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  • 學位論文

聚氯乙烯工人慢性肝危害與基因多形性相關研究

Association of VCM exposure, chronic liver diseases and genetic polymorphisms in polyvinyl chloride workers

指導教授 : 鄭尊仁

摘要


氯乙烯為人類已知的致癌物質,過去的研究亦證實氯乙烯暴露與肝弁鉦妤`及慢性肝疾病有關,然而劑量-反應關係並不清楚;本研究的目的是利用職務暴露矩陣模式及世代工人之詳細工作史重建累積暴露劑量,探討慢性肝疾病與氯乙烯暴露是否有劑量劑量-反應關係。另外,因氯乙烯暴露代謝後所產生的活化性中間產物亦可能對肝細胞弁鉦ㄔ芞v響,所以本研究進一步分析基因多形性於氯乙烯暴露造成慢性肝疾病的影響。研究對象為1995-1999年327名氯乙烯暴露的男性員工,採集其血液、健檢資料及詳細的問卷資料,包括基本資料和生活習慣 (抽煙及喝酒情形等)及詳細工作史,利用超音波診斷慢性肝疾病,並根據工作史建立累積暴露劑量。研究結果發現,氯乙烯暴露工人之慢性肝疾病程度隨累積暴露劑量增加而有上升的趨勢,與氯乙烯累積暴露劑量小於40 ppm-years工人相比,40-1000 ppm-years,1000-10000 ppm-years,大於10000 ppm-years工人的慢性肝疾病危險性分別為OR=3.5, 95%CI=0.4-32.1, OR=4.1, 95%CI=0.4-43.9, OR=5.6 , 95%CI=0.5-68.4;此外,我們亦發現B型或C型肝炎病毒感染是慢性肝疾病重要的危險因子 (OR=6.2, 95%CI=2.3-16.9);然而氯乙烯暴露與B型或C型肝炎病毒感染對於慢性肝疾病並沒有顯著交互作用的情形。在易感性基因分析方面,以氯乙烯累積暴露劑量小於1000 ppm-years具XRCC1 Arg-Arg/Arg-Gln基因型者為對照,氯乙烯累積暴露劑量小於1000 ppm-years具XRCC1 Gln-Gln基因型者對慢性肝疾病的危險性為2.7 (95%CI=0.3-29.3),在氯乙烯累積暴露劑量大於1000 ppm-years中,具XRCC1 Arg-Arg/Arg-Gln基因型者對慢性肝疾病的危險性為1.3 (95%CI=0.4-4.2),而具有 XRCC1 Gln-Gln基因型者對慢性肝疾病則有較高的危險性(OR=10.1, 95%CI=1.2-85.1);相似的,以氯乙烯累積暴露劑量小於1000 ppm-years具CYP2E1 c1c1/c1c2基因型者為對照,氯乙烯累積暴露劑量小於1000 ppm-years具CYP2E1 c2c2基因型對慢性肝疾病的危險性為3.3 (95%CI=0.3-33.7),在氯乙烯累積暴露劑量大於1000 ppm-years中,具有CYP2E1 c1c1/c1c2基因型者對慢性肝疾病的危險性為1.2 (95%CI=0.4-4.0),而具有CYP2E1 c2c2基因型者對慢性肝疾病有較高的危險性 (OR=7.8, 95%CI=1.3-46.1)。進一步分析,以B型或C型肝炎病毒感染呈現陰性具XRCC1 Arg-Arg/Arg-Gln基因型者為對照組,B型或C型肝炎病毒感染呈現陰性且具XRCC1 Gln-Gln基因型對於慢性肝疾病的危險性為3.9 (95%CI=0.4-36.9),在呈現有B型或C型肝炎病毒感染陽性中,具XRCC1 Arg-Arg/Arg-Gln基因型者對慢性肝疾病的危險性為6.2 (95%CI=2.1-18.3),而具XRCC1 Gln-Gln基因型者有較高的危險性 (OR=28.0, 95%3.4-231.8)。我們的研究顯示,氯乙烯暴露工人發生慢性肝疾病的危險性隨著累積暴露劑量增加而上升;具有易感性CYP2E1及XRCC1基因型的氯乙烯工人,較易發生慢性肝疾病;同時,具有XRCC1易感性基因型並有B型或C型肝炎病毒感染的工人更為容易發生慢性肝疾病。因此,具有易感性基因或有B型或C型肝炎病毒感染者,應避免在高暴露濃度的區域工作。

關鍵字

肝硬化 CYP2E1 XRCC1 GSTT1 ALDH2 脾腫大 氯乙烯 肝纖維化

並列摘要


Vinyl chloride monomer (VCM) is a known human carcinogen. Previous studies also showed that vinyl chloride exposure might lead to abnormal liver function and chronic liver diseases. However, the dose-response between vinyl chloride and chronic liver diseases remains unclear. Thus, we reconstructed the VCM cumulative dose according to job exposure matrix model, environmental assessment and detail working history of PVC workers. The aim of this study is to evaluate the dose-response relationship between chronic liver diseases and VCM exposure. Further, VCM is metabolized by CYP2E1 to the electrophilic metabolites. These metabolites may affect the function of cell. Thus, we also investigate the effects of genetic polymorphism of metabolic genes and DNA repair gene on VCM-induced chronic liver diseases. A total of 327 male workers with VCM exposure from five polyvinyl chloride plants were included in this study. Their specimens and epidemiology information had been collected during 1995 to 1999. The chronic liver diseases were diagnosed by ultrasonography. The result revealed that the OR of chronic liver diseases increased with increasing cumulative dose. The lowest exposure group (less than 40 ppm-years) was used as a reference group. The adjusted odds ratio for the presence of the chronic liver diseases increased from 3.5 (95%CI=0.4-32.1) for those with dose of 40-1000 ppm-years to 4.1 (95%CI=0.4-43.9) for those dose of 1000-10000 ppm-years and 5.6 (95%CI=0.5-68.4) for those with dose more than 10000 ppm-years. HBs-Ag positive and/or anti-HCV positive were independent factors for chronic liver diseases (OR=6.2, 95%CI=2.3-16.9). We did not observe an interaction between VCM exposure and chronic liver diseases. Subjects experiencing the cumulative dose more than 1000 ppm-years and with variants of XRCC1 Gln-Gln demonstrated greater risk of chronic liver diseases among those having different combinations of VCM cumulative dose and XRCC1 genotypes (OR=10.1, 95%CI=1.2-85.1 ). Similarly, individuals experiencing the cumulative dose more than 1000 ppm-years and with CYP2E1 c2c2 genotype had higher risk of chronic livers diseases among those having different combinations of VCM cumulative dose and CYP2E1 genotypes (OR=7.8, 95%CI=1.3-46.1). Further, we found the polymorphism of DNA repair gene XRCC1 and HBs-Ag and/or anti-HCV infection for chronic liver diseases had greater risk among those having different combinations of HBV and/or HCV infection and XRCC1 genotypes (OR=28.0, 95%CI=3.4-231.8). Our results revealed that VCM exposed workers had increased risk with VCM exposure and the workers with susceptible XRCC1 and CYP2E1 genes had higher risk for chronic liver diseases. Lastly, the workers with susceptible XRCC1 gene and HBs-Ag and/or anti-HCV infection had greater risk for chronic liver diseases. Thus, the VCM levels at worksite need to be considered, when workers with susceptible genotype and HBV or HCV infection are placed in this environment.

並列關鍵字

vinyl chloride liver fibrosis cirrhosis spleno

參考文獻


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