摘要
目的：苯是重要的工业生产原料，近年来苯的生产和消费年均增长10%以上。苯对人体健康存在着极大的潜在性危害。职业流行病学调查发现，苯中毒的发生与个体易感性有关，是环境因素和遗传因素等共同作用的结果。本研究旨在较全面系统地探讨在当前卫生标准下职业性苯接触是否引起健康危害及其遗传损伤，并对苯作业工人健康监护的易感性生物标志物进行研究。方法：本研究应用职业流行病学调查方法，选取安徽省某汽车制造厂的接苯工人为研究对象，进行健康危害调查和职业接触评估，应用胞质分裂阻滞微核试验测定结果作为接苯工人外周血淋巴细胞染色体损伤的效应指标，探讨染色体损伤与苯接触之间的关系；应用聚合酶链反应（polymerase chain reaction，PCR）-限制性片段长度多态性（restriction fragment lengthpolymorphism，RFLP）和创造酶切位点的限制性片段长度多态性（create restrictionsite combined with restriction fragment length polymorphism，CRS-RFLP）检测技术检测与苯致染色体损伤相关的DNA损伤修复通路中几个关键基因的多态性，包括XRCC1基因、APE1基因、XPC基因、hOGG1基因、MGMT基因、和hMYH基因，分析各基因多态及相关因素对微核率的影响，应用SPSS16.0软件进行统计分析。结果：1）车间空气各监测点苯浓度均＜0.6mg/m3，低于国家职业接触限值；接苯工人防护用品使用率仅为63.0%，工人自我防护意识较差；2）暴露工人发生失眠多梦、头晕头痛、牙龈出血、鼻腔出血、皮下瘀斑、月经异常等症状与苯暴露无相关性（P＞0.05）；低浓度苯接触会引起白细胞异常（波动、降低）率及红细胞降低率升高（P＜0.001）。Logistic回归分析显示苯接触、接苯工龄及年龄是白细胞异常（波动、降低）的主要影响因素，苯接触是红细胞降低的主要影响因素，各组血红蛋白降低率及血小板降低率差异无统计学意义（P＞0.05）；3）苯暴露组外周血淋巴细胞微核率（2.12‰±1.87‰）明显高于对照组（1.19‰±1.68‰），差异有统计学意义（P＜0.001）。多因素Poisson回归分析微核率影响因素发现女性、高龄（＞35岁）和苯接触是微核率升高的危险因素。采用百分位数法，以对照组微核率95%的上限值作为界限值，认为本研究人群双核细胞微核发生率正常值界限值应为4‰，以该界限值作为判断苯作业工人是否发生遗传损伤的划分标准，超过该界限则认为个体发生了染色体损伤。依据白细胞分类的各接苯组微核率均高于对照组，其差异均有统计学意义（P＜0.001），暴露组中白细胞正常组的微核率比非接苯对照组高54%，FR（95%CI）为1.54（1.23～1.95）；4）对照组各基因型与微核率的关系分析发现携带XRCC1399基因AA型的个体与携带GG型的个体相比微核率升高，差异具有统计学意义（P＜0.05），其FR（95%CI）为2.44（1.30～4.33）。携带XPC.PAT基因PAT+/+型的个体与携带PAT-/-型的个体相比微核率升高，差异具有统计学意义（P＜0.05），其FR（95%CI）为2.40（1.44～3.92）。携带XPC499基因TT型和（CT+TT）型的个体与携带CC型的个体相比微核率降低，差异均具有统计学意义（P＜0.05），其FR（95%CI）分别为0.28（0.08～0.68）和0.62（0.42～0.92）。携带XPC939基因AC型和（AC+CC）型的个体与携带AA型的个体相比微核率降低，差异均具有统计学意义（P＜0.05），其FR（95%CI）分别为0.51（0.33～1.30）和0.54（0.37～0.79）。携带hOGG1326基因GG型的个体与携带CC型的个体相比微核率升高，差异具有统计学意义（P＜0.05），其FR（95%CI）为1.97（1.10～3.84）。其余多态位点不同基因型与野生型相比微核率差异无统计学意义（P＞0.05）；5）接触组各基因型与微核率的关系分析发现携带XRCC1280基因AA型的个体与携带GG型的个体相比微核率显著降低，差异具有统计学意义（P＜0.05），其FR（95%CI）为0.40（0.14-0.86）。携带MGMT84基因（CT+TT）型的个体与携带CC型的个体相比微核率降低，差异具有统计学意义（P＜0.05），其FR（95%CI）为0.85（0.72-0.99）。其余多态位点不同基因型与野生型相比微核率差异无统计学意义（P＞0.05）；6）对照组多因素Poisson逐步回归分析微核率危险因素结果表明年龄、性别、饮酒、XPC939和APE1148为影响因素，其中，高龄（＞35岁）和女性为危险因素，饮酒为保护因素，XPC939突变基因和APE1148突变基因为保护因素。接触组多因素Poisson逐步回归分析微核率危险因素结果表明年龄、XPC.PAT和MGMT84为影响因素，其中，高龄为危险因素，XPC.PAT（PAT+）基因和MGMT84突变基因为保护因素；7）XRCC1194，XRCC1280，XRCC1399三个等位基因双体型与微核率的关系分析显示，以携带AAA/AAA双体型的个体作为参比，携带AAA/BAA、AAB/AAB、ABA/ABA、ABB/ABB双体型的接苯工人微核率显著升高（P＜0.05）；XPC499、XPC.PAT和XPC939三个等位基因双倍型与微核率的关系分析显示，以携带AAA/AAA双体型的个体作为参比，携带ABB/ABB双体型的接苯工人微核率显著升高（P＜0.05）。结论：在我国现行职业卫生标准下，职业性苯暴露仍可能造成遗传物质的损伤。以双核微核为基础的染色体损伤可以作为低浓度苯职业接触评估的一个参考指标，外周血淋巴细胞微核率作为评价低浓度苯暴露的效应指标具备一定的推广应用价值，部分DNA修复基因多态及双体型对苯接触所致染色体损伤具有修饰作用。
