Toxicological Sciences, Vol 49, 186-201, Copyright © 1999 by Society of Toxicology
KA Richardson, MM Peters, BA Wong, RH Megens, PA van Elburg, ED Booth, PJ Boogaard, JA Bond, MA Medinsky, WP Watson and NJ van Sittert
1,3-Butadiene (butadiene) is a potent carcinogen in mice, but not in rats.
Metabolic studies may provide an explanation of these species differences
and their relevance to humans. Male Sprague-Dawley rats and B6C3F1 mice
were exposed for 6 h to 200 ppm [2,3-14C]-butadiene (specific radioactivity
[sa] 20 mCi/mmol) in a Cannon nose-only system. Radioactivity in urine,
feces, exhaled volatiles and 14C-CO2 were measured during and up to 42 h
after exposure. The total uptake of butadiene by rats and mice under these
experimental conditions was 0.19 and 0.38 mmol (equivalent to 3.8 and 7.5
mCi) per kg body weight, respectively. In the rat, 40% of the recovered
radioactivity was exhaled as 14C-CO2, 70% of which was trapped during the
6-h exposure period. In contrast, only 6% was exhaled as 14C-CO2 by mice,
3% during the 6-h exposure and 97% in the 42 h following cessation of
exposure. The formation of 14C-CO2 from [2,3-14C]-labeled butadiene
indicated a ready biodegradability of butadiene. Radioactivity excreted in
urine accounted for 42% of the recovered radioactivity from rats and 71%
from mice. Small amounts of radioactivity were recovered in feces, exhaled
volatiles and carcasses. Although there was a large measure of commonality,
the exposure to butadiene also led to the formation of different
metabolites in rats and mice. These metabolites were not found after
administration of [4-14C]-1,2-epoxy-3-butene to animals by i.p. injection.
The results show that the species differences in the metabolism of
butadiene are not simply confined to the quantitative formation of
epoxides, but also reflect a species-dependent selection of metabolic
pathways. No metabolites other than those formed via an epoxide
intermediate were identified in the urine of rats or mice after exposure to
14C-butadiene. These findings may have relevance for the prediction of
butadiene toxicity and provide a basis for a revision of the existing
physiologically based pharmacokinetic models.
ARTICLES
Quantitative and qualitative differences in the metabolism of 14C-1,3- butadiene in rats and mice: relevance to cancer susceptibility
Shell International Chemicals, Toxicology Department, Shell Research and Technology Centre Amsterdam, The Netherlands.
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