Document 7MYQZ02RG8ZRL81M5vww3p9DB

107 M7 Articles Arsenic Concentrations in Weil Water and Risk of Bladder and Kidney Cancer in Finland Paivi Kurttio,1 Eero Pukkala,2 Hanna KaheUn,3 Anssi Auvinen,4 and Juha Pekkanen1 'National Public Health Institute, Unit of Environmental Epidemiology, Kuopio, Finland; 2Finnish Cancer Registry, Helsinki, Finland; 3Geological Survey of Finland, Espoo, Finland; 4Radiation and Nuclear Safety Authority, Helsinki, Finland We assessed die levels of arsenic in drilled wells in Finland and studied the association of arsenic exposure with the risk of bladder and kidney cancers. The study persons were selected from a reg ister-based cohort of all Finns who had lived at an address outside the municipal drinking-water system during 1967-1980 ( 144,627). The final study population consisted of 61 bladder can cer cases and 49 kidney cancer cases diagnosed between 1981 and 1995, as well as an age- and sex-balanced random sample of 275 subjects (reference cohort). Water samples were obtained from the wells used by the study population at least during 1967-1980. The total arsenic concen trations in die wells of the reference cohort were low (median = 0.1 pg/L; maximum = 64 pg/L), and 1% exceeded 10 pg/L. Arsenic exposure was estimated as arsenic concentration in the well, daily dose, and cumulative dose of arsenic. None of the exposure indicators was statistically significandy associated with the risk of kidney cancer. Bladder cancer tended to be associated with arsenic concentration and daily dose during the third to ninth years prior to the cancer diagnosis; the risk ratios for arsenic concentration categories 0.1-0.5 and > 0.5 pg/L relative to the category with < 0.1 pg/L were 1.53 (95% confidence interval (Cl), 0.75--3.09] and 2.44 (Cl, 1.11-5-37), respectively. In spite of very low exposure levels, we found some evidence of an association between arsenic and bladder cancer risk. More studies are needed to confirm the possible associa tion between arsenic and bladder cancer risk at such low exposure levels. Key words, arsenic, blad der cancer, drinking water, kidney cancer, rural, urinary organ cancers, well water. Environ Health Persptct 107:705-710 (1999). [Online 27 July 1999] http://ehpnetl.niehs.nih.govldoall999H07p705-710kurttiofabstnict.html Natural mineral deposits containing frsenic may result in elevated levels of arsenic in ground water. The World Health Organization (WHO) classifies inorganic arsenic as a human carcinogen; chronic ingestion is associated with skin cancer and inhalation is associated with lung cancer (I). Arsenic concentrations in noncontaminated drinking water are usually below 3 pg/L (1--4). The present WHO drinking-water guideline value of 10 pg/L (4) is based main ly on epidemiologic studies on arsenic expo sure and skin cancer in Taiwan. Epidemiologic studies based on high arsenic exposure in Taiwan (5-11), Argentina (12,15), Japan (14,15), and Chile (16) sug gest an increased risk of cancer of the urinary organs. The lowest arsenic exposure levels associated with detrimental health effects have been reported in a case-control study in the United States in which the arsenic concentra tions in drinking water ranged from 0.5 to 180 pg/L (17). In that study, no overall asso ciation was found between arsenic exposure and cancer risk, but arsenic and cigarette smoking tended to have a synergistic effect on the risk of bladder cancer. As much as 12-14% of the Finnish popu lation live outside areas with municipal water jly and use private wells (18). Water qual- bf private welts is seldom monitored. - Concentrations of arsenic measured in a rural town in central Finland were up to 100 rimes higher than drinking-water quality guideline values (19). According to geologic surveys, there are several other areas in Finland that are prone to high arsenic concentrations (20), but no countrywide survey on arsenic concen trations in well water has been carried out. The aims of the present study were to deter mine whether arsenic exposure from well water is associated with increased risk of blad der and kidney cancers and to assess die con centrations of arsenic in drilled wells used for drinking water in Finland. Materials and Methods Selection ofstudy population. Town quarters or villages, in which less than 10% of the population belong to the municipal drink ing-water system, were identified based on the 1985 Population Census file of the Statistics Finland. The source population was defined from the Population Registry as 144,627 persons born in 1900-1930 who had lived in these areas at the same address at least from 1967 to 1980 (Figure 1). The year 1967 was chosen because it