PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL USEFUL IN PREDICTION OF THE INFLUENCE OF SPECIES, DOSE, AND EXPOSURE ROUTE ON PERCHLOROETHYLENEPHARMACOKINETICS

The ability of a physiologically based pharmacokinetic (PBPK) model to predict the uptake and elimination oi perchloroethylene (PCE) in veno us blood was evaluated by comparison of model simulations with experim ental data for two species, two routes of exposure, and three dosage l evels. Unanesthetized male Sprague-Dawley rats and beagle dogs were ad ministered 1, 3, or 10 mg PCE/kg body weight in polyethylene glycol 40 0 as a single Dolus, either by gavage or by intraarterial (ia) injecti on. Serial blood samples were obtained from a jugular vein cannula for up to 96 h following dosing. The PCE concentrations were analyzed by headspace gas chromatography. For each dose and route of administratio n, terminal elimination half-lives in rats were shorter than in dogs, and areas ender the blood concentration-time curve were smaller in rat s than in dogs. Over a 10-fold range of doses, PCE blood levels in the rat were well predicted by the PBPK model following ia administration , and slightly underpredicted following oral administration. The PCE c oncentrations in dog blood were generally overpredicted, except for fa irly precise predictions for the 3 mg/kg oral dose. These studies prov ide experimental evidence oi the utility of the PBPK model for PCE in interspecies, route-to-route, and dose extrapolations.