Using Exhaled Breath to Evaluate the Long-term Mechanisms of Early-life Arsenic Exposure

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Millions of people in the US are exposed to arsenic in food and drinking water. Ingested arsenic is an established cause of malignant and non-malignant lung disease, with the developing lung seeming to be particularly susceptible. We have been investigating a unique situation in Chile involving >100,000 adults who were exposed to a well-documented period of high arsenic drinking water concentrations while in utero or as young children, but not later. This scenario, with its large population and excellent data on past exposure, is unprecedented in environmental epidemiology and has offered us a rare opportunity to investigate the long-term impacts of early- life exposure. To date, we have found 5-fold increases in