was the ear liest for which information on residency had been recorded systematically. During 1981-1995, 884 bladder cancer cases and 644 kidney cancer cases were iden tified within the cohort through a record link with the Finnish Cancer Registry. Because there are plans to conduct similar studies based on the same reference cohort for stomach cancer and leukemia, a case-cohort design was used (21). Random selection of the reference cohort was stratified by single birth year (range 1900-1930) and sex (i.e., 62 strata). The number of persons selected to the reference cohort within each stratum was four rimes the highest number of site-specific can cer cases in that stratum (i.e., either kidney, bladder, leukemia, or stomach cancer). Altogether, 4,590 persons were selected in the reference cohort. Final study series. The current residents ar the addresses occupied by the case and ref erent persons in 1967-1980 were contacted initially either by the local health inspectors or by mailed questionnaire. The following questions were asked: Did the house have a drilled well? When was the drilled well established? Had the drilled well been used as the primary source ofdrinking water? Because drilled wells have been reported to contain essentially higher arsenic concen trations than other types of wells (22), only those addresses where drinking water from drilled wells was consumed before the yeat 1981 were selected for further study (Table I). The use of the drilled wells for drinking water had started before 1981 but may have continued until 1996. Local health inspec tors collected well-water samples from the selected addresses of 509 subjects. Those 380 subjects (76% of cases and 74% of reference cohort eligible) for whom arsenic exposure could be estimated (i.e., the well-water sample was available and well water had been used as drinking water) were includ ed in the final analysis (Table 1). The excluded and included subjects did not differ by vital status (40%/52% alive), age (mean birth year 1917/1916), sex (42%/39% women), occupa tion (6l%/64% farmers), or education Address correspondence to P. Kurttio, National Public Health Institute, Unit of Environmental Epidemiology, PO Box 95, FIN-70701 Kuopio, Finland. Telephone: 358-17-201 362. Fax: 358-17 201 155. E-mail: paivi.kurtdo@kd.fi Wc thank E. Kokki, M. Vahteristo, and P. Tiittanen from the Narional Public Health Institute; T. Luostarinen from the Finnish Cancer Registry; and the local environmental health personnel and the study subjects. The Academy of Finland, Research Council of Health (grant 34213), the Yrjojahnsson Foundation (grants 3772 and 4133), and the Environment, Health and Society Programme of the University of Kuopio financially supported the study. Received 1 February 1999: accepted 7 May 1999. Environmental Health Perspectives Volume 107, Number?, September 1999  Articles Kurttio et al. (2%/5% with more than 9 years of educa tion). Sixty-one cases with bladder cancer and 49 with kidney cancer were included (includ ing 3 cases with cancer of the renal pelvis, 41 with unilateral kidney cancer, 1 with cancer in both kidneys, and 4 with cancer in an uniden tified site). The reference cohort consisted of 275 subjects (including 3 subjects who devel oped bladder cancer and 1 subject who was diagnosed with kidney cancer). Questionnaire. Information on residen tial history and drinking-water consumption at the selected addresses and potential confounders such as smoking, use of anal gesics and diuretics in the 1970s, education, and occupadon was collected using a ques tionnaire mailed to the study subjects (i.e., cases and referents who had lived at the selected addresses during 1967--1980) or their next of kin (Tables 2 and 3). Subjects received the questionnaires before the water sampling in 1996. In addirion, information on the present occupation (previous occupa don for reared persons) and education was obtained from the Population Censuses of 1970,1975, and 1980. 