氯乙烯單體 (Vinyl Chloride Monomer, VCM)為聚氯乙烯 (Polyvinyl chloride, PVC)製造的主要原料，流行病學研究指出VCM過量暴露可能與肝血管肉瘤和肝細胞癌有關，國際癌症研究署 (International Agency for Research on Cancer, IARC)及美國環保署 (United States Environmental Protection Agency, US EPA)皆將其歸為人類的確定致癌物質。藥物動力學資料顯示，VCM在人體中的主要代謝產物為Thiodiglycolic acid (TDGA)，暴露經過12~20小時後，可觀察到尿液中TDGA之最高濃度值。職業暴露評估研究調查發現，尿液中TDGA可反映高濃度VCM之暴露實態，且尿液中的TDGA濃度隨著VCM暴露濃度上升而增加，達統計上之顯著相關 (r2=0.65, p <0.01)，但是低濃度的VCM暴露則因尿液TDGA分析的偵測極限 (1 ppm) 偏高，導致無法有效以尿液中的TDGA濃度評估低濃度的VCM暴露實態。根據VCM暴露之健康效應的相關研究指出，職業勞工長期暴露於高濃度的VCM環境中，可能與胰島素阻抗、脂聯素調控異常有關。本研究同時採用個人暴露監測與生物偵測技術，探討職業暴露勞工之VCM暴露實態與健康指標的相關性。本研究針對國內4間主要VCM製造或使用工廠進行調查，共招募134位勞工，採用勞委會公告之標準採樣方法 (CLA 2301)，進行個人空氣中VCM及1,2-二氯乙烷 (1,2-dichloroethane, EDC)暴露樣本採集，並以GC-MS分析；此外，亦於勞工個人上、下班前收集30mL之尿液，並以HPLC/MS/MS分析尿液中TDGA濃度。個人健康指標檢測分別進行肝功能 (Liver function tests, LFTs)及脂肪代謝異常指標分析。最後搭配個人問卷，調查生活習慣、疾病史及採樣當日的時間活動模式記錄。個人空氣VCM暴露濃度分析結果發現，四座工廠勞工的VCM與EDC幾何平均暴露濃度分別為363.0 g/m3 (ND-41120.8 g/m3)及183.8 g/m3 (ND-53976.8 g/m3)，暴露實態與過去研究的結果相似。依據過去研究的資料顯示，藥物及維他命攝取會導致尿液中TDGA濃度升高，因此本研究篩選無服用藥物或維他命的勞工(n=47)，並以個人空氣中VCM暴露濃度之中位數劃分高、低VCM濃度組，結果發現高VCM濃度組勞工的上班前尿液中TDGA濃度顯著高於低VCM濃度組 (662.02 mg/g-Cre 與 372.8 mg/g-Cre, P=0.044)。進一步依照勞工 (n=47)的個人空氣中VCM暴露濃度，以四分位數劃分為四個組別，結果發現勞工的VCM暴露濃度越高之組別，其上班前尿液中的TDGA濃度較高，呈現升高之趨勢，且趨勢具有統計上顯著之意義 (p-trend =0.009)。透過相關性檢定勞工 (n=47)的個人VCM暴露濃度與上班前尿液中TDGA濃度，發現兩者之相關係數 (r)為0.614，達統計上顯著相關 (p =0.002)。以複迴歸校正干擾因子，個人空氣中VCM暴露濃度與上班前尿液TDGA濃度的線性R2值為0.382 (p <0.001)，綜合上述的結果皆顯示，暴露勞工的上班前尿液中TDGA為VCM暴露的生物暴露指標。進一步利用暴露劑量推估公式，將尿液中的代謝物TDGA劑量回推每位勞工的VCM暴露劑量，並與實際量測的VCM暴露濃度值比較，結果發現實測之空氣中VCM暴露濃度與代謝物回推之空氣中VCM暴露濃度無顯著差異 (507.8 g/m3與494.8 g/m3, p>0.05)，相關係數 (r)為0.288 (p=0.018)，顯示本研究的回推公式具可利用性。在健康效應上，於排除干擾因子後，以72位勞工的上班前尿液中TDGA中位數濃度劃分高、低TDGA濃度組，結果發現高TDGA濃度組之胰島素濃度及胰島素阻抗指標 (HOMA-IR)顯著較高 (胰島素濃度：10.5 mIU/mL與5.9 mIU/mL, p =0.011、HOMA-IR：2.7與1.3, p =0.013)，脂聯素濃度顯著較低 (6.0 g/mL與8.2 g/mL, p =0.031)，表示VCM暴露可能導致胰島素阻抗及脂聯素調控異常。風險評估的部分，利用勞工的個人空氣VCM及EDC濃度進行健康風險評估，結果顯示有4位勞工的VCM致癌風險高於職業暴露族群之可接受風險 (10-3)，EDC致癌風險發現有14位勞工高於職業暴露族群之可接受風險 (10-3)，此外， VCM作業廠勞工的平均總致癌風險顯著高於PVC廠勞工 (5.23×10-4與3.58×10-4, p<0.001)，原因為VCM作業廠的勞工同時操作VCM及EDC兩種物質，共同暴露導致VCM作業廠的勞工之致癌風險明顯較高。
本研究發現國內VCM作業勞工的VCM暴露濃度多數已降低至1 ppm (2.55 mg/m3)以下，顯示情況明顯改善。勞工的上班前尿液中的TDGA濃度可作為VCM暴露評估的生物暴露指標，本研亦驗證以尿液中TDGA回推VCM暴露濃度的劑量回推公式具可利用性，未來此公式可應用在VCM勞工的生物偵測研究。此外，本研究發現VCM暴露可能導致胰島素阻抗及脂聯素調控異常，建議未來可考慮將胰島素及脂聯素納入特殊健康檢查之項目。

