TCDD and its structural analogs such as the polychlorinated dibenzofurans (PCDFs) appear to exert their effects through a mechanism requiring an initial interaction with the Ah receptor. Our goals are to determine dose response relationships for dioxin following chronic exposure in rodent models and accidental or occupational exposure in humans. We also attempt to characterize the molecular mechanisms that regulate cell specific actions of dioxin. Our studies have demonstrated that TCDD-mediated changes in cytochrome P-450 isozymes and growth factor pathways in a rat liver tumor promotion model are linear in the low dose region. In order to determine changes in gene expression at levels which approximate human exposures, we have developed a reverse transcriptase PCR method which can detect less than one mRNA per cell of some dioxin responsive genes. This method is also permitting us to examine TCDD's biochemical effects in blood samples from humans who had been occupationally or accidentally exposed to dioxin. These and other approaches have provided evidence that there is considerable interindividual variation in the magnitude of response to a given exposure. However, not all dioxin's effects are linearly related to target tissue dose. For example, we have shown that TCDD-mediated changes in hepatocyte cell proliferation and growth of preneoplastic lesions require relatively high doses to cause detectable changes. Our animal and human data are being used to construct biologically-based models for dioxin's effects. These models have been an important element in the estimation of human risks from dioxin exposure.
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