Carcinogenicity of inhaled butadiene diepoxide in female B6C3F1 mice and Sprague-Dawley rats

Previous studies suggest that the greater sensitivity of mice, compared to rats, to the carcinogenicity of 1,3-butadiene (BD) is linked to higher rate s of ED metabolism to butadiene diepoxide (BDO2) by mice than rats. The pur pose of this study was to determine the tumorigenicity of BDO2 in mice and rats exposed by inhalation to the same concentrations of the agent. Female B6C3F1 mice and Sprague-Dawley rats, 10-11 weeks old, 56/ group, were expos ed to 0, 2.5, or 5.0 ppm BDO2, 6 h/day, 5 days/week for 6 weeks. At the end of the BDO2 exposure, 8 animals/group were evaluated for toxicity. The rem ainder of the exposed rats and mice were held for up to 18 months for obser vation of tumor development. At the end of the exposure, rats had no biolog ically significant alteration in standard hematological parameters, but mic e had a dose-dependent increase in neutrophils and decrease in lymphocytes. Most of the significant lesions in both species were in the nose, concentr ated around the main airflow pathway. Necrosis, inflammation, and squamous metaplasia of the nasal mucosa, as well as atrophy of the turbinates, were all present in animals exposed to 5.0 ppm. In mice, necrosis and inflammati on subsided within 6 months, but squamous metaplasia remained. In rats that died after exposure, squamous metaplasia was seen in areas of earlier infl ammation and extended beyond those areas with time. The metaplasia was seve re enough to restrict and occlude the nasopharyngeal duct. Later, keratiniz ing squamous-cell carcinomas developed from metaplastic foci in rats, but t hese were not seen in mice. At the end of 18 months, the only significant i ncrease in neoplasia in the exposed rats was a dose-dependent increase in n eoplasms of the nasal mucosa (0/47, 12/48, and 21/48 for the control, 2.5 p pm, and 5.0 ppm exposures, respectively). Neoplasia of the nasal mucosa did not increase significantly in the mice. Neoplastic lesions in the mice wer e observed in reproductive organs, lymph nodes, bone, liver, Harderian glan d, pancreas, and lung, but the only significant increase in neoplasms in a single organ in the mice was in the Harderian gland (0/40, 2/42, and 5/36 f or the control, 2.5 ppm, and 5.0 ppm exposures, respectively). This tumor a ccounts for the apparent trend toward an increase in total neoplastic lesio ns in mice as a function of dose (10/40, 7/42, and 16/36 for control, 2.5 p pm, and 5.0 ppm, respectively). These findings indicate that the metabolite of ED, BDO2, is carcinogenic in the upper respiratory tract of rats. An in crease in upper respiratory tract tumors was not observed in similarly expo sed mice, despite the fact that preliminary studies indicated mice should h ave received twice the dose to tissue than did the rats. Higher cytosolic a ctivity of detoxication enzymes has been reported in the liver and lung cel ls of the mouse compared to the rat, and this may account, in part, for the differences in response. The transport of externally administered BDO2, in to the cell and through the cytoplasm, might allow detoxication of the mole cule before it reaches critical sites on the DNA. The results indicate that the site of formation of the BDO2 is important for tumor induction.