| Vinyl chloride monomer (CH2=CHC1, VCM) is widely used in industry, 95％ofvinyl chloride was polymerized to polyvinyl chloride (PVC) With the fastdevelopment of petroleum industry, the total output of VCM in the world increasedrapidly. China is one of the important PVC production countries, and its annualproduction accounts for about 10％of the global production. So the health of VCMexposed workers should be paid more attention.VCM is a certain human carcinogen and it has been proved to be a multi-organand multi-system carcinogen. The mechanism of carcinogenesis was presumed to berelated to the genetic material damage induced by electrophilic metabolites of VCM.At present, the permissible exposure limit (PEL)of VCM in developed countries is 1ppm (2.79rng/m3), while the STEL and TWA in China are 25mg/m3 and 10mg/m3respectively. This study analyzed occupational health effects in VCM-exposedworkers whose exposure level was lower than the national occupational healthstandard. Since VCM is a human carcinogen, the majority of VCM-exposed workersdo not develop neoplasm, suggesting the susceptibility is modulated, at least in part,by polymorphisms in genes encoding metabolic enzymes, DNA repair proteins, andcell-cycle control proteins. Many studies have been done to investigate the effect ofgenetic polymorphisms of genes involved in VCM metabolism. But only a fewstudies paid attention to the DNA repair genes, and to our knowledge, there was noreports concerning the effect of genetic polymorphisms of genes involved incell-cycle control.In order to explore effect biomarkers under low level VCM exposure, this studyevaluated the relationship between the cumulative exposure dose and VCM-inducedliver lesion, chromosome damage. Occupational epidemiological study wasperformed to investigate the relationship between chromosome damage induced byVCM and polymorphisms of DNA damage repair genes and cell-cycle control related genes, in order to provide scientific evidence to screen the susceptible workers.Using ALT as an indicator of liver function and liver ultrasonography to detectliver morphological changes, we found VCM exposure was not associated with ALTlevel and liver morphological changes. Cytokinesis-block micronucleus (CB-MN)assay was used to detect chromosome damage of the peripheral blood lymphocyte inVCM-exposed workers. The results showed that the frequency of CB-MN ofVCM-exposed group was significantly higher than the control group. So thefrequency of CB-MN of peripheral blood lymphocyte can be used as an effectbiomarker under low level VCM exposure.Next, PCR-RFLP and CRS-RFLP were used to detect polymorphisms of DNArepair genes and cell-cycle control related genes. Using Poisson regression analysis,we analyzed the relationship between polymorphism of DNA repair genes andcell-cycle control related genes and the frequency of CB-MN. The PHASE 2.0.2software was used to obtain maximum-likelihood estimates of the haplotypefrequencies.In this study, we detected the polymorphism of seven DNA repair genes: APE1,XPC, XPG, XPA, ERCC1, XPF, XPD which participate in the pathways of BER andNER. When the confounding factors such as age, gender, VCM exposure, drinkingand smoking habit were adjusted, the MN frequency in subjects with XPC PATmutant homozygous and heterozygous is lower than their wild-type homozygouscounterparts, the frequency ratio (FR) and its 95％confidence interval (95％CI) were0.8486 (0.7322～0.9891)(P＜0.05). Similar result was obtained with XPF T2063A(FR=0.5275, 95％CI: 0.3303～0.7943). But the MN frequency in subjects with XPAA23G and XPD Lys751Gln mutant homozygous and heterozygous is higher thantheir wild-type homozygous counterparts, FR and 95％CI were 1.2435(95％CI: 1.0472～1.4835 ) and 1.1976 (95％CI:0.9834～1.4474) respectively. Theseresults suggest XPC PAT and XPF T2063A variant may be protective factors whileXPA A23G and XPD Lys751Gln variant may be risk factors for the chromosomedamageinduced by VCM. Haplotype analysis of XPC (c.499-PAT-c.939)demonstrated the MN frequency in subjects with Hap(AAA/BAA, A: wild allele; B:variant allele) was significantly higher than that in subjects with Hap (AAA/AAA).Haplotype analysis of XPD (c.312-c.751) showed the MN frequency in subjects withHap(BA/BB) was significantly higher than that in subjects with Hap (AA/AA). We also detected the polymorphism of three cell-cycle control related genes:P53, P21 and CCND1. The results showed that only P53Intron6 variant wasassociated with chromosome damage induced by VCM (FR=1.23, 95％CI:0.97～1.55, P＜0.05). Haplotype analysis of P53 (c.72-intron3-intron6) demonstrated theMN frequency in subjects with Hap(BBB/AAA) and Hap(BAB/AAA) wassignificantly higher than that in subjects with Hap(AAA/AAA). The mRNAexpression of the three cell-cycle control related genes (P53, P21 and CCND1) wereexamined using SYBR real-time PCR. We found the level of P53 and P21 mRNAexpression increased with the increase of VCM cumulative dose, but there was nosignificant difference. The result also showed that P53mRNA expression wassignificantly correlated with the expression of P21. So the chromosome damageinduced by VCM may be repaired by the classical pathway-P53-P21-CDK-Cyclin.In conclusion, VCM can induce chromosome damage even when the exposurelevel is lower than the national occupational health standard of China; thepolymorphism of DNA damage repair gene and cell-cycle control related gene may beassociated with chromosome damage induced by VCM.
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