氯乙烯作业工人生物标志物研究
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摘要
氯乙烯(vinyl chloride monomer,VCM)是一种重要的化工原料,主要应用于合成聚氯乙烯(polyvinyl chloride,PVC),用于塑料工业。我国于1957年开始投产使用氯乙烯,2005年聚氯乙烯年产能力达550万吨,成为世界聚氯乙烯生产大国。随着氯乙烯生产规模的扩大,人们逐渐认识到它的危害。1974年美国首次报道职业性接触氯乙烯引起人肝血管肉瘤,氯乙烯的毒理学研究在全球范围内引起了极大重视,相应卫生标准也大幅度降低。我国在2002年对氯乙烯的职业接触限值进行修订,将工业企业车间最高容许浓度30mg/m~3(约11ppm)修订为时间加权平均容许浓度10mg/m~3(近4ppm),短时间接触容许浓度降至25mg/m~3(约9ppm)。但发达国家VCM容许接触限值多为1ppm(约2.79mg/m~3)。虽然我国许多氯乙烯生产车间空气中氯乙烯浓度可保持在国家卫生标准范围内,但我国氯乙烯职业卫生标准与许多西方发达国家相比高出数倍,因此有必要研究在较低的接触水平下,氯乙烯是否仍可对机体造成危害及其是否能够建立较敏感特异的生物标志物。
有关VCM作业工人的生物标志物研究,国内外的研究多关注于氯乙烯代谢酶基因和核苷酸切除修复基因多态与氯乙烯所致染色体损伤的关系等有关遗传易感性生物标志物研究,以及氯乙烯致肝损伤等效应生物标志物研究。有关氯乙烯致染色体损伤与碱基切除修复基因多态性关系的研究报道尚少;另外国内氯乙烯致机体氧化损伤、与氯乙烯暴露相关的DNA加合物检测以及其与氯乙烯接触的关系的研究尚未见报道。本研究通过氯乙烯工人累积接触剂量的估算,评估累积接触剂量与职业危害间的关系,探讨在接触较低浓度氯乙烯情况下,氯乙烯暴露和DNA加合物之间的关系,为提供氯乙烯接触生物标志物提供依据;探讨VCM致氧化损伤、肝损伤和遗传物质损伤作为效应生物标志物的可能性;通过碱基切除修复基因多态性及其与VCM致遗传物质损伤的关系研究,寻找VCM遗传损伤的易感性生物标志物。通过本次研究,探讨氯乙烯与机体损伤的相关指标的内在联系,为进行个体危险度评价提供理论基础,同时为确定氯乙烯接触人群的危害阈值和寻找早期发现易感人群的方法提供科学依据。
本次研究对VCM接触工人进行常规体检调查和进行问卷调查以及利用酶联免疫反应对1-氮-6-乙烯(脱氧)腺嘌呤(1,N(6)-etheno(deoxy)adenosine,εdA)进行检测,相关分析和偏相关分析结果显示1-氮-6-乙烯(脱氧)腺嘌呤含量与累积接触剂量存在相关关系(P＜0.05)。按累积接触剂量分组,当累积接触剂量大于23740mg时,1-氮-6-乙烯(脱氧)腺嘌呤含量明显升高(P=0.006)。随着累积接触剂量的升高,1-氮-6-乙烯(脱氧)腺嘌呤含量异常率增高,具有剂量-反应关系。提示1-氮-6-乙烯(脱氧)腺嘌呤可作为氯乙烯的接触生物标志物,能够较准确的评估工人接触氯乙烯的剂量。
以超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(malondialchehyche,MDA)、谷胱甘肽硫转移酶(glutathione S-transferases,GST)、乙醇脱氢酶(alcoholdehydrogenase,ADH)和遗传物质损伤(微核和DNA加合物)作为氯乙烯致机体损伤的效应生物标志物,应用多因素线性回归和协方差分析氧化损伤和肝损伤指标与VCM接触之间的关系。多因素线性回归分析结果表明性别、年龄、吸烟、饮酒和是否VCM接触均未对SOD、MDA和GST活性产生明显影响,饮酒和VCM接触对ADH活性产生明显影响,同时协方差分析结果表明各氯乙烯接触剂量组的SOD和MDA活性均与对照组不存在显著性差异。累积接触剂量30000mg～组GST和ADH活性明显高于＜6000mg组(P＜0.05)。