Document Eq31EQmvqNRzVreNkadv04ny0

\Olrbb NOTA RESEARCH NOTE 193 Catterina Ferreccio 1 Claudia Gonzalez Psych 1 Vivian Milosavjlevlc Stat1 Guillermo Marshall Gredis 2 Ana Marla Sancha 2 Lung cancer and arsenic exposure in drinking water: a case-control study in northern Chile Cancer de pulmdn y exposicidn a arsdnico en el agua potable: un estudio de casos y controles en el norte de Chile 1 Grupo para el Desarrollo de la InvestlgacJdn en Salud (GREDIS). Casllla 52750. Correo Central. Santiago. Chile. 2 Departamento Estadlstica, Facultad de MatemAticas, Pondfida Universldad Catdllca de Chile. Vicuha Mackenna.4860. Santiago 22, Casllla 306, Chile. 3 Facultad de Ciencias Flslcasy MatemAticas. Universldad de Chile. Av. Blanco Encalada.2120, 4a piso of. 17,Santiago, Chile. Abstract In some Chilean cities, levels ofarsenic (As) in drinking water reached 800 fig/L be tween 1950 and 1970, while current levels are 40 fJg/L. To evaluate the causal role of this expo sure in lung and bladder cancers, we conducted a case-control study in Regions I, II, and III of the country. From 1994 to 1996, cases diagnosed as lung cancer and two hospital controls were entered in the study; one control was a patient with a cancer, while the other was a patient with out cancer, both conditions unrelated to As. Controls were matched with cases by age and sex. A standard survey containing questions about residence, employment, health history, was admin istered to study subjects. Data on As concentrations in water were obtained from records of the municipal water companies. A total of 151 lung cancer cases and 419 controls (167 with cancer and 242 without cancer) were enrolled. Median level oflifetime As exposure was significantly higher among cases, with a clear dose-response relationship between mean As exposure levels, with an OR (95% Cl) of: 1,1.7 (0.5-5.1), 3.9 (1.2-13.4), 5.5(2.2-13.5), and 9.0 (3.6-22) for strata one to five respectively. This study provides new evidence that As in drinking water can cause in ternal cancers and gives an estimate ofthe form of this relationship. Key words Lung Neoplasms; Environmental Exposure; Arsenic Resumen En algunas ciudades de Chile, entre 1950y 1970, los niveles de arsenico (As) en el agua potable alcanzaron los 800 pg/1, estando hoy en 40pg/l; para evaluar el rol de esta exposicidn, se llevd a cabo este estudio de casos de c&ncer de pulmdn y controles en las Regiones I, IIy III. Entre 1994y 1996, se ingresaron casos de c&ncer de pulmdn ydos controles hospitalarios: un control, un paciente con c&ncery el otro, un paciente sin c&ncer, ambos diagndsticos no relacionados con arsdnico. Los controles fueron pareados grupalmente por edadysexo con los casos. A cada sujeto, se le aplicd una encuesta estandarizada sobre resldencia, empleo y salud. La Informacidn sobre niveles de As en el agua provino de registros de las compahlas de agua. Se ingresa ron 151 casos de c&ncer pulmonary 419 controles (167 con c&ncer y 242 sin c&ncer). La mediana de As en el agua potable a lo largo de la vida fue significativamente mayor entre los casos, con una clara relacidn dosis-respuesta entre el promedio de Asyel riesgo, con OR (95% IC) de 1,1,7 (0,5-5,1), 3,9 (1,2-13,4), 5,5 (2,2-13,5),y 9,0 (3,6-22) para los estratos 1 al 5, respectivamente. Este estudio provee nueva evidencia sobre el rol causal del As en el agua potable en c&nceres intemos y sobre la forma de la relacidn entre exposicidny riesgo de c&ncer. Palabras clave Neoplasias de Pulmdn; Exposicidn Ambiental; Arsdnico Cad. SaOde PObUca, Riode Janeiro. 