Toxicological Sciences, Vol 52, 33-44, Copyright © 1999 by Society of Toxicology
RF Henderson, FF Hahn, EB Barr, SA Belinsky, MG Menache and JM Benson
Previous studies suggest that the greater sensitivity of mice, compared to
rats, to the carcinogenicity of 1,3-butadiene (BD) is linked to higher
rates of BD metabolism to butadiene diepoxide (BDO2) by mice than rats. The
purpose 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
exposed 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 remainder of the exposed rats and mice were held for up to 18 months
for observation of tumor development. At the end of the exposure, rats had
no biologically significant alteration in standard hematological
parameters, but mice had a dose-dependent increase in neutrophils and
decrease in lymphocytes. Most of the significant lesions in both species
were in the nose, concentrated 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 inflammation subsided within 6 months, but squamous
metaplasia remained. In rats that died after exposure, squamous metaplasia
was seen in areas of earlier inflammation and extended beyond those areas
with time. The metaplasia was severe enough to restrict and occlude the
nasopharyngeal duct. Later, keratinizing squamous-cell carcinomas developed
from metaplastic foci in rats, but these were not seen in mice. At the end
of 18 months, the only significant increase in neoplasia in the exposed
rats was a dose- dependent increase in neoplasms of the nasal mucosa (0/47,
12/48, and 21/48 for the control, 2.5 ppm, and 5.0 ppm exposures,
respectively). Neoplasia of the nasal mucosa did not increase significantly
in the mice. Neoplastic lesions in the mice were observed in reproductive
organs, lymph nodes, bone, liver, Harderian gland, 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 for the control, 2.5 ppm,
and 5.0 ppm exposures, respectively). This tumor accounts for the apparent
trend toward an increase in total neoplastic lesions in mice as a function
of dose (10/40, 7/42, and 16/36 for control, 2.5 ppm, and 5.0 ppm,
respectively). These findings indicate that the metabolite of BD, BDO2, is
carcinogenic in the upper respiratory tract of rats. An increase in upper
respiratory tract tumors was not observed in similarly exposed mice,
despite the fact that preliminary studies indicated mice should have
received twice the dose to tissue than did the rats. Higher cytosolic
activity of detoxication enzymes has been reported in the liver and lung
cells of the mouse compared to the rat, and this may account, in part, for
the differences in response. The transport of externally administered BDO2,
into the cell and through the cytoplasm, might allow detoxication of the
molecule before it reaches critical sites on the DNA. The results indicate
that the site of formation of the BDO2 is important for tumor induction.
ARTICLES
Carcinogenicity of inhaled butadiene diepoxide in female B6C3F1 mice and Sprague-Dawley rats
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185- 5890, USA. rhenders@Irri.org
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