趋势卡方检验结果表明随着累积接触剂量的增高,GST和ADH活性增高。单因素分析结果表明VCM接触工人外周血淋巴细胞微核率明显高于对照组(P＜0.05)。多因素Poisson回归分析结果表明年龄作为连续变量FR(Frequency ratio)值为1.0128(95%CI:1.0018～1.0238)。女性发生染色体损伤的危险度是男性的1.2386倍(95%CI:1.0751～1.4262)。VCM接触个体发生染色体损伤的危险度是对照组的3.5726倍(P＜0.05)。提示目前氯乙烯接触浓度下,氯乙烯对机体的氧化损伤作用不显著,SOD和MDA作为效应生物标志物仍有待商讨。低剂量接触氯乙烯时GST和ADH作为效应生物标志物意义不明显,但高剂量接触时,GST和ADH作为效应生物标志物仍有一定的意义。外周血淋巴细胞微核率可作为VCM接触早期健康损害的效应指标。
应用PCR-RFLP和CRS-RFLP法对VCM接触工人的碱基切除修复基因APE1、ADPRT和TDG的多态位点进行检测,应用Poisson回归分析各基因多态位点与染色体损伤之间的关系。调整年龄、性别、累计接触剂量以及吸烟、饮酒等因素,多因素Poisson回归分析结果表明,TDG 199Gly/Ser这一多态位点突变型Gly/Ser+Ser/Ser与野生型Gly/Gly相比,FR=1.198(95%CI:1.026-1.397;P＜0.05),提示该位点突变是VCM致染色体损伤的危险因素。未见ADPRTVα1762A1α和APE1 Ile64Val基因多态与氯乙烯致染色体损伤相关。结果说明携带TDG 199Gly/Ser+Ser/Ser基因型的个体为VCM致染色体损伤的易感人群,通过对易感性生物标志物的研究,可为早期发现易感人群,保护氯乙烯接触工人健康,提供科学依据。
综上所述,在我国现行职业卫生标准下,氯乙烯仍可产生一定的健康危害;DNA加合物可作为职业性接触氯乙烯工人健康监护的一种监测指标,可以较准确地反映氯乙烯工人的内暴露剂量。GST和ADH可作为接触氯乙烯致机体损伤的效应生物标志物。外周血淋巴细胞微核率可作为VCM接触早期健康损害的效应指标。同样的作业环境,同样接触水平的工人中,仅有部分工人表现出DNA损伤,提示个体对氯乙烯接触易感性存在着差异。TDG 199Gly/Ser多态位点突变型是氯乙烯致染色体损伤的危险因素。
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.
有关VCM作业工人的生物标志物研究,国内外的研究多关注于氯乙烯代谢酶基因和核苷酸切除修复基因多态与氯乙烯所致染色体损伤的关系等有关遗传易感性生物标志物研究,以及氯乙烯致肝损伤等效应生物标志物研究。有关氯乙烯致染色体损伤与碱基切除修复基因多态性关系的研究报道尚少;另外国内氯乙烯致机体氧化损伤、与氯乙烯暴露相关的DNA加合物检测以及其与氯乙烯接触的关系的研究尚未见报道。本研究通过氯乙烯工人累积接触剂量的估算,评估累积接触剂量与职业危害间的关系,探讨在接触较低浓度氯乙烯情况下,氯乙烯暴露和DNA加合物之间的关系,为提供氯乙烯接触生物标志物提供依据;探讨VCM致氧化损伤、肝损伤和遗传物质损伤作为效应生物标志物的可能性;通过碱基切除修复基因多态性及其与VCM致遗传物质损伤的关系研究,寻找VCM遗传损伤的易感性生物标志物。通过本次研究,探讨氯乙烯与机体损伤的相关指标的内在联系,为进行个体危险度评价提供理论基础,同时为确定氯乙烯接触人群的危害阈值和寻找早期发现易感人群的方法提供科学依据。
