Urethane is a
carcinogen to which there is widespread exposure through the consumption of fermented foods and alcoholic beverages. In this study, we have assessed the carcinogenicity of
urethane in combination with
ethanol. Male and female B6C3F(1) mice (48 mice per sex per group) were exposed to 0, 10, 30, or 90 ppm
urethane in the presence of 0%, 2.5%, or 5%
ethanol in
drinking water ad libitum for two years, at which time the extent of
tumorigenesis was assessed. Additional mice (four per sex per group) received the same doses for four weeks to assess serum levels of
urethane and
ethanol,
DNA adduct formation, and the induction of microsomal
cytochromes P450, cell proliferation, and apoptosis.
Urethane decreased cell replication in the livers of female, but not male, mice, decreased cell replication in the lungs of both sexes, and induced
cytochrome P450 2E1 in the livers of female mice. Hepatic levels of the
DNA adduct 1,N(6)-ethenodeoxyadenosine were increased by exposure to
urethane and decreased by treatment with
ethanol. Animal weights and survival were not affected by
ethanol; in contrast,
urethane administration decreased
body weights and survival.
Urethane caused dose-dependent increases in liver, lung, and harderian gland
adenoma or
carcinoma and
hemangiosarcoma of the liver and heart in both sexes, mammary gland and ovarian
tumors in females, and
squamous cell papilloma or
carcinoma of the skin and forestomach in males. The increase in hepatocellular
tumors occurred in a relatively linear manner and was attributed to the formation of
1,N(6)-ethenodeoxyadenosine in hepatic
DNA coupled with an increase in cell replication.
Hemangiosarcomas were observed only at the 90 ppm
urethane dose and were probably a result of high-dose
urethane-induced toxicity. Lung alveolar/bronchiolar and harderian gland
adenoma or
carcinoma increased in a relatively linear manner, suggestive of a genotoxic mechanism for
tumor induction.
Ethanol induced a dose-dependent trend in
hepatocellular adenoma or
carcinoma in male mice, with the incidence being marginally increased at the highest dose. In female mice administered 10 ppm and 90 ppm
urethane,
ethanol caused dose-related increases in alveolar/bronchiolar
adenoma or
carcinoma and
hemangiosarcoma of the heart, respectively. This may be due to
ethanol decreasing the first-pass clearance of
urethane, thus, increasing systemic distribution. In male mice a different relationship was observed:
ethanol caused a dose-related decrease in alveolar/bronchiolar and harderian gland
adenoma or
carcinoma in mice administered 30 ppm
urethane.