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kidney changes indicative of chronic nephropathy were seen in all treated males and in mid- and highdose
females. All treated males had increases in the severity of mineralization and interstitial fibrosis of
the kidney, while increases in mild to moderate glomerulosclerosis, interstitial fibrosis, and tubular
proteinosis were observed in females.
Groups of 50 male and 50 female eight-week old CD-1 mice were exposed to 0, 400, 3000 or 8000
ppm MTBE vapor by inhalation (corresponding to analytical mean concentrations of 402, 3014 or
7973 ppm or 1442, 10816, or 28843 mg/m 3 ) (Burleigh-Flayer et al., 1992; Bird et al., 1997). The
animals were exposed for six hours/day, five days/week for 18 months. Increased mortality and
decreased mean survival time were observed only for male mice in the high-dose group. A slightly
increased frequency of obstructive uropathy, a condition that occurs spontaneously in this mouse strain,
was observed in high-dose males. However, deaths due to the condition were within the range noted
for historical controls. Body weight gain and absolute body weights were decreased in high-dose males
and females. Dose-dependent increases in liver weights were observed in both sexes. Kidney weights
were increased in high-dose females and in low- and mid-dose males.
Burleigh-Flayer et al. (1992) concluded that the MTD was exceeded in both sexes at the high-dose
level. Other observed effects of MTBE exposure included anesthetic effects in mice of both sexes in the
mid- and high-dose groups.
A detailed histopathology examination was performed on all animals in the control and high-dose
groups, and on all animals that died or were sacrificed moribund. Only a limited histopathology
examination was performed on non-moribund animals from the low- and mid-dose groups that survived
to terminal sacrifice; for males, only the liver, spleen and submandibular lymph nodes were evaluated,
while for females, only the liver, uterus and stomach were examined microscopically (Bird et al. 1997).
In females, a statistically significant increased incidence of hepatocellular adenomas was observed in the
high-dose group (Table 3). The incidence of hepatocellular adenomas and carcinomas (combined) was
also increased in high-dose females; however, only two hepatocellular carcinomas were reported, one
each in the low- and high-dose groups. In males, a statistically significant increase in hepatocellular
carcinomas was observed in the high-dose group (Table 3). Bird et al. (1997) noted that the combined
incidence of adenomas and carcinomas in high-dose males was similar to the historical incidence for
male CD-1 mice of 33%. However, after correcting for the number of animals alive at 49 weeks, when
the first hepatocellular adenoma was observed in males, the incidence in the high-dose group was 43%
(16/37, see Table 3), representing a clear increase above the cited historical incidence in male CD-1
mice. Burleigh-Flayer et al. (1992) concluded that the increased incidence of liver tumors in the highdose
groups (adenomas in females and carcinomas in males) could be attributed to MTBE exposure.
The ability of this study to detect increases in tumor incidence was likely decreased by the shortened
study length (18 versus 24 months).
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