半導體業砷暴露作業勞工體內砷甲基化作用與氧化壓力研究

Study on Methylation Efficiency in Relation to Oxidative Stress in Semiconductor Workers Exposed to Arsenic

潘致弘(Chih-Hong Pan)；方亭予(Ting-Yu Fang)

砷 ； 無機砷代謝物 ； 體內砷甲基化作用 ； 半導體業勞工 ； 氧化壓力 ； Arsenic ； Inorganic arsenic metabolites ； Methylation efficiency ； Semiconductor workers ； Oxidative stress

勞動及職業安全衛生研究季刊

31卷2期（2023 / 06 / 20）

65 - 78

繁體中文;英文

本篇研究調查半導體業勞工體內之氧化壓力與砷暴露及體內砷甲基化作用之關聯性。研究對象可分成砷暴露組（n=427）及控制組（n=91）。其中砷暴露組由高暴露組之維護人員（n=149）以及低暴露組之生產人員（n=278）所組成。對照組則是由幾乎沒有或很少暴露於砷之行政人員（n=91）組成。職業暴露評估是透過量測受試者之尿液、頭髮及指甲中的砷濃度以瞭解受試者之砷暴露濃度。量化尿液中三價砷As(III)、五價砷As(V)、一甲基砷（monomethylarsonic acid, MMA）及二甲基砷（dimethylarsinic acid, DMA）以評估無機砷之內部劑量。量測尿液中8-羥基去氧鳥苷（8-OHdG）及丙二醛（MDA）評估氧化性DNA損傷及脂質過氧化。砷暴露組之尿液、頭髮及指甲中砷濃度顯著高於控制組（p值<0.05）。砷暴露組之尿液中砷、8-OHdG及MDA幾何平均濃度皆高於控制組。與對照組相比，暴露於砷的勞工其8-OHdG濃度有增加。此外，半導體業勞工其尿中8-OHdG濃度與尿中總砷之代謝物濃度（As（III）+As（V）+MMA+DMA）呈現正相關。而也發現砷暴露組的勞工其尿液樣本之8-OHdG濃度與尿液中MMA及主要體內砷甲基化指數（MMA與無機砷之比值）呈現正相關。然而，指甲和頭髮樣本對於量測由砷暴露所引起的氧化壓力之表現不如尿液樣本。相較於MDA，8-OHdG為更可靠之可評估體內砷甲基化之生物指標。而對於無機砷的職業暴露與半導體業勞工之氧化壓力增加有關。

This study examined associations between oxidative stress and arsenic (As) exposure and methylation efficiency in semiconductor workers. An As-exposed group (n = 427) and a control group (n = 91) were included. The As-exposure group (n = 427) included 149 maintenance staff members and 278 production staff members representing high As exposure and low As exposure, respectively. The control group included 91 administrative staff members with no or minimal As exposure. An occupational exposure assessment was conducted to assess personal As exposure by measuring As concentrations in urine, hair, and fingernails of the subjects. Urinary As(III), As(V), monomethylarsonic (MMA), and dimethylarsinic acid (DMA) were quantified to assess an internal dose of inorganic As. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured to asses oxidativeDNAdamage and lipid peroxidation, respectively. As concentrations in urine, hair, and fingernails significantly increased (p < 0.05) in the As-exposed group in comparison to the control group. Geometric mean urinary concentrations of As, 8-OHdG, and MDA in the As exposed group significantly exceeded those in the control group. As exposure to As-exposed workers had increased concentrations of 8-OHdG in contrast to those in control subjects. Moreover, urinary 8 OHdG concentrations in the semiconductor workers were positively correlated with urinary total As metabolite (As(III) + As(V) + MMA + DMA) concentrations. Furthermore, urinary excretion of 8 OHdG concentrations in As-exposed workers were positively associated with urinary excretion of MMA concentrations and primary methylation index values (the ration of MMA/inorganic As). However, fingernail and hair samples did not perform as well as urinary samples to measure oxidative stress induced by As exposure. 8-OHdG could serve as a more reliable biomarker for assessing As methylation than MDA did. Occupational exposure to inorganic As was associated with increased oxidative stress among semiconductor workers.

