Genotoxic properties of 1,3-butadiene

Meester, Conrad De

doi:10.1016/0165-1110(88)90005-x

Cited by 65 publications

(33 citation statements)

References 49 publications

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“…Inhaled 1,3-butadiene is genotoxic and cytotoxic in the mouse bone marrow, as demonstrated in the studies summarized here and in others (11). Induction of chromosomal effects are concentration dependent over a two order of magnitude range of exposures.…”

Section: Discussionmentioning

confidence: 58%

Results of NTP-Sponsored Mouse Cytogenetic Studies on 1,3-Butadiene, Isoprene, and Chloroprene

Shelby¹

1990

Environmental Health Perspectives

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Studies were conducted to determine the cytotoxic and cytogenetic effects of 1,3-butadiene and two structural analogs, chloroprene and isoprene, in the bone marrow cells of B6C3F, mice exposed to the chemicals by inhalation. In one study, animals were exposed to 1,3-butadiene concentrations of 6.25, 62.5, or 625 ppm 6 hr/day on 10 exposure days and in the second study, to the same concentrations on weekdays for 13 weeks. Chloroprene and isoprene treatments involved 6 hr/day exposures on 12 exposure days at concentrations of 0, 12, 32, 80, and 200 ppm for chloroprene and 0, 438, 1750, and 7000 ppm for isoprene. In the 10-day study, 1,3-butadiene induced significant increases in sister chromatid exchange (SCE) at 6.25 ppm, micronuclei at 62.5 ppm, and chromosomal aberrations at 625 ppm. In the 13-week study, the frequency of micronucleated normochromatic erythrocytes in the peripheral blood was significantly elevated in all exposure groups including the 6.25-ppm group. Isoprene induced both SCE and micronuclei, whereas chloroprene gave negative results for all cytogenetic end points assessed in bone marrow cells.

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Section: Discussionmentioning

confidence: 58%

Results of NTP-Sponsored Mouse Cytogenetic Studies on 1,3-Butadiene, Isoprene, and Chloroprene

Shelby¹

1990

Environmental Health Perspectives

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“…Using microsomes from Wistar rats, they observed that the Km for this pathway was relatively high compared to that of the initial epoxidation step, suggesting that the activation of butadiene to BDMO is favored over hydration of BDMO to the diol. BDMO can also serve as a substrate for a further round of epoxidation, leading to the production of diepoxybutane, which is more highly reactive and carcinogenic than the monoepoxide (22). Whether this metabolite is actually produced in vivo is unsure given the lack of detection of diepoxybutane-induced DNA crosslinks in vivo in either rats or mice (45).…”

Section: Pharmacokineticsmentioning

confidence: 98%

“…Butadiene is a potent mutagen both in vivo and in vitro (22). In studies involving bacterial mutagenicity, butadiene has been shown to be a base-pair mutagen in Salmonella typhimurium strains TA1530 and 1535 (23).…”

Section: Toxicitymentioning

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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“…The genotoxicity of butadiene has been studied using a variety of in vitro and in vivo mutagenicity assays [see review by de Meester (16)]. For example, butadiene displayed mutagenic activity in bacteria (Ames test), but only in the presence of liver S9 fractions (17).…”

Section: Introductionmentioning

confidence: 99%

Biomonitoring of 1,3-butadiene and related compounds.

Osterman-Golkar

Bond²

1996

Environ Health Perspect

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The 1990 Clean Air Act Amendments list several volatile organic chemicals as hazardous air pollutants, including ethylene oxide, butadiene, styrene, and acrylonitrile. The toxicology of many of these compounds shares several common elements such as carcinogenicity in laboratory animals, genotoxicity of the epoxide intermediates, involvement of cytochrome P450 for metabolic activation (except ethylene oxide), and involvement of at least two enzymes for detoxication of the epoxides (e.g., hydrolysis or conjugation with glutathione). These similarities facilitate research strategies for identifying and developing biomarkers of exposure. This article reviews the current knowledge about biomarkers of butadiene. Butadiene is carcinogenic in mice and rats, which raises concern for potential carcinogenicity in humans. Butadiene is metabolized to DNAreactive metabolites, including 1,2-epoxy-3-butene and diepoxybutane. These epoxides are thought to play a critical role in butadiene carcinogenicity. Butadiene and some of its metabolites (e.g., epoxybutene) are volatile. Exhalation of unchanged butadiene and excretion of butadiene metabolites in urine represent major routes of elimination. Therefore, biomonitoring of butadiene exposure could be based on chemical analysis of butadiene in exhaled breath, blood levels of butadiene epoxides, excretion of butadiene metabolites in urine, or adducts of butadiene epoxides with DNA or blood proteins. Mutation induction in specific genes (e.g., HPRT) following butadiene exposure can be potentially used as a biomarker. Excretion of 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane or the product of epoxybutene with N-7 in guanine in urine, epoxybutene-hemoglobin adducts, and HPRT mutation have been used as biomarkers in recent studies of occupational exposure to butadiene. Data in laboratory animals suggest that diepoxybutane may be a more important genotoxic metabolite than epoxybutene. Biomonitoring methods need to be developed for diepoxybutane and other putative reactive butadiene metabolites. With butadiene and related compounds, the ultimate challenge is to identify useful biomarkers of exposure in which quantitative linkages between exposure and internal dose of the important DNA-reactive metabolites are established. Environ Health Perspect 104(Suppl 5): 907-915 (1996)

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Genotoxic properties of 1,3-butadiene

Cited by 65 publications

References 49 publications

Results of NTP-Sponsored Mouse Cytogenetic Studies on 1,3-Butadiene, Isoprene, and Chloroprene

Results of NTP-Sponsored Mouse Cytogenetic Studies on 1,3-Butadiene, Isoprene, and Chloroprene

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

Biomonitoring of 1,3-butadiene and related compounds.

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