研究背景與目的：
過去，台灣西南沿海地區居民飲用含高濃度無機砷之地下水，引起烏腳病及許多健康危害之流行，現已知暴露於高濃度的無機砷會增加許多慢性疾病發生的風險，如癌症、心血管疾病、糖尿病、神經病變等；且砷引起血管增生、阻塞之病變，亦與許多眼疾之發生有關。然而全球失明的第二主要因素青光眼，為視神經萎縮、損壞之疾病，其明確的致病機轉目前仍不清楚，但供應視神經養分的血管之病變可能影響視神經的健康。且尚未有相關文獻探討砷暴露與青光眼之相關性。
雖然台灣已普遍不再飲用地下水，但仍有許多人民飽受砷的慢性效應影響著健康，而世界各地仍有許多國家暴露於地下水含高濃度砷的危險之下，因此砷引起的健康效應仍值得關切。青光眼為全球失明的第二主因，盛行率亦逐年攀升，釐清其致病機轉遏止流行與預防極為重要。此篇研究目的為使用族群回溯性世代追蹤研究資料，欲探討過去曾飲用高濃度砷地下水之居民是否與其後續青光眼之發生有關。
材料與方法：
研究設計為回溯性世代追蹤研究。研究對象選取自台灣健康保險資料庫2000年承保抽樣百萬歸人檔(LHID2000)其年齡大於40歲者，排除在1998年前青光眼盛行之個案，後續進一步追蹤研究對象青光眼的發生。而研究對象砷暴露的評估則利用1974至1976年台灣全省311個鄉鎮水井調查地下水砷濃度的環境監測數據作為依據；並且使用ArcGIS軟體以鄉鎮為單位繪製熱點。統計方法則使用Kaplan Meier(K-M)方法繪製暴露與非暴露兩組之青光眼存活曲線，並以對數等級檢定(Log-rank test) 進行檢定；最後使用Cox比例風險回歸校正潛在之干擾因子，獲得高濃度砷暴露地區相較於低濃度砷暴露地區，發生青光眼之危險性比值(Hazard ratio, HR )。
結果：
365,894位研究世代中，有5,244人在研究期間發生青光眼，發生率為1.43%。而居住於地下水含高濃度砷之107,840位研究對象，有1,562位確診青光眼。暴露組之平均年齡、性別、月收入、居住地都市化程度、及共病症如：糖尿病、高血壓、腦中風、冠狀動脈疾病、高血脂症、動脈粥狀硬化、周邊血管疾病、腎臟疾病…等的分布情形與非暴露組達統計上的顯著差異。後續以Log Rank test檢定暴露與非暴露兩組青光眼發生之情形，亦達統計上之顯著差異。最後利用Cox比例風險回歸再校正潛在之干擾因子後，暴露組相較於非暴露組其發生青光眼之HR為1.13 (95% CI, 1.06-1.21)。

Background:
Arsenic is a naturally occurring metalloid that exists in inorganic as well as organic forms and often transported by groundwater. The association between arsenic exposure and the development of cancers and chronic diseases has been noted in humans since many years ago, such as vascular disease, neuropathy, and diabetes. Furthermore, arsenic toxicity may cause proliferation, and occlusion of vascular, which is associated with many eye diseases. Glaucoma is the second-leading of blindness and a complicated eye disease in which damage to the optic nerve leads to progressive, irreversible vision loss. Although the mechanism of glaucoma remains unclear, microangiopathy and insufficiency of blood flow may play an important role of optic nerve damage and there was no study to investigate the association between arsenic exposure and glaucoma.
However, there are many people suffer from the health effects of arsenic exposure in drinking water, and the prevalence of the second-leading of blindness, glaucoma, increases year after year. It’s important to clarify the cause of glaucoma. Therefore, arsenic exposure might be a risk factor for glaucoma. We conducted a study in Taiwan to evaluate the association between arsenic in drinking water and glaucoma.
