results showed that there were no mortality, no significant differences in the body and relative organ weight between control and treated animals, except for the kidney. Hematological analysis showed no significant difference in any of the parameters examined (WBC count, platelet, RBC count, hematocrit, total leucocyte count and hemoglobin estimation between control and treated groups. There were also no significant change in blood chemistry parameters, including creatinine, urea nitrogen (UN, alkaline phosphatase, aspartate amino transferase (ASAT, calcium, alpha amylase, total protein and phosphorus, except alanine aminotransferase (ALAT between control and treated groups. Histopathological abnormalities changes were detected in organs of animals treated with various doses of product.

  11. Development of in vitro models for cellular and molecular studies in toxicology and chemoprevention

    Energy Technology Data Exchange (ETDEWEB)

    Mace, K.; Offord, E.A.; Harris, C.C.; Pfeifer, A.M.A. [Nestle Research Center, Lausanne (Switzerland)

    1998-12-31

    Many natural dietary phytochemicals found compounds found in fruits, vegetables, spices and tea have been shown in recent years to be protective against cancer in various animal models. In the light of the potential impact of these compounds on human health it is important to elucidate the mechanisms involved. We therefore developed and characterized relevant in vitro models using immortalized human epithelial cell lines derived from target tissues in carcinogenesis, such as lung, liver and colon. Assays were established, allowing the evaluation of the cytotoxic and genotoxic effects of various procarcinogens, including nitrosamines, mycotoxins and heterocyclic amines on these metabolically-competent human epithelial cell lines. These cellular models appeared to be a useful tool to study the capacity of certain food components to block the initiation stage of carcinogenesis. The ability of carnosol and carnosic acid from rosemary as well as the synthetic dithiolethione, oltipraz, to block the formation of DNA adducts, and their effects on the expression of phase I and phase II enzymes was investigated. We have observed that both rosemary extracts and oltiprax inhibited benzo(a)pyrene- or aflatoxin B{sub 1}-induced DNA adduct formation by strongly inhibiting CYP{sub 450} activities and inducing the expression of glutathione S-transferase. These results in human cell models give some insight into the different mechanisms involved in the chemopreventive action of both natural and synthetic compounds in relation to phase I and phase II enzymes. (orig.)

  12. Development of Nutraceutical Emulsions as Risperidone Delivery Systems: Characterization and Toxicological Studies.

    Science.gov (United States)

    Igartúa, Daniela Edith; Calienni, María Natalia; Feas, Daniela Agustina; Chiaramoni, Nadia Silvia; Valle Alonso, Silvia Del; Prieto, María Jimena

    2015-12-01

    Emulsions are gaining increasing interest to be applied as drug delivery systems. The main goal of this work was the formulation of an oil/water nutraceutical emulsion (NE) for oral administration, enriched in omega 3 (ω3) and omega 6 (ω6), and able to encapsulate risperidone (RISP), an antipsychotic drug widely used in the treatment of autism spectrum disorders (ASD). RISP has low solubility in aqueous medium and poor bioavailability because of its metabolism and high protein binding. Coadministration of ω3, ω3, and vitamin E complexed with RISP might increase its bioavailability and induce a synergistic effect on the treatment of ASD. Here, we developed an easy and quick method to obtain NEs and then optimized them. The best formulation was chosen after characterization by particle size, defects of the oil-in-water interface, zeta potential (ZP), and in vitro drug release. The formulation selected was stable over time, with a particle size of around 3 μm, a ZP lower than -20 mV and controlled drug release. To better understand the biochemical properties of the formulation obtained, we studied in vitro toxicity in the Caco-2 cell line. After 4 h of treatment, an increase in cellular metabolism was observed for all RISP concentrations, but emulsions did not change their metabolic rate, except at the highest concentration without drug (25 μg/mL), which showed a significant reduction in metabolism respect to the control. Additionally, locomotor activity and heart rate in zebrafish were measured as parameters of in vivo toxicity. Only the highest concentration (0.625 μg/mL) showed a cardiotoxic effect, which corresponds to the decrease in spontaneous movement observed previously. As all the materials contained in the formulations were US FDA approved, the NE selected would be good candidate for clinical trials.

  13. Toxicological study on aqueous extract of Allanblackia froribunda (Clusiaceae on rats

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    Dieudonn and eacute; Massoma Lemb and egrave;

    2013-02-01

    Full Text Available Aim: The acute and sub-acute toxic effects of aqueous extract of Allanblackia froribunda (Clusiaceae were studied in rats. Methods: The acute toxicity was carried out orally with 0, 14, 16, 18 and 20 g kg-1 b/w and intraperitoneally with 0, 50, 100, 150, 200 mg kg-1 body weight, while the subacute was only carried out orally with 0(distilled water, 400, 500 and 600 mg kg-1 b/w for four weeks. Results: In acute test, the oral administration did not cause any death treatment related signs. The LD50 estimated to be 125 mg kg-1 (Intraperitoneal route. We noted a decrease in food, water consumption and body weight of treated animals. Diarrhea occurred in rats at dose 150 mg kg-1. Analysis of serum showed an increase in ALT at dose 50 mg kg-1 (p <0.05 and serum creatinine at doses 50 and 100 mg kg-1 (p <0.05 and p <0.01 respectively while serum proteins decreased at dose 100 mg kg-1 (p <0.001. The histological changes of the main target organs (liver and lung were observed while section of kidney and gonads remained normal (data not shown. In subacute treatment, neither significant difference was observed on body weight, food and water consumption nor organs and haematological parameters. The biochemical analysis showed that the level of ALT dose dependently decreased (p <0.01 at all doses in male and female while tissue creatinine decreased (p <0.05 only in female. Conclusion: These results suggest that the extract does not present danger orally, but parenteral administration is not recommended. [J Intercult Ethnopharmacol 2013; 2(1.000: 23-28

  14. Toxicological studies for some agricultural waste extracts on mosquito larvae and experimental animals

    Institute of Scientific and Technical Information of China (English)

    Somia El-Maghraby; Galal A Nawwar; Reda FA Bakr; Nadia Helmy; Omnia MHM Kamel

    2012-01-01

    Objective: To evaluate some agricultural waste extracts as insecticide and their effects on enzyme activities in liver and kidney of male mice. Methods: The insecticidal activity of five tested compounds (one crude extract and 4 waste compounds) was bioassay against the 3rd instars of the Culex pipiens (Cx. pipiens) larvae in the laboratory. The LC50 values of eucalyptol, apricot kernel, Rice bran, corn, black liquor and white liquor are 91.45, 1 166.1, 1 203.3, 21 449.65, 4 025.78 and 6 343.18 ppm, respectively. Selection of the compounds for the subsequent studies was not only dependent on LC50 values but also on the persistence of these wastes products on large scale. Results:White and black liquor did not produce any gross effect at 200 mg/Kg body weight. No apparent toxic symptoms were observed in tested animals during the whole period of the experiment which run out for 14 days. No statistically significance was observed in the enzyme cholinesterase activity, the activities of liver enzymes and kidney function in treated mice with black and white liquors. While, no and slight inhibition was observed after the 2 weeks of treatment period with deltamethrin and fenitrothion reached to about 24%in plasma cholinesterase enzyme activity. Significantly increase in the activities of liver enzymes and kidney function in treated mice with deltamethrin and fenitrothion. Conclusions:Black liquor can be used efficiently to control Cx. pipiens larvae under laboratory condition. Environmental problem caused by rice straw can be solved by converting the waste material to beneficial natural selective insecticide.

  15. Tissue-specific toxicological effects of cadmium in green mussels (Perna viridis): nuclear magnetic resonance-based metabolomics study.

    Science.gov (United States)

    Wu, Huifeng; Wang, Wen-Xiong

    2011-04-01

    Toxicity tests for metals have traditionally focused on selected biomarkers to characterize the biological stress induced by metals in marine organisms. Here nuclear magnetic resonance (NMR)-based metabolomics, a system biology tool, was applied to the marine green mussel, Perna viridis, to investigate the toxicological effects of Cd in both digestive gland and adductor muscle tissues. After Cd exposure for either two or four weeks, there was no significant metabolic change in the mussels exposed to Cd at 2 µg/L. At 20 µg/L, there were major metabolite changes related to amino acids, osmolytes, and energy metabolites. Digestive gland tissue was more sensitive to Cd than adductor muscle tissue. The adductor muscle tissue showed elevated levels of glutamine, glutamate, and lactate, and reduced levels of branched chain amino acids, aspartate, phenylalanine, and tyrosine. Overall, four weeks of Cd exposure produced neurotoxicity and metabolic disturbances and disturbed osmoregulation. These results suggest that the adductor muscle tissue of mussels may be a suitable supplemental biomarker for exposure to toxicants. In addition, the results demonstrate that (1) H-NMR-based metabolomic analysis can provide a systematic view of the toxicological effects of metals on mussels, suggesting that it might be employed to investigate the toxicological effects of other marine pollutants. Copyright © 2011 SETAC.

  16. Unexpected Toxicology Findings in Rats Dosed With an Antihuman IL-13 Monoclonal Antibody.

    Science.gov (United States)

    Martin, Pauline L; Nnane, Ivo P; Branigan, Patrick; Louden, Calvert

    2015-01-01

    Interleukin 13 (IL-13) is a type 2 helper T cytokine involved in allergic inflammation and immune responses to parasites. CNTO5825 is an antihuman IL-13 monoclonal antibody that inhibits the pharmacological activity of human, cynomolgus monkey, and rat IL-13. Repeated dose toxicology studies of 1- to 6-month duration were conducted in both rats and monkeys at doses of 20 to 100 mg/kg/wk. A decrease in the T cell-dependent antibody response to Keyhole Limpet Hemocyanin immunization was observed in monkeys but not in rats. In the 6-month rat study, there was a 2.2-fold increase in eosinophils in males at 3 and 6 months that was reversible. At necropsy (main and 4-month recovery), rats from control and CNTO5825-dosed groups were found to have pin worms, which may have contributed to the elevations in eosinophil. Testicular toxicity (dilatation of seminiferous tubules, atrophy, and degeneration of the germinal epithelium) was observed in 2 rats at 20 mg/kg and in 5 rats at 100 mg/kg (main and recovery). Brain lesions (unilateral focal accumulation of cells in the white matter of the cerebral cortex) were observed in 2 rats at 100 mg/kg, and vascular neoplasms (1 fatal multicentric hemangiosarcoma and 1 benign hemangioma) were observed at 100 mg/kg/wk. Overall, these studies show that CNTO5825 was without toxicity when administered to rats for up to 6 weeks and to monkeys for up to 6 months. However, when administered to rats for 6 months, a number of seemingly unrelated events occurred that could not be clearly linked to CNTO5825 administration, inhibition of IL-13, or to the immunological status of the animals.

  17. Toxicology of melatonin.

    Science.gov (United States)

    Guardiola-Lemaître, B

    1997-12-01

    Despite the fact that melatonin has been released for public use in the United States by the Food and Drug Administration and is available over the counter nationwide, there currently is a total lack of information on the toxicology of melatonin. In Europe, melatonin has a completely different status in that it is considered a "neurohormone" and cannot be sold over the counter. Even though administration of melatonin in humans, as well as in animals (even at supraphysiological doses), has not shown evidence of toxicological effects (i.e., no deaths), a drug toxicological file still would need to be prepared and approved by the regulatory authorities. Several features that are specific to this neurohormone need to be taken into consideration. Whatever the species concerned, melatonin is secreted during the night; it is the "hormone of darkness." It presents a circadian rhythm and a circannual rhythm (in photoperiodic species). The duration of these secretions could have an impact on the reproductive system, for example, showing the importance of the pharmacodynamics of melatonin. An inappropriate time schedule of melatonin administration could induce supraphysiological concentrations of the neurohormone and a desensitization of melatonin receptors. A long duration of exposure to melatonin also could mimic an "artificial darkness" condition when a circadian rhythm with a basal zero level during the day needs to be conserved for a physiological function. Furthermore, administration of large doses of melatonin could induce high concentrations of melatonin and of different metabolites that could have deleterious effects per se. Numerous books, magazines, and articles have praised melatonin as a "miraculous cure-all" for ailments ranging from sleeplessness, to aging, without any clinical evidence of efficacy (with the exception of its chronobiotic and resynchronizing effect). Very little attention has been paid to the possible side effects of melatonin. Nightmares

  18. [Clinical toxicology of the Academy: yesterday, today and tomorrow].

    Science.gov (United States)

    Sofronov, G A; Khalimov, Iu Sh; Matveev, S Iu; Kuz'mich, V G; Fomichev, A V

    2013-12-01

    National toxicology school of the Kirov Military Medical Academy, demonstrates the unity of clinical and experimental approaches related to one purpose throughout its history--saving human life and health from exposure to toxic substances of chemical nature. For more than three centuries the russian science of toxicology has been steadily developing, often ahead of the world science. It helped to create the means of protection and develop methods of treatment for chemical lesions. Currently, toxicology departments of military field therapy and military toxicology and medical protection are actively involved in the current study of military medicine, restructuring policy to provide toxicological aid in the Armed Forces, the development and introduction of Innovative methods of diagnosis and treatment of victims of toxicological etiology.

  19. Shuttle Lesson Learned - Toxicology

    Science.gov (United States)

    James, John T.

    2010-01-01

    This is a script for a video about toxicology and the space shuttle. The first segment is deals with dust in the space vehicle. The next segment will be about archival samples. Then we'll look at real time on-board analyzers that give us a lot of capability in terms of monitoring for combustion products and the ability to monitor volatile organics on the station. Finally we will look at other issues that are about setting limits and dealing with ground based lessons that pertain to toxicology.

  20. Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties

    Directory of Open Access Journals (Sweden)

    Monika Batke

    2016-09-01

    Full Text Available 1.AbstractInterest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g. the European Union´s Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the project presented in this publication was to develop substance categories for a read-across with complex endpoints of toxicity based on existing databases. The basic conceptual approach was to combine structural similarity with shared mechanisms of action. Substances with similar chemical structure and toxicological profile form candidate categories suitable for read-across. We combined two databases on repeated dose toxicity, RepDose database and ELINCS database to form a common database for the identification of categories. The resulting database contained physicochemical, structural and toxicological data, which were refined and curated for cluster analyses. We applied the Predictive Clustering Tree (PCT approach for clustering chemicals based on structural and on toxicological information to detect groups of chemicals with similar toxic profiles and pathways/mechanisms of toxicity. As many of the experimental toxicity values were not available, this data was imputed by predicting them with a multi-label classification method, prior to clustering. The clustering results were evaluated by assessing chemical and toxicological similarities with the aim of identifying clusters with a concordance between structural information and toxicity profiles/mechanisms. From these chosen clusters, seven were selected for a quantitative read-across, based on a small ratio of NOAEL of the members with the highest and the lowest NOAEL in the cluster (<5. We discuss

  1. Toxicología Vegetal

    OpenAIRE

    García Fernández, Antonio Juan

    2010-01-01

    Presentaciones de clase de los temas de Toxicología Vegetal de la licenciatura de Veterinaria de la Universidad de Murcia del curso 2011/12. Presentaciones de Toxicología Vegetal de la asignatura de Toxicología de la Licenciatura de Veterinaria del curso 2011/12

  2. Toxicología Vegetal

    OpenAIRE

    García Fernández, Antonio Juan

    2010-01-01

    Presentaciones de clase de los temas de Toxicología Vegetal de la licenciatura de Veterinaria de la Universidad de Murcia del curso 2011/12. Presentaciones de Toxicología Vegetal de la asignatura de Toxicología de la Licenciatura de Veterinaria del curso 2011/12

  3. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) in toxicological analysis. Studies on the detection of clobenzorex and its metabolites within a systematic toxicological analysis procedure by GC-MS and by immunoassay and studies on the detection of alpha- and beta-amanitin in urine by atmospheric pressure ionization electrospray LC-MS.

    Science.gov (United States)

    Maurer, H H; Kraemer, T; Ledvinka, O; Schmitt, C J; Weber, A A

    1997-02-07

    GC-MS is the method of choice for toxicological analysis of toxicants volatile in GC while non-volatile and/or thermally labile toxicants need LC-MS for their determination. Studies are presented on the toxicological detection of the amphetamine-like anorectic clobenzorex in urine by GC-MS after acid hydrolysis, extraction and acetylation and by fluorescence polarization immunoassay (FPIA, TDx (meth)amphetamine II). After ingestion of 60 mg of clobenzorex, the parent compound and/or its metabolites could be detected by GC-MS for up to 84 h or by FPIA for up to 60 h. Since clobenzorex shows no cross-reactivity with the used immunoassay, the N-dealkylated metabolite amphetamine is responsible for the positive TDx results. The intake of clobenzorex instead of amphetamine can be differentiated by GC-MS detection of hydroxyclobenzorex which is detectable for at least as long as amphetamine. In addition, the described GC-MS procedure allows the simultaneous detection of most of the toxicologically relevant drugs. Furthermore, studies are described on the atmospheric pressure ionization electrospray LC-MS detection of alpha- and beta-amanitin, toxic peptides of amanita mushrooms, in urine after solid-phase extraction on RP-18 columns. Using the single ion monitoring mode with the ions m/z 919 and 920 the amanitins could be detected down to 10 ng/ml of urine which allows us to diagnose intoxications with amanita mushrooms.

  4. Non-precautionary aspects of toxicology.

    Science.gov (United States)

    Grandjean, Philippe

    2005-09-01

    Empirical studies in toxicology aim at deciphering complex causal relationships, especially in regard to human disease etiologies. Several scientific traditions limit the usefulness of documentation from current toxicological research, in regard to decision-making based on the precautionary principle. Among non-precautionary aspects of toxicology are the focus on simplified model systems and the effects of single hazards, one by one. Thus, less attention is paid to sources of variability and uncertainty, including individual susceptibility, impacts of mixed and variable exposures, susceptible life-stages, and vulnerable communities. In emphasizing the need for confirmatory evidence, toxicology tends to penalize false positives more than false negatives. An important source of uncertainty is measurement error that results in misclassification, especially in regard to exposure assessment. Standard statistical analysis assumes that the exposure is measured without error, and imprecisions will usually result in an underestimation of the dose-effect relationship. In testing whether an effect could be considered a possible result of natural variability, a 5% limit for "statistical significance" is usually applied, even though it may rule out many findings of causal associations, simply because the study was too small (and thus lacked statistical power) or because some imprecision or limited sensitivity of the parameters precluded a more definitive observation. These limitations may be aggravated when toxicology is influenced by vested interests. Because current toxicology overlooks the important goal of achieving a better characterization of uncertainties and their implications, research approaches should be revised and strengthened to counteract the innate ideological biases, thereby supporting our confidence in using toxicology as a main source of documentation and in using the precautionary principle as a decision procedure in the public policy arena.

  5. Inhibition of coagulation proteases and thrombosis and sub-chronic toxicological study of a sulfated polysaccharidic fraction from the red alga Gelidiella acerosa

    Directory of Open Access Journals (Sweden)

    Ismael Nilo Lino de Queiroz

    2014-10-01

    Full Text Available Metabolites isolated from Gelidiella species (Rhodophyta have been few studied. We evaluated a sulfated polysaccharidic fraction from G. acerosa collected from two Brazilian beaches on the northwestern coast of Brazil (Flecheiras-F and Pedra Rachada-PR on coagulation proteases and thrombosis. Their toxicity in vivo was also assessed. Enzymatic extractions yielded 1.40%, and similar chromatographic profiles (DEAE-cellulose were obtained, with fractions (Ga-I→V containing differences among the relative proportions of sulfate (5-42%, and revealing charge density patterns by electrophoresis. Ga-IV-PR had a discrete effect (3.01 IU mg-1 on normal human coagulation compared with heparin (193 IU mg-1 and was tested on coagulation proteases (thrombin and factor Xa in the presence of antithrombin and in a model of venous thrombosis in rats using thromboplastin as the thrombogenic stimulus. The systems were inhibited; but at higher doses (>1.0 mg kg-1, this fraction reverted the antithrombotic effect. Regarding the toxicological study, consecutive Ga-IV (9 mg kg-1 for 14 days did not cause mortality in mice, but some biochemical and hematological parameters were discretely altered. Histopathological analysis revealed that increased liver and spleen sizes had no toxicological significance. Therefore, G. acerosa does not biochemically change its matrix polysaccharide composition and proved to be safe antithrombotic agent.

  6. Studies on the metabolism and toxicological detection of the amphetamine-like anorectic mefenorex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay.

    Science.gov (United States)

    Kraemer, T; Vernaleken, I; Maurer, H H

    1997-11-21

    Studies on the metabolism and on the toxicological analysis of mefenorex [R,S-N-(3-chloropropyl)-alpha-methylphenethylamine, MF] using gas chromatography-mass spectrometry (GC-MS) and fluorescence polarization immunoassay (FPIA) are described. The metabolites were identified in urine samples of volunteers by GC-MS. Besides MF, thirteen metabolites including amphetamine (AM) could be identified and three partially overlapping metabolic pathways could be postulated. For GC-MS detection, the systematic toxicological analysis procedure including acid hydrolysis, extraction at pH 8-9 and acetylation was suitable (detection limits 50 ng/ml for MF and 100 ng/ml for AM). Excretion studies showed, that only AM but neither MF nor its specific metabolites were detectable between 32 and 68 h after ingestion of 80 mg of MF. Therefore, misinterpretation can occur. The Abbott TDx FPIA amphetamine/methamphetamine II gave positive results up to 68 h. All the positive immunoassay results could be confirmed by the described GC-MS procedure.

  7. Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay.

    Science.gov (United States)

    Kraemer, T; Theis, G A; Weber, A A; Maurer, H H

    2000-01-28

    Studies on the metabolism and the toxicological analysis of fenproporex (R,S-3-[(1-phenyl-2-propyl)-amino]-propionitrile, FP) using GC-MS and fluorescence polarization immunoassay are described. The metabolites were identified in urine samples of volunteers by GC-MS after cleavage of conjugates, extraction and acetylation. Besides unchanged FP, fourteen metabolites, including amphetamine, could be identified. Two partially overlapping metabolic pathways could be postulated: ring degradation by one- and two-fold aromatic hydroxylation followed by methylation and side chain degradation by N-dealkylation to amphetamine (AM). A minor pathway leads via beta-hydroxylation of AM to norephedrine. For GC-MS detection, the systematic toxicological analysis procedure including acid hydrolysis, extraction at pH 8-9 and acetylation was suitable (detection limits 50 ng/ml for FP and 100 ng/ml for AM). Excretion studies showed, that only AM but neither FP nor its specific metabolites were detectable 30-60 h after ingestion of 20 mg of FP. Therefore, misinterpretation can occur. The Abbott TDx FPIA amphetamine/methamphetamine II gave positive results up to 58 h. All the positive immunoassay results could be confirmed by the described GC-MS procedure.

  8. Toxicology, an STS Approach.

    Science.gov (United States)

    Wagner, Richard

    1990-01-01

    Presented are activities suggested through Project L.A.B.S. that involve the topic of toxicology. Activities include suggested research, the risk benefit seesaw, human-made compounds, legislation, a historical perspective, and health. A suggested readings list is provided. (KR)

  9. Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028 — For human safety in clinical study

    Energy Technology Data Exchange (ETDEWEB)

    Nishizato, Yohei, E-mail: yohei-nishizato@ds-pharma.co.jp [Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan); Imai, Satoki [Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan); Okahashi, Noriko [Research Planning and Intelligence, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan); Yabunaka, Atsushi; Kunimatsu, Takeshi [Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan); Kikuchi, Kaoru [Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan); Yabuki, Masashi [Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94, Enoki-cho, Suita, Osaka 564-0053 (Japan)

    2014-05-01

    SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. - Highlights: • SMP-028 inhibits neutral CEase more strongly than other steroidogenic enzymes in rats. • Inhibition of neutral CEase in rats by SMP-028 suppresses steroidogenesis in vivo. • SMP-028 does not inhibit neutral CEase in monkeys in vivo. • Steroidogenesis pathway in monkeys treated with SMP-028 was not suppressed. • SMP-028 may not inhibit LIPE in humans in vivo.

  10. Designer drug 2,4,5-trimethoxyamphetamine (TMA-2): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.

    Science.gov (United States)

    Ewald, Andreas H; Fritschi, Giselher; Maurer, Hans H

    2006-09-01

    Studies are described on the metabolism and the toxicological detection of the amphetamine-derived designer drug 2,4,5-trimethoxyamphetamine (TMA-2) in rat urine using gas chromatographic/mass spectrometric (GC/MS) techniques. The identified metabolites indicated that TMA-2 was metabolized by oxidative deamination to the corresponding ketone followed by reduction to the corresponding alcohol, O-demethylation followed by oxidative deamination, and finally O,O-bis-demethylation. All metabolites carrying hydroxy groups were found to be partly excreted in urine as glucuronides and/or sulfates. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the detection, in rat urine, of an intake of TMA-2 that corresponds to a common drug users' dose. Assuming similar metabolism, the described STA procedure in human urine should be suitable as proof of an intake of TMA-2. Copyright (c) 2006 John Wiley & Sons, Ltd.

  11. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs.

    Science.gov (United States)

    Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Wang, Jiang; Phelps, Mitch; Potter, Philip M; Goins, William B; Fernandez, Soledad A; Chiocca, E Antonio

    2013-08-06

    MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 10(8) pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 10(8) pfus in the absence of prodrugs and at 10(6) pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.Molecular Therapy-Nucleic Acids (2013) 2, e113; doi:10.1038/mtna.2013.38; published online 6 August 2013.

  12. Emerging approaches in predictive toxicology.

    Science.gov (United States)

    Zhang, Luoping; McHale, Cliona M; Greene, Nigel; Snyder, Ronald D; Rich, Ivan N; Aardema, Marilyn J; Roy, Shambhu; Pfuhler, Stefan; Venkatactahalam, Sundaresan

    2014-12-01

    Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. This commentary provides an overview of the state of the current science and a brief discussion on future perspectives for the field of predictive toxicology for human toxicity. Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described.

  13. Clinical toxicology: clinical science to public health.

    Science.gov (United States)

    Bateman, D N

    2005-11-01

    1. The aims of the present paper are to: (i) review progress in clinical toxicology over the past 40 years and to place it in the context of modern health care by describing its development; and (ii) illustrate the use of clinical toxicology data from Scotland, in particular, as a tool for informing clinical care and public health policy with respect to drugs. 2. A historical literature review was conducted with amalgamation and comparison of a series of published and unpublished clinical toxicology datasets from NPIS Edinburgh and other sources. 3. Clinical databases within poisons treatment centres offer an important method of collecting data on the clinical effects of drugs in overdose. These data can be used to increase knowledge on drug toxicity mechanisms that inform licensing decisions, contribute to evidence-based care and clinical management. Combination of this material with national morbidity datasets provides another valuable approach that can inform public health prevention strategies. 4. In conclusion, clinical toxicology datasets offer clinical pharmacologists a new study area. Clinical toxicology treatment units and poisons information services offer an important health resource.

  14. Toxicology research for precautionary decision-making and the role of Human & Experimental Toxicology.

    Science.gov (United States)

    Grandjean, P

    2015-12-01

    A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published articles. Links in SciFinder showed that the 530 articles published in four selected volumes between 1984 and 2014 primarily dealt with metals (126 links) and other toxicants that have received substantial attention in the past. Thirteen compounds identified by US authorities in 2006 as high-priority substances, for which toxicology documentation is badly needed, were not covered in the journal issues at all. When reviewing published articles, reliance on p values was standard, and non-significant findings were often called 'negative.' This tradition may contribute to the perceived need to extend existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology is particularly prone to bias because of the known paucity of false positives and, in particular, the existence of a vast number of toxic hazards which by default are considered innocuous due to lack of documentation. The Precautionary Principle could inspire decision-making on the basis of incomplete documentation and should stimulate a change in toxicology traditions and in toxicology research publication.

  15. Veterinary Forensic Toxicology.

    Science.gov (United States)

    Gwaltney-Brant, S M

    2016-09-01

    Veterinary pathologists working in diagnostic laboratories are sometimes presented with cases involving animal poisonings that become the object of criminal or civil litigation. Forensic veterinary toxicology cases can include cases involving animal cruelty (malicious poisoning), regulatory issues (eg, contamination of the food supply), insurance litigation, or poisoning of wildlife. An understanding of the appropriate approach to these types of cases, including proper sample collection, handling, and transport, is essential so that chain of custody rules are followed and proper samples are obtained for toxicological analysis. Consultation with veterinary toxicologists at the diagnostic laboratory that will be processing the samples before, during, and after the forensic necropsy can help to ensure that the analytical tests performed are appropriate for the circumstances and findings surrounding the individual case. © The Author(s) 2016.

