臺灣博碩士論文加值系統

氯乙烯單體(vinyl chloride monomer, VCM)的慢性暴露，因為會誘發肝血管肉瘤(liver angiosarcoma, LAS)的發生，被國際癌症研究機構（International Agency for Research on Cancer）列為人類致癌物(group 1 human carcinogen)。過去的研究顯示VCM的暴露除了可造成工人發生肝炎(hepatitis)、肝硬化(liver cirrhosis)等急慢性肝臟疾病外，也可能誘發肝血管肉瘤以外的癌症，特別是肝細胞癌(hepatocellular carcinoma)，但是因為機轉尚不清楚且存有爭議，因此需要更多的研究。在肝細胞癌的致病機轉中，慢性肝炎、肝硬化是肝細胞癌發生病程中的主要的過渡性疾病，而暴露劑量(exposure dose)、基因易感受性(genetic susceptibility)或原有的健康狀況(health conditions)等均會影響氯乙烯暴露的肝臟危害效應，而因此對上述相關因子或疾病進行研究亦有助於瞭解氯乙烯肝臟危害，特別是肝細胞癌發生的機轉。
台灣的聚氯乙烯工業發展約50年，在超過4000位工人中相信有許多工人的健康可能因曾暴露於高濃度的VCM而受到影響；本研究的目的在於對台灣聚氯乙烯職業世代進行追蹤，除了瞭解VCM職業暴露與相關癌症的關聯性，也藉以探討除了VCM暴露以外之因子對VCM引發之肝臟危害發生之影響，以作為VCM暴露與肝細胞癌發生之支持性證據。
在第一個子研究中，利用回溯性研究分析6家PVC廠3,336位男性工人在1980至2007年間之個別死因標準化死亡比 (standardized mortality ratio, SMR)及其移動平均線(moving average)來分析工人之相關癌症死亡率之變動趨勢。結果顯示與台灣一般民眾相比，工人之肝癌標準化死亡比之上昇達統計顯著性，且相關臨床證據支持肝癌患者多為肝細胞癌。白血病(leukemia)或淋巴造血系統癌症之死亡率比與肝癌有相似、平行但約早5年發生的倒U型變動趨勢。因此本研究支持職業氯乙烯暴露與肝細胞癌、淋巴造血系統癌症與白血病的發生有關，而作業現場氯乙烯單體空氣濃度的管制可能是相關癌症發生風險降低的可能原因。
第二個子研究則是利用橫斷式研究以了解PVC或VCM廠工人之健康狀況對於VCM(或混合ethylene dichloride)暴露工人之肝功能異常的影響。在568位工人中，未感染B型或C型肝炎病毒之工人，在不同暴露劑量分組間，工人之肝功能異常率未呈顯著差異；但在肝炎病毒感染的工人中，肝功能異常率在暴露分組呈顯著之劑量-反應關係，研究結果也證實職業性VCM或EDC暴露與肝炎病毒感染對於工人肝臟傷害的發生，具有協同性交互作用。
第三個子研究是是利用橫斷式研究來了解VCM代謝酵素基因多型性(metabolic genetic polymorphism)對於PVC廠工人肝纖維化(liver fibrosis)發生的影響。320位PVC工人的CYP2E1、ALDH2與GSTT1基因多型性是以PCR-RFLP方法進行分析，同時以job exposure matrix model重建VCM累積暴露劑量。研究結果顯示在13名經超音波診斷之肝纖維化的個案中，除了證實VCM暴露與肝纖維化的發生有反應-劑量關係外，也發現CYP2E1 c2c2基因型對肝纖維的發生有顯著影響，但其它代謝酵素基因型對肝纖維化發生的影響則不顯著；因此在VCM代謝路徑中，CYP2E1的基因多型性對於VCM暴露誘發肝纖維化具有顯著的影響，因此代謝基因的分析有助於辨識氯乙烯肝毒性易感受族群。
總結，本研究持續追蹤已建立VCM職業暴露世代，發現PVC工人較一般台灣男性族群容易罹患肝癌、白血病或淋巴造血系統癌症；此外具有較高的VCM暴露劑量、肝炎病毒感染者或是具有CYP2E1 c2c2基因型，會增加氯乙烯所導致之肝臟危害發生的風險。上述研究對於VCM暴露與工人之肝炎、肝纖維化或肝細胞癌發生之關係與致病機轉，提供重要的科學證據，也可作為對預防VCM相關肝臟疾病發生的指引。

Exposure to vinyl chloride monomer (VCM) may induce a rare cancer, liver angiosarcoma (LAS), and thus VCM is classified as a group 1 human carcinogen by the International Agency for Research on Cancer. Previous studies found occupational VCM exposure increased the risk of developing acute and chronic liver diseases. VCM exposure may also increase the risk of developing cancers other than LAS, especially hepatocellular carcinoma (HCC). However, because the evidence on the association between VCM exposure and diseases or cancers other than LAS is less consistent and the pathogenesis is less clear, more studies should be conducted. First, factors affecting carcinogenesis include age, genetic susceptibility, exposure dose, and general health conditions. Second, chronic hepatitis and liver cirrhosis are the major risk factors associated with HCC; therefore, studies on known factors and certain diseases should contribute to our understanding of the mechanisms involved in VCM-related liver damage, especially those that lead to HCC.
