Share this article on:

Kidney Cancer Mortality: Fifty-year Latency Patterns Related to Arsenic Exposure

Yuan, Yana; Marshall, Guillermob,c; Ferreccio, Catterinab; Steinmaus, Craiga,d; Liaw, Janea; Bates, Michaele; Smith, Allan H.a

doi: 10.1097/EDE.0b013e3181c21e46
Cancer: Original Article

Background: Arsenic in drinking water is associated with kidney cancer. Beginning in 1958, a region of Chile experienced a rapid onset of high arsenic exposure in drinking water, followed by sharp declines when water treatment plants were installed in 1971.

Methods: For the years 1950–1970, we obtained mortality data from death certificates for an exposed region and an unexposed region in Chile. We obtained computerized mortality data for all of Chile for 1971–2000.

Results: Kidney cancer risks for the exposed region compared with the unexposed started to increase about 10 years after high arsenic exposures began in 1958. The peak kidney cancer mortality rate ratio (RR) was 3.4 (95% confidence interval = 2.2–5.1) for men in 1981–1985, with subsequent declines to 1.6 (1.2–2.1) by 1996–2000. Mortality RRs among women were 2.9 (1.8–4.7) in 1981–1985 but remained high longer than for men, increasing further to a RR of 4.4 (3.0–6.4) in 1991–1995. Early-life exposure resulted in an increased RR of 7.1 (3.1–14) for young adults aged 30–39 years, born just before or during the high exposure period.

Conclusions: This study shows a latency pattern of increased mortality from kidney cancer, continuing for at least 25 years after the high exposures began to decline. Early life exposure resulted in markedly higher kidney cancer mortality in young adults.

From the aArsenic Health Effects Research Program, University of California, Berkeley, CA; bDepartamento de Salud Pública, Escuela de Medicina, Universidad Católica de Chile, Santiago, Chile; cDepartamento de Estadística, Facultad de Matemáticas, Universidad Católica de Chile, Santiago, Chile; dOffice of Environmental Health Hazard Assessment, California Environmental Protection Agency, Berkeley, CA; and eSchool of Public Health, University of California, Berkeley, CA.

Submitted 17 December 2008; accepted 28 May 2009.

Supported by National Institute of Environmental Health Sciences grants R01 ES10033–03 and P42-ES04705 and by the University of California Center for Occupational and Environmental Health.

Correspondence: Allan H. Smith, Arsenic Health Effects Research Program, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94720–7360. E-mail:

Kidney cancer risks have been found to increase with exposure to arsenic in drinking water in Taiwan,1–8 Argentina,9 Japan,10 Finland,11 and Chile.12 However, relative risk estimates for kidney cancer are generally lower than those for urinary bladder cancer, and no studies had reported dose-response relationships on the basis of individual exposure assessment. Evidence for causation has been regarded by the International Agency for Research on Cancer (IARC) as insufficient to classify kidney cancer among the cancers caused by arsenic in drinking water.13

Region II in the north of Chile (Fig. 1), with a population of 477,000 in 2000, provides a valuable opportunity to investigate the long-term health effects of arsenic. It is one of the driest places on earth, and almost all drinking water in this region is supplied by a few large municipal water sources. Arsenic concentrations have been documented for the past 50 years. This is in contrast to other countries with high arsenic exposures, such as Argentina, Bangladesh, China, India, Taiwan, and the United States, where high arsenic exposures come primarily from wells. Assessing exposure in these other areas is extremely difficult because of the large number of wells, the high variability in arsenic concentrations from well to well, and the general lack of historical arsenic measurements.



