Hepatotoxicity and halothane metabolism in an animal model with application for human toxicity.

Centrilobular necrosis and a ten-fold elevation in serum alanine amino-transferase (ALT) consistently followed 2 hours of 1% halothane anaesthesia in an animal model. Conditional factors were the presence of enzyme induction and moderate hypoxia (14% oxygen), indicating an association between reductive metabolism and hepatotoxicity. Under these conditions there was at least a four-fold increase in reductive metabolites detected in the exhaled air. In clinical studies, reductive metabolites were also detected in the exhaled air of all patients examined, even after halothane anaesthesia with 100% oxygen. The amounts of reductive metabolites were comparable in man and the model, following equivalent halothane doses. It appears that a model with a similar route and rate of halothane biotransformation to man has been identified. The lesion of halothane hepatotoxicity in this model appears to be similar to that reported in man - centrilobular hepatic necrosis.