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.
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