1. Abdulrahman, F.I.,Akan, J.C.,Chellube, Z.M.,Waziri, M.(2012).Levels of Heavy Metals in Human Hair and Nail Samples from Maiduguri Metropolis, Borno State, Nigeria.World Environ.,2,81-89.
2. Aposhian, H.V.,Gurzau, E.S.,Le, X.C.,Gurzau, A.,Healy, S.M.,Lu, X.,Ma, M.,Yip, L.,Zakharyan, R.A.,Maiorino, R.M.(2002).Occurrence of monomethylarsonous acid in urine of human exposed to inorganic arsenic.Chem. Res. Toxicol.,13,693-697.
3. Apostoli, P.,Bartoli, D.,Alessio, L.,Buchet, J.P.(1999).Biological monitoring of occupational exposure to inorganic arsenic.Occup. Environ. Med.,56,825-832.
4. Byun, K.,Won, Y.L.,Hwang, Y.I.,Koh, D.H.,Im, H.,Kim, E.A.(2013).Assessment of arsenic exposure by measurement of urinary speciated inorganicarsenic metabolites in workers in a semiconductor manufacturing plant.Ann. Occup. Environ. Med.,25,21.
5. Chen, Y.C.,Guo, Y.L.,Su, H.J.,Hsueh, Y.M.,Smith, T.J.,Ryan, L.M.,Lee, M.S.,Chao, S.C.,Lee, J.Y.,Christiani, D.C.(2003).Arsenic methylation and skin cancer risk in southwestern Taiwan.J. Occup. Environ. Med.,45,241-248.
6. Chen, Y.C.,Su, H.J.,Guo, Y.L.,Hsueh, Y.M.,Smith, T.J.,Ryan, L.M.,Lee, M.-S.,Christiani, D.(2003).Arsenic methylation and bladder cancer risk in Taiwan.Cancer Causes Control,14,303-310.
7. De Peyster, A.,Silvers, J.A.(1995).Arsenic levels in hair of workers in a semiconductor fabrication facility.Am. Ind. Hyg. Assoc. J.,56,377-383.
8. Erhola, M.,Toyokuni, S.,Okada, K.,Tanaka, T.,Hiai, H.,Ochi, H.,Uchida, K.,Osawa, T.,Nieminen, M.M.,Alho, H.(1997).Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2' -deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment.FEBS Lett.,409,287-291.
9. Fujino, Y.,Guo, X.,Liu, J.,Matthews, I.P.,Shirane, K.,Wu, K.,Kasai, H.,Miyatake, M.,Tanabe, K.,Kusuda, T.(2005).Chronic arsenic exposure and urinary 8-hydroxy-2' deoxyguanosine in an arsenic- effected area in inner Mongolia, China.Expo. Annal. Environ. Epidemiol.,15,147-152.
10. Ghatak, S.,Biswas, A.,Dhali, G.K.,Chowdhury, A.,Boyer, J.L.,Santra, A.(2011).Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice.Toxicol. Appl. Pharmacol.,251,59-69.
11. He, Y.,Zhang, R.,Song, X.,Shang, L.,Wu, X.,Huang, D.(2018).Inorganic arsenic exposure increased expression of Fas and Bax gene in vivo and vitro.Gene,671,135-141.
12. Hsueh, Y.M.,Chiou, H.Y.,Huang, Y.L.,Wu, W.L.,Huang, C.C.,Yang, M.H.,Lue, L.C.,Chen, G.S.,Chen, C.J.(1997).Serum _-carotene level arsenic methylation capability and incidence of skin cancer.Cancer Epidemol. Biomark. Prev.,6,589-596.
13. Hsueh, Y.M.,Hsu, M.K.,Chiou, H.Y.,Yang, M.H.,Huang, C.C.,Chen, C.J.(2002).Urinary arsenic speciation in subjects with or without restriction from seafood dietary intake.Toxicol. Lett.,133,83-91.
14. Hu, C.W.,Cooke, M.S.,Tsai, Y.H.,Chao, M.R.(2015).8-Oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-20-deoxyguanosine concentrations in various human body fluids: Implications for their measurement and interpretation.Arch. Toxicol.,89,201-210.
15. Hu, C.W.,Pan, C.H.,Huang, Y.L.,Wu, M.T.,Chang, L.W.,Wang, C.J.,Chao, M.R.(2006).Effects of arsenic exposure among semiconductor workers: Acautionary note on urinary 8-oxo-7,8-dihydro-2' -deoxyguanosine.Free Radic. Biol. Med.,40,1,273-1,278.
16. Hu, C.W.,Wang, C.J.,Chang, L.W.,Chao, M.R.(2006).Clinical-scale high-throughput analysis of urinary 8-oxo-7,8-dihydro-2' -deoxyguanosine by isotope-dilution liquid chromatography-tandem mass spectrometry with on-line solid phase extraction.Clin. Chem.,52,1,381-1,388.
17. Huang, Y.L.,Hsueh, Y.M.,Huang, Y.K.,Yip, P.K.,Yang, M.H.,Chen, C.J.(2009).Urinary arsenic methylation capability and carotid atherosclerosis risk in subjects living in arsenicosis-hyperendemic areas in southwestern Taiwan.Sci. Total Environ.,407,2,608-2,614.
18. Hwang, Y.H.,Lee, Z.Y.,Wang, J.D.,Hsueh, Y.M.,Lu, I.C.,Yao, W.L.(2002).Monitoring of arsenic exposure with speciated urinary inorganic arsenic metabolites for ion implanter maintenance engineers.Environ. Res.,90,207-216.
