Johanna Acevedo

Increased Lung and Bladder Cancer Incidence in Adults after In Utero and Early-Life Arsenic Exposure

Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer. Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls. Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110, 110 to 800, and >800 μg/L were 1.00, 1.88 [95% confidence interval (CI), 0.96–3.71], and 5.24 (3.05–9.00; Ptrend < 0.001) for lung cancer, and 1.00, 2.94 (1.29–6.70), and 8.11 (4.31–15.25; Ptrend < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed. Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure. Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease. Cancer Epidemiol Biomarkers Prev; 23(8); 1529–38. ©2014 AACR.

Arsenic Methylation and Lung and Bladder Cancer in a Case-control Study in Northern Chile

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., <200μg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99-3.67), and 3.26 (1.76-6.04) (p-trend <0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06-3.11), and 2.02 (1.15-3.54) (p-trend <0.001). In analyses confined to subjects only with arsenic water concentrations <200μg/L (median=60μg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08-5.68) and 2.37 (1.01-5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations.

Arsenic, tobacco smoke, and occupation: associations of multiple agents with lung and bladder cancer.

Background: Millions of people worldwide are exposed to arsenic in drinking water, and many are likely coexposed to other agents that could substantially increase their risks of arsenic-related cancer. Methods: We performed a case-control study of multiple chemical exposures in 538 lung and bladder cancer cases and 640 controls in northern Chile, an area with formerly high drinking water arsenic concentrations. Detailed information was collected on lifetime arsenic exposure, smoking, secondhand smoke, and other known or suspected carcinogens, including asbestos, silica, and wood dust. Results: Very high lung and bladder cancer odds ratios (ORs), and evidence of greater than additive effects, were seen in people exposed to arsenic concentrations >335 µg/L and who were tobacco smokers (OR = 16, 95% confidence interval = 6.5–40 for lung cancer; and OR = 23 [8.2–66] for bladder cancer; Rothman Synergy Indices = 4.0 [1.7–9.4] and 2.0 [0.92–4.5], respectively). Evidence of greater than additive effects were also seen in people coexposed to arsenic and secondhand tobacco smoke and several other known or suspected carcinogens, including asbestos, silica, and wood dust. Conclusions: These findings suggest that people coexposed to arsenic and other known or suspected carcinogens have very high risks of lung or bladder cancer.

Case-Control Study of Arsenic in Drinking Water and Kidney Cancer in Uniquely Exposed Northern Chile

Millions of people worldwide are exposed to arsenic in drinking water. The International Agency for Research on Cancer has concluded that ingested arsenic causes lung, bladder, and skin cancer. However, a similar conclusion was not made for kidney cancer because of a lack of research with individual data on exposure and dose-response. With its unusual geology, high exposures, and good information on past arsenic water concentrations, northern Chile is one of the best places in the world to investigate the carcinogenicity of arsenic. We performed a case-control study in 2007-2010 of 122 kidney cancer cases and 640 population-based controls with individual data on exposure and potential confounders. Cases included 76 renal cell, 24 transitional cell renal pelvis and ureter, and 22 other kidney cancers. For renal pelvis and ureter cancers, the adjusted odds ratios by average arsenic intakes of <400, 400-1,000, and >1,000 µg/day (median water concentrations of 60, 300, and 860 µg/L) were 1.00, 5.71 (95% confidence interval: 1.65, 19.82), and 11.09 (95% confidence interval: 3.60, 34.16) (Ptrend < 0.001), respectively. Odds ratios were not elevated for renal cell cancer. With these new findings, including evidence of dose-response, we believe there is now sufficient evidence in humans that drinking-water arsenic causes renal pelvis and ureter cancer.

Elevated Lung Cancer in Younger Adults and Low Concentrations of Arsenic in Water

