Methyl tertiary butyl ether lacks tumor-promoting activity in N-nitrosodiethylamine-initiated B6C3F1 female mouse liver.

Abstract

Methyl tertiary butyl ether (MTBE) is an additive in some formulations of unleaded gasoline (UG) that enhances octane and reduces carbon monoxide emissions from motor vehicles. MTBE in CD-1 mice and UG in B6C3F1 mice increased the incidence of liver tumors selectively in female mice in their chronic bioassays. Both agents were negative in in vitro tests of genotoxicity, and exhibit similar hepatic microsomal cytochrome P450 activity and hepatocyte proliferation after short-term exposure. We previously demonstrated that UG has hepatic tumor-promoting activity in DEN-initiated female B6C3F1 mice. Thus, we hypothesized that MTBE would have hepatic tumor-promoting activity in the same initiation-promotion model system in which UG was a hepatic tumor promoter. Twelve-day-old female B6C3F1 mice were initiated with a single i.p. injection of the mutagen N-nitrosodiethylamine (DEN) (5 mg DEN/kg, 7.1 ml/kg body weight) or saline. Beginning at 8 weeks of age, mice were exposed to 0 ppm or the hepatocarcinogenic dose of approximately 8000 ppm MTBE. After subchronic exposure, MTBE significantly increased liver weight and hepatic microsomal cytochrome P450 activity without hepatotoxicity or an increase in non-focal hepatocyte DNA synthesis. These are subchronic effects similar to those produced by UG. However, MTBE did not significantly increase the mean size of hepatic foci and volume fraction of the liver occupied by foci as compared to DEN-initiated controls at either 16 or 32 weeks. The lack of tumor-promoting ability of MTBE in DEN-initiated female mouse liver was unexpected and suggests that MTBE does not produce liver tumors through a tumor-promoting mechanism similar to that of UG.