Objective: Benzene is an important raw materials in industrial production, and theproduction and consumption of benzene in recent years has been in the growth, theannual growth rate is over10%. Benzene has a major potential hazard to human health.Occupational epidemiological survey found that the benzene poisoning was associatedwith individual susceptibility, it was the result of the role of environmental factors andgenetic factors. This study aimed to explor whether occupational benzene exposure underthe current standards would cause heath hazards and genetic damage, and to detectsusceptibility biomarker of benzene-exposed workers. Methods: The subjects of thisstudy came from one automobile manufacturing factory of Anhui province in China. Thehealth status of benzene-exposed workers was obtained through health examination andgenetic damage detecting. The relationship between benzene exposure and chromosomedamage was explored in this study. Cytokinesis-block micronucleus (CB-MN) assay wasused to detect chromosome damage in peripheral lymphocyte. PCR-RFLP andCRS-RFLP technique was applied to detect genes polymorphisms. Through exploring theassociation between several key gene polymorphisms in DNA repair pathways and therisk of benzene-induced genetic damage, we identified the susceptible biomarkers,including XRCC1gene, APE1gene, the XPC gene, hOGG1gene, MGMT gene, andhMYH genes. SPSS16.0software was applicated in this study. Results:1) The benzeneconcentration of the workplace air monitoring sites＜0.6mg/m3was lower than thenational occupational exposure limit; the utilization rate of protective equipment wasonly63.0%in benzene-exposed workers, and benzene-exposed workers had less aware ofself-protection.2) There was not associated between the clinical symptoms of workersand the benzene exposure, such as insomnia and more dreams, dizziness, headache,bleeding gums, nasal bleeding, ecchymosis, abnormal menstruation, et al (P＞0.05); lowlevel benzene exposure could lead to the rate increases of white blood cells abnormality (fluctuation or reduction) and red blood cells reduction (P＜0.001). Logistic regressionanalysis showed that the main factors of white blood cell abnormality (fluctuation orreduction) were benzene exposure, length of service and age, the main factor of red bloodcell reduction was benzene exposure. Hemoglobin and platelet count were no significantdifferences in different groups (P＞0.05).3) The MN frequency of the exposed group(2.12‰±1.87‰) was significantly higher than that of the control group(1.19‰±1.68‰)(P＜0.001), Multi-factor Poisson regression analysis found thatwomen, older age (＞35years) and benzene exposure were the risk factors of increasingmicronucleus rate. The95-percentile of the controls CBMN (i.e.4‰) distribution, maybeused to define chromosomal damage caused by benzene-exposure, above which the MNfrequency may indicate an aberration from being normal, hence indicating chromosomaldamage; the MN frequency of the exposed groups according to the classification of WBCwas significantly higher than that of the control group (P＜0.001), and the MN frequencyof benzene-exposed with WBC normal group was significantly higher than that of thecontrol group by54%, FR (95%CI) was1.54(1.23～1.95).4) In control group, this studyshowed that the MN frequency of the subjects with XRCC1399AA genotype wassignificantly