Xenobiotic Kinetics and Toxicity Among Fish and Mammals.

The purpose of this project is to develop techniques that account for interspecies differences in the pharmacokinetics of xenobiotics. The hypothesis proposed is that toxicity occurs after exposure of the target organ to a characteristic concentration of toxicant for a particular period of time. To test the hypothesis, experiments were proposed to characterize the pharmacokinetics of three representative chemicals (lindane, pentachlorophenol and paraoxon) in small trout via water exposure, and large trout and rats via intravascular injection. Compartmental toxicokinetic models were to be used. The fraction of a dose of each test compound converted to each of its metabolites by the test animals were to be determined to account for possible metabolic differences that might contribute to interspecies differences in toxicity. Binding of the test substances in blood to formed elements and plasma proteins were to also be characterized. The LC50s and LD50s of the test compounds were to be determined and the values were to be converted to free concentrations using various toxicokinetic transformations. The transformation that gave a common concentration for toxicity in the three groups of animals were to be an 'index of relative exposure' that would provide an estimate of the dose to the target organ rather than the dose to the animal. The area under the free concentration- time curve was to be the starting point for development of the exposure index. Successful development of such an index should result in substitution for research purposes of fish for mammalian species, and in a better understanding of interspecies differences in the dosage of chemicals that produce toxicity. The research was also to provide useful information about the toxicokinetic and toxicologic properties of the test compounds.