The second important aspect of the arsenic exposure scenario in Region II is that the region experienced a rapid onset of very high arsenic exposure in the late 1950s when rivers contaminated with arsenic began to be used for drinking water. Exposure was greatly reduced starting in 1971, when installation of water treatment plants began.12 More than half of the population in this region lives in Antofagasta and Mejillones (current population: 318,000)—cities that were exposed to levels of arsenic greater than 850 μg/L for a 13-year period (1958–1970) (Table 1). 12



We recently reported lung cancer, bladder cancer and circulatory disease mortality in Region II from 1950 to 2000.14,15 Mortality rates from lung and bladder cancers started to increase about 10 years after the high exposures to arsenic in drinking water commenced and did not peak until about 20 years after exposures began to decrease.14 In contrast, mortality rates from acute myocardial infarction started to increase at the same time that high exposures began and decreased about 10 years after exposures were reduced.15 The purpose of the present analysis is to investigate kidney cancer mortality in Region II before, during, and after the period of very high arsenic exposure. We also assess the impact of early life exposure to arsenic, in light of our previous findings of increased mortality from lung cancer, bronchiectasis, and acute myocardial infarction in young adults who had in utero and early childhood exposure to arsenic,15,16 and increased childhood liver cancer mortality.17

Back to Top | Article Outline


Exposure Data and Comparison Population

Details concerning the arsenic concentrations in water in Region II have been reported previously.12,18,19 The concentration of arsenic in drinking water for the cities of Antofagasta and Mejillones (which shared the same water source) increased in 1958 from about 90 μg/L to an average of 870 μg/L (Table 1). With the introduction of a water treatment plant in 1971, Antofagasta's water arsenic concentration dropped to about 110 μg/L, and further reductions occurred with further improvements in treatment.

We selected Region V of Chile as a comparison population.15–17 The major city of this region (Valparaíso) has had water concentrations close to 1 μg/L.19 To ensure that Region V was an appropriate choice, preliminary investigations were conducted to compare per capita income, smoking rates, and death certification in Regions II and V.20–22

Back to Top | Article Outline

Mortality Data Collection

For years 1950–1970, all death certificates for Region II and Region V were photographed and coded by trained nosologists according to the International Classification of Diseases, Ninth Revision (ICD-9). Death certificates from both regions were intermingled, and nosologists were kept unaware as to the region from which death certificates came. After 1970, death certificates in Chile were coded in the capital Santiago, following the same rules regardless of the region of origin. Computerized mortality data first became available in Chile in 1971. These data were obtained from the Chilean National Institute of Statistics and from the Ministry of Health. The Tenth Revision (ICD-10) codes had been used for 1999 and 2000. For our analysis, all the ICD-10 codes were translated to ICD-9 codes.

Annual estimates of the population living in Regions II and V stratified by age and sex for the period 1950–2000 were obtained from the National Institute of Statistics.

Back to Top | Article Outline

Statistical Analysis

We estimated rate ratios (RRs) for kidney cancer mortality (ICD-9 code 189, ICD-10 codes C64–C66, C68) for Region II compared with Region V from 1950 to 2000, using Poisson regression (SAS version 9.2, SAS Institute, Inc, Cary, NC). To examine trends in kidney cancer mortality RRs, for each year in the study period we estimated the RR for that year combined with the 4 years before and the 4 years after it, thus smoothing short-term fluctuations.

A separate analysis evaluated the impact of early life arsenic exposure on risk of kidney cancer mortality later in life. We defined 2 major birth cohorts: those born during the high-exposure period, who would have experienced exposure in utero, as well as in early childhood, and those born in 1950–1957, just before the high exposure period, who would have experienced high exposure during childhood but not in utero. We focused on the mortality in young adults aged 30–39 years, because those born in the high exposure period 1958–1970 were over 30 years old by the year 2000. For the years 1989–2000, deaths and population estimates were available for 2 major cities in Region II (Antofagasta and Mejillones), which had the highest arsenic exposure. We compared mortality rates in Antofagasta and Mejillones with the rest of Chile using standardized mortality ratios (SMRs). We tested for differences between men and women, and between those born in 1950–1957 and 1958–1970, using Poisson regression interaction terms. There was little difference between sexes (P = 0.75) or between those born in 1950–1957 and those born in 1958–1970 (P = 0.73). We therefore pooled these 2 birth periods, and also present early life exposure results with the sexes combined.

