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. Most of these studies will be performed in intact laboratory rats and/or mice. Some studies may require the use of human and rodent liver slice incubations in vitro for extrapolation of results from rodents to humans and for mechanistic studies. Extrapolation of results from animal testing to possible human health effects requires knowledge of metabolic pathways and of in vivo kinetic behavior. Investigation of mechanistic aspects of metabolic processes allows greater understanding of how metabolism of a xenobiotic might lead either to detoxification or to a reactive intermediate with greater toxicity. Most studies will address the disposition of organic chemicals; however, studies of inorganic compounds may be performed. A study shall consist of the determination of the absorption, distribution, metabolism and excretion of a compound in a given system and includes estimation of toxicokinetic parameters. The long-range goal of this contract is the accumulation of data that will permit a better assessment of structure-activity relationships of chemical absorption, metabolism and disposition in laboratory animals and to better interpret the significance of these data to humans.
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