The purpose of this contract is to procure detailed chemical disposition data from a number of studies of selected environmental contaminants or model compounds per year. Such studies are designed to provide both applied knowledge of the fate of chemicals in the intact animal in support of toxicity tests conducted by the National Toxicology Program and basic knowledge of mechanisms of chemical toxicity. These data will help to predict more accurately the correct doses for compounds to be studied in animal bioassays. Developing fundamental information on chemical structure-activity relationships will permit a more accurate prediction of the fate and toxicity of chemicals that have similar structural or physical properties. Most of these studies are performed in intact laboratory rats and/or mice although some studies may require the use of human and rodent liver slice incubations in vitro for more accurate extrapolation of results from rodents to humans and for mechanistic studies. Disposition and metabolism studies are being conducted on the industrial intermediate cyclohexene oxide. Methyl styryl ketone is being studied to provide data to determine the appropriate route of exposure for the subchronic and chronic toxicity tests. Four peroxisome proliferators, dibutyl phthalate, Wyeth 14,643, 2,4-dichlorophenoxyacetic acid, and gemfibrozil, are being studied in rat, mouse and human liver and kidney slices. These data will provide data for risk assessments from human exposure to these chemicals. The comparative biotransformation in rodent and human hepatocytes for eugenol, isoeugenol, methyleugenol and myristicin are being compared to the known carcinogen safrole for risk comparison purposes. Additional studies on this class study include unscheduled DNA synthesis, DNA binding and analysis of adducts, and toxicity to human and rodent hepatocytes.