100 200 300 Kilometers A Bladder cancer I Kidney cancer I Q Reference cohort | Figure 1. Selection of the study population. (4) Location of the members of the cohort of 144,627 persons who were bom in 1900-13% and had lived outside the area of a municipal water source at least for 13 years before 1980. (8) Location of the bladder cancer cases In = 61), kidney cancer-cases In = 49), and members of the reference cohort In = 275). . Table 1. Selection of the study population. Number of persons eligible after first contact Water sample available Drilled well water used as drinking water and water sample available (final study series) Questionnaire available Both water sample and questionnaire available Bladder cancer* No. % 79 100 68 86 61 77 52 66 42 53 Kidney cancer* No. % 65 10) 58 89 49 75 49 75 36 55 Reference cohort No. % 371* 313* 275* 100 84 74 240^ 183* 65 49 *0ne person had both kidney and bladder cancers and is included in both case series, includes three bladder cancer cases and two kidney cancer cases. `Includes three bladder cancer cases and one kidney cancer case, includes two bladder cancer cases and two kidney cancer cases. `Includes two bladder cancer cases and one kidney cancer case. Arsenic measurements. The well-water samples were collected between July and November 1996. The samples were collected in random order, blinded in regard to the case-referent status. Each sample was filtered through a 0.45-pm membrane filter and acid ified with HNOj at the sample site. The sam ples were sent to the laboratory within 2 days. -Total arsenic was determined by Perkin Elmer Sciex Elan 6000 inductively coupled plasma mass spectrometry (Perkin-Elmer, Rotkreuz, Switzerland). The detection limit for arsenic was 0.05 pg/L. The performance of the analytical method was monitored con tinuously including certified reference mate rials within the analytical batches. Sixty-four of the samples were analyzed twice. The median coefficient ofvariation was 2.2%. To evaluate the validity ofwater sampling two water samples were taken from 36 ran domly selected wells at two different times (on average 31 days apart; range 2 hr-88 days). The arsenic concentrations in the original samples and field duplicates were not signifi cantly different (median of the absolute differ ence between two samples was 0.02 pg/L; p = 0.2 in the Wilcoxon signed ranks test). Estimates of arsenic exposure. The arsenic exposure for cases with cancer and members of reference cohort was estimated in two periods; from the'third to ninth cal endar years (shorter latency) and from the tenth or earlier calendar years (longer latency) prior to the cancer diagnosis (or the respec tive year for referent persons). The daily dose of arsenic from drinking water was calculated from the arsenic con centration of well water and from the report ed consumption of well water in the 1970s. If questionnaire data were not available, the consumption of drinking water was set as the mean from the reference cohort. Men consumed on average 1.6 L/day (range 0.1--4.5 L/day) and women consumed 1.6 L/day (0.6-3.0 L/day) of well water. At two addresses (one member of the reference cohort and one kidney cancer case), water samples from two drilled wells were avail able. In those cases, the higher arsenic con centration was included in the calculations of arsenic concentration and daily dose, and actual use for cumulative exposure. Consumption of well water started on average in 1970 [standard deviation (SD) = . 8 years] and stopped in 1990 (SD = 6 years). ) The cumulative dose was defined as an inte- I gral of duration and intensity of arsenic i exposure from well water. The cumulative | dose for the shorter latency was calculated 1 from the beginning of the use of well water | until 2 years before the cancer diagnosis. For the longer latency, the cumulative dose was calculated until 10 years before the cancer diagnosis. The arsenic concentration in 706 Volume 107, Number 9, September 1999 Environmental Health Perspectives Articles Well water, arsenic, and urinary organ cancers drinking water before the beginning and Table 2. Demographic description of the cases and reference cohort after the end of the consumption of the well ter was considered as null. Exposure from Iter sources was not taken into account. Statistical analyses. The study was based on the case-cohort design described by Prentice (21) and Barlow (23). In the analysis of a case-cohort study, the risk set at each event time (year of cancer diagnosis) consists Women Year of birth 1900-1910 1911-1920 1921-1930 Bladder cancer (r?=61) No. % 11 18 14 23 22 36 25 41 Kidney cancer (n=49) No. % 25 51 8 16 21 43, 20 - -'''4V of the case chat tailed at that particular time and all members of the reference cohort who were at risk at the time. Members of the ref erence cohort were weighted in inverse pro portion to the sampling fraction (4,590/ 144,627). The robust variance matrix was estimated using SAS/IML (Interactive Matrix Programming Language; SAS Institute, Cary, NC). The 95% confidence intervals (CIs) were calculated from the robust variance esti Vital status in end of 1995 Alive Education Primary school or less Higher than primary school Missing Occupation Farming Transport, construction. service, and administration Missing 32 52 41 67 12 19 31 38 62 20 33 35 16 33 37 75 24 10 20 31 63 12 24 6 12 mates and standard