Polymorphisms in BER and NER pathway genes: effects on micronucleus frequencies among vinyl chloride-exposed workers in Northern China.

In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65)‰ showed higher micronucleus frequency than the unexposed workers (2.51±1.96)‰ (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A, XPG Exon15 G-C, ERCC13'-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 -77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13'-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05-1.39; P<0.01); (FR=1.14, 95% CI: 1.00-1.38; P<0.05) and (FR=1.26, 95% CI: 1.11-1.44; P<0.01); (FR=1.23, 95% CI: 1.08-1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene-MN association changed with exposure for XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.

Genetic polymorphisms of DNA repair genes and chromosomal damage in workers exposed to 1,3-butadiene.

The base excision repair (BER) pathway is important in repairing DNA damage incurred from occupational exposure to 1,3-butadiene (BD). This study examines the relationship between inherited polymorphisms of the BER pathway (x-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg280His, Arg399Gln, T-77C, ADPRT Val762Ala, MGMT Leu84Phe and APE1 Asp148Glu) and chromosomal damage in BD-exposed workers, using the cytokinesis-blocked (CB) micronucleus (MN) assay in peripheral lymphocytes of 166 workers occupationally exposed to BD and 41 non-exposed healthy individuals. The MN frequency of exposed workers (3.39 +/- 2.42) per thousand was higher than that of the non-exposed groups (1.48 +/- 1.26) per thousand (P < 0.01). Workers receiving greater than median annual BD exposures had higher MN values than lower exposed workers: frequency ratio (FR) of 1.30, 95% confidence interval (CI) 1.14-1.53; P < 0.05. Workers who carried the following genotypes were associated with greater frequency of MN (P < 0.05 for each comparison, unless specified): XRCC1 -77 C/T genotype (FR = 1.28, 95% CI: 1.04-1.57; reference C/C), ADPRT 762 Ala/Ala (FR = 1.54, 95% CI: 1.17-2.03; P < 0.01), XRCC1 194 Arg/Trp (FR = 1.13, 95% CI: 0.87-1.27; reference, Arg/Arg), XRCC1 280 Arg/His (FR = 1.67, 95% CI: 1.10-2.42; reference, Arg/Arg), XRCC1 399 Arg/Gln and Gln/Gln genotypes (FR = 1.26, 95% CI: 1.03-1.53 and FR = 1.24, 95% CI 1.03-1.49; reference Arg/Arg, respectively). As XRCC1 polymorphisms were linked, workers carrying the XRCC1 (-77)-(194)-(280)-(399) diplotype, TCGA/TCGA, had a higher MN frequency compared with individuals carrying the wild-type CCGG/CCGG (FR = 1.57, 95% CI: 1.02-2.41; P < 0.05). In conclusion, CB-MN is a sensitive index of early damage among BD-exposed workers. In workers exposed to BD, multiple BER polymorphisms and a XRCC1 haplotype were associated with differential levels of chromosome damage.

Estimation of benchmark dose for micronucleus occurrence in Chinese vinyl chloride-exposed workers.

In this study, we estimated the possibility of using benchmark dose (BMD) to assess the dose-response relationship between vinyl chloride monomer (VCM) exposure and chromosome damage. A group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed control in Shandong Province northern China were examined for chromosomal damage in peripheral blood lymphocytes (PBL) using the cytokinesis-blocked micronucleus (CB-MN) assay of DNA damage. The exposed group (3.47 ± 2.65)‰ showed higher micronucleus frequency than the control (1.60 ± 1.30)‰ (P < 0.01). Occupational exposure level based on micronucleus occurrence in all individuals was analyzed with benchmark dose (BMD) methods. The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. Results showed a dose-response relationship between cumulative exposure and MN frequency, and a BMDL of 0.54 mg/m3 and 0.23 mg/m3 for males and females, respectively. Female workers were more susceptible to MN damage than male workers.

Estimation of a safe level for occupational exposure to vinyl chloride using a benchmark dose method in central China.

OBJECTIVES: The aim of this study was to estimate a benchmark dose (BMD) for chromosome damage induced by vinyl chloride monomer (VCM) in VCM-exposed workers in central China and validate the published results in Shanghai. METHODS: VCM-exposed workers who had been exposed to VCM for at least one year (n=463) and matched subjects not exposed to VCM or other toxins (n=273) were asked to participate in this study. Micronucleus (MN) frequency based on the cytokinesis-block micronucleus assay (CBMN) was used as a biomarker for chromosome damage induced by VCM exposure. RESULTS: The MN frequency in the VCM-exposed workers was significantly higher than that in the control group, and multivariate Poisson regression suggested that gender, smoking status and VCM exposure were the significant factors influencing the risk of increased MN frequency. When subjects were further stratified according to gender and smoking status, the results showed that female VCM-exposed workers were more susceptible than the males to the risk of increased MN frequency. The MN frequency of smokers was significantly higher than that of nonsmokers in the control group. Our study also suggested that there was a strong dose-response relationship between VCM CED and the increased risk of MN frequency in the total group, males and females. The BMDL(10) was found to be 630.6, 670.2 and 273.7 mg-year for all VCM-exposed workers, males and females, respectively. CONCLUSIONS: These results invite further scrutiny of the current VCM occupational exposure limits and warrant further study of the risk of VCM genotoxicity and carcinogenicity.