  16. Prospects for applying synthetic biology to toxicology

    DEFF Research Database (Denmark)

    Behrendorff, James Bruce Yarnton H; Gillam, Elizabeth M.J.

    2017-01-01

    The 30 years since the inception of Chemical Research in Toxicology, game-changing advances in chemical and molecular biology, the fundamental disciplines underpinning molecular toxicology, have been made. While these have led to important advances in the study of mechanisms by which chemicals...... damage cells and systems, there has been less focus on applying these advances to prediction, detection, and mitigation of toxicity. Over the last ∼15 years, synthetic biology, the repurposing of biological "parts" in systems engineered for useful ends, has been explored in other areas of the biomedical...... and life sciences, for such applications as detecting metabolites, drug discovery and delivery, investigating disease mechanisms, improving medical treatment, and producing useful chemicals. These examples provide models for the application of synthetic biology to toxicology, which, for the most part, has...

  17. Assessment of food toxicology

    OpenAIRE

    2016-01-01

    The interest in food toxicology is evident by the dependency of humankind on nutrition by virtue of their heterotrophic metabolism. By means of modern biochemistry, molecular and cell biology, computer science, bioinformatics as well as high-throughput and high-content screening technologies it has been possible to identify adverse effects and characterize potential toxicants in food. The mechanisms of toxicant actions are multifactorial but many toxic effects converge on the generation of ox...

  18. Assessment of food toxicology

    Directory of Open Access Journals (Sweden)

    Alexander Gosslau

    2016-09-01

    Full Text Available The interest in food toxicology is evident by the dependency of humankind on nutrition by virtue of their heterotrophic metabolism. By means of modern biochemistry, molecular and cell biology, computer science, bioinformatics as well as high-throughput and high-content screening technologies it has been possible to identify adverse effects and characterize potential toxicants in food. The mechanisms of toxicant actions are multifactorial but many toxic effects converge on the generation of oxidative stress and chronic inflammation resulting in cell death, aging and degenerative diseases. Integration of food toxicology data obtained throughout biochemical and cell-based in vitro, animal in vivo and human clinical settings has enabled the establishment of alternative, highly predictable in silico models. These systems utilize a combination of complex in vitro cell-based models with computer-based algorithms. A decrease of rodent animal testing with its limitations of high costs, low throughput readouts, inconsistent responses, ethical issues and concerns of extrapolability to humans have led to an increased use of these but also alternative lower hierarchy surrogate animal models (e.g. Drosophila melanogaster; Caenorhabditis elegans or Danio rerio and efforts to integrate organotypic systems and stem cell-based assays. Despite those achievements, there are numerous challenges in various disciplines of food toxicology.

  19. Toxicological Benchmarks for Wildlife

    Energy Technology Data Exchange (ETDEWEB)

    Sample, B.E. Opresko, D.M. Suter, G.W.

    1993-01-01

    Ecological risks of environmental contaminants are evaluated by using a two-tiered process. In the first tier, a screening assessment is performed where concentrations of contaminants in the environment are compared to no observed adverse effects level (NOAEL)-based toxicological benchmarks. These benchmarks represent concentrations of chemicals (i.e., concentrations presumed to be nonhazardous to the biota) in environmental media (water, sediment, soil, food, etc.). While exceedance of these benchmarks does not indicate any particular level or type of risk, concentrations below the benchmarks should not result in significant effects. In practice, when contaminant concentrations in food or water resources are less than these toxicological benchmarks, the contaminants may be excluded from further consideration. However, if the concentration of a contaminant exceeds a benchmark, that contaminant should be retained as a contaminant of potential concern (COPC) and investigated further. The second tier in ecological risk assessment, the baseline ecological risk assessment, may use toxicological benchmarks as part of a weight-of-evidence approach (Suter 1993). Under this approach, based toxicological benchmarks are one of several lines of evidence used to support or refute the presence of ecological effects. Other sources of evidence include media toxicity tests, surveys of biota (abundance and diversity), measures of contaminant body burdens, and biomarkers. This report presents NOAEL- and lowest observed adverse effects level (LOAEL)-based toxicological benchmarks for assessment of effects of 85 chemicals on 9 representative mammalian wildlife species (short-tailed shrew, little brown bat, meadow vole, white-footed mouse, cottontail rabbit, mink, red fox, and whitetail deer) or 11 avian wildlife species (American robin, rough-winged swallow, American woodcock, wild turkey, belted kingfisher, great blue heron, barred owl, barn owl, Cooper's hawk, and red

  20. Estudio toxicologico de un inyectable apocrifo conteniendo hierro como principio activo Toxicological study of a counterfeit medicinal product containing iron sorbitol

    Directory of Open Access Journals (Sweden)

    María Paula Bezzi

    2006-07-01

    Full Text Available Una mujer embarazada murió luego de la administración parenteral de un preparado de hierro (sorbitol, producto que fue identificado por la Autoridad Sanitaria Argentina como un medicamento apócrifo. Su análisis químico determinó que el contenido de hierro era 3.5 veces mayor al rotulado. Los estudios toxicológicos demostraron que su administración representa un riesgo sanitario y podría ser el causante de la muerte.After the injection of an iron sorbitol preparation a pregnant woman died. Its chemical analysis determined a huge amount of iron (3.5-fold higher than the labeled. Results obtained by toxicological studies show that such medicinal product represents a sanitary risk and probably it could be presumed as the cause of death.

  1. From alternative methods to a new toxicology.

    Science.gov (United States)

    Hartung, Thomas

    2011-04-01

    Mechanistic toxicology has evolved by relying, to a large extent, on methodologies that substitute or complement traditional animal tests. The biotechnology and informatics revolutions of the last decades have made such technologies broadly available and useful, but regulatory toxicology has been slow to embrace these new approaches. Major validation efforts, however, have delivered the evidence that new approaches do not lower safety standards and can be integrated into regulatory safety assessments. Particularly in the EU, political pressures, such as the REACH legislation and the 7th Amendment to the cosmetic legislation, have prompted the need of new approaches. In the US, the NRC vision report calling for a toxicology for the 21st century (and its most recent adaptation by EPA for their toxicity testing strategy) have initiated a debate about how to create a novel approach based on human cell cultures, lower species, high-throughput testing, and modeling. Lessons learned from the development, validation, and acceptance of alternative methods support the creation of a new approach based on identified toxicity pathways. Conceptual steering and an objective assessment of current practices by evidence-based toxicology (EBT) are required. EBT is modeled on evidence-based medicine, which has demonstrated that rigorous systematic reviews of current practices and meta-analyses of studies provide powerful tools to provide health care professionals and patients with the current best scientific evidence. Similarly, a portal for high-quality reviews of toxicological approaches and tools for the quantitative meta-analyses of data promise to serve as door opener for a new regulatory toxicology.

  2. Preclinical Toxicology of New Drugs.

    Science.gov (United States)

    1986-04-04

    8217 . -. . . . . . 3. . ANNUAL REPORT Contract No. DAMD17-84-C-4088 on PRECLINICAL TOXICOLOGY OF NEW DRUGS Report 8740-86-2 to UNITED STATES ARMY MEDICAL RESEARCH...N RECIPIENTS CATALOG NUMBER 8740-86-2 /1 4. TITLE (mid Subtitle) TYPE OF REPORT & PERIOD COVERED , ; Annual Report PRECLINICAL TOXICOLOGY OF NEW DRUGS March...9 It P V .---, - 77 T ANNUAL REPORT Contract No. DAMD17-84-C-4088 on PRECLINICAL TOXICOLOGY OF NEW DRUGS Report

  3. 全氟烷酸类化合物的毒理学研究%Toxicological study on perfluoroalkyl acids

    Institute of Scientific and Technical Information of China (English)

    陈思怀; 石志敏

    2014-01-01

    全氟烷酸类化合物是一类新型的持久性有机污染物,已被广泛应用于工业生产以及生活用品中,在全球各地的环境介质和人群中均检测到了该化合物的存在,该类化合物的环境健康效应已经引起了广泛的关注。本文对该化合物的特征、来源、毒代动力学特征、毒性效应以及相关的机制进行了总结,以进一步了解该化合物毒理学方面的研究进展。%Perfluoroalkyl acids (PFAAs) are an emerging persistent organic pollutant. With the wide application in industrial and general products, these compounds have been detected in the environmental matris and human population. The concerns about the effects of PFAAs on environment and health have been generated. This review summarizes the characteristics, source, toxicokinetics, toxic effects of PFAAs and related mechanisms for further understanding PFAAs progress in toxicology.

  4. A longitudinal study assessing lens thickness changes in the eye of the growing beagle using ultrasound scanning: relevance to age of dogs in regulatory toxicology studies.

    Science.gov (United States)

    Maynard, Juliana; Sykes, Angela; Powell, Helen; Healing, Guy; Scott, Marietta; Holmes, Andrew; Ricketts, Sally-Ann; Stewart, Jane; Davis, Stewart

    2014-12-01

    The lens is formed in utero with new secondary lens fibres added as outer layers throughout life in a growth pattern characteristic of the species. This study examined the time course of beagle lens growth to better understand the optimal starting age of dogs for safety studies to support adult versus paediatric indications, and to assess the feasibility of non-invasively monitoring lens growth with high frequency ultrasound. Ultrasound scanning was performed in six female beagle dogs using the Vevo770. All dogs were imaged in B-mode using local anaesthetic but without sedation. Imaging was carried out every 2 weeks from 8 to 22 weeks of age and then monthly until 62 weeks of age. The dogs tolerated the procedure well. The lens was visible in all dogs and measuring the lens thickness with high frequency ultrasound demonstrated good analytical reproducibility [Root Mean Square (RMS) = 3.13%]. No differences between the left and right eye existed and lens thickness correlated with body weight. The highest weekly growth rate was before 12 weeks of age. A statistically significant difference between monthly thickness was detected until 42 weeks of age at which point growth reached a plateau. During the experiment, lenses grew by 29.7% reaching an average thickness of 6.4 mm ± 0.03. By 10 months of age (the typical age used for routine toxicological evaluation), beagles have reached a plateau in lens growth that is analogous to human adults. Where lens is a target organ of concern it is suggested that beagles under 6 months old may be a better model for determining paediatric safety.

  5. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Two-Generation Reproduction Study of Lewisite in Rats Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Mellick, P. W.; Buschbom, R. L.

    1989-07-15

    Occupational health standards have not been established for Lewisite [bis(2-chlorethyl)arsine], a potent toxic vesicant which reacts with the sulfhydryl groups of proteins through its arsenic group. The purposes of this study were to determine the reproductive consequences and dose~response of continuing Lewisite exposure of parental males and females and their offspring in a 42-week two-generation study. Solutions of Lewisite were prepared for administration by diluting the neat agent with sesame oil. Rats were administered Lewisite (0, 0.10, 0.25 or 0.60 mg/kg/day for 5 days a week) via intragastric intubation prior to mating, during mating and after mating until the birth of their offspring. The dams continued to receive Lewisite during lactation. At weaning, male and female offspring of each group were selected to continue on the study; rece1v1ng Lewisite during adolescence, mating and throughout gestation. Again, the dams continued to receive Lewisite until weaning of the offspring. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effect to offspring were attributed to Lewisite exposure. Minor changes in growth was the only maternal effect observed. Lewisite exposure of parental rats caused no gross or microscopic lesions in testes, epididymis, prostrate, seminal vesicles, ovaries, uterus or vagina. Severe inflammation of the lung was observed at necropsy in cases in which Lewisite gained access to the respiratory system from accidental dosing or reflux and aspiration; this usually caused early death of the animal. The NOEL for reproductive effects in this study was greater than 0.60 mg/kg/day.

  6. Inhalation reproductive toxicology studies: Male dominant lethal study of n-hexane in Swiss (CD-1) mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Rommereim, R.L.; Evanoff, J.J.; Sasser, L.B.; Decker, J.R.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.

    1988-08-01

    The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments; consequently, the opportunity for industrial, environmental or accidental exposure to hexane vapors is significant. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate male dominant lethal effects in Swiss (CD-1) mice after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Each exposure concentration consisted of 30 randomly selected, proven male breeders; 4 groups. The mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. Ten males in each dose group were sacrificed one day after the cessation of exposure, and their testes and epididymides were removed for evaluation of the germinal epithelium. The remaining male mice, 20 per group, were individually housed in hanging wire-mesh breeding cages where they were mated with unexposed, virgin females for eight weekly intervals; new females were provided each week. The mated females were sacrificed 12 days after the last day of cohabitation and their reproductive status and the number and viability of the implants were recorded. The appearance and behavior of the male mice were unremarkable throughout the study period and no evidence of n-hexane toxicity was observed. 18 refs., 3 figs., 11 tabs.

  7. Toxicological consequences of TiO{sub 2}, SiC nanoparticles and multi-walled carbon nanotubes exposure in several mammalian cell types: an in vitro study

    Energy Technology Data Exchange (ETDEWEB)

    Barillet, Sabrina; Simon-Deckers, Angelique [CEA-CNRS UMR9956, IRAMIS, CEA Saclay, Laboratoire Pierre Suee (France); Herlin-Boime, Nathalie; Mayne-L' Hermite, Martine; Reynaud, Cecile [CEA-CNRS URA2453, IRAMIS, CEA Saclay, Laboratoire Francis Perrin (France); Cassio, Doris [INSERM UMR-S 757, Centre Universitaire (France); Gouget, Barbara; Carriere, Marie, E-mail: marie.carriere@cea.f [CEA-CNRS UMR9956, IRAMIS, CEA Saclay, Laboratoire Pierre Suee (France)

    2010-01-15

    The development of nanotechnologies may lead to dissemination of potentially toxic nanoparticles in the environment. Toxicology of these nano-sized particles is thus attracting attention of public and governments worldwide. Our research is focused on the in vitro response of eukaryotic cells to nanoparticles exposure. For this purpose, we used cellular models of primary target organs (lung: A549 alveolar epithelial cells), or secondary target organs (liver: WIF-B9, Can-10 and kidneys: NRK-52E, LLC-PK1 proximal cells), i.e., organs exposed if nanoparticles are translocated through epithelial barriers. These cells were exposed to TiO{sub 2}, SiC nanoparticles or multi-walled carbon nanotubes (MWCNT). The influence of nanoparticles physico-chemical characteristics on various toxicological endpoints (cytotoxicity, reactive oxygen species generation, genotoxicity) was specified. Our data demonstrate that nanoparticles toxicity depend on their size, morphology, and chemical composition, the finest, spherical shaped, and anatase TiO{sub 2} nanoparticles being the more cytotoxic to NRK-52E cells, while SiC nanoparticles exert almost no cytotoxicity. MWCNT cytotoxicity neither depended on their length, nor on the presence of metal impurities. Nanoparticles cytotoxicity also depended on the exposed cell line. All the tested nanoparticles were uptaken by cells and caused intracellular reactive oxygen species generation. Relative to genotoxic effects, DNA strand breaks were detected in NRK-52E cells via the alkaline comet assay after exposure of cells to TiO{sub 2} nanoparticles and to a lesser extent after exposure to MWCNT, but no double strand breaks were detected. The originality of this study lies on the panel of nanomaterials which were tested on a variety of cell lines. All these data may lead to a better understanding of nanomaterial toxicity and hazards for health.

  8. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    Science.gov (United States)

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  9. Repeated dose 28-day oral toxicity study in Wistar rats with a mixture of five pesticides often found as residues in food: alphacypermethrin, bromopropylate, carbendazim, chlorpyrifos and mancozeb

    DEFF Research Database (Denmark)

    Jacobsen, H.; Østergaard, G.; Lam, Henrik Rye;

    2004-01-01

    , haematocrite and haemoglobin concentration was significantly reduced in both male and female rats of groups 5 and 6. Relative liver weight was significantly increased in groups 3-6 male and female rats. Absolute thyroid gland weight was significantly increased in groups 3, 5 and 6 male rats and of groups 3......-6 female rats, and relative thyroid gland weight was significantly increased in groups 2-6 male rats and of groups 3-6 female rats. Absolute thymus weight of groups 3-6 male and female rats and relative thymus weight of groups 3-6 male rats and groups 3 and 4 female rats was significantly decreased. A mild...... degree of centrilobular cell hypertrophy of the liver was seen in all male rats and of three female rats of group 6. In the thyroid gland follicular cell hypertrophy was present in one female in the control group and in six females and seven males of group 6. It was concluded that inhibition...

  10. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Modified Dominant Lethal Study of Sulfur Mustard in Rats Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Buschbom, R. L.

    1989-05-01

    Occupational health standards have not been established for sulfur mustard (HD) [bis{2-chloroethyl)-sulfide) ' a strong alkylating agent with known mutagenic properties. Little, however, is known about the mutagenic activity of HD in mammalian species and data regarding the dominant lethal effects of HD are ambiguous. The purpose of this study was to determine the dominant lethal effect in male and female rats orally exposed to HD. The study was conducted in two phases; a female dominant lethal phase and a male dominant lethal phase. Sprague-Dawley rats of each sex were administered 0.08, 0.20, or 0.50 mg/kg HD in sesame oil 5 days/week for 10 weeks. For the female phase, treated or untreated males were mated with treated females and their fetuses were evaluated at approximately 14 days after copulation. For the male dominant lethal phase, treated males cohabited with untreated femal (during 5 days of each week for 10 weeks) and females were sacrificed for fetal evaluation 14 days after the midweek of cohabitation during each of the 10 weeks. The appearance and behavior of the rats were unremarkable throughout the experiment and there were no treatment-related deaths. Growth rates were reduced in both female and male rats treated with 0.50 mg/kg HD. Indicators of reproductive performance did not demonstrate significant female dominant lethal effects, although significant male dominant lethal effects were observed at 2 and 3 week post-exposure. These effects included increases of early fetal resorptions and preimplantation losses and decreases of total live embryo implants. These effects were most consistently observed at a dose of 0.50 mg/kg, but frequently occurred at the lower doses. Although no treatment-related effects on male reproductive organ weights or sperm motility were found, a significant increase in the percentage of abnormal sperm was detected in males exposed to 0. 50 mg/kg HD. The timing of these effects is consistent with an effect during the

  11. Research Models in Developmental Behavioral Toxicology.

    Science.gov (United States)

    Dietrich, Kim N.; Pearson, Douglas T.

    Developmental models currently used by child behavioral toxicologists and teratologists are inadequate to address current issues in these fields. Both child behavioral teratology and toxicology scientifically study the impact of exposure to toxic agents on behavior development: teratology focuses on prenatal exposure and postnatal behavior…

  12. Synthetic toxicology: where engineering meets biology and toxicology.

    Science.gov (United States)

    Schmidt, Markus; Pei, Lei

    2011-03-01

    This article examines the implications of synthetic biology (SB) for toxicological sciences. Starting with a working definition of SB, we describe its current subfields, namely, DNA synthesis, the engineering of DNA-based biological circuits, minimal genome research, attempts to construct protocells and synthetic cells, and efforts to diversify the biochemistry of life through xenobiology. Based on the most important techniques, tools, and expected applications in SB, we describe the ramifications of SB for toxicology under the label of synthetic toxicology. We differentiate between cases where SB offers opportunities for toxicology and where SB poses challenges for toxicology. Among the opportunities, we identified the assistance of SB to construct novel toxicity testing platforms, define new toxicity-pathway assays, explore the potential of SB to improve in vivo biotransformation of toxins, present novel biosensors developed by SB for environmental toxicology, discuss cell-free protein synthesis of toxins, reflect on the contribution to toxic use reduction, and the democratization of toxicology through do-it-yourself biology. Among the identified challenges for toxicology, we identify synthetic toxins and novel xenobiotics, biosecurity and dual-use considerations, the potential bridging of toxic substances and infectious agents, and do-it-yourself toxin production.

  13. Postmortem Biochemistry and Toxicology

    Directory of Open Access Journals (Sweden)

    Robert Flanagan

    2017-04-01

    Full Text Available The aim of postmortem biochemistry and toxicology is either to help establish the cause of death, or to gain information on events immediately before death. If self-poisoning is suspected, the diagnosis may be straightforward and all that could be required is confirmation of the agents involved. However, if the cause of death is not immediately obvious then suspicion of possible poisoning or of conditions such as alcoholic ketoacidosis is of course crucial. On the other hand, it may be important to investigate adherence to prescribed therapy, for example with anticonvulsants or antipsychotics, hence sensitive methods are required. Blood sampling (needle aspiration, peripheral vein, for example femoral, ideally after proximal ligation before opening the body minimizes the risk of sample contamination with, for example, gut contents or urine. Other specimens (stomach contents, urine, liver, vitreous humor may also be valuable and may be needed to corroborate unexpected or unusual findings in the absence of other evidence. The site of sampling should always be recorded. The availability of antemortem specimens should not necessarily preclude postmortem sampling. Appropriate sample preservation, transport, and storage are mandatory. Interpretation of analytical toxicology results must take into account what is known of the pharmacokinetics and toxicology of the agent(s in question, the circumstances under which death occurred including the mechanism of exposure, and other factors such as the stability of the analyte(s and the analytical methods used. It is important to realise that changes may occur in the composition of body fluids, even peripheral blood, after death. Such changes are likely to be greater after attempted resuscitation, and with centrally-acting drugs with large volumes of distribution given chronically, and may perhaps be minimised by prompt refrigeration of the body and performing the autopsy quickly.

  14. Microbiological and toxicological effects of Perla black bean (Phaseolus vulgaris L.) extracts: in vitro and in vivo studies.

    Science.gov (United States)

    Lara-Díaz, Víctor Javier; Gaytán-Ramos, Angel A; Dávalos-Balderas, Alfredo José; Santos-Guzmán, Jesús; Mata-Cárdenas, Benito David; Vargas-Villarreal, Javier; Barbosa-Quintana, Alvaro; Sanson, Misu; López-Reyes, Alberto Gabriel; Moreno-Cuevas, Jorge E

    2009-02-01

    We investigated the microbiological and toxicological effects of three Perla black bean extracts on the growth and culture of selected pathogenic microorganisms, the toxicity over Vero cell lines and an in vivo rat model. Three different solvents were used to obtain Perla black bean extracts. All three Perla black bean extracts were tested for antibacterial and antiparasitic activity and further analysed for intrinsic cytotoxicity (IC(50)). Methanol Perla black bean extract was used for acute toxicity test in rats, with the up-and-down doping method. All Perla black bean extracts inhibited bacterial growth. Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella oxytoca, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis and Listeria monocytogenes showed inhibition, while Escherichia coli and Enterobacter aerogenes did not. Acidified water and acetic acid Perla black bean extract were tested in parasites. The best IC(50) was observed for Giardia lamblia, while higher concentrations were active against Entamoeba histolytica and Trichomonas vaginalis. The Vero cells toxicity levels (IC(50)) for methanol, acidified water and acetic acid Perla black bean extract were [mean +/- S.D. (95% CI)]: 275 +/- 6.2 (267.9-282.0), 390 +/- 4.6 (384.8-395.2) and 209 +/- 3.39 (205.6-212.4) microg/ml, respectively. In vivo acute toxicity assays did not show changes in absolute organ weights, gross and histological examinations of selected tissues or functional tests. The acetic acid and methanol Perla black bean extract proved to exhibit strong antibacterial activity and the acidified water Perla black bean extract exerted parasiticidal effects against Giardia lamblia, Entamoeba hystolitica and Trichomonas vaginalis. The three Perla black bean extracts assayed over Vero cells showed very low toxicity and the methanol Perla black bean extract in vivo did not cause toxicity.

  15. [Antidotes in clinical toxicology].

    Science.gov (United States)

    Hruby, K

    2013-09-01

    This overview describes antidotes, and their clinical pharmacology, that have an established significance in the currently practiced clinical toxicology because of their proven effectiveness in the treatment of serious poisonings. For the proper, efficient, and targeted use of an antidote, pharmacological knowledge is required, which is a central subject of this article. Current data from the literature are used as reference along with the accumulated experiences about possible adverse effects in order to include them in therapeutic considerations. The dosage of antidotes is the subject of several other review articles and is therefore not included in this synopsis.

  16. Unintentional Pharmaceutical-Related Medication Errors Caused by Laypersons Reported to the Toxicological Information Centre in the Czech Republic.

    Science.gov (United States)

    Urban, Michal; Leššo, Roman; Pelclová, Daniela

    2016-07-01

    The purpose of the article was to study unintentional pharmaceutical-related poisonings committed by laypersons that were reported to the Toxicological Information Centre in the Czech Republic. Identifying frequency, sources, reasons and consequences of the medication errors in laypersons could help to reduce the overall rate of medication errors. Records of medication error enquiries from 2013 to 2014 were extracted from the electronic database, and the following variables were reviewed: drug class, dosage form, dose, age of the subject, cause of the error, time interval from ingestion to the call, symptoms, prognosis at the time of the call and first aid recommended. Of the calls, 1354 met the inclusion criteria. Among them, central nervous system-affecting drugs (23.6%), respiratory drugs (18.5%) and alimentary drugs (16.2%) were the most common drug classes involved in the medication errors. The highest proportion of the patients was in the youngest age subgroup 0-5 year-old (46%). The reasons for the medication errors involved the leaflet misinterpretation and mistaken dose (53.6%), mixing up medications (19.2%), attempting to reduce pain with repeated doses (6.4%), erroneous routes of administration (2.2%), psychiatric/elderly patients (2.7%), others (9.0%) or unknown (6.9%). A high proportion of children among the patients may be due to the fact that children's dosages for many drugs vary by their weight, and more medications come in a variety of concentrations. Most overdoses could be prevented by safer labelling, proper cap closure systems for liquid products and medication reconciliation by both physicians and pharmacists.

  17. Epidemiological Approaches to Metal Toxicology

    DEFF Research Database (Denmark)

    Grandjean, Philippe; Budtz-Jørgensen, Esben

    2014-01-01

    to their propensity to cause chronic or delayed toxicity, epidemiological studies of metal toxicity have focused on a wide variety of organ systems, subtle effects as well as mortality, and differences in susceptibility. Toxic metals often serve as paradigms of environmental and occupational toxicity....... For these reasons, this chapter highlights the fields within epidemiology that are most relevant to toxic metals and discusses where these substances serve to illustrate important epidemiological concepts. Chapter sections include subjects such as epidemiological terms, study design, study population, exposure......Epidemiological methods are crucial to extract as much valid information as possible from human metal exposures. Thus, modern epidemiological approaches have elucidated human health effects that were not apparent in the past. At the same time, metal toxicology has served as a useful arena...

  18. Application of PCR techniques in toxicology

    Directory of Open Access Journals (Sweden)

    Maja Kazubek

    2010-10-01

    Full Text Available Molecular biology techniques have become widely used in toxicology, leading to the creation of a new science – molecular toxicology. The goal of molecular toxicology is to detect and study the changes induced by xenobiotics at the molecular level. The research scope of molecular toxicology includes examination of mutations in genomic DNA, differences in mRNA expression and study of genotype indicating individual sensitivity.The processes of activation and detoxification of xenobiotics, drugs and environmental carcinogens involve several enzymes (xenobiotic-metabolizing enzymes – XMEs. Most of the chemicals entering our bodies, regardless of whether they have medical, pathogenic or carcinogenic properties, require metabolic activation by phase I enzymes (cytochrome P-450. In the next process the phase I products are usually detoxified by phase II enzymes, mainly by epoxide hydrolase, glutathione transferase, N-acetyltransferase or sulfotransferase. PCR techniques allow precise study of the effects of xenobiotics on cells and tissues by examining the level of activation of genes coding for phase I and II enzymes, or by testing the activity of other elements of the transcriptome. Studies of sensitivity of individual cells or tissues based on examination of mutation or gene polymorphism presence are also relevant.This paper presents the possibility of using various PCR techniques in toxicology and especially in the study of genetically determined sensitivity to xenobiotics. It also covers the possibilities of applying qPCR and qRT-PCR methods in the search for exposure biomarkers with particular emphasis on individual cytochrome P450 isoforms. Furthermore, it provides information about the possibility of implementing the differential display technique in the identification of new genes activated by toxic agents.

  19. The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

    Science.gov (United States)

    Funk, Felix; Ryle, Peter; Canclini, Camillo; Neiser, Susann; Geisser, Peter

    2010-01-01

    An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow

  20. Toxicology: Old Art, New Science.

    Science.gov (United States)

    Timbrell, John A.

    1983-01-01

    Examines the need for a science of toxicology and training at both the undergraduate and graduate levels in response to legislation controlling drugs, food additives and toxic substances in the work environment, and concern about effects on man. Stresses need for putting toxicology on a scientific base with adequate funding. (JM)

  1. NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1990-03-01

    Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain

  2. Utilizing relative potency factors (RPF) and threshold of toxicological concern (TTC) concepts to assess hazard and human risk assessment profiles of environmental metabolites: a case study.