errors. Risk ratios (RRs) were estimated using PHREG (Cox's Multivariable Proportional Table 1 Characteristics of the cases and reference cohort Regression Analysis) procedure of SAS, calrulated both lor continuous and categorical ttsenic exposure (class limits set roughly at Bladder cancer (o = 61) No. % Kidney cancer (o = 49) No. % he 50th and 75th percentiles of the tefernce cohon). To limit the influence of the ew observations with high levels of arsenic, ve estimated linear models after log-transorming the arsenic exposure indicator. Cigarette smoking is an established risk facorJor both bladder and kidney cancers and high body mass index (BMI) is iHffiablished risk factor for kidney cancer 26). The multivariate models of bladder incer were adjusted for age, sex, and smokig (never smoked, ex-smoker stopped noking before 1970, smoker in the 1970s). he multivariate models of kidney cancer ere adjusted for age, sex, smoking, and BMI 25, 25 weight in kilograms/(height in eters)2]. Subjects with missing data on toking and BMI (Table 3) were included the models as a separate category. Use of algesics and diuretics in the 1970s and ucation were not associated with the risk of idder or kidney cancers and were therefore t included in the final models. Questionnaire respondent Study person Spouse Child, grandchild Start of using well water Before 1965 1966-1975 After 1976 Cigarette smoking in the 1970s Never Ex-smoker Smoker Missing data . Use of diuretics in the 1970s Never Ever Missing data Use of painkillers with phenacetin or phenylbutazon in die 1970s Never Ever Missing data BMI (kg/m2) in the end of the 1970s <25 2 25 (overweight) Missing data 18 29 15 25 9 15 15 25 32 52 14 23 18 29 47 18 29 21 34 25 41 12 20 24 39 12 20 35 46 75 25 41 14 23 22 36 7 14 15 31 14 29 17 35 19 39 13 26 22 45 7 14 7 14 13 26 15 31 12 24 22 45 7 14 5 10 37 75 13 26 21 43 15 31 SSllltS BMI, body mass index. sertic concentrations in reference wells. The enic concentrations in the wells of the refnce cohort ranged from < 0.05 to 64 pg/L edian 0.14 pg/L; Cl, < 0.05-4.5; Table 4). e percent of the reference cohort had enic concentrations > 5 pg/L, and 1% 275) had consumed well water exceeding WHO drinking-water quality guideline ie of 10 pg/L The median daily dose of nic from well water was 0.2 pg (5th and h percentiles were 0.04 and 7 pg, respec- cumulative dose before 1980 was ^Pl^th and 95th percentiles were 0.08 26 mg, respectively). Table 4. Arsenic exposure among cases and the reference cohort Arsenic concentration in well water (pg/l) Daily dose of arsenic from well water (pg) Cumulative dose of arsenic from well water before 1980 (mg) Duration of well use before 1980 (years) Bladder cancer (rt=61) Percentile 50th 75th 95th 0.1 0.6 3.0 Kidney cancer (rt=49) Percentile 50th 75th 95th 0.1 0.6 1.8 0.2 0.9 4.8 0.2 0.9 3.0 0.6 2.6 28 0.7 2.8 24 9 15 24 9 17 25 Reference cohort (n = 275) No. % 112 41 86 31 115 42 74 27 152 55 169 61 16 6 90 33 179 65 64 23 32 12 Reference cohort (o=275| ~~Nu 73 27 39 14 71 26 72 26 156 57 47 17 106 38 28 10 35 13 106 38 80 29 72 26 123 45 39 14 25 9 211 77 68 25 97 35 110 40 Reference cohort |/j = 275) Percentile 50th 75th 95th 0.1 0.5 4.5 0.2 0.7 7.2 0.8 2.6 26 10 15 23 -onmental Health Perspectives Volume 107, Number 9, September 1999 Articles Kurttio et al. Ninety-four percent of the drilled wells were still in use in 1996. The depth of the well (median 42 m, range 5-172 m) did not correlate (Pearson correlation coefficient 0.06) with the (log-transformed) arsenic concentrations. Water treatment was rare: it was reported for only 11 wells, most frequendy for iron removal. Characteristics of cases versus controls. The study population was a demographically rather homogeneous group of people with a mainly agricultural background (Table 2). The residence locations of cancer cases and referents did not differ systematically (Figure 1). Residential mobility was remarkably low; 71% of those alive in 1996 still lived in the same place where they had lived in 1967. Cigerette smoking in the 1970s was more common among the cancer cases than among the reference cohort; the association between smoking and bladder cancer was statistically significant (Tables 3 and 5). Arsenic and bladder cancer. We observed an increasing trend for arsenic con centrations in drinking water and the. daily dose of arsenic with shorter latency, but not with longer latency (Table 6). The point estimate for arsenic concentration > 0.5 pg/L was statistically significantly elevated. The association between arsenic exposure and bladder cancer tended to be stronger among those who smoked in the 1970s (Table 7). Arsenic and kidney cancer. We found