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Tumor incidences according to the review are also presented in Table 1. Both observed types of tumor
were reexamined:
Testicular tumors: Diagnosis was carried out according to criteria developed by the National Toxicology
Program (NTP), and adenomas and hyperplasia were reported separately. In addition, adenomas were
further characterized as having single or multiple histiotypes, and the number of multifocal adenomas in
each dose group was reported. The results confirmed the diagnosis of the Leydig cell tumors as
adenomas, as initially reported. According to the NTP diagnostic criteria, the incidence of Leydig cell
adenomas was 3, 5, and 11 in the control, low- and high-dose groups, respectively, compared to the
originally reported incidences of 2, 2, and 11 in control, low- and high-dose animals. The review
indicated that all four multifocal adenomas observed occurred in the high-dose group. No dose-related
increase in atrophy or testicular tissue degeneration was observed. Therefore, the tumors were not
considered likely to be secondary to cell death.
Lymphoid tumors: The cell type of origin and tumor sites were reported. All neoplasms were of
lymphoid origin. Corrected incidences were 2, 7 and 12 in the control, low- and high-dose groups,
respectively, compared to the previously reported incidence data of 2, 6 and 12 in the same groups.
Cancers were classified as lymphoblastic lymphomas, lymphoblastic leukemias and
lymphoimmunoblastic lymphomas. The latter category was the most prevalent, accounting for 1, 6 and 8
of the tumors observed in the respective dose groups. The data on site distribution indicated that most
animals with lymphoid cancers were affected at multiple sites. The tissues involved in treated animals
were lung, liver, spleen and lymph node, and “other”, with the lung being the most commonly affected
site in treated animals.
Inhalation
Male and female Fischer 344 rats (50 animals/sex/group) were exposed to target concentrations of 0,
400, 3000, or 8000 ppm MTBE by inhalation (actual concentrations of 403, 3023, or 7977 ppm)
(Chun et al., 1992; Bird et al., 1997). The animals were exposed for 6 hours/day, 5 days/week for 24
months, except for the mid- and high-dose males, which were terminated at 97 and 82 weeks,
respectively, due to a dose-dependent increased mortality rate from chronic progressive nephropathy.
Low-dose males also experienced an increase in nephropathy that was associated with a slight increase
in mortality and a decrease in survival. Survival times for females were not significantly different
between exposed and control rats. However, there were slightly more deaths due to chronic
progressive nephropathy in the mid- and high-dose females than in the low-dose and control females.
Exposure-related increases in kidney and liver weights were reported in mid- and high-dose females,
but not in males. Chun et al. (1992) concluded that the maximum tolerated dose (MTD) was exceeded
in both sexes at high- and mid-dose levels, based on increased mortality. Other observed effects of
MTBE exposure included anesthetic effects in rats 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
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