Studies of the toxicology of methyl tertiary butyl ether (MTBE) were reviewed as a possible information base for evaluating the health effects of evaporative emissions from reformulated gasoline (RFG). The major metabolites of the oxidative demethylation of MTBE in vivo were methanol and tertiary butyl alcohol (TBA), whereas formaldehyde and TBA were the principal products of hepatic microsomal oxidation by cytochrome P-450. Pharmacokinetic studies in rats treated with intragastric MTBE in corn oil gave an initial disposition T1/2 for MTBE of 0.32 h. The decline in the serum drug versus time curve for MTBE in rats was accompanied by a progressive increase in serum methanol concentrations to levels more than 50-200 times those of the parent compound. Repeated exposure of MTBE vapor by inhalation in rats resulted in dose-dependent increases in MTBE in the blood, brain, and adipose tissue compartments. Blood concentrations of TBA were also dose dependent and provided an estimate of the total amount of MTBE distributed to peripheral drug metabolizing compartments. Perirenal fat/blood MTBE concentration ratios ranged from 9.7 to 11.6 after 15 wk of intermittent exposure. During an oxyfuels program in Fairbanks, AK, blood levels of occupationally exposed workers were 0.2-31.5 microgram/L MTBE and 1.6 to 72.2 microgram/L TBA with a mean TBA:MTBE blood concentration ratio of 4.2. In patients who received MTBE by percutaneous, transhepatic puncture for the dissolution of cholesterol gallstones, concentrations of MTBE in fat tissue reached 60 and 300 microgram/g at a treatment time when mean blood MTBE was less than 20 microgram/ml. The results of laboratory and clinical studies indicate that metabolites of MTBE may contribute to the nephropathy, neoplasms, and other pathological changes associated with repeated exposure to MTBE in experimental animals. It is concluded that such studies can provide a well-defined database for quantitative safety comparisons and health risk-benefit analyses of MTBE and other oxygenates in RFG.