| Vinyl chloride monomer (CH2=CHC1, VCM) is an important chemical material, more than 95% of which was used to produce polyvinyl chloride. In 2009, the world production is 40.0 million ton. Among them,45.1% came from Asian and Pacific regions, where China is the most productive country. Up to October 2009, the production of PVC was 17 million ton in China, ranking the first in the world. The health issues of VCM exposure workers need to be addressed.Since VCM is a human carcinogen confirmed by IARC in 1987, more and more VCM-related investigations were carried out. At present, the mechanism of VCM inducing tumor development is considered as VCM metabolites induce genetic damage and promote tumor development. In the past years, most countries modulated the hygienic standard accordingly. Currently, the occupational exposure limit of VCM is 1ppm (2.79mg/m3) in most western developed countries, the hygienic standard in China is much higher (PC-TWA:10mg/m3). Therefore under this standard in my country, it is important to investigate whether VCM can induce damage for VCM-exposed workers, especially genetic damage. Poison induced genetic damage may be affected by genetic susceptibility, especially in metabolic enzymes and DNA repair enzymes. A clarification of the association between genetic variations in metabolic pathway and DNA repair pathway and genetic damage occurrence will help to understand the mechanism of VCM-induced damage and promote health risk assessment.The subjects of this study come from one chemical company of Henan province in China. The health status of VCM-exposed workers was obtained through health examination and genetic damage detecting. The workers'exposure dose and cumulate exposure dose were assessed. The relationship between VCM exposure and genetic damage and the relationship between VCM cumulate exposure dose and genetic damage were explored in this study. The results suggest that the VCM occupational exposure limit need to be emended and a reference is provided for the emendation. Through exploring the association between gene polymorphisms in VCM metabolic and DNA repair pathways and the risk of VCM-induced genetic damage, we identified the susceptible biomarkers and provided new evidence for the mechanism of VCM carcinogenesis and health risk assessment.The results show that VCM cumulate exposure dose is mainly associated with cumulate exposure time. The cumulate exposure dose increased with older age and longer exposure time. The chromosome damage results indicated that the damage degree was higher in the VCM exposure group than the control group. A dose-response relationship between VCM exposure and chromosome damage was identified: the chromosome damage increased with higher VCM exposure dose. This study suggests that peripheral lymphocyte micronucleus rate can be considered as an effect index for assessing VCM-exposed workers health risk under low VCM exposure concentration.We assessed the relationship between VCM cumulate exposure dose and chromosome damage using Benchmark Dose Software (BMDS). Our results indicated a BMDL level of 4.82g for male VCM-exposed workers and a BMDL level of 3.44 g for female VCM-exposed workers. The results could serve reference materials for emending the hygienic standard for VCM exposure limits.We regarded the peripheral lymphocyte micronucleus rate as an effect index and detected the polymorphisms of VCM-exposed metabolic enzyme genes and DNA repair enzyme genes using PCR-RFLP method. We examined the relationships among each gene polymorphism, haplotype and chromosomal damage. We assessed the relationships among micronucleus rate, micronucleus damage, other related factors and 15 SNPs from 12 genes including ADH2, ADPRT, ALDH2, APE1, CYP2E1, GSTT1, GSTM1, hMYH, MGMT, OGG1,XPD and XRCC1.In this study, we developed a method to detect ADH2 (rs1229984) SNPs using CRS-PCR-RFLP technique. The method is less expensive, more efficient and requires fewer specimens than the traditional methods. The development of this method benefits the future resemble research and other SNPs research.Multivariate Poisson regression analysis suggested that the risk factors of micronucleus include ADH2, ALDH2, ADPRT, OGG1, XRCC1399, XRCC1194 and XPD751. Compared to VCM-exposed workers with ADH2 AA genotype, those with ADH2 GG genotype had lower risk of micronucleus rate; compared to VCM-exposed workers with ALDH2 G allele, those with ALDH2 A allele had higher risk of micronucleus rate; compared to VCM-exposed workers with ADPRT T allele, those with ADPRT C allele had higher risk of micronucleus rate; compared to VCM-exposed workers with APE1 TT genotype, those with APE1 GG genotype had lower risk of micronucleus rate; compared to VCM-exposed workers with XRCC1399 G allele, those with XRCC1399 A allele had lower risk of micronucleus rate; compared to VCM-exposed workers with XRCC1194 CC genotype, those with XRCC1194 CT genotype had higher risk of micronucleus rate; compared to VCM-exposed workers with XPD151 AA genotype, those with XPD151 AC genotype had lower risk of micronucleus rate. Multivariate logistic regression on chromosome damage indicated that compared with VCM-exposed workers with ADPRT TT genotype, VCM-exposed workers with ADPRT TC genotype had a higher risk of chromosome damage than those with ADPRT TT genotype [OR(95%CI): 1.93(1.21-3.08)].Haplotype analyses showed that compared to VCM-exposed workers carrying with XRCC1399 wild genotype, XRCC1280 wild genotype and XRCC1194 wild genotype, those with XRCC1399 wild genotype, XRCC1280 wild genotype and XRCC1194 mutant genotype had an increased risk of micronucleus rate, as well as VCM-exposed workers carrying XRCC1399 mutant genotype, XRCC1280 wild genotype and XRCC1194 wild genotype and VCM-exposed workers carrying XRCC1399 wild genotype. Compared to VCM-exposed workers with XRCC1399 wild genotype, XRCC1280 wild genotype and XRCC1194 wild genotype, those with XRCC1399 wild genotype, XRCC1280 wild genotype and XRCC1194 mutant genotype had a 3.67 fold risk of chromosome damage.ALDH2(rs671) SNPs significantly modified the association between drinking exposure and risk of chromosome damage (P=0.0389).The analyses on gene-gene interaction for chromosome damage risk indicated that joint effect of the following SNPs may modify the relationship between VCM exposure and chromosome damage risk:ADH2 and APE1 (P=0.0199), XRCC1194 (P=0.0138), respectively; ALDH2 and XRCC1194 (P=0.043); CYP2E1 and XPD312(P=0.0451), XRCC1280(P=0.0104),XRCC1194(P=0.0093), respectively; MGMT and ADPRT(P=0.0351), XRCC1399 (P=0.0197), XRCC1280 (P=0.0498), respectively; hMYH and OGG1 (P=0.0261). The results of cumulate exposure dose of VCM and gene interaction on risk of chromosome damage indicated that there were no the interaction effects. All our investigations need confirmation by future studies.In summary, genetic damage induced by VCM exposure still exists under current occupational exposure limit in China. Genetic variations in VCM related metabolic enzymes, DNA repair enzymes and occupational environment factors may all impact the occurrence and development of damage. |
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