14{Sup. S):193-198,1998 I -|g4 FERRECCIO, C.etal. Introduction Identification of lung cancer cases Humans are exposed to organic and inorganic arsenic (As) from environmental and occupa tional sources. The main source of exposure (in terms of number ofpeople affected) is environ mental, naturally occurring inorganic As in drinking water (Hesse et al., 1990; Bates et al., 1995). Occupational exposure affects workers engaged in smelting and refining copper, gold, and lead ores and in the production of agricul tural pesticides, pigments, dyes, glass, semi conductors, and various pharmaceutical sub stances, including the possibility of high expo sure to airborne arsenic (WHO, 1981). Arsenic has been implicated as one of the main risk factors for skin, lung and bladder cancer deaths in northern Chile, where residents have used water with high As content for decades. In this region, besides the naturally occurring arsenic, copper smelting has been implicated as a risk factor for workers (Ferreccio et al.,1995). The aim of this study is to assess the doseresponse relationship between mean arsenic exposure in drinking water and risk of lung cancer among residents in northern Chile. Material and methods Study areas Northern Chile includes Regions I-m. This area contains the Atacama Desert, known as the mining zone of the country. The desert is 1,700 km long and an average of 300 km wide, with a population of 900,000. The main occupations are related to the mining and fishing indus tries. The highest exposure to arsenic has been in Region n, through drinking water. Measurement of exposure Water companies supply the region with well or surface water. They supply the same water to all households in a given city. In these re gions, 100% of the urban households are cov ered by the municipal water utilities systems. The utilities companies sire required to per form detailed chemical tests of the water, in cluding As levels, at least once a year. We col lected data on As levels from 1950 to 1996 for the 350 counties from the entire country. Nurses were recruited for the study and trained in interviewing techniques in each city of north ern Chile (Arica, Iquique, Copiapd, Antofagas ta). They were responsible for identifying cases in the hospitals. In the main hospitals, inter viewers made daily visits to the admissions de partments and to pathology laboratories to identify any patients admitted with lung can cer. Patients not identified until after discharge were visited and interviewed in their homes. Eligible cases were all those diagnosed with lung cancer in the study region between No vember 1994 and July 1996, confirmed by biop sy, and whose first diagnosis was either at the current hospitalization, or no more than one year before the current hospitalization. Selection of controls Two controls were selected for each lung can cer case from patients admitted to hospitals within one month of the index case. The first control (for control group A) was selected from patients with another cancer, unrelated to ar senic (Smith et al., 1988). Cancers of the liver, skin, kidney, bladder, and prostate were ex cluded. The second control (for control group B) was selected from patients with a diagnosis unrelated to arsenic and excluding cancer. Pa tients admitted with cardiovascular, skin, or neurological conditions were excluded. Con trols were not matched by hospital, since expo sure is closely related to the region in which patients resided. Instead, eligible controls in cluded all patients admitted to any hospital in the whole study region. The number of patients admitted to each hospital in 1994 was first identified, and a frequency distribution of numbers of admissions by hospital was calcu lated. Controls were selected to result in the same frequency distribution as those for ad missions. Thus, for each index case a control was selected as a hospital admission within a month of the index case, of the same sex and within four years of the case's age. Data collection The nurse administered a structured question naire to collect information for all subjects, in cluding: socioeconomic status (SES), lifetime residential history, occupational and health history, and smoking. To validate