of Work: This project is designed to characterize parameters of dose, distribution, metabolism, and elimination ofxenobiotic 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, naphthalene, dichlorodiphenyl sulfone (DDS), naphthalene, isoprene, 1,3-butadiene, TCDD, AIDS drugs singly and in combinations, and the disposition of inhaled mercury vapor in pregnant rats and neonates. The physiologically based toxicokinetic (PBTK) model developed for naphthalene characterized the disposition of naphthalene in rats and mice, including estimates of the amount of naphthalene inhaled by both species at the exposure concentrations used in the 2-year carcinogenicity studies and the rates of metabolism of naphthalene in the lung (target organ in mice but not in rats) and liver of rats and mice during exposure. The model for sodium nitrite characterized the dose-dependent oral absorption and elimination of nitrite, as well as the rates of induction methemoglobinemia and recovery of ferrous hemoglobin in exposed rats. The methyleugenol model indicates that this agent is rapidly absorbed following oral exposure in rats and humans and that a large first-pass metabolic effect occurs in the liver. The model structure used to fit the rat plasma concentration data also simulates human plasma data, with metabolism being slower in humans than in rats. The model that was created to describe the disposition of orally administered anthraquinone in rats and mice required a unique absorption pathway. This highly lipophilic chemical is likely packaged in chylomicrons, taken up into the lymph that drains the small intestine, and passed 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. The model on the disposition of DDS in rats and mice indicated that this agent is rapidly absorbed following oral exposure, there is little first pass liver metabolism, the parent compound and metabolites are excreted via the bile, and DDS induces enzymes involved in its metabolism. The latter observation was consistent with liver hypertrophy observed in rats and mice fed diets containing DDS for 13 weeks or 2 years.
