- 學位論文
中部石化區附近學童硫代二乙酸暴露與肝臟毒性之相關性研究
Association between Urinary TDGA Exposure and Risk of Hepatotoxicity in School-aged Children Living near a Petrochemical Complex
摘要
背景: 中華民國第六套輕油裂解廠 (六輕) 包含有氯乙烯 (Vinyl chloride monomer, VCM) 及聚氯乙烯 (Polyvinyl chloride, PVC) 工廠。氯乙烯已經被國際癌症研究機構 (International Agency for Research on Cancer，IARC) 歸類為第一級致癌物。美國毒性物質及疾病登記署 (Agency for Toxic Substances and Disease Registry, ATSDR) 建議尿液中硫代二乙酸 (thiodiglycolic acid，TDGA) 可以作為氯乙烯暴露的生物標記物。兒童是氯乙烯暴露的易感族群，但是目前仍然不清楚生活在石化工業區附近的學齡兒童是否會因氯乙烯暴露而增加肝臟毒性的風險。目的：我們的目的是評估生活在石化工業區附近的學齡兒童尿液中硫代二乙酸濃度及暴露的相關性，並調控干擾因素，同時探討硫代二乙酸與肝臟功能異常，肝臟纖維化 (hepatic fibrosis) 和非酒精性脂肪肝 (non-alcoholic fatty liver disease) 之間的相關性。方法：本研究自2013年10月至2014年9月在台灣中部石化工業區附近10公里範圍內，建立了一個學齡兒童（6 - 13歲）的前瞻性研究世代。我們收集學童早上的第一次尿液及完成一分暴露評估問卷後，使用液相層析串聯式質譜儀(Liquid chromatography tandem-mass spectrometry, LC-MS/MS)進行分析尿液中硫代二乙酸濃度。使用血清天冬氨酸氨基轉移酶（aspartate aminotransferase，AST）和丙氨酸氨基轉移酶（alanine aminotransferase，ALT）來評估兒童肝臟功能， AST to platelet ratio index（APRI）和fibrosis-4 score（FIB-4）評估肝臟纖維化嚴重程度。依據北美和歐洲兒科胃腸肝臟營養學會（NASPGHAN和ESPGHAN）的推薦指引來診斷學童的非酒精性脂肪肝。因此，在調控相關干擾因子，使用多變量邏輯回歸分析硫代二乙酸暴露與肝臟毒性，肝臟纖維化和非酒精性脂肪肝風險的相關性。結果: 本研究發現最靠近石化工業區（約１公里）的學校學童尿液中硫代二乙酸濃度顯著最高，而且在學期期間學童尿液中硫代二乙酸濃度比暑假時高出4.1倍。學童的肝臟功能AST和ALT的中位數（範圍，亞臨床異常 subclinically abnormal ％）值分別為26.0（17.0 - 99.0, 25.7％）和15.0（7.0 - 211.0, 5.9％）IU / L。尿液硫代二乙酸最高四分位數（≥160.0 μg/g creatinine）的學童肝臟功能AST比最低四分位數（<35.4 μg/g creatinine）學童有顯著上升 (p = 0.033）。進一步研究，在調整潛在的干擾因素後，尿液硫代二乙酸最高四分位數學童對比最低四分位數，subclinically abnormal AST的風險顯著增加 3.86倍（OR = 3.86; 95％ confidence interval：1.54 - 9.67, p = 0.004），並且有顯著的劑量反應趨勢（ptrend= 0.004）。非酒精性脂肪肝研究方面，在調整年齡，性別，身體質量指數，三酸甘油酯，HOMA-IR和學校與石化工業區的距離後，發現學童尿液中硫代二乙酸最高四分位數比最低四分位數NAFLDNASPGHAN的風險顯著增加4.95倍（OR= 4.95; 95％ confidence interval= 1.15 - 21.38; P = 0.032），並且有顯著的劑量反應趨勢（Ptrend= 0.045），而相同分組比較下NAFLDESPGHAN的風險則增加3.45倍（OR = 3.45; 95％ confidence interval= 0.89 - 13.42; P = 0.074），但仍未達統計上顯著差異。結論：在環境曝露方面，學童尿液硫代二乙酸濃度會隨著學校與石化工業區的距離減少而上升。本研究成果提供學童尿液中硫代二乙酸濃度升高與肝臟功能異常，肝臟纖維化和非酒精性脂肪肝之風險顯著增加的證據。最後，我們建議血清ALT值及NAFLDNASPGHAN可以作為工業區附近學童非酒精性脂肪肝與環境曝露相關性田野調查有用的預測指標。
並列摘要
Background: The No.6 Naphtha Cracking Complex (namely a petrochemical complex) has a vinyl chloride monomer (VCM) and polyvinyl chloride factories. VCM is classified as a Group 1 human carcinogen by IARC and urinary thiodiglycolic acid (TDGA) is a suggestive biomarker of VCM by ATSDR. Children are susceptible population to VCM exposure; however, it is not clear whether school-aged children living near a petrochemical complex will have increased risk of hepatotoxicity. Objectives: We aimed to evaluate the confounding factors associated with urinary TDGA exposure in school-aged children living near a petrochemical complex and to investigate the association of urinary TDGA level between abnormal liver function, hepatic fibrosis and pediatric non-alcoholic fatty liver disease (NAFLD). Methods: We established a cohort of school-aged children (6-13 years) living within 10 km nearby a