    Science.gov (United States)

    Terry, C; Rasoulpour, R J; Knowles, S; Billington, R

    2015-03-01

    There is currently no standard paradigm for hazard and human risk assessment of environmental metabolites for agrochemicals. Using an actual case study, solutions to challenges faced are described and used to propose a generic concept to address risk posed by metabolites to human safety. A novel approach - built on the foundation of predicted human exposures to metabolites in various compartments (such as food and water), the threshold of toxicological concern (TTC) and the concept of comparative toxicity - was developed for environmental metabolites of a new chemical, sulfoxaflor (X11422208). The ultimate aim was to address the human safety of the metabolites with the minimum number of in vivo studies, while at the same time, ensuring that human safety would be considered addressed on a global regulatory scale. The third component, comparative toxicity, was primarily designed to determine whether the metabolites had the same or similar toxicity profiles to their parent molecule, and also to one another. The ultimate goal was to establish whether the metabolites had the potential to cause key effects - such as cancer and developmental toxicity, based on mode-of-action (MoA) studies - and to develop a relative potency factor (RPF) compared to the parent molecule. Collectively, the work presented here describes the toxicology programme developed for sulfoxaflor and its metabolites, and how it might be used to address similar future challenges aimed at determining the relevance of the metabolites from a human hazard and risk perspective. Sulfoxaflor produced eight environmental metabolites at varying concentrations in various compartments - soil, water, crops and livestock. The MoA for the primary effects of the parent molecule were elucidated in detail and a series of in silico, in vitro, and/or in vivo experiments were conducted on the environmental metabolites to assess relative potency of their toxicity profiles when compared to the parent. The primary metabolite

  3. Textile dye degradation by bacterial consortium and subsequent toxicological analysis of dye and dye metabolites using cytotoxicity, genotoxicity and oxidative stress studies.

    Science.gov (United States)

    Phugare, Swapnil S; Kalyani, Dayanand C; Patil, Asmita V; Jadhav, Jyoti P

    2011-02-15

    The present study aims to evaluate Red HE3B degrading potential of developed microbial consortium SDS using two bacterial cultures viz. Providencia sp. SDS (PS) and Pseudomonas aeuroginosa strain BCH (PA) originally isolated from dye contaminated soil. Consortium was found to be much faster for decolorization and degradation of Red HE3B compared to the individual bacterial strain. The intensive metabolic activity of these strains led to 100% decolorization of Red HE3B (50 mg l(-1)) with in 1h. Significant induction of various dye decolorizing enzymes viz. veratryl alcohol oxidase, laccase, azoreductase and DCIP reductase compared to control, point out towards their involvement in overall decolorization and degradation process. Analytical studies like HPLC, FTIR and GC-MS were used to scrutinize the biodegradation process. Toxicological studies before and after microbial treatment was studied with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation analysis using root cells of Allium cepa. Toxicity analysis with A. cepa signifies that dye Red HE3B exerts oxidative stress and subsequently toxic effect on the root cells where as biodegradation metabolites of the dye are relatively less toxic in nature. Phytotoxicity studies also indicated that microbial treatment favors detoxification of Red HE3B.

  4. NTP Toxicology and Carcinogenesis Studies of Isobutene (CAS No. 115-11-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    1998-12-01

    Isobutene is produced during the fractionation of refinery gases or through the catalytic cracking of methyl-t-butyl ether. Isobutene is primarily used to produce diisobutylene, trimers, butyl rubber, and other polymers. In addition, it is used in the production of isooctane, high-octane aviation gasoline, methyl-t-butyl ether, and copolymer resins with butadiene and acrylonitrile. Isobutene was selected for evaluation because of the potential for human exposure due to its large production volume and the lack of adequate data on its carcinogenic potential. The toxicity and carcinogenicity of isobutene were determined in male and female F344/N rats and B6C3F1 mice exposed to isobutene (greater than 98% pure) by inhalation for 14 weeks or 2 years. The mutagenicity of isobutene was assessed in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed by inhalation for 14 weeks. 14-WEEK STUDIES: Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to isobutene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm 6 hours per day, 5 days per week, for 14 weeks. Concentrations greater than 8,000 ppm isobutene were not used because of the danger of explosion. All rats and mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the chamber controls. No exposure-related gross lesions were observed in male or female rats or mice at necropsy. Microscopically, minimal hypertrophy of goblet cells lining the nasopharyngeal duct in the most caudal nose section was observed in some rats in each exposed group of males and females. 2-YEAR STUDIES: Based on the lack of significant exposure-related toxicologic effects in the 14-week rat and mouse studies, 8,000 ppm was selected as the highest exposure concentration in the 2-year studies. Concentrations of 0, 500, 2,000, and 8,000 ppm were selected for rats and mice with the

  5. NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1997-05-01

    Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations

  6. Toxicological studies for adults and children of insecticide residues with common mode of action (MoA) in pome, stone, berries and other small fruit

    Energy Technology Data Exchange (ETDEWEB)

    Lozowicka, B., E-mail: B.Lozowicka@iorpib.poznan.pl [Plant Protection Institute - National Research Institute, Laboratory of Pesticide Residues, Chelmonskiego 22, 15-195 Bialystok (Poland); Mojsak, P.; Jankowska, M.; Kaczynski, P.; Hrynko, I.; Rutkowska, E.; Szabunko, J. [Plant Protection Institute - National Research Institute, Laboratory of Pesticide Residues, Chelmonskiego 22, 15-195 Bialystok (Poland); Borusiewicz, A. [Department of Agronomy, The Academy of Agrobusiness in Łomza (Poland)

    2016-10-01

    The presence of pesticide residues in fruit is a serious health concern. This paper for the first time demonstrated the Hazard Index (HI) method to carry out acute, chronic and cumulative health risk assessment to the 14 groups of insecticides for three subpopulations. The challenge of this study was to present results from a long period of research (years 2005–2014) with toxicological aspects, especially in multiresidue samples. Near 1000 fresh pome, stone, berries and small fruit were prepared by two accredited MSPD and QuEChERS methods followed by liquid and gas chromatography analyses with various systems of detection ECD/NPD/MS/MS. Twenty percent of the fruit samples contained 16 insecticide residues in the range of 0.01–0.81 mg/kg and 3% over MRL. The class of pesticide with the highest contribution to the ADI was found to be OPPs: dimethoate and diazinon for adults 48% and 66% of the ADI whereas for infants 144% and 294% of the ADI. The highest contributions of the cHQ to common MoA pesticides were AChE inhibitors: 135% for adults and 528% for infants, sodium channel modulators 4.9% and 20%, nicotic acetylocholine receptor < 2.9% and < 10.6% for adults and infants, respectively. The fruit with the highest contribution to the ADI were found to be apples (316%, 58%), cherries (96%, 37%) and pears (129%, 33%) for infants and adults. The study findings indicated that dietary exposures to insecticide residues in fruit would be unlikely to pose unacceptable health risks for the infants, toddlers and adults. - Highlights: • Health risk assessment of insecticide via dietary intake of fruit was estimated. • Sixteen residues in pome, stone, berries and small fruit ranged from 0.01 to 0.8 mg/kg. • Organophosphates were the most frequently occurring group with common MoA. • Dietary exposures for adults and children were below the safety reference values. • Toxicological study provided important date of human health.

  7. Opportunities and challenges of strengthening veterinary toxicology in Africa in the 21st century.

    Science.gov (United States)

    Rumbeiha, W K

    2001-04-01

    Veterinary toxicology is the specialty of veterinary medicine dealing with the study, diagnosis and treatment of effects of natural and man-made chemicals, forms of energy, and gasses in the animal kingdom. Historically, veterinary toxicology has been narrowly defined as the diagnosis and treatment of poisoning in domesticated animals and poultry, but the profession has grown to include food safety and environmental toxicology. Veterinary toxicology is most well-developed and recognized as a specialty in North America where professional societies and specialty board certification exist. In many parts of Africa, perhaps with the exception of South Africa, veterinary toxicology has not evolved in more than 40 years. The importance of veterinary toxicology in the modern era can not be over emphasized. This report examines the status of veterinary toxicology in Africa at the beginning of the 21st century and offers arguments why it is important for African governments to devote more resources to strengthen it.

  8. Overview: developmental toxicology: new directions.

    Science.gov (United States)

    Shuey, Dana; Kim, James H

    2011-10-01

    Since regulatory agencies began implementing the use of standardized developmental toxicology protocols in the mid-1960s, our knowledge base of embryo-fetal development and technologies for experimentation has grown exponentially. These developmental toxicology protocols were a direct result of the thalidomide tragedy from earlier that decade, when large numbers of women were exposed to the drug and over 10,000 cases of phocomelia resulted. In preventing a recurrence of such tragedies, the testing protocols are immensely successful and the field of toxicology has been dedicated to using them to advance safety and risk assessment of chemicals and pharmaceuticals. Recently, our perspectives on toxicity testing have been challenged by a growing awareness that while we have excelled in hazard identification, we are in dire need of improved methodologies for human health risk assessment, particularly with respect to the large numbers of environmental chemicals for which we have little toxicology data and to the growing sentiment that better alternatives to whole animals tests are needed. To provide a forum for scientists, researchers, and regulators, the Developmental and Reproductive Toxicology Technical Committee of the Health and Environmental Sciences Institute organized a 2-day workshop titled "Developmental Toxicology-New Directions" to evaluate lessons learned over the past 30 years and discuss the future of toxicology testing. The following four articles describe different presentations and discussions that were held over the course of those 2 days.

  9. [New antidotes in toxicology].

    Science.gov (United States)

    Bédry, Régis

    2008-04-30

    New antidotes appeared in the French pharmacopoeia (fomepizole, Viperfav), and old drugs, usually unused in toxicology, saw their indications enlarged in an antidotic activity (glucose and insulin, L-carnitine, octreotide). Fomepizole is an antidote for toxic alcohol and glycol intoxications, which is much easier to handle than ethylic alcohol and as efficient as the classical antidote of this kind of intoxication. Octreotide improves the result of hypertonic glucose infusion in sulfonylurea derivatives intoxications, by blocking insulin release. The glucose-insulin association allows the myocardium to use the main energy substrate necessary for its action in the setting of beta-blocking and calcium channel blocking agents intoxications when they are associated to a cardiogenic shock. Viperfav is a polyvalent antivenom used in European adders envenomations, which showed its effectiveness and safety. Levocarnitine allows to correct the wrong metabolic pathway induced by a deficit in carnitine in valproïc acid intoxications.

  10. Diagnostic and forensic toxicology.

    Science.gov (United States)

    Galey, F D

    1995-12-01

    In most competent veterinary diagnostic laboratories, analytical findings are interpreted by the veterinary toxicologist to determine the significance of the finding in view of historic, clinical, and pathologic findings. A veterinary toxicologist also will provide consultation about possible toxic rule-outs for a case, treatment of affected animals, and prevention of additional cases. Once all of the information is available, a complete summary of the findings can be provided to the client. When the procedures outlined are followed, including a systematic approach to collecting all the evidence (historic, clinical, pathologic, and analytic), proper sampling techniques, and good communication between the clinician and the client and laboratory, the usefulness of the toxicology investigation will be maximized.

  11. Honey bee toxicology.

    Science.gov (United States)

    Johnson, Reed M

    2015-01-01

    Insecticides are chemicals used to kill insects, so it is unsurprising that many insecticides have the potential to harm honey bees (Apis mellifera). However, bees are exposed to a great variety of other potentially toxic chemicals, including flavonoids and alkaloids that are produced by plants; mycotoxins produced by fungi; antimicrobials and acaricides that are introduced by beekeepers; and fungicides, herbicides, and other environmental contaminants. Although often regarded as uniquely sensitive to toxic compounds, honey bees are adapted to tolerate and even thrive in the presence of toxic compounds that occur naturally in their environment. The harm caused by exposure to a particular concentration of a toxic compound may depend on the level of simultaneous exposure to other compounds, pathogen levels, nutritional status, and a host of other factors. This review takes a holistic view of bee toxicology by taking into account the spectrum of xenobiotics to which bees are exposed.

  12. Immunization of mice with the nef gene from Human Immunodeficiency Virus type 1: Study of immunological memory and long-term toxicology

    Directory of Open Access Journals (Sweden)

    Engström Gunnel

    2007-07-01

    Full Text Available Abstract Background The human immunodeficiency virus type 1 (HIV-1 regulatory protein, Nef, is an attractive vaccine target because it is involved in viral pathogenesis, is expressed early in the viral life cycle and harbors many T and B cell epitopes. Several clinical trials include gene-based vaccines encoding this protein. However, Nef has been shown to transform certain cell types in vitro. Based on these findings we performed a long-term toxicity and immunogenicity study of Nef, encoded either by Modified Vaccinia virus Ankara or by plasmid DNA. BALB/c mice were primed twice with either DNA or MVA encoding Nef and received a homologous or heterologous boost ten months later. In the meantime, the Nef-specific immune responses were monitored and at the time of sacrifice an extensive toxicological evaluation was performed, where presence of tumors and other pathological changes were assessed. Results The toxicological evaluation showed that immunization with MVAnef is safe and does not cause cellular transformation or other toxicity in somatic organs. Both DNAnef and MVAnef immunized animals developed potent Nef-specific cellular responses that declined to undetectable levels over time, and could readily be boosted after almost one year. This is of particular interest since it shows that plasmid DNA vaccine can also be used as a potent late booster of primed immune responses. We observed qualitative differences between the T cell responses induced by the two different vectors: DNA-encoded nef induced long-lasting CD8+ T cell memory responses, whereas MVA-encoded nef induced CD4+ T cell memory responses. In terms of the humoral immune responses, we show that two injections of MVAnef induce significant anti-Nef titers, while repeated injections of DNAnef do not. A single boost with MVAnef could enhance the antibody response following DNAnef prime to the same level as that observed in animals immunized repeatedly with MVAnef. We also demonstrate

  13. Knowledge and Confidence of Emergency Clinicians in Managing Toxicological Presentations

    Directory of Open Access Journals (Sweden)

    Joseph Monteith

    2016-06-01

    Full Text Available Background: Acute poisonings are common presentations to emergency departments (EDs worldwide and require rapid assessment. Consultant emergency physicians (EPs faced with various toxicological presentations must initiate rapid investigations and empirical management. This study aimed to determine emergency department doctors’ level of knowledge and confidence in toxicological presentations, and factors that predicted these outcomes. Methods: Target participants included members of the Australasian College for Emergency Medicine (ACEM and readers of the emergency medicine website, “Life in the Fast Lane”. The survey was distributed electronically via the ACEM bulletin and posted on Life in the Fast Lane. A survey was designed based on toxicology multiple choice questions (MCQs. The questionnaire comprised 59 items: 10 demographic items; 20 items about confidence; 28 MCQs assessing knowledge of common and serious toxicological presentations. Results: There were 467 consenting respondents from 31 countries, with most residing in Australia (306/467, 66%. Respondents comprised similar proportions of consultant emergency physicians (196/467, 42.0%, and trainees (197/467, 42.2%.  Almost two-thirds (292/467; 62.1% had received formal training in toxicological emergencies, while a third (166/467, 35.5% had participated in a relevant conference or workshop. A total of 284/339 (83.8% participants completing all items achieved a knowledge test score >50%. More than 65% incorrectly answered questions on pharmacology of serotonin syndrome and lithium toxicity, and more than half incorrectly answered questions on use of 12 lead ECG in toxicology, calcium channel antagonist or tricyclic antidepressant toxicities. Predictors of overall knowledge for toxicology were receipt of formal toxicology education, and clinicians’ experience and seniority. Conclusion: The knowledge and confidence of doctors working in emergency departments is varied, yet

  14. Novel and future applications of microarrays in toxicological research.

    Science.gov (United States)

    Gant, Timothy W

    2007-08-01

    Microarray technologies have both fascinated and frustrated the toxicological community since their introduction around a decade ago. Fascination arose from the possibility offered by the technology to gain a profound insight into the cellular response to chemically mediated stress, and the potential that this genomic signature would be indicative of the biological mechanism by which that stress was induced. Frustrations have arisen primarily from technical factors such as data variance, the requirement for the application of advanced statistical and mathematical analysis, and difficulties associated with actually recognising signature gene expression patterns, and discerning mechanisms. Toxicogenomics was predicted to make toxicological assessment and extrapolation easier, faster and cheaper. The reality has been somewhat different; toxicogenomics is difficult. However, its potential when properly applied has been indicated by some well designed toxicogenomics studies, particularly in the differentiation of genotoxins from non-genotoxins. Technology waits though for no man. While the toxicological community has been working to apply transcriptomics (mRNA levels) in toxicology, the technology has moved beyond this application into new arenas. Some have application to toxicology and are reviewed here, except transcriptomics which has been extensively written about before. This review discusses the application of microarray technologies applied to the genome per se (amplifications, deletions, epigenetic change), mRNA translation and its control mechanisms through miRNA. Which of the new genomics technoï¿(1/2)logies will find most application in toxicology? In the opinion of the author there are three potentially major applications: i) arrayCGH in assessment and recognition of genotoxicity; ii) epigenetic assessment in developmental and transgenerational toxicology; and iii) miRNA assessment in all toxicology types, but particularly developmental toxicology.

  15. NTP Toxicology and Carcinogenesis Studies of Diethanolamine (CAS No. 111-42-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

    Science.gov (United States)

    1999-07-01

    Diethanolamine is widely used in the preparation of diethanolamides and diethanolamine salts of long-chain fatty acids that are formulated into soaps and surfactants used in liquid laundry and dishwashing detergents, cosmetics, shampoos, and hair conditioners. Diethanolamine is also used in textile processing, in industrial gas purification to remove acid gases, as an anticorrosion agent in metalworking fluids, and in preparations of agricultural chemicals. Aqueous diethanolamine solutions are used as solvents for numerous drugs that are administered intravenously. Diethanolamine was selected for evaluation because its large-scale production and pattern of use indicate the potential for widespread human exposure. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 2 years. Genetic toxicology studies were performed in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and B6C3F1 mouse peripheral blood erythrocytes. RATS: Groups of 50 male rats were administered 0, 16, 32, or 64 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Groups of 50 female rats were administered 0, 8, 16, or 32 mg/kg in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of vehicle control and dosed male and female rats was similar. Mean body weights of 64 mg/kg males were less than those of the vehicle controls beginning week 8, and mean body weights of females were generally similar to those of the vehicle control group. The only clinical finding attributed to diethanolamine administration was irritation of the skin at the site of application. Pathology Findings: Minimal to mild nonneoplastic lesions occurred at the site of application in the epidermis of dosed male and female rats. The incidence of acanthosis in 64 mg/kg males, the incidences of hyperkeratosis in 32 and 64 mg/kg males and in all dosed female groups, and the incidences of exudate

  16. A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

    Energy Technology Data Exchange (ETDEWEB)

    HABER, S.B.

    1987-06-26

    This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

  17. Toxicogenomic approaches in developmental toxicology testing.

    Science.gov (United States)

    Robinson, Joshua F; Piersma, Aldert H

    2013-01-01

    The emergence of toxicogenomic applications provides new tools to characterize, classify, and potentially predict teratogens. However, due to the vast number of experimental and statistical procedural steps, toxicogenomic studies are challenging. Here, we guide researchers through the basic framework of conducting toxicogenomic investigations in the field of developmental toxicology, providing examples of biological and technical factors that may influence response and interpretation. Furthermore, we review current, diverse applications of toxicogenomic-based approaches in teratology testing, including exposure-response characterization (dose and duration), chemical classification studies, and cross-model comparisons study designs. This review is intended to guide scientists through the challenging and complex structure of conducting toxicogenomic analyses, while considering the many applications of using toxicogenomics in study designs and the future of these types of "omics" approaches in developmental toxicology.

  18. Preclinical Toxicology Studies of Recombinant Human Platelet-Derived Growth Factor-BB Either Alone or in Combination with Beta-Tricalcium Phosphate and Type I Collagen

    Directory of Open Access Journals (Sweden)

    Conan S. Young

    2010-01-01

    Full Text Available Human platelet-derived growth factor-BB (hPDGF-BB is a basic polypeptide growth factor released from platelets at the injury site. It is a multifunctional molecule that regulates DNA synthesis and cell division and induces biological effects that are implicated in tissue repair, atherosclerosis, inflammatory responses, and neoplastic diseases. This paper is an overview of the toxicology data generated from a broad testing platform to determine bone, soft tissue, and systemic responses following administration of rhPDGF-BB. Moreover, the systemic and local toxicity of recombinant human PDGF-BB (rhPDGF-BB in combination with either beta-tricalcium phosphate (β-TCP or collagen combined with β-TCP was studied to determine dermal sensitization, irritation, intramuscular tissue responses, pyrogenicity, genotoxicity, and hemolytic properties. All data strongly suggest that rhPDGF-BB either alone or in combination with β-TCP or collagen with β-TCP is biocompatible and has neither systemic nor local toxicity, supporting its safe use in enhancing wound healing in patients.

  19. Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: A 3-day repeated exposure study.

    Science.gov (United States)

    Zanetti, Filippo; Titz, Bjoern; Sewer, Alain; Lo Sasso, Giuseppe; Scotti, Elena; Schlage, Walter K; Mathis, Carole; Leroy, Patrice; Majeed, Shoaib; Torres, Laura Ortega; Keppler, Brian R; Elamin, Ashraf; Trivedi, Keyur; Guedj, Emmanuel; Martin, Florian; Frentzel, Stefan; Ivanov, Nikolai V; Peitsch, Manuel C; Hoeng, Julia

    2017-03-01

    Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems toxicology approach, we investigated and compared the exposure effects of a reference cigarette (3R4F) and a heat-not-burn technology-based candidate MRTP, the Tobacco Heating System (THS) 2.2. Human gingival epithelial organotypic cultures were repeatedly exposed (3 days) for 28 min at two matching concentrations of cigarette smoke (CS) or THS2.2 aerosol. Results showed only minor histopathological alterations and minimal cytotoxicity upon THS2.2 aerosol exposure compared to CS (1% for THS2.2 aerosol vs. 30% for CS, at the high concentration). Among the 14 proinflammatory mediators analyzed, only 5 exhibited significant alterations with THS2.2 exposure compared with 11 upon CS exposure. Transcriptomic and metabolomic analysis indicated a general reduction of the impact in THS2.2 aerosol-exposed samples with respect to CS (∼79% lower biological impact for the high THS2.2 aerosol concentration compared to CS, and 13 metabolites significantly perturbed for THS2.2 vs. 181 for CS). This study indicates that exposure to THS2.2 aerosol had a lower impact on the pathophysiology of human gingival organotypic cultures than CS. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. The first toxicological study of the antiozonant and research tool ethylene diurea (EDU) using a Lemna minor L. bioassay: Hints to its mode of action.

    Science.gov (United States)

    Agathokleous, Eugenios; Mouzaki-Paxinou, Akrivi-Chara; Saitanis, Costas J; Paoletti, Elena; Manning, William J

    2016-06-01

    The antiozonant and research tool ethylene diurea (EDU) is widely studied as a phytoprotectant against the widespread pollutant ground-surface ozone. Although it has been extensively used, its potential toxicity in the absence of ozone is unknown and its mode of action is unclear. The purpose of this research was to toxicologically assess EDU and to further investigate its mode of action using Lemna minor L. as a model organism. Application of EDU concentrations greater than 593 mg L(-1) (practically 600 mg L(-1)) resulted in adverse inhibition of colony growth. As no-observed-toxic-effects concentration (NOEL) we recommend a concentration of 296 mg L(-1) (practically 300 mg L(-1)). A hormetic response was detected, i.e. stimulatory effects of low EDU concentrations, which may indicate overcompensation in response to disruption in homeostasis. Growth inhibition and suppressed biomass were associated with impacted chlorophyll a fluorescence (ΦPSII, qP and ETR). Furthermore, EDU increased mesophyll thickness, as indicated by frond succulence index. Applications of concentrations ≥593 mg L(-1) to uncontrolled environments should be avoided due to potential toxicity to sensitive organisms and the environment.

  1. Predictive toxicology in drug safety

    National Research Council Canada - National Science Library

    Xu, Jinghai J; Urban, Laszlo

    2011-01-01

    .... It provides information on the present knowledge of drug side effects and their mitigation strategy during drug discovery, gives guidance for risk assessment, and promotes evidence-based toxicology...

  2. Aggregated Computational Toxicology Online Resource

    Data.gov (United States)

    U.S. Environmental Protection Agency — Aggregated Computational Toxicology Online Resource (AcTOR) is EPA's online aggregator of all the public sources of chemical toxicity data. ACToR aggregates data...

  3. Behavioral assays in environmental toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Weiss, B.

    1979-01-01

    Environmental toxicology is too permeated by questions about how the whole organism functions to abandon intact animals as test systems. Behavior does not participate as a single entity or discipline. It ranges across the total spectrum of functional toxicity, from tenuous subjective complaints to subtle sensory and motor disturbances demanding advanced instrumentation for their evaluation. Three facets of behavioral toxicology that illustrate its breadth of interests and potential contributions are discussed.

  4. Analysis of Statistical Methods Currently used in Toxicology Journals.

    Science.gov (United States)

    Na, Jihye; Yang, Hyeri; Bae, SeungJin; Lim, Kyung-Min

    2014-09-01

    Statistical methods are frequently used in toxicology, yet it is not clear whether the methods employed by the studies are used consistently and conducted based on sound statistical grounds. The purpose of this paper is to describe statistical methods used in top toxicology journals. More specifically, we sampled 30 papers published in 2014 from Toxicology and Applied Pharmacology, Archives of Toxicology, and Toxicological Science and described methodologies used to provide descriptive and inferential statistics. One hundred thirteen endpoints were observed in those 30 papers, and most studies had sample size less than 10, with the median and the mode being 6 and 3 & 6, respectively. Mean (105/113, 93%) was dominantly used to measure central tendency, and standard error of the mean (64/113, 57%) and standard deviation (39/113, 34%) were used to measure dispersion, while few studies provide justifications regarding why the methods being selected. Inferential statistics were frequently conducted (93/113, 82%), with one-way ANOVA being most popular (52/93, 56%), yet few studies conducted either normality or equal variance test. These results suggest that more consistent and appropriate use of statistical method is necessary which may enhance the role of toxicology in public health.

  5. Avian models in teratology and developmental toxicology.

    Science.gov (United States)

    Smith, Susan M; Flentke, George R; Garic, Ana

    2012-01-01

    The avian embryo is a long-standing model for developmental biology research. It also has proven utility for toxicology research both in ovo and in explant culture. Like mammals, avian embryos have an allantois and their developmental pathways are highly conserved with those of mammals, thus avian models have biomedical relevance. Fertile eggs are inexpensive and the embryo develops rapidly, allowing for high-throughput. The chick genome is sequenced and significant molecular resources are available for study, including the ability for genetic manipulation. The absence of a placenta permits the direct study of an agent's embryotoxic effects. Here, we present protocols for using avian embryos in toxicology research, including egg husbandry and hatch, toxicant delivery, and assessment of proliferation, apoptosis, and cardiac structure and function.

  6. 75 FR 21003 - National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the NTP Board...

    Science.gov (United States)

    2010-04-22

    ... HUMAN SERVICES National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the... ``Request for Comments'' below). The NTP welcomes toxicology study information from completed, ongoing, or... concept may also encompass larger public health issues or topics in toxicology that could be...

  7. NTP Toxicology and Carcinogenesis Studies of Trichloroethylene (CAS No. 79-01-6) in Four Strains of Rats (ACI, August, Marshall, Osborne-Mendel) (Gavage Studies).

