Int Arch Occup Environ Health (2011) 84:591–600 Discussion The decreases in FEV1 and FVC and the PORs above 1.0 for breathlessness identiﬁed in this study suggest that early- life exposure to arsenic in drinking water affects lung function, and these effects remain many years after ces- sation of high exposure. Assuming each pack-year smoked is associated with a 7.4-ml decrease in FEV1 (Dockery et al. 1988), the decrease in lung function we observed was similar in magnitude to that of 45 pack-years. To our knowledge, this is the ﬁrst time a drinking water contam- inant has been linked to lung function and respiratory symptoms 4 decades after peak exposure. The exact mechanisms by which arsenic causes lung disease are unknown, and further research may be needed in this area. However, the biological plausibility that ingested arsenic can cause toxicity to the lungs is supported by a variety of studies. In rabbits, the species most similar to humans in terms of arsenic metabolism (NRC 1999), arsenic has been shown to accumulate in the lung more than other organs except the liver and kidney, which are the primary sites of metabolism and excretion (Bertolero et al. 1981; Marafante et al. 1981). Other animal studies show that the primary metabolite of arsenic, dimethylarsinic acid (DMA), is retained longer in the lungs than in other tissues (Kenyon et al. 2008; Vahter et al. 1984). In humans, ingested arsenic is an established cause of lung cancer (IARC 2004), and several studies have linked it to non- malignant respiratory effects including respiratory symp- toms, pulmonary function, and a 10-fold increase in radiographically conﬁrmed bronchiectasis (De et al. 2004; Guha Mazumder et al. 2000, 2005; Guo et al. 2007; Milton and Rahman 2002; Parvez et al. 2008; Smith et al. 2006; von Ehrenstein et al. 2005). In fact, increases in human lung cancer risk are similar whether arsenic is ingested or inhaled (Smith et al. 2009). This body of research provides evidence that the human lung is particularly susceptible to arsenic in drinking water. Environmental exposures may be particularly harmful in early life because of rapid organogenesis and differences in children’s water intake, metabolism, and detoxiﬁcation (Landrigan et al. 2004). Arsenic is known to cross the placenta and reach the fetus, and total arsenic levels in umbilical cord blood and maternal blood are similar (Concha et al. 1998b; Hall et al. 2007; Vahter 2009). Several studies have shown that metabolism of arsenic to its less toxic metabolite, DMA, is increased in pregnant women (Vahter 2009). However, a recent study of mother– infant pairs in Bangladesh found that less than half of total arsenic in cord blood was DMA (Hall et al. 2007). Other data suggest that arsenic metabolism may differ between children and adults, but these ﬁndings are not entirely consistent (Hall et al. 2009). In a study in a highly exposed 597 region of Argentina, children could not metabolize ingested inorganic arsenic to DMA as well as adults (Concha et al. 1998a). In utero arsenic exposures have been linked to reproductive outcomes including stillbirth (Hopenhayn- Rich et al. 2000; Vahter 2008, 2009; von Ehrenstein et al. 2006) and, in male infants, smaller thymus size and acute respiratory illnesses (Raqib et al. 2009). In mice, in utero drinking water arsenic exposure caused irreversible chan- ges in airway reactivity to methacholine, altered gene and protein expression (Lantz et al. 2009) and, at concentra- tions C42,500 ug/l, tumors in the lungs of offspring but not dams (Waalkes et al. 2007). An ecologic study comparing the arsenic-exposed city of Antofagasta to other regions of Chile found that those exposed in early life had higher death rates from lung cancer (standardized mortality ratio (SMR) = 6.1, 95% CI 3.5–9.9), bronchiectasis (SMR = 46.2, 95% CI 21.1–87.7), and other COPD (SMR = 7.6, 95% CI 3.1–15.6) in adulthood (Smith et al. 2006). These studies all support our results linking early-life arsenic ingestion to long-term respiratory effects. Our results are consistent with the 2 previously pub- lished studies of ingested arsenic and lung function in people with probable adult exposures. In a study involving 31 subjects in Bangladesh, urinary arsenic concentration (indicative of current exposure) was inversely associated with percent predicted FEV1 and FVC (Parvez et al. 2008). In 287 subjects from West Bengal, India, men with arsenic- caused skin lesions had 256 and 288 ml lower FEV1 and FVC, respectively, than those without skin lesions or known high arsenic exposures (von Ehrenstein et al. 2005). The FEV1 deﬁcits were much smaller in women (64 ml). We also found much smaller effects in women (17-ml FEV1 reduction versus 440 ml for men). Other studies have reported greater arsenic-associated health effects in men (Marshall et al. 2007; Rahman et al. 2006), perhaps due to sex-related differences in arsenic metabolism, water intake, occupational and other exposures (Hertz-Picciotto et al. 1992; Lindberg et al. 2010; Vahter 2009). The greater effects observed in men in this study were not likely due to interactions with smoking since larger arsenic-associated lung function deﬁcits were seen in never smokers, yet men smoked more than women in terms of the proportion of ever smokers (71% vs. 63%), pack-years (5.2 vs. 4.0), and cigarettes per day (4.2 vs. 3.4). Strengths of our study include the accuracy of data on past arsenic exposure. In other places with widespread exposure, the abundance of private wells and other water sources, coupled with a lack of historical arsenic records, makes studies of long-term health effects much more dif- ﬁcult. By contrast, northern Chile has limited water sources and has arsenic records dating back more than 50 years, providing a unique opportunity to study the long-term impacts of exposure. The main limitation of this study is 123