ONCOGENICITY STUDIES OF INHALED METHYL TERTIARY-BUTYL ETHER (MTBE) INCD-1 MICE AND F344 RATS

Oncogenicity studies of methyl tertiary-butyl ether (MTBE) vapor were conducted in CD-1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (m ice) and 24 months (rats). Both species showed reversible central nerv ous system depression at 8000 ppm for the first week of exposure, whic h continued for mice for the study duration. For the 8000 ppm mice, re duced body weight gain and early mortality prior to terminal euthanasi a were exposure related. In the males, these deaths appear to be due t o exacerbation of uropathy or dysuria, which occurs spontaneously in t his strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decrease s in brain and spleen weights were also noted (the latter decreases we re without microscopic lesions and occurred at 8000 ppm only). An incr ease in hepatocellular hypertrophy occurred in both sexes at the two h ighest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in femal es at the 8000 ppm exposure. In a follow-up study, a statistically sig nificant elevation of cell proliferation in female mouse liver has bee n shown to occur following 5 days, but not 28 days, of exposure to 800 0 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, e arly euthanasia was required at week 82 and week 97 for the 8000 and 3 000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this l esion and mortality for exposed females was comparable to control fema les. No exposure-related changes in hematological parameters were obse rved for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and r elative kidney and liver weight increases occurred in 3000 and 8000 pp m exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incid ence and severity of a chronic nephropathy in mates from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralizatio n of tissues. Renal tubular cell tumors were increased in male rats ex posed to 3000 and 8000 ppm. This may be associated with an accumulatio n of a protein (stainable by Mallory's Heidenhain) in kidney tubular e pithelial cells after 4 weeks of exposure. An increased incidence of i nterstitial cell adenomas of the testes was seen in males exposed to 3 000 and 8000 ppm but was believed to be an artefact of an unusually lo w control incidence and not considered to be exposure related. Based o n the above effects, the no-observed-effect level (NOEL) for chronic t oxicity is 400 ppm, and the NOEL for carcinogenic effects is 3000 ppm (mice) and 400 ppm (rats). (C) 1997 John Wiley & Sons, Ltd.