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研究生:蕭舒庭
研究生(外文):Shu-Tin Hsiao
論文名稱:聚氯乙烯工人慢性肝危害與基因多形性相關研究
論文名稱(外文):Association of VCM exposure, chronic liver diseases and genetic polymorphisms in polyvinyl chloride workers
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:57
中文關鍵詞:肝硬化CYP2E1XRCC1GSTT1ALDH2脾腫大氯乙烯肝纖維化
外文關鍵詞:vinyl chlorideliver fibrosiscirrhosisspleno
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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。
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.
目錄
致謝 i
摘要 ii
Abstract iv
目錄 vi
圖表目錄 vii

第一章 前言 8

第二章 文獻探討 9

第一節 氯乙烯健康危害與慢性肝傷害 9
第二節 氯乙烯暴露與累積暴露劑量 10
第三節 氯乙烯的代謝 12
第四節 代謝基因CYP2E1基因多形性 13
第五節 代謝基因ALDH2基因多形性 13
第六節 代謝基因GSTT1基因多形性 14
第七節 修補基因XRCC1基因多形性 14

第三章 材料與方法 16

第一節 研究族群 16
第二節 暴露評估 16
第三節 腹部超音波診斷標準 19
第四節 代謝與DNA修補基因型分析 19
第五節 統計分析 21

第四章 結果 22

第五章 討論 27

第一節 暴露評估 27
第二節 氯乙烯暴露、B型或C型肝炎病毒與慢性肝疾病之相關 28
第三節 代謝及DNA修補基因多形性 30
第四節 研究限制 32

第六章 參考文獻 33

圖表目錄
表1 氯乙烯暴露工人之基本資料 41
表2 不同的氯乙烯累積暴露劑量之慢性肝疾病盛行率 42
表3 氯乙烯暴露工人慢性肝疾病各決定因子的單變項邏輯式回歸分析 43
表4 氯乙烯暴露工人各種慢性肝疾病之多變項邏輯式迴歸分析 44
表5 曾經從事手工清槽工作對慢性肝疾病的危險性 45
表6 B型或C型肝炎病毒感染與氯乙烯暴露對慢性肝病之交互作用 46
表7 不同氯乙烯累積暴露劑量之XRCC1, CYP2E1, ALDH及GSTT1基因型盛行率 47
表8 氯乙烯暴露工人基因多形性對慢性肝疾病單變項邏輯式迴歸分析 48
表9 氯乙烯暴露工人基因多形性對慢性肝疾病多變項邏輯式迴歸分析 49
表10 氯乙烯累積暴露劑量及基因多形性對慢性肝疾病之交互作用 50
表11B型或C型肝炎病毒感染與XRCC1對慢性肝疾病之交互作用 51

圖1 氯乙烯暴露與環境因子及宿主易感性因子對肝臟疾病進展可能性 52

附表1 氯乙烯暴露工人各種慢性肝疾病之多變項邏輯式迴歸分析 53
附表2 氯乙烯累積暴露劑量與基因多形性對肝纖維化之交互作用 54
附表3 氯乙烯累積暴露劑量與基因多形性對脾腫大之交互作用 55
附表4 B型或C型肝炎病毒感染與XRCC1對肝纖維化之交互作用 56
附表5 B型或C型肝炎病毒感染與XRCC1對脾腫大之交互作用 57
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