Arsenic in drinking water is known to cause cancer and noncancer diseases, but little is known about its association with age at exposure. Here, we investigated age at arsenic exposure and mortality in Antofagasta, Chile, 30-40 years after a distinct period of very high water arsenic concentrations (1958-1970). We calculated standardized mortality ratios (SMRs) comparing Antofagasta with the rest of Chile for 2001-2010 by sex and age at potential first exposure. A remarkable relationship with age at first exposure was found for bronchiectasis, with increased risk in adults 30-40 years after exposure being confined to those who were in utero (SMR = 11.7, 95% confidence interval (CI): 4.3, 25.4) or aged 1-10 years (SMR = 5.4, 95% CI: 1.1, 15.8) during the high-exposure period. Increased SMRs for lung, bladder, and laryngeal cancer were evident for exposures starting at all ages, but the highest SMRs were for exposures beginning at birth (for bladder cancer, SMR = 16.0 (95% CI: 10.3, 23.8); for laryngeal cancer, SMR = 6.8 (95% CI: 2.2, 15.8); for lung cancer, SMR = 3.8 (95% CI: 2.9, 4.9)). These findings suggest that interventions targeting early-life arsenic exposure could have major impacts in reducing long-term mortality due to arsenic 30-40 years after exposure ends.

Background

Beginning in 1958, the city of Antofagasta in northern Chile was exposed to high arsenic concentrations (870 µg/L) when it switched water sources. The exposure abruptly stopped in 1970 when an arsenic-removal plant commenced operations. A unique exposure scenario like this--with an abrupt start, clear end, and large population (125,000 in 1970), all with essentially the same exposure--is rare in environmental epidemiology. Evidence of increased mortality from lung cancer, bronchiectasis, myocardial infarction, and kidney cancer has been reported among young adults who were in utero or children during the high-exposure period.

Objective

We investigated other causes of mortality in Antofagasta among 30- to 49-year-old adults who were in utero or ≤ 18 years of age during the high-exposure period.

Methods

We compared mortality data between Antofagasta and the rest of Chile for people 30-49 years of age during 1989-2000. We estimated expected deaths from mortality rates in all of Chile, excluding Region II where Antofagasta is located, and calculated standardized mortality ratios (SMRs).

Results

We found evidence of increased mortality from bladder cancer [SMR = 18.1; 95% confidence interval (CI): 11.3, 27.4], laryngeal cancer (SMR = 8.1; 95% CI: 3.5, 16.0), liver cancer (SMR = 2.5; 95% CI: 1.6, 3.7), and chronic renal disease (SMR = 2.0; 95% CI: 1.5, 2.8).

Conclusions

Taking together our findings in the present study and previous evidence of increased mortality from other causes of death, we conclude that arsenic in Antofagasta drinking water has resulted in the greatest increases in mortality in adults < 50 years of age ever associated with early-life environmental exposure.

Background

Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstrate that arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced very high concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958 until an arsenic removal plant was installed in 1970.

Methods

We investigated breast cancer mortality from 1950 to 2010 among women in Region II compared to Region V, which had low arsenic water concentrations. We conducted studies on human breast cancer cell lines and compared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies.

Findings

Before 1958, breast cancer mortality rates were similar, but in 1958-1970 the rates in Region II were half those in Region V (rate ratio RR = 0·51, 95% CI 0·40-0·66; p<0·0001). Women under the age of 60 experienced a 70% reduction in breast cancer mortality during 1965-1970 (RR=0·30, 0·17-0·54; p<0·0001). Breast cancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurred in people in Region II.

Interpretation

We found biologically plausible major reductions in breast cancer mortality during high exposure to inorganic arsenic in drinking water which could not be attributed to bias or confounding. We recommend clinical trial assessment of inorganic arsenic in the treatment of advanced breast cancer.

Arsenic in drinking water is an established cause of lung cancer, and preliminary evidence suggests that ingested arsenic may also cause nonmalignant lung disease. Antofagasta is the second largest city in Chile and had a distinct period of very high arsenic exposure that began in 1958 and lasted until 1971, when an arsenic removal plant was installed. This unique exposure scenario provides a rare opportunity to investigate the long-term mortality impact of early-life arsenic exposure. In this study, we compared mortality rates in Antofagasta in the period 1989-2000 with those of the rest of Chile, focusing on subjects who were born during or just before the peak exposure period and who were 30-49 years of age at the time of death. For the birth cohort born just before the high-exposure period (1950-1957) and exposed in early childhood, the standardized mortality ratio (SMR) for lung cancer was 7.0 [95% confidence interval (CI), 5.4-8.9; p<0.001] and the SMR for bronchiectasis was 12.4 (95% CI, 3.3-31.7; p<0.001). For those born during the high-exposure period (1958-1970) with probable exposure in utero and early childhood, the corresponding SMRs were 6.1 (95% CI, 3.5-9.9; p<0.001) for lung cancer and 46.2 (95% CI, 21.1-87.7; p<0.001) for bronchiectasis. These findings suggest that exposure to arsenic in drinking water during early childhood or in utero has pronounced pulmonary effects, greatly increasing subsequent mortality in young adults from both malignant and nonmalignant lung disease.

Background

Millions of people worldwide are exposed to arsenic-contaminated water. In the largest city in northern Chile (Antofagasta), more than 250,000 people were exposed to high arsenic drinking water concentrations from 1958 until 1970 when a water treatment plant was installed. Because of its unique geology, limited water sources, and good historical records, lifetime exposure and long-term latency patterns can be assessed in this area with better accuracy than in other arsenic-exposed areas worldwide.

Methods

We conducted a population-based case-control study in northern Chile from October 2007 to December 2010 involving 232 bladder and 306 lung cancer cases and 640 age- and gender-matched controls, with detailed information on past exposure and potential confounders, including smoking and occupation.

Results

Bladder cancer ORs for quartiles of average arsenic concentrations in water before 1971 (<11, 11-90, 91-335, and >335 μg/L) were 1.00, 1.36 [95% confidence interval (CI), 0.78-2.37], 3.87 (2.25-6.64), and 6.50 (3.69-11.43), respectively. Corresponding lung cancer ORs were 1.00, 1.27 (0.81-1.98), 2.00 (1.24-3.24), and 4.32 (2.60-7.17). Bladder and lung cancer ORs in those highly exposed in Antofagasta during 1958 to 1970 but not thereafter were 6.88 (3.84-12.32) and 4.35 (2.57-7.36), respectively.

Conclusions

The lung and bladder cancer risks that we found up to 40 years after high exposures have ended are very high.

Impact

Our findings suggest that prevention, treatment, and other mortality reduction efforts in arsenic-exposed countries will be needed for decades after exposure cessation.