Extended Abstract
Exposure assessment of vinyl chloride monomer for workers in vinyl chloride manufacturing and using plants

Student: Chun-Wei Hsu
Advisor: Dr. Ching-Chang Lee
Department of Environmental and Occupational Health Medical College National Cheng Kung university

SUMMARY
The aims of present study are to assess exposure profile and health effects in VCM workers by biological monitoring and environmental monitoring. 134 workers from four VCM manufacturing/using plants were recruited and signed inform consent. Personal air sampling, urinary sampling, examination of blood biochemistry were been conducted, respectively. Personal exposure data and time activity pattern were been collected with questionnaires.
pre-shift of urinary TDGA levels in high VCM level group is significantly higher than low VCM level group. The airborne VCM concentration is significantly correlated with pre-shift of urinary TDGA levels (r=0.614, p=0.002). A significant liner correlation adjusted by multiple linear regression was found (R2 =0.382, p<0.001) between airborne VCM concentration and pre-shift of urinary TDGA levels. The levels of insulin and HOMA-IR in high TDGA levels group are significantly higher than those of low TDGA levels group, levels of adiponectin in high TDGA group is significant lower than low TDGA group after excluded the confounding factors. It means VCM exposure may promote insulin resistance and adiponectin indicators abnormalities. In conclusion, VCM exposure concentration have been below 1 ppm (2.55 mg/m3)in the most of workers. However, the carcinogenic risk are still unacceptable (>10-3) in part of VCM plant’s workers because of the co-exposure.
Key word: Vinyl chloride monomer (VCM), TDGA, LFTs, Insulin resistance, Adiponectin

INTRODUCTION
Vinyl chloride (VCM) was used primarily to manufacture PVC. Epidemiology studies reported that angiosarcoma of the liver (ASL) and hepatocellular carcinoma (HCC) are significantly and positively associated with VCM exposure, and VCM was already classified as human carcinogen by International Agency for Research on Cancer (IARC) and United States Environmental Protection Agency (US EPA).