本次研究对VCM接触工人进行常规体检调查和进行问卷调查以及利用酶联免疫反应对1-氮-6-乙烯(脱氧)腺嘌呤(1,N(6)-etheno(deoxy)adenosine,εdA)进行检测,相关分析和偏相关分析结果显示1-氮-6-乙烯(脱氧)腺嘌呤含量与累积接触剂量存在相关关系(P＜0.05)。按累积接触剂量分组,当累积接触剂量大于23740mg时,1-氮-6-乙烯(脱氧)腺嘌呤含量明显升高(P=0.006)。随着累积接触剂量的升高,1-氮-6-乙烯(脱氧)腺嘌呤含量异常率增高,具有剂量-反应关系。提示1-氮-6-乙烯(脱氧)腺嘌呤可作为氯乙烯的接触生物标志物,能够较准确的评估工人接触氯乙烯的剂量。
以超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(malondialchehyche,MDA)、谷胱甘肽硫转移酶(glutathione S-transferases,GST)、乙醇脱氢酶(alcoholdehydrogenase,ADH)和遗传物质损伤(微核和DNA加合物)作为氯乙烯致机体损伤的效应生物标志物,应用多因素线性回归和协方差分析氧化损伤和肝损伤指标与VCM接触之间的关系。多因素线性回归分析结果表明性别、年龄、吸烟、饮酒和是否VCM接触均未对SOD、MDA和GST活性产生明显影响,饮酒和VCM接触对ADH活性产生明显影响,同时协方差分析结果表明各氯乙烯接触剂量组的SOD和MDA活性均与对照组不存在显著性差异。累积接触剂量30000mg～组GST和ADH活性明显高于＜6000mg组(P＜0.05)。趋势卡方检验结果表明随着累积接触剂量的增高,GST和ADH活性增高。单因素分析结果表明VCM接触工人外周血淋巴细胞微核率明显高于对照组(P＜0.05)。多因素Poisson回归分析结果表明年龄作为连续变量FR(Frequency ratio)值为1.0128(95%CI:1.0018～1.0238)。女性发生染色体损伤的危险度是男性的1.2386倍(95%CI:1.0751～1.4262)。VCM接触个体发生染色体损伤的危险度是对照组的3.5726倍(P＜0.05)。提示目前氯乙烯接触浓度下,氯乙烯对机体的氧化损伤作用不显著,SOD和MDA作为效应生物标志物仍有待商讨。低剂量接触氯乙烯时GST和ADH作为效应生物标志物意义不明显,但高剂量接触时,GST和ADH作为效应生物标志物仍有一定的意义。外周血淋巴细胞微核率可作为VCM接触早期健康损害的效应指标。
应用PCR-RFLP和CRS-RFLP法对VCM接触工人的碱基切除修复基因APE1、ADPRT和TDG的多态位点进行检测,应用Poisson回归分析各基因多态位点与染色体损伤之间的关系。调整年龄、性别、累计接触剂量以及吸烟、饮酒等因素,多因素Poisson回归分析结果表明,TDG 199Gly/Ser这一多态位点突变型Gly/Ser+Ser/Ser与野生型Gly/Gly相比,FR=1.198(95%CI:1.026-1.397;P＜0.05),提示该位点突变是VCM致染色体损伤的危险因素。未见ADPRTVα1762A1α和APE1 Ile64Val基因多态与氯乙烯致染色体损伤相关。结果说明携带TDG 199Gly/Ser+Ser/Ser基因型的个体为VCM致染色体损伤的易感人群,通过对易感性生物标志物的研究,可为早期发现易感人群,保护氯乙烯接触工人健康,提供科学依据。
综上所述,在我国现行职业卫生标准下,氯乙烯仍可产生一定的健康危害;DNA加合物可作为职业性接触氯乙烯工人健康监护的一种监测指标,可以较准确地反映氯乙烯工人的内暴露剂量。GST和ADH可作为接触氯乙烯致机体损伤的效应生物标志物。外周血淋巴细胞微核率可作为VCM接触早期健康损害的效应指标。同样的作业环境,同样接触水平的工人中,仅有部分工人表现出DNA损伤,提示个体对氯乙烯接触易感性存在着差异。TDG 199Gly/Ser多态位点突变型是氯乙烯致染色体损伤的危险因素。
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.
引文
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