    Science.gov (United States)

    1988-04-01

    Trichloroethylene is an industrial solvent used primarily for vapor degreasing and cold cleaning. It was selected for study because of its industrial use and for potential for human exposure. (An estimated 3.5 million workers are exposed to trichloroethylene.) In an earlier study trichloroethylene (stabilized with epichlorohydrin and 1,2-epoxybutane) administered by gavage caused hepatocellular carcinomas in male and female B6C3F1 mice. Trichloroethylene administration did not increase the incidence of tumors in male or female Osborne-Mendel rats. However, the survival of dosed rats was reduced, thereby compromising the sensitivity of the study to detect a carcinogenic effect. The studies described in this report were conducted to compare the sensitivities of four strains of rats (ACI, August, Marshall, and Osborne-Mendel) to diisopropylamine-stabilized trichloroethylene. The results of the present studies demonstrate that long-term administration of trichloroethylene produces nephrotoxicity in four strains of rats and that the susceptibilities of these strains to the nephrotoxic effects of the chemical are similar. Because of chemically induced toxicity, reduced survival, and incomplete documentation of the experimental data, the studies are considered inadequate for either comparing or assessing trichloroethylene-induced carcinogenesis in these strains of rats. Toxicology and carcinogenesis studies of trichloroethylene (more than 99% pure, stabilized with 8 ppm diisopropylamine) were conducted by administering the chemical in corn oil gavage at doses of 0, 500, or 1,000 mg/kg per day, 5 day per week, for 103 weeks to groups of 50 male and 50 female ACI, August, Marshall, and Osborne-Mendel rats. The doses were selected on the basis of results from 13-week gavage studies in which groups of 10 male and 10 female ACI, August, and Marshall rats received daily doses or trichloroethylene (male: 125-2,000 mg/kg; female: 63-1,000 mg/kg). Doses for Osborne-Mendel rats

  8. Chemical mixture toxicology: from descriptive to mechanistic, and going on to in silico toxicology.

    Science.gov (United States)

    Yang, Raymond S H; El-Masri, Hisham A; Thomas, Russell S; Dobrev, Ivan D; Dennison, James E; Bae, Dong-Soon; Campain, Julie A; Liao, Kai H; Reisfeld, Brad; Andersen, Melvin E; Mumtaz, Moiz

    2004-11-01

    Because of the pioneering vision of certain leaders in the biomedical field, the last two decades witnessed rapid advances in the area of chemical mixture toxicology. Earlier studies utilized conventional toxicology protocol and methods, and they were mainly descriptive in nature. Two good examples might be the parallel series of studies conducted by the U.S. National Toxicology Program and TNO in The Netherlands, respectively. As a natural course of progression, more and more sophistication was incorporated into the toxicology studies of chemical mixtures. Thus, at least the following seven areas of scientific achievements in chemical mixture toxicology are evident in the literature: (a) the application of better and more robust statistical methods; (b) the exploration and incorporation of mechanistic bases for toxicological interactions; (c) the application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling; (d) the studies on more complex chemical mixtures; (e) the use of science-based risk assessment approaches; (f) the utilization of functional genomics; and (g) the application of technology. Examples are given for the discussion of each of these areas. Two important concepts emerged from these studies and they are: (1) dose-dependent toxicologic interactions; and (2) "interaction thresholds". Looking into the future, one of the most challenging areas in chemical mixture research is finding the answer to the question "when one tries to characterize the health effects of chemical mixtures, how does one deal with the infinite number of combination of chemicals, and other possible stressors?" Undoubtedly, there will be many answers from different groups of researchers. Our answer, however, is first to focus on the finite (biological processes) rather than the infinite (combinations of chemical mixtures and multiple stressors). The idea is that once we know a normal biological process(es), all stimuli and insults from external stressors

  9. NTP Toxicology and Carcinogenesis Studies of Roxarsone (CAS No. 121-19-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1989-03-01

    Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular

  10. Toxicological assessment of Ashitaba Chalcone.

    Science.gov (United States)

    Maronpot, Robert R

    2015-03-01

    The plant Angelica keiskei contains two main physiologically active flavonoid chalcones, 4-hydroxyderricin and xanthoangelol. Known as ashitaba in Japan, powder from the sap is widely consumed for its medicinal properties in Asia as a dietary supplement. Limited previously reported mammalian studies were without evidence of toxicity. GLP studies reported here, including a bacterial reverse mutation assay, a chromosome aberration assay, and an in vivo micronucleus assay are negative for genotoxicity. A GLP- compliant 90-day repeated oral gavage study of ashitaba yellow sap powder containing 8.45% chalcones in Sprague Dawley rats resulted in expected known physiological effects on coagulation parameters and plasma lipids at 300 and 1000 mg/kg/day. Ashitaba-related pathology included a dose-related male rat-specific alpha 2-urinary globulin nephropathy at 100, 300, and 1000 mg/kg/day and jejunal lymphangiectasia in both sexes at 1000 mg/kg/day. All other study parameters and histopathological changes were incidental or not of toxicological concern. Based on these studies ashitaba chalcone powder is not genotoxic with a NOAEL of 300 mg/kg in male and female rats.

  11. Evaluation of the Tobacco Heating System 2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke.

    Science.gov (United States)

    Wong, Ee Tsin; Kogel, Ulrike; Veljkovic, Emilija; Martin, Florian; Xiang, Yang; Boue, Stephanie; Vuillaume, Gregory; Leroy, Patrice; Guedj, Emmanuel; Rodrigo, Gregory; Ivanov, Nikolai V; Hoeng, Julia; Peitsch, Manuel C; Vanscheeuwijck, Patrick

    2016-11-30

    The objective of the study was to characterize the toxicity from sub-chronic inhalation of test atmospheres from the candidate modified risk tobacco product (MRTP), Tobacco Heating System version 2.2 (THS2.2), and to compare it with that of the 3R4F reference cigarette. A 90-day nose-only inhalation study on Sprague-Dawley rats was performed, combining classical and systems toxicology approaches. Reduction in respiratory minute volume, degree of lung inflammation, and histopathological findings in the respiratory tract organs were significantly less pronounced in THS2.2-exposed groups compared with 3R4F-exposed groups. Transcriptomics data obtained from nasal epithelium and lung parenchyma showed concentration-dependent differential gene expression following 3R4F exposure that was less pronounced in the THS2.2-exposed groups. Molecular network analysis showed that inflammatory processes were the most affected by 3R4F, while the extent of THS2.2 impact was much lower. Most other toxicological endpoints evaluated did not show exposure-related effects. Where findings were observed, the effects were similar in 3R4F- and THS2.2-exposed animals. In summary, toxicological changes observed in the respiratory tract organs of THS2.2 aerosol-exposed rats were much less pronounced than in 3R4F-exposed rats while other toxicological endpoints either showed no exposure-related effects or were comparable to what was observed in the 3R4F-exposed rats. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. Toxicology of Nanomaterials: Permanent interactive learning

    Directory of Open Access Journals (Sweden)

    Castranova Vince

    2009-10-01

    Full Text Available Abstract Particle and Fibre Toxicology wants to play a decisive role in a time where particle research is challenged and driven by the developments and applications of nanomaterials. This aim is not merely quantitative in publishing a given number of papers on nanomaterials, but also qualitatively since the field of nanotoxicology is rapidly emerging and benchmarks for good science are needed. Since then a number of things have happened that merit further analysis. The interactive learning issue is best shown by report and communications on the toxicology of multi-wall carbon nanotubes (CNT. A special workshop on the CNT has now been organized twice in Nagano (Japan and this editorial contains a summary of the most important outcomes. Finally, we take the opportunity discuss some recent reports from the nanotech literature, and more specifically a Chinese study that claims severe consequences of nanoparticle exposure.

  13. The toxicology expert: what is required?

    Science.gov (United States)

    Bass, R; Vamvakas, S

    2000-03-15

    In contrast to many traditional professions, toxicologists form a group with very different backgrounds, i.e. they may have been educated to become medical doctors, veterinarians, pharmacists, chemists, biochemists or biologists. Professional competence can be gained in different ways by candidate toxicologists, and according to the European system, their training can be divided into two parts. (i) Theoretical training on several topics such as analytical methods, organ toxicity, mutagenicity, carcinogenicity can be obtained by attending courses organised by the national societies of toxicology. (ii) Spending several years on active experimental work in the fields of modern toxicology (e.g. analytical methods, toxic and genotoxic mechanisms, reproductive toxicity) is necessary to develop the capability to design and carry out experimental studies and to evaluate one's own and other people's research results. Candidate toxicologists should learn to evaluate data with a strictly scientific 'plausibility above numbers' approach.

  14. Multiscale Toxicology- Building the Next Generation Tools for Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Retterer, S. T. [ORNL; Holsapple, M. P. [Battelle Memorial Institute

    2013-10-31

    A Cooperative Research and Development Agreement (CRADA) was established between Battelle Memorial Institute (BMI), Pacific Northwest National Laboratory (PNNL), Oak Ridge National Laboratory (ORNL), Brookhaven National Laboratory (BNL), Lawrence Livermore National Laboratory (LLNL) with the goal of combining the analytical and synthetic strengths of the National Laboratories with BMI's expertise in basic and translational medical research to develop a collaborative pipeline and suite of high throughput and imaging technologies that could be used to provide a more comprehensive understanding of material and drug toxicology in humans. The Multi-Scale Toxicity Initiative (MSTI), consisting of the team members above, was established to coordinate cellular scale, high-throughput in vitro testing, computational modeling and whole animal in vivo toxicology studies between MSTI team members. Development of a common, well-characterized set of materials for testing was identified as a crucial need for the initiative. Two research tracks were established by BMI during the course of the CRADA. The first research track focused on the development of tools and techniques for understanding the toxicity of nanomaterials, specifically inorganic nanoparticles (NPs). ORNL"s work focused primarily on the synthesis, functionalization and characterization of a common set of NPs for dissemination to the participating laboratories. These particles were synthesized to retain the same surface characteristics and size, but to allow visualization using the variety of imaging technologies present across the team. Characterization included the quantitative analysis of physical and chemical properties of the materials as well as the preliminary assessment of NP toxicity using commercially available toxicity screens and emerging optical imaging strategies. Additional efforts examined the development of high-throughput microfluidic and imaging assays for measuring NP uptake, localization, and

  15. Studies on the relationship between sinomenine distribution and its organic toxicology%青藤碱在大鼠体内分布与脏器毒理的关系研究

    Institute of Scientific and Technical Information of China (English)

    叶木荣; 刘良; 曾元儿; 张立群; 谭永恒; 邓素坚; 黄桂英

    2001-01-01

    s internal organs were in order of liver, heart, lung and brain either in single-dosed treated animals or in repeat-dosed treated animals for 6 wk. However,the concentration of sinomenine could not be detected by HPLC after l wk drug-suspension,the histopathological examination showed that sinomenine at the dosage of l50 mg*kg-l per day for 6wk treatment could slightly damage liver ce11s, dominant1y caused the cell edema,but no any influence on the sero1ogy of liver and kidney. Sinomenine ip could also cause a mild hyperaemia of the rats heart tissues but no any histopathological changes had been observed. In testis tissues no sinomenine had beed detected although the animals were treated by repeat treatment for 6 wk and no any histopathological changes had been found yet. However, Sinomenine could partialy inhibit the sperm vitalities and amount of the dead sperms were a1so augmented. It was similar to in vitro eperiments. These influences of sinomenine on testis could be quickly recovered by drug suspension. CONCLUSION Sinomenine concentration were in order of liver, heart, kidney, lung and brain either in treatment by single dose or by repeat-dose administration. The histopathological changes were only abserved in liver cells of the animals which indicates that it should be in consideration of the liver functions during treatment course of the drug.

  16. Toxicology-based cancer causation analysis of CoCr-containing hip implants: a quantitative assessment of genotoxicity and tumorigenicity studies.

    Science.gov (United States)

    Christian, Whitney V; Oliver, Lindsay D; Paustenbach, Dennis J; Kreider, Marisa L; Finley, Brent L

    2014-09-01

    In this paper, quantitative methods were used to evaluate the weight of evidence regarding a causative relationship between cobalt-chromium (CoCr)-containing hip implants and increased cancer risk. We reviewed approximately 80 published papers and identified no-observed-adverse-effect level (NOAEL) and/or lowest-observed-adverse-effect level (LOAEL) values for specific endpoints of interest: genotoxic effects from in vitro studies with human cell lines as well as genotoxicity and tumor formation in animal bioassays. Test articles included Co particles and ions, Cr particles and ions, and CoCr alloy particles as well as CoCr alloy implants. The NOAEL/LOAEL values were compared with body burdens of Co/Cr particles and ions we calculated to exist in systemic tissues of hip implant patients under normal and excessive wear conditions. We found that approximately 40 tumor bioassays have been conducted with CoCr alloy implants or Co/Cr particles and ions at levels hundreds to thousands of times higher than those present in hip implant patients, and none reported a statistically significant increased incidence of systemic tumors. Results from in vitro and in vivo genotoxicity assays, which are relatively less informative owing to false positives and other factors, also indicated that DNA effects would be highly unlikely to occur as a result of wear debris from a CoCr implant. Hence, the toxicological weight of evidence suggests that CoCr-containing hip implants are unlikely to be associated with an increased risk of systemic cancers, which is consistent with published and ongoing cancer epidemiology studies involving patients with CoCr hip implants. Copyright © 2014 John Wiley & Sons, Ltd.

  17. Toxicology as a nanoscience? – Disciplinary identities reconsidered

    Directory of Open Access Journals (Sweden)

    Maasen Sabine

    2006-04-01

    Full Text Available Abstract Toxicology is about to establish itself as a leading scientific discipline in addressing potential health effects of materials on the nanosize level. Entering into a cutting-edge field, has an impact on identity-building processes within the involved academic fields. In our study, we analyzed the ways in which the entry into the field of nanosciences impacts on the formation of disciplinary identities. Using the methods of qualitative interviews with particle toxicologists in Germany, Holland, Switzerland and the USA, we could demonstrate that currently, toxicology finds itself in a transitional phase. The development of its disciplinary identity is not yet clear. Nearly all of our interview partners stressed the necessity of repositioning toxicology. However, they each suggested different approaches. While one part is already propagandizing the establishment of a new discipline – 'nanotoxicology'- others are more reserved and are demanding a clear separation of traditional and new research areas. In phases of disciplinary new-orientation, research communities do not act consistently. Rather, they establish diverse options. By expanding its disciplinary boundaries, participating in new research fields, while continuing its previous research, and only vaguely defining its topics, toxicology is feeling its way into the new fields without giving up its present self-conception. However, the toxicological research community is also discussing a new disciplinary identity. Within this, toxicology could develop from an auxiliary into a constitutive position, and take over a basic role in the cognitive, institutional and social framing of the nanosciences.

  18. NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    1985-11-01

    Propylene is used as a starting material in the production of polypropylene plastics and various other chemicals, including acrylonitrile, isopropyl alcohol, propylene oxide, butyraldehyde, cumene, dodecane, nonene, and allyl chloride. The major derivatives are polypropylene (25%), acrylonitrile (15%), isopropyl alcohol (10%), and propylene oxide (10%). It is also a valuable feed-stock chemical for the production of gasoline. Other miscellaneous applications include use as a starting material for polymerization reactions to form vinyl chloride copolymers and low-molecular-weight homopolymers that are used as additives in lubricating oils and in the manufacture of hydroquinone. The chemical is also used as an aerosol propellant or component. The major end uses of propylene are in the production of fabricated plastics (50%) and fibers (15%). Toxicology and carcinogenesis studies of propylene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats and 49 or 50 B6C3F1 mice of each sex to propylene in air by inhalation at concentrations of 5,000 or 10,000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats and 50 mice of each sex in chambers received air only on the same schedule and served as chamber controls. The highest concentration of propylene that was considered safe for these studies was 10,000 ppm because of the risk of explosion that can occur at higher concentrations. The survival of exposed and control rats and mice was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration related. After week 59 of the study, mean body weights of 10,000-ppm male mice were usually slightly lower (5%) than those of the controls, whereas those in other exposed groups of male and female mice were generally comparable with those of the controls. No compound-related adverse clinical signs were

  19. Multiscale Toxicology - Building the Next Generation Tools for Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Thrall, Brian D.; Minard, Kevin R.; Teeguarden, Justin G.; Waters, Katrina M.

    2012-09-01

    A Cooperative Research and Development Agreement (CRADA) was sponsored by Battelle Memorial Institute (Battelle, Columbus), to initiate a collaborative research program across multiple Department of Energy (DOE) National Laboratories aimed at developing a suite of new capabilities for predictive toxicology. Predicting the potential toxicity of emerging classes of engineered nanomaterials was chosen as one of two focusing problems for this program. PNNL’s focus toward this broader goal was to refine and apply experimental and computational tools needed to provide quantitative understanding of nanoparticle dosimetry for in vitro cell culture systems, which is necessary for comparative risk estimates for different nanomaterials or biological systems. Research conducted using lung epithelial and macrophage cell models successfully adapted magnetic particle detection and fluorescent microscopy technologies to quantify uptake of various forms of engineered nanoparticles, and provided experimental constraints and test datasets for benchmark comparison against results obtained using an in vitro computational dosimetry model, termed the ISSD model. The experimental and computational approaches developed were used to demonstrate how cell dosimetry is applied to aid in interpretation of genomic studies of nanoparticle-mediated biological responses in model cell culture systems. The combined experimental and theoretical approach provides a highly quantitative framework for evaluating relationships between biocompatibility of nanoparticles and their physical form in a controlled manner.

  20. Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies

    Science.gov (United States)

    Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH4+PFBA) at doses up to 150 and 30 mg/kg/d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30 mg/kg/d in the 28-d study. Fe...

  1. Evaluation of 90-day Repeated Dose Oral Toxicity, Glycometabolism, Learning and Memory Ability, and Related Enzyme of Chromium Malate Supplementation in Sprague-Dawley Rats.

    Science.gov (United States)

    Feng, Weiwei; Wu, Huiyu; Li, Qian; Zhou, Zhaoxiang; Chen, Yao; Zhao, Ting; Feng, Yun; Mao, Guanghua; Li, Fang; Yang, Liuqing; Wu, Xiangyang

    2015-11-01

    Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the 90-day oral toxicity of chromium malate in Sprague-Dawley rats. The present study inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, lipid metabolism, and learning and memory ability in metabolically healthy Sprague-Dawley rats. The results showed that all rats survived and pathological, toxic, feces, and urine changes were not observed. Chromium malate did not cause measurable damage on liver, brain, and kidney. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of normal rats in chromium malate groups had no significant change when compared with control group and chromium picolinate group under physiologically relevant conditions. The serum and organ content of Cr in chromium malate groups had no significant change compared with control group. No significant changes were found in morris water maze test and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and true choline esterase (TChE) activity. The results indicated that supplementation with chromium malate did not cause measurable toxicity and has no obvious effect on glycometabolism and related enzymes, learning and memory ability, and related enzymes and lipid metabolism of female and male rats. The results of this study suggest that chromium malate is safe for human consumption.

  2. DDT毒性及毒理机制的研究进展%Study the Progress on the Toxicity and Toxicological Mechanism of DDT

    Institute of Scientific and Technical Information of China (English)

    李孟楠; 雷磊; 刘欣

    2011-01-01

    DDT hadbeen extensively used all over the world as a broad--spectrum organochlorine pesticide in the first half of 20th century. It's widely used in prevention and control of agricultural pests and diseases,and in control of mosquito--borne diseases such as Malaria,typhoid and so on. The toxic effects of DDT emerged day by day with its extensive use. If taken in DDT, Human will be of headache,dizziness, convulsions, respiratory failure even death, and could cause pathological changes in liver, kidney and other organs. DDT possesses potential endocrine disrupting effects to mimic estrogen activity,interfere the functions of endocrine system, and accumulate in breast milk or impact on future generations directly through the placenta. So,the research in DDT is with great practical significance. The paper summarizes and analyzes the recent studies on the toxicity and toxicological mechanism of DDT.%指出了DDT作为一种广谱有机氯杀虫剂,被广泛应用于防治农业病虫害以及传播疟疾和伤寒疾病的蚊蝇等害虫。分析了DDT具有潜在的内分泌干扰作用,表现出类雌激素作用,干扰生殖系统的功能,并能蓄积在母乳之中,或直接通过胎盘,对后代产生影响。在对近年来国内外关于DDT研究的热点问题进行讨论的基础上,对DDT的毒性、内分泌干扰作用和毒理机制的研究进行了综合评述。

  3. [Toxicological evaluation in the childhood].

    Science.gov (United States)

    Arroyo, Amparo; Rodrigo, Carlos; Marrón, M Teresa

    2014-03-01

    Intoxications in infancy require urgent medical treatment within national health systems. In our country they represent 0.3% of paediatric urgencies. Most of them are accidental intoxications but is not infrequent to find some related to child abuse or to suicidal intentions, especially in adolescence. The objectives of the study are to evaluate both clinical health care and medical legal aspects in intoxications in infancy. Medical assistance is described and it includes clinical diagnosis, typology of the more common toxics, percentages and referral to social work and emergency care equipment units of the Ministry of Social Welfare and the Department of Health or, where appropriate, directly to prosecutors and courts for their intervention. In cases of detection of alcohol, drugs or medication in infants, the importance of the correct interpretation of the results of toxicological findings is discussed. Several studies for the interpretation of results concerning the detection of these toxics are reported. Both legal aspects and the forensic medical opinion are assessed. The findings will be analysed by the judicial authority in order to circumscribe responsibilities or to take appropriate decisions concerning the protection of infants' interests. In conclusion intoxication in infancy can lead to legal proceedings requiring specific actions for their protection. Both physicians and hospitals must comply with the legal requirement of the submission to the court of judicial parties. On the other hand, this information is an interesting step toward reinforcing public health surveillance. Copyright © 2014 Elsevier España, S.L. All rights reserved.

  4. Gordon Research Conference on Genetic Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Project Director Penelope Jeggo

    2003-02-15

    Genetic toxicology represents a study of the genetic damage that a cell can incur, the agents that induce such damage, the damage response mechanisms available to cells and organisms, and the potential consequences of such damage. Genotoxic agents are abundant in the environment and are also induced endogenously. The consequences of such damage can include carcinogenesis and teratogenesis. An understanding of genetic toxicology is essential to carry out risk evaluations of the impact of genotoxic agents and to assess how individual genetic differences influence the response to genotoxic damage. In recent years, the importance of maintaining genomic stability has become increasingly recognized, in part by the realization that failure of the damage response mechanisms underlies many, if not all, cancer incidence. The importance of these mechanisms is also underscored by their remarkable conservation between species, allowing the study of simple organisms to provide significant input into our understanding of the underlying mechanisms. It has also become clear that the damage response mechanisms interface closely with other aspects of cellular metabolism including replication, transcription and cell cycle regulation. Moreover, defects in many of these mechanisms, as observed for example in ataxia telangiectasia patients, confer disorders with associated developmental abnormalities demonstrating their essential roles during growth and development. In short, while a decade ago, a study of the impact of DNA damage was seen as a compartmentalized area of cellular research, it is now appreciated to lie at the centre of an array of cellular responses of crucial importance to human health. Consequently, this has become a dynamic and rapidly advancing area of research. The Genetic Toxicology Gordon Research Conference is biannual with an evolving change in the emphasis of the meetings. From evaluating the nature of genotoxic chemicals, which lay at the centre of the early

  5. [Modern toxicology of magnetic nanomaterials].

    Science.gov (United States)

    Cywińska, Monika A; Grudziński, Ireneusz P

    2012-01-01

    Current advances in nanobiotechnology have led to the development of new field of nanomedicine, which includes many applications of nano(bio)materials for both diagnostic and therapeutic purposes (theranostics). Major expectations and challenges are on bioengineered magnetic nanoparticles when their come to delivering drug compounds, especially to targeting anticancer drugs to specific molecular endpoints in cancer therapy. The unique physicochemical properties of these nanoparticles offer great promise in modern cancer nanomedicine to provide new technological breakthroughs, such as guided drug and gene delivery, magnetic hyperthermia cancer therapy, tissue engineering, cancer cell tracking and molecular magnetic resonance imaging. Along with the expanding interest in bio-engineered magnetic nanoproducts their potential toxicity has become one of the major concerns. To date, a number of recent scientific evidences suggest that certain properties of magnetic nanoparticles (e.g., enhanced reactive area, ability to cross cell membranes, resistance to biodegradation) may amplify their cytotoxic potential relative to bulk non-nanoscale counterparts. In other words, safety assessment developed for ordinary magnetic materials may be of limited use in determining the health and environmental risks of the novel bio-engineered magnetic nanoproducts. In the present paper we discuss the main directions of research conducted to assess the toxicity of magnetic nanocompounds in experimental in vitro and in vivo models, pointing to the key issues concerning the toxicological analysis of magnetic nanomaterials. In addition new research directions of nanotoxicological studies elucidating the importance of developing alternative methods for testing magnetic nano(bio)products are also presented.

  6. Introduction: biomarkers in neurodevelopment toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Needleman, H.L.

    1987-10-01

    The search for markers of toxicant exposure and effect upon the development of organisms presents a set of challenges that differ in many ways from those encountered in the study of markers in reproduction or pregnancy. These latter two fields specify a relatively narrow set of organs or biological systems. The term development, on the other hand, can apply to any organ system, or to any set of phenomena that changes in an ordered way over time. For this reason the papers presented in the session on development were chosen to narrow the focus to neurodevelopmental markers, as such markers may be altered by neurotoxic exposure. In attempting to meet this task, the authors have been able to select a group of investigators who work at the leading edges of their respective fields of developmental neuroanatomy, neurotoxicology, neuroendocrinology, neuropsychology, and infant development. The notion that toxicants could affect behavior certainly is not new. Recent knowledge that behavioral aberrations can occur at exposures below those which produce organic changes, and that behavioral aberrations can occur at exposures below those which produce organic changes, and that behavioral observation might provide early markers of effect has given rise to two new fields: behavioral toxicology and behavioral teratology.

  7. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    Science.gov (United States)

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

  8. Toxicological assessment of enzyme-treated asparagus extract in rat acute and subchronic oral toxicity studies and genotoxicity tests.

    Science.gov (United States)

    Ito, Tomohiro; Ono, Tomoko; Sato, Atsuya; Goto, Kazunori; Miura, Takehito; Wakame, Koji; Nishioka, Hiroshi; Maeda, Takahiro

    2014-03-01

    The safety of enzyme-treated asparagus extract (ETAS) developed as a novel anti-stress functional material was assessed in acute and subchronic studies and genotoxicity assays. In the acute oral dose toxicity study, all rats survived during the test period and ETAS did not influence clinical appearance, body weight gain and necropsy findings at a dosage of 2000mg/kg body weight. Thus, the 50% lethal dose (LD50) of ETAS was determined to be greater than 2000mg/kg. The 90-day subchronic study (500, 1000 and 2000mg/kg body weight, delivered by gavage) in rats reported no significant adverse effects in food consumption, body weight, mortality, urinalysis, hematology, biochemistry, necropsy, organ weight and histopathology. In the micronucleus test of mice, the incidence of micronuclei in ETAS-administered groups (500, 1000 and 2000mg/kg/day, injected twice) was equivalent to that of the negative control group, while the positive control group receiving mitomycin C showed a high incidence. The potential of ETAS to induce gene mutation was tested using four Salmonella typhimurium strains and Escherichia coli WP2uvrA. The test sample was not mutagenic to the test strains. These results support the safety of ETAS as food and dietary supplement.

  9. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

    Science.gov (United States)

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

    2014-05-01

    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

  10. IRIS Toxicological Review of Acrolein (2003 Final)

    Science.gov (United States)

    EPA announced the release of the final report, Toxicological Review of Acrolein: in support of the Integrated Risk Information System (IRIS). The updated Summary for Acrolein and accompanying toxicological review have been added to the IRIS Database.

  11. Developmental and Reproductive Toxicology Database (DART)

    Data.gov (United States)

    U.S. Department of Health & Human Services — A bibliographic database on the National Library of Medicine's (NLM) Toxicology Data Network (TOXNET) with references to developmental and reproductive toxicology...

  12. A 90-day toxicology study of meat from genetically modified sheep overexpressing TLR4 in Sprague-Dawley rats.

    Science.gov (United States)

    Bai, Hai; Wang, Zhixian; Hu, Rui; Kan, Tongtong; Li, Yan; Zhang, Xiaosheng; Zhang, Jinlong; Lian, Ling; Han, Hongbing; Lian, Zhengxing

    2015-01-01

    Genetic modification offers alternative strategies to traditional animal breeding. However, the food safety of genetically modified (GM) animals has attracted increasing levels of concern. In this study, we produced GM sheep overexpressing TLR4, and the transgene-positive offsprings (F1) were confirmed using the polymerase chain reaction (PCR) and Southern blot. The expression of TLR4 was 2.5-fold compared with that of the wild-type (WT) sheep samples. During the 90-day safety study, Sprague-Dawley rats were fed with three different dietary concentrations (3.75%, 7.5%, and 15% wt/wt) of GM sheep meat, WT sheep meat or a commercial diet (CD). Blood samples from the rats were collected and analyzed for hematological and biochemical parameters, and then compared with hematological and biochemical reference ranges. Despite a few significant differences among the three groups in some parameters, all other values remained within the normal reference intervals and thus were not considered to be affected by the treatment. No adverse diet-related differences in body weights or relative organ weights were observed. Furthermore, no differences were observed in the gross necropsy findings or microscopic pathology of the rats whose diets contained the GM sheep meat compared with rats whose diets contained the WT sheep meat. Therefore, the present 90-day rat feeding study suggested that the meat of GM sheep overexpressing TLR4 had no adverse effect on Sprague-Dawley rats in comparison with WT sheep meat. These results provide valuable information regarding the safety assessment of meat derived from GM animals.

