Document 06Mmxn1oXeEgyLB717gjEnN6n

I ORIGINAL CONTRIBUTION WZ8 Ingested Arsenic, Cigarette Smoking, and Lung Cancer Risk A Follow-up Study in Arseniasis-Endemic Areas in Taiwan Chi-Ling Chen, PhD Lin-I Hsu, PhD Hung-Yi Chiou, PhD Yu-Mei Hsueh, PhD Shu-Yuan Chen, PhD Meei-Maan Wu, PhD Chien-Jen Chen, ScD for the Blackfoot Disease Study Group Context Arsenic has been documented as a lung carcinogen in humans in only a few follow-up studies, which were limited by a small number of cases or the lack of information on cigarette smoking. Objectives To elucidate the dose-response relationship between ingested arsenic and lung cancer and to assess the effect of cigarette smoking on the arsenic-lung can cer association. Design, Setting, and Participants A total of 2503 residents in southwestern and 8088 in northeastern arseniasis-endemic areas in Taiwan were followed up for an average period of 8 years. Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire inter view. rsenic is a naturally occur Main Outcome Measures The incidence of lung cancer was ascertained through ring element in soil. Medici linkage with national cancer registry profiles in Taiwan (January 1985-December 2000). Anal use of arsenic for the treat The joint effect of arsenic and cigarette smoking was estimated by both etiologic frac ment of leukemia and tion and synergy index. psoriasis, occupational exposureRveiasuinlts There were 139 newly diagnosed lung cancer cases during a follow-up pe halation, and drinking arsrieodnoicf-83 783 person-years. After adjustment for cigarette smoking and other risk fac contaminated water are important tors, there was a monotonic trend of lung cancer risk by arsenic level in drinking water of less than 10 to 700 pg/L or more (P<.001). The relative risk was 3.29 (95% con sources of arsenic exposure. The Inter fidence interval, 1.60-6.78) for the highest arsenic level compared with the lowest. national Agency for Research on Can The etiologic fraction of lung cancer attributable to the joint exposure of ingested ar cer1 documented that inorganic arsenic senic and cigarette smoking ranged from 32% to 55%. The synergy indices ranged compounds are skin and lung carcino from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smok gens in humans. Recent epidemiologic ing on lung cancer. studies2 have shown that arsenic expo Conclusions There was a significant dose-response trend of ingested arsenic on lung sure via drinking water was associated cancer risk, which was more prominent among cigarette smokers. The risk assess with an increased risk of lung cancer. ment of lung cancer induced by ingested arsenic should take cigarette smoking into Residents of the southwestern and consideration. northeastern coasts ofTaiwan had been JAMA 2004;292:2984-2990 www.jama.com drinking well water contaminated with a high concentration of arsenic before the establishment of the public tap wa ter system.3-4 They were found to have an increased risk of cancers, including lung cancer.2 Our previous study2 fol lowed up residents of the southwest ern coast for 7 years and found a sig- See also pp 2977 and 3026. nificant dose-response relationship between cumulative arsenic exposure and risk of lung cancer (relative risk [RR], 4.01; 95% confidence interval [Cl], 1.00-16.12; for the highest level of arsenic exposure [s20 mg/L per yearl) compared with unexposed resi dents. However, there were only 27 lung cancer cases identified; hence, the Author Affiliations: Graduate Institute of Epidemiol ogy. College of Public Health, National Taiwan Uni versity (Drs C.-L. Chen, Hsu, and C.-J. Chen), School of Public Health, Taipei Medical University (Drs Chiou, Hsueh, and Wu), and Division of Siostatisties and Bio informatics, National Health Research Institute (DrS.-Y. Chen), Taipei, Taiwan. A complete list of the Blackfoot Disease Study Group appears at the end of this article. Corresponding Author. Chien-Jen Chen. ScD, Col lege of Public Health, National Taiwan University, 1 Jen-Ai Rd, Section 1, Taipei 10018, Taiwan (ejehen @ha.mc.ntu.edu.tw). 