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 dioxin?s effects (gene expression, hormonal changes and cellular effects) in the female Sprague-Dawley rat which is the animal model used by virtually all regulatory agencies in the world to estimate dioxin?s risks to humans. 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. - dioxin, dose-response, hepatocarcinogenesis, risk assessment, quantitative RT-PCR, interindividual variability
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