The dominating feature of our research approach is to integrate data from a number of levels to address knowledge gaps that create uncertainty in risk assessment for receptor-mediated toxicants. These studies focus primarily on dioxin and its structural analogs as a prototypical receptor-mediated toxicant. Dioxin-like compounds are ubiquitous environmental contaminants and their persistence in the environment, their lipophilicity and subsequent bioaccumulation through the food chain, results in chronic human exposure. While dioxin has been classified as a known human carcinogen, considerable controversy exists over the potential human health risk posed by daily exposure to these compounds. It is our belief that the science foundation is strongest when relevant data is available from animal models, cell systems, and human studies, and when data are translated into risk assessment models that permit extensions of the data in a scientifically credible way. Specific objectives of this research is (1) To determine the shape of the dose response for effects of dioxin on gene expression, hormonal changes and cellular effects, in the female Sprague-Dawley rat. This is the animal model used by virtually all regulatory agencies in the world to estimate risk for human expopsure to dioxin. These studies focus on liver, lung, thyroid and reproductive tract which are target tissues for dioxin. (2) To collaborate with biomathematicians to develop biologically based dose response models for dioxin based on tissue dosimetry, binding to the aryl hydrocarbon receptor (AHR), changes in expression of critical target genes, growth characteristics of target cells and adverse health outcomes (3) To compare responses to dioxins in cell systems, rodents and humans in order to determine the relevance of experimental models for estimating human risks from exposure to dioxin and its structural analogs. Human samples are obtained from populations representing environmental, accidental, and high-level occupational exposure to dioxins(4) To determine the magnitude of interindividual variation in human responses to dioxin by integrating information on biological half lives, changes in gene expression, human and adverse health outcomes. These studies attempt to identify sensitive subpopulations and also to develop strategies for replacing default methods for estimating the range of expected risks in the population.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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Xie, An; Walker, Nigel J; Wang, Desuo (2006) Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) enhances triggered afterdepolarizations in rat ventricular myocytes. Cardiovasc Toxicol 6:99-110
Haws, Laurie C; Su, Steave H; Harris, Mark et al. (2006) Development of a refined database of mammalian relative potency estimates for dioxin-like compounds. Toxicol Sci 89:4-30
Yoshizawa, Katsuhiko; Walker, Nigel J; Jokinen, Micheal P et al. (2005) Gingival carcinogenicity in female Harlan Sprague-Dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Toxicol Sci 83:64-77
Nyska, Abraham; Yoshizawa, Katsuhiko; Jokinen, Micheal P et al. (2005) Olfactory epithelial metaplasia and hyperplasia in female Harlan Sprague-Dawley rats following chronic treatment with polychlorinated biphenyls. Toxicol Pathol 33:371-7
Walker, Nigel J; Crockett, Patrick W; Nyska, Abraham et al. (2005) Dose-additive carcinogenicity of a defined mixture of ""dioxin-like compounds"". Environ Health Perspect 113:43-8
Brix, Amy E; Nyska, Abraham; Haseman, Joseph K et al. (2005) Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program. Toxicol Pathol 33:477-83
Yoshizawa, Katsuhiko; Marsh, Tiwanda; Foley, Julie F et al. (2005) Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley Rats. Toxicol Sci 85:594-606
Hailey, James R; Walker, Nigel J; Sells, Donald M et al. (2005) Classification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol Pathol 33:165-74
Vezina, Chad M; Walker, Nigel J; Olson, James R (2004) Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression. Environ Health Perspect 112:1636-44
Wyde, Michael E; Braen, Angelique P J M; Hejtmancik, Milton et al. (2004) Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. Toxicol Sci 82:34-45

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