全台灣有五十萬以上的居民曾經飲用含砷量超過0.05 ppm的水，且根據台灣、墨西哥、智利以及美國的許多研究已經發現無機砷的暴露會增加皮膚癌、膀胱癌、腎臟癌以及肺癌的發生率，因此砷的健康效應乃是公共衛生的重要課題。在無機砷的致癌機轉部分，有研究指出在細胞實驗中，無機砷會促使細胞改變以及腫瘤發展，並會調節mitogen-activated protein kinase一連串的反應，進而促使上皮生長因子受器過度表現。近年來台灣地區雖然有不少研究在探討砷暴露和泌尿道癌症的相關性，但大多是針對西南烏腳病地區和蘭陽盆地做劑量效應的探討，而且沒有較具特異性的生物指標。因此本研究擴大研究範圍，探討全台灣飲水含砷量和泌尿道癌症（包括膀胱、腎臟、輸尿管、尿道以及前列腺癌）的相關性，並評估用上皮生長因子受器當作砷暴露生物指標的可行性。
　　在飲水含砷量部分，本研究採用1976年政府所發表的井水砷濃度之測量報告，其中共包含有311個鄉鎮。此調查結果將水中砷濃度分成3組，分別為低於0.05 ppm、0.05-0.35 ppm以及高於0.35 ppm。泌尿道癌症死亡率則是收集1971年到2000年之全國死亡檔及人口檔資料庫，選取死於膀胱癌、腎臟癌、輸尿管癌、尿道癌及前列腺癌的人，並使用多變項線性回歸模式，分析飲水含砷量和泌尿道癌症的劑量效應關係。
　　此外，我們收集某教學醫院之住院病人作為研究族群，並同時尋找來院健檢的病人當作對照組，針對性別、年齡，以及抽煙等可能的干擾因子進行配對之後，評估上皮生長因子受器表現量與泌尿道癌症之關係，並比較不同病理組織診斷病患血清上皮生長因子受器之濃度，用Wilcoxon rank sum test來分析結果是否有達統計學上顯著性。血清中上皮生長因子受器是以酵素結合免疫吸附分析法測量其表現量，所有數據分析是使用SAS 8.1版統計軟體檢定。
　　在劑量效應關係研究中，共有8649名男性及4829名女性死亡泌尿道癌，另外還有4891名男性死於前列腺癌。在調整年齡並以最低砷濃度組作為參考，發現到飲水含砷量高於0.35ppm會增加泌尿道癌死亡率，不論男性或是女性都有達到統計顯著相關，但飲水含砷量在0.05-0.35 ppm則無此相關。在前列腺癌，不論是在飲水含砷量高於0.35ppm或是在0.05-0.35 ppm都沒有相關。
　　在上皮生長因子受器研究中，病例組有55樣本，對照組則有12個樣本。所測得上皮生長因子受體的平均濃度，病例組與對照組濃度以Wilcoxon rank sum test作檢定後發現沒有達統計上顯著差異（83.97 ± 34.90 fmol/mL比76.19 ± 17.84 fmol/mL, p=0.28）。經配對可能的干擾因子（性別、年齡、抽煙狀態）之11組個案，其血清中上皮生長因子受器平均值表現量依舊是病例組比對照組高，但無達到統計顯著（p=0.16）。另外再比較組織學型態，結果發現移行細胞癌比腎細胞癌的表現量略高。評估砷暴露和上皮生長因子受器的關係，結果顯示並沒有相關。
　　本研究發現高濃度砷(＞0.35 ppm)和泌尿道癌症的相關性，更加確定了烏腳病地區居民的長期健康效應不容忽視。未來則希望進一步辨識出上皮生長因子受體在與砷相關泌尿道癌致病機轉中所扮演的角色，以期能實際應用於烏腳病地區高危險族群尋求早期診斷、早期治療。

　　More than half a million residents in Taiwan had drunk water with arsenic levels higher than the current safety standard of 0.05 ppm. Epidemiological studies have demonstrated strong associations between exposure to arsenic and incidence of skin, urinary bladder, and lung cancers in arseniasis-endemic areas throughout the world. Therefore, health effects of arsenic constitute an important public health problem. Studies have reported that in vitro arsenic exposure can induced changes in cells and development of tumor. Furthermore, it had also been found that the arsenic exposures can regulate series of the mitogen-activated protein kinase action and induce over-expression of the epidermal growth factor receptor (EGF-R). However, previous studies in Taiwan have been focused on the blackfoot disease endemic area and Lanyang Basin, and the dose response relationship between arsenic in drinking and the mortality of urinary cancer has not been studied in the Taiwan area as a whole. The objectives of this study are to evaluate the dose-response relationship using data from a large study and to evaluate the feasibility of using epidermal growth factor receptor as a biomarker for identifing susceptible and high-risk individuals of urinary cancer (cancers of the kidney, ureter, bladder, urethra, and prostate) for possible early intervention.
　　In 1976 summary measurement results on the arsenic levels in the drinking water from a census survey of wells conducted by the government were published for 311 townships. According to the method applied in the survey, arsenic levels were categorized into three categories: below 0.05 ppm, 0.05-0.35 ppm above 0.35 ppm. Death certificates gathered by the township household registry offices between 1971 and 2000 were reviewed to identify cases of bladder, kidney, ureter, urethra, and prostate cancers. Multivariate linear regression models were applied to assess correlations between arsenic levels in drinking water and mortality of urinary cancer.
　　In addition, we have established a study group of cancer patients at a teaching hospital and recruited hospital-based controls. Then, we compared serum levels of EGF-R among patients of different pathological cell-types and used Wilcoxon rank sum test to evaluate the statistical significance of differences. EGF-R levels in sera were determined by enzyme-linked immunosorbent assay (ELISA), and SAS 8.1 was used to conduct statistical analyses.
　　During the 30-year period, 8649 male and 4829 female mortality cases of urinary cancer, as well as 4891 mortality cases of prostate cancer were identified. After adjusting for age, in comparison with the reference group (below 0.05 ppm), arsenic levels above 0.35 ppm were associated with a significant increase in the mortality of urinary cancer in both genders. No significant effect was observed for arsenic level between 0.05 and 0.35 ppm, and no association between the arsenic level and prostate cancer was observed.
　　In the EGF-R study, we analyzed 55 cases and 12 controls and found that urinary cancer had EGF-R expressions higher than control group (case: 83.97 ± 34.90 fmol/ mL; control: 76.19 ± 17.84 fmol/mL). After matching for sex, age, and smoking state, the EGF-R expression was still higher in the cancer group. In addition, the EGF-R expression in transitional cell carcinoma was slightly higher than that in renal cell carcinoma. No association between arsenic exposure and EGF-R expression was observed.
Our study found an association between arsenic level in drinking water and urinary cancer and confirmed the health effects of residents in the blackfoot endemic area. Further studies should be conducted to clarify the role of EGFR as a biomarker in the carcinogenic mechanism of urinary cancer, so that it can be applied to identify the high-risk population for possible early intervention.

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