臺灣博碩士論文加值系統

背景
雲林縣麥寮鄉第六套輕油裂解廠工業區(六輕工業區)其中的製程使用1,2二氯乙烷(Ethylene dichloride, EDC)作為原料生產氯乙烯單體(vinyl chloride monomer, VCM)進而加工生產聚氯乙烯(polyvinyl chloride, PVC)，這些製程會排放或是逸散VCM與EDC到空氣中。International Agency for Research on Cancer (IARC)將VCM分類為1類的人類致癌物質，將EDC分類為2B類可能致癌物質，VCM與EDC兩者都具有肝毒性會造成肝臟損傷、肝臟纖維化甚至肝硬化，人體暴露這兩個化學物質後會透過肝臟的P450酵素主要代謝成為硫代二乙酸(thiodiglycolic acid, TdGA)再經由尿液排出體外。
目的
透過尿液中的代謝物TdGA濃度分析推測居民暴露VCM、EDC的程度再以個案的血液分析資料計算非侵襲性肝纖維指標，Fibrosis-4 (FIB-4)。探討尿液TdGA濃度、研究個案住家和六輕工業區的距離與非侵襲性肝纖維指標之間的關係。
方法
研究個案為彰化縣大城鄉與竹塘鄉之成人居民，收案日期2016年4月10日與4月16日，收案內容包含尿液、血液樣本以及生活習慣問卷調查，將個案中分析結果未能符合實驗分析QA/QC、有服用維他命B群者、患有B、C肝炎者、血小板異常偏低者排除，並限制兩地區年齡分布區間(70歲以下)後個案共447位。TdGA的尿液樣本分析使用LC-MS/MS並用肌酐酸(creatinine)校正尿液濃度，並以四分位距分組，作為VCM、EDC的暴露指標，血液樣本生化檢查項目中以天冬氨酸氨基轉移酶(aspartate aminotransferase, AST)、丙氨酸轉氨酶(alanine aminotransferase, ALT)與血小板數量(Platelet count)當作非侵襲肝纖維指數的計算因子來評估研究個案肝損傷的程度，以多重羅吉斯迴歸分析探討TdGA與FIB-4之間的關聯性。
結果
TdGA與個案距離六輕工業區VCM/PVC廠的相關係數為-0.20，P值<0.05，距離六輕工業區較近的彰化縣大城鄉研究個案平均TdGA濃度為269.6 μg/g creatinine，距離六輕工業區較近的竹塘鄉研究個案平均TdGA濃度為199.25 μg/g creatinine。以FIB-4數值1.29當切分點預測個案肝纖維化，大城鄉個案FIB-4值大於1.29的個案比例為39%，竹塘鄉則為32%。在TdGA與FIB-4的多重羅吉斯迴歸分析中，校正性別、是否有在六輕工業區工作、抽菸習慣、飲酒習慣、BMI以及總膽固醇後發現TdGA變項中最高濃度的組別OR值為2.092
( 95%CI: [1.171-3.774])並達到統計上的顯著。
結論
本研究發現個案住家距離六輕工業區VCM/PVC廠的距離越近，其尿液中TdGA濃度越高，個案中尿液TdGA濃度最高組別較濃度最低組別有2.092倍的風險其FIB-4>1.29，預測為具顯著肝纖維化者。本研究的結論認為六輕石化工業區的VCM/PVC工廠逸散或排放的VCM與EDC可能對南彰化地區的居民造成肝臟健康上的影響，使該地區居民肝纖維化的風險上升。

Background
No.6 Naphtha Cracking Complex, one of the industrial processes, produces vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) by Ethylene dichloride (EDC), which might release trace level of VCM and EDC in the atmosphere. International Agency for Research on Cancer (IARC) classified VCM, EDC as group 1, 2B respectively. Both VCM and EDC can also cause liver damage and lead to liver fibrosis even cirrhosis. Upon exposure, these will be metabolized by the cytochrome P450 enzymes and be excreted through urine as thiodiglycolic acid (TdGA).
Aim
Our objective is to estimate the VCM and EDC exposure level with urinary thiodiglycolic acid (TdGA) as biomarker and utilize non-invasive index (FIB-4) to evaluate the liver damages caused by VCM and EDC among residents in Southern Changhua County, then establish the correlation between TdGA and FIB-4.
Methods
Urine samples, blood samples and life style questionnaire were collected during 2016 April 10 and Apri 16 in Dacheng Township and Zhutang Township, South Changhua, Taiwan. The TdGA level in urine samples were analyzed by LC-MS/MS with the adjustment of creatinine, also divided into 4 groups dummy variables by IQR. Bases on the study population age distribution, subjects older than 70 years old were excluded. Subjects who take Vitamin B complex, have hepatitis B virus infection, hepatitis C virus infection and abnormal platelet counts were also excluded, then there are total 447 subjects. Non-invasive, Fibrosis-4 (FIB-4) were utilized to evaluate the liver fibrosis level caused by VCM and EDC. The Logistic regression model were developed to assess the relationship between urinary TdGA and FIB-4.
Results
The correlation betweenTdGA and the distances to industry of subjects is -0.20, and
p-value <0.05. Subjects in Dacheng Township, is nearer to complex than Zhutang Townhip, average TdGA level is 269.6 μg/g creatinine, Subjects in Zhutang Township average TdGA level is 199.25 μg/g creatinine. With FIB-4 cuttof 1.29, subjects whos FIB-4 value over 1.29 were predicted to have significant liver fibrosis. Proportion of FIB-4 >1.29, in Dacheng Township is 39%, in Zhutang Township is 32%. In the logistic regression model , after adjusting gender, wrok in complex or not, smoke habbit, drink habbit, BMI and total cholesterol variables, we found that the highest TdGA concentration group (>Q3), OR is 2.092( 95%CI: [1.171-3.774]), p-value <0.05.


