Disposition of butadiene monoepoxide and butadiene diepoxide in various tissues of rats and mice following a low-level inhalation exposure to 1,3-butadiene

Abstract

1,3-Butadiene (BD), a chemical used extensively in the production of styrene-butadiene rubber, is carcinogenic in Sprague-Dawley rats and B6C3F1 mice. Chronic inhalation studies revealed profound species differences in the potency and organ-site specificity of BD carcinogenesis between rats and mice. BD is a potent carcinogen in mice and a weak carcinogen in rats. Previous studies from our laboratory and others have shown marked differences between rats and mice in the metabolism of BD, which may account for species differences in carcinogenicity. The purpose of the present study was to examine the production and disposition of two mutagenic BD metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), in blood and other tissues of rats and mice during and following inhalation exposures to a target concentration of 62.5 p.p.m. BD. BDO was increased above background in blood, bone marrow, heart, lung, fat, spleen and thymus tissues of mice after 2 h and 4 h exposures to BD. In rats, levels of BDO were increased in blood, fat, spleen and thymus tissues. No increases in BDO were observed in rat lungs. BDO2, the more mutagenic of the two epoxides, was increased in the blood of rats and mice at 2 and 4 h after initiation of exposure to BD. In mice, BDO2 was detected in all tissues examined immediately following the 4 h exposure. This metabolite was detected in heart, lung, fat, spleen and thymus of rats, but at levels 40- to 160-fold lower than those seen in mice. Immediately after the 4 h exposure, blood levels of BDO2 were 204 +/- 15 pmol/g for mice but were 41-fold lower for rats. In the sensitive mouse target organs, heart and lungs, levels of BDO2 exceeded BDO levels immediately after the exposure. This study shows that the levels of BD epoxides are markedly greater in the mouse BD target organs. The high concentrations of BDO2 in these organs suggest that this compound may be particularly important in BD-induced carcinogenesis. Thus, although BD is oxidatively metabolized by similar metabolic pathways in rats and mice, the substantial quantitative differences in tissue levels of mutagenic epoxides between species may be responsible for the increased sensitivity of mice to BD-induced carcinogenicity.

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

“…These results are strengthened by reports on the DNA adducts from EB and EBdiol, showing that approximately the same level of the respective adduct was present in all tissues examined (33,34). However, the concentrations of the epoxide metabolites in organs were found to be one half of the concentration in blood (32). This has earlier also been shown for the chemically related compound ethylene oxide through the comparison of Hb-and DNA-adduct levels (35).…”

“…To estimate a common risk coefficient, b, for all tumor sites on the basis of dose in blood, it is a necessity that the cancer causative agent(s) is (are) evenly distributed in the different organs. Measurements of the concentrations of EB and DEB in mice and rats after a 4-hour exposure to 62.5 ppm BD in earlier studies have shown that the concentration of the respective epoxide is similar in all vessel-rich organs (32). These results are strengthened by reports on the DNA adducts from EB and EBdiol, showing that approximately the same level of the respective adduct was present in all tissues examined (33,34).…”

Biomonitoring of 1,3-butadiene and related compounds.

“…Albrecht et al (48) exposed mice and rats at 0, 50, 200, 500, and 1300 ppm and showed a nonlinear dose response in mice at concentrations above 200 ppm and a linear dose response for rats. The adduct data are in general agreement with concentrations of epoxybutene measured in blood and tissues that were lower in rats than in mice exposed to butadiene (42)(43)(44)50 (47). The workers, all nonsmokers, were divided into two groups on the basis of work location.…”

“…Diepoxybutane could not be detected in livers of mice or lungs and livers of rats. Thornton-Manning et al (44) recently reported that concentrations of epoxybutene were 3 to 74 times greater in tissues of mice compared with rats following exposure to 62.5 ppm butadiene for 4 hr. Levels of diepoxybutane in blood and tissues of rats were 40-to 163-fold lower than in corresponding mouse tissues.…”

Quantitative High-Performance Liquid Chromatography−Electrospray Ionization−Tandem Mass Spectrometry Analysis of the Adenine−Guanine Cross-Links of 1,2,3,4-Diepoxybutane in Tissues of Butadiene-Exposed B6C3F1 Mice

“…In chronic inhalation experiments with B6C3F1 mice and Sprague-Dawley rats, BD was carcinogenic in both species (10,28). However, B6C3F1 mice developed tumors at BD exposure concentrations three orders of magnitude lower than those that cause cancer in Sprague-Dawley rats (10,(28)(29)(30). Furthermore, the mutational spectrum found in BD-induced tumors of mice was different from that in rats (31).…”