Animal pharmacokinetic data reported that VCM essentially metabolize and partially excrete in urine as thiodiglycolic acid (TDGA) within 20 hours. Few studies had showed the significant correlation (r2=0.65, p<0.01) between high airborne VCM concentration and urinary TDGA levels. However, the higher detection limit of TDGA (>1 ppm) was the limitation for low VCM exposure workers.
insulin resistance and indicators of adipokine abnormalities had been found in long-term VCM exposure workers. The aims of present study are to assess the VCM exposure profile and health effects in VCM workers, and to discuss the correlation between low-VCM exposure levels and urinary TDGA levels.
MATERIALS AND METHODS
In present study, 134 workers from four VCM manufacturing/using plants were recruited and signed inform consent. Personal air sampling referring form CAL analytical methods (CLA 2301) were been conducted by GC/MS to assess personal VCM and EDC exposure levels. Furthermore, urinary sampling were been collected from each workers before beginning and after finishing their works. TDGA levels were been analyzed by HPLC/MS/MS.
Examination of blood biochemistry including liver function tests (LFTs) and insulin resistance were been conducted, respectively. Personal exposure data and time activity pattern were been collected with questionnaires.
RESULTS AND DISCUSSION
In the results, the geometric mean and range of airborne VCM and EDC concentrations were 363.0 g/m3 (ND-41120.8 g/m3) and 183.8 g/m3 (ND-53976.8 g/m3). According to the past studies, confounding factors involving medications and vitamins had been excluded in this study. Results show that pre-shift of urinary TDGA levels in high VCM level group is significantly higher than low VCM level group (662.02 mg/g-Cre versus 372.8 mg/g-Cre, p =0.044). The pre-shift of urinary TDGA levels are significantly increased in four VCM levels group dividing by quartile (p-trend =0.009). The airborne VCM concentration is significantly correlated with pre-shift of urinary TDGA levels (r=0.614, p=0.002). A significant liner correlation adjusted by multiple linear regression was found (R2 =0.382, p<0.001) between airborne VCM concentration and pre-shift of urinary TDGA levels (Fig 1). It suggest that pre-shift of urinary TDGA levels could be used as biomarkers to assess VCM exposure profile in the future.
The dose assessment equation was used to assess VCM exposure dose back-estimated from urinary TDGA levels. Results showed that median of VCM concentration measured in ambient and estimated form dose assessment equation is no significant difference (p>0.05), and a significant correlation (r=0.288, p=0.018) is found between VCM concentration estimated form equation and measured in ambient. Accordingly, the back-estimate equation established in this study is an useful equation.
The levels of insulin and insulin resistance (HOMA-IR) in high TDGA levels group are significantly higher than those of low TDGA levels group (Insulin: 10.5 mIU/mL v.s. 5.9 mIU/mL, p =0.011; HOMA-IR: 2.7 v.s.1.3, p =0.013), and levels of adiponectin in high TDGA group is significant lower than low TDGA group (6.0 g/mL v.s. 8.2 g/mL, p =0.031) after excluded the confounding factors. It means VCM exposure may promote insulin resistance and adiponectin indicators abnormalities (Table 1).
The results of health risk assessment shows that 4 worker's carcinogenic risk of VCM exposure are higher than acceptable risk (10-3), and 14 worker's carcinogenic risk of EDC exposure are higher than acceptable risk (10-3). In addition, VCM plant's workers had higher total carcinogenic risk than PVC plant's workers (.5.23×10-4 v.s. 3.58×10-4, p<0.001). It may associate with co-exposure of VCM and EDC in VCM plant's workers.

