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.

Such large increases in total population cancer mortality rates have, to our knowledge, not been documented for any other environmental exposure. The long latency pattern is noteworthy, with mortality from lung and bladder cancers continuing to be high until the late 1990s, even though major decreases in arsenic exposure occurred more than 25 years earlier.

Numerous epidemiologic investigations have identified links between high concentrations of arsenic in drinking water and cancer, although the risks at lower exposures are largely unknown. This paper presents the results of a case-control study of arsenic ingestion and bladder cancer in seven counties in the western United States. These counties contain the largest populations historically exposed to drinking water arsenic at concentrations near 100 microg/liter. All incident cases diagnosed from 1994 to 2000 were recruited. Individual data on water sources, water consumption patterns, smoking, and other factors were collected for 181 cases and 328 controls. Overall, no increased risks were identified for arsenic intakes greater than 80 microg/day (odds ratio=0.94, 95% confidence interval: 0.56, 1.57; linear trend, p=0.48). These risks are below predictions based on high dose studies from Taiwan. When the analysis was focused on exposures 40 or more years ago, an odds ratio of 3.67 (95% confidence interval: 1.43, 9.42; linear trend, p<0.01) was identified for intakes greater than 80 microg/day (median intake, 177 microg/day) in smokers. These data provide some evidence that smokers who ingest arsenic at concentrations near 200 microg/day may be at increased risk of bladder cancer.

Arsenic in drinking water is known to be a cause of lung, bladder, and skin cancer, and some studies report cardiovascular disease effects. The authors investigated mortality from 1950 to 2000 in the arsenic-exposed region II of Chile (population: 477,000 in 2000) in comparison with the unexposed region V. Increased risks were found for acute myocardial infarction (AMI), with mortality rate ratios of 1.48 for men (95% confidence interval (CI): 1.37, 1.59; p < 0.001) and 1.26 for women (95% CI: 1.14, 1.40; p < 0.001) during the high-exposure period in region II from 1958 to 1970. The highest rate ratios were for young adult men aged 30-49 years who were born during the high-exposure period with probable exposure in utero and in early childhood (rate ratio = 3.23, 95% CI: 2.79, 3.75; p < 0.001). Compared with lung and bladder cancer, AMI mortality was the predominant cause of excess deaths during and immediately after the high-exposure period. Ten years after reduction of exposures, AMI mortality had decreased, and longer latency excess deaths from lung and bladder cancer predominated. With these three causes of death combined, increased mortality peaked in 1991-1995, with estimated excess deaths related to arsenic exposure constituting 10.9% of all deaths among men and 4.0% among women.

Background Millions of people worldwide are exposed to arsenic-contaminated water. In the largest city in northern Chile (Antofagasta) >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 performed a population-based case-control study in northern Chile from October 2007 to December 2010 involving 232 lung and 306 bladder 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 odds ratios 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, 0.78 to 2.37), 3.87 (2.25 to 6.64), and 6.50 (3.69 to 11.43), respectively. Corresponding lung cancer odds ratios were 1.00, 1.27 (0.81 to 1.98), 2.00 (1.24 to 3.24), and 4.32 (2.60 to 7.17). Bladder and lung cancer odds ratios in those highly exposed in Antofagasta during 1958–70 but not thereafter were 6.88 (3.84 to 12.32) and 4.35 (2.57 to 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.

Focal adhesion kinase (FAK) is an important mediator of extracellular matrix integrin signaling, cell motility, cell proliferation and cell survival. Increased FAK expression is observed in a variety of solid human tumors and increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Herein we identify miR-7 as a direct regulator of FAK expression. miR-7 expression is decreased in malignant versus normal breast tissue and its expression correlates inversely with metastasis in human breast cancer patients. Forced expression of miR-7 produced increased E-CADHERIN and decreased FIBRONECTIN and VIMENTIN expression in breast cancer cells. The levels of miR-7 expression was positively correlated with E-CADHERIN mRNA and negatively correlated with VIMENTIN mRNA levels in breast cancer samples. Forced expression of miR-7 in aggressive breast cancer cell lines suppressed tumor cell monolayer proliferation, anchorage independent growth, three-dimensional growth in Matrigel, migration and invasion. Conversely, inhibition of miR-7 in the HBL-100 mammary epithelial cell line promoted cell proliferation and anchorage independent growth. Rescue of FAK expression reversed miR-7 suppression of migration and invasion. miR-7 also inhibited primary breast tumor development, local invasion and metastatic colonization of breast cancer xenografts. Thus, miR-7 expression is decreased in metastatic breast cancer, correlates with the level of epithelial differentiation of the tumor and inhibits metastatic progression.

Millions of people worldwide are exposed to arsenic-contaminated drinking water, and ingestion of inorganic arsenic (InAs) has been associated with increased risks of cancer. The primary metabolic pathway of ingested InAs is methylation to monomethyl arsenic (MMA) and dimethyl arsenic (DMA). However, people vary greatly in the degree to which they methylate InAs, and recent evidence suggests that those who excrete high proportions of ingested arsenic as MMA are more susceptible than others to arsenic-caused cancer. To date, little is known about the factors that determine interindividual differences in arsenic methylation. In this study, we assessed the effect of diet on arsenic metabolism by measuring dietary intakes and urinary arsenic methylation patterns in 87 subjects from two arsenic-exposed regions in the western United States. Subjects in the lower quartile of protein intake excreted a higher proportion of ingested InAs as MMA (14.6 vs. 11.6%; p = 0.01) and a lower proportion as DMA (72.3 vs. 77.0%; p = 0.01) than did subjects in the upper quartile of protein intake. Subjects in the lower quartile of iron, zinc, and niacin intake also had higher urinary percent MMA and lower percent DMA levels than did subjects with higher intakes of these nutrients. These associations were also seen in multivariate regression analyses adjusted for age, sex, smoking, and total urinary arsenic. Given the previously reported links between high percent MMA and increased cancer risks, these findings are consistent with the theory that people with diets deficient in protein and other nutrients are more susceptible than others to arsenic-caused cancer.

During 1998-2000, the authors investigated relations between lung function, respiratory symptoms, and arsenic in drinking water among 287 study participants, including 132 with arsenic-caused skin lesions, in West Bengal, India. The source population involved 7,683 participants who had been surveyed for arsenic-related skin lesions in 1995-1996. Respiratory symptoms were increased among men with arsenic-caused skin lesions (versus those without lesions), particularly "shortness of breath at night" (odds ratio (OR) = 2.8, 95% confidence interval (CI): 1.1, 7.6) and "morning cough" (OR = 2.8, 95% CI: 1.2, 6.6) in smokers and "shortness of breath ever" (OR = 3.8, 95% CI: 0.7, 20.6) in nonsmokers. Among men with skin lesions, the average adjusted forced expiratory volume in 1 second (FEV1) was reduced by 256.2 ml (95% CI: 113.9, 398.4; p < 0.001) and the average adjusted forced vital capacity (FVC) was reduced by 287.8 ml (95% CI: 134.9, 440.8; p < 0.001). In men, a 100-microg/liter increase in arsenic level was associated with a 45.0-ml decrease (95% CI: 6.2, 83.9) in FEV1 (p = 0.02) and a 41.4-ml decrease (95% CI: -0.7, 83.5) in FVC (p = 0.054). Women had lower risks than men of developing skin lesions and showed little evidence of respiratory effects. In this study, consumption of arsenic-contaminated water was associated with respiratory symptoms and reduced lung function in men, especially among those with arsenic-related skin lesions.