Species differences in urinary butadiene metabolites; identification of l,2-dihydroxy-4-(<i>N</i>-acetylcysteinyl)butane, a novel metabolite of butadiene

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)

Section: 3-butadiene Biomarkers Urinary Metabolitessupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Biomonitoring of 1,3-butadiene and related compounds.

Osterman-Golkar

Bond²

1996

“…The proportion of this conjugate in the urine of mice, rats, hamsters, and monkeys increases in proportion to the levels of hepatic epoxide hydrotase (31). While the human metabolic pattern appears more like that of monkeys or rats than that of mice, the high correlation of butadiene metabolite excretion with hprt Vf indicates that genotoxic intermediates are being formed in proportion to the level of formation of this metabolite.…”

Section: Discussionmentioning

confidence: 97%

“…Glutathione conjugation products of butadiene have been quantitatively detected in the urine of animals (31) and humans (32).…”

mentioning

confidence: 99%

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

Ward

Ammenheuser

Bechtold

et al. 1994

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...

“…In vivo studies examining the profile ofurinary metabolites after butadiene exposure have lent support to the hypothesis that while mice preferentially metabolize BDMO via conjugation with glutathione, rats use this pathway, as well as epoxide hydrolase, and monkeys favor diol formation almost exclusively (60). Inhalation exposure of monkeys to butadiene resulted in the presence of only one major metabolite in the urine, which has been identified as the N-acetylcysteine conjugate of butanediol.…”

Section: Pharmacokineticsmentioning

confidence: 98%

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

Birnbaum

1993

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.