  13. Toxicological study of injuries of rat's hippocampus after lead poisoning by synchrotron microradiography and elemental mapping

    Energy Technology Data Exchange (ETDEWEB)

    Liang Feng [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Zhang Guilin, E-mail: glzhang@sinap.ac.c [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Xiao Xianghui; Cai Zhonghou; Lai, Barry [Advanced Photon Source, Argonne (United States); Hwu Yeukuang [Institute of Physics, Academia Sinica, Nankang, Taipei (China); Yan Chonghuai; Xu Jian [Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Children' s Environmental Health, Shanghai 200092 (China); Li Yulan; Tan Mingguang; Zhang Chuanfu [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Li Yan, E-mail: liyan@sinap.ac.c [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China)

    2010-09-15

    The hippocampus, a major component of the brain, is one of the target nervous organs in lead poisoning. In this work, a rat's hippocampal injury caused by lead was studied. The lead concentrations in blood, bone and hippocampus collected from rats subject to lead poisoning were quantified by Inductively Coupled Plasma Mass Spectrometry while morphological information and elemental distributions in the hippocampus were obtained with synchrotron radiation X-ray phase contrast imaging and synchrotron radiation micro-beam X-ray fluorescence, respectively. For comparison, identical characterization of the specimens from the rats in the control group was done in parallel. Results show that the ratios between the lead content in the treated group and that in the control group of the hippocampus, bone, and blood are about 2.66, 236, and 39.6, respectively. Analysis also revealed that some health elements such as S, K, Cl and P increase in the regions with high lead content in the treated hippocampus. Morphological differences between the normal and lead-exposed hippocampus specimens in some local areas were observed. Explicitly, the structure of the lead-exposed hippocampus was tortuous and irregular, and the density of the neurons in the Dentate Gyrus was significantly lower than that from the control group. The study shows that the synchrotron radiation methods are very powerful for investigating structural injury caused by heavy metals in the nervous system.

  14. Toxicological study of injuries of rat’s hippocampus after lead poisoning by synchrotron microradiography and elemental mapping

    Science.gov (United States)

    Liang, Feng; Zhang, Guilin; Xiao, Xianghui; Cai, Zhonghou; Lai, Barry; Hwu, Yeukuang; Yan, Chonghuai; Xu, Jian; Li, Yulan; Tan, Mingguang; Zhang, Chuanfu; Li, Yan

    2010-09-01

    The hippocampus, a major component of the brain, is one of the target nervous organs in lead poisoning. In this work, a rat's hippocampal injury caused by lead was studied. The lead concentrations in blood, bone and hippocampus collected from rats subject to lead poisoning were quantified by Inductively Coupled Plasma Mass Spectrometry while morphological information and elemental distributions in the hippocampus were obtained with synchrotron radiation X-ray phase contrast imaging and synchrotron radiation micro-beam X-ray fluorescence, respectively. For comparison, identical characterization of the specimens from the rats in the control group was done in parallel. Results show that the ratios between the lead content in the treated group and that in the control group of the hippocampus, bone, and blood are about 2.66, 236, and 39.6, respectively. Analysis also revealed that some health elements such as S, K, Cl and P increase in the regions with high lead content in the treated hippocampus. Morphological differences between the normal and lead-exposed hippocampus specimens in some local areas were observed. Explicitly, the structure of the lead-exposed hippocampus was tortuous and irregular, and the density of the neurons in the Dentate Gyrus was significantly lower than that from the control group. The study shows that the synchrotron radiation methods are very powerful for investigating structural injury caused by heavy metals in the nervous system.

  15. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity of Sulfur Mustard (HD) In Rats Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Sasser, L. B.; Miller, R. A.; Kalkwarf, D, R.; Buschbom, R. L.; Cushing, J. A.

    1989-06-30

    Occupational health standards have not been established for sulfur mustard [bis(2- chlorethyl)-sulfide], a strong alkylating agent with known mutagenic properties. Seventytwo Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12/group/ sex) and gavaged with either 0, 0.003 , 0.01 , 0.03 , 0.1 or 0.3 mg/kg of sulfur mustard in sesame oil 5 days/week for 13 weeks. No dose-related mortality was observed. A significant decrease (P ( 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg/kg group. Hematological evaluations and clinical chemistry measurements found no consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathologic evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg/kg and males at 0.1 mg/kg. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, an apparent increase in mitotic activity of the basilar epithelial cells, and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated NOEL for HD in this 90-day study is 0.1 mg/kg/day when administered orally.

  16. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies

    Directory of Open Access Journals (Sweden)

    Elnaggar YSR

    2015-08-01

    -targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD. Keywords: piperine, monoolein, cubosome, nanoparticles, Alzheimer’s disease, liquid crystalline 

  17. 42 CFR 493.937 - Toxicology.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Toxicology. 493.937 Section 493.937 Public Health... Proficiency Testing Programs by Specialty and Subspecialty § 493.937 Toxicology. (a) Program content and frequency of challenge. To be approved for proficiency testing for toxicology, the annual program...

  18. 42 CFR 493.1213 - Condition: Toxicology.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Toxicology. 493.1213 Section 493.1213 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES....1213 Condition: Toxicology. If the laboratory provides services in the subspecialty of Toxicology,...

  19. The new toxicology of sophisticated materials: nanotoxicology and beyond.

    Science.gov (United States)

    Maynard, Andrew D; Warheit, David B; Philbert, Martin A

    2011-03-01

    It has long been recognized that the physical form of materials can mediate their toxicity--the health impacts of asbestiform materials, industrial aerosols, and ambient particulate matter are prime examples. Yet over the past 20 years, toxicology research has suggested complex and previously unrecognized associations between material physicochemistry at the nanoscale and biological interactions. With the rapid rise of the field of nanotechnology and the design and production of increasingly complex nanoscale materials, it has become ever more important to understand how the physical form and chemical composition of these materials interact synergistically to determine toxicity. As a result, a new field of research has emerged--nanotoxicology. Research within this field is highlighting the importance of material physicochemical properties in how dose is understood, how materials are characterized in a manner that enables quantitative data interpretation and comparison, and how materials move within, interact with, and are transformed by biological systems. Yet many of the substances that are the focus of current nanotoxicology studies are relatively simple materials that are at the vanguard of a new era of complex materials. Over the next 50 years, there will be a need to understand the toxicology of increasingly sophisticated materials that exhibit novel, dynamic and multifaceted functionality. If the toxicology community is to meet the challenge of ensuring the safe use of this new generation of substances, it will need to move beyond "nano" toxicology and toward a new toxicology of sophisticated materials. Here, we present a brief overview of the current state of the science on the toxicology of nanoscale materials and focus on three emerging toxicology-based challenges presented by sophisticated materials that will become increasingly important over the next 50 years: identifying relevant materials for study, physicochemical characterization, and

  20. Latin America's present and future challenges in toxicology education.

    Science.gov (United States)

    Rojas, M

    2005-09-01

    Industrialization that Latin America has experienced during the past 50 years, the increase of population and the growth of chemical-related industries has generated a variety of environmental problems that must be addressed. After assessing these profound changes, greater emphasis should be placed on the study of environmental health and toxicology. Latin American countries face many problems that are common to other developing nations. Therefore, there is a demand for safety assessment and regulatory control of chemicals that create a need for increasing numbers of toxicologists. To meet this demand, educational programs in toxicology have to be designed. This paper utilizes a consultation questionnaire that includes toxicology-network members, scientists and educational institutions where toxicology is taught. An analysis of the information collected is made, with an emphasis on what we currently lack and on future challenges for toxicology professionals. Although the response from the study institutions was 65% (13 countries out of 20), the paper aims to assess the present situation of toxicology. The convenience for a certification/recognition for toxicologists is also evaluated. Action needs to be taken to promote scientific development based on regional specific needs that require increasing at the number of toxicology programs, and promoting of cooperation between academics and researchers. Among the limitations we have are the variability of curricula, objectives and priorities. The increasing globalization of markets and regulations requires the harmonization of graduate/postgraduate programs to ensure that risk assessment and management are dealt with uniformly. Cooperation among our countries and international assistance should play a more prominent role in the promotion of regional integration and the more efficient utilization of international experience in defining educational policies.

  1. Toxicology and carcinogenesis studies of 1-bromopropane (CAS No. 106-94-5) in F344/N rats and B6C3F1 mice (inhalation studies).

    Science.gov (United States)

    2011-08-01

    In the early to mid 1990s, 1-bromopropane was used primarily as an intermediate in the production of pesticides, quaternary ammonium compounds, flavors and fragrances, pharmaceuticals, and other chemicals in well-controlled, closed processes. In the mid to late 1990s, it was introduced as a less toxic replacement for methylene chloride in emissive applications such as vapor and immersion degreasing operations and critical cleaning of electronics and metals. 1-Bromopropane was also introduced as a nonflammable, nontoxic, fast-drying, and inexpensive solvent for adhesive resins, and has been marketed as a replacement for ozone depleting refrigerants. 1-Bromopropane was nominated for study by the Occupational Safety and Health Administration based on the potential for widespread occupational and environmental exposure and a lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 1-bromopropane (99% or greater pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study except one 500 ppm male. Mean body weights of 2,000 ppm rats were significantly less than those of the chamber controls. The absolute kidney weight of 1,000 ppm males, relative kidney weights of all exposed groups of males, and absolute and relative kidney weights of all exposed groups of females were significantly increased. The absolute and relative liver weights of 1,000 ppm males, relative liver weights of 500 and 2,000 ppm males, and absolute and relative liver weights of 500 ppm or greater females were significantly increased. Nasal lesions included suppurative inflammation in

  2. Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes.

    Science.gov (United States)

    Malloy, Timothy; Zaunbrecher, Virginia; Beryt, Elizabeth; Judson, Richard; Tice, Raymond; Allard, Patrick; Blake, Ann; Cote, Ila; Godwin, Hilary; Heine, Lauren; Kerzic, Patrick; Kostal, Jakub; Marchant, Gary; McPartland, Jennifer; Moran, Kelly; Nel, Andre; Oguseitan, Oladele; Rossi, Mark; Thayer, Kristina; Tickner, Joel; Whittaker, Margaret; Zarker, Ken

    2017-03-01

    Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational models, and other tools to expedite toxicological data generation in more cost-effective manner than traditional approaches. This article briefly reviews the challenges associated with using predictive toxicology in regulatory AA, then presents four recommendations for its advancement. It recommends using case studies to advance the integration of predictive toxicology into AA; adopting a stepwise process to employing predicative toxicology in AA beginning with prioritization of chemicals of concern; leveraging existing resources to advance the integration of predictive toxicology into the practice of AA, and supporting trans-disciplinary efforts. The further incorporation of predictive toxicology into AA would advance the ability of companies and regulators to select alternatives to harmful ingredients, and potentially increase the use of predictive toxicology in regulation more broadly. This article is protected by copyright. All rights reserved.

  3. Toxicological evaluation of organic residues

    Directory of Open Access Journals (Sweden)

    Eduardo de la Peña de Torres

    2005-12-01

    Full Text Available It is pointed out the importance of short term assays for the characterization of organic residues, specially some methods for toxicological, mutagenic, genotoxic and cytotoxic evaluation (Vibrio fischeri, Salmonella typhimurium and Allium cepa, used in the characterization of environmental complex mixtures lixiviates. These methods take part together with other bioassays in the evaluation by toxicological identification (VIT, which allows the evaluation of other ecotoxicological effects: a bioluminescence inhibition of Vibrio fischeri; b germination and root length of Lepidum sativum; c root length of Allium cepa and Tradescantia sp.; d inhibition of the mobility of Daphnia magna; and e abnormalities in the development of Oryzias latipes, or medaka fish. All these assays take part in the EU battery of bioassays, applied to discriminate and select between those environmental matrixes which must be subject to more complex and specific chemical characterizations.We make a review of the methods for toxicological evaluation, used for the characterization of chemical compounds or complex mixtures, as well as the use of its results for the human and environmental risk assessment. This evaluation consists, in short, of the identification of dangers, evaluation of dose-response ratio, evaluation of exposure and risk characterization, resulting in the analysis, use and communication of this risk. It is emphasized the high predictive value for carcinogenicity of some of these bioassays.It is shown the utility of short term assays for the evaluation of substances, products and complex mixtures, which would contribute to improve the toxicological knowledge of a greater number substances. This is a vital need in the EU, due to the lack of complete toxicological information of about the 70% of the 106.000 existing and used substances.It is emphasized the great value that mutagenicity assays represent inside the toxicological tests in the basic level, which

  4. Regulatory issues in accreditation of toxicology laboratories.

    Science.gov (United States)

    Bissell, Michael G

    2012-09-01

    Clinical toxicology laboratories and forensic toxicology laboratories operate in a highly regulated environment. This article outlines major US legal/regulatory issues and requirements relevant to accreditation of toxicology laboratories (state and local regulations are not covered in any depth). The most fundamental regulatory distinction involves the purposes for which the laboratory operates: clinical versus nonclinical. The applicable regulations and the requirements and options for operations depend most basically on this consideration, with clinical toxicology laboratories being directly subject to federal law including mandated options for accreditation and forensic toxicology laboratories being subject to degrees of voluntary or state government–required accreditation.

  5. Study on acute toxicological evaluation of ethanol extracts from fusty tea%莓茶乙醇提取物的急性毒性研究

    Institute of Scientific and Technical Information of China (English)

    谭平; 姚茂君; 辛益妹; 马美湖

    2011-01-01

    The acute toxicological evaluation was studied of ethanol extracts from fusty tea (Ampelopsis grossedentata). The rats were given the ethanol extracts from fusty tea with the maximum concentration and capacity by gastric perfusion. Twice a day, for 14 days. The result showed that compared with Wistar control group, there were no abnormal reactions during the observation period on skin, mucosa, coat color, eyes, breath, circulation, locomotor activity, central nervous system, behavior etc. In Wistar sample group, without rats' death, and the maximum tolerance was 10. Og/kg by gastric perfusion. There were no change in the tissues and organs on volume, color and texture, which showed the extracts were low toxic and are better safe to eat.%对莓荼乙醇提取物的急性毒性进行研究.取Wistar大鼠40只,清洁级,随机分为2组,每组20只,雌雄各半,以最大耐受量法灌胃给予受试样品组大鼠最大使用浓度和最大灌胃容量的莓茶乙醇提取物,1天2次(相隔4h),连续观察14d.结果表明,受试样品组大鼠毛色,皮肤,粘膜,眼睛,呼吸,循环,自主活动及中枢神经系统、行为表现等均与阴性对照组大鼠无明显差别,整个试验期内无大鼠死亡,莓茶乙醇提取物大鼠口服灌胃的最大耐受量为10.0g/kg大鼠体重;对所有试验大鼠进行大体解剖,组织器官未见有颜色、体积、质地等改变,说明莓荼乙醇提取物的毒性很小,具有较好的食用安全性.

  6. Predictive toxicology of cobalt ferrite nanoparticles: comparative in-vitro study of different cellular models using methods of knowledge discovery from data.

    Science.gov (United States)

    Horev-Azaria, Limor; Baldi, Giovanni; Beno, Delila; Bonacchi, Daniel; Golla-Schindler, Ute; Kirkpatrick, James C; Kolle, Susanne; Landsiedel, Robert; Maimon, Oded; Marche, Patrice N; Ponti, Jessica; Romano, Roni; Rossi, François; Sommer, Dieter; Uboldi, Chiara; Unger, Ronald E; Villiers, Christian; Korenstein, Rafi

    2013-07-29

    Cobalt-ferrite nanoparticles (Co-Fe NPs) are attractive for nanotechnology-based therapies. Thus, exploring their effect on viability of seven different cell lines representing different organs of the human body is highly important. The toxicological effects of Co-Fe NPs were studied by in-vitro exposure of A549 and NCIH441 cell-lines (lung), precision-cut lung slices from rat, HepG2 cell-line (liver), MDCK cell-line (kidney), Caco-2 TC7 cell-line (intestine), TK6 (lymphoblasts) and primary mouse dendritic-cells. Toxicity was examined following exposure to Co-Fe NPs in the concentration range of 0.05 -1.2 mM for 24 and 72 h, using Alamar blue, MTT and neutral red assays. Changes in oxidative stress were determined by a dichlorodihydrofluorescein diacetate based assay. Data analysis and predictive modeling of the obtained data sets were executed by employing methods of Knowledge Discovery from Data with emphasis on a decision tree model (J48). Different dose-response curves of cell viability were obtained for each of the seven cell lines upon exposure to Co-Fe NPs. Increase of oxidative stress was induced by Co-Fe NPs and found to be dependent on the cell type. A high linear correlation (R2=0.97) was found between the toxicity of Co-Fe NPs and the extent of ROS generation following their exposure to Co-Fe NPs. The algorithm we applied to model the observed toxicity belongs to a type of supervised classifier. The decision tree model yielded the following order with decrease of the ranking parameter: NP concentrations (as the most influencing parameter), cell type (possessing the following hierarchy of cell sensitivity towards viability decrease: TK6 > Lung slices > NCIH441 > Caco-2 = MDCK > A549 > HepG2 = Dendritic) and time of exposure, where the highest-ranking parameter (NP concentration) provides the highest information gain with respect to toxicity. The validity of the chosen decision tree model J48 was established by yielding a higher accuracy than that

  7. HaSNPV几丁质酶的分离纯化与毒理学研究%Purification and Toxicological Studies of HaSNPV Chitinase

    Institute of Scientific and Technical Information of China (English)

    惠有为; 夏天; 赵亚玲; 贾静芳

    2011-01-01

    Recombinant bacterium GS115-pPIC 9k-ChiA 4.0 fermented chitinase, which was purified by ammomum sulfate precipitation, dialysis , DEAE Sepharose Fast Flow ion exchange chromatography and Sephadex G-1OO gel filtration chromatography, obtained electrophoretically pure chitinase. Rate of recovery was 19. 64% , and purification factor was 17. 74. Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus ( HaSNPV) chitinase toxicological studies carried out by contact toxicity and stomach toxicity, chitinase liquefied Plutella xylostella larvae cell and caused death. The effect and the concentration of chitinase is proportional to time, and the effect caused by stomach toxicity was more intense than by action of contact toxicity. The result of antibacterial experiments which were performed on Helminthosporium sativum , Tomato botrytis cinerea , Tobacco brown spot , and Colletotrichum gloeosporioides , indicated that chitinase can inhibit fungal by enzymatic hydrolysis of chitin in fungal cell wall.%利用重组工程茵GSl 15-pPIC 9k-ChiA 4.0发酵几丁质酶粗液,经(NH4)2SO4盐析、透析、DEAE SepIlarose Fast F1ow离子交换层析以及Sephadex G-100凝胶过滤层析分离纯化,获得电泳纯的棉铃虫单粒包埋型核型多角体病毒(HasNPV)几丁质酶,回收率为19.64%,纯化17.74倍;经HaSNPV几丁质酶毒理学研究,通过触杀作用和胃毒作用,几丁质酶使小菜蛾幼虫细胞液化,导致死亡,其作用效果与几丁质酶浓度和作用时间成正比,且胃毒作用大于触杀作用;经小麦根腐、烟草赤星、番茄灰霉和苹果炭疽等植物病原真菌的抑菌实验,表明几丁质酶可以通过酶解真菌细胞壁中的几丁质达到抑茵作用.

  8. A toxicological and dermatological assessment of macrocyclic lactone and lactide derivatives when used as fragrance ingredients

    DEFF Research Database (Denmark)

    Belsito, D.; Bickers, D.; Bruze, M.;

    2011-01-01

    /kg/day. The MLs had low acute toxicity and no significant toxicity in repeat dose oral ordermal toxicity studies. Effects on blood biochemistry were reversible after 2 weeks of no treatment. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Reproductive and developmental...... or photosensitization was observed. In animal studies, the MLs are not sensitizers at lower exposures from consumer products. Eleven ML materials were evaluated for human sensitization. Of these, only ethylene brassylate showed evidence of sensitization in 2/27 studies (sensitization frequency 4/2059 total). Based...

  9. Ecological and toxicological responses in a multistressor scenario: Are monitoring programs showing the stressors or just showing stress? A case study in Brazil.

    Science.gov (United States)

    López-Doval, Julio C; Meirelles, Sergio Tadeu; Cardoso-Silva, Sheila; Moschini-Carlos, Viviane; Pompêo, Marcelo

    2016-01-01

    The Metropolitan Region of São Paulo (MRSP) is located in the Brazilian State of São Paulo and reservoirs in this region are vital for water supply and energy production. Changes in economic, social, and demographic trends produced pollution of water bodies, decreasing water quality for human uses and affecting freshwater populations. The presence of emerging pollutants, classical priority substances, nutrient excess and the interaction with tropical-climate conditions require periodic reviews of water policies and monitoring programs in order to detect and manage these threats in a global change scenario. The objective of this work is to determine whether the monitoring program of the São Paulo's Environmental Agency, is sufficient to explain the toxicological and biological responses observed in organisms in reservoirs of the MRSP, and whether it can identify the possible agents causing these responses. For that, we used publicly available data on water quality compiled by this agency in their routine monitoring program. A general overview of these data and a chemometric approach to analyze the responses of biotic indexes and toxicological bioassays, as a function of the physical and chemical parameters monitored, were performed. Data compiled showed temporal and geographical information gaps on variables measured. Toxicological responses have been observed in the reservoirs of the MRSP, together with a high incidence of impairments of the zooplankton community. This demonstrates the presence of stressors that affect the viability of organisms and populations. The statistical approach showed that the data compiled by the environmental agency are insufficient to identify and explain the factors causing the observed ecotoxicological responses and impairments in the zooplankton community, and are therefore insufficient to identify clear cause-effect relationships. Stressors different from those analyzed could be responsible for the observed responses.

  10. Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

    OpenAIRE

    Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Wang, Jiang, 1959-; Phelps, Mitch; Potter, Philip M.; Goins, William B; Fernandez, Soledad A.; Chiocca, E. Antonio

    2013-01-01

    MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantl...

  11. Reproduction and juvenile animal toxicology studies in the rat with a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL(®)) for the treatment of grass pollen allergy.

    Science.gov (United States)

    Baldrick, Paul; Hewings, Simon; Skinner, Murray

    2011-11-01

    Pollinex(®) Quattro Grass has been developed for the prevention or relief of allergic symptoms caused by pollen in both adults and children. Reproduction and juvenile animal toxicology studies have been performed. Subcutaneous injection on Day 14 prior to pairing and on Days 6 and 13 of gestation to pregnant rats at 2000SU/0.5 mL elicited no signs of maternal or embryo-foetal toxicity. Mating, fertility, fecundity and pup parameters were all unaffected by treatment. Once-weekly subcutaneous administration at ascending doses of 300, 800, 2000 and 2000SU/0.5 mL followed by a 4 week non-dose period to juvenile rats from 3 weeks of age showed no signs of obvious toxicity. As in a previously performed adult animal toxicology study with the vaccine, not unexpected, but relatively minor, immuno-stimulatory effects were seen in this study along with injection site reaction which can largely be attributed to the presence of tyrosine in the formulation.

  12. Transgenic mice in developmental toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Woychik, R.P.

    1992-01-01

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  13. Transgenic mice in developmental toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Woychik, R.P.

    1992-12-31

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  14. PIXE applications to the toxicological field

    Energy Technology Data Exchange (ETDEWEB)

    Santos, C.E.I. dos; Dias, J.F.; Jobim, P.F.C.; Yoneama, M.L. [Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil). Instituto de Fisica. Laboratorio de Implantacao Ionica; Andrade, V.M. [Universidade do Extremo Sul Catarinense, Criciuma, SC (Brazil). Laboratorio de Biologia Celular e Molecular; Amaral, L.; Silva, J. da [Universidade Luterana do Brasil, Canoas, RS (Brazil). Laboratorio de Toxicologia Generica

    2013-07-01

    Full text: Several studies have been carried out in order to investigate the toxicological properties of some chemical elements in different type of biological samples. lon beam techniques, in particular PIXE, have been successfully used to analyze the elemental composition of food, beverage, plants and animal tissues. In this context, the PIXE line of the lon Implantation Laboratory (Porto Alegre, Brazil) have been used in the last few years to study food and beverage processing and biological specimens exposed to contaminated environment. The aim of this study is to present some of our results using PIXE analysis applied to toxicological research field. For instance, a recent published research [1] investigated the genotoxic and mutagenic effects in tobacco farmers exposed to metal-based formulated pesticides. Levels of Mg, AI, CI, Zn, Cr and Br, elements associated with DNA damage, were higher in the blood samples of tobacco farmers exposed to pesticide than in the non-exposed group. The occupational genotoxicity among copper smelters was also investigated [2]. The elemental content of blood samples were analyzed by PIXE. DNA damage in the peripheral blood Iymphocytes of workers exposed to copper smelter was observed. However, no clear correlation was found between the metal content and DNA damage. [1] F. R. da Silva, J. da Silva, M. C. AlIgayer, C. F. Simon, J. F. Dias, C. E. I. dos Santos, M. Salvador, C. Branco, N. B. Schneider, V. Kahl, P. Rohr, K. Kvitko, J. Hazard. Mat., 225-226 (2012) 81-90. (author)

  15. Confusion of concepts in mixture toxicology.

    Science.gov (United States)

    Könemann, W H; Pieters, M N

    1996-01-01

    Regulatory limit values are generally set for single compounds. However, humans are exposed both simultaneously and sequentially to a wide variety of compounds. Some concepts on mixture toxicology are discussed in this introduction to the European Conference on Combination Toxicology. Studies on mixtures are often accompanied by statements about the type of combined action, which can be, for example, additive, synergistic or antagonistic. Unfortunately, comparison of results is hardly possible for various reasons. First, the terminology for indicating combined action is far from consistent. Bearing this in mind, researchers should be explicit in the definitions of terms. Secondly, depending on the model, different conclusions may be drawn from the same results. It is therefore important to provide clear definitions of the null hypothesis. Thirdly, adequate statistical methods should be used for testing the null hypothesis. In the past, many mixtures studies either used no statistics or used statistics incorrectly. Last, but not least, the study should be designed in such a way that it should be possible to obtain clear answers. In this introduction, it is stressed that environmental toxicologists should focus on the low-dose region of the dose-effect curves. It appears that interactions are less plausible at low doses. Dose additivity, however, cannot be excluded.

  16. 21 CFR 862.3280 - Clinical toxicology control material.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Clinical toxicology control material. 862.3280... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3280 Clinical toxicology control material. (a) Identification. A clinical toxicology...

  17. Resource Guide to Careers in Toxicology, 3rd Edition.

    Science.gov (United States)

    Society of Toxicology, Reston, VA.

    This resource guide was prepared by the Tox 90's Educational Issues Task Force of the Society of Toxicology. The introduction provides information on the Society of Toxicology and financial support for graduate students in toxicology. Other sections include career opportunities in toxicology, academic and postdoctoral programs in toxicology, and…

  18. 21 CFR 862.3200 - Clinical toxicology calibrator.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Clinical toxicology calibrator. 862.3200 Section... (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862.3200 Clinical toxicology calibrator. (a) Identification. A clinical toxicology calibrator...

  19. Toxicological Effects of Fullerenes on Caenorhabditis elegans

    Science.gov (United States)

    Schomaker, Justin; Snook, Renee; Howell, Carina

    2014-03-01

    The nematode species Caenorhabditis elegans is a useful genetic model organism due to its simplicity and the substantial molecular, genetic, and developmental knowledge about the species. In this study, this species was used to test the toxicological effects of C60 fullerene nanoparticles. In previous studies using rats, a solution of C60 fullerenes in olive oil proved to extend the life of the subjects. The purpose of this experiment was to subject C. elegans to varying concentrations of C60 fullerenes and observe their toxicological effects. Initial findings indicate a link between fullerene exposure and enlargement of the vulva as well as the formation of a small nodule at the base of the tail in some individuals. While the fullerenes are not lethally toxic in C. elegans, results will be presented that pertain to changes in life span and progeny of the nematodes exposed to varying concentrations of fullerenes as well as the mechanisms of toxicity. High magnification imaging via SEM and/or AFM will be used to characterize the fullerene nanoparticles. Testing the toxicity of fullerenes in a wide variety of organisms will lead to a more complete understanding of the effects of fullerenes on living organisms to ultimately understand their effects in humans. This work was supported by National Science Foundation grants DUE-1058829, DMR-0923047, DUE-0806660 and Lock Haven FPDC grants.

  20. Toxicología General y Aplicada

    OpenAIRE

    García Fernández, Antonio Juan

    2011-01-01

    Presentaciones de los temas de Toxicología General y Aplicada: clínica, alimentaria y ambiental impartidos en la asignatura de Toxicología de la licenciatura de Veterinaria en la Universidad de Murcia en el curso 2011/12. Presentaciones de los temas de Toxicología General y Aplicada: clínica, alimentaria y ambiental impartidos en la Facultad de Veterinaria en el curso 2011/12.

