The Biomarkers Of Vinyl Chloride Monomer Exposed Workers

Vinyl chloride monomer(VCM) is widely used in industry.Most of VCM is polymerized to form polyvinyl chloride,a plastic resin formed into innumerable products such as flooring materials,packaging materials,and pipes.In 1950's,China began to produce PVC,and the annual output in 2005 was 5.5 millions tons.In 1974,three cases of hepatic angiosarcoma were reported in workers of a polymer production facility in Louisville,Kentucky.Recent epidemiological studies have shown VCM to be a multi-organ and multi-system carcinogen that induces a wide spectrum of tumors,including hepatic angiosarcomas and other liver tumors, brain tumors,and lung cancer.To avoid the potential health hazard,many countries have developed some techniques to make a great progress in reducing exposure concentration of VCM.In China,the exposure level of workers is lower than the national occupational health standard(STEL and TWA are 25mg/m~3 and 10mg/m~3 respectively in China).The permissible exposure limit of VCM in developed countries is 1 ppm(2.79mg/m~3).Thus,more studies are needed to investigate the potential health effect and what's more important,to find the specific and sensitive biomarkers.VCM is biotransformed by human liver cytochrome P4502E1 to generate alkylating intermediates chloroethylene oxide and chloroacetaldehyde,which react with DNA bases to form etheno DNA adducts,namely,1,N(6)-ethenoadenine, 3,N(4)-ethenocytosine,and N(2)-3-ethenoguanine.These etheno DNA adducts are promutagenic and genotoxic and,if not repaired,may eventually induce base pair substitution,chromosomal aberrations,micronuclei,sister chromatid exchange,and DNA strand breaks observed in lymphocytes of individuals occupationally exposed to VCM.The study evaluated the relationship between VCM exposure and occupational hazards based on calculated cumulative exposure dose of the workers exposed to VCM.Occupational epidemiological study was performed to investigate the relationship between DNA adducts and cumulative exposure dose in such concentration and to provide evidence of possible exposure biomarkers.This study also investigated the potential oxidative injury,liver lesion and chromosome damage induced by VCM and the association between DNA damage and polymorphisms of base excision repair genes.In this study,DNA adduct was used as the VCM exposure indicator.The relationship between VCM exposure andεdA was examined.Significant correlation was found betweenεdA and VCM exposure(P＜0.05).According to this finding,εdA of individuals with exposure dose more than 23740mg was significant higher than that of individuals with exposure dose less than 8150mg(P=0.006).We demonstrated that there was a significantly increased abnormal rate of DNA adduct with respect to the level of dose in a dose-dependant manner.The results demonstrated thatεdA could be used as an indicator of VCM exposure dose.It has been reported that VCM exposure may induce the oxidative injury,hepatic hazard and chromosome damage.In this study,the activities of SOD,MDA,GST and ADH in serum were used as the effect biomarkers of the VCM exposure.There was no significant difference between the VCM-exposed workers and those without VCM exposure in the activity of SOD,MDA and GST.The activity of ADH of VCM-exposed workers was significantly higher than that of non-exposed workers (P＜0.05).There was no significant difference between the groups with different exposure dose and the control group in the activity of SOD and MDA.The activity of GST and ADH of individuals with exposure dose more than 30000mg was higher than that of control group(P＜0.05).There was a dose-response relationship between dose and abnormal rate of GST and ADH.The results of cytokinesis-block micronucleus assay showed that the frequency of MN of VCM-exposed group was higher than the control group(P＜0.01).There was a small but significant increase in micronucleus frequency among females,compared with males.Furthermore,subjects who were at older ages demonstrated higher levels of micronucleus frequency(P＜0.05).No significant effects of smoking and alcohol drinking were found in the micronucleus test results.So the frequency of MN of peripheral blood lymphocyte can be used as an effect biomarker.The oxidative hazard of VCM exposure is not obvious under the current VCM exposure level.The activity of serum GST and ADH could be used as effect biomarkers under high exposure level.Genetic polymorphisms in base excision repair pathway may alter the function of DNA repair enzymes,thereby influencing individual susceptibility to chromosomal damage.In this study,we evaluated whether base excision repair gene polymorphisms contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer in Chinese workers.Genotypes of ADPRT Va1762A1a and TDG Gly199Ser were identified by the create restriction site combined with restriction fragment length polymorphism.PCR-restriction fragment length polymorphism assay was used to determine APE1 Ile64Val genotypes.After adjustments by age,sex,smoking status, alcohol drinking,and cumulative VCM exposure,there was a 1.198-fold increased micronucleus frequency for individuals carrying TDG 199Gly/Ser+Ser/Ser genotypes compared with those carrying Gly/Gly genotype(P＜0.05).No association with micronucleus frequency was found for the APE1 Ile64Val and ADPRT Va1762A1a polymorphisms.VCM-exposed workers carrying TDG 199Gly/Ser+Ser/Ser genotypes could be susceptible to chromosomal damage.In conclusion,VCM can induce some occupational health hazards of workers under the current exposure level.In this study,it has been indicated thatεdA could be used as an exposure biomarker of VCM.We found that the activity of serum GST and ADH might be used as effect biomarkers under high exposure level.The frequency of MN of peripheral blood lymphocyte could be used as an effect biomarker.We also found that VCM-exposed workers carrying TDG 199Gly/Ser+Ser/Ser genotypes could be susceptible to chromosomal damage.DNA damage repair system play important roles in the repair process of DNA damage induced by VCM.