2984 JAMA December 22/29, 2001--Vo! 292, No. 24 (Reprinted) @2004 American Medical Association. All rights reserved. INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER'RISK arsenic-exposed residents could only be divided into 3 groups. Cigarette smoking has been found to be a major cause of lung cancer during the past 50 years, and it was estimated that quitting cigarette smoking may pre vent more than 90% of lung cancers.5 A meta-analysis6 of studies on occupa tional arsenic exposure via inhalation found a synergistic effect of cigarette smoking and arsenic on lung cancer, and 30% to 54% of lung cancer cases were attributable to both exposures. A popu lation-based case-control study re ported an odds ratio (OR) of 32.0 (95% Cl, 7.2-198.0) for cigarette smokers who had an ingested arsenic exposure level of 200 pg/L or higher compared with nonsmokers exposed to an arsenic level of less than 49 pg/L.2 The OR was much higher than that for cigarette smoking alone (OR, 6.1; 95% Cl, 1.3-39.2; for cigarette smokers compared with non smokers) and elevated arsenic expo sure alone (OR, 8.0; 95% Cl, 1.7-52.3; for arsenic exposure of S200 pg/L com pared with <49 pg/L). This study combined 2 study co horts recruited from southwestern and northeastern Taiwan with 10591 resi dents who had been followed up for an average of 8 years in an effort to eluci date the dose-response relationship be tween ingested arsenic exposure and lung cancer risk. The larger number of study participants, longer period offol low-up with more incident lung can cer cases, andwider range of arsenic ex posure levels provided us with a unique opportunity to further investigate die modifying effect of cigarette smoking on the association between ingested ar senic and lung cancer. METHODS A total of 2503 residents in southwest ern and 8088 in northeastern arseniasisendemic areas of Taiwan were fol lowed up for an average period of 8 years. Information on arsenic expo sure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire in terview, whereas the incident lung can cer cases were identified through link age with a national cancer registry in Taiwan. Thejoint effect of arsenic and cigarette smoking was estimated by both etiologic fraction and synergy in dex. All participants provided oral or written informed consent to partici pate in this study, and the data collec tion procedures were reviewed and ap proved by the institutional review board of the College of Public Health, Na tional Taiwan University, Taipei. Study Areas This study recruited study partici pants from 2 arseniasis-endemic areas in Taiwan: one included the 4 town ships of Peimen, Hsuehchia, Putai, and Ichu on the southwestern coast, and the other included the 4 townships of Tungshan, Chuangwei, Chiaohsi, and Wuchieh in the northeastern Lanyang Basin.3 4 Residents in the southwest ern endemic area had consumed arte sian well water (100-300 m in depth) because of the high salinity of shallow well water (6-8 m in depth) for more than 50 years before the implementa tion of the tap water supply system in the early 1960s.7 The estimated amount of ingested arsenic mainly from drink ing water was as high as 1 mg/d in this area.8 Residents in the northeastern en demic area had consumed water from shallow wells (<40 m in depth) since the late 1940s through the early 1990s, when the tap water system was imple mented. Arsenic levels in well water in the northeastern Lanyang Basin ranged from less than 0.15 pg/L (undetect able) to more than 3000 pg/L.4 Study Cohorts Southwestern Cohort. Participants in 2 studies conducted in the arseniasisendemic area of southwestern Taiwan were followed up in the current study, and a detailed description of the re cruitment procedure for both studies has been reportedpreviously.2-9 The first study included 257 patients with blackfoot disease (a unique peripheral arte rial disease characterized by systemic atherosclerosis and dry gangrene of ex tremities in arseniasis-endemic areas) and 753 healthy community controls matched for age, sex, and residential townships. The second study in cluded 1571 residents in 3 villages of Putai Township, including Homei, Fuhsin, and Hsinming, where the preva lence of blackfoot disease was the high est. Among these 2581 residents, 25 participated in both studies, and since national identification numbers were used for linkage with the national can cer registry profiles, the 53 (42 incom plete and 11 missing) without these numbers were also excluded from the analyses, resulting in 2503 study par ticipants for the southwestern cohort. Northeastern Cohort. The enroll ment of study participants from the northeastern arseniasis-endemic area has been described in detail else where.4 Briefly, a total of 8102 resi dents from 4586 households of 18 vil lages participated in the baseline