Materials and Methods:
We conducted a retrospective cohort study of whose age is more than 40 years old and had no glaucoma before 1998 in the Longitudinal Health Insurance Database 2000 (LHID2000), which contains claim data on a random sample of one million residents in Taiwan. We adopted measurement data on 311 townships obtained by a nationwide survey of drinking water to assess arsenic levels for each subject and used ArcGIS to draw hot spot maps of exposure down to the township level. In addition, we followed the cohort member to assess the incidence of glaucoma from the index date and analyzed the difference of incidence among exposure group and non-exposure group by plotting Kaplan–Meier survival curves and conducting log-rank tests. Cox proportional hazard models were used to calculate the hazard ratio (HR) associated with arsenic exposure and adjust for the effects of potential confounders.
Results:
Of the study cohort, 365894 subjects, 5244 diagnosed OAG during the study period, including 1562 from the exposure group and 2082 from non-exposure group, and the incidence rate of OAG is 1.43%. Between exposure group and non-exposure group, the age, gender, and comorbidity such as DM, hypertension, Stroke, CAD, stroke, hyperlipidemia, Atherosclerosis, PVD, CKD are significance difference. And the incidence rate among these two group is also difference by log rank test. Furthermore, after adjusting for potential confounders, the HR for OAG was 1.13 (95% CI 1.06-1.21) in the exposure group in comparison with the non-exposure group.

Agahian B, Lee J, Nelson J, Johns R. 1990. Arsenic levels in fingernails as a biological indicator of exposure to arsenic. American Industrial Hygiene Association journal 51:646-651.
Antonova AI, Vasilenko IV. 1989. [pathogenetic mechanisms of optic nerve lesions in acute vascular optic neuropathies]. Vestnik oftalmologii 105:7-10.
ATSDR. 2007. Toxicological profile for arsenic.
Bencko V, Fabianova E, Franek P, Gotzl M, Rames J. 2006. Non-melanoma skin cancer incidence in relation to arsenic exposure - 20 years of observation:Springer, Po Box 17, 3300 Aa Dordrecht, Netherlands.
Chen CJ, Chuang YC, Lin TM, Wu HY. 1985. Malignant neoplasms among residents of a blackfoot disease endemic area in taiwan - high-arsenic artesian well water and cancers. Cancer Research 45:5895-5899.
Chen CJ, Chuang YC, You SL, Lin TM, Wu HY. 1986. A retrospective study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in taiwan. British Journal of Cancer 53:399-405.
Chen CJ, Kuo TL, Wu MM. 1988. Arsenic and cancers. Lancet 1:414-415.
Chen CJ, Chen CW, Wu MM, Kuo TL. 1992. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking-water. British Journal of Cancer 66:888-892.
Chen CJ, Hsueh YM, Lai MS, Shyu MP, Chen SY, Wu MM, et al. 1995. Increased prevalence of hypertension and long-term arsenic exposure. Hypertension 25:53-60.
Chen CJ, Chiou HY, Chiang MH, Lin LJ, Tai TY. 1996. Dose-response relationship between ischemic heart disease mortality and long-term arsenic exposure. Arteriosclerosis Thrombosis and Vascular Biology 16:504-510.
Chen CL, Hsu LI, Chiou HY, Hsueh YM, Chen SY, Wu MM, et al. 2004. Ingested arsenic, cigarette smoking, and lung cancer risk - a follow-up study in arseniasis-endemic areas in taiwan. Jama-Journal of the American Medical Association 292:2984-2990.
Chen Y, Wu F, Liu M, Parvez F, Slavkovich V, Eunus M, et al. 2013. A prospective study of arsenic exposure, arsenic methylation capacity, and risk of cardiovascular disease in bangladesh. Environmental Health Perspectives 121:832-838.
Cheng T-J, Ke D-S, Guo H-R. 2010. The association between arsenic exposure from drinking water and cerebrovascular disease mortality in taiwan. Water Research 44:5770-5776.
Chhuttan.Pn, Chawla LS, Sharma TD. 1967. Arsenical neuropathy. Neurology 17:269-&.
Chiang HS, Guo HR, Hong CL, Lin SM, Lee EF. 1993. The incidence of bladder-cancer in the black foot disease endemic area in taiwan. British Journal of Urology 71:274-278.
Chiou HY, Hsueh YM, Liaw KF, Horng SF, Chiang MH, Pa YS, et al. 1995. Incidence of internal cancers and ingested inorganic arsenic - a 7-year follow-up-study in taiwan. Cancer Research 55:1296-1300.