Back to Top | Article Outline


Table 2 presents the mortality rates for kidney cancer in Region II and Region V in 1950–2000. The kidney cancer mortality rates in both regions increased rapidly throughout this period. Table 2 also presents the age-adjusted mortality rate ratios for kidney cancer in Region II compared with Region V from 1950 through 2000. Kidney cancer mortality rate ratios for Region II compared with Region V started to increase about 10 years after high arsenic exposures began in 1958, with an RR of 2.5 (95% confidence interval (CI) = 1.2–5.2) among men for the 5-year period centered in 1967, and an RR of 3.7 (1.8–7.6) for women for the 5-year period centered in 1972. The peak kidney cancer mortality rate ratio was 3.4 (2.2–5.1) for men in 1981–1985, with subsequent declines to 1.6 (1.2–2.1) in 1996–2000. Mortality RRs among women reached 2.9 (1.8–4.7) in 1981–1985 but remained high longer than for men, with an RR of 4.4 (3.0–6.4) in 1991–1995; then the mortality rate ratio declined to 2.3 (1.6–3.3) in 1996–2000. Figure 2 presents the time pattern using 9-year mortality rate ratio estimates.





Table 3 shows SMRs comparing Antofagasta and Mejillones (the 2 major cities in Region II) with the rest of Chile. For young adults aged 30–39 years, born in 1950–1970, who had early life exposure, the SMR was 7.1 (3.1–14). This increased risk is most unlikely to be due to chance (P < 0.001).



Back to Top | Article Outline


This 50-year mortality study shows a marked increase in deaths from kidney cancer in both Region II and Region V over the time period of the study. The mortality rate ratio estimates show a latency pattern of increases in Region II above those in Region V in relation to the period of high arsenic exposure. A long latency was apparent, with increased kidney cancer mortality rate ratios continuing for at least 25 years after the high exposure levels began to decline. The latency patterns are consistent with a causal interpretation and strengthen the epidemiologic evidence that arsenic in water causes increased rates of kidney cancer mortality. Adding to this evidence is the similar latency pattern for lung and bladder cancer, both related to arsenic exposure.14,15 This is the first study on kidney cancer to show an increase in rate ratios after exposure begins. The reductions in relative risk seen following reductions in exposure have also been reported in Taiwan.8

Mortality rates of kidney cancer have been reported to be increasing in some countries.23–26 In the United States, kidney cancer mortality increased from 1.5 per 100,000 deaths in 1983 to 6.5 per 100,000 deaths in 2002.25 The reasons for these increases are not clear. The rising incidence of kidney cancer may be largely attributable to an increased ability to detect small renal masses, but this does not explain the marked increase in mortality.24 As seen in Table 2, kidney cancer mortality greatly increased in the 50-year period of the study, and this increase suggests caution in interpreting the findings. Differences in time patterns of the upward trends could result in variations in RRs between the 2 Regions. Nevertheless, rate ratios increasing about 10 years after high exposure began are consistent with arsenic effects.

The findings of increased mortality rate ratios in young adults who had early life exposure are based on small numbers, but the standardized mortality rate ratios are high, with a 7-fold increased mortality for those born before or during the high exposure period (Table 3). We have previously reported increased mortality in young adults following early-life exposure to arsenic for lung cancer, bronchiectasis,16 and myocardial infarction.15 Biologic plausibility for the cancer findings can be found in arsenic experiments conducted on pregnant mice showing increased tumors in offspring.27,28

A limitation of our study is the lack of individual exposure data.29 However, we do not believe that ecologic bias is a problem in our study. Essentially everyone living in Region II was exposed to arsenic at high concentrations, while those in Region V and the rest of Chile were not. This exposure contrast is markedly different from that of most ecologic studies in which it is unclear whether the individuals who get disease are those who were actually exposed. Here we can state that there were increased rates of kidney cancer in the place where virtually everyone was exposed to high concentrations of arsenic in drinking water (Region II) compared with the place where all drinking water sources contained low arsenic concentrations (Region V). Some people who died in Region II may have recently migrated from another part of Chile where they were not exposed, and some from Region II may have migrated in the opposite direction. However, the effect of such migration would be to dilute exposure contrasts and would reduce, rather than cause, the positive associations. From 1965 to 2000, annual internal migration among regions was only 0.6%, compared with 1.2% in Argentina, 3.1% in the United Kingdom, and 6.6% in United States.30 Although our ecologic study lacks individual data on exposure, the only likely ecologic bias would be a small bias toward the null due to migration.