home interview from 1991 to 1994. The na tional identification numbers were missing for 14 participants; therefore, 8088 study participants remained in the northeastern cohort. Arsenic Exposure Southwestern Cohort. A structured questionnaire was developed to ob tain detailed information on sociode mographic characteristics, residential and occupational history, history of drinking well water, and cigarette smok ing and alcohol consumption by 2 welltrained public health nurses. For ev ery study participant, both residential history and duration of drinking arte sian well water were used to derive the cumulative arsenic exposure. Since only a few wells were in the same village, those who lived in each village shared these wells. Therefore, the median ar senic level ofwell water in a specific vil lage tested in the early 1960s10 was used as the arsenic concentration. Migra tion from one village to another also oc curred, and the arsenic concentration in well water from different villages var ied; thus, lifetime cumulative expo sure was the best method of estima tion, because it took into account not only arsenic concentration in well wa ter, but also duration of drinking wa- 2004 American Medical Association. All rights reserved. (Reprinted) JAMA, December 22/29, 2004--Vol 292, No. 24 2985 INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER RISK ter. The lifetime cumulative arsenic ex posure was obtained by multiplying the median arsenic concentration in 1 spe cific village by the duration of consum ing artesian well water in that village and summing the values across the en tire period when residing in the arseniasis-endemic area. Because resi dents in the northeastern cohort had their own well, from which they had drunk water for more than 50 years, the arsenic exposure could be estimated by direct testing of their well water.4 To be compatible with this, we decided to use average arsenic concentration as a mea surement of arsenic exposure, and this was calculated by dividing the lifetime cumulative arsenic exposure by the total years ofdrinking artesian well water. Ar senic exposures were available only for those who have complete information on arsenic exposure throughout their lifetime. If the median level of arsenic concentration was unknown for any vil lage where a given study participant lived, the arsenic exposures of the study participant were classified as un known, resulting in 775 study partici pants with unknown arsenic expo sures. Northeastern Cohort. Four welltrained local public health nurses con ducted personal interviews with the same questionnaire developed for the southwestern cohort There were a total of 3216 water samples (82.4%) col lected from individual wells of 3901 households during the home inter view. Because the wells of 685 house holds were no longer existent, the ar senic exposure of 1198 residents was classified as unknown.4 For both study areas, we used a simi lar water sampling technique, and al though the analysis methods differed (Natelson method11 for southwestern cohort and Hydride Generation Atomic Absorption Spectrophotometer method2 for northeastern cohort), it was found that the results were highly corre lated.12 The detection limits were 30 and 0.15 pg/L for the southwestern and northeastern cohorts, respectively.2,9 Among 1973 study participants with unknown arsenic exposure, 42% were men, with a mean age of 57.6 years; this was compatible with those who had ar senic exposure information. Identification of Lung Cancer Cases Each participant's unique national iden tification number was used to link with the computerized national cancer reg istry profiles in Taiwan to identify newly diagnosed lung cancer cases between January 1, 1985, and December 31, 2000. The cancer registry system was implemented in 1978 in Taiwan and was considered a nationwide cancer Table 1. Average Arsenic Level in Well Water, Age at Recruitment, and Follow-up Period in the Southwestern and Northeastern Cohorts* Southwestern Cohort Risk Factor Blackfoot Disease Cases and Matched Controls Residents in 3 Arseniasis-Hyperendemic Villages Average arsenic level in well water, |jg/L <10 277 (29.5) 219(14.0) 10-99.9 60 (6.4) 8 (0.5) 100-299.9 43 (4.6) 34 (2.2) 300-699.9 148(15.7) 108(6.9) 2700 9(1.0) 822 (52.6) Unknown 403 (42.9) 372 (23.8) Mean (SD) 182.99 (253.5) 592.88 (324.0) Age at recruitment, mean (SD), y 59.7 (10.5) 48.8(11.1) Male 449 (47.8) 705(45.1) Female 