responses, a proxy questionnaire was applied to a family or close person to the subject. Nurses also con ducted a physical exam in all study subjects Cad. S8tlde Publics, Rio de Janeiro, 14($up. 3):193*198,1998 195LUNG CANCER AND ARSENIC EXPOSURE (looking for As-related lesions) and reviewed clinical records to register all other health con ditions. A letter of consent was read to all study sub jects, explaining the method of the study and the general objective. Only those who accepted and were able to answer the one-hour inter view were included in the study. Statistical analysis Arsenic Exposure: Histories of residential and work addresses were used to derive mean ar senic concentration in drinking water. This lifetime average was the mean level across all residential levels and periods. Lifetime As ex posure was analyzed as a continuous and cate gorical variable, where 5 exposure strata were developed based on subject distribution. The lowest exposure category was used as a refer ence to derive Odds Ratios (ORs) using uncon ditional regression analysis with the Stata Pro gram. ORs were estimated with univariate as well as multivariate models, controlling by age, sex, SES, smoking, and occupational history. Results from skin tests were combined with da ta from medical records to classify study sub jects in 4 categories: no lesions, pigmentation, keratoses, and skin cancer. Analyses were re peated separately for each type of control. A separate model was derived for women and men. A test for trend was done based on Cochran (1954). Results During the 20 months of enrollment, 217 new lung cases were diagnosed in the hospitals. A total of 151 (70%) had complete information to enter into the study. There were very few re fusals among cases and controls (less than 5%). The main reasons for not entering the study were that the patients were not at the hospital at the moment we attempted to contact them, had moved, or were too sick to fill out the ques tionnaire. A total of 419 controls entered the study, achieving the goal of one control per case for type B controls (252; 0.9 controls per case) but not for type A controls (167; 0.6 con trols per case). Lifetime mean As exposure in cases and controls is presented in Table 1. The data are arranged in five exposure strata, and crude and adjusted ORs are given for each stratum. Ad justed ORs were obtained with a logistical re gression model (Stata) including sex, age, and smoking status. There is a clear dose-response relationship (Cochrane test p<0.05) that is stronger when adjusted by age, sex, and smoking status (ever or never). OR estimations reaches statistical significance when As concentration was above 0.03mg/l. When control A was used as the ref erence group, the ORs were even higher than with control B (Table 2). Nevertheless, both ex press the same type of effect. Most of the analy sis was done with combined controls. When males and females were analyzed separately, males showed higher and more sig nificant ORs: 1,2.2 (0.6-8.7), 4.1 (0.9-17), 7.1 (2.3-21), and 9.7 (3.2-29) for strata 1 through 5, respectively, compared with females: ORs: 1,0.9 (0.1. -6.3), 3.6 (0.4-32.6), 2.7 (0.5-14.1), and 7.1 Table 1 Lifetime arsenic levels in drinking water for lung cases and controls. Average As 1930-1994. Mean (mg/L) 0-0.01 0.01-0.029 0.03-0.049 0.05-0.199 0.20-0.40 Controls (N:419) 70 68 24 130 127 Cases (N:151) 6 9 7 52 77 OR (crude) (95% C 1) 1 1.5 (.5-4.6) 3.4 (1.04-11.1) 4.7 (1.9-11.4) 7.1 (2.9-17.1) OR adjusted l' 1.7 (0.5-5.1) 3.9 (1.2-13.4) 5.5 (2.2-13.5) 9.0 (3.6-22.0) Cad. SaOde Publics, Rio de Janeiro, 14(Sup. 3):193-198,1993 196 FERRECCIO, C. et al. Table 2 Lifetime arsenic level in drinking water for lung cases and each type of control. Average As 1930-1994. Mean As (mg/L) 0-0.01 0.01-0.029 0.03-0.049 0.05-0.199 0.20-0.40 Control A (N:167) 30 27 7 59 44 Control B (N:242) 40 41 