The pharmacokinetics of the solvent methylene chloride have been studied using a physiologically based model that was developed for iv administrations to mice. Subsequently, the model was expanded to simulate pharmacokinetic behavior in mice and rats following single and repeated oral exposures. Through computer simulations, how different dosing variables, such as dose vehicle and exposure route, could influence the time course of methylene chloride concentrations at potentially critical sites of toxicity was examined. With this technique, methods of quantifying tissue exposure as it relates to externally applied doses was sought. In this way pharmacokinetic models help investigators design experiments that lead to more appropriate and reliable toxicologic assessment studies.