no evidence for an association between arsenic concentration, daily dose, or cumulative dose and the risk of kidney cancer (Table 8). Discussion High concentrations of arsenic in drilled wells were previously detected in southwestern Finland (19,22), and geochemical surveys (20) suggest high arsenic concentrations in other areas as well. However, our findings indicate that substantial arsenic exposure, through drilled well water in Finland is uncommon. Assuming that the entire arsenic dose from drinking water was in inorganic form, the median dose of inorganic arsenic from well water in the reference cohort was approximately 0.2 pg/day. This is similar to the estimated dose from drinking water in the Czech Republic (2), but lower than that esti mated in the United States (4 pg/day) (27). We have previously shown that the steady-state current arsenic exposure can be adequately estimated by asking subjects about daily drinking-water consumption at home (79). In the present study, however, we were interested in the water consump tion in the 1970s, which is more prone to misclassification and affected by recall bias. The earlier arsenic concentrations were con sidered to be the same as they were at the time of the sampling, which may introduce errors. No published data on annual varia tions of arsenic concentrations in well water in Finland were available, but the concen trations may fluctuate depending on the water catchment basin of the well (i.e., the level of groundwater). Some studies have, however, reported that arsenic concentra tions in wells in arsenic-rich areas remain relatively constant for decades (11, 12). The calculation of cumulative dose is more sensitive to errors than daily dose or concentration. The year of beginning of well-water use may not have been recalled adequately, and an error in the duration of well-water use has a significant influence on the amount of cumulative dose. The arsenic concentrations in drinking water other than those measured from drilled wells were con sidered zero. This may introduce misclassifi cation in the cumulative dose, especially when arsenic concentrations in drilled wells were as low as in other sources of drinking water. This misclassification, however, likely to be nondifferential. The arsenic doses found in previous stut ies (5-17) on arsenic exposure and cancer i urinary organs were much higher than tho< found in this study. In the present study, v, used individual arsenic exposure variable . instead of area-based measures used in mos previous studies. Studies in Taiwan have sug gested that cancers of the bladder, kidney lung, liver, skin, and possibly some other site are associated with drinking-water arsenit concentrations ranging from 10 to 1,80( pg/L (5-8,28) and from 350 to 1,140 pg/1 (9). Furthermore, ingested arsenic exposun has been associated with the increased risk ot cancers in urinary organs in Argentina, Japan, and Chile. The lowest cut points ol the categorical arsenic concentrations were 40 pg/L in Argentina (12,13) and 50 pg/L in Japan (14,15). In Chile, the regional average arsenic concentrations in drinking water ranged from 43 to 570 pg/L (16). The only earlier nonecological study on bladder cancer risk and lower arsenic concentrations (from 0.5 to 180 pg/L) in drinking water in the United States did not show a clear associa tion (17). A follow-up study among English patients showed that orally administered arsenic medication with substantially higher doses was associated with an increase in blad der cancer mortality (29). We found some suggestion of an increased bladder cancer risk associated with low arsenic exposure levels in the present study. The risk estimates for bladder cancer and arsenic concentration, as well as daily dose from 2 to 9 years before the cancer diag nosis, were above unity, and there was some indication of a dose response. A statistically significantly elevated risk of bladder cancer was observed for arsenic concentrations > 0.5 pg/L. Exposures earlier than 10 years Table 5. Age- and sex-adjusted univariate risk ratios (RR) for cancer of tfie urinary organs and 95% confidence intervals (Cl) for confounder variables. n RR Cl Bladder cancer Cigarette smoking in the 1970s Never 18 1 Ex-smoker 4 0.44 0.13-1.49 Smoker 18 2.32 1.02-5.30 Missing data 21 1.04 0.50-2.20 Kidney cancer Cigarette smoking in the 1970s Never 22 1 Ex-smoker 7 1.49 0.53-4.24 Smoker 7 1.52 0.52-4.41 Missing data 13 0.73 0.35-1.55 BMI (kg/m2) in the end of the 1970s <25 > 25 (overweight) Missing data 13 1 21 1.85 0.55-2.56 15 0.81 0.36-1.83 Table 6. Age-, sex-, and smoking-adjusted risk ratios (RR) and 95% confidence intervals (Cl) of bladder cancer in the