  1. Toxicología clínica comunitaria Community Clinical Toxicology

    Directory of Open Access Journals (Sweden)

    María Elena Leal

    2011-08-01

    Full Text Available En algunos países de América Latina las intoxicaciones agudas se manejan de manera profesional por médicos especialistas en la mate-ria. Algo similar ocurre con las intoxicaciones crónicas de origen laboral en el sector formal. No obstante, una realidad diferente ocurre en cuanto a la evaluación de las intoxicaciones crónicas de origen ambiental, dado que éstas por su naturaleza, son más difíciles de diagnosticar. Para el tratamiento de las intoxicaciones agudas se han organizado Centros de Información y Atención Toxicológica, pero para las intoxicaciones crónicas ambientales no se ha generado organismos semejantes. Por consiguiente, en este trabajo sugerimos un modelo de atención de la intoxicaciones crónicas a través de grupos multidisciplinarios bajo el esquema de una nueva disciplina: la Toxicología Clínica Comunitaria, cuyo objetivo sería la atención simultánea de las intoxicaciones agudas que generalmente se atienden en un ámbito hospitalario y de las intoxicaciones ambientales que por lo normal se presentan a nivel comunitario. El objetivo final es aprovechar la experiencia que existe en la Región en cuanto a Toxicología Clínica para organizar el trabajo comunitario.In some Latin American countries acute intoxication is professionally managed by specialized physicians qualified in the area. Something similar occurs with work-related chronic intoxication in the formal sector. However, a different reality prevails for the assessment of chronic intoxication of environmental origin, since it is by definition more difficult to diagnose. For treatment of acute intoxication, Toxicological Information and Care Centers have been set up, though similar bodies have not been created for chronic environmental intoxication. Therefore, in this study a model of chronic intoxication care is proposed, using multidisciplinary teams adopting a new approach, namely Community Clinical Toxicology, the goal of which would be the

  2. TRANSGENIC FISH MODEL IN ENVIRONMENTAL TOXICOLOGY

    Directory of Open Access Journals (Sweden)

    Madhuri Sharma

    2012-05-01

    Full Text Available A number of experiments and the use of drugs have been performed in fish. The fish may be used as model organism in various biological experiments, including environmental toxicology. Aquatic animals are being engineered to increase aquaculture production, for medical and industrial research, and for ornamental reasons. Fish have been found to play an important role in assessing potential risks associated with exposure to toxic substances in aquatic environment. Hence, it has been thought that the development of transgenic fish can enhance the use of fish in environmental toxicology. India has developed experimental transgenics of rohu fish, zebra fish, cat fish and singhi fish. Genes, promoters and vectors of indigenous origin are now available for only two species namely rohu and singhi for engineering growth. Development of fish model carrying identical transgenes to those found in rodents is beneficial and has shown that several aspects of in vivo mutagenesis are similar between the two classes of vertebrates. Fish shows the frequencies of spontaneous mutations similar to rodents and respond to mutagen exposure consistent with known mutagenic mechanisms. The feasibility of in vivo mutation analysis using transgenic fish has been demonstrated and the potential value of transgenic fish as a comparative animal model has been illustrated. Therefore, the transgenic fish can give the significant contribution to study the environmental toxicity in animals as a whole.

  3. Problem definition study on techniques and methodologies for evaluating the chemical and toxicological properties of combustion products of gun systems, Volume 1: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Ross, R.H.; Pal, B.C.; Lock, S.; Ramsey, R.S.; Jenkins, R.A.; Griest, W.H.; Guerin, M.R.

    1988-03-01

    Gun exhaust is a complex mixture of both organic and inorganic chemical species. Similar to other mixtures, it has both vapor and particulate phases. This report contains information concerning the chemical characterization of gun exhaust and offers recommendations for its chemical and toxicological investigation. Propellent compositions used in munitions are all nitrocellulose based but are categorized by the inclusion of the other major ingredients (i.e., single-based propellants contain nitrocellulose only, double-base propellants contain nitrocellulose and nitroglycerin, and triple-base propellants contain nitrocellulose, nitroguanidine, and nitroglycerin). The principal decomposition products present in gun exhaust are carbon monoxide, hydrogen, carbon dixiode, water, and nitrogen (approximately 99% by volume). A number of minor products have been reported to be present in gun exhaust including nitrogen oxides, ammonia, inorganic particulates (e.g., lead and copper), and polycylic aromatic hydrocarbons (of unknown origin). 233 refs., 19 figs., 19 tabs.

  4. Toxicology and epidemiology: improving the science with a framework for combining toxicological and epidemiological evidence to establish causal inference.

    Science.gov (United States)

    Adami, Hans-Olov; Berry, Sir Colin L; Breckenridge, Charles B; Smith, Lewis L; Swenberg, James A; Trichopoulos, Dimitrios; Weiss, Noel S; Pastoor, Timothy P

    2011-08-01

    Historically, toxicology has played a significant role in verifying conclusions drawn on the basis of epidemiological findings. Agents that were suggested to have a role in human diseases have been tested in animals to firmly establish a causative link. Bacterial pathogens are perhaps the oldest examples, and tobacco smoke and lung cancer and asbestos and mesothelioma provide two more recent examples. With the advent of toxicity testing guidelines and protocols, toxicology took on a role that was intended to anticipate or predict potential adverse effects in humans, and epidemiology, in many cases, served a role in verifying or negating these toxicological predictions. The coupled role of epidemiology and toxicology in discerning human health effects by environmental agents is obvious, but there is currently no systematic and transparent way to bring the data and analysis of the two disciplines together in a way that provides a unified view on an adverse causal relationship between an agent and a disease. In working to advance the interaction between the fields of toxicology and epidemiology, we propose here a five-step "Epid-Tox" process that would focus on: (1) collection of all relevant studies, (2) assessment of their quality, (3) evaluation of the weight of evidence, (4) assignment of a scalable conclusion, and (5) placement on a causal relationship grid. The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causality.

  5. Graduate Training in Toxicology in Colleges of Veterinary Medicine.

    Science.gov (United States)

    Robens, J. F.; Buck, W. B.

    1979-01-01

    Presented are an American Board of Veterinary Toxicology survey and evaluation of the training resources available in graduate programs in toxicology located in colleges of veterinary medicine. Regulatory toxicology, number of toxicologists needed, and curriculum are also discussed. (JMD)

  6. Correlation Between Physicochemical Characteristics and Toxicological Properties of Nanomaterials

    Science.gov (United States)

    2012-01-25

    Schlager, and Hussain. “Crystal Structure Mediates Mode of Death in TiO2 Nanotoxicity”. J. Nanopart . Res. (2009) 11: 1361-1374. Cho and Biswas...nanoparticle dispersions for toxicological studies. J Nanopart . Res. (on-line June, 2008), 11:77-89, 2009. Kim, SC, Chen, D-R, Qi, C., Gelein RM

  7. Toxicologic profile of acrylonitrile.

    Science.gov (United States)

    Woutersen, R A

    1998-01-01

    Acrylonitrile is a monomer used extensively as a raw material in the manufacturing of acrylic fibers, plastics, synthetic rubbers, and acrylamide. It has been classified as a probable human carcinogen according to the results of numerous chronic rat bioassays. The present report summarizes the toxicity data on acrylonitrile and reviews available data concerning the mechanism (genetic versus epigenetic) by which acrylonitrile is carcinogenic in rats. From the evaluation of the relevant toxicity data, it can be concluded that acrylonitrile is indeed carcinogenic to rats after either oral or inhalational exposure. However, information on other mammalian species is lacking, and, moreover, the exact mechanism of the carcinogenic process is unclear. Therefore, it is recommended to conduct an additional long-term inhalation carcinogenicity study with acrylonitrile in mice, as well as studies into the mechanism by which acrylonitrile induces (brain) tumors in rats (genetic versus epigenetic).

  8. Operational Toxicology Research

    Science.gov (United States)

    2006-08-01

    Modeling of Chemical Warfare Agent Exposure """""""""."".""""".,,.,, 25 Study Request 131 ... Development of a Reference Dose ( IUD ) for Ammonium Perchlorate...development of technology for Detection of Microorganisms in for devising a pOltable instrument that recovers Water On-going microorganisms from drinking...ofTechn010gy 2001-2003 Conduct research to determine efficacy of metallic for Decontamination of Microorganisms oxide nanopartic!es amended to an air

  9. Toxicology for the Equine Practitioner.

    Science.gov (United States)

    Al-Dissi, Ahmad

    2015-08-01

    A wide variety of toxins cause diseases in the horse and are investigated routinely by veterinarians and veterinary pathologists to identify the cause of illness and death. A complete investigation involves performing a thorough necropsy and requires macroscopic and microscopic examination of lesions and a variety of laboratory testing to obtain an accurate diagnosis. The identification of gross lesions by equine practitioners is often the first step in formulating a diagnostic plan. This article provides a description of selected common toxins producing detectable gross lesions in horses in North America. The article is useful to equine practitioners and veterinary pathologists investigating a toxicology-related death.

  10. Toxicological evaluation of pure hydroxytyrosol.

    Science.gov (United States)

    Auñon-Calles, David; Canut, Lourdes; Visioli, Francesco

    2013-05-01

    Of all the phenolic constituents of olives and extra virgin olive oil, hydroxytyrosol is currently being actively exploited as a potential supplement or preservative to be employed in the nutraceutical, cosmeceutical, and food industry. In terms of safety profile, hydroxytyrosol has only been investigated as the predominant part of raw olive mill waste water extracts, due to the previous unavailability of appropriate quantities of the pure compound. We report the toxicological evaluation of hydroxytyrosol and, based on the results, propose a No Observed Adverse Effects Level (NOAEL) of 500mg/kg/d.

  11. Toxicology of perfluorinated compounds

    Energy Technology Data Exchange (ETDEWEB)

    Stahl, Thorsten [Hessian State Laboratory, Wiesbaden (Germany); Mattern, Daniela; Brunn, Hubertus [Hessian State Laboratory, Giessen (Germany)

    2011-12-15

    Perfluorinated compounds [PFCs] have found a wide use in industrial products and processes and in a vast array of consumer products. PFCs are molecules made up of carbon chains to which fluorine atoms are bound. Due to the strength of the carbon/fluorine bond, the molecules are chemically very stable and are highly resistant to biological degradation; therefore, they belong to a class of compounds that tend to persist in the environment. These compounds can bioaccumulate and also undergo biomagnification. Within the class of PFC chemicals, perfluorooctanoic acid and perfluorosulphonic acid are generally considered reference substances. Meanwhile, PFCs can be detected almost ubiquitously, e.g., in water, plants, different kinds of foodstuffs, in animals such as fish, birds, in mammals, as well as in human breast milk and blood. PFCs are proposed as a new class of 'persistent organic pollutants'. Numerous publications allude to the negative effects of PFCs on human health. The following review describes both external and internal exposures to PFCs, the toxicokinetics (uptake, distribution, metabolism, excretion), and the toxicodynamics (acute toxicity, subacute and subchronic toxicities, chronic toxicity including carcinogenesis, genotoxicity and epigenetic effects, reproductive and developmental toxicities, neurotoxicity, effects on the endocrine system, immunotoxicity and potential modes of action, combinational effects, and epidemiological studies on perfluorinated compounds). (orig.)

  12. Toxicology of blast overpressure.

    Science.gov (United States)

    Elsayed, N M

    1997-07-25

    Blast overpressure (BOP) or high energy impulse noise, is the sharp instantaneous rise in ambient atmospheric pressure resulting from explosive detonation or firing of weapons. Blasts that were once confined to military and to a lesser extent, occupational settings, are becoming more universal as the civilian population is now increasingly at risk of exposure to BOP from terrorist bombings that are occurring worldwide with greater frequency. Exposure to incident BOP waves can cause auditory and non-auditory damage. The primary targets for BOP damage are the hollow organs, ear, lung and gastrointestinal tract. In addition, solid organs such as heart, spleen and brain can also be injured upon exposure. However, the lung is more sensitive to damage and its injury can lead to death. The pathophysiological responses, and mortality have been extensively studied, but little attention, was given to the biochemical manifestations, and molecular mechanism(s) of injury. The injury from BOP has been, generally, attributed to its external physical impact on the body causing internal mechanical damage. However, a new hypothesis has been proposed based on experiments conducted in the Department of Respiratory Research, Walter Reed Army Institute of Research, and later in the Department of Occupational Health, University of Pittsburgh. This hypothesis suggests that subtle biochemical changes namely, free radical-mediated oxidative stress occur and contribute to BOP-induced injury. Understanding the etiology of these changes may shed new light on the molecular mechanism(s) of injury, and can potentially offer new strategies for treatment. In this symposium. BOP research involving auditory, non-auditory, physiological, pathological, behavioral, and biochemical manifestations as well as predictive modeling and current treatment modalities of BOP-induced injury are discussed.

  13. Overview of the "epigenetic end points in toxicologic pathology and relevance to human health" session of the 2014 Society Of Toxicologic Pathology Annual Symposium.

    Science.gov (United States)

    Hoenerhoff, Mark J; Hartke, James

    2015-01-01

    The theme of the Society of Toxicologic Pathology 2014 Annual Symposium was "Translational Pathology: Relevance of Toxicologic Pathology to Human Health." The 5th session focused on epigenetic end points in biology, toxicity, and carcinogenicity, and how those end points are relevant to human exposures. This overview highlights the various presentations in this session, discussing integration of epigenetics end points in toxicologic pathology studies, investigating the role of epigenetics in product safety assessment, epigenetic changes in cancers, methodologies to detect them, and potential therapies, chromatin remodeling in development and disease, and epigenomics and the microbiome. The purpose of this overview is to discuss the application of epigenetics to toxicologic pathology and its utility in preclinical or mechanistic based safety, efficacy, and carcinogenicity studies.

  14. The Toxicology Education Summit: building the future of toxicology through education.

    Science.gov (United States)

    Barchowsky, Aaron; Buckley, Lorrene A; Carlson, Gary P; Fitsanakis, Vanessa A; Ford, Sue M; Genter, Mary Beth; Germolec, Dori R; Leavens, Teresa L; Lehman-McKeeman, Lois D; Safe, Stephen H; Sulentic, Courtney E W; Eidemiller, Betty J

    2012-06-01

    Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.

  15. 42 CFR 493.845 - Standard; Toxicology.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Standard; Toxicology. 493.845 Section 493.845 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... These Tests § 493.845 Standard; Toxicology. (a) Failure to attain a score of at least 80 percent...

  16. Study on Toxicology of Anti-dysentery Powder in Chinese Veterinary Pharmacopoeia%药典方剂止痢散的毒理学研究

    Institute of Scientific and Technical Information of China (English)

    孟庆大; 谢闪闪; 付本懂; 张长帅; 韦旭斌

    2011-01-01

    为了从现代药理学角度评价止痢散临床用药的安全性,对其进行了毒理学研究.通过小鼠灌胃给药对止痢散的急性毒性进行了测定;以生理盐水对照组、止咳散低剂量组(4 g/kg)、中剂量组(8 g/kg)、高剂量组(16 g/kg)对大鼠连续灌胃给药4周,记录每日饮水量、饲料采食量及每周体重,测定末次给药后24 h及停药2周后血液生化指标及血常规,做病理切片,评定其长期毒性.结果显示:小鼠口服止痢散的LD50为124.8g/kg,95%可信限111.2~142.5 g/kg,单味雄黄的LD50为10.5g/kg,95%可信限9.7~11.1 g/kg;且对大鼠连续灌胃给药4周期间,止痢散低剂量组大鼠没有出现可见的毒性反应;中、高剂量组大鼠呈现出明显毒性反应,具体表现为采食及饮水量减少,体重减轻,消化道充血、出血,肝脏存在炎性细胞浸润、肝细胞水泡变性,肾脏、心脏轻度出血,血清尿素氮、谷丙转氨酶,谷草转氨酶、与碱性磷酸酶升高等;不过高剂量组大鼠用药期间也没有出现死亡;上述毒性反应在停药2周后基本消失.以上结果表明,止痢散的毒性较低,按兽药典规定剂量用药是安全的,但长期使用能引起蓄积作用,造成肝肾损伤,其毒性具有可逆性.%To evaluate the prescription's clinical safety from the perspective of modern pharmacology, studies were made on the toxicology of anti-dysentery powder.In this experiment we examined the acute toxicity of anti-dysentery powder and realgar by intragastric administration in mice; assessed its long-term toxicity in rats through recording the amount of hydroposia and feeds-foraging per day and body weight per week, measuring hematologic and blood biochemical indexed after administration for 24 hours and withdrawal for 2 weeks,and made pathological section after intragastric administration for 4 weeks in rats with low(4 g/kg), middle(8 g/kg), and high( 16 g/kg) dosage groups.The results showed that: the medial

  17. 统计学在临床前药物毒理学安全性评价中的应用%Application of the Statistical Methods in Toxicology Studies of Preclinical Safety Evaluation of Drugs

    Institute of Scientific and Technical Information of China (English)

    吕建军; 霍桂桃; 王三龙; 屈哲; 林志; 杨艳伟; 张頔; 范玉明; 汪巨峰

    2016-01-01

    Objective: To introduce the statistical methods to analyze data of general toxicology, genetic toxicology, reproductive studies, safety pharmacology and carcinogenicity studies for preclinical safety evaluation of drugs.Methods:This paper brielfy introduced the design, experimental animal species, endpoints, experimental unit, and checks for biologically relevant changes. In addition, we comprehensively reviewed statistical methods that used in data analysis of in vivo micronucleus study, comet study, organ weight analysis in general toxicology study, dog telemetry study, central nervous system study and carcinogenicity study. We further discussed the current issues and possible solutions of the statistical methods.Results: The statistical methods of in vivo micronucleus study include general linear model, exact trend tests, nonparametric trend tests, pairwise test, and generalized linear model. Summary of statistic (median of the log response) at the general level and general linear model to the animal data is adopted for comet study. Analysis of covariance (ANCOVA), absolute organ weights, and relative organ weights are selected for organ weight analysis. The statistical methods used for quantitative data of CNS assay include ANCOVA, analysis of variance, Williams’ trend test or Dunnett’s t-test. Peto test and poly-k test are the statistical methods of carcinogenicity study.Conclusion: This paper introduced the statistical methods used in general toxicology, genetic toxicology, reproductive studies, safety pharmacology and carcinogenicity studies, which may provide references for data statistical analysis of toxicology studies in preclinical safety evaluation of drugs in China.%目的:介绍临床前药物毒理学安全性评价一般毒理学、遗传毒理学、生殖毒性实验、安全药理学和致癌性实验中的数据分析的统计学方法。方法:本文简要介绍了一般毒理实验、遗传毒理实验、生殖毒性实验、安全药

  18. Evolution of toxicology information systems

    Energy Technology Data Exchange (ETDEWEB)

    Wassom, J.S.; Lu, P.Y. [Oak Ridge National Laboratory, TN (United States)

    1990-12-31

    Society today is faced with new health risk situations that have been brought about by recent scientific and technical advances. Federal and state governments are required to assess the many potential health risks to exposed populations from the products (chemicals) and by-products (pollutants) of these advances. Because a sound analysis of any potential health risk should be based on the use of relevant information, it behooves those individuals responsible for making the risk assessments to know where to obtain needed information. This paper reviews the origins of toxicology information systems and explores the specialized information center concept that was proposed in 1963 as a means of providing ready access to scientific and technical information. As a means of illustrating this concept, the operation of one specialized information center (the Environmental Mutagen Information Center at Oak Ridge National Laboratory) will be discussed. Insights into how toxicological information resources came into being, their design and makeup, will be of value to those seeking to acquire information for risk assessment purposes. 7 refs., 1 fig., 4 tabs.

  19. Toxicological management of chlorophacinone poisoning.

    Science.gov (United States)

    Lagrange, F; Corniot, A G; Titier, K; Bedry, R; Pehourcq, F

    1999-01-01

    A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL). The examination revealed excitation and nausea, with a normal prothrombin index (PI). Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide. In a search for easy toxicological management of chlorophacinone poisoning treated by phytomenadione and a cytochrome P450 inducer (phenobarbital), PI and chlorophacinone plasma levels were monitored concomitantly during 17 days. A simple HPLC procedure for the determination of chlorophacinone in human plasma is reported for that purpose. Under phenobarbital 200 mg/day, chlorophacinone exhibited an apparent elimination half-life (3.27 days) shorter than in previously reported cases. If PI is useful for planning phytomenadione treatment and used for therapeutic monitoring of AVK, the chlorophacinone concentrations follow-up may provide a better estimation of the duration of hospitalisation. Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone. This case illustrates how toxicological management may facilitate toxicokinetics and therapeutic data acquisition.

  20. Toxicological Assessment of Noxious Inhalants

    Directory of Open Access Journals (Sweden)

    Kleinsasser, N. H.

    2004-12-01

    Full Text Available In the past centuries mankind has been exposed to various forms of air pollution not only at his occupational but also in his social environment. He mainly gets exposed with these pollutants through the respiratory organs and partially absorbs them into the body. Many of these airborne substances can be harmful for humans and some of them may account for tumorigenic effects.The following essay describes the main features of toxicological assessment of inhalative environmental and workplace xenobiotics. The essay also explains relevant characteristics and limit values of noxious compounds and gases and depicts modern testing methods. To this end, emphasis is given on methods characterizing the different stages of tumorigenic processes. Various test systems have been developed which can be used in vivo, ex vivo or in vitro. They are to a great part based on the evidence of changes in DNA or particular genes of cells. Among others they have highlighted the impact of interindividual variability on enzymatic activation of xenobiotics and on susceptibility of the host to tumor diseases.Unfortunately, for many inhalative environmental noxious agents no sufficient risk profiles have been developed. The completion of these profiles should be the goal of toxicological assessment in order to allow reasonable socioeconomic or individual-based risk reduction.

  1. Nutritional toxicology: basic principles and actual problems.

    Science.gov (United States)

    Hathcock, J N

    1990-01-01

    Nutritional toxicology is a specialty that combines the backgrounds and research approaches of nutrition and toxicology. Many problems of substantial importance to health and food safety involve interactions of nutrition process and requirement with the effects of toxicological impact. Solution of these problems requires research that meets the procedural and design criteria of experimental nutrition and these of experimental toxicology. The relationships may be described in three basic categories: (1) influence of nutrition on toxicities; (2) influence of toxicants on nutrition; and (3) toxicities of nutrients. Trypsin inhibitor research, an example of diet impacting on toxicological response, illustrates the necessity of controlling nutritional composition aspects that can confound the results. Prolonged acetaminophen administration provides an example of the effects of toxicants on nutritional requirement and function which could be important for persons with marginal sulphur amino acid intake.

  2. The use of kestrels in toxicology

    Science.gov (United States)

    Wiemeyer, Stanley N.; Lincer, J.L.; Bird, David M.; Bowen, Reed

    1987-01-01

    Various species of kestrels have become important bioindicators of environmental quality and test species for comparative toxicology in captivity. At least 7 species of kestrels have been used to document the presence of environmental contamination primarily organochlorines and metals, in at least 15 countries. Captive kestrels have been used in studies involving a wide variety of environmental contaminants and toxicants examining: bioaccumulation; lethal toxicity using acute, chronic, and secondary exposures; effects on reproduction, eggshell thickness, and related enzyme systems; and effects on a wide variety of physiological and biochemical parameters. Field studies have examined the response of kestrels to exposure to insecticides. Kestrels should continue to play a vital role as a bioindicator and raptorial 'white mouse', especially because of their relationship to other falconiformes, several of which have been shown to be extremely sensitive to environmental changes.

  3. Toxicology

    Science.gov (United States)

    Macewen, J. W.

    1973-01-01

    Oxygen toxicity is examined, including the effects of oxygen partial pressure variations on toxicity and oxygen effects on ozone and nitrogen dioxide toxicity. Toxicity of fuels and oxidizers, such as hydrazines, are reported. Carbon monoxide, spacecraft threshold limit values, emergency exposure limits, spacecraft contaminants, and water quality standards for space missions are briefly summarized.

  4. Predictive toxicology: the paths of the future; Toxicologie predictive: les voies du futur

    Energy Technology Data Exchange (ETDEWEB)

    Detilleux, Ph.; Vallier, L.; Legallais, C.; Leclerc, E.; Prot, J.M.; Choucha, L.; Baudoin, R.; Dufresne, M.; Gautier, A.; Carpentier, B.; Mansuy, D.; Pery, A.; Brochot, C.; Manivet, Ph.; Rabilloud, Th.; Spire, C.; Coumoul, X.; Junot, Ch.; Laprevote, O.; Le pape, A.; Le Guevel, R.; Tourneur, E.; Ben Mkaddem, S.; Chassin, C.; Aloulou, M.; Goujon, J.M.; Hertif, A.; Ouali, N.; Vimont, S.; Monteiro, R.; Rondeau, E.; Elbim, C.; Werts, C.; Vandewalle, A.; Ben Mkaddem, S.; Pedruzzi, E.; Coant, N.; Bens, M.; Cluzeaud, F.; Ogier-Denis, E.; Pongnimitprasert, N.; Babin-Chevaye, C.; Fay, M.; Bernard, M.; Dupuy, C.; Ei Benna, J.; Gougerot-Pocidale, M.A.; Braut-Boucher, F.; Pinton, Ph.; Lucioli, J.; Tsybulskyy, D.; Joly, B.; Laffitte, J.; Bourges-Abella, N.; Oswald, I.P.; Kolf-Clauw, M.; Pierre, St.; Bats, A.S.; Chevallier, A.; Bui, L.Ch.; Ambolet-Camoit, A.; Garlatti, M.; Aggerbeck, M.; Barouki, R.; Al Khansa, I.; Blanck, O.; Guillouzo, A.; Bars, R.; Rouas, C.; Bensoussan, H.; Suhard, D.; Tessier, C.; Grandcolas, L.; Pallardy, M.; Gueguen, Y.; Sparfel, L.; Pinel-Marie, M.L.; Boize, M.; Koscielny, S.; Desmots, S.; Pery, A.; Fardel, O.; Alvergnas, M.; Rouleau, A.; Lucchi, G.; Mantion, G.; Heyd, B.; Richert, L.; Ducoroy, P.; Martin, H.; Val, St.; Martinon, L.; Cachier, H.; Yahyaoui, A.; Marfaing, H.; Baeza-Squiban, A.; Martin-Chouly, C.; Bonvallet, M.; Morzadec, C.; Fardel, O.; Vernhet, L.; Baverel, G.; El Hage, M.; Nazaret, R.; Conjard-Duplany, A.; Ferrier, B.; Martin, G.; Legendre, A.; Desmots, S.; Lecomte, A.; Froment, P.; Habert, R.; Lemazurier, E.; Robinel, F.; Dupont, O.; Sanfins, E.; Dairou, J.; Chaffotte, A.F.; Busi, F.; Rodrigues Lima, F.; Dupret, J.M.; Mayati, A.; Le Ferrec, E.; Levoin, N.; Paris, H.; Uriac, Ph.; N' Diaye, M.; Lagadic-Gossmann, D.; Fardel, O.; Assemat, E.; Boublil, L.; Borot, M.C.; Marano, F.; Baeza-Squiban, A.; Martiny, V.Y.; Moroy, G.; Badel, A.; Miteva, M.A.; Hussain, S.; Ferecatu, I.; Borot, C.; Andreau, K.; Baeza-Squiban, A. [and others

    2010-07-01

    Prevention of possible noxious effects in relation with the exposure to one or several chemical, physical or biological agents present in our domestic or professional environment is one of today's big public health stakes. Another stake is the better assessment of the risks linked with the use of health-care products. The efficacy and predictiveness of toxicology studies are directly related to the combination of alternate complementary methods and animal experiments (obtaining data from different species and with different models: in vitro, ex vivo and in vivo). Despite important efforts, the toxicological evaluation remains perfectible. The proceedings of this 2010 congress of the French Society of cell pharmaco-toxicology deal with recent advances, both scientific and technological, in 'predictive toxicology'. Four main topics are approached: cell and organ models, 'omics', in silico modeling, and new technologies (imaging, cell ships, high-speed processing). Among the different presentations, 3 abstracts present some recent advances in imaging techniques applied to toxicology studies. These are: 1 - first uses in toxicology of TOF-SIMS mass spectroscopy imaging (O. Laprevote, Paris-Descartes Univ. (FR)); 2 - Small animal imaging, a tool for predictive toxicology (A. Le Pape, CNRS Orleans (FR)); 3 - uranium localization at cell level using SIMS imaging technique (C. Rouas et al., IRSN Fontenay-aux-Roses (FR)). (J.S.)

