TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

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This project is designed to characterize parameters of dose, distribution, metabolism, and elimination of xenobiotic materials. This information can aid in the design and interpretation of toxicology studies and to strengthen the scientific basis for low-dose extrapolation of risk to humans. Furthermore, biologically realistic biomathematical models provide a rigorous structure to formulate and test hypotheses on mechanisms of action of environmental hazards. Toxicokinetic models can also be adapted to different routes of exposure and dosage regimens and can accommodate factors that contribute to interindividual variabilities. During the past fiscal year, toxicokinetic models have been created or partially developed for nearly 20 chemicals under study by the National Toxicology Program (NTP). A more in-depth physiologically-based toxicokinetic model was constructed for the uptake, metabolism, and clearance of 1,3-butadiene (BD) and its principal metabolite, 1,2-epoxy-3-butene (EB). This model showed that differences in tissue dosimetry of EB are not sufficiently large to account for differences in tumor response between rats and mice exposed to BD. Recent models demonstrate the need for greater anatomical realism and fuller characterization of the enzymology and cofactor changes that are involved in the biotransformation processes.