491 (52.2) 858 (54.9) Cigarette smokngt Never 649 (69.0) 1164(74.5) Past 49 (5.2) 49 (3.1) Current 242 (25.7) 350 (22.4) Habitual alcohol consumption^ No 822 (87.5) 1356(86.8) Yes 118(12.5) 206(13.2) Years of schooling 0 393(41.8) 558 (35.7) 1-6 480(51.1) 741 (47.4) >6 58 (6.2) 260(16.6) Follow-up years, mean (SD) 11.5(5.2) 11.3(2.5) Data are number (percent) of study participants unless otherwise indicated. fTwo residents of the northeastern oohort had unknown cigarette smoking status. $One resident of the southwestern cohort and 15 of the northeastern cohort had unknown habitual alcohol consumption. Thirteen residents of the southwestern cohort and 451 of the northeastern cohort had unknown years of schooling. Northeastern Cohort 2288 (23.3) 3002 (37.1) 909(11.2) 441 (5.5) 250 (3.1) 1198(14.8) 117.26(297.2) 59.1 (11.0) 4053 (50.1) 4035 (49.9) 4821 (59.6) 997(12.3) 2268(23.1) 6540 (80.9) 1533(19.0) 2268 (28.0) 4776 (59.1) 593 (7.3) 6.9 (1.6) 2986 JAMA, December 22/29, 2004--Vol 292, No. 24 (Reprinted) 2004 American Medical Association. All rights reserved. INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER RISK registry system with updated, accu rate, and complete information. Statistical Analyses Follow-up person-years for each par ticipant were calculated from the date of questionnaire interview to the date of cancer diagnosis, death, or Decem ber 31, 2000, whichever came first. Av erage arsenic concentration was arbi trarily divided into less than 10, 10 through 99.9,100 through 299.9,300 through 699.9, and 700 pg/L or higher so that there were enough lung cancer cases in each category. Measurements of cigarette smoking included smok ing status (never, current, or past), numbers of cigarettes smoked per day, total years of cigarettes smoked, and cu mulative exposure of cigarette smok ing (pack-years). We defined past smokers as those who quit smoking at recruitment and current smokers as those who were still smoking at inter view. The RRs and 95% CIs were esti mated by Cox proportional hazards re gression models. The adjustment variables in the final model included age (continuous), sex, years ofschooling (0, 1-6, or >6 years), study cohort (blackfoot disease cases and matched con trols of the southwestern coast, resi dents in arseniasis-hyperendemic villages of the southwestern coast, and residents of Lanyang Basin on the northeastern coast), cigarette smok ing status (never, past, or current), and habitual alcohol consumption (no or yes). All analyses were performed with Stata statistical software (version 7.0, Stata Corp, College Station, Tex). The joint effect of arsenic and ciga rette smoke was estimated by 2 indices of synergism. The first index was the etiologic fraction, which indicated the percentage of cases with both expo sures that was due to the synergism13 ([RRn - RRoi-- RRio + RRfloJ/RRn). The range of departure from additivity was estimated from the 95% Cl of the etio logic fraction based on the methods de scribed by Walker.13 The second index was the synergy index, which was the ratio between the observed excess risk in those with exposures to 2 risk fac tors (RRU - 1) and the excess risk pre dicted under simple additivity (the sum of 2 excess risks with only exposure to 1 risk factor, ie, [RRio-1] + [RRoi-1]).14 A synergy index greater than 1 indi cated the synergistic effect of 2 risk fac tors on a disease. RESULTS A total of83 783 person-years were ob served during the follow-up period from January 1,1985, to December 31,2000. There were 139 newly developed lung cancers, yielding an incidence of 165.9 per 100000 person-years. Table 1 com- Table 2. Follow-up Person-Years and Newly Diagnosed Lung Cancer Cases by Age at Recruitment, Sex, Years of Schooling, Habitual Alcohol Consumption, and Cigarette Smoking Risk Factor Follow-up ' Person-Years Newly Diagnosed Lung Cancer Cases (n = 139) Age- and Sex-Adjusted RR (95% Cl)* Age at recruitment, yt <50 50-54 55-59 60-64 2=65 Sex$ Male Female 25507 14898 13807 11828 17744 39870 43913 15 20 21 36 47 100 39 1.00 (Referent) 2.35(1.20-4.59) 2.60 (1.34-5.05) 5.32 (2.90-9.75) 4.87(2.71-8.77) 1.00 (Referent) 0.35 (0.24-0.50) Years of schooling 0 24563 34 1.00 (Referent) 1-6 >6 Habitual alcohol consumption No Yes 48045 8126 69938 13735 91 1.52(0.98-2.36) 6 0.64 (0.26-1.60) 96 1.00 (Referent) 43 1.51 (1.02-2.23) Cigarette smoking at recruitment Never Past 54513 7443 44 1.00 (Referent) 23 3.60(1.78-7.27) Current 21 729 