Table 1. Comparison of health indicators between low- and high-TDGA levels group
Subjects References value Low-TDGA levels group (n=36)a High-TDGA levels group (n=36) p-value d
Value Abnormal rate Value Abnormal rate
Total protein (g/dL) 6.4-8.3 7.3 (6.6-8.1)b 1 (2.8%)c 7.5 (6.7-8.5) 0 (0%) NS NS
Albumin (g/dL) 3.5-5.0 4.7 (4.0-5.5) 8 (22.2%) 4.9 (4.3-5.3) 6 (16.7%) NS NS
Total cholesterol (mg/dL) <200 189 (115-270) 9 (25%) 185 (128-258) 14 (38.9%) NS NS
GOT (U/L) 0-39 26 (17-117) 3 (8.3%) 24 (15-96) 5 (13.8%) NS NS
GPT (U/L) 0-54 26 (14-73) 1 (2.7%) 27 (11-128) 4 (11.1%) NS NS
GGT (U/L) 10-71 24 (10-497) 4 (11.1%) 29 (3.1-539) 6 (16.7%) NS NS
Total bilirubin (mg/dL) 0.2-1.4 0.62 (0.3-1.4) 0 (0%) 0.69 (0.3-2.5) 3 (8.3%) NS NS
Direct bilirubin (mg/dL) 0.0 - 0.3 0.2 (0.1-0.4) 3 (8.3%) 0.21 (0.1-0.4) 3 (8.3%) NS NS
Alkaline phosphatase (U/ L) 30-110 64 (6.9-94) 1 (2.8%) 64 (35-114) 1 (2.8%) NS NS
Insulin (mIU/ml) <22 5.5 (1.7-23.5) 2 (5.5%) 7.8 (1.7-42.2) 5 (13.9%) 0.008 NS
A.C glucose (mg/dL) 60-100 91 (75-140) 3 (8.3%) 89 (77-175) 8 (22.2%) NS NS
HOMA-IR <3.16 1.16 (0.32-27.1) 3 (8.3%) 1.83 (0.34-11.3) 11 (30.5%) 0.008 NS
Adiponectin (mg /mL) > 2.0 9.8 (4.0-21.9) 0 (0%) 6.4 (1.6-25.8) 1 (2.8%) 0.05 NS
Leptin (mg /mL) < 7.0 3.0 (0.65-11) 6 (16.7%) 5.2 (0.65-23.7) 10 (27.8%) NS NS
Triglycerides (mg/dL) <150 105 (43-420) 14 (38.9%) 105 (34-439) 9 (25%) NS NS
a no medicine intake, hepatitis virus worker (n=72). Divided by pre-shift TDGA median concentration (616.01 mg/g-Cre)
b Median (range)
c Number (%)
d Analysis by wlcoxon rank sum test and chi-square tes
NS: Non significant

Fig 1. Scatter plot of the multiple regression analysis of VCM in air and pre-shift of urinary TDGA
CONCLUSION
VCM exposure concentration have been below 1 ppm (2.55 mg/m3)in the most of workers. However, the carcinogenic risk are still unacceptable (>10-3) in part of VCM plant’s workers because of the co-exposure. Pre-shift of urinary TDGA levels could be used as exposure biomarkers for VCM exposure workers. In this study, the VCM exposure assessment model using urinary TDGA to estimate the ambient exposure of VCM had been verified, and it could be used in biological monitoring research. Additionally, we suggest that VCM exposure may promote insulin resistance and abnormal lipid metabolism.

Antonino-Green, D., Linder, M.W., Fortwengler, P., Looney, S., Geoghegan, T. E. & Valdes, R. J. (2000). Cytochrome P4502E1 polymorphism and glutathione Stransferase genotypes are linked to vinyl chloride-induced angiosarcoma. American Association for Cancer Research, 41, Abstract.
Goldstein, B. J. (2002). Insulin Resistance as the Core Defect in Type 2 Diabetes Mellitus. American Journal of Cardiology, 90 (5A) pp.3~10.
Bartsch, H., & Nair, J. (2000). New DNA-based biomarkers for oxidative stress and cancer chemoprevention studies. European Journal of Cancer, 36 (10) pp.1229~1234.
Bolt, H.M. (2005). Vinyl chloride - A classical industrial toxicant of new interest. Critical Reviews in Toxicology, 35 (4) pp.307~323.
Borruso, A.V. (2006). CEH Product Review: Vinyl chloride Monomer (VCM). Chemical Economics Handbook, Zürich: SRI Consulting.