  5. Studies on the Simultaneous Formation of Aroma-Active and Toxicologically Relevant Vinyl Aromatics from Free Phenolic Acids during Wheat Beer Brewing.

    Science.gov (United States)

    Langos, Daniel; Granvogl, Michael

    2016-03-23

    During the brewing process of wheat beer, the desired aroma-active vinyl aromatics 2-methoxy-4-vinylphenol and 4-vinylphenol as well as the undesired and toxicologically relevant styrene are formed from their respective precursors, free ferulic acid, p-coumaric acid, and cinnamic acid, deriving from the malts. Analysis of eight commercial wheat beers revealed high concentrations of 2-methoxy-4-vinylphenol and 4-vinylphenol always in parallel with high concentrations of styrene or low concentrations of the odorants in parallel with low styrene concentrations, suggesting a similar pathway. To better understand the formation of these vinyl aromatics, each process step of wheat beer brewing and the use of different strains of Saccharomyces cerevisiae were evaluated. During wort boiling, only a moderate decarboxylation of free phenolic acids and formation of desired and undesired vinyl aromatics were monitored due to the thermal treatment. In contrast, this reaction mainly occurred enzymatically catalyzed during fermentation with S. cerevisiae strain W68 with normal Pof(+) activity (phenolic off-flavor) resulting in a wheat beer eliciting the typical aroma requested by consumers due to high concentrations of 2-methoxy-4-vinylphenol (1790 μg/L) and 4-vinylphenol (937 μg/L). Unfortunately, also a high concentration of undesired styrene (28.3 μg/L) was observed. Using a special S. cerevisiae strain without Pof(+) activity resulted in a significant styrene reduction (beer aroma.

  6. Functional Toxicogenomics: Mechanism-Centered Toxicology

    Directory of Open Access Journals (Sweden)

    Chris D. Vulpe

    2010-11-01

    Full Text Available Traditional toxicity testing using animal models is slow, low capacity, expensive and assesses a limited number of endpoints. Such approaches are inadequate to deal with the increasingly large number of compounds found in the environment for which there are no toxicity data. Mechanism-centered high-throughput testing represents an alternative approach to meet this pressing need but is limited by our current understanding of toxicity pathways. Functional toxicogenomics, the global study of the biological function of genes on the modulation of the toxic effect of a compound, can play an important role in identifying the essential cellular components and pathways involved in toxicity response. The combination of the identification of fundamental toxicity pathways and mechanism-centered targeted assays represents an integrated approach to advance molecular toxicology to meet the challenges of toxicity testing in the 21st century.

  7. Biosynthesis and toxicological effects of patulin.

    Science.gov (United States)

    Puel, Olivier; Galtier, Pierre; Oswald, Isabelle P

    2010-04-01

    Patulin is a toxic chemical contaminant produced by several species of mold, especially within Aspergillus, Penicillium and Byssochlamys. It is the most common mycotoxin found in apples and apple-derived products such as juice, cider, compotes and other food intended for young children. Exposure to this mycotoxin is associated with immunological, neurological and gastrointestinal outcomes. Assessment of the health risks due to patulin consumption by humans has led many countries to regulate the quantity in food. A full understanding of the molecular genetics of patulin biosynthesis is incomplete, unlike other regulated mycotoxins (aflatoxins, trichothecenes and fumonisins), although the chemical structures of patulin precursors are now known. The biosynthetic pathway consists of approximately 10 steps, as suggested by biochemical studies. Recently, a cluster of 15 genes involved in patulin biosynthesis was reported, containing characterized enzymes, a regulation factor and transporter genes. This review includes information on the current understanding of the mechanisms of patulin toxinogenesis and summarizes its toxicological effects.

  8. Handbook of toxicology of chemical warfare agents

    CERN Document Server

    2010-01-01

    This groundbreaking book covers every aspect of deadly toxic chemicals used as weapons of mass destruction and employed in conflicts, warfare and terrorism. Including findings from experimental as well as clinical studies, this one-of-a-kind handbook is prepared in a very user- friendly format that can easily be followed by students, teachers and researchers, as well as lay people. Stand-alone chapters on individual chemicals and major topics allow the reader to easily access required information without searching through the entire book. This is the first book that offers in-depth coverage of individual toxicants, target organ toxicity, major incidents, toxic effects in humans, animals and wildlife, biosensors, biomarkers, on-site and laboratory analytical methods, decontamination and detoxification procedures, prophylactic, therapeutic and countermeasures, and the role of homeland security. Presents a comprehensive look at all aspects of chemical warfare toxicology in one reference work. This saves research...

  9. Toxicological implications of extended space flights

    Science.gov (United States)

    Weiss, Bernard; Utell, Mark; Morrow, Paul

    1992-01-01

    This paper draws attention to the needs and mechanisms for shielding crewmembers on long-duration space flights from hazards related to chemical toxicants. Specific attention is given to existing data on sources of impaired performance, namely, neurotoxicants, respiratory infections, pulmonary function. The behavioral effects associated with long-term exposure to volatile organic solvents can impair crucial functional parameters of space flight and mission objectives. Respiratory infections contribute to performance decrements of up to 20 percent, and pulmonary function can be impaired by contaminants such as ozone leading to reduced performance. It is concluded that these and other sources of toxicologically induced performance reductions be studied since they impinge on vehicle design and mission objectives.

  10. NTP Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitrate (CAS No. 78-11-5) with 80% D-Lactose Monohydrate (PETN, NF) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1989-08-01

    Pentaerythritol tetranitrate (PETN, NF) is a drug used to prevent angina pectoris. PETN without a lactose stabilizer is used as an explosive. NTP Toxicology and Carcinogenesis studies were conducted by administering PETN, NF, to groups of F344/N rats and B6C3F1 mice of each sex once by gavage or in feed for 14 days, 13 or 14 weeks, or 2 years. The PETN component was greater than 99% pure. Genetic toxicology studies were conducted with Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: All rats and mice lived to the end of the 14-day studies (dietary concentrations up to 50,000 ppm). Final mean body weights of dosed and control rats were comparable. The final mean body weight of female mice that received 50,000 ppm was 13% lower than that of controls. No clinical signs or toxic lesions were attributed to PETN, NF, administration. All rats and mice lived to the end of the 13-week (mice) and 14-week (rats) studies (dietary concentrations up to 50,000 ppm). Final mean body weights of dosed and control rats and mice were similar, although weight gains of female rats at 25,000 and 50,000 ppm were less than that of controls. The nitrite level in urine of rats and methemoglobin levels in whole blood of rats and mice were not affected by administration of PETN, NF. An adenoma of the Zymbal gland was seen in a female rat that received 50,000 ppm. A hepatocellular adenoma was seen in a female mouse that received 50,000 ppm. Based on these results and the NTP convention of limiting concentrations in 2-year feed studies to 5% of the diet, the 2-year studies were conducted by administering 0, 25,000 or 50,000 ppm PETN, NF, in feed for 104 weeks to groups of 50 male rats and for 103 weeks to groups of 49 or 50 mice of each sex. Groups of 50 female rats were given feed containing 0, 6,200, or 12,500 ppm PETN, NF, for 104 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 2

  11. Electronic cigarettes in the USA: a summary of available toxicology data and suggestions for the future

    Science.gov (United States)

    Orr, Michael S

    2014-01-01

    Objective To review the available evidence evaluating the toxicological profiles of electronic cigarettes (e-cigarettes) in order to understand the potential impact of e-cigarettes on individual users and the public health. Methods Systematic literature searches were conducted between October 2012 and October 2013 using five electronic databases. Search terms such as ‘e-cigarettes’ and ‘electronic delivery devices’ were used to identify the toxicology information for e-cigarettes. Results As of October 2013, the scientific literature contains very limited information regarding the toxicity of e-cigarettes commercially available in the USA. While some preliminary toxicology data suggests that e-cigarette users are exposed to lower levels of toxicants relative to cigarette smokers, the data available is extremely limited at this time. At present, there is insufficient toxicological data available to perform thorough risk assessment analyses for e-cigarettes; few toxicology studies evaluating e-cigarettes have been conducted to date, and standard toxicological testing paradigms have not been developed for comparing disparate types of tobacco products such as e-cigarettes and traditional cigarettes. Conclusions Overall, the limited toxicology data on e-cigarettes in the public domain is insufficient to allow a thorough toxicological evaluation of this new type of tobacco product. In the future, the acquisition of scientific datasets that are derived from scientifically robust standard testing paradigms, include comprehensive chemical characterisation of the aerosol, provide information on users’ toxicant exposure levels, and from studies replicated by independent researchers will improve the scientific community's ability to perform robust toxicological evaluations of e-cigarettes. PMID:24732158

  12. [The challenges of the ethics of personalism to clinical toxicology].

    Science.gov (United States)

    Brusiło, Jerzy

    2011-01-01

    The fields of philosophical anthropology and the ethics of personalism overlap in the area of many difficult personal situations involving clinical toxicology. These therapeutic situations need an integral, multidimensional, and personal approach for both the patient and the toxicologist. This means that man is treated not only as a physical (biological) being but also there is an appreciation for the mental sphere, which includes rational, emotional, and spiritual elements while not forgetting that the human person is also part of the human community. Studying such an individual's personal decision as suicide, we must realize that it's not just physiological or biochemical poisons but also includes the poisoning of the psyche, as well as poisoning relationships with loved ones (family), poisoning social relations (in school or the workplace) and poisoning the spirit, in other words, there is no meaning in life itself, nor the meaning of God's existence, nor the meaning of faith, hope and love. Not only is there a greater "variety of poisons" than before, they are much more extensive and deep. For example, we can name environmental pollution, industrial poisons, chemical waste, genetic modification, powerful medications, or even the toxic social environment of evil ideas, malicious manipulation of the human mind (destructive religious sects). In approaching the challenges of clinical toxicology, the doctor must not only be a specialist in chemistry, biochemistry and pharmacology. What then is of future of toxicology because of this human dimension (anthropological, ethical and spiritual) of this teaching? As today marks the occasion of the 45th anniversary of the Clinic of Toxicology CM UJ, should we shape the ethos of young doctors who want to deal with toxicology seriously?

  13. Defining the toxicology of aging.

    Science.gov (United States)

    Sorrentino, Jessica A; Sanoff, Hanna K; Sharpless, Norman E

    2014-07-01

    Mammalian aging is complex and incompletely understood. Although significant effort has been spent addressing the genetics or, more recently, the pharmacology of aging, the toxicology of aging has been relatively understudied. Just as an understanding of 'carcinogens' has proven crucial to modern cancer biology, an understanding of environmental toxicants that accelerate aging ('gerontogens') will inform gerontology. In this review, we discuss the evidence for the existence of mammalian gerontogens, as well as describe the biomarkers needed to measure the age-promoting activity of a given toxicant. We focus on the effects of putative gerontogens on the in vivo accumulation of senescent cells, a characteristic feature of aging that has a causal role in some age-associated phenotypes.

  14. TOXNET: A computerized collection of toxicological and environmental health information.

    Science.gov (United States)

    Fonger, G C; Stroup, D; Thomas, P L; Wexler, P

    2000-01-01

    The Toxicology and Environmental Health Information Program, managed by the National Library of Medicine's Division of Specialized Information Services, provides access to a number of online bibliographic and factual computer files concerned with the toxicology, safety and handling, and environmental fate of chemicals, along with other files that cover genetic toxicology, developmental and reproductive toxicology, mutagenesis, carcinogenesis and toxic chemical releases.

  15. Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): Detection, quantification and studies on human metabolism by GC-MS.

    Science.gov (United States)

    Grapp, Marcel; Kaufmann, Christoph; Ebbecke, Martin

    2017-02-02

    3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone belonging to the class of α-pyrrolidinophenones that become increasingly popular as a designer psychostimulant. Here, we report a comprehensive collection of MDPV exposure with quantitative serum level confirmation in Germany. During the years 2014-2016, we could proof consumption of MDPV in 23 cases where urine and blood samples were submitted to our laboratory by the police of Lower Saxony. Most of the samples underwent systematic toxicological analysis by gas chromatography-mass spectrometry (GC-MS), where MDPV could be detected in urine and/or serum samples. The determined concentrations of MDPV in serum showed a high variability, ranging from traces (<10ng/mL) up to 576ng/mL with a mean concentration of 118ng/mL and median of 47ng/mL. The majority of MDPV users were men (87%) and the age ranged from 23 to 49 years (mean 35.9, median 37 years). For most of the analytically confirmed MDPV cases we could prove co-consumption of other psychotropic drugs with frequent occurrence of opiates and cannabinoids in 22% of the cases, followed by benzodiazepines and cocaine in 17%. Analysis of urine samples by GC-MS disclosed the presence of MDPV and its metabolites 2'-oxo-MDPV, demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-oxo-MDPV, demethylenyl-methyl-oxo-MDPV and demethylenyl-methyl-N,N-bisdealkyl-MDPV. The metabolite pattern substantiates previous suggestions for principle metabolic pathways of MDPV in humans.

  16. Principles and procedures in forensic toxicology.

    Science.gov (United States)

    Wyman, John F

    2012-09-01

    The principles and procedures employed in a modern forensic toxicology lab are detailed in this review. Aspects of Behavioral and Postmortem toxicology, including certification of analysts and accreditation of labs, chain of custody requirements, typical testing services provided, rationale for specimen selection, and principles of quality assurance are discussed. Interpretation of toxicology results in postmortem specimens requires the toxicologist and pathologist to be cognizant of drug-drug interactions, drug polymorphisms and pharmacogenomics, the gross signs of toxic pathology, postmortem redistribution, confirmation of systemic toxicity in suspected overdoses, the possibility of developed tolerance, and the effects of decomposition on drug concentration.

  17. Decavanadate toxicology and pharmacological activities: V10 or V1, both or none?

    OpenAIRE

    2016-01-01

    This review covers recent advances in the understanding of decavanadate toxicology and pharmacological applications. Toxicological in vivo studies point out that V10 induces several changes in several oxidative stress parameters, different from the ones observed for vanadate (V1). In in vitro studies with mitochondria, a particularly potent V10 effect, in comparison with V1, was observed in the mitochondrial depolarization (IC50 = 40 nM) and oxygen consumption (99 nM). It is suggested that mi...

  18. NTP Toxicology and Carcinogenesis Studies of Polyvinyl Alcohol (CAS No.9002-89-5) in Female B6C3F1 Mice (Intravaginal Studies).

    Science.gov (United States)

    1998-05-01

    Polyvinyl alcohol is produced primarily for use in textile sizing, adhesives, polymerization aids, and paper coatings. It is also used in surgical drapes, towels, and gauze sponges; protective gloves; cosmetic formulations; topical ophthalmic preparations; plastic sponge implants for reconstructive surgery; and intravaginal contraceptive foam and film. In addition, polyvinyl alcohol is used with magnesium sulfate to dilate the cervix of women prior to induction of labor. It is estimated that hundreds of thousands of women in the United States use an intravaginal product containing polyvinyl alcohol each year. The Food and Drug Administration nominated low-viscosity polyvinyl alcohol for a 2-year study because of concern about the lack of information about the long-term toxic and carcinogenic effects by the intravaginal route. Female B6C3F1 mice received polyvinyl alcohol (approximately 99% pure) in deionized water by intravaginal administration for 30 days or 2 years. 30-DAY STUDY IN MICE: Three groups of 50 female B6C3F1 mice were used in this intravaginal study. The vehicle control group received only 20 &mgr;L of a deionized water vehicle. The other two groups each received 20 &mgr;L of 25% polyvinyl alcohol in deionized water. Animals in one dose group were returned to their cages after dosing; animals in the other dose group were restrained in a vertical nose-down position in restraint bags for several minutes after dosing. Animals were dosed daily for 30 consecutive days. All mice survived to the end of the study. The final mean body weights and body weight gains of dosed mice were similar to those of the vehicle control group. Abnormalities noted in the vaginal area after dosing included vaginal plugs, secretions, and swelling. These vaginal changes were minimal to mild and occurred in vehicle controls as well as in dosed mice. Restraint of mice after dosing appeared to eliminate vaginal secretions but increased both the incidence of vaginal irritation and

  19. Inhalation reproductive toxicology studies: Sperm morphology study of n-hexane in B6C3F1 mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Hackett, P.L.; Decker, J.R.; Westerberg, R.B.; Sasser, L.B.; McClanahan, B.J.; Rommereim, R.L.; Evanoff, J.J.

    1988-08-01

    The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate the epididymal sperm morphology of male B6D3F1 mice 5 weeks after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Two concurrent positive control groups of animals were injected intraperitoneally with either 200 or 250 mg/kg ethyl methanesulfonate, a known mutagen, once each day for 5 consecutive days. The mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. During the fifth post-exposure week the animals were killed and examined for gross lesions of the reproductive tract and suspensions of the epididymal sperm were prepared for morphological evaluations. The appearance and behavior of the mice were unremarkable throughout the experiment and there were no deaths. No evidence of lesions in any organ was noted at sacrifice. Mean body weights of male mice exposed to n-hexane were not significantly different from those for the 0-ppM animals at any time during the study. Analyses of the sperm morphology data obtained 5 weeks post-exposure (the only time point examined) indicated that exposure of male mice to relatively high concentrations of n-hexane vapor for 5 days produced no significant effects on the morphology of sperm relative to that of the 0-ppM control group. 24 refs., 2 figs., 7 tabs.

  20. Systems toxicology from genes to organs.

    Science.gov (United States)

    Jack, John; Wambaugh, John; Shah, Imran

    2013-01-01

    This unique overview of systems toxicology methods and techniques begins with a brief account of systems thinking in biology over the last century. We discuss how systems biology and toxicology continue to leverage advances in computational modeling, informatics, large-scale computing, and biotechnology. Next, we chart the genesis of systems toxicology from previous work in physiologically based models, models of early development, and more recently, molecular systems biology. For readers interested in further details this background provides useful linkages to the relevant literature. It also lays the foundations for new ideas in systems toxicology that could translate laboratory measurements of molecular responses from xenobiotic perturbations to adverse organ level effects in humans. By providing innovative solutions across disciplinary boundaries and highlighting key scientific gaps, we believe this chapter provides useful information about the current state, and valuable insight about future directions in systems toxicity.

  1. Space Toxicology: Human Health during Space Operations

    Science.gov (United States)

    Khan-Mayberry, Noreen; James, John T.; Tyl, ROchelle; Lam, Chiu-Wing

    2010-01-01

    Space Toxicology is a unique and targeted discipline for spaceflight, space habitation and occupation of celestial bodies including planets, moons and asteroids. Astronaut explorers face distinctive health challenges and limited resources for rescue and medical care during space operation. A central goal of space toxicology is to protect the health of the astronaut by assessing potential chemical exposures during spaceflight and setting safe limits that will protect the astronaut against chemical exposures, in a physiologically altered state. In order to maintain sustained occupation in space on the International Space Station (ISS), toxicological risks must be assessed and managed within the context of isolation continuous exposures, reuse of air and water, limited rescue options, and the need to use highly toxic compounds for propulsion. As we begin to explore other celestial bodies in situ toxicological risks, such as inhalation of reactive mineral dusts, must also be managed.

  2. Informing mechanistic toxicology with computational molecular models.

    Science.gov (United States)

    Goldsmith, Michael R; Peterson, Shane D; Chang, Daniel T; Transue, Thomas R; Tornero-Velez, Rogelio; Tan, Yu-Mei; Dary, Curtis C

    2012-01-01

    Computational molecular models of chemicals interacting with biomolecular targets provides toxicologists a valuable, affordable, and sustainable source of in silico molecular level information that augments, enriches, and complements in vitro and in vivo efforts. From a molecular biophysical ansatz, we describe how 3D molecular modeling methods used to numerically evaluate the classical pair-wise potential at the chemical/biological interface can inform mechanism of action and the dose-response paradigm of modern toxicology. With an emphasis on molecular docking, 3D-QSAR and pharmacophore/toxicophore approaches, we demonstrate how these methods can be integrated with chemoinformatic and toxicogenomic efforts into a tiered computational toxicology workflow. We describe generalized protocols in which 3D computational molecular modeling is used to enhance our ability to predict and model the most relevant toxicokinetic, metabolic, and molecular toxicological endpoints, thereby accelerating the computational toxicology-driven basis of modern risk assessment while providing a starting point for rational sustainable molecular design.

  3. Pulmonary toxicology of respirable particles. [Lead abstract

    Energy Technology Data Exchange (ETDEWEB)

    Sanders, C.L.; Cross, F.T.; Dagle, G.E.; Mahaffey, J.A. (eds.)

    1980-09-01

    Separate abstracts were prepared for the 44 papers presented in these proceedings. The last paper (Stannard) in the proceedings is an historical review of the field of inhalation toxicology and is not included in the analytics. (DS)

  4. Data governance in predictive toxicology: A review

    National Research Council Canada - National Science Library

    Fu, Xin; Wojak, Anna; Neagu, Daniel; Ridley, Mick; Travis, Kim

    2011-01-01

    .... In order to better manage and make full use of such large amount of toxicity data, there is a trend to develop functionalities aiming towards data governance in predictive toxicology to formalise...

  5. Antisense oligonucleotides on neurobehavior, respiratory, and cardiovascular function, and hERG channel current studies.

    Science.gov (United States)

    Kim, Tae-Won; Kim, Ki-Suk; Seo, Joung-Wook; Park, Shin-Young; Henry, Scott P

    2014-01-01

    Safety Pharmacology studies were conducted in mouse, rat, and non-human primate to determine in vivo effects of antisense oligonucleotides (ASOs) on the central nervous system, respiratory system, and cardiovascular system. Effects on the hERG potassium channel current was evaluated in vitro. ASOs contained terminal 2'-O-methoxyethyl nucleotides, central deoxy nucleotides, and a phosphorothioate backbone. Neurobehavior was evaluated by Functional Observatory Battery in rodents. Respiratory function was directly measured in rodents by plethysmograph; respiratory rate and blood gases were measured in monkey. Basic cardiovascular endpoints were measured in rat; cardiovascular evaluation in monkey involved implanted telemetry units. In single and repeat dose studies ASOs were administered by subcutaneous injection at up to 300 mg/kg, 250 mg/kg, and 40 mg/kg in mouse, rat, or monkey, respectively. Assays were performed in HEK293 or CHO-K1 cells, stably transfected with hERG cDNA, at ASO concentrations of up to 300 μM. No apparent effects were noted for respiratory or CNS function. Continuous monitoring of the cardiovascular system in monkey demonstrated no ASO-related changes in blood pressures, heart rate, or ECG and associated parameters (i.e., QRS duration). Specific assessment of the hERG potassium channel indicated no potential for actions on ventricular repolarization or modest effects only at excessive concentrations. The absence of direct actions on neurobehavior and respiratory function associated with the administration of ASOs in safety pharmacology core battery studies is consistent with published toxicology studies. The combination of in vitro hERG studies and in vivo studies in rat and monkey are consistent with no direct actions by ASOs on cardiac cell function or electrical conduction at relevant concentrations and dose levels. Taken as a whole, dedicated studies focused on the safety pharmacology of specific organ systems do not appear to add

  6. Food for thought ... A toxicology ontology roadmap.

    Science.gov (United States)

    Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae

    2012-01-01

    Foreign substances can have a dramatic and unpredictable adverse effect on human health. In the development of new therapeutic agents, it is essential that the potential adverse effects of all candidates be identified as early as possible. The field of predictive toxicology strives to profile the potential for adverse effects of novel chemical substances before they occur, both with traditional in vivo experimental approaches and increasingly through the development of in vitro and computational methods which can supplement and reduce the need for animal testing. To be maximally effective, the field needs access to the largest possible knowledge base of previous toxicology findings, and such results need to be made available in such a fashion so as to be interoperable, comparable, and compatible with standard toolkits. This necessitates the development of open, public, computable, and standardized toxicology vocabularies and ontologies so as to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. Such ontology development will support data management, model building, integrated analysis, validation and reporting, including regulatory reporting and alternative testing submission requirements as required by guidelines such as the REACH legislation, leading to new scientific advances in a mechanistically-based predictive toxicology. Numerous existing ontology and standards initiatives can contribute to the creation of a toxicology ontology supporting the needs of predictive toxicology and risk assessment. Additionally, new ontologies are needed to satisfy practical use cases and scenarios where gaps currently exist. Developing and integrating these resources will require a well-coordinated and sustained effort across numerous stakeholders engaged in a public-private partnership. In this communication, we set out a roadmap for the development of an integrated toxicology ontology

  7. Modern instrumental methods in forensic toxicology.

    Science.gov (United States)

    Smith, Michael L; Vorce, Shawn P; Holler, Justin M; Shimomura, Eric; Magluilo, Joe; Jacobs, Aaron J; Huestis, Marilyn A

    2007-06-01

    This article reviews modern analytical instrumentation in forensic toxicology for identification and quantification of drugs and toxins in biological fluids and tissues. A brief description of the theory and inherent strengths and limitations of each methodology is included. The focus is on new technologies that address current analytical limitations. A goal of this review is to encourage innovations to improve our technological capabilities and to encourage use of these analytical techniques in forensic toxicology practice.

  8. Integrative Systems Biology Applied to Toxicology

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning

    associated with combined exposure to multiple chemicals. Testing all possible combinations of the tens of thousands environmental chemicals is impractical. This PhD project was launched to apply existing computational systems biology methods to toxicological research. In this thesis, I present in three...... of a system thereby suggesting new ways of thinking specific toxicological endpoints. Furthermore, computational methods can serve as valuable input for the hypothesis generating phase of the preparations of a research project....

  9. Modern Instrumental Methods in Forensic Toxicology*

    Science.gov (United States)

    Smith, Michael L.; Vorce, Shawn P.; Holler, Justin M.; Shimomura, Eric; Magluilo, Joe; Jacobs, Aaron J.; Huestis, Marilyn A.

    2009-01-01

    This article reviews modern analytical instrumentation in forensic toxicology for identification and quantification of drugs and toxins in biological fluids and tissues. A brief description of the theory and inherent strengths and limitations of each methodology is included. The focus is on new technologies that address current analytical limitations. A goal of this review is to encourage innovations to improve our technological capabilities and to encourage use of these analytical techniques in forensic toxicology practice. PMID:17579968

  10. Toxicological interactions of silver nanoparticles and non-essential metals in human hepatocarcinoma cell line

    DEFF Research Database (Denmark)

    Miranda, Renata Rank; Bezerra, Arandi Ginane; Ribeiro, Ciro Alberto Oliveira

    2017-01-01

    Toxicological interaction represents a challenge to toxicology, particularly for novel contaminants. There are no data whether silver nanoparticles (AgNPs), present in a wide variety of products, can interact and modulate the toxicity of ubiquitous contaminants, such as nonessential metals....... In the current study, we investigated the toxicological interactions of AgNP (size=1-2nm; zeta potential=-23mV), cadmium and mercury in human hepatoma HepG2 cells. The results indicated that the co-exposures led to toxicological interactions, with AgNP+Cd being more toxic than AgNP+Hg. Early (2-4h) increases...... (MTT), cell viability (neutral red uptake assay), cell proliferation (crystal violet assay) and ABC-transporters activity (rhodamine accumulation assay) were also more pronounced in the co-exposure groups. Foremost, co-exposure to AgNP and metals potentiated cell death (mainly by necrosis) and Hg(2...

  11. In vitro toxicological characterisation of three arsenic-containing hydrocarbons

    OpenAIRE

    Francesconi, Kevin; Meyer, S. de; Matissek, M.; Müller, S. M.; Taleshi, M. S.; Ebert, F.; Schwerdtle, T. (Tanja)

    2014-01-01

    Arsenic-containing hydrocarbons are one group of fat-soluble organic arsenic compounds (arsenolipids) found in marine fish and other seafood. A risk assessment of arsenolipids is urgently needed, but has not been possible because of the total lack of toxicological data. In this study the cellular toxicity of three arsenic-containing hydrocarbons was investigated in cultured human bladder (UROtsa) and liver (HepG2) cells. Cytotoxicity of the arsenic-containing hydrocarbons was comparable to th...

  12. [Cosmetic colorants. Toxicology and regulation].

    Science.gov (United States)

    Platzek, T; Krätke, R; Klein, G; Schulz, C

    2005-01-01

    Some recent publications raised concern over a possible link between hair dye use and the incidence of bladder tumours in a Californian population. The Scientific Committee for Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) demanded the toxicological testing of all hair dyes used in Europe to exclude any risk. The EU commission initiated corresponding measures. Only safe hair dyes will be included on a positive list while all other hair dyes will be banned. The hair dye lawsone--the dyeing ingredient of henna--was evaluated by the SCCNFP as genotoxic but the BfR came to another conclusion. The regulation of both lawsone and henna remains an open question. Furthermore, some cosmetic colorants were critically discussed. The azo dyes CI 12150, CI 26100, CI 27290 and CI 20170 are allowed for use in cosmetics. On cleavage they form the carcinogenic aromatic amines o-anisidine, 4-aminoazobenzene and 2,4-xylidine, respectively. For three of these dyes the cleavage by human skin bacteria in vitro to the respective arylamine was shown experimentally. Further problems may arise from colorants used for tattoos and permanent makeup. These products up to now are not subject to legislation and there are no regulatory stipulations with respect to health safety and purity for colorants used for these purposes.

