Assessment of 1,3-Butadiene Exposure in Polymer Production Workers Using HPRT Mutations in Lymphocytes as a Biomarker

Ammenheuser, Marinel M.; Bechtold, William E.; Abdel‐Rahman, Sherif Z.; Rosenblatt, Judah; Hastings-Smith, Darlene A.; Ward, Jonathan B.

doi:10.2307/3454747

Cited by 8 publications

(16 citation statements)

References 34 publications

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“…There was more than a 2-fold increase (P Ͻ 0.02) in the frequencies of HPRT mutant lymphocytes in the group of workers with exposure above our criterion level of 150 ppb of BD compared to the group of workers exposed to Ͻ150 ppb. These results are consistent with our earlier observations, which established that occupational exposure to BD in either BD monomer or SBR polymer production is associated with an increase in the frequency of somatic cell mutations in lymphocytes [Ward et al, 1994[Ward et al, , 1996Ma et al, 2000;Ammenheuser et al, 2001]. Our studies indicate that, for at least some workers, there is an elevation in the frequency of somatic cell mutations under current exposure conditions .…”

Section: Discussionsupporting

confidence: 95%

“…Exposure to BD was assessed during three shifts in a 28-day work period by collecting breathing zone air samples using 3M 3520 Organic Vapor Monitors (OVMs) (3M, St. Paul, MN) as discussed in detail in our previous publications Ammenheuser et al, 2001;Abdel-Rahman et al, 2001;Chung et al, 1999]. From each study subject a blood sample (approximately 65 ml) was obtained at the end of a 28-day work cycle.…”

Section: Study Population Sample Collection and Bd Exposure Assessmentmentioning

confidence: 99%

“…For a number of years our laboratory has evaluated occupational exposure to BD in workers in the synthetic rubber industry using the HPRT mutant lymphocyte assay as a biomarker of mutagenic effect [Ward et al, 1994[Ward et al, , 1996Ma et al, 2000;Ammenheuser et al, 2001;Abdel-Rahman et al, 2001]. We have used the autoradiographic version of the HPRT assay in several studies [Ward et al, 1994[Ward et al, , 1996Ammenheuser et al, 2001;Abdel-Rahman et al, 2001] and the cloning assay in one study . As the metabolism of BD has become better understood, polymorphic alleles of enzymes that are important in the detoxification of BD have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Variability in human sensitivity to 1,3‐butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene

Abdel‐Rahman

El‐Zein

Ammenheuser

et al. 2003

Environ and Mol Mutagen

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The carcinogenic effects of 1,3-butadiene (BD), a chemical widely used in the rubber industry, are thought to be due to its epoxide metabolites. In humans, these epoxides are detoxified predominantly by hydrolysis, a reaction mediated by the microsomal epoxide hydrolase (mEH) enzyme. The mEH gene is polymorphic and the most common mEH coding-region variants detected in human populations are the two amino acid polymorphisms Tyr113His and His139Arg. Polymorphic amino acid substitutions at residues 113 and 139 in the human mEH protein can associate in four distinct combinations: Tyr113/His139, Tyr113/Arg139, His113/His139, and His113/Arg139. In vitro studies have shown that each of these genotypes has a unique mEH protein level that can affect net mEH enzymatic activity. In the current study, we examined the relationships among the genotypes involving these two polymorphisms and the mutagenic responses associated with occupational exposure to BD. We studied 49 nonsmoking workers from two styrene-butadiene rubber facilities in southeast Texas using the autoradiographic HPRT mutant lymphocyte assay as a biomarker of genotoxic effect. We genotyped the study participants simultaneously for both polymorphisms, using a multiplex PCR assay developed in our laboratory, and the subjects were assigned to a specific group based on the predicted mEH activity associated with their genotypes (low, intermediate, and high). In the study population, 67% were exposed to low BD levels of <150 ppb (measured by personal badge dosimeters) and 33% were exposed to >150 ppb (mean 2,244 ppb). In the BD low-exposure group, the mEH genotypes had no significant effect on the HPRT variant (mutant) frequency (Vf). In the high-exposure group (BD > 150 ppb), individuals with genotypes associated with low mEH activity had a significant (P < 0.05) 3-fold increase in HPRT Vf (Vf +/- SEM = 13.95 +/- 2.15 x 10(-6)) compared to high-activity individuals (4.41 +/- 1.19 x 10(-6)), and a 2-fold increase in Vf compared to intermediate-activity individuals (6.44 +/- 2.09 x 10(-6)). Our results indicate that mEH genotypes may play a significant role in human sensitivity to the genotoxic effects of exposure to BD.