Finnish case-cohort study on arsenic exposure from well water. Exposure Concentration of arsenic in water (pg/L) <0.1 0.1--0.5 >0.5 (tog) continuous2 Daily dose of arsenic (pg/day) <0.2 0.2-1.0 >1.0 (tog) continuous2 Cumulative dose of arsenic (mg) <0.5 0.5-2.0 >2.0 (log) continuous2 Shorter latency* No. RR Cl 23 1 19 1.53 0.75-3.09 19 2.44 1.11-5.37 61 1.37 0.95-1.96 29 1 17 1.34 0.66-2.69 15 1.84 0.84-4.03 61 1.34 0.95-1.90 16 1 20 1.61 0.74-3.54 25 1.50 0.71-3.15 61 0.92 0.57-1.47 Longer latency4 No. RR Cl 26 1 18 0.81 0.41-1.63 17 1.51 0.67-3.38 61 0.96 0.59-1.55 32 1 16 0.76 0.38-1.52 13 1.07 0.48-2.38 61 0.91 0.55-1.48 27 1 21 0.81 0.33-1.69 13 0.53 0.25-1.10 61 0.78 0.51-1.20 "Exposure in the third to ninth calendar years prior to the cancer diagnosis. `Exposure in the tenth calendar year and earlier prior to the cancer diagnosis. "Result from the model using log-transformed exposure values. 708 Volume 107 NumherO Cpnrpmhor loao - c-.. -----11--,,. Articles Well water; arsenic, and urinary organ cancers before cancer diagnoses did nor show an association with bladder cancer risk. Hence, Relatively recent arsenic exposure appears to 'be more relevant for bladder cancer risk. This is in concordance with the hypothesis that arsenic compounds act as promoters and/or co-carcinogens in the late stage of carcinogenesis {30-32). Cigarette smoking in the 1970s was more common among bladder cancer cases chan among referents; this is in agreement with previous studies which reported that smoking is associated with bladder cancer (25). In addition, there was some suggestion of a syn ergistic effect of arsenic and smoking (Table 7). This finding is consistent with earlier studies in which elevated arsenic exposure tended to increase the bladder cancer risk (9,17) among smokers. Experimental studies also suggest that arsenic compounds pro mote the carcinogenicity and genotoxicity of the known carcinogens and genoroxic com pounds (31-33). In this scudy, no association was observed between kidney cancer and arsenic exposure from drinking water. In earlier epi demiologic studies, an association between arsenic exposure and kidney cancer was somewhat weaker than the association to bladder cancer (6-8,10,11,13,16). It is difficult to compare the cancer risks between various studies because arsenic expo sure has been expressed in different ways and because the extension and duration ofarsenic exposure in these studies are different. The differences in the effect estimates in the stud ies may also be due to the differences in the possible misdassification of arsenic exposure, other sources of arsenic or other carcinogens, genetic background, health status, or nutri tional status. Most of the previous studies have had a cancer mortality as an end point. The partidpants in this study were older than persons in previous epidemiologic studies. Applying the results for cancer mortality obtained by Smith et al. (3) from Taiwanese data, the highest exposure categories in the present study population (median arsenic concentration 1.99 pg/L) would have a rela tive risk for bladder cancer of 1.01 in men Table 7. Age-adjusted risk ratios (RR) and 95% confidence intervals (Cl) for bladder cancer and arsenic exposure indicators among the men who smoked cigarettes in the 1970s and never or ex-smokers. Exposure Smoking in the 1970s Smoker (n= 181 No. RR Cl Never or ex-smoker (n = 17) No. RR Cl ^Kpncentration of arsenic in water (pg/L) ^bO.I ^^0.1-0.5 >0.5 81 3 UO 0.19-6.24 7 10.3 1.16-92.6 81 4 0.95 0.25-3.64 5 0.87 0.25-3.02 Daily dose of arsenic (pg/dayl <0.2 0.2-1.0 >1.0 81 5 1.99 0.40-9.78 5 6.91 0.80-59.5 91 5 t .53 0.44-5.31 3 0.61 0.14-2.65 Cumulative dose of arsenic (mg) <0.5 0.5--2.0 >2.0 31 8 4.0) 0.71-22.5 7 3.29 0.56-19.3 71 3 0.66 0.14-3.01 7 0.74 0.22-2.46 Only data for shorter latency and known smoking status are presented. Table 8. Age-, sex-, and smoking-adjusted risk ratios (RR) of kidney cancer and 95% confidence intervals (CIs) of the Finnish case-cohort study on arsenic exposure through well water. Exposure Concentration of arsenic in water |pg/L) <0.1 0.1-0.5 >0.5 (log) continuous17 Daily dose of arsenic (pg/day) <0.2 0.2-1.0 >1.0 (log) continuous17 Cumulative dose of arsenic (mg) <0.5 0.5--2.0 K2.0 g) continuous'7 Shorter latency3 No. RR Cl 23 1 12 0.78 0.37-1.66 14 1.49 0.67-3.31 49 1.16 0.80-1.69 26 1 13 1.08 0.52-2.25 10 1.21 0.52-2.82 49 1.10 0.77-1.58 18 1 12 0.74 0.33-1.68 19 0.80 0.42-1.86 49 0.59 0.28-1.23 ______ longer latency6 No. RR Cl 25 1 9 0.33 0.14-0.77 15 1.07 0.46-2.52 49 0.72 0.38-1.36 27 1 11 0.55 0.25-1.21 11 0.94 0.39-2.27 49 0.59 0.28-1.23 24 1 11 0.36 0.16-0.81 11 0.47 0.21-1.04 49 0.76 0.44-1.30 Exposure