  13. Toxicologically relevant phthalates in food.

    Science.gov (United States)

    Kappenstein, Oliver; Vieth, Bärbel; Luch, Andreas; Pfaff, Karla

    2012-01-01

    Various phthalates have been detected in a wide range of food products such as milk, dietary products, fat-enriched food, meat, fish, sea food, beverages, grains, and vegetables as well as in breast milk. Here we present an overview on toxicologically considerable phthalate levels in food reported in the literature. The most common phthalates detected are di-(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP). Milk analyses demonstrate that background levels in unprocessed milk are usually low. However, during processing the phthalate contents may significantly increase due to migration from plastic materials in contact with food. Among dietary products fat-enriched food such as cheese and cream were identified with highest levels of DEHP. Plasticized PVC from tubes, conveyor belts, or disposable gloves used in food processing is an important source for contamination of food, especially of fatty food. Paper and cardboard packaging made from recycled fibers are another important source of contamination. In addition, gaskets used in metal lids for glass jars have been identified as possible source for the contamination of foodstuffs with phthalates. The highest concentrations of DEHP reported (>900 mg kg(-1)) were detected in food of high fat content stored in such glass jars. Beyond classical food, DEHP and DnBP were identified in human breast milk samples as the main phthalate contaminants. Phthalate monoesters and some oxidative metabolites were also quantified in breast milk.

  14. Acute and 28-day repeated oral toxicological evaluation of Kuruthi Azhal Chooranam – a Siddha preparation on rodents

    OpenAIRE

    Marimuthu Kannadasana; Ganesan Sumathy; Palanivel Thirusangu Sangeetha; Chidambaram Saravanababu; Kathirvelu Baskar

    2016-01-01

    Objective: To determine the effect of phytochemicals in acute and repeated dose of 28-day oral toxicity of Kuruthi Azhal Chooranam (KAC) in Sprague Dawley rats of both sexes. Methods: Acute oral toxicity was conducted with 2000 mg/kg body weight of KAC orally and the treated animals were observed for signs of toxicity at 30 min, 1, 2, 4 and 24 h and for up to 14 days. In repeated 28-day oral toxicity study, the KAC formulation was administered orally with 600, 900 and 1200 mg/k...

  15. Data governance in predictive toxicology: A review.

    Science.gov (United States)

    Fu, Xin; Wojak, Anna; Neagu, Daniel; Ridley, Mick; Travis, Kim

    2011-07-13

    Due to recent advances in data storage and sharing for further data processing in predictive toxicology, there is an increasing need for flexible data representations, secure and consistent data curation and automated data quality checking. Toxicity prediction involves multidisciplinary data. There are hundreds of collections of chemical, biological and toxicological data that are widely dispersed, mostly in the open literature, professional research bodies and commercial companies. In order to better manage and make full use of such large amount of toxicity data, there is a trend to develop functionalities aiming towards data governance in predictive toxicology to formalise a set of processes to guarantee high data quality and better data management. In this paper, data quality mainly refers in a data storage sense (e.g. accuracy, completeness and integrity) and not in a toxicological sense (e.g. the quality of experimental results). This paper reviews seven widely used predictive toxicology data sources and applications, with a particular focus on their data governance aspects, including: data accuracy, data completeness, data integrity, metadata and its management, data availability and data authorisation. This review reveals the current problems (e.g. lack of systematic and standard measures of data quality) and desirable needs (e.g. better management and further use of captured metadata and the development of flexible multi-level user access authorisation schemas) of predictive toxicology data sources development. The analytical results will help to address a significant gap in toxicology data quality assessment and lead to the development of novel frameworks for predictive toxicology data and model governance. While the discussed public data sources are well developed, there nevertheless remain some gaps in the development of a data governance framework to support predictive toxicology. In this paper, data governance is identified as the new challenge in

  16. NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1990-01-01

    Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular

  17. The current state and future directions of marine turtle toxicology research.

    Science.gov (United States)

    Finlayson, Kimberly A; Leusch, Frederic D L; van de Merwe, Jason P

    2016-09-01

    Chemical contamination of marine turtles has been well documented in the literature, although information on the toxicological effects of these contaminants is poorly understood. This paper systematically and quantitatively presents the available marine turtle toxicological research (excluding oil chemicals and natural toxins) and the related fields of cell line establishment and biomarkers as indicators of exposure. Examination of the published literature identified a total of 49 papers on marine turtle toxicology, which were split into three categories: toxicity studies (n=33, 67%), cell line establishment (n=7, 14%), and publications using biomarkers (n=13, 27%). Toxicity studies were further broken down into four subcategories: those correlating contaminants with toxicological endpoints (n=16, 48%); in vitro exposure experiments (n=11, 33%); in vivo exposure experiments (n=5, 15%); and screening risk assessments using hazard quotients (n=3, 9%). In quantitatively assessing the literature, trends and gaps in this field of research were identified. This paper highlights the need for more marine turtle toxicology research on all species, particularly using high throughput and non-invasive in vitro assays developed for marine turtle cells, including investigations into further toxicological endpoints and mixture effects. This will provide more comprehensive species-specific assessment of the impacts of chemical contaminants on these threatened animals, and improve conservation and management strategies globally.

  18. Modern imaging technologies in toxicologic pathology: An overview.

    Science.gov (United States)

    Ying, Xiaoyou; Monticello, Thomas M

    2006-01-01

    Modern imaging technology, now utilized in most biomedical research areas (bioimaging), enables the detection and visualization of biological processes at various levels of the molecule, organelle, cell, tissue, organ and/or whole body. In toxicologic pathology, the impact of modern imaging technology is becoming apparent from digital histopathology to novel molecular imaging for in vivo studies. This overview summarizes recent progresses in digital microscopy imaging and newly developed digital slide techniques. Applications of virtual microscopy imaging are discussed and compared to traditional optical microscopy reading. New generation digital pathology approaches, including automatic slide inspection, digital slide databases and image management are briefly introduced. Commonly used in vivo preclinical imaging technologies are also summarized. While most of these new imaging techniques are still undergoing rapid development, it is important that toxicologic pathologists embrace and utilize these technologies as advances occur.

  19. Toxicological perspectives on perfluorinated compounds in avian species

    Energy Technology Data Exchange (ETDEWEB)

    Giesy, J.; Jones, P. [Michigan State Univ., East Lansing, MI (United States)

    2004-09-15

    Perfluorinated chemicals have been widely used in commerce for the last few decades. Until recently little was known about their environmental fate and even less was known about their potential environmental effects. Since Giesy and co-workers first demonstrated the widespread occurrence of perfluorooctane sulfonic acid (PFOS) in wildlife there has been renewed interest in determining the biological and possible ecological effects of these compounds. The assessment of possible effects of these chemicals has been hampered by a limited understanding of their mode of action and by a lack of toxicological data for wildlife species. Here we summarize recently obtained toxicological studies available for perfluorinated compounds (PFCs) in two avian species and use this information and environmental concentration data to evaluate the potential for environmental risk that these compounds pose.

  20. Hair: a complementary source of bioanalytical information in forensic toxicology.

    Science.gov (United States)

    Barroso, Mário; Gallardo, Eugenia; Vieira, Duarte Nuno; López-Rivadulla, Manuel; Queiroz, João António

    2011-01-01

    Hair has been used for years in the assessment and documentation of human exposure to drugs, as it presents characteristics that make it extremely valuable for this purpose, namely the fact that sample collection is performed in a noninvasive manner, under close supervision, the possibility of collecting a specimen reflecting a similar timeline in the case of claims or suspicion of a leak in the chain of custody, and the increased window of detection for the drugs. For these reasons, testing for drugs in hair provides unique and useful information in several fields of toxicology, from which the most prominent is the possibility of studying individual drug use histories by means of segmental analysis. This paper will review the unique role of hair as a complementary sample in documenting human exposure to drugs in the fields of clinical and forensic toxicology and workplace drug testing.

  1. Aspects of matrix effects in applications of liquid chromatography-mass spectrometry to forensic and clinical toxicology--a review.

    Science.gov (United States)

    Peters, Frank T; Remane, Daniela

    2012-06-01

    In the last decade, liquid chromatography coupled to (tandem) mass spectrometry (LC-MS(-MS)) has become a versatile technique with many routine applications in clinical and forensic toxicology. However, it is well-known that ionization in LC-MS(-MS) is prone to so-called matrix effects, i.e., alteration in response due to the presence of co-eluting compounds that may increase (ion enhancement) or reduce (ion suppression) ionization of the analyte. Since the first reports on such matrix effects, numerous papers have been published on this matter and the subject has been reviewed several times. However, none of the existing reviews has specifically addressed aspects of matrix effects of particular interest and relevance to clinical and forensic toxicology, for example matrix effects in methods for multi-analyte or systematic toxicological analysis or matrix effects in (alternative) matrices almost exclusively analyzed in clinical and forensic toxicology, for example meconium, hair, oral fluid, or decomposed samples in postmortem toxicology. This review article will therefore focus on these issues, critically discussing experiments and results of matrix effects in LC-MS(-MS) applications in clinical and forensic toxicology. Moreover, it provides guidance on performance of studies on matrix effects in LC-MS(-MS) procedures in systematic toxicological analysis and postmortem toxicology.

  2. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

    Science.gov (United States)

    Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

    2016-12-12

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  3. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

    Directory of Open Access Journals (Sweden)

    E.L. Andrade

    Full Text Available The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics, absorption, distribution, metabolism and elimination (ADME and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  4. Threshold of toxicological concern values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification.

    Science.gov (United States)

    Kalkhof, H; Herzler, M; Stahlmann, R; Gundert-Remy, U

    2012-01-01

    The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255-276, 1978) by Munro et al. (Food Chem Toxicol 34:829-867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43-46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.

  5. Toxicological evaluation of lactase derived from recombinant Pichia pastoris.

    Science.gov (United States)

    Zou, Shiying; He, Xiaoyun; Liu, Yifei; Chen, Delong; Luo, Yunbo; Huang, Kunlun; Zhang, Wei; Xu, Wentao

    2014-01-01

    A recombinant lactase was expressed in Pichia pastoris, resulting in enzymatic activity of 3600 U/mL in a 5 L fermenter. The lactase product was subjected to a series of toxicological tests to determine its safety for use as an enzyme preparation in the dairy industry. This recombinant lactase had the highest activity of all recombinant strains reported thus far. Acute oral toxicity, mutagenicity, genotoxic, and subchronic toxicity tests performed in rats and mice showed no death in any groups. The lethal dose 50% (LD50) based on the acute oral toxicity study is greater than 30 mL/kg body weight, which is in accordance with the 1500 L milk consumption of a 50 kg human daily. The lactase showed no mutagenic activity in the Ames test or a mouse sperm abnormality test at levels of up to 5 mg/plate and 1250 mg/kg body weight, respectively. It also showed no genetic toxicology in a bone marrow cell micronucleus test at levels of up to 1250 mg/kg body weight. A 90-day subchronic repeated toxicity study via the diet with lactase levels up to 1646 mg/kg (1000-fold greater than the mean human exposure) did not show any treatment-related significant toxicological effects on body weight, food consumption, organ weights, hematological and clinical chemistry, or histopathology compared to the control groups. This toxicological evaluation system is comprehensive and can be used in the safety evaluation of other enzyme preparations. The lactase showed no acute, mutagenic, genetic, or subchronic toxicity under our evaluation system.

  6. Toxicological evaluation of lactase derived from recombinant Pichia pastoris.

    Directory of Open Access Journals (Sweden)

    Shiying Zou

    Full Text Available A recombinant lactase was expressed in Pichia pastoris, resulting in enzymatic activity of 3600 U/mL in a 5 L fermenter. The lactase product was subjected to a series of toxicological tests to determine its safety for use as an enzyme preparation in the dairy industry. This recombinant lactase had the highest activity of all recombinant strains reported thus far. Acute oral toxicity, mutagenicity, genotoxic, and subchronic toxicity tests performed in rats and mice showed no death in any groups. The lethal dose 50% (LD50 based on the acute oral toxicity study is greater than 30 mL/kg body weight, which is in accordance with the 1500 L milk consumption of a 50 kg human daily. The lactase showed no mutagenic activity in the Ames test or a mouse sperm abnormality test at levels of up to 5 mg/plate and 1250 mg/kg body weight, respectively. It also showed no genetic toxicology in a bone marrow cell micronucleus test at levels of up to 1250 mg/kg body weight. A 90-day subchronic repeated toxicity study via the diet with lactase levels up to 1646 mg/kg (1000-fold greater than the mean human exposure did not show any treatment-related significant toxicological effects on body weight, food consumption, organ weights, hematological and clinical chemistry, or histopathology compared to the control groups. This toxicological evaluation system is comprehensive and can be used in the safety evaluation of other enzyme preparations. The lactase showed no acute, mutagenic, genetic, or subchronic toxicity under our evaluation system.

  7. Aerospace toxicology overview: aerial application and cabin air quality.

    Science.gov (United States)

    Chaturvedi, Arvind K

    2011-01-01

    Aerospace toxicology is a rather recent development and is closely related to aerospace medicine. Aerospace toxicology can be defined as a field of study designed to address the adverse effects of medications, chemicals, and contaminants on humans who fly within or outside the atmosphere in aviation or on space flights. The environment extending above and beyond the surface of the Earth is referred to as aerospace. The term aviation is frequently used interchangeably with aerospace. The focus of the literature review performed to prepare this paper was on aerospace toxicology-related subject matters, aerial application and aircraft cabin air quality. Among the important topics addressed are the following: · Aerial applications of agricultural chemicals, pesticidal toxicity, and exposures to aerially applied mixtures of chemicals and their associated formulating solvents/surfactants The safety of aerially encountered chemicals and the bioanalytical methods used to monitor exposures to some of them · The presence of fumes and smoke, as well as other contaminants that may generally be present in aircraft/space vehicle cabin air · And importantly, the toxic effects of aerially encountered contaminants, with emphasis on the degradation products of oils, fluids, and lubricants used in aircraft, and finally · Analytical methods used for monitoring human exposure to CO and HCN are addressed in the review, as are the signs and symptoms associated with exposures to these combustion gases. Although many agricultural chemical monitoring studies have been published, few have dealt with the occurrence of such chemicals in aircraft cabin air. However, agricultural chemicals do appear in cabin air; indeed, attempts have been made to establish maximum allowable concentrations for several of the more potentially toxic ones that are found in aircraft cabin air. In this article, I emphasize the need for precautionary measures to be taken to minimize exposures to aerially

  8. Functional toxicology: tools to advance the future of toxicity testing

    Directory of Open Access Journals (Sweden)

    Brandon David Gaytán

    2014-05-01

    Full Text Available The increased presence of chemical contaminants in the environment is an undeniable concern to human health and ecosystems. Historically, by relying heavily upon costly and laborious animal-based toxicity assays, the field of toxicology has often neglected examinations of the cellular and molecular mechanisms of toxicity for the majority of compounds – information that, if available, would strengthen risk assessment analyses. Functional toxicology, where cells or organisms with gene deletions or depleted proteins are used to assess genetic requirements for chemical tolerance, can advance the field of toxicity testing by contributing data regarding chemical mechanisms of toxicity. Functional toxicology can be accomplished using available genetic tools in yeasts, other fungi and bacteria, and eukaryotes of increased complexity, including zebrafish, fruit flies, rodents, and human cell lines. Underscored is the value of using less complex systems such as yeasts to direct further studies in more complex systems such as human cell lines. Functional techniques can yield (1 novel insights into chemical toxicity; (2 pathways and mechanisms deserving of further study; and (3 candidate human toxicant susceptibility or resistance genes.

  9. Toxicology profiles of chemical and radiological contaminants at Hanford

    Energy Technology Data Exchange (ETDEWEB)

    Harper, B.L.; Strenge, D.L.; Stenner, R.D.; Maughan, A.D.; Jarvis, M.K.

    1995-07-01

    This document summarizes toxicology information required under Section 3.3 (Toxicity Assessment) of HSRAM, and can also be used to develop the short toxicology profiles required in site assessments (described in HSRAM, Section 3.3.5). Toxicology information is used in the dose-response step of the risk assessment process. The dose-response assessment describes the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data are derived from animal studies or, less frequently, from studies in exposed human populations. The risks of a substance cannot be ascertained with any degree of confidence unless dose-response relations are quantified. This document summarizes dose-response information available from the US Environmental Protection Agency (EPA). The contaminants selected for inclusion in this document represent most of the contaminants found at Hanford (both radiological and chemical), based on sampling and analysis performed during site investigations, and historical information on waste disposal practices at the Hanford Site.

  10. Reflections on the origins and evolution of genetic toxicology and the Environmental Mutagen Society.

    Science.gov (United States)

    Wassom, John S; Malling, Heinrich V; Sankaranarayanan, K; Lu, Po-Yung

    2010-01-01

    This article traces the development of the field of mutagenesis and its metamorphosis into the research area we now call genetic toxicology. In 1969, this transitional event led to the founding of the Environmental Mutagen Society (EMS). The charter of this new Society was to "encourage interest in and study of mutagens in the human environment, particularly as these may be of concern to public health." As the mutagenesis field unfolded and expanded, new wording appeared to better describe this evolving area of research. The term "genetic toxicology" was coined and became an important subspecialty of the broad area of toxicology. Genetic toxicology is now set for a thorough reappraisal of its methods, goals, and priorities to meet the challenges of the 21st Century. To better understand these challenges, we have revisited the primary goal that the EMS founders had in mind for the Society's main mission and objective, namely, the quantitative assessment of genetic (hereditary) risks to human populations exposed to environmental agents. We also have reflected upon some of the seminal events over the last 40 years that have influenced the advancement of the genetic toxicology discipline and the extent to which the Society's major goal and allied objectives have been achieved. Additionally, we have provided suggestions on how EMS can further advance the science of genetic toxicology in the postgenome era. Any oversight or failure to make proper acknowledgment of individuals, events, or the citation of relevant references in this article is unintentional.

  11. Pilot in vivo toxicological investigation of boron nitride nanotubes

    Directory of Open Access Journals (Sweden)

    Ciofani G

    2012-01-01

    Full Text Available Gianni Ciofani1, Serena Danti2, Giada Graziana Genchi1,3, Delfo D'Alessandro2, Jean-Luc Pellequer4, Michaël Odorico4, Virgilio Mattoli1, Mario Giorgi51Italian Institute of Technology, Center of MicroBioRobotics co Scuola Superiore Sant'Anna, 2Department of Neuroscience, University of Pisa, 3The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy; 4Commissariat à l'Energie Atomique, Institut de Biologie Environnementale et Biotechnologie, Department of Biochemistry and Nuclear Toxicology, Bagnols-sur-Cèze, France; 5Division of Pharmacology and Toxicology, Veterinary Clinics Department, University of Pisa, Pisa, ItalyAbstract: Boron nitride nanotubes (BNNTs have attracted huge attention in many different research fields thanks to their outstanding chemical and physical properties. During recent years, our group has pioneered the use of BNNTs for biomedical applications, first of all assessing their in vitro cytocompatibility on many different cell lines. At this point, in vivo investigations are necessary before proceeding toward realistic developments of the proposed applications. In this communication, we report a pilot toxicological study of BNNTs in rabbits. Animals were injected with a 1 mg/kg BNNT solution and blood tests were performed up to 72 hours after injection. The analyses aimed at evaluating any acute alteration of hematic parameters that could represent evidence of functional impairment in blood, liver, and kidneys. Even if preliminary, the data are highly promising, as they showed no adverse effects on all the evaluated parameters, and therefore suggest the possibility of the realistic application of BNNTs in the biomedical field.Keywords: boron nitride nanotubes, in vivo testing, toxicology

  12. The minipig as a platform for new technologies in toxicology.

    Science.gov (United States)

    Forster, Roy; Ancian, Philippe; Fredholm, Merete; Simianer, Henner; Whitelaw, Bruce

    2010-01-01

    The potential of the minipig as a platform for future developments in genomics, high density biology, transgenic technology, in vitro toxicology and related emerging technologies was reviewed. Commercial interests in the pig as an agricultural production species have driven scientific progress in these areas. There is no equivalent economic driver for progress in the dog or the monkey. As a result the available knowledge-bases are much greater for pigs (than for dogs or monkeys) in many areas (physiology, disease, genetics, immunology etc). Fundamental genomic knowledge and phenotypic characterization in regard to the pig is well in advance of the dog or the monkey and basic knowledge of the pig is therefore likely to stay ahead of the other two species. While the emerging technologies are essentially "species neutral" and can in principle be applied to all species, for all the technologies that we examined, basic knowledge and technical capabilities are greater for the pig than the dog or monkey. In concrete terms, in application to safety testing we have seen that: (i) The Göttingen minipig is well positioned for the performance of toxicogenomics studies, (ii) The close sequence homology between pigs and humans suggest that minipigs will be useful for the testing of biotechnology products (and possibly for in silico toxicology) and (iii) the minipig is the only non-rodent toxicology model where transgenic animals can be readily generated, and reproductive technologies are well developed in the pig. These properties should also make the minipig an interesting model for the testing of biotechnology products. These factors all support the idea that the minipig is well placed to meet the challenges of the emerging technologies and the toxicology of the future; it also seems likely that the minipig can be an advantageous model for the testing of biotechnology products.

  13. Selecting the best design for nonstandard toxicology experiments.

    Science.gov (United States)

    Webb, Jennifer M; Smucker, Byran J; Bailer, A John

    2014-10-01

    Although many experiments in environmental toxicology use standard statistical experimental designs, there are situations that arise where no such standard design is natural or applicable because of logistical constraints. For example, the layout of a laboratory may suggest that each shelf serve as a block, with the number of experimental units per shelf either greater than or less than the number of treatments in a way that precludes the use of a typical block design. In such cases, an effective and powerful alternative is to employ optimal experimental design principles, a strategy that produces designs with precise statistical estimates. Here, a D-optimal design was generated for an experiment in environmental toxicology that has 2 factors, 16 treatments, and constraints similar to those described above. After initial consideration of a randomized complete block design and an intuitive cyclic design, it was decided to compare a D-optimal design and a slightly more complicated version of the cyclic design. Simulations were conducted generating random responses under a variety of scenarios that reflect conditions motivated by a similar toxicology study, and the designs were evaluated via D-efficiency as well as by a power analysis. The cyclic design performed well compared to the D-optimal design.

  14. What is toxicology and how does toxicity occur?

    Science.gov (United States)

    Mückter, Harald

    2003-03-01

    Toxicology has matured since it was defined as the 'science of poisons'. Modern toxicology is no longer anthropocentric but takes on different views at various biological systems, including ecosystems. Each will interact specifically when exposed to defined chemical agents, including drugs. Adverse effects during drug therapy or after (accidental) poisoning are the result of some negative interactions between the agent and the exposed biological system. Toxicity is no longer a specific property of drugs and chemicals but an operative term to describe the adverse outcome of a specific drugs-host interaction. Newer developments in toxicology have focused on the host. Toxicogenetics continues to provide answers to variations of host response to xenobiotics, including drugs. Clinically relevant genetic polymorphisms and gene defects have been detected, and their number is rapidly growing. The key to understanding is in the host proteins that interact with the drug and mediate the cellular response. Hence, the proteom, i.e. the complete set of proteins of a cell, an individual or a species, determines how an exposed biological system may interact with the manifold of different xenobiotics. Structure-activity studies try to find out useful predictive parameters for risk and toxicity assessment.

  15. Molecular mechanism study on the toxicological effects of polybrominated diphenyl ethers and perfluoroalkyl acids%多溴联苯醚和全氟烷基酸的分子毒理机制研究

    Institute of Scientific and Technical Information of China (English)

    任肖敏; 张连营; 郭良宏

    2014-01-01

    Polybrominated diphenyl ethers ( PBDEs) and perfluoroalkyl acids ( PFAAs) are two groups of persistent organic pollutants ( POPs ) which are widely used, broadly existing in the environment, and frequently detected in humans. In 2009 they were added to the POPs list of the Stockholm Convention. However, the toxicological effects and mechanisms of PBDEs and PFAAs are still not well understood. This review summarizes our recent work on the studies of molecular toxicological mechanisms of PBDEs and PFAAs, focusing on their disruption effects on thyroid hormone system, estrogen system and hepatic fatty acid metabolism system. From the molecular, cellular and in vivo level, we investigated the direct binding interaction of these chemicals with hormone nuclear receptors, receptor conformational change after ligand binding, receptor mediated transcriptional activity in cells, and change of gene expression in experimental animals. Based on the results, we established a direct link between receptor binding and change of biological functions in cells and in vivo. Using molecular docking, we investigated the structural basis for the observed agonistic or antagonistic activity. It was found that their activity was determined by the binding geometry with the receptor, and their potency depended on the binding affinity with the protein, which were dominated by the hydrophobic and hydrogen-bond interactions. We also studied the binding interaction of these chemicals with transport proteins, and estimated their potential disruption effect on the in vivo transport of endogenous substances. Through these studies, we put forward a multi-level, multi-target strategy for the investigation of molecular toxicological mechanisms of POPs, established and introduced new methods for the study of POPs interactions with biological macromolecules, identified new binding modes of PBDEs and PFAAs with ER, TR and PPARγnuclear receptors. Our work has provides new information on the molecular

  16. Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

    Science.gov (United States)

    2012-07-01

    Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

  17. 注射用右旋雷贝拉唑钠大鼠13周重复给药毒性研究%Study on Repeated Dose Toxicity of Dexrabeprazole Sodium Injection in Rats for 13 Weeks

    Institute of Scientific and Technical Information of China (English)

    戴晓莉; 戴学栋; 郭峰; 胡建庭; 马玉奎

    2016-01-01

    目的:研究SD大鼠连续静脉给予注射用右旋雷贝拉唑钠13周的毒性作用。方法选取SD大鼠190只,雌性各半,分为溶媒对照组、注射用雷贝拉唑钠市售对照80 mg·kg-1组、注射用右旋雷贝拉唑钠80、20、5 mg·kg-1组及注射用雷贝拉唑钠、注射用右旋雷贝拉唑钠各剂量毒代卫星组,每天给药1次,连续给药13周,停药恢复4周。试验期间,全部动物每周称量体重和摄食量,给药13周及停药恢复4周时腹主动脉取血进行血液相关指标检测,剖检摘取脏器进行组织病理学检查;卫星组动物分别于首次和末次给药后颈静脉采血进行毒代动力学检测。结果注射用右旋雷贝拉唑钠80、20 mg·kg-1剂量下可导致大鼠出现呼吸急促、步态不稳、俯卧不动等症状,血液中RBC、HGB、HCT含量降低、甲状腺出现小滤泡形成增多,停药4周后血液学异常指标均恢复正常,但甲状腺病理学改变未能完全恢复。结论重复静脉注射给予注射用右旋雷贝拉唑钠80、20 mg·kg-1剂量下可导致SD大鼠红细胞相关指标可逆性改变、甲状腺病理改变。%Objective To observe the toxicity damage of dexrabeprazole sodium injection in rats for 13 Weeks.Methods One hundred and ninety rats(female half)were randomly divided into vehicle control group, rabeprazole sodium injection control group, three dexrabeprazole sodium injection groups with different dosages (80, 20 and 5 mg·kg-1), in addition, rabeprazole sodium injection and dexrabeprazole sodium injection satellite group. Then the group should be given the injection once a day for 13 weeks, after that, stopped to recovery for 4 weeks. During the test, all the animals should weigh weight and food intake. When stopped injection and ifnishing recovery, blood taken from abdominal aorta, organ coefifcient and histopathology were measured for the overall toxicity assessment. Respectively, Satellite animals were taken the blood at ifrst and last injection for toxicokinetics. Results The rats in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 apperanced shortness of breath, unsteady gait, prone motionless and other symptoms. The levels of RBC,HGB,HCT in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 were significantly lower than those in vehicle control group at 13 weeks (P<0.05). The change of these parameters regained to normal at 4 weeks after withdrawal. The amount of small follicular in the thyroid gland increased at 13 weeks, and failed to fully recover at 4 weeks after the withdrawal.Conclusion Repeated administration of dexrabeprazole Sodium injection (80, 20 mg·kg-1) for 13 weeks could lead to abnormal indicators related erythrocyte and pathological lesions of thyroid in rats.