Knowledge of the fate of xenobiotic chemicals in intact animals is fundamental to any characterization of their toxicity. These data are also critical to extrapolations of observations made in toxicity tests with laboratory animals to predict risks associated with human exposure to the respective chemicals. These studies are designed to provide both applied knowledge of the fate of chemicals in the intact animals in support of toxicity tests conducted by the National Toxicology Program and basic knowledge of mechanisms of chemical toxicity. Each study is designed to address those properties unique to the compound studied as well as to provide data that will permit structural characterization of the respective chemical class. Disposition studies conducted during the current year have addressed the fate and mechanisms of toxicity of 2,2- Bis(bromomethyl)-1,3-propanediol and 2-methylimidazole. These studies have determined that both compounds are rapidly absorbed from the gastrointestinal tract and rapidly excreted, primarily in urine. A newly initiated study is addressing the metabolism of model substrates by two strains of transgenic mice, TGAC and P-53 knockouts. Chemicals selected for study represent major metabolic pathways, e.g. P-450 reactions, esterase and acetylase activity and phase two metabolism. Data obtained will permit a determination of the effect of genetic modification on the rate of clearance and xenobiotics by transgenic mice versus the parent strains.