Chiou HY, Huang WI, Su CL, Chang SF, Hsu YH, Chen CJ. 1997. Dose-response relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 28:1717-1723.
Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, et al. 2005. Endothelial function and dysfunction. Part i: Methodological issues for assessment in the different vascular beds: A statement by the working group on endothelin and endothelial factors of the european society of hypertension. Journal of hypertension 23:7-17.
Depeyster A, Silvers JA. 1995. Arsenic levels in hair of workers in a semiconductor fabrication facility. American Industrial Hygiene Association Journal 56:377-383.
Ellinsworth DC. 2015. Arsenic, reactive oxygen, and endothelial dysfunction. The Journal of pharmacology and experimental therapeutics 353:458-464.
EPA ROC. 2013. Groundwater pollution control standard.
EPA ROC. 2014. Drinking water regulations.
EPA US. 1984. Health assessment document for inorganic arsenic. Washington, DC.
EPA US. 2002. Integrated risk information system (iris) on arsenic. Washington, DC.
Ferreccio C, Gonzalez C, Milosavjlevic V, Marshall G, Sancha AM, Smith AH. 2000. Lung cancer and arsenic concentrations in drinking water in chile. Epidemiology 11:673-679.
Flammer J, Orgul S. 1998. Optic nerve blood-flow abnormalities in glaucoma. Progress in Retinal and Eye Research 17:267-289.
Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. 2002. The impact of ocular blood flow in glaucoma. Progress in Retinal and Eye Research 21:359-393.
Flanagan SV, Johnston RB, Zheng Y. 2012. Arsenic in tube well water in bangladesh: Health and economic impacts and implications for arsenic mitigation. Bull World Health Organ 90:839-846.
Galassi F, Sodi A, Ucci F, Harris A, Chung HS. 1998. Ocular haemodynamics in glaucoma associated with high myopia. International Ophthalmology 22:299-305.
GRF. What is glaucoma.
Hamard P, Hamard H, Dufaux J, Quesnot S. 1994. Optic-nerve head blood-flow using a laser-doppler velocimeter and hemorheology in primary open-angle glaucoma and normal-pressure glaucoma. British Journal of Ophthalmology 78:449-453.
Hayreh SS. 1999. Retinal and optic nerve head ischemic disorders and atherosclerosis: Role of serotonin. Prog Retin Eye Res 18:191-221.
Hopenhayn-Rich C, Biggs ML, Smith AH. 1998. Lung and kidney cancer mortality associated with arsenic in drinking water in cordoba, argentina. International Journal of Epidemiology 27:561-569.
HopenhaynRich C, Biggs ML, Fuchs A, Bergoglio R, Tello EE, Nicolli H, et al. 1996. Bladder cancer mortality associated with arsenic in drinking water in argentina. Epidemiology 7:117-124.
Hsu W-M. 2011. Epidemiology of eye diseases among ethnic chinese: Data from the shihpai eye study. Journal of Experimental & Clinical Medicine 3:166-170.
Hsueh Y-M, Chung C-J, Shiue H-S, Chen J-B, Chiang S-S, Yang M-H, et al. 2009. Urinary arsenic species and ckd in a taiwanese population: A case-control study. American Journal of Kidney Diseases 54:859-870.
Hsueh YM, Chiou HY, Huang YL, Wu WL, Huang CC, Yang MH, et al. 1997. Serum beta-carotene level, arsenic methylation capability, and incidence of skin cancer. Cancer Epidemiol Biomarkers Prev 6:589-596.
IARC. 2012. Arsenic and arsenic compounds.
Kaimbo DK, Buntinx F, Missotten L. 2001. Risk factors for open-angle glaucoma: A case-control study. Journal of clinical epidemiology 54:166-171.
Karagas MR, Morris JS, Weiss JE, Spate V, Baskett C, Greenberg ER. 1996. Toenail samples as an indicator of drinking water arsenic exposure. Cancer Epidemiol Biomarkers Prev 5:849-852.
Kleiman NJ, Quinn AM, Fields KG, Slavkovich V, Graziano JH. 2016. Arsenite accumulation in the mouse eye. Journal of toxicology and environmental health Part A 79:339-341.
Koban Y, Bilgin G, Cagatay H, Bitargil M, Ozlece H, Ekinci M, et al. 2014. 'The association of normal tension glaucoma with buerger's disease: A case report'. BMC ophthalmology 14:130.