Conclusion
Subjects living near to VCM/PVC factory with increasing level of urinary TdGA.
Subjects with the highest TdGA concentration (>Q3) has 2.092 times than subjects with the lowest TdGA concentration group (<Q1) to be led to FIB-4 >1.29. VCM/PVC factory of No.6 Naphtha Cracking Complex has probably affects residents living in South Changhua County, and increase the risk of liver fibrosis.

目錄
i. 誌謝 ii
ii. Abstract v
目錄 viii
圖表目錄 ix
1. 前言 1
2. 文獻探討 2
2.1 六輕氯乙烯廠和聚氯乙烯廠簡介 2
2.2 VCM與EDC的性質簡介 4
2.3 VCM與EDC和肝纖維化、肝硬化之間的關係 5
2.4 VCM與EDC的代謝途徑 7
2.5 尿液中生物指標 9
2.6 非侵襲性肝纖維指標的應用 11
3. 材料方法 13
3.1 研究目的 13
3.2 研究架構 14
3.3 研究地區 15
3.4 研究對象 16
3.5 研究問卷 17
3.6 生物樣本與生化指標 18
3.7 尿液分析 19
3.7.1 試藥與分析儀器 19
3.7.2 分析方法 20
3.8 統計分析方法 22
4. 結果 23
4.1未排除血小板異常個案之南彰化地區人口學變項、TdGA濃度與非侵襲性指標FIB-4 23
4.2 已排除血小板異常之南彰化地區人口學變項、TdGA濃度與非侵襲性指標FIB-4 28
4.3高低暴露地區比較 33
5. 討論 37
5.1 TdGA與血液生化指標 37
5.2彰化縣大城鄉歷年成人尿液TdGA濃度比較 39
5.3 肝臟腫瘤 41
5.4法規標準 42
5.5研究限制 44
6. 結論建議 45
6.1結論 45
6.2建議 45
7. 文獻探討 46
8. 附錄 52

圖表目錄
圖1 六輕工業區內氯乙烯單體廠(VCM廠)、聚氯乙烯廠(PVC廠)與個案分布位置圖 11
圖2 1,2-二氯乙烷(EDC)之化學式 12
圖3氯乙烯單體(VCM)之化學式 12
圖4 EDC與VCM代謝流程簡圖 16
圖6. 研究架構 22
圖5 FIB-4 公式 26
圖7. AGILENT1200串聯 API 4000 Q-TRAP (HPLC-MS/MS) 27
圖8 質譜儀Q0-Q3簡圖 28
來源:(SCIEX, 2010) 28
表1.鄰近六輕工業區之南彰化地區基本人口學變項 (N=476) 32
表2.鄰近六輕工業區之南彰化地區的生化指標與肝臟非侵襲性指標值(N=476) 33
表3.南彰化地區個案肝臟非侵襲性指標FIB-4A與尿液生物指標TDGA的多重羅吉斯迴歸模型(N=476) 35
表4.鄰近六輕工業區之南彰化地區基本人口學變項 (N=447) 37
表5.鄰近六輕工業區之南彰化地區的生化指標與肝臟非侵襲性指標值(N=447) 38
表6.南彰化地區個案肝臟非侵襲性指標FIB-4A與尿液生物指標TDGA的多重羅吉斯迴歸模型 (N=447) 40
表7.大城鄉與竹塘鄉基本人口學變項比較 42
表8大城鄉與竹塘鄉的生化指標與肝臟非侵入性指標比較表 44
表6. 103-105年彰化縣大城鄉成人尿中TDGAA濃度比較 49

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