in the third to ninth calendar years prior to the cancer diagnosis. `Exposure in the tenth calendar year and earlier prior to the cancer diagnosis. `Result from the model using log-transformed exposure values. and 1.03 in women. Hence, the present results, relative risk > 2, are higher than expected and raise a concern of the possible role ofbias or chance. Nutritional factors may modify the metabolism and possibly carcinogenicity of arsenic. Selenium is an important anticar cinogen (34), artcUxt has been suggested to reduce-the'fbxicity of arsenic (35) and to inhibit the methylation of inorganic arsenic in vitro (36). Therefore, deficiency of seleni um may increase the cancer risk ofarsenic. In Finland, the daily intake of selenium (average 30 pg) (37) was below the recommended 50-200 pg (38) before selenium supplemen tation in fertilizers started in 1985. The crude risk ratios of arsenic exposure and bladder cancer increased only slightly after adjustment for smoking. This suggests that, although the proportion of missing data on smoking was large, the results are probably not confounded by smoking. We believe that serious differential misclassification is unlikely in the present study. There were no differences between cases and non cases in the sampling or analyzing procedure. Furthermore, there were no differences in the demographic parameters of the eligible and the final study populations. It has previ ously been shown that relatives ate able to provide rather reliable information on smok ing and other major demographic and lifestyle factors (39-41). Our results show that high arsenic levels in Finnish drilled wells used in the 1970s were uncommon and exposure through drinking water was low. We found no statis tically significant association between arsenic and risk of kidney cancer. However, consis tent with earlier studies, there was some evi dence for an increased risk of bladder cancer associated with arsenic exposure 2-9 years before the diagnosis and some suggestion of a synergistic effect between aisenic and smok ing. Due to low exposure levels in the present study, the positive association between arsenic exposure and risk of bladder cancer was not expected, and the role of bias and chance needs to be carefully considered. References and Notes I. IARC. Arsenic and arsenic compounds. IARC Monogr Eval Carcinog Risk Cham Hum 23:39-141 119801. Z KlimentV. Modal of multiple exposure to contaminants in monitoring the environmental impact on population health. Cent Eur J Public Health 4:248-249 (19%). 3. Smith AH. Nopenhayn-Rich C, Bates MN, Goeden HM, Kertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith MT. Cancer risks from arsenic in drinking water. Environ Health Perspact 97:259-267 (1992). 4. WHO. Guidelines for Drinking-Water Quality. 2nd ed. Geneva:World Health Organization International Programme on Chemical Safety. 1996:156-167. 5. Tseng W-P. Effects and dose-response relationships of skin cancer and Biackfont disease with arsenic Environ Health Perspact 19:109-119 (1977). ' Environmental Health Perspectives Volume 107, Number 9, September 1999 709 Articles - Kurttio et al. 6. Chen C-J, Kuo TL Wu M. Arsenic and cancers. Lancet 1:414-415(1988). 7. Chen C-J. Chen CWr Wu M-M. Kuo T-L Cancer potential in liver, lung, bladder and kidney due to ingested Inorganic arsenic in drinking water. Br J Cancer 66:888-892 (1992). 8. Wu MM, Kuo TL Hwang Y, Chen C. Dose-response rela tion between arsenic concentration in wed water and mortality from cancers and vascular diseases. Am J Epidemiol 130:1123-1132 (1989). 9. Chiou HY, Hsush YM. Uaw KF, Homg SF. Chiang MH, Pa YS, Lin JS. Huang CH, Chen CJ. Incidence of internal can cers and ingested inorganic arsenic: e seven-year follow up study in Taiwan. Cancer Res 55:1296-1300 (1995). 10. Chen C-J, Wang CJ. Ecological correlation between arsenic level in weB water and age-adjusted mortality from malignant neoplasms. Cancer Res 50:5470-5474 (1990). 11. Guo H-R, Chiang H-S, Hu H, Lipsitz SR, Monson RR. Arsenic in drinking water and incidence of urinary can cers. Epidemiology 8:545-550 (19971. 12. Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Teilo EE, Nicolli H, Smith AH. Bladder cancer mortality associated with arsenic in drinking water in Argentina. Epidemiology 7:117-124 (1996). 13. Hopenhayn-Rich C, Biggs ML, Smith AH. Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina, lot J Epidemiol 27:561-569 (1998). 14. Tsuda T, Nagire T, Yamamoto M, Kume Y. An epidemiolog ical study on cancer in certified arsenic poisoning patients in Toruku. Ind Health 28:53-62 (1990). 