The polyvinyl chloride (PVC) industry had a history of more than 50 years in Taiwan. More than 4,000 workers have participated in the related processes and some workers have been exposed to high levels of VCM. The aim of the thesis is to study the association between VCM exposure and certain cancers, and investigate the modifying effects of other known risk factors on the VCM-induced liver damage through a continuing follow-up of a Taiwanese occupational cohort. The findings could provide evidence of how VCM induces HCC.
In the first part of this thesis, a retrospective study was conducted to estimate the cause-specific mortality, from 1980 and 2007, among 3,336 workers from six PVC factories in Taiwan. The standardized mortality ratio (SMR) was calculated and the moving average of the SMR was used to observe the mortality trends for cancers of a priori interest. 360 deaths were found with an excess risk of liver cancer mortality as compared to the general Taiwanese male population. Time trend analysis revealed that there is an inverted U-shape curve of mortality from liver cancer, hemolymphopoietic cancer and leukemia. Clinical evidence supported the suggestion that most liver cancer deaths should be HCC cases. The results of our study add more evidence to the association between VCM exposure and HCC, hemolymphopoietic cancer and leukemia. Adequate control of VCM exposure at worksites may thus contribute to the decline of the cancer mortality.
In the second part of the thesis, a cross-sectional study was conducted to study the synergistic effect of occupational chemical exposure and hepatitis viral infection on serum aminotransferase activity. 568 male workers who were employed in five PVC or four VCM factories were enrolled. Among workers without hepatitis viral infection, the differences in prevalence of abnormal AST and ALT were not significant between the different chemical exposure groups. In workers with hepatitis viral infection, those with high exposure had a higher prevalence of abnormal AST and ALT compared to those with low exposure. Mixed exposures to 1,2-ethylene dichloride and VCM appear to have a positive synergistic effect with hepatitis viral infection on liver damage.
In the third part of the thesis, a cross-sectional study was conducted to evaluate if metabolizing genetic polymorphisms could modify individual susceptibility to liver fibrosis with VCM exposure. CYP2E1, ALDH2, and GSTT1 polymorphisms were determined by the PCR-RFLP method among 320 workers who were employed in five PVC plants. Cumulative VCM exposure levels for study subjects were calculated using a job exposure matrix model. Thirteen workers were diagnosed as having liver fibrosis by ultrasound. We observed a dose–response trend between VCM exposure and liver fibrosis. Regarding the results on genetic polymorphisms, the CYP2E1 c2c2 genotype showed a significant effect on liver fibrosis as compared to those with other genotypes. No differences were observed between GSTT1 and ALDH2 genotypes. Our results suggest that the CYP2E1 genotype may be responsible for individual differences in susceptibility to liver fibrosis with regard to chronic VCM exposure. Thus, polymorphism analysis of metabolizing enzymes might be useful in the risk assessment of liver damage in VCM-exposed workers.