Lagerkvist BEA, Linderholm H, Nordberg GF. 1988. Arsenic and raynauds-phenomenon - vasospastic tendency and excretion of arsenic in smelter workers before and after the summer vacation. International Archives of Occupational and Environmental Health 60:361-364.
Lai MS, Hsueh YM, Chen CJ, Shyu MP, Chen SY, Kuo TL, et al. 1994. Ingested inorganic arsenic and prevalence of diabetes-mellitus. American Journal of Epidemiology 139:484-492.
Leske MC, Connell AMS, Wu SY, Hyman LG, Schachat AP, Leske MC, et al. 1995. Risk-factors for open-angle glaucoma - the barbados eye study. Archives of Ophthalmology 113:918-924.
Lin S, Singh K, Lin SC. 2015. Association between body levels of trace metals and glaucoma prevalence. JAMA Ophthalmology 133:1144-1150.
Lin W, Wang S-L, Wu H-J, Chang K-H, Yeh P, Chen C-J, et al. 2008. Associations between arsenic in drinking water and pterygium in southwestern taiwan. Environmental Health Perspectives 116:952-955.
Liu CH, Su WW, Shie SS, Cheng ST, Su CW, Ho WJ. 2016. Association between peripheral vascular endothelial function and progression of open-angle glaucoma. Medicine (Baltimore) 95:e3055.
Liu J, Zheng BS, Aposhian HV, Zhou YS, Chen ML, Zhang AH, et al. 2002. Chronic arsenic poisoning from burning high-arsenic-containing coal in guizhou, china. Environmental Health Perspectives 110:119-122.
Lubin JH, Pottern LM, Stone BJ, Fraumeni JF. 2000. Respiratory cancer in a cohort of copper smelter workers: Results from more than 50 years of follow-up. American Journal of Epidemiology 151:554-565.
Lubin JH, Moore LE, Fraumeni JF, Jr., Cantor KA. 2008. Respiratory cancer and inhaled inorganic arsenic in copper smelters workers: A linear relationship with cumulative exposure that increases with concentration. Environmental Health Perspectives 116:1661-1665.
Marshall G, Ferreccio C, Yuan Y, Bates MN, Steinmaus C, Selvin S, et al. 2007. Mw-year study of lung and bladder canceir mortality in chile related to arsenic in drinking water. Journal of the National Cancer Institute 99:920-928.
Meliker JR, Wahl RL, Cameron LL, Nriagu JO. 2007. Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in michigan: A standardized mortality ratio analysis. Environmental Health 6.
Milham S, Strong T. 1974. Human arsenic exposure in relation to a copper smelter. Environ Res 7:176-182.
MOI. 2015. Statistical yearbook of interior.
Moon K, Guallar E, Navas-Acien A. 2012. Arsenic exposure and cardiovascular disease:An updated systematic review. Current Atherosclerosis Reports 14:542-555.
Moore D, Harris A, Wudunn D, Kheradiya N, Siesky B. 2008. Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma? Clinical ophthalmology (Auckland, NZ) 2:849-861.
Mostafa MG, McDonald JC, Cherry NM. 2008. Lung cancer and exposure to arsenic in rural bangladesh. Occupational and Environmental Medicine 65:765-768.
NEI. Facts about glaucoma.
NIOSH. 2010. All workplace safety & health topics, chemicals, arsenic, niosh pocket guide to chemical hazards
Nita M, Grzybowski A. 2016. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxidative medicine and cellular longevity 2016:3164734.
Ohguro I, Ohguro H, Ohta T, Nakazawa M. 2006. A case of normal tension glaucoma associated with buerger's disease. The Tohoku journal of experimental medicine 209:49-52.
OSHA US. 1998. Occupational safety and health standards, toxic and hazardous substances, inorganic arsenic substance information sheet.
Reynolds DC. 1977. Relative risk-factors in chronic open-angle glaucoma - epidemiological-study. American Journal of Optometry and Physiological Optics 54:116-120.
See LC, Chiou HY, Lee JS, Hsueh YM, Lin SM, Tu MC, et al. 2007. Dose-response relationship between ingested arsenic and cataracts among residents in southwestern taiwan. J Environ Sci Health Part A-Toxic/Hazard Subst Environ Eng 42:1843-1851.
