We contributed to NTP technical reports of rodent bioassays on 1-bromopropane, ginseng, pulegone, milk thistle extract, bis(2-chloroethyoxy)methane, and diethylamine that were reviewed and accepted by the NTP Board of Scientific Counselors. We also participated in study design committees for over 10 chemicals that will be tested by the NTP. We also published papers in the scientific literature on chemicals that were recently tested by the NTP: dichloroacetic acid;cresols;3,3,4,4-tetrachloroazobenzene (TCAB);sodium dichromate dihydrate;chromium picolinate monohydrate;methylphenidate hydrochloride;di-(2-ethylhexyl)phthalate (DEHP);and dioxins. In the DEHP paper, we proposed modifications to the traditional reproductive toxicity study design that will improve the statistical power to detect effects of reproductive toxins. The NTP is interested in reducing, replacing and refining the use of rodents in laboratory studies. As part of this effort, we are evaluating the utility of growth, reproduction, feeding and movement assays using the nematode, C. elegans, for testing toxicity of chemicals. Under typical conditions, C. elegans has a lifespan of about 4-5 days during which it undergoes 4 larval stages then adulthood. We developed a mathematical model of the progression through larval stages into adulthood, then applied the model to data from assays of a large number of chemicals (>1000) to determine which chemicals inhibited growth and which did not. In addition to the growth assay, we also analyze movement of the nematodes as capture by a high speed camera mounted on a microscope. By tracking the (x,y) coordinates of each nematode at each time point, we can calculate the distance, velocity and other characteristics of the path traveled. We then compare these characteristics across groups of C. elegans exposed to different doses of a chemical, exposed to different chemicals or across groups having different genetic mutations. This work is ongoing. We continued to provide advice on statistical methods for evaluating alternative methods for NTP's toxicity and carcinogenicity testing. These include: 1) evaluating electrocardiogram data from a dog model for testing whether drugs prolong the QT wave in the heart beat which may ultimately lead to lethal arrhythmias, and 2) providing advice about the analysis of high throughput data from cell-based assays of chemicals selected by the NTP, that were generated by the NIH Chemical Genomics Center.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2010
Total Cost
$160,189
Indirect Cost
City
State
Country
Zip Code
Cora, Michelle C; Gwinn, William; Wilson, Ralph et al. (2017) A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice. Toxicol Pathol 45:614-623
Sanders, J Michael; Coulter, Sherry J; Knudsen, Gabriel A et al. (2016) Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A. Toxicol Appl Pharmacol 298:31-9
Catlin, Natasha R; Herbert, Ron; Janardhan, Kyathanahalli et al. (2016) Dose-response assessment of the dermal toxicity of Virginia cedarwood oil in F344/N rats and B6C3F1/N mice. Food Chem Toxicol 98:159-168
Frawley, Rachel P; Smith, Matthew J; White Jr, Kimber L et al. (2016) Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water. J Immunotoxicol 13:666-75
Willson, C J; Flake, G P; Sills, R C et al. (2016) Immunohistochemical Expression of Cyclin D1, Cytokeratin 20, and Uroplakin III in Proliferative Urinary Bladder Lesions Induced by o-Nitroanisole in Fischer 344/N Rats. Vet Pathol 53:682-90
Ryan, Kristen R; Cesta, Mark F; Herbert, Ronald et al. (2016) Comparative pulmonary toxicity of inhaled metalworking fluids in rats and mice. Toxicol Ind Health :
Rider, Cynthia V; Chan, Po; Herbert, Ron A et al. (2016) Dermal Exposure to Cumene Hydroperoxide: Assessing Its Toxic Relevance and Oxidant Potential. Toxicol Pathol 44:749-62
Dunnick, J K; Sanders, J M; Kissling, G E et al. (2015) Environmental chemical exposure may contribute to uterine cancer development: studies with tetrabromobisphenol A. Toxicol Pathol 43:464-73
Hong, Hue-Hua L; Hoenerhoff, Mark J; Ton, Thai-Vu et al. (2015) Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal. Toxicol Pathol 43:872-82
Rider, Cynthia V; Nyska, Abraham; Cora, Michelle C et al. (2014) Toxicity and carcinogenicity studies of Ginkgo biloba extract in rat and mouse: liver, thyroid, and nose are targets. Toxicol Pathol 42:830-43

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