We believe that this is the first evidence that arsenic in water may be related to pulmonary tuberculosis. The strength of the evidence includes the large population exposed, resulting in good precision in mortality rate ratio estimates, and the clear latency pattern that emerged among men, who are more susceptible to arsenic health effects than women are. Adding plausibility to the findings are the clear latency patterns that we have previously found in this population for causes of death known to be related to arsenic, including lung cancer and bladder cancer (16
), kidney cancer (23
), and mortality from myocardial infarction (15
), as well as bronchiectasis (9
). All health effects from chronic exposure to arsenic in drinking water, including skin lesions (24
), have latencies from first exposure of 10 years or more.
Although initially it may seem counterintuitive that arsenic in water would affect the lungs, it has become increasingly apparent that the lung is one of the main target sites for the effects of ingesting arsenic in water. In fact, lung cancer is the major cause of long-term mortality from ingested arsenic (9
). Urinary arsenic concentrations give a good biomarker of the absorbed dose of arsenic, since about 70% is excreted in the urine (25
). When related to urinary arsenic concentrations, lung cancer risks are about the same whether arsenic is ingested or inhaled (17
). This is a surprising finding that indicates that arsenic ingested in drinking water not only reaches the lungs but has major toxic effects there, including causing lung cancer.
The biologic plausibility for finding arsenic in drinking water affecting pulmonary tuberculosis rates can also be based on the fact that arsenic is a known immunosuppressant, based in part on animal experimental studies. Evidence in mice includes the arsenic-compromised immune response to influenza A infection (26
) and evidence that it alters expression of immune response genes in the mouse lung (27
). In addition, an increasing body of evidence shows arsenic to be an immunosuppressant in humans (6
). Interesting recent evidence suggests that this effect is greater in males than in females. In a prospective study of in utero arsenic exposure and child immunity in Bangladesh, evidence of reduced thymic development was seen especially in male infants, along with evidence of increased acute respiratory infections (8
The incidence of many arsenic health effects is higher in males than females. Evidence from studies in different countries shows that the characteristic skin lesions resulting from arsenic in drinking water are more common among men than women (28
). Mortality attributable to arsenic in drinking water includes lung cancer, bladder cancer, and myocardial infarction, but the incidence is much greater in men than in women. For example, in Region II of Chile, we estimated that there were 3,277 excess deaths among men due to these 3 causes of death compared with 947 excess deaths among women (15
). It has been suggested that the enhanced male response is due to higher proportions of the inorganic arsenic metabolite monomethylated arsenic in men compared with women, which includes a trivalent form of monomethylated arsenic that is the most toxic form of inorganic arsenic in vitro, having greater toxicity than arsenite (24
The strengths of this study include the large size of the exposed population: There were over 125,000 residents in Antofagasta and Mejillones combined in 1970 exposed to arsenic water concentrations of 870 μg/L. The second largest city in Region II, Calama, also had high arsenic water concentrations, as did nearly all towns and villages. This study is by far the largest study in the world of a population with known high concentrations of arsenic in drinking water. The largest cohort study conducted in Taiwan involved only 698 subjects exposed to arsenic concentrations of greater than 300 μg/L (31
). Recently published cohort studies in Bangladesh involved 10,431 subjects exposed to concentrations of greater than 300 μg/L in the largest study (32
) and 2,889 subjects exposed to concentrations of greater than 150 μg/L in the second (33
). In addition, each of these cohort studies had major problems with exposure ascertainment in the distant past. In contrast, our study region is the driest inhabited place on earth (34
), and all residents had only 1 water source, the city water supply. The contrast in exposure between Antofagasta in the period 1958–1970 (water arsenic concentration, 870 μg/L) and the rest of Chile, including Region V, is very large and clear-cut. Other highly exposed populations, including those in Taiwan and Bangladesh, have received their water from town wells or individual private wells with wide variations in arsenic concentrations, even between closely located wells. Wells used decades ago may now be closed, and water arsenic concentrations in early life are usually unknown. None of these complicated exposure scenarios is present in Region II of Chile; for example, children who drink water at school drink from the same town water supply that they drink from at home.
One apparent weakness of this study is that it is ecologic in nature, comparing 2 regions of Chile. However, the study does not have the usual problems associated with what is sometimes termed the “ecologic fallacy” (35
), since everyone drinks water, and in the exposed region all water sources were contaminated with arsenic. The only other ecologic bias would be from in-out migration. People migrating into Region II would dilute overall exposure and, therefore, would dilute the evidence of effects. The bias would thus be to underestimate real effects and not to produce spurious increased risks. Clearly, with the increased mortality reported here, this bias is not an issue. A weakness of the study is that there are no data for risk factors for tuberculosis including human immunodeficiency virus infection, substance abuse, silicosis, and diabetes. However, there is no reason that these risk factors should follow the latency time pattern in relation to arsenic exposure found here. Another weakness of this study is that it involves mortality data with no information on incidence rates. This means that we cannot tell if arsenic is increasing the incidence of disease, or increasing mortality among incident cases, or both. In addition, the main effects found were before 1990, and most Region II medical records for that time period are not available, so we could not confirm the cause of death given on the death certificates. Confirmatory studies are needed in other arsenic-exposed populations, preferably with diagnosis of incident cases.
In conclusion, we have presented evidence from Chile suggesting that increased mortality from pulmonary tuberculosis could be yet another serious outcome from exposure to arsenic in drinking water. If verified, the findings will have important public health implications, since some of the largest arsenic-exposed populations are in developing countries with widespread tuberculosis. If arsenic in water increases mortality from tuberculosis, then particular attention will be needed to ensure that patients with tuberculosis are not drinking arsenic-contaminated water.