The reason for sensitivity to valproic acid (VPA) hepatotoxicity in humans is not known and requires further investigation. We investigated two in vitro animal models that might represent the unpredictably sensitive and the predictably non-sensitive populations of patients. VPA-induced hepatotoxicity was evaluated in vitro using precision-cut liver slices prepared from adult Sprague-Dawley rats and 4-wk-old domestic pigs. Protein synthesis, K(+) retention and cytosolic lactate dehydrogenase leakage in the slices were used as parameters of viability, with protein synthesis being the most sensitive indicator of viability. Exposure to 300 or 500 mug/ml produced damage in the rat liver slices after 24 hr. However, these VPA concentrations produced damage after 12 hr in slices from rats in which hepatic metabolism had been induced by administering phenobarbital. Damage to liver slices from domestic pigs was more severe than in those from rats. Slices from non-induced pigs showed damage 8 hr after culturing in the presence of 100, 300 or 500 mug VPA/ml. These data suggest that these two animal models may illustrate the different profiles of VPA-induced hepatotoxicity that are seen in the human population.