Species differences in the disposition of inhaled butadiene

Bond, James A.; Dahl, Alan R.; Henderson, Rogene F.; Dutcher, John S.; Mauderly, Joe L.; Birnbaum, Linda S.

doi:10.1016/0041-008x(86)90268-1

Cited by 91 publications

(55 citation statements)

References 16 publications

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“…Butadiene monoxide has been identified in the expired air of Sprague-Dawley rats exposed to 1,3-butadiene (29). Although the rate of butadiene metabolism is greater in B6C3F1 mice than Sprague-Dawley rats at equivalent exposure concentrations (30)(31)(32), the magnitude of this difference at carcinogenic exposure levels in these species does not seem to be sufficient to account for the species difference in carcinogenicity of 1,3-butadiene. The present studies indicate that 200 ppm butadiene is carcinogenic to the heart, lung, Harderian gland, mammary gland, and ovary of B6C3F1 mice; however, other than for the mammary gland, neoplasms were not induced at these sites in Sprague-Dawley rats exposed to 1000 or 8000 ppm 1,3-butadiene.…”

Section: -Week Evaluationmentioning

confidence: 88%

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Melnick¹,

Huff²,

Roycroft³

et al. 1990

Environmental Health Perspectives

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1,3-Butadiene, a large-production volume chemical used mainly in the manufacture of synthetic rubber, was found to induce multiple-organ carcinogenicity in male and female B6C3F1 mice at exposure concentrations (625 and 1250 ppm) equivalent to and below the OSHA standard of 1000 ppm. Since this study was terminated after 60 weeks of exposure because of reduced survival due to fatal tumors, and because dose-response relationships for 1,3-butadiene-induced neoplastic and nonneoplastic lesions were not clearly established, a second long-term inhalation study of 1,3-butadiene in B6C3F1 mice was conducted at lower exposure concentrations, ranging from 6.25 to 625 ppm. Both the histopathological findings from animals dying through week 65 and the results of evaluations of animals exposed for 40 and 65 weeks are presented in this report. Exposure to 1,3-butadiene caused a regenerative anemia at concentrations of 62.5 ppm and higher. Testicular atrophy was induced at 625 ppm, and ovarian atrophy was observed at 20 ppm and higher. During the first 50 weeks of the study, lymphocytic lymphoma was the major cause of death of mice exposed to 625 ppm 1,3-butadiene. Neoplasms of the heart, forestomach, lung, Harderian gland, mammary gland, ovary, and liver were frequently observed in 1,3-butadiene-exposed mice that died between week 40 and week 65 of the study. Studies in which exposure to 1,3-butadiene was stopped after limited periods were also included to assess the relationship between exposure levels and duration of exposures on the outcome of 1,3-butadiene-induced carcinogenicity. In these studies, lymphocytic lymphomas were induced in male mice exposed to 625 ppm 1,3-butadiene for only 13 weeks. The incidence of lymphocytic lymphoma in male mice exposed to 625 ppm 1,3-butadiene for 26 weeks was two times that in mice exposed to 625 ppm for 13 weeks. However, when the exposure concentration was reduced by half to 312 ppm and the exposure duration extended to 52 weeks, the incidence of lymphocytic lymphoma was reduced by 90%. Thus, the multiple of the exposure concentration times the exposure duration did not predict the incidence of lymphocytic lymphoma in mice. The early mortalities resulting from lymphocytic lymphomas in male mice exposed to 625 ppm 1,3-butadiene limited the expression of tumors at other sites. A clearer dose-response for 1,3-butadieneinduced neoplasia should be apparent from experiments in mice exposed to lower concentrations of this chemical for 2 years.

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Section: -Week Evaluationmentioning

confidence: 88%

Inhalation Toxicology and Carcinogenicity of 1,3-Butadiene in B6C3F 1 Mice Following 65 Weeks of Exposure

Melnick¹,

Huff²,

Roycroft³

et al. 1990

Environmental Health Perspectives

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“…The elimination of butadiene-derived radioactivity was examined in the exhaled air, urine, and feces after exposure. At the same exposure concentration, mice retained more of the butadiene-derived radioactivity than rats (49), resulting in a higher dose. This may be due to the greater minute volume in mice as compared to rats.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…The distribution of butadiene-derived radioactivity was also examined in the tissues of mice and rats (51). Few differences were observed.…”

Section: Pharmacokineticsmentioning

confidence: 99%

A brief survey of butadiene health effects: a role for metabolic differences.

Birnbaum

1993

Environ Health Perspect

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1,3-Butadiene is a major monomer in the rubber and plastics industry and is one of the highest-production industrial chemicals in the United States. Although not highly acutely toxic to rodents, inhalation of concentrations as low as 6.25 ppm causes tumors in mice. Butadiene is oncogenic in rats, but much higher exposure concentrations are required than in mice. Chronic toxicity targets the gonads and hematopoetic system. Butadiene is also a potent mutagen and clastogen. Differences in the absorption, distribution, and elimination of butadiene appear to be relatively minor between rats and mice, although mice do retain more butadiene and its metabolites after exposure to the same concentration and have a higher rate of metabolic elimination. Recent studies have demonstrated that major species differences appear to occur in the rate of detoxication of the primary metabolite, 3-epoxybutene (butadiene monoepoxide [BDMO]). Mice have the greatest rate of production of BDMO as compared to other species, but the rate of removal of BDMO appears to be less than in other species. Mice have low levels of epoxide hydrolase; rats have intermediate levels; monkeys and humans appear to have high levels of this detoxifying enzyme. Thus, while only low levels of butadiene exposure may result in an accumulation of BDMO in the mouse, much higher levels would be required to result in an elevation of circulating BDMO in other species. The level of this reactive metabolite may be correlated with the species differences in butadiene sensitivity.

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“…After the initial series ofmodels were constructed, rat model predictions were compared with the high-dose glutathionedepletion data of McKelvey and Zemaitis (22) (33). To the degree that butadiene was processed and active metabolites effectively lost from the animals before being measured at the end ofthe 6-hr exposures, delivered doses in the animal bioassays wold be underestmated by this approach.…”

Section: Philosophy Of Science Issuesmentioning

confidence: 99%