petrochemical complex during October 2013 to September 2014. First morning spot urine was sampling for analyzing urinary TDGA by liquid chromatography-tandem mass spectrometry. Fasting blood sample was drawn from participants to assess their liver function. Liver function was determined by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Hepatic fibrosis was assessed using the AST to platelet ratio index (APRI) and fibrosis-4 score (FIB-4). NAFLD was diagnosed by the recommendation of the North American and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN and ESPGHAN). Ultrasonography (U) was examined in each participant. Risk of subclinically abnormal liver function, liver fibrosis and NAFLD induced by TDGA exposure was estimated using multivariate logistic regression. Results: We found that children living closest the petrochemical complex (< 1 km) had significantly highest urinary TDGA level (~ 2 fold) and children at school time had 4.1-fold higher urinary TDGA level than those at summer vacation. The median (range, subclinically abnormal %) AST and ALT levels of all subjects were 26.0 (17.0 - 99.0, 25.7%) and 15.0 (7.0 - 211.0, 5.9%) IU/L, respectively. Children in the highest urinary TDGA quartile (≥160.0 μg/g creatinine) showed significantly elevated median AST levels compared with those in the lowest quartiles (<35.4 mg/g creatinine, p= 0.033). After adjustment for individual factors, children in the highest quartiles of TDGA level had significantly 3.8 fold increased risk of subclinically abnormal AST (OR= 3.86; 95% confidence interval: 1.54 - 9.67) compared with those in the lowest quartile. A dose response trend (p= 0.004) was observed. Children in the highest urinary TDGA quartile had a significantly 4.95 fold increased risk (odds ratio= 4.95; 95 % confidence interval = 1.15 - 21.38; P= 0.032) and dose-response trend (P trend= 0.045) for NAFLDNASPGHAN compared with those in the lowest urinary TDGA quartile after adjustment for age, gender, BMI, triglycerides, HOMA-IR and distance of elementary schools from the petrochemical complex. Children in the highest quartile had borderline significantly 3.45 fold increased risk (OR= 3.45; 95 % confidence interval= 0.89-13.42; P= 0.074) correlated with NAFLDESPGHAN compared with those in the lowest quartile after adjustment for confounders. Conclusion: Urinary TDGA levels elevated with decreasing distances between elementary schools and the petrochemical complex in school-aged children. Our findings are consistent with the hypothesis that urinary TDGA level in children living near petrochemical complex is associated with the children's susceptibility to hepatotoxicity. We obtained evidence of a significantly increased risk of subclinically abnormal AST, FIB-4 and pediatric NAFLDNASPGHAN in children with elevated urinary TDGA levels. Serum ALT levels can be a useful predictor for screening pediatric NAFLD in field studies.