Title

聚氯乙烯工人慢性肝危害與基因多形性相關研究

Translated Titles

Association of VCM exposure, chronic liver diseases and genetic polymorphisms in polyvinyl chloride workers

DOI

10.6342/NTU.2004.00291

Authors

蕭舒庭

Key Words

肝硬化 ; CYP2E1 ; XRCC1 ; GSTT1 ; ALDH2 ; 脾腫大 ; 氯乙烯 ; 肝纖維化 ; vinyl chloride ; liver fibrosis ; cirrhosis ; spleno

PublicationName

臺灣大學職業醫學與工業衛生研究所學位論文

Volume or Term/Year and Month of Publication

2004年

Academic Degree Category

碩士

Advisor

鄭尊仁

Content Language

繁體中文

Chinese Abstract

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。

English Abstract

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.

Topic Category 醫藥衛生 > 預防保健與衛生學
公共衛生學院 > 職業醫學與工業衛生研究所
Reference
  1. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan. Lancet 1981; 2(8256):1129-33..
    連結:
  2. Cappelli E, Taylor R, Cevasco M, Abbondandolo A, Caldecott K, and Frosina G. Involvement of XRCC1 and DNA ligase III gene products in DNA base excision repair. J. Biol. Chem. 1997; 272(38):23970-23975.
    連結:
  3. Casse C, Hu YC, Ahrendt SA. The XRCC1 codon 399 allele is associated with adenine to guanine p53 mutation in non-small cell lung cancer. Munt. Res. 2003; 528:19-27.
    連結:
  4. Chen CJ, Liang KY, Chang AS, Chang YC, Lu SN, Liaw YF, Chang WY, Sheen MC, Lin TM. Effects of hepatitis B virus, alcohol, drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology. 1991; 13(3):398-406.
    連結:
  5. Chen DS, and Sung JL. Hepatitis B virus infection on Taiwan. N. Engl. J. Med. 1977; 297(12):668-669.
    連結:
  6. Chen WJ, Loh EW, Hsu YP, Chen CC, Yu JM, and Cheng AT. Alcohol-metabolising genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3 and ALDH2. Br. J. Psychiatry 1996; 168(6): 762-767.
    連結:
  7. Divine KK, Gilliland FD, Crowell RE, Stidley CA, Bocklage TJ, Cook DL, Belinsky SA. The XRCC 399 glutamine allele is a risk factor for adenocarcinoma of th lung. Mutat. Res. 2001; 461:273-278.
    連結:
  8. Donato F, Tagger A, Chiesa R, Ribero ML, Tomasoni V, Fasola M, Gelatti U, Portera G, Boffetta P, Nardi G. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy. Brescia HCC study. Hepatology. 1997; 26(3):579-84.
    連結:
  9. Dosanjh MK, Chenna A, Kim E, Fraenkel-Conrat H, Samson L, Singer B. All four known cyclic adducts formed in DNA by the vinyl chloride metabolite chloroacetaldehyde are released by a human DNA glycosylase. Proc. Natl. Acad. Sci. USA 1994; 91:1024-1028.
    連結:
  10. Du CL, Chan CC, and Wang JD. Comparison of personal and area sampling strategies in assessing worker’s exposure to vinyl chloride monomer. Bull. Environ. Contam. Toxicol. 1996; 56(4): 534-542,
    連結:
  11. Du CL, Wang JD. Increased morbidity odds ratio of primary liver cancer and cirrhosis of the liver among vinyl chloride monomer workers. Occup. Environ. Med. 1998; 55:528-532.
    連結:
  12. Duell EJ, Wiencke JK, Cheng TJ, Varkonyi A, Zuo ZF, Ashok TD, Mark EJ, Wain JC, Christiani DC, and Kelsey KT. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in humane blood mononuclear cells. Carcinogenesis 2000; 21(5):965-971.
    連結:
  13. Easter MD, Von BR. Toxicology update-vinyl chloride. J. Appl. Toxicol. 1994; 14:301-307.
    連結:
  14. el Ghissassi F, Barbin A, Bartsch H. Metabolic activation of vinyl chloride by rat liver microsomes:low-dose kinetics and involvement of cytochrome P450 2E1. Biochem Pharmacol. 1998; 55(9):1445-52.