19. Kasai, H.,Crain, P.F.,Kuchino, Y.,Nishimura, S.,Ootsuyama, A.,Tanooka, H.(1986).Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair.Carcinogenesis,7,849-851.
20. Kitchin, K.T.(2001).Recent advances in arsenic carcinogenesis: Modes of action, animal model systems, and methylated arsenic metabolites.Toxicol. Appl. Pharmacol.,172,249-261.
21. Kosugi, H.,Enomoto, H.,Ishizuka, Y.,Kikugawa, K.(1994).Variations in the level of thiobarbituric acid reactant in health humans under different physiological conditions.Biol. Pharm. Bull.,17,1,645-1,650.
22. Kumar, A.,Kaundal, R.K.,Iyer, S.,Sharma, S.S.(2007).E_ects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy.Life Sci.,80,1,236-1,244.
23. Langård, S.,Gundersen, N.,Tsalev, D.L.,Gylseth, B.(1978).Whole blood chromium level and chromium excretion in the rat after zinc chromate inhalation.Acta Pharmacol. Toxicol.,42,142-149.
24. Li, X.,Pi, J.,Li, B.,Xu, Y.,Jin, Y.,Sun, G.(2008).Urinary arsenic speciation and its correlation with 8-OHdG in Chinese residents exposed to arsenic through coal burning.Bull. Environ. Contam. Toxicol.,81,406-411.
25. Lo_redo, C.A.,Aposhian, H.V.,Cebrian, M.E.,Yamauchi, H.,Silbergeld, E.K.(2003).Variability in human metabolism of arsenic.Environ. Res.,92,85-91.
26. Morton, J.,Leese, E.(2011).Arsenic speciation in clinical samples: Urine analysis using fast micro-liquid chromatography ICP-MS.Anal. Bioanal. Chem.,399,1781-1788.
27. Pan, C.H.,Chan, C.C.,Wu, K.Y.(2008).E_ects on Chinese restaurant workers of exposure to cooking oil fumes: A cautionary note on urinary 8-Hydroxy-2' -Deoxyguanosine.Cancer Epidemiol. Biomark. Prev.,17,3,351-3,357.
28. Park, D.,Yang, H.,Jeong, J.,Ha, K.,Choi, S.,Kim, C.,Yoon, C.,Park, D.,Paek, D.(2010).A comprehensive review of arsenic levels in the semiconductor manufacturing industry.Ann. Occup. Hyg.,54,869-879.
29. Ramos, O.,Carrizales, L.,Yáñez, L.,Mejia, J.,Batres, L.,Ortiz, D.,Diaz-Barriga, F.(1995).Arsenic increased lipidperoxidation in rat tissues by a mechanism independent of glutathione levels.Environ. Health Perspect.,103(Suppl. 1),85-88.
30. Singh, B.,Kulawiec, M.,Owens, K.M.,Singh, A.,Singh, K.K.(2016).Sustained Early Disruption of Mitochondrial Function Contributes to Arsenic-Induced Prostate Tumorigenesis.Biochemistry (Mosc.),81,1,089-1,100.
31. Takeuchi, T.,Matsugo, S.,Morimoto, K.(1997).Mutagenicity of oxidative DNA damage in Chinese hamster V79 cells.Carcinogenesis,18,2,051-2,055.
32. Toraason, M.,Hayden, C.,Marlow, D.,Rinehart, R.,Mathias, P.,Werren, D.,DeBord, D.G.,Reid, T.M.(2001).DNA strand breaks, oxidative damage, and 1-OH pyrene in roofers with coal-tar pitch dust and/or asphalt fume exposure.Int. Arch. Occup. Environ. Health,74,396-404.
33. Vahter, M.(1999).Methylation of inorganic arsenic in di_erent mammalian species and population groups.Sci. Prog.,821,69-88.
34. Weimann, A.,Belling, D.,Poulsen, H.E.(2002).Quantification of 8-oxo-guanine and guanine as the nucleobase, nucleoside and deoxynucleoside forms in human urine by high-performance liquid chromatography-electrospray tandem mass spectrometry.Nucleic Acids Res.,30,e7.
35. Wen, J.,Wen, W.,Li, L.,Liu, H.(2012).Methylation capacity of arsenic and skin lesions in smelter plant workers.Environ. Toxicol. Pharmacol.,34,624-630.
36. Williams, M.E.(Ed.),Baldwin, D.G.(Ed.)(1994).Semiconductor Industrial Hygiene Handbook.Park Ridge, NJ, USA:Noyes.
37. Yager, J.W.,Hicks, J.B.,Fabianova, E.(1997).Airborne arsenic and urinary excretion of arsenic metabolites during boiler cleaning operations in a Slovak coal-fired power plant.Environ. Health Perspect.,105,836-842.
38. Zaprianov, Z.,Tsalev, D.,Georgieva, R.,Kaloianova, F.,Nikolova, V.(1989).New toxicokinetic exposure tests for metals based on atomic absorption analysis of the fingernails.Probl. Khigi.,14,75-97.