This study is limited to data from death certificates, most of which are completed by physicians (90% in Region II and 95% in Region V).22 We did not have death certificate information regarding types of kidney cancer; in particular, we cannot differentiate renal cell carcinoma from transitional cell cancer of the renal pelvis. It is possible that arsenic would have greater impact on transitional cell cancers than on renal cell cancers.31,32

Our study also did not have individual data on confounding factors, but it is nevertheless unlikely that our findings are due to confounding. For confounding factors to explain the observed rise and fall in kidney cancer mortality rate ratios, they would have to have a similar relation in time to the rise and fall in arsenic concentrations. In addition, confounding is unlikely to explain the magnitude of mortality rate ratios observed, which increased to more than 3-fold for both men and women. The major population risk factors for kidney cancer are smoking and obesity33,34; the relative risks reported for these factors are generally quite low. Relative risk estimates for smoking are usually between 1.5 and 2.33 We have previously reported that there is little difference in smoking rates between Region II and Region V.21 Regarding obesity, limited data are available on regional differences in Chile. Mean body mass index (BMI) values by region were reported in the 2003 national health survey involving over 3000 randomly selected adults throughout Chile. BMI levels were higher in Region II (mean = 27.6 kg/cm2 [95% CI = 26.5–28.7 kg/cm2]) than in Region V (26.8 kg/cm2 [26.1–27.5 kg/cm2]) or the country as a whole (26.8 kg/cm2 [26.6–27.1 kg/cm2]).35 These differences are small and could not have accounted for the relative risks we identified in this study.

In conclusion, the latency patterns of kidney cancer mortality increase in Region II are consistent with arsenic being the causal factor. Given the magnitude of the increased mortality rate ratios, it is unlikely that the differences are due to confounding. Finally, our evidence suggests early life exposure to inorganic arsenic results in markedly increased kidney cancer mortality in young adults.