Arsenic concentrations greater than 100 µg/L in drinking water are a known cause of cancer, but the risks associated with lower concentrations are less well understood. The unusual geology and good information on past exposure found in northern Chile are key advantages for investigating the potential long-term effects of arsenic. We performed a case-control study of lung cancer from 2007 to 2010 in areas of northern Chile that had a wide range of arsenic concentrations in drinking water. Previously, we reported evidence of elevated cancer risks at arsenic concentrations greater than 100 µg/L. In the present study, we restricted analyses to the 92 cases and 288 population-based controls who were exposed to concentrations less than 100 µg/L. After adjustment for age, sex, and smoking behavior, these exposures from 40 or more years ago resulted in odds ratios for lung cancer of 1.00, 1.43 (90% confidence interval: 0.82, 2.52), and 2.01 (90% confidence interval: 1.14, 3.52) for increasing tertiles of arsenic exposure, respectively (P for trend = 0.02). Mean arsenic water concentrations in these tertiles were 6.5, 23.0, and 58.6 µg/L. For subjects younger than 65 years of age, the corresponding odds ratios were 1.00, 1.62 (90% confidence interval: 0.67, 3.90), and 3.41 (90% confidence interval: 1.51, 7.70). Adjustments for occupation, fruit and vegetable intake, and socioeconomic status had little impact on the results. These findings provide new evidence that arsenic water concentrations less than 100 µg/L are associated with higher risks of lung cancer.

High risks of lung disease associated with early-life and moderate lifetime arsenic exposure in northern Chile

BACKGROUND Arsenic in drinking water has been associated with increases in lung disease, but information on the long-term impacts of early-life exposure or moderate exposure levels are limited. METHODS We investigated pulmonary disease and lung function in 795 subjects from three socio-demographically similar areas in northern Chile: Antofagasta, which had a well-described period of high arsenic water concentrations (860μg/L) from 1958 to 1970; Iquique, which had long-term arsenic water concentrations near 60μg/L; and Arica, with long-term water concentrations ≤10μg/L. RESULTS Compared to adults never exposed >10μg/L, adults born in Antofagasta during the high exposure period had elevated odds ratios (OR) of respiratory symptoms (e.g., OR for shortness of breath=5.56, 90% confidence interval (CI): 2.68-11.5), and decreases in pulmonary function (e.g., 224mL decrease in forced vital capacity in nonsmokers, 90% CI: 97-351mL). Subjects with long-term exposure to arsenic water concentrations near 60μg/L also had increases in some pulmonary symptoms and reduced lung function. CONCLUSIONS Overall, these findings provide new evidence that in utero or childhood arsenic exposure is associated with non-malignant pulmonary disease in adults. They also provide preliminary new evidence that long-term exposures to moderate levels of arsenic may be associated with lung toxicity, although the magnitude of these latter findings were greater than expected and should be confirmed.

Salmonella enterica serovar Typhi and gallbladder cancer: a case–control study and meta‐analysis

In Chile, where gallbladder cancer (GBC) rates are high and typhoid fever was endemic until the 1990s, we evaluated the association between Salmonella enterica serovar Typhi (S. Typhi) antibodies and GBC. We tested 39 GBC cases, 40 gallstone controls, and 39 population‐based controls for S. Typhi Vi antibodies and performed culture and quantitative polymerase chain reaction for the subset with bile, gallstone, tissue, and stool samples available. We calculated gender and education‐adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association with GBC. We also conducted a meta‐analysis of >1000 GBC cases by combining our results with previous studies. GBC cases were more likely to have high Vi antibody titer levels than combined controls (OR: 4.0, 95% CI: 0.9–18.3), although S. Typhi was not recovered from bile, gallstone, tissue, or stool samples. In our meta‐analysis, the summary relative risk was 4.6 (95% CI: 3.1–6.8, Pheterogeneity=0.6) for anti‐Vi and 5.0 (95% CI: 2.7–9.3, Pheterogeneity = 0.2) for bile or stool culture. Our results are consistent with the meta‐analysis. Despite differences in study methods (e.g., S. Typhi detection assay), most studies found a positive association between S. Typhi and GBC. However, the mechanism underlying this association requires further investigation

Obesity and excess weight in early adulthood and high risks of arsenic-related cancer in later life.

