of Work: 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 dioxin and related chemicals. It is our belief that the science foundation is strongest when relevant data are 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. Our studies have demonstrated that dose-response relationships for dioxin-mediated changes in gene expression are linearly consistent with theoretical analysis of hormone-receptor gene response elements. Our models using these data accurately predict tissue distribution and changes in gene expression, and wh have linked them to liver and thyroid tumor models. In the case of the thyroid, the rate-limiting step is induction of a TCDD-responsive UDP glucoronyltransferase which enhances clearance of T-3 and T-4 leading to pituitary synthesis and release of TSH. Human samples are obtained from individuals exposed accidentally or occupationally to dioxin. Current studies are evaluating samples for dioxin responsive genes from Boeringer (dioxins and furans) and Seveso, Italy (TCDD only). We are also attempting to identify sensitive subpopulations and also to develop strategies for replacing default methods for estimating the range of expected risks in the population. Preliminary models predict a wide distribution of risks based on differences in pharmacokinetics, pharmacodynamics and genetic predisposition including differences in Ah receptor.
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