Back to Top | Article Outline


1. Chen CJ, Chuang YC, Lin TM, Wu HY. Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res. 1985;45:5895–5899.
2. Chen CJ, Kuo TL, Wu MM. Arsenic and cancers. Lancet. 1988;1:414–415.
3. Chen CJ, Wu MM, Lee SS, Wang JD, Cheng SH, Wu HY. Atherogenicity and carcinogenicity of high-arsenic artesian well water. Multiple risk factors and related malignant neoplasms of blackfoot disease. Arteriosclerosis. 1988;8:452–460.
4. Wu MM, Kuo TL, Hwang YH, Chen CJ. Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. Am J Epidemiol. 1989;130:1123–1132.
5. Chen CJ, Wang CJ. Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. Cancer Res. 1990;50:5470–5474.
6. Chen CJ, Chen CW, Wu MM, Kuo TL. Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer. 1992;66:888–892.
7. Tsai SM, Wang TN, Ko YC. Mortality for certain diseases in areas with high levels of arsenic in drinking water. Arch Environ Health. 1999;54:186–193.
8. Yang CY, Chiu HF, Wu TN, Chuang HY, Ho SC. Reduction in kidney cancer mortality following installation of a tap water supply system in an arsenic-endemic area of Taiwan. Arch Environ Health. 2004;59:484–488.
9. Hopenhayn-Rich C, Biggs ML, Smith AH. Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina. Int J Epidemiol. 1998;27:561–569.
10. Tsuda T, Babazono A, Yamamoto E, et al. Ingested arsenic and internal cancer: a historical cohort study followed for 33 years. Am J Epidemiol. 1995;141:198–209.
11. Kurttio P, Pukkala E, Kahelin H, Auvinen A, Pekkanen J. Arsenic concentrations in well water and risk of bladder and kidney cancer in Finland. Environ Health Perspect. 1999;107:705–710.
12. 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. 1998;147:660–669.
13. International Agency for Research on Cancer. Some drinking-water disinfectants and contaminants, including arsenic. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol 84. Lyon, France: World Health Organization; 2004.
14. Marshall G, Ferreccio C, Yuan Y, et al. Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst. 2007;99:920–928.
15. Yuan Y, Marshall G, Ferreccio C, et al. Acute myocardial infarction mortality in comparison with lung and bladder cancer mortality in arsenic-exposed region II of Chile from 1950 to 2000. Am J Epidemiol. 2007;166:1381–1391.
16. Smith AH, Marshall G, Yuan Y, et al. Increased mortality from lung cancer and bronchiectasis in young adults following exposure to arsenic in utero and early childhood. Environ Health Perspect. 2006;114:1293–1296.
17. Liaw J, Marshall G, Yuan Y, Ferreccio C, Steinmaus C, Smith AH. Increased childhood liver cancer mortality and arsenic in drinking water in Northern Chile. Cancer Epidemiol Biomarkers Prev. 2008;17:1982–1987.
18. Ferreccio C, Gonzalez CA, Milosavjlevic V, Marshall G, Sancha AM, Smith AH. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology. 2000;11:673–679.
19. Hopenhayn C, Ferreccio C, Browning SR, et al. Arsenic exposure from drinking water and birth weight. Epidemiology. 2003;14:593–602.
20. Instituto Nacional de Estadistica y Censos. Censo '91. Censo Nacional de Poblacion y Vivienda 1991. Resultados Definitivos–Caracteristicas Seleccionadas Cordoba Serie B No 4. Buenos Aires, Argentina: Republica Argentina Ministerio de Economia y Obras y Servicios Publicos Secretaria de Programacion Economica; 1993.
21. CASEN. Ministerio de Planificacion y Cooperacion Nacional Republica de Chile. 15th ed. Santiago, Chile: Illa Encuestra CASEN (Caracterizacion Socio Economica Nacional); 1992.
22. Castillo B, Mardones G. Medical certification of deaths in the health services of Chile [in Spanish]. Rev Med Chil. 1986;114:693–700.
23. Kiemeney L, Van Berkel H, Witjes JA, Sonke GS, Debruyne FM, Straatman H. Kidney cancer mortality in the Netherlands, 1950–94: prediction of a decreasing trend. J Epidemiol Biostat. 1999;4:303–311.
24. Chow WO, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281:1628–1631.
25. Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst. 2006;98:1331–1334.
26. Levi F, Ferlay J, Galeone C, et al. The changing pattern of kidney cancer incidence and mortality in Europe. BJU Int. 2008;101:949–958.
27. Waalkes MP, Keefer LK, Diwan BA. Induction of proliferative lesions of the uterus, testes, and liver in swiss mice given repeated injections of sodium arsenate: possible estrogenic mode of action. Toxicol Appl Pharmacol. 2000;166:24–35.
28. Waalkes MP, Liu J, Diwan BA. Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol. 2007;222:271–280.
29. Morgenstern H, Thomas D. Principles of study design in environmental epidemiology. Environ Health Perspect. 1993;101:23–38.
30. Soto R, Torche A. Spatial inequality, migration, and economic growth in Chile. Cuadernos de Economía. 2004;41:401–424.
31. Guo HR, Chiang HS, Hu H, Lipsitz SR, Monson RR. Arsenic in drinking water and incidence of urinary cancers. Epidemiology. 1997;8:545–550.
32. Chiou HY, Chiou ST, Hsu YH, et al. Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol. 2001;153:411–418.
33. Moore LE, Wilson RT, Campleman SL. Lifestyle factors, exposures, genetic susceptibility, and renal cell cancer risk: a review. Cancer Invest. 2005;23:240–255.
34. Adam KF, Leitzmann MF, Albanes D, et al. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol. 2008;168:268–277.
35. Gobierno de Chile, Ministerio de salud. Resultados 1 encuesta de salud, Chile 2003. Available at: Accessed December 15, 2008.
© 2010 Lippincott Williams & Wilkins, Inc.