BACKGROUND Elevated body mass index (BMI) is a risk factor for cardiovascular disease, diabetes, cancer, and other diseases. Inflammation or oxidative stress induced by high BMI may explain some of these effects. Millions of people drink arsenic-contaminated water worldwide, and ingested arsenic has also been associated with inflammation, oxidative stress, and cancer. OBJECTIVES To assess the unique situation of people living in northern Chile exposed to high arsenic concentrations in drinking water and investigate interactions between arsenic and BMI, and associations with lung and bladder cancer risks. METHODS Information on self-reported body mass index (BMI) at various life stages, smoking, diet, and lifetime arsenic exposure was collected from 532 cancer cases and 634 population-based controls. RESULTS In subjects with BMIs <90th percentile in early adulthood (27.7 and 28.6 kg/m(2) in males and females, respectively), odds ratios (OR) for lung and bladder cancer combined for arsenic concentrations of <100, 100-800 and >800 µg/L were 1.00, 1.64 (95% CI, 1.19-2.27), and 3.12 (2.30-4.22). In subjects with BMIs ≥90th percentile in early adulthood, the corresponding ORs were higher: 1.00, 1.84 (0.75-4.52), and 9.37 (2.88-30.53), respectively (synergy index=4.05, 95% CI, 1.27-12.88). Arsenic-related cancer ORs >20 were seen in those with elevated BMIs in both early adulthood and in later life. Adjustments for smoking, diet, and other factors had little impact. CONCLUSION These findings provide novel preliminary evidence supporting the notion that environmentally-related cancer risks may be markedly increased in people with elevated BMIs, especially in those with an elevated BMI in early-life.

Hypertension among adults exposed to drinking water arsenic in Northern Chile

Background: A growing number of studies have identified an association between exposure to inorganic arsenic and hypertension. However, results have not been consistent across studies. Additional studies are warranted, given the global prevalence of both arsenic exposure and morbidity attributable to hypertension. Methods: We analyzed data collected from October 2007‐December 2010 for a population‐based cancer case‐control study in northern Chile. Data included lifetime individual arsenic exposure estimates and information on potential confounders for a total of 1266 subjects. Those self‐reporting either a physician diagnosis of hypertension or use of an anti‐hypertensive medication were classified as having hypertension (n=612). The association between hypertension and drinking water arsenic exposure was analyzed using logistic regression models. Results: Compared to those in the lowest category for lifetime highest 5‐year average arsenic exposure (<60 &mgr;g/L), those in the middle (60–623 &mgr;g/L) and upper (>623 &mgr;g/L) exposure categories had adjusted hypertension ORs of 1.49 (95% CI: 1.09, 2.05) and 1.65 (95% CI: 1.18, 2.32), respectively. Similar results were observed in analyses of lifetime cumulative exposures and analyses restricted to exposures from the distant past. Conclusions: We identified evidence of increased odds of hypertension with exposure to arsenic in drinking water among study participants. Our findings add to the growing body of research supporting this association, which could have important public health implications. HighlightsNorthern Chile is one of the driest places on earth.Historical arsenic water measurements allow for estimation of lifetime exposure.Associations between arsenic and hypertension were identified using these data.Control for body mass index, smoking and other factors had little impact on results.

Study protocol for the Maule Cohort (MAUCO) of chronic diseases, Chile 2014–2024

BackgroundMaule Cohort (MAUCO), a Chilean cohort study, seeks to analyze the natural history of chronic diseases in the agricultural county of Molina (40,000 inhabitants) in the Maule Region, Chile. Molina´s population is of particular interest because in the last few decades it changed from being undernourished to suffering excess caloric intake, and it currently has the highest national rates of cardiovascular diseases, stomach cancer and gallbladder cancer. Between 2009 and 2011 Molina´s poverty rate dropped from 24.1 % to 13.5 % (national average 20.4 %); in this period the county went from insufficient to almost complete basic sanitation. Despite these advances, chemical pollutants in the food and air are increasing. Thus, in Molina risk factors typical of both under-developed and developed countries coexist, generating a unique profile associated with inflammation, oxidative stress and chronic diseases.Methods/DesignMAUCO is the core project of the recently established Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile & Pontificia Universidad Católica de Chile. In this study, we are enrolling and following 10,000 adults aged 38 to 74 years over 10 years. All eligible Molina residents will be enrolled. Participants were identified through a household census. Consenting individuals answer an epidemiological survey exploring risk factors (psycho-social, pesticides, diet, alcohol, and physical activity), medical history and physical and cognitive conditions; provide fasting blood, urine, and saliva samples; receive an electrocardiogram, abdominal ultrasound and bio-impedance test; and take a hand-grip strength test. These subjects will be re-interviewed after 2, 5 and 7 years. Active surveillance of health events is in place throughout the regional healthcare system. The MAUCO Bio-Bank will store 30 to 50 aliquots per subject using an NIH/NCI biorepository system for secure and anonymous linkage of samples with data.DiscussionMAUCO´s results will help design public health interventions tailored to agricultural populations in Latin America.