Smedley PL, Kinniburgh DG. 2002. A review of the source, behaviour and distribution of arsenic in natural waters. Applied Geochemistry 17:517-568.
Smith AH, Goycolea M, Haque R, Biggs ML. 1998. Marked increase in bladder and lung cancer mortality in a region of northern chile due to arsenic in drinking water. American Journal of Epidemiology 147:660-669.
Su WW, Cheng ST, Ho WJ, Tsay PK, Wu SC, Chang SH. 2008. Glaucoma is associated with peripheral vascular endothelial dysfunction. Ophthalmology 115:1173-1178.e1171.
Suhendrayatna, Ohki A, Nakajima T, Maeda S. 2001. Metabolism and organ distribution of arsenic in the freshwater fish tilapia mossambica. Applied Organometallic Chemistry 15:566-571.
Takatsu A. 1998. Abnormal arsenic accumulation by fish living in a naturally acidified lake[dagger]. Analyst 123:73-75.
Takatsu A, Kuroiwa T, Uchiumi A. 1999. Arsenic accumulation in organs of the fresh water fish tribolodon hakonensis. Journal of Trace Elements in Medicine and Biology 13:176-179.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. 2014. Global prevalence of glaucoma and projections of glaucoma burden through 2040 a systematic review and meta-analysis. Ophthalmology 121:2081-2090.
Tham YC, Cheng CY. 2016. Associations between chronic systemic diseases and primary open angle glaucoma: An epidemiological perspective. Clinical & experimental ophthalmology.
Tondel M, Rahman M, Magnuson A, Chowdhury IA, Faruquee MH, Ahmad SA. 1999. The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in bangladesh. Environmental Health Perspectives 107:727-729.
Tsai SY, Chou HY, The HW, Chen CM, Chen CJ. 2003. The effects of chronic arsenic exposure from drinking water on the neurobehavioral development in adolescence. Neurotoxicology 24:747-753.
Tseng CH, Tai TY, Chong CK, Tseng CP, Lai MS, Lin BJ, et al. 2000. Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: A cohort study in arseniasis-hyperendemic villages in taiwan. Environmental Health Perspectives 108:847-851.
Valentine JL, Kang HK, Spivey G. 1979. Arsenic levels in human-blood, urine, and hair in response to exposure via drinking-water. Environ Res 20:24-32.
von Ehrenstein OS, Poddar S, Yuan Y, Mazumder DG, Eskenazi B, Basu A, et al. 2007. Children's intellectual function in relation to arsenic exposure. Epidemiology 18:44-51.
Wang CH, Jeng JS, Yip PK, Chen CL, Hsu LI, Hsueh YM, et al. 2002. Biological gradient between long-term arsenic exposure and carotid atherosclerosis. Circulation 105:1804-1809.
Wasserman GA, Liu X, Parvez F, Ahsan H, Factor-Litvak P, Kline J, et al. 2007. Water arsenic exposure and intellectual function in 6-year-old children in araihazar, bangladesh. Environmental Health Perspectives 115:285-289.
Wax MB. 2011. The case for autoimmunity in glaucoma. Experimental eye research 93:187-190.
WHO. 2004. Glaucoma is second leading cause of blindness globally.
WHO. 2011. Guidelines for drinking-water quality.
WRA. 2014. Water resources demand and supply.
Wu MM, Kuo TL, Hwang YH, Chen CJ. 1989. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. American Journal of Epidemiology 130:1123-1132.
Yan DB, Coloma FM, Metheetrairut A, Trope GE, Heathcote JG, Ethier CR. 1994. Deformation of the lamina-cribrosa by elevated intraocular-pressure. British Journal of Ophthalmology 78:643-648.
Yoshinaga J, Chatterjee A, Shibata Y, Morita M, Edmonds JS. 2000. Human urine certified reference material for arsenic speciation. Clin Chem 46:1781-1786.
Yu H-S, Liao W-T, Chai C-Y. 2006. Arsenic carcinogenesis in the skin. Journal of Biomedical Science 13:657-666.
葉崇明. 2005. 臺灣西南地區視網膜病變之盛行率及其與砷暴露的相關性:國立成功大學.