Evidence on the carcinogenicity of Methyl Tertiary Butyl Ether (MTBE): Executive Summary
Executive Summary
Methyl tertiary butyl ether (MTBE) (CAS No. 1634-04-4) is a synthetic solvent used almost exclusively as an oxygenate in unleaded gasoline to improve combustion efficiency. Currently, MTBE is added at 11% volume to almost all of the gasoline used in California. It also has had limited use as a therapeutic drug for dissolving cholesterol gallbladder stones. Due to its use as a fuel additive, MTBE is a high volume production chemical. It was the second most-produced chemical in the U.S. in 1997.
Epidemiological studies of the carcinogenic effects of MTBE are not available. Carcinogenicity of MTBE has been observed in animal studies, by oral and inhalation routes. Specifically, tumors have been observed in rats of both sexes in lifetime gavage studies, in male rats in a 24-month inhalation study of a different strain, and in male and female mice in 18-month inhalation studies. Statistically significant increases in Leydig interstitial cell tumors of the testes were observed in both the inhalation and gavage studies involving the two different strains of rats. Statistically significant increases in renal tubular tumors were also observed in male rats exposed via inhalation, and increases in leukemias and lymphomas (combined) in female exposed orally. In the inhalation studies in mice, statistically significant increases in hepatocellular carcinomas were observed in males, and adenomas and combined adenomas and carcinomas in females.
At present, the mechanism by which MTBE induces the various tumors observed in animals remains unknown. MTBE has demonstrated little or no genotoxicity in vitro or in vivo. Two primary metabolites of MTBE, formaldehyde and tertiary butyl alcohol (TBA), both exhibit tumorigenic activity in animal studies. TBA and MTBE both induce renal tumors in the male Fisher rat; and formaldehyde and MTBE both have produced lymphohematopoietic cancers in Sprague Dawley rats exposed orally.
There is evidence for the carcinogenicity of methyl tertiary butyl ether (MTBE), based on several findings from animal studies. However, critics have questioned the interpretation of each of the individual findings. Some have questioned the use of a combined incidence category for statistical analysis of the leukemias and lymphomas observed in female rats. Some have argued that the cancers observed in male rats -- the renal tubular in the Fisher rat and the Leydig cell tumors in the Fisher and Sprague Dawley rat -- are not relevant to humans because of species specific mechanisms of carcinogenesis. For the renal tubular tumors, some hypothesize the possible involvement of a 2u-microglobulin nephropathy, and for the testicular tumors, on possible interspecies differences in the hormonal control of Leydig cells. In mice, the increase in hepatocellular tumors was observed in the high dose male and female groups. An argument has been made that the mechanism of induction of these tumors, although unknown, may be non-genotoxic, and consequently the findings may not be relevant to humans exposed at environmental levels. In this report, the carcinogenicity studies are reviewed and the issues that have been raised are addressed in the context of a detailed discussion of pathology and mechanisms for each tumor site.
- Methyl Tertiary Butyl Ether