Bonora, E., Formentini, G., Calcaterra, F., Lombardi, S., Marini, F., Zenari, L., Saggiani, F., Poli, M., Perbellini, S., Raffaelli, A., Cacciatori, V., Santi, L., Targher, G., Bonadonna, R., & Muggeo, M. (2002). HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care, 25 (7) pp.1135~1141.
Calafat, A. M., Barr, D. B., Pirkle, J. L., & Ashley, D. L. (1999). Reference range concentrations of N-acetyl-S-(2-hydroxyethyl)-L-cysteine, a common metabolite of several volatile organic compounds, in the urine of adults in the United States. Journal of Exposure Analysis and Environmental Epidemiology, 9 (4) pp.336~342.
Chen, Z. Y., Gu, X. R., Cui, M. Z., & Zhu, X. X. (1983). Sensitive Flame-Photometric-Detector Analysis of Thiodiglycolic Acid in Urine as a Biological Monitor of Vinyl Chloride. International Archives of Occupational and Environmental Health, 52 (3) pp.281~284.
Cheng, T. J., Chou, P. Y., Huang, M. L., Du, C. L., Wong, R. H., & Chen, P. C. (2000).Increased lymphocyte sister chromatid exchange frequency in workers with exposure to low level of ethylene dichloride. Mutation Research, 470 (2) pp.109~114.
Cheng, T. J., Huang, Y.F., & Ma, Y. C. (2001). Urinary thiodiglycolic acid levels for vinyl chloride monomer-exposed polyvinyl chloride workers. Journal of Occupational and Environmental Medicine, 43 (11) pp.934~938.
Chitturi, S., Abeygunasekera, S., Farrell, G. C., Holmes-Walker J,, Hui, J. M., Fung, C., Karim, R., Lin, R., Samarasinghe, D., Liddle, C., Weltman, M., & George, J. (2002). NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology, 35 (2) pp.373~379.
Ciroussel, F., Barbin, A., Eberle, G., & Bartsch, H. (1990). Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility. Biochemical Pharmacology, 39 (6) pp.1109~1113.
D’Souza, R.W., Francis, W.R., & Andersen, M.E. (1988). Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure. J. Pharmacol. Exp. Ther, 245 (2) pp. 563~568.
De Bont, R., & van Larebeke, N. (2004). Endogenous DNA damage in humans: A review of quantitative data. Mutagenesis, 19 (3) pp.169~185.
Dramiñski, W., & Trojanowska, B. (1981). Chromatographic determination of thiodiglycolic acid - a metabolite of vinyl chloride. Archives of Toxicology, 48 (4) pp.289~292.
Drew, R.T., Boorman, G. A., Haseman, J. K., McConnell, E. E., Busey, W. M., & Moore, J. A. (1983). The effect of age and exposure duration on cancer induction by a known carcinogen in rats mice and hamsters. Toxicology and Applied Pharmacology, 68 (1) pp.120~130.
Du, C. L., Chan, C. C., & Wang, J. D. (1996). Comparison of personal and area sampling strategies in assessing workers' exposure to vinyl chloride monomer. Environmental Contamination and Toxicology, 56 (4) pp.534~542.
Eric, S., Alan, S., & Stephen, L. (2007). Insulin Resistance, the Metabolic Syndrome, and Complication Risk in Type 1 Diabetes. Diabetes Care, 30 (3) pp.707-712.
Fei, L., Andrew D. P., Hofer C. C., Krausz K. W., Gonzalez, F. J., & Idle J. R. (2010). Comparative metabolism of cyclophosphamide and ifosfamide in the mouse using UPLC–ESI-QTOFMS-based metabolomics. Biochemical Pharmacology, 80 (7) pp.1063~1074.
Gáliková, E., Tomíková, K., Zigová, A., Mesko, D., Buchancová, J., Petrisková, J., L’uptáková, M., Ja, M. & Karaffová, N. (1994). General health of workers in the Nováky chemical works exposed to vinyl chloride. Prac. Lék. journal, 46 pp.251~256.
Gargas, M.L., Clewell III, H.J., & Andersen, M.E. (1986). Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways. Toxicol. Appl. Pharmacol, 82 (2) pp. 211~223.
