1,3-Butadiene and its epoxides induce sister-chromatid exchanges in human lymphocytes in vitro

Sasiadek, Maria M.; Norppa, Hannu; Sorsa, Marja

doi:10.1016/0165-1218(91)90057-s

Cited by 70 publications

(45 citation statements)

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“…It induced base substitution mutations in Salmonella strains TA1530 and 1535 after exogenous metabolic activation (5). Sister chromatid exchanges were induced in human lymphocytes exposed to butadiene, with or without exogenous metabolic activation, when the agent was added directly to the culture medium (6) but not when cells were exposed to an atmosphere containing butadiene (7). Sister chromatid exchanges were also induced in Chinese hamster ovary cells when the chemical was added to the medium together with a metabolic activation system (8).…”

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confidence: 81%

“…Sister chromatid exchanges were also induced in Chinese hamster ovary cells when the chemical was added to the medium together with a metabolic activation system (8). The mono-and diepoxide derivatives of butadiene are directly genotoxic in a variety of short-term test systems (5,6,8). These derivatives are thought to be the intermediates largely responsible for the genetic toxicity of butadiene.…”

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confidence: 99%

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hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant.

Ward

Ammenheuser

Bechtold

et al. 1994

Environ Health Perspect

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1,3-Butadiene is a major industrial chemical that has been shown to be a carcinogen at multiple sites in mice and rats at concentrations as low as 6.25 ppm. Occupational exposures have been reduced in response to these findings, but it may not be possible to determine by using traditional epidemiological methods, whether current exposure levels are adequate for protection of worker health. However, it is possible to evaluate the biological significance of exposure to genotoxic chemicals at the time of exposure by measuring levels of genetic damage in exposed populations. We have conducted a pilot study to evaluate the effects of butadiene exposure on the frequencies of lymphocytes containing mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt locus in workers in a butadiene production plant. At the same time, urine specimens from the same individuals were collected and evaluated for the presence of butadiene-specific metabolites. Eight workers from areas of the plant where the highest exposures to butadiene occur were compared to five workers from plant areas where butadiene exposures were low. In addition, six subjects with no occupational exposure to butadiene were also studied as outside controls. All of the subjects were nonsmokers. An air sampling survey conducted for 6 months, and ending about 3 months before the study, indicated that average butadiene levels in the air of the high-exposure areas were about 3.5 ± 7.5 ppm. They were 0.03 ± 0.03 ppm in the low-exposure areas. Peripheral blood lymphocytes from the subjects were assayed using an autoradiographic test for hprt mutations. The weighted mean variant (mutant) frequency (Vf) (± SE) in the eight exposed subjects was 3.84(±0.70) x 106 per evaluatable cell, as compared to 1.16±(0.27) x 104 in the low-exposed and 1.03(±0.07) x 106 in the outside controls. The Vf of the low-exposed controls and the outside controls were not significantly different, but the mean frequency of mutant lymphocytes in the seven exposed subjects was significantly higher when compared to the mean Vf of the nonexposed controls (p<0.01) and the low-exposed controls (p<0.05). A single metabolite of butadiene, 1,2-dihydroxy-4-(N-acetlylcysteinyl-S) butane, was detected in the urine of all subjects. The concentration in the urine of the workers in the high-exposed group was significantly greater than in the low-exposed or nonexposed groups. The correlation between the level of the metabolite in urine and the frequency of hprt mutants was r = 0.85. The observation of an elevated Vf in the exposed subjects and the strong correlation of Vf with the level of excreted metabolite suggests that butadiene exposures under these conditions were sufficient to induce somatic cell mutations. This degree of increase in Vf is similar to what we have observed in cigarette smokers. The results available at this time indicate that current levels of occupational exposure to butadiene may not be sufficiently low to protect workers from the adverse effects that may result from exposure...

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confidence: 81%

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confidence: 99%

hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant.

Ward

Ammenheuser

Bechtold

et al. 1994

Environ Health Perspect

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“…DEB is 50x more effective in inducing sister chromatid exchanges and chromosomal aberrations in human lymphocytes than EB (20)(21)(22) and is two orders of magnitude more mutagenic than EB in TK6 lymphoblasts (23). The types of mutations induced by the two epoxides are distinct.…”

Section: Introductionmentioning

confidence: 87%

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

Goggin

Anderson

Park

et al. 2008

Chem. Res. Toxicol.

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Abstract1,3-Butadiene (BD) is an important industrial chemical used in the rubber and plastics manufacture, as well as an environmental pollutant present in automobile exhaust and cigarette smoke. It is classified as a known human carcinogen based on the epidemiological evidence in occupationally exposed workers and its ability to induce tumors in laboratory animals. BD is metabolically activated to several reactive species, including 1,2,3,4-diepoxybutane (DEB) which is hypothesized to be the ultimate carcinogenic species due to its bifunctional electrophilic nature and its ability to form DNA-DNA and DNA-protein cross-links. While 1,4-bis-(guan-7-yl)-2,3,-butanediol (bis-N7G-BD) is the only type of DEB-specific DNA adduct previously quantified in vivo, four regioisomeric guanineadenine (G-A) cross-links have been observed in vitro, e.g. 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD), 1-(guan-7-yl)-4-(aden-3-yl)-2,3,-butanediol (N7G-N3A-BD), 1-(guan-7-yl)-4-(aden-7-yl)-2,3-butanediol (N7G-N7A-BD), and 1-(guan-7-yl)-4-(aden-6-yl)-2,3-butanediol (N7G-N 6 A-BD) (Park et al., Chem. Res. Toxicol. 2004, 17, 1638-1651. The goal of the present work was to develop an isotope dilution HPLC-ESI + -MS/MS method for the quantitative analysis of guanine-adenine DEB cross-links in DNA extracted from BD-exposed laboratory animals. In our approach, G-A butanediol conjugates are released from the DNA backbone by thermal or mild acid hydrolysis. Following solid phase extraction, samples are subjected to capillary HPLCpositive mode electrospray ionization-tandem mass spectrometry (HPLC-ESI + -MS/MS) analysis with 15 N 3 , 13 C 1 -labeled internal standards. The detection limit of our current method is 0.6 to 1.5 adducts per 10 8 normal nucleotides. The new method was validated by spiking G-A cross-link standards (10 fmol each) into control mouse DNA (0.1 mg), followed by sample processing and HPLC-ESI + -MS/MS analysis. The accuracy and precision were calculated as 105 ± 17 %

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“…Diepoxybutane is a more potent carcinogen in mice than epoxybutene (21) and is nearly 100 times more mutagenic on a molar basis than epoxybutene in mammalian systems (26). Diepoxybutane also induces genetic damage in vitro in mammalian cells (Chinese hamster ovary cells and human peripheral blood lymphocytes) at lower concentrations than epoxybutene (27,28 appear to play major roles in the overall metabolism of butadiene: cytochrome P450 monooxygenase, epoxide hydrolase, and glutathione (GSH) S-transferase. The metabolic activation of butadiene proceeds by cytochrome P450-mediated oxidation to epoxybutene (29)(30)(31)(32)(33).…”

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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1,3-Butadiene and its epoxides induce sister-chromatid exchanges in human lymphocytes in vitro

Cited by 70 publications

References 14 publications

hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant.

hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant.

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

Biomonitoring of 1,3-butadiene and related compounds.

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