17 71 83 Cases (N:151) 6 9 7' 52 77 OR Controls A i 2.0 (0.6-6.7) 5.7 (1.4-23.5) 5.3 (1.9-14.3) 11.7 (4.3-32.0) OR Controls B 1 1.5 (0.5-4.7) 3.1 (0.9-11.1) 5.7 (2.1-14.7) 7.4 (2.9-18.9) Table 3 Discussion Skin status among study subjects. Skin Status No As lesion Pigmentation Keratosis Cancer Any As lesion Controls (%) 384 (92) 26(6) 8(2) 1 (0.2) 35 (8) Cases(%) 101 (66) 33 (22) 12(8) 5 (3.3) 50 (33) OR 1 4.8 5.7 19.0 5.4 (Cl 95%) (2.7-8.8) (2.1-15.8) (2-400) (3.0-9.1) (1.6-7.4) for strata 1 to 5, respectively. Both se ries present the same type of relationship be tween exposure and cancer risk, and they were thus combined for most of the analysis. Skin lesions related to arsenic (Table 3) were more frequent among cases (34%) than among controls (8%). with a linear trend from no lesions to skin cancer. We did not conduct a validity study of the nurses' diagnoses or the potential bias, given that they were not blinded to the subjects' conditions. Table 4 presents study groups classified as ever or never smoked. Odds ratios of As expo sure Eire presented separately for the two groups. There is a slightly higher OR among the smokers. Average number of packs of cigarettes smoked per year by cases and controls showed a clear dose-response relationship, with an OR of 1,1.8, 4.0, 5.4, and 14 for the strata: 0; 1-90; 91-180; 181-400; and >400 packs of cigarettes/ year, respectively. Males and females showed a similar curve, but there were no females in the highest exposure group Most of the association between arsenic and cancer risk in Chile has been based on ecologi cal data showing a correlation between excess risk of some cancers and high levels of As in drinking water (Ferreccio et al., 1997). Ecologi cal studies have the potential for many confounders such as other risk factors, different di agnostic criteria, and hospitalization rates, amongst others. This individual-based study intended to address some of these limitations by estimat ing the exposure level for each subject based on personal history and controlling for all known confounders. Previous evidence of the association be tween As and internal cancers had been ques tioned because all the evidence was based mainly on Taiwanese data, which might have been a highly susceptible population (Bates et al., 1992; Smith et al., 1992; Brown & Chen, 1995; Chiou et al., 1995; Mushak & Crocetti, 1995). This study confirms Taiwanese findings in a very different context. This is the first study of this kind in Chile and supported the ecologi cal evidence as well as previous studies done elsewhere. Among the limitations of this study is the potentially incomplete case identification. In fact, some cases in high socioeconomic groups may have been missed. When members of this group develop severe health conditions like suspected cancer, they seek medical care in the Greater Metropolitan Area. There is no rea son to believe that this group of potential cas es will have a different exposure rate to ar senic than the cases from the general popula tion, since every household gets the same wa- Cad. SaOde Pobllca, Rio de Janeiro, 14(Sup. 3):193-198,1998 Table 4 Risk of lung cancer and exposure to arsenic by smoking status. Lifetime average As drinking water (mg/L) < 0.001 0.001-0.029 0.03-0.049 0.05-0.199 > 0.200 Never smoked Controls Cases 189 30 OR 25 1 1 28 1 1.1 10 0 Inc 59 11 5.7 67 17 8.3 197LUNG CANCER AND ARSENIC EXPOSURE Ever smoked Controls Case 230 121 45 5 . 