Guengerich, F. P., Crawford, W.M. Domoradzki, J.Y., Macdonald, T.L., & Watanabe, P.G. (1980). In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol. Appl. Pharmacol, 55 (2) pp. 303~317.
Mastrangelo, G., Fedeli, U., Fadda, E., Valentini, F., Agnesi, R., Magarotto, G., Marchì, T., Buda, A., Pinzani, M., & Martines, D. (2004). Increased Risk of Hepatocellular Carcinoma and Liver Cirrhosis in Vinyl Chloride Workers: Synergistic Effect of Occupational Exposure with Alcohol Intake. Environmental Health Perspectives, 112 pp.1188~1192.
Hotamisligil, G. S. (2006). Inflammation and metabolic disorders.Nature, 444 (7121) pp.860~867.
Gwinn, M. R., Johns, D. O., Bateson T. F., & Guyton, K. Z. (2011). A review of the genotoxicity of 1,2-dichloroethane. Mutation Research, 727 (1-2) pp.42~53.
Hefner, R. E., Watanabe, P. G., & Gehring, P. J. (1975). Preliminary studies on the fate of inhaled vinyl chloride monomer (VCM) in rats. Environmental Health Perspectives, 11 pp.85~95.
Heger, M., Müller, G. & Norpoth, K. (1981). Investigations on the correlation between vinyl chloride (=VCM)-uptake and excretion of its metabolites by 15 VCM-exposed workers. International Archives of Occupational and Environmental Health, 48 (2) pp.205~210.
Itoh, H., Yoshida, K., & Masunaga, S. (2007). Quantitative Identification of Unknown Exposure Pathways of Phthalates Based on Measuring Their Metabolites in Human Urine. Environmental Science & Technology, 41 (13) pp.4542~4547.
Koch, H. M., Drexler, H., & Angerer, J. (2003). An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population. International Journal of Hygiene and Environmental Health, 206 (2) pp.77~83.

Hong, C. B., Winston, J. M., Thornburg, L. P., Lee, C. C., & Soods, J. S. (1981). Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent to exposure. Journal of Toxicology and Environmental Health, 7 (6) pp.909~924.
Hsiao, T. J., Wang, J. D., Yang, P. M., Yang, P. C., & Cheng, T. J. (2004). Liver Fibrosis in Asymptomatic Polyvinyl Chloride Workers. Journal of Occupational and Environmental Medicine, 46 (9) pp.962~966.
Hsieh, H. I., Chen, P. C., Wong, R. H., Du, C. L., Chang, Y. Y., Wang, J. D., & Cheng, T. J. (2011). Mortality from liver cancer and leukaemia among polyvinyl chloride workers in Taiwan an updated study. Occupational and Environmental Medicine, 68 (2) pp.120~125.
Hsieh, H. I., Wang, J. D., Chen, P. C., & Cheng, T. J. (2003). Synergistic effect of hepatitis virus infection and occupational exposures to vinyl chloride monomer and ethylene dichloride on serum aminotransferase activity. Occupational and Environmental Medicine, 60 (10) pp.774~778.
Hui, J. M., Sud, A., Farrell, G. C., Bandara, P., Byth, K., Kench, J. G., McCaughan, G. W., & George, J. (2003). Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology, 125 (6) pp.1695~1704.
International Agency for Research on Cancer (1987). IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, overall evaluations of carcinogenicity: an updating of IARC monographs, 1-42. WHO, IARC, 7 pp.373~376.
IOSH. (2012). The Development of Biological Monitoring Index for Vinyl Chloride Exposure Workers. IOSH, 100-A322.
Sass, J. B., Castleman, B., & Wallinga, D. (2005). Vinyl Chloride A Case Study of Data Suppression and Misrepresentation. Environmental Health Perspectives, 113 (7) pp.809~812.
Joseph, L. E., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M. (2003). Are Oxidative Stress Activated Signaling Pathways Mediators of Insulin Resistance and -Cell Dysfunction? Diabetes, 52 (1) pp.1~8.