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Section: Discussionsupporting

confidence: 95%

Section: Study Population Sample Collection and Bd Exposure Assessmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Variability in human sensitivity to 1,3‐butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene

Abdel‐Rahman

El‐Zein

Ammenheuser

et al. 2003

Environ and Mol Mutagen

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“…BD exposures of the workers in this study were 3.5 ± 7.5 ppm in the high-exposure areas. Another study by this same group, using the HPRT cloning assay, was positive according to the authors and the mutational spectrum data were compatible with the HPRT mutations being induced by BD, in which an excess of deletions were found [28]. By contrast, our studies in BD-exposed Chinese workers [7] and those in Czech workers by other groups [11,15], using the cloning assay, have failed to find increases in HPRT mutations even though the level of BD exposure was similar to the Texas studies.…”

Section: Discussionmentioning

confidence: 88%

Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes

Zhang

Hayes

Guo

et al. 2004

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Abstract1,3-Butadiene (BD) is an important industrial chemical and pollutant. Its ability to induce genetic damage and cause hematological malignancies in humans is controversial. We have examined chromosome damage by fluorescence in situ hybridization (FISH) and mutations in the HPRT gene in the blood of Chinese workers exposed to BD. Peripheral blood samples were collected and cultured from 39 workers exposed to BD (median level 2 ppm, 6 h time-weighted average) and 38 matched controls in Yanshan, China. No difference in the level of aneuploidy or structural changes in chromosomes 1, 7, 8, and 12 was detected in metaphase cells from exposed subjects in comparison with matched controls, nor was there an increase in the frequency of HPRT mutations in the BDexposed workers. Because genetic polymorphisms in glutathione S-transferase (GST) enzymes and microsomal epoxide hydrolase (EPHX1) may affect the genotoxic effects of BD and its metabolites, we also related chromosome alterations and gene mutations to GSTT1, GSTM1 and EPHX1 genotypes. Overall, there was no effect of variants in these genotypes on numerical or structural changes in chromosomes 1, 7, 8 and 12 or on HPRT mutant frequency in relation to BD exposure, but the GST genotypes did influence background levels of both hyperdiploidy and HPRT mutant frequency. In conclusion, our data show no increase in chromosomal aberrations or HPRT mutations among workers exposed to BD, even in potentially susceptible genetic subgroups. The study is, however, quite small and the levels of BD exposure are not extremely high, but our findings in China do support those from a similar study conducted in the Czech Republic. Together, these studies suggest that low levels of occupational BD exposure do not pose a significant risk of genetic damage.

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“…The primary goal of our research program is to evaluate variation in human sensitivity following exposure to environmentally relevant levels of BD (Ward et al, 1996Abdel-Rahman et al, 2001, 2003Ammenheuser et al, 2001). To address individual susceptibility to BD and develop an accurate assessment of risk, however, variation in responses attributable to genetic and physiological factors must be considered.…”

Section: Discussionmentioning

confidence: 99%

A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

Wickliffe

Ammenheuser

Salazar

et al. 2003

Environ and Mol Mutagen

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The specific role that polymorphisms in xenobiotic metabolizing enzymes play in modulating sensitivity to 1,3-butadiene (BD) genotoxicity has been relatively unexplored. The enzyme microsomal epoxide hydrolase (mEH) is important in detoxifying the mutagenic epoxides of BD (butadiene monoepoxide [BDO], butadiene diepoxide [BDO(2)]). Polymorphisms in the human mEH gene appear to affect the function of the enzyme. We exposed mice with normal mEH activity (WT) and knockout mice without mEH activity (KO) to 20 ppm BD (inhalation) or 30 mg/kg BDO(2) (intraperitoneal [IP] injection). We then compared Hprt mutant frequencies (MFs) among these groups. KO mice exposed to BD exhibited a significant (P < 0.05) 12.4-fold increase in MF over controls and a significant 5.4-fold increase in MF over exposed WT mice. Additionally, KO mice exposed to BDO(2) exhibited a significant 4.5-fold increase in MF over controls and a significant 1.7-fold increase in MF over exposed WT mice. We also compared genomic damage in WT and KO mice (comet tail moment) following IP exposure to 3 mg/kg and 30 mg/kg BDO(2). KO mice exposed to 3 mg/kg exhibited significantly more DNA damage than controls (7.5-12.1-fold increase) and exposed WT mice (3 mg/kg; 4.8-fold increase). KO mice exposed to 30 mg/kg BDO(2) exhibited significantly more DNA damage than all other groups (2.3-27.9-fold increase). Correlation analysis indicated that a significant, positive relationship (r(2) = 0.92) exists between comet-measured damage and Hprt MFs. The lack of mEH activity increases the genetic sensitivity of mice exposed to BD and BDO(2). This model should facilitate a mechanistic understanding of the observed variation in human genetic sensitivity following exposure to BD.

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Assessment of 1,3-Butadiene Exposure in Polymer Production Workers Using HPRT Mutations in Lymphocytes as a Biomarker

Cited by 8 publications

References 34 publications

Variability in human sensitivity to 1,3‐butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene

Variability in human sensitivity to 1,3‐butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene

Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes

A model of sensitivity: 1,3‐butadiene increases mutant frequencies and genomic damage in mice lacking a functional microsomal epoxide hydrolase gene

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