71 4.19 (2.28-7.70) Years of cigarette smoking 0 1-35 54513 15117 44 1.00 (Referent) 29 3.27(1.66-6.43) >35 13281 63 4.95 (2.57-9.51) Cigarettes smoked per day|| 0 54513 44 1.00 (Referent) 1-19 20 11325 17946 29 3.08 (1.57-6.04) 66 5.00 (2.63-9.51) Pack-years of cigarette smoking^ 0 1-25 >25 54513 12016 16193 44 1.00 (Referent) 26 3.26(1.65-6.43) 66 4.98 (2.60-9.56) Average arsenic levels in well water, pg/L <10 21677 27 1.00 (Referent) 10-99 21201 31 1.15(0.69-1.94) 100-299 7053 17 2.04(1.11-3.75) 300-699 5675 18 2.65(1.46-4.82) 700 10843 26 2.50(1.42-4.40) Unknown 17334 20 0.98(0.55-1.74) Abbreviations: G, confidence interval; RR, relative risk. *P for trend <.001. Those without an average arsenic level In well water were excluded from the trend test, tAdjusted for sex. ^Adjusted for age In 1 -yea- increment. Beven study participants of the southwestern cohort and 118 of the northeastern cohort had unknown duration of cigarette smoking. |[Two study participants of the northeastern cohort had unknown quantity of cigarette smoking. 11Eleven study participants of the southwestern cohort and 147 of the northeastern cohort had unknown data. 2004 American Medical Association. All rights reserved. (Reprinted) JAMA, December 22/29, 2004--Vol 292, No. 24 2987 INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER RISK pares the average arsenic exposure level, age at recruitment, sex, years ofschool ing, cigarette smoking and alcohol con sumption status at enrollment, and fol low-up years among the 3 groups of study participants in the 2 cohorts. The average arsenic exposure level was high est among residents who lived in arse- Table 3. Multivariate-Adjusted Relative Risk of Lung Cancer for Various Risk Factors Among Residents in Arseniasis-Endemic Areas in Taiwan* Risk Factor Multivariate-Adjusted RR (95% Cl)* Age in 1 -year increment Sex Male 1.06(1.04-1.08) 1.00 (Referent) Female 1.31 (0.66-2.59) Cigarette smoking status at recruitment Never 1.00 (Referent) Past 4.03(1.92-8.44) Current 4.39 (2.30-8.39) Cohort Southwestern cohort Blackfoot disease cases and controls 1.00 (Referent) Residents in arseniasis-hyperendemic villages 1.16(0.50-2.66) Northeastern cohort 1.33(0.67-2.63) Years of schooling 0 1.00 (Referent) 1-6 1.63 (1.04-2.56) >6 0.87 (0.35-2.19) Habitual alcohol consumption No 1.00 (Referent) Yes 1.15(0.77-1.73) Average arsenic level in well water, pg/L <10 1.00 (Referent) 10-99 1.09(0.63-1.91) 100-299 2.28(1.22-4.27) 300-699 3.03 (1.62-5.69) 2700 3.29 (1.60-6.78) Unlmown 1.10(0.60-2.03) Abbreviations: Cl, confidence interval; RR, relative risk. *P for trend <.001. Those without an average arsenic level In well water were excluded from the trend test. Figure. Relative Risks of Lung Cancer by Average Arsenic Exposure and Pack-Years of Cigarette Smoking Smoking Status Nonsmoker Average Arsenic Relative Risk Exposure, jig/L (95% Confidence Interval) <10 10-699 2700 1.00 1.24(0.53-2.91) 2.21 (0.71-6.86) <25 Pack-Years <10 10-699 2700 2.55 (0.68-9.52) 5.50(1.96-15.5) 6.28 (1.53-25.7) 225 Pack-Years <10 10-699 2700 3.80 (159-112) 5.93 (2.19-16.1) 11.10(3.32-37.2) 0 2 4 6 8 10 12 14 16 Relative Risk (95% Confidence Interval) Relative risks and 95% confidence intervals are shown. The reference group was study participants who were exposed to the lowest level of arsenic (<10 pg/L) and never smoked cigarettes. Data have been adjusted for age at recruitment, sex, years of schooling, and habitual alcohol consumption in a proportional hazards analysis. niasis-hyperendemic southwestern vil lages and lowest among those who lived in the northeastern endemic area. Most of the southwestern cohort consumed an average arsenic level greater than 100 pg/L, and most of the northeastern co hort consumed an average arsenic level less than 100 pg/L. The mean age at re cruitment was lowest among resi dents in arseniasis-hyperendemic vil lages, and the sex distribution was similar in the 3 groups. Residents in the northeastern cohort reported the high est percentage of cigarette smoking and alcohol consumption. The average fol low-up years were similar in the 2 study groups of the southwestern cohort (11 years) and shorter in the northeastern cohort (7 years). Table 2 gives the numbers ofpersonyears offollow-up and lung cancer cases by age at recruitment, sex, years of schooling, habitual alcohol consump tion; and cigarette smoking. Since the RRs associated with various risk fac tors were similar in the