higher than those with XRCC1399GG genotype (P＜0.05), FR (95%CI)was2.44(1.30～4.33); the MN frequency of the subjects with XPC.PAT PAT+/+genotype was significantly higher than those with XPC.PAT PAT-/-genotype (P＜0.05),FR (95%CI) was2.40(1.44～3.92); the MN frequency of the subjects with XPC499TTor XPC499(CT+TT) genotype was significantly lower than those with XPC499CCgenotype (P＜0.05), FR (95%CI) was0.28(0.08～0.68) or0.62(0.42～0.92); the MNfrequency of the subjects with XPC939AC or XPC939(AC+CC) genotype wassignificantly lower than those with XPC939AA genotype (P＜0.05), FR (95%CI) was0.51(0.33～1.30) or0.54(0.37～0.79); the MN frequency of the subjects withhOGG1326GG genotype was significantly higher than those with hOGG1326CCgenotype (P＜0.05), FR (95%CI) was1.97(1.10～3.84); others genetic polymorphismswere not significantly different compared with wild-type (P＞0.05).5) Inbenzene-exposed workers, this study showed that the MN frequency of the subjects withXRCC1280AA genotype was significantly lower than those with XRCC1280GGgenotype (P＜0.05), FR (95%CI) was0.40(0.14～0.86); the MN frequency of thesubjects with MGMT84(CT+TT) genotype was significantly lower than those withMGMT84CC genotype (P＜0.05), FR (95%CI) was0.85(0.72～0.99); others geneticpolymorphisms were not significantly different compared with wild-type (P＞0.05).6) Multivariate Poisson regression analysis suggested that the impact factors ofmicronucleus include age, gender, drinking, XPC939and APE1148in control group,older age (＞35years) and female were risk factors, and drinking, XPC939mutant geneand APE1148mutant gene were protective factors. While age, XPC.PAT, and MGMT84were impact factors in exposure group, older age (＞35years) was risk factors, andXPC.PAT (PAT+) gene and MGMT84mutant gene were protective factors.7) Diplotypeanalysis of relationship between MN frequency and diplotype of194,280,399sites ofXRCC1gene demonstrated that the MN frequency in subjects with AAA/BAA、AAB/AAB、ABA/ABA、ABB/ABB (A: wild allele; B: variant allele) was significantlyhigher than that in subjects with AAA/AAA in benzene-exposed group (P＜0.05).Diplotype analysis of relationship between MN frequency and diplotype of499, PAT,939sites of XPC gene demonstrated that the MN frequency in subjects with ABB/ABB wassignificantly higher than that in subjects with AAA/AAA in benzene-exposed group (P＜0.05). Conclusion: Occupational benzene exposure could induce chromosome damageeven when the exposure level was lower than the national occupational health standard ofChina. Chromosome damage based on CBMN could be a reference index to assessmentlow level occupational benzene exposure. MN frequency had certain application value asa effect biomarker in low level benzene exposure. Some of the polymorphisms of DNArepair genes and diplotypes may be associated with chromosome damage inbenzene-exposed workers.
引文
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