Krajewski, J., Dobecki, M., & Gromiec, J. (1980). Retention of vinyl chloride in the human lung. British Journal of Industrial Medicine, 37 (4) pp.373~374.
Kyriakis, J. M. & Avruch, J. (1996). Sounding the alarm: protein kinase cascades activated by stress and inflammation. The Journal of Biological Chemistry, 271 (40) pp.24313~24316.
Lee, C. C., Bhandari, J. C., Winston, J. M., House, W. B., Dixon, R. L., & Woods, J. S. (1978). Carcinogenicity of vinyl chloride and vinylidene chloride. Journal of Toxicology and Environmental Health, 4 (1) pp.15~30.
Lewis, R., Rempala, G., Dell, L.D., & Mundt, K.A. (2003) Vinyl chloride and liver and brain cancer at polymer production plant in Louisville, Kentucky. Journal of Occupational and Environmental Medicine, 45 (5) pp.533~537.
Luc, F., Van, G., Ilse L.M., & Christophe, E. D. (2006). Mechanisms linking obesity with cardiovascular disease. Nature, 444 (14) pp.875~880.
Lyman, W. J. (1985). Environmental Exposure From Chemicals. Boca Raton, Florida, USA: CRC Press, Vol (I) p.31.
Maltoni, C., Lefemine, G., Ciliberti, A., Cotti, G., & Carretti, D. (1981). Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environmental Health Perspectives, 41 pp.3~29.
Marco, M. A., & Anna C. F. (2006). Liver function assessment in workers exposed to vinyl chloride. International Archives of Occupational and Environmental Health, 79(1) pp.57~65.
Maroni, M., Mocci, F., Visentin, S., Preti, G., & Fanetti, C. F. (2003). Periportal fibrosis and other liver ultrasonography findings in vinyl chloride workers. Occupational and Environmental Medicine, 60 (1) pp.60~65.
Cave, M., Deaciuc, I., Mendez, C., Song, Z., Joshi-Barve, S., & Barve, S. (2007). Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. The Journal of Nutritional Biochemistry, 18 (3) pp.184~195.
Cave, M., Falkner, K. C., Ray, M., Swati, J.B., Brock, G., Khan, R., MarjorieB. H., & Craig, J. M. (2010). Toxicant- Associated Steatohepatitis In Vinyl Chloride Workers. Hepatology, 51 (2) pp.474~481.
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F. & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28 (7) pp.412~419.
Maureen, R. G., Douglas, O. J., Thomas, F. B., & Kathryn, Z. G. (2011). A review of the genotoxicity of 1,2-dichloroethane (EDC). Mutation Research, 727 (1-2) pp.42~53.
McKillop, I. H., & Schrum, L.W. (2009). Role of alcohol in liver carcinogenesis. Semin Liver Disease, 29 (2) pp.222~232.
Michailova, A., Kuneva, T., & Popov, T.(1998). A comparative assessment of liver function in workers in the petroleum industry. International Archives of Occupational and Environmental Health, 71 pp.46~49.
Morris, S. (2009). Vinyl chloride and the liver. Journal of Hepatology, 51 (6) pp.1074~1081.
Müller, G., Norpoth, K., Kusters, E., Herweg, K., & Versin, E. (1978). Determination of thiodiglycolic acid in urine specimens of vinyl chloride exposed workers. International Archives of Occupational and Environmental Health, 41 (3) pp.199~205.
Mundt, K. A., Dell, L. D., Austin, R. P., Luippold, R. S., Noess, R., & Bigelow, C. (2000). Historical cohort study of 10109 men in the North American vinyl chloride industry, 1942–72, update of cancer mortality to 31 December 1995. Occupational and Environmental Medicine, 57 (11) pp.774~781.
Wolfson, N., Gavish, D., Matas, Z., Boaz, M., & Shargorodsky, M. (2012). Relation of Adiponectin to Glucose Tolerance Status, Adiposity, and Cardiovascular Risk Factor Load. Experimental Diabetes Research 250621 pp.10.