different study cohorts, only pooled data are given in Table 2. Older age, male sex, and ha bitual alcohol consumption were asso ciated with an increased risk of lung cancer, whereas years of schooling was not. Compared with nonsmokers, those who smoked cigarettes at recruitment had an increased risk of lung cancer (RR, 4.19; 95% Cl, 2.28-7.70). Signifi cant dose-response trends were ob served for the duration (years), quan tity (cigarettes smoked per day), and cumulative exposure (pack-years) of cigarette smoking, showing a 5-fold risk for the highest exposure group. A sig nificant dose-response trend (P<.001) associated with increasing levels of ar senic exposure and risk of lung cancer was found with only age and sex ad justment. Past and current smokers had a 4-fold risk of lung cancer compared with non smokers after adjustment for other risk factors, including ingested arsenic ex posure (Table 3). Similarly, after ad justment for other risk factors, includ ing cigarette smoking, a significant dose-response trend was found for ar senic exposure (P<.001). The RR as 2988 JAMA, December 22/29, 2004--Vol 292, No. 24 (Reprinted) <92004 American Medical Association. All rights reserved. INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER RISK sociated with the highest arsenic level (a700 Pg/L) was 3.29 (95% Cl, 1.60 6.78) after adjusting for age, sex, ciga rette smoking status at recruitment, years ofschooling, habitual alcohol con sumption, and the cohort where they were originally recruited. Among nonsmokers, those who were exposed to the highest arsenic level (>700 pg/L) had an RR of lung cancer around 2-fold (RR, 2.21; 95% Cl, 0.71 6.86) when compared with those with the lowest level (<10 pg/L) (Figure). Among participants with the lowest ar senic level, those who had the highest cumulative cigarette smoking expo sure had a 4-fold risk of lung cancer (RR, 3.80; 95% Cl, 1.29-11.2) com pared with nonsmokers. When com pared with nonsmokers with an ar senic exposure level less than 10 pg/L, those who consumed well water with an arsenic level of700 pg/L or more and smoked for more than 25 pack-years had a more than 11-fold risk of lung cancer (RR, 11.1; 95% Cl, 3.32-37.2). Similar results were found when dura tion and quantity of cigarette smoking were used as indicators of cigarette smoking (data not shown). In addi tion, the etiologic fractions oflung can cer due tojoint effect ofcigarette smok ing and ingested arsenic ranged from 0.32 to 0.55. In other words, 32% to 55% of lung cancer cases were attrib utable to both arsenic exposure and cigarette smoking. Furthermore, all syn ergy indices were greater than 1 (range, 1.62-2.52), indicating the existence of synergism in an additive way (Table 4). However, the multiplicative interac tion was not statistically significant (data not shown). COMMENT The association between ingested ar senic and lung cancer mortality was first reported through both ecologic corre lation studies3,7 and a case-control study2 conducted in the southwestern arseniasis-endemic area ofTaiwan. The only follow-up study was based on the southwestern cohort of the current study with a 7-year follow-up period and 27 lung cancer cases. A 4-fold risk (95% Cl, 1.00-16.12) was found for the highest cumulative arsenic exposure (s20 mg'Lper year) comparedwith the unexposed.2 In this study with a longer follow-up period and more lung can cer cases, we confirmed the elevated risk of lung cancer associated with arsenic exposure. In addition, we found a sig nificant dose-response relationship in finer categories of arsenic exposure from less than 10 to 700 pg/L or more. Similar results were found in a hospitalbased case-control study (OR, 8.9; 95% Cl, 4.0-19.6; for an average arsenic con centration of 200-400 pg/L compared with <10 pg/L).10 The lung cancer risk among those with the highest exposures to ciga rette smoking and arsenic could be as high as 11-fold when compared with nonsmokers with die lowest arsenic ex posure. Approximately 32% to 55% of lung cancer cases were estimated to be attributable to the combined effect of cigarette smoking and ingested ar senic, depending on the levels of both exposures. The synergy indices ranged from 1.62 to 2.52, which were all above 1, indicating a synergistic effect under an additive scale. This finding was con sistent with a meta-analysis6 of occu pational arsenic exposure via inhala tion and cigarette smoking, with 30% to 