The objective of this research is to identify the mechanisms of total body clearance of volatile halogenated anesthetics and their metabolites in man as they may contribute to potential organ system toxicity. By measuring the absorbed dose of drug during clinical anesthesia and the amount exhaled and excreted as urinary metabolites, we have shown that the larger the fraction of the dose excreted as urinary metabolites, the larger the fraction which cannot be accounted for by these methods. We will test the hypothesis that irreversible binding to intracellular components, particularly in the liver, accounts for a portion of the missing fraction by analyzing tissues obtained at autopsy of patients who have died within fourteen days of receiving a general anesthetic. Studies of the amounts of fluoride ion released and of halothane metabolites retained in tissues will be carried out on rats made susceptible to a post halothane hepatic necrosis by pretreatment with triiodothyronine. Studies of the safety, efficacy and biotransformation of sevoflurane and other new, experimental inhalation anesthetics will be continued. The effect on rate of biotransformation of substituting deuterium for the two protons on the methoxy group of sevoflurane will be studied in the rat.