Species differences in carcinogenicity: the role of metabolism in human risk evaluation

The assessment of human risk from exposure to chemicals is frequently confounded by differences in response to those chemicals in laboratory animals. In many cases, the basis of the species differences is differences in metabolism and pharmacokinetics. Since metabolic and pharmacokinetic data are readily accessible in both laboratory animals and humans, risk assessments can be significantly improved if these data are incorporated into the process. Several chlorinated solvents, perchloroethylene, trichloroethylene, and methylene chloride, have been investigated, and the species differences in carcinogenicity have been shown to be the result of pharmacokinetic differences between the species. The rates of metabolism of these chemicals have been measured in rats and mice in vivo, and the species differences observed have been reproduced in vitro using tissue fractions and hepatocytes. Identical experiments have been carried out using human tissues. The results of these studies together with species-specific physiological parameters have been used in a mathematical model to predict human cancer risk over a wide range of exposures. This approach provides both an explanation for the species differences in response to these chemicals and also a more rational approach to human risk assessment.