50% of lung cancer cases attribut able to both exposures. Other studies2 also provided evidence ofsynergism be tween ingested arsenic and smoking but did not quantify the etiologic fraction. Because lung cancer is a rare disease, we followed up all study participants to increase statistical power to detect a sig nificant association at minimal expo sure levels. Because most northeastern residents were at lower arsenic expo sure levels and southwestern residents were at higher levels, we were able to stratify arsenic exposures into finer cat egories. The detection limits for arsenic analysis methods were also different in the 2 study areas (30 pg/L for the south western cohort and <0.15 pg/L for the northeastern cohort), but the arsenic concentration ranged from 350 to 1140 pg/L in the southwestern study area and less than 0.15 to 3590 pg/L in the north- Table 4. Synergy Indices and Etiologic Fractions of Average Arsenic Exposure and Cumulative Cigarette Smoking on the Risk of Lung Cancer in Arseniasis-Endemic Areas in Taiwan________ ____________________________________ Etiologic Average Arsenic Synergy Fraction Exposure, pg/L Index*________(95% CO Participants Who Smoked <25 Pack-Years 10-699 251 7001.91 0.49 (-0.06 to 1.04) 0.40 (-0.31 to 1.11) Participants Who Smoked 25 Pack-Years 10-699 1.62 7002.52 0.32 (-0.11 to 0.75) 0.55 (0.21 to 0.89)t Abbreviation: Cl, confidence hterval. `Based on relative risks that were adjusted for age, sex, studycohort yearsofschoo6ng, and habitual alcohol con sumption. flbe 95% Cl did not Include 0. eastern study area. The misclassification of exposure due to detection limits should be minimal. In addition, the 3 study groups were compatible in their oc cupations, ethnic backgrounds, life , styles, and dietary patterns. Although there were differences in age, cigarette smoking, habitual alcohol consump tion, and years of schooling, these fac tors were adjusted in the regression analyses. To avoid any residual con founding of unknown factors among groups, a variable ofstudy group was in cluded in the analyses. A great effort was made to control for potential confound ing factors, such as age, sex, education levels, and habitual alcohol consump tion and status of cigarette smoking by adding them to the model. Since the ar senic exposure was estimated not only by water concentration but also by the duration of living in one specific vil lage, the potential effects of immigra tion and emigration should be mini mal. All lung cancer cases were pathologically confirmed, and the can cer registration rate was estimated to be as high as 98% during 1996 to 1999. Even ifwe might miss some cancer cases in earlier follow-up years, there was no reason to believe that the few missing cases would relate to the arsenic expo sure and cigarette smoking in a selec tive way. Furthermore, the distribution of histologic types of lung cancers were similar to those of the whole country, with' squamous cell carcinomas (45%) as @2004 American Medical Association. AO rights reserved. (Reprinted) JAMA December 22/29, 2004--Vol 292, No. 24 2989 INGESTED ARSENIC, CIGARETTE SMOKING, AND LUNG CANCER RISK the most common and adenocarcino mas (22%) the next most common. The arsenic exposure was unknown for 31% of study participants in the southwestern cohort and 15% in the northeastern cohort. Because all these study participants were exposed to ar senic to some extent, their RR of devel oping lung cancer lay between the low est and highest exposure levels. The exclusion of this group from the analy ses did not alter the study outcome, and they were not included in analyses of dose-response trend and effect modifi cation. For the southwestern cohort, most residents started drinking artesian well water in the 1910s, and the tap watersys tem was first introduced in the 1960s.2 Most residents in Lanyang Basin had been drinking water from shallow wells since the 1940s, and the tap water sys temwas notimplemented in this area un til the late 1990s.4 Although the arsenic concentrationinwell water might change over time, it was reported that after re checking the same well water 2 years af ter the survey, the concentrations were stable in the endemic areas.15 However, there was no information on the long term stability ofarsenic concentration in the well water. In addition, the measure ment of arsenic exposure was based on only 1 large-scale survey in the south western and northeastern endemic