Pei, S. (1986). Study on the excretive regularity of thiodiglycolic acid in the urine of vinyl chloride exposed workers. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine], 20 (2) pp.87~89.
Pirastu, R., Baccini, M., Biggeri, A., & Comba, P. (2003). Epidemiological study of workers exposed to vinyl chloride in a Porto Marghera factory: Mortality update. Epidemiologia & Prevenzione, 27 pp.161~172.
Resnick, H. E., Jones, K., Ruotolo, G., Jain, A. K., Henderson, J., Lu, W., & Howard, B. V. (2003). Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic american indians: the Strong Heart Study. Diabetes Care, 26 (3) pp.861~867.
Stephen, A. (2008). Harrison. Insulin Resistance Among Patients With Chronic Hepatitis C: Etiology and Impact on Treatment. Clinical Gastroenterology and Hepatology, 6 (8) pp.864~876.
Tommaso, A., Dragani, A., & Zocchetti, C. (2008). Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma. Cancer Causes Control, 19 (10) pp. 1193~1200.
Cheng, T. J., Chou, P. Y., Huang, M. L., Du, C. L., Wong, R. H., & Chen, P.C. (2000). Increased lymphocyte sister chromatid exchange frequency in workers with exposure to low level of ethylene dichloride. Mutation Research, 470 (2) pp.109~114.
Viinanen, R. (1993). Monitoring Results of VC in a PVC plant in 1981–1993. Research Report No. 93025T, Porvoo: Neste Environmental and Industrial Hygiene Institute.
Ward, E., Boffetta, P., Andersen, A., Colin, D., Comba, P., Deddens, J.A., De Santis, M., Engholò, G., Hagmar, L., Langard, S., Lundberg, I., Mcelvenny, D., Pirastu, R., Sali, D., & Simonato, L. (2001). Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry. Epidemiology, 12 (6) pp.710~718.
Watanabe, P. G., McGowan, G. R., & Gehring, P. J. (1976). Fate of [14C]Vinyl Chloride after Single Oral Administration in Rats. Toxicology and Applied Pharmacology, 36 (2) pp. 399~352.
Wang, w., Qiu, Y. L., Jiao, J., Liu, J., Fang, J., Miao, W. B., Zhu, Y., & Xia, Z. L., (2011). Genotoxicity in vinyl chloride-exposed workers and its implication for occupational exposure limit. American Journal of Industrial Medicine, 54 (10) pp.800~810.
Wong, O., Chen, P. C., Du, L. C., Wang, J. D., & Cheng, T. J. (2002). An increased standardized mortality ratio for liver cancer among polyvinyl chloride workers in Taiwan. Occupational and Environmental Medicine, 59 (6) pp.405~409.
Wong, R.H., Chen, P.C., Wang, J.D., Du, C.L., & Cheng, T.J. (2003). Interaction of vinyl choride monomer exposure and hepatitis B viral infection on liver cancer. Journal of Occupational and Environmental Medicine, 45 (4) pp.379~383.
Lei, Y. C., Yang, H. T., Ma, Y. C., Huang, M. F., Wushou, P., Chang, T. J., Wong, R. H., Wang, J. D., Hsieh, L. L., Du, C. L., & Cheng, T. J. (1998). Effects on sister chromatid exchange frequency of aldehyde dehydrogenase 2 genotype and smoking in vinyl chloride workers. Mutation Research, 420 (1-3) pp.99~107.
Zhu, S. M., Ren, X. F., Wan, J. X., & Xia, Z. L. (2005). Evaluation in vinyl chloride monomer (VCM)-exposed workers and the relationship between liver lesions and gene polymorphisms of metabolic enzymes. World Journal of Gastroenterology, 11 (37) pp.5821~5827.
行政院勞委會勞工安全衛生研究所(2010)，「勞工作業環境空氣中有害物容許濃度標準」，行政院勞委會。
沈穎(2012)，「氯乙烯暴露工人之生物偵測指標開發研究」，國立成功大學環境醫學研究所碩士論文。