    連結:
  15. Evans DM, Williams WJ, Kung IT. Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology. 1983; 7(3):377-88.
    連結:
  16. Farinati F, Cardin R, Degan P, Maria ND, Floyd RA, Thiel DHV, Naccarato R. Oxidative damage in circulating leukocytes occurs as an early event in chronic HCV infection. Free Rad. Biol. Med. 1999; 27:1284-1291.
    連結:
  17. Gedigk P, Muller R, Bechtelsheimer H. Morphology of liver damage among polyvinyl chloride production workers. A report of 51 cases. Ann N Y Acad Sci. 1975; 246:278-85.
    連結:
  18. Grabb DW, Edenberg HJ, Borson HW. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. J. Clin. Invest. 1989; 83314-316.
    連結:
  19. Guengerich FP. Roles of vinyl chloride oxidation productis 2-chlorooxirane and 2-chloriacetaldehyde in the vitro formation of etheno adducts of nucleic acid bases. Chem Res Toxicol. 1992; 5(1):2-5.
    連結:
  20. Hagen TM, Huang S, Curnutte J, Fowler P, Martinez V, Wwhr CM, Ames B N, Chisari FV. Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc. Natl. Acad. Sci. U. S. A. 1994; 91:12808-12812.
    連結:
  21. Harada S, and Zhang S. New strategy for detection of ALDH2 mutant. Alcohol Alcohol. 1993; 28(suppl 1A):11-13.
    連結:
  22. Hayashi S, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450 2E1 gene. J. Biochem. 1991; 110(4):559-565.
    連結:
  23. Heldaas SS, Langard SL, Andersen A. Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Ind Med. 1984; 41(1):25-30.
    連結:
  24. Ho SF, Phoon WH, Gan SL, Chan YK. Persistent liver dysfunction among workers at a vinyl chloride monomer polymerization plant. J Soc Occup Med. 1991; 41(1):10-6.
    連結:
  25. Hsiao TJ, Wang JD, Yang PM, Yang PM, Cheng TJ. Liver fibrosis in asymptomatic poly-vinyl chloride workers. (been accepted by JOEM)
    連結:
  26. Huang CY, Huang KL, Cheng TJ, Wang JD, Heish LL. The GSTT1 and CYP2E1 genotypes are possible factor causing vinyl chloride induced abnormal liver function. Arch Toxicol 1997; 71:482-488.
    連結:
  27. Kempkes M, Wiebel FA, Golka K, Heitmann P, and Bolt H M. Comparative genotyping and phenotyping og glutathione S-transferase GSTT1. Arch. Toxicol. 1996; 70:306-309.
    連結:
  28. Lelbach WK, A 25-years follow-up study of heavily exposed to vinyl chloride workers in Germany. Am. J. Ind. Med. 1996; 29:446-458.
    連結:
  29. Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology. 1988; 8(3):493-6.
    連結:
  30. Lilis R, Anderson H, Nicholson WJ, Daum S, Fischbein AS, Selikoff IJ. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann N Y Acad Sci. 1975; 246:22-41.
    連結:
  31. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, and Bell DA. XRCC1polymorphism: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res.1999; 59(11)2557-2561.
    連結:
  32. Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J. and de Murcia G. XRCC1 is specifically associated with poly (ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol. Cell. Biol. 1998; 18(6):3563-3571.
    連結:
  33. Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, Oda S, Katoh T. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003; 129(6):355-60.
    連結:
  34. Nelson HH, Wiencke JK, Christiani DC, Cheng TJ, Zuo ZF, Schwartz BS, Lee BK, Spitz MR, Wang M, Xu X, and Kelsey KT. Ethnic differences in the prevalence of homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis 1995; 16(5):1243-1245.