areas, so there might be some misclassification of arsenic exposure. Nevertheless, this misdassification was considered nondifferential, and the observed asso ciations between lung cancer and in gested arsenic could be underesti mated. The information on cigarette smoking was obtained only once at re cruitment, and it was possible that some of the study participants might have changed their smoking status, which would lead to underestimation of lung cancer risk associated with cigarette smoking. .' In this analysis, we confirm our ear lier finding of an increased risk of lung cancer associated with increasing levels of arsenic exposure via drinking water. In addition, we found a significant dose- response trend in the finer categories. Al though this study is an extension of the previous findings, the results are rel evant and of general medical interest. Furthermore, this effect was found to be stronger among those who smoked ciga rettes, and the risk could be as high as more than 10-fold. Our study provides evidence ofa syn ergistic relationship between cigarette smoking and ingested arsenic on the risk of lung cancer. The reductions in ciga rette smoking would likely reduce the lung cancer risk accompanied by expo sure to arsenic, and similarly, reduc tions in arsenic exposure would reduce the lung cancer risk among cigarette smokers. Appropriate public health in terventions, such as cigarette smoking cessation programs and reduction in ar senic concentration ofdrinkingwater, are warranted. Furthermore, it is essential to take cigarette smoking into consider ation in the risk assessment and the de termination of the maximal contamina tion level of arsenic in drinking water. Author Contributions: Dr C.-J. Chen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conceptand design: C.-L. Chen, Chiou. Hsueh, C.-J. Chen. Acquisition of data: C.-L. Chen, Hsu, Hsueh, S.-Y. Chen, Wu, C.-J. Chen. Analysis and interpretation ofdata: C.-L. Chen, S.-Y. Chen, Wu, C.-J. Chen. Drafting of the manuscript C.-L. Chen. Critical revision of the manuscript for important in tellectual content C.-L. Chen, Hsu. Chiou, Hsueh, S..-Y. Chen, Wu, C.-J. Chen. Statistical analysis: C.-L. Chen, Hsu, S.-Y. Chen, Wu. Obtained funding: C.-J. Chen. Administrative, technical, or materialsupport Chiou, Hsueh, C.-J. Chen. Study supervision: Hsueh, C.-J. Chen. The Blackfoot Disease Study Croup: Graduate Insti tute of Epidemiology, College of Public Health (ChienJen Chen. ScD. Chi-Ling Chen, PhD, Un-I Hsu, PhD, Wei-Liang Shih, MS, Yi-Hsiang Hsu, MS, Chia-Yen Chen, BS, Yu-Chin Cheng, BS, and Li-Hua Wang, BS) and Graduate Institute of Medical Technology, Col lege of Medicine (Cheng-Yeh Lee, MS), National Tai wan University, Taipei; School of Public Health, Tai pei Medical University, Taipei, Taiwan (Hung-Yi Chiou, PhD, Yu-Mei Hsueh, PhD, Meei-Maan Wu, PhD, luanHomg Wang, MS, Yu-Chun Lin, MS); Division of Bio statistics and Bioinformatics, National Health Re search Institute, Taipei, Taiwan (Shu-Yuan Chen, PhD); Division of Environmental Health and Occupational Medicine. National Health Research Institute. Kaohsiung, Taiwan (Wei-Un Chou, MS); Department of Car diology, Cardinal Tien Hospital. Fu-Jen Catholic Uni versity, Taipei, Taiwan (Chih-Hao Wang, MD. PhD); Department of Dermatology, National Taiwan Uni versity Hospital, Taipei (Mei-Ping Tseng, MS). Funding/Support: This study was supported by grants NSC 83-0412-B002-231. NSC91-2320-B002-075, NSC 92-2320-B002-136, and NSC92-2320-B002-135 from the National Science Council and DOHB5-HR-503PL from Department of Health, Executive Yuan, Taiwan. Role of the Sponsors: The National Science Council and Department of Health, Executive Yuan, Taiwan, were not involved in the design and conduct of the study, In the collection, management analysis, and interpretation of the data, or in the preparation, re view, or approval of the manuscript REFERENCES 1. International Agencyfor Research on Cancer./ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Mian: Some Metals and Metal loid Compounds, Volume 23. Lyon, France: Interna tional Agency for Research on Cancer; 1980:139 141. 2. Inter-OrganizationProgrammefortheSoundMan agement of Chemicals, World Health Organization. Arsenic and Arsenic Compounds. 2nd ed. Geneva, Switzerland: Inter-Organization Programme for the Sound Management of Chemicals, World Health Or ganization; 2001. 3. 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