We continued to observe the PVC cohort and found that workers had a high risk of mortality from liver cancer, leukemia and hemolymphopoietic cancer. High exposure doses of VCM with hepatitis viral infection and the CYP2E1 c2c2 genotype increased the risk of liver damage. Our study provides evidence on the association between VCM exposure and the development of hepatitis, liver fibrosis and HCC. Our study also contributes to an understanding of the mechanisms involved in VCM-related liver damage and can be used as a guide for the prevention of such damage.

論文口試委員審定書 i
致 謝 iii
Abstract v
中文摘要 ix
Contents xi
List of Tables xiii
List of Figures xv
Chapter 1. Background 1
1.1. Study Goals 1
1.2. Hypotheses of the Study 4
Chapter 2. Literature Review 7
2.1. Introduction of Vinyl Chloride Monomer and Polyvinyl Chloride 7
2.2. Exposure to Vinyl Chloride Monomer 7
2.3. Regulations for the Control of Vinyl Chloride Monomer 10
2.4. Metabolic Pathway of Vinyl Chloride Monomer 11
2.5. Mechanisms of VCM-induced Hepatotoxicity 13
2.6. Interaction with Hepatitis Viral Infection on Hepatotoxicity 17
2.7. Interaction with Metabolic Genetic Polymorphisms on Hepatotoxicity 19
2.8. Epidemiological Studies on VCM-related Liver Diseases 21
Chapter 3. Mortality from Liver Cancer and Leukemia among Polyvinyl Chloride Workers in Taiwan: An Updated Study 55
3.1. Introduction 55
3.2. Subjects and Methods 55
3.2.1. Enrollment of Cohort Subjects 55
3.2.2. Determination of Individual Vital Status 58
3.2.3. Analysis of Causes of Death using the LTAS.NET 58
3.2.4. Selection of the Underlying Cause of Death 59
3.2.5. Statistical Analyses 59
3.3. Results 60
3.3.1. Descriptive Analysis 60
3.3.2. Cause-specific Mortality Analysis 63
3.3.3. Age at Death from Cancers of Iinterest 68
3.4. Discussion 68
Chapter 4. Effects of the Metabolic Genotype Polymorphisms on Vinyl Chloride Monomer-induced Liver Fibrosis among Polyvinyl Chloride Workers 75
4.1. Introduction 75
4.2. Subjects and Methods 76
4.2.1. Enrollment of Study Subjects 76
4.2.2. Exposure Assessment 77
4.2.3. Medical Examination 79
4.2.4. Statistical Analyses 81
4.3. Results 84
4.4. Discussion 89
Chapter 5. Synergistic Effects of Hepatitis Virus Infection and Occupational Chemical Exposure on Serum Aminotransferase Activity 95
5.1. Introduction 95
5.2. Subjects and Methods 96
5.2.1. Enrollment of Cohort Subjects 96
5.2.2. Exposure Assessment 96
5.2.3. Medical Surveillance 97
5.2.4. Statistical Analysis 98
5.3. Results 99
5.3.1. Descriptive Analysis 99
5.3.2. Multiple Logistic Regression Analysis 101
5.3.3. Interaction Analysis of Factors on Serum Aminotransferase 102
5.4. Discussion 106
Chapter 6. Conclusion 111
References 117
Appendix 129
Appendix 1. Hsieh HI, Chen PC, Wong RH, Du CL, Chang YY, Wang JD, Cheng TJ. Mortality from Liver Cancer and Leukemia among Polyvinyl Chloride Workers in Taiwan: An Updated Study. (Accepted by Occupational and Environmental Medicine) 131
Appendix 2. Hsieh HI, Chen PC, Wong RH, Wang JD, Yang PM, Cheng TJ. Effect of the CYP2E1 genotype on vinyl chloride monomer-induced liver fibrosis among polyvinyl chloride workers. Toxicology 2007;239:34-44. 137
Appendix 3. Hsieh HI, Wang JD, Chen PC, Cheng TJ. Synergistic effect of hepatitis viral infection and occupational exposures to vinyl chloride monomer and ethylene dichloride on serum aminotransferase activity. Occup Environ Med 2003;60:774-8. .... 149

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