15. Tsuda T, Babazono A. Yamamoto E, Kurumatani N, Mino Y, Ogawa T, Kishi Y, Aoyama H. Ingested arsenic and internal cancer: a historical cohort study followed for 33 years. Am JEpidemtoI 141:198-209(1995). 16. Smith AH. Goycolea M, Haque R, Biggs ML. Marked increase in bladder and lung cancer mortality in a region of northern Chile due to arsenic in drinking water. Am J Epidemiol 147:660-669 (1998). 17. Bates MN, Smith AH, Cantor KP. Case-control study of bladder cancer and arsenic in drinking water. Am J Epidemiol 111:523-530(1995). 18. Kujala-Raty K, Hiisvirta L, Kaukonen M, Uponkoski M, Sipda A. Duality of Household Water in Finland in 1996 [in Finnish}. Finnish Environment 181. He!sinki:Edita Ltd, 1998. 19. Kurttio P, Komularnen H, Hakala E, Kahelin H, Pekkanen J. Urinary excretion of arsenic species after exposure to arsenic present in drinking water. Arch Environ Contam Toxicol 34:297-305 (1998). 3). Lahermo P. V3nSnen P, Tarvainen T, Saiminen R. Geochemical Atlas of Finland, Part 3: Environmental Geochemistry--stream waters and sediments [in Finnish). Espoo, Fin!and:Geologica! Survey of Finland, 1996. 21. Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Bicmetrika 73:1-11(1986). 22. lahermo P, AJfthan G, Wang O. Selenium and arsenic in the environment in Finland. J Environ Pathol Toxicol Oncol 17205-216 (1998). 23. Barlow WE. Robust variance estimation of case-cohort design. Biometrics 50:1064-1072(1994). 24. Dreyer L Winther JF, Pukkaia E, Andersen A. Tobacco smoking. APMIS Suppl.76:9-47 (1997). 25. McLaughlin JK, Blot WJ, Devesa SS, Fraumeni JF Jr. Renal cancer. In: Cancer Epidemiology and Prevention (Schottenfeld D, Fraumeni JF Jr, eds). New York:0xford University Press, 1996;T142-1155. 26. Muscat JE, Hoffmann D, Wynder EL The epidemiology of renal ceil carcinoma: a second look. Cancer 75:2552-2557 (1995). 27. Valberg PA, Beck BD, Bowers TS, Keating JL Bergstrom PD. Boardman PD. issues in setting health-based cleanup levels for arsenic in soil. Reg Toxicol Pharmacol 26:219-22911997). 28. Tseng WP, Chu HM, How S, Fong J, Lin C, Yeh S. Prevalence of skin cancer in an endemic area of chronic arsenicism m Taiwan. J Natl Cancer Inst 40:453-483 (1968). 29. Cuzick J, Sasieni P, Evans S. Ingested arsenic, keratoses and bladder cancer. Am J Epidemiol 136:417-421 (1992). 30. Brown JL, Kitchin KT. Arsenite, but not cadmium, induces ornithine decarboxylase and heme oxygenase activity in rat liver relevance to arsenic cercinog Cancer Lett 98227-231 (1996). 31. Mass MJ, Wang L Arsenic otters cytosine metf patterns of the promoter of the tumor suppresso p53 in human lung cells: a model for a mechanism cinogenesis. Mutat Res 386263-277 (1997). 32. Li JH, Rossman TG. Mechanism of comutagem _.... sodium arsenite with n-methyl-n-nrtrosourea. Biol Elem Res 21373-381 (1989). 33. Wang TC, Huang JS, Yang VC, Lan HJ, Un CJ, J Delay of the excision of UV right-induced DNA add involved in the coclastogenicrty of UV light plus ar Int J Radial Biol 66267-372 0994). 34. Schrauzer 6N. Selenium. Mechanistic aspects of a crnogenic action. Biol Trace Element Res 33:51--62 ( 35. Berry JP, Galie P. Selenium-arsenic interaction ir cells: role of lysosomes. Electron microprobe st Submicrosc Cytol Pathol 26:203-210 (1994). 36. Stybfo M. Delnomdedieu M. Thomas DJ. Monc dimethylation of arsenic in rat liver cytosol in Chem-6iol Interact 99:147-164 (1996). 37. Varo P, Koivistoinen P. XII. Mineral element compos! Finnish foods. Acta Agric Scand Suppl 22:165-171 (19 38. National Public Health Institute. Expert Grot Nutritional Follow-up, Report on Nutrition 19 Finnish]. National Public Health institute 81/ HetsinkhNationai Public Health Institute, 1996. 39. Boyfa CA, Brann EA. Proxy respondents and the v of occupational and other exposure data. The Sel Cancers Cooperative Study Group. Am J Epid 136:712-721(1992). 40. Lyon JL, Egger MJ, Robison LM, Freneh TK, G Misclassification of exposure in a case-controls the effects of different types of exposure and dift proxy respondents in a study of pancreatic ca Epidemiology 3:223-231 (1992). 41. Nelson LM, Longstreth WT Jr, Koepsail TD, Check H, van Belle G. Completeness and accuracy of inta data from proxy respondents: demographic, madica life-style factors, Epidemiology 5204-217 (1994). IARC Scientific Publication 150 Exocyclic DNA Adducts in Mutagenesis and Carcinogenesis Edited by B. Singer and H. Bartsch A 350-page international compilation of expert reviews on exocyclic DNA adducts covering: Identification, analysis and chemical synthesis Formation through natural endogenous processes and by exogenous carcinogens 4- Use as biomarkers Effects on DNA repair and replication Role in mutagenesis and carcinogenesis US$75 from IAJRC/Vew http://www.iarc.fr/ Email: press@iarc.fr Fax: +33 4 72 73 83 02