The major issues regarding estimates of human risks from dioxin exposure are: (1) the shape of the dose response curve for dioxin's effects in the low dose region, (2) the relevance of animal models for human risk assessment, (3) the possible existence of sensitive subpopulations, and (4) the molecular mechanisms responsible for dioxin's effects. Our approaches have involved isolated cell systems, experimental rodent models, and human samples to address a number of issues that impact on risk assessment of dioxin and its structural analogs: (a) Determine the shape of the dose-response curve for the effects of TCDD in rat liver and lung by quantifying transcriptional activation of dioxin responsive regions and comparing responses to more complex biological effects such as cell proliferation and growth including exposure levels encountered by humans from day to day living, (b) Quantitatively and qualitatively compare human and rodent responses to dioxin. Human samples are obtained from groups exposed to dioxin either occupationally or environmentally, (c) Determine the extent of interindividual variation in human responses to dioxin, (d) Develop biologically-based dose response models for predicting dioxin's effects. There is considerable controversy on the use of current methods to estimate health risks on the use of current methods to estimate health risks from low-level dioxin exposure. This project is addressing key knowledge gaps which have created uncertainty in risk assessments by clarifying the shape of the dose-response curve in the low-dose region, by determining if animal models are appropriate for estimating human risks, and by characterizing the potential importance of interindividual variation in human responses to dioxin and its structural analogs. In order to determine changes in gene expression at levels which approximate human exposures, a reverse transcript PCR method has been developed which can detect less than on mRNA per cell of some dioxin responsive genes. This method is permitting examination of TCDD's biochemical effects in blood samples from humans occupationally or accidentally exposed to dioxin. Dose-response studies have demonstrate that the response to different levels of dioxin exposure cannot be predicted solely on the basis that the response is receptor mediated. Animal and human data are being used to construct biologically-based models for dioxin~s effects and are an important element in estimation of human risk from exposure. Results have demonstrated that dose response relationships for dioxin-responsive genes do not necessarily predict the shape of the dose response curve for cell proliferation or growth of preneoplastic lesions. Moreover, there is considerable interindividual variation in human responses to dioxin but in general rodent and human response are qualitatively and quantitatively similar. Plans for 1996 involve further development and refinement of biologically-based dose response models and the characterization of novel dioxin responsive genes which are more closely linked to adverse health outcomes and identifying susceptibility genes in humans occupationally or environmentally exposed to dioxin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES046004-11
Application #
5202182
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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
Brix, Amy E; Jokinen, Michael P; Walker, Nigel J et al. (2004) Characterization of bronchiolar metaplasia of the alveolar epithelium in female Sprague-Dawley rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126). Toxicol Pathol 32:333-7
Martinez, Jeanelle M; Baek, Seung Joon; Mays, Donna M et al. (2004) EGR1 is a novel target for AhR agonists in human lung epithelial cells. Toxicol Sci 82:429-35

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