40 8 14 7 71 41 60 60 OR 1 1.9 5.1 5.4 9.2 ter in urban areas, regardless of socioeconom ic status. Another limitation relates to the exposure identification. Although arsenic exposure data were thorough, there were some years with no data. This incompleteness could lead to over or underestimation of exposure. The exposed areas have the most complete data series, so fluctuations in exposure levels are well-docu mented. The main distortion in estimates could affect the comparison group, i.e., the control groups. Since As can affect any organ system, diseased patients may have been more exposed to arsenic than the general population, thus producing an underestimation of the real risk. Thus, our results may be a very conservative es timation of the real risk of As in drinking water. There has also been a debate about the form of the dose-response relation between ar senic and CEincer risk (Hertz-Piccioto & Smith, 1993; Wu et Ed., 1989). This study supports the linearity assumption for this relationship The safety level for arsenic in drinking wa ter established by the US EPA (USA EPA, 1988) and by the Chilean Ministry of Health is 0.05 mg/L, but the current WHO recommendation is much lower (0.01 mg/L). This study supports the assertion that As is an etiologic factor for internal cancers and that the current norm for As levels could be unsafe. Acknowledgements References The authors are grateful to Dr. Allan Smith for his re view ofthe manuscript. BATES, M.; SMITH, A. & HOPENHAYN-RICH, C.. 1992. Arsenic ingestion and internal cancers: a review. AmericanJournal ofEpidemiology, 135:462-474. BATES, M.; SMITH, A. & CANTOR, K,, 1955. Case-con trol study of bladder cancer and arsenic in drink ing water. American Journal ofEpidemiology, 141: 523-530. . BROWN, K. & CHEN. C. H.. 1995. Significance of ex posure assessment to analysis of cancer risk from inorganic arsenic drinking water in Taiwan. Risk Analysis, 15:475-483. CHIOU, H.; HSUEH, Y.; LIAW, K. F.; HORNG, S. F.; CHIANG, M. H.; PU. Y. S.; LIN, J. S.; HUANG, C. H. & CHEN, C. J., 1995. Incidence ofintemal cancers smd ingested inorganic arsenic: a seven-year fol low-up study in Taiwan. Cancer Research, 55: 1296-1300. COCHRAN, W,, 1954. Some methods for strengthen ing the common Chi2 tests. Biometrics, 10:417 451 Cad. SaOde Publics, Rio de Janeiro, 14(Sup. 3):193*198,1998 u gg1 FERRECCIO. C. et al. FERRECCIO, C.; GONZALEZ, C.; SOLARI, J. & NODER, C-, 1995. CAncer broncopulmonar entre trabajadores expuestos a arsdnico: un estudio de casos y controles. Revista M6dica de Chile, 124:119-123. FERRECCIO, C.; GONZALEZ, C.; MILOSAVJLEVIC. V.; MARSHALL, G. & SANCHA, A. M,, 1997. Impacto en Salud Atribulble a Exposicidn a Arsinlco: Un Estudio Ecoldgico. Informe Final FONDEFProyecto 2-24. Santiago: Facultad de Ciencias Fisicas y Matemdticas, Unlversldad de Chile. HERTZ-PICCIOTTO, I. & SMITH, A., 1993. Observa tions on the dose-response curve for arsenic ex posure and lung cancer. ScandinavianJournal of Work and Environmental Health, 19:217-226. HESSE, J.; JANUS, J.; KRAJNC, E. & KROESE, E,, 1990. Integrated Criteria Document Arsenicum Effects. The Hague: National Institute of Public Health and Environmental Protection. MUSHAK, P. & CROCETTI, A., 1995. Risk and revision ism in arsenic cancer risk assessment. Environ mental Health Perspectives, 103:684-688. SMITH, A; PEARCE, N. & CALLAS. P,, 1988. Cancer case-control studies with other cancers as con trols. InternationalJournal ofEpidemiology, 17: 298-309. SMITH, A.: HOPENHAYN-RICH, C.; BATES, M. N.; GOEDEN, H. M.; HERTZ-PICCIOTO, I.: DUGGAN, H. M.; WOOD. R.; KOSNETT, M. J. & SMITH, M. T,, 1992. Cancer risk from arsenic in drinking water. Environmental Health Perspectives, 97:259-267. USA EPA (United States Environmental Protection Agency), 1988. Evaluation of the Potential Car cinogenicity ofArsenic and Inorganic Compounds. Washington, D.C.: Carcinogen Assesment Group. Office of Health and Environmental Assessment. WU, M. M.; KUO, T.; HWUANG, Y. & CHEN, C. J., 1989. Dose-response relation between arsenic concen tration in well water and mortality from cancers and vascular diseases? American Journal ofEpi demiology, 130:1123-1132. WHO (World Health Organization). 1981. Environ mental Health Criteria 18: Arsenic. Geneva: WHO. Cad. SaOde POblica, Rio de Janeiro, 14(Sup. 3):193-198,1998