In vivo experiments in rats and mice and in vitro experiments in rats, mice, and humans have been used to develop and validate a "2nd generation" physiologically based pharmacokinetic (PBPK) model for perchloroethylene (PERC). The refined PBPK model should be useful in the preparation of carcinogenic risk assessment based on amounts of PERC metabolites formed in the livers of rodents and humans according to procedures developed by EPA. A sensitivity analysis of the PBPK model revealed that the most significant uncertainties in this process (other than the choice of the appropriate dose/response model based on mechanism of action of PERC) were in the techniques used to estimate rates of PERC metabolism in humans. In vitro studies with human tissues reported help define what some have called the range of "equally reasonable alternatives" for estimating human risk.