    連結:
  35. Pemble S, Schroder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, and Taylor JB. Human glutathions S-transferase theta (GSTT1):cDNA cloning and the characterization of a genetic polymorphism. Biochem. J. 1994; 300(Pt 1): 271-276.
    連結:
  36. Popper H, and Tomas LB. Alteration of liver and spleen among workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci. 1975; 246:172-194.
    連結:
  37. Rossit AR, Cabral IR, Hackel C, da Silva R, Froes ND, Abdel-Rahman SZ. Polymorphisms in the DNA repair gene XRCC1 and susceptibility to alcoholic liver cirrhosis in older southeastern Brazilians. Cancer Lett. 2002; 180(2):173-82.
    連結:
  38. Sheu JC, Wang JT, Wang TH, Wang CY, Yang PM, Huang GT, Shih LN, Lee HS, Chen DS. Prevalence of hepatitis C viral infection in a community in Taiwan detection by synthetic peptide-based assay and polymerase chain reaction. J Hepatol. 1993; 17(2):192-8.
    連結:
  39. Smith PM, Crossley IR, Williams DM. Portal hypertension in vinyl chloride production workers. Lancet 1976; 2(7986):602-4.
    連結:
  40. Smith SJ, Li Y, Whitley R, Marion MJ, Partilo S, Carney WP, Brandt-Rauf P W. Molecular epidemiology of p53 protein mutations in workers exposed to vinyl chloride. Am. J. Epidemiol. 1998; 147(3):302-308.
    連結:
  41. Stern MC, Umbach DM, Gils CHV, Lunn MR, Talor JA. DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev. 2001; 10:125-131.
    連結:
  42. Sturgis EM, Castillo EJ, Li L, Zheng R, Eicher SA, Clayman GL, Strom SS, Spitz M R, Wei Q. Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck. Carcinogenesis 1999; 20 (11):2125-2129.
    連結:
  43. Tamburro CH, Makk L, Popper H. Early hepatic histologic alterations among chemical (vinyl chloride) workers. Hepatology. 1984; 4(3):413-8.
    連結:
  44. Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, and Yin SJ. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am. J. Hum. Genet.1991; 48(4): 677-681.
    連結:
  45. Thompson LH, Brookman KW, Jones NJ, Allen SA, and Carrano AV. Molecular cloning of the human XRCC1 gene, which corrects effective DNA strand break repair and sister chromatide exchange. Mol. Cell. Biol. 1990; 10(12):6160-6171.
    連結:
  46. Ward E, Boffetta P, Colin D, Comba P, Deddens JA, De Santis M, Engholm G, Habmar L. Update of the follow-up of mortality and cancer incidence among European workers emplyed in vinyl chloride in vinyl chloride industry. Epidemiology 2001; 12:710-718,
    連結:
  47. Whysner J, Conaway CC, Verna L, and Willian GM. Vinyl chloride mechanistic data and risk assessment: DNA reactivity and cross-species quantitative risk extrapolation. Pharmacol. Ther. 1996; 71(1-2):7-28,.
    連結:
  48. Wong RH, Chen CP, Du CL, Wang JD, Cheng TJ. An increased standardized mortality ratio for liver cancer among polyvinyl chloride workers in Taiwan. Occup. Eviron. Med. 2002; 59:405-409
    連結:
  49. Wong RH, Chen PC, Wang JD, Du CL, Cheng TJ. Interaction of vinyl chloride monomer exposure and hepatitis B viral infection on liver cancer. JOEM 2003;45(4):379-383.
    連結:
  50. Wong RH, Wang JD, Hsieh LL, Cheng TJ. XRCC1, CYP2E1 and ALDH2 genetic polymorphisms and sister chromatid exchange frequency alterations amongst vinyl chloride monomer-exposed polyvinyl chloride workers. Arch Toxicol 2003; 77:433-440.
    連結:
  51. Wong RH, Yeh CY, Hsueh YM, Wang JD, Lei YC, Cheng TJ. Association of hepatitis virus infection, alcohol consumptionand plasma vitamin A levels with urinary 8-hydroxydeoxyguanosine in chemical workers. Mut. Res. 2003; 535:181-186.
    連結:
  52. World Health Organization Geneva Vinyl chloride. Environmental Health Criteria 215, 1999
    連結:
  53. Yeh FS, Yu MC, Mo CC, Luo S, Tong MJ, Henderson BE. Hepatitis B virus aflatoxins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res. 1989; 49(9):2506-9.
    連結:
  54. Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw YF, and Chen CJ. Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology 1995; 109(4): 1366-2173.
    連結:
  55. Yu MW, Yang SY, Pan IJ, Lin CL, Liu CJ, Liaw YF, Lin SM, Chen PJ, Lee SD, Chen CJ. Polymorphism in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. J. Nati. Can. Int. 2003; 95 (19):1485-1488.
    連結:
  56. Yu MW, You SL, Chang AS, Lu SN, Liaw YF, Chen CJ. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res. 1991; 51:5621-5625.
    連結:
  57. Zdzienicka MZ, van der Schans GP, Natarajan AT, Thompson LH, Neuteboom I, and Simons JWA. Chinese hamster ovary cell mutant (EM-C11) with sensitivity to simple alkylating agents and a very high level of sister chromatid exchange. Mutagenesis 1992; 7(4):265-269.
    連結:
  58. 台灣塑膠工業股份有限公司 工業減廢報告 1992
    連結:
  59. 行政院勞工委員會,勞工作業環境空氣中有害物質容鹵@度標準,中華名國84年。
    連結:
  60. 杜宗禮、詹長權、王榮德 聚氯乙烯場作業勞工職務暴露矩陣模式之建立。勞工安全衛生研究季刊 民國九十年六月 第九卷第二期 第151-166頁
    連結:
  61. 翁瑞宏 氯乙烯暴露工人世代研究 國立台灣大學職業醫學與工業衛生研究所 中華民國九十年六月
    連結:
  62. 蕭敦仁 一.台灣地區氯乙烯聚合工人之慢性肝臟危害 二.台灣地區氯乙烯聚合工人之Anti-p53抗體研究 國立台灣大學職業醫學與工業衛生研究所 中華民國八十七年六月
    連結:
  63. 楊培銘,楊培鎮,黃冠堂 彩色都卜勒超音波診斷肝門靜脈高血壓之價值。 中華民國消化系醫學會雜誌 10 (1):103, 1993
    連結:
  64. Barnes AW. Vinyl chloride and the production of PVC. Proc R Soc Med. 1976; 69(4):277-81.
  65. Benjamin Lewin. Genes VII, 2002
  66. Berk PD, Martin JF, Young RS, Creech J, Selikoff IJ, Falk H, Watanabe P, Popper H, Thomas L. Vinyl chloride-associated liver disease. Ann Intern Med. 1976; 84(6):717-31.
  67. Chen CJ, Yu MW, Liaw YF, Wang LW, Chiamprasert S, Matin F, Hirvonen A, Bell DA, and Santella RM. Chronic hepatitis B carriers with null genotypes of glutathione S-transferase M1 and T1 polymorphism who are exposed to alfatoxin are at increase risk of hepatocellular carcinoma. Am. J. Hum. Genet. 1996; 59(1):128-134.
  68. Creech JL, Johnson MN. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med. 1974; 16(3):150-1.
  69. Henery PH, Longo DL, Enlargement of lymph nodes and spleen. Harrison’s principle of internal medicine. 14th edi. 1997 chaper 61: p345-51
  70. Hsieh LL, Chien HT, Chen IH, Liao CT, Wang HM, Jung SM, Wang PF, Chang JT, Chen MC, Cheng AJ. The XRCC1 399Gln polymorphism and frequency of p53 mutations in Taiwanese oral squamous cell caecinomas. Cancer Epidemiol Biomarkers Prev. 2003; 12(5):439-43.
  71. Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, Kasai H. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res. 1994; 54:3171-3172.
  72. Wong RH, Du CL, Wang JD, Chan CC, Luo JCJ, and Cheng TJ. XRCC1 and CYP2E1 polymorphisms as susceptibility factor of plasma mutant p53 protein and anti-p53 antibody expression in vinyl chloride monomer-exposed polyvinyl chloride workers. Cancer Epid. Biom. Prev. 2002; 11:475-482.
  73. 竹原靖明、秋本申、木村邦夫 腹部超音波速成 合記圖書出版社發行