TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS

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Summary of Work: 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 accomodate factors that contribute to interindividual variabilities. Toxicokinetic models have been created, partially developed, or expanded upon for several chemicals, including anthraquinone, methyleugenol, primidone and its metabolite phenobarbital, isoprene, isobutene, 1,3-butadiene, TCDD, AIDS drugs singly and in combinations, melatonin, and the disposition of inhaled mercury vapor in pregnant rats and neonates. A unique feature of the anthraquinone dosimetry model is its unusual absorption pathway characterized by absorption from the lower intestine, packaging in chylomicrons, transport into the lymph and transfer into the mixed venous blood, avoiding first-pass liver metabolism. The anthraquinone model, which was developed from from single intravenous and oral dose plasma-time course data, was extended to chronic feed exposures. For methyleugenol, physiologically based pharmacokinetic models were created for rats and humans. The human model, which was structurally similar to the rat model, was based on blood methyleugenol data obtained from volunteers who consumed commericially available cookies containing methyleugenol. - toxicokinetic modeling, target organ dosimetry, disinfection byproducts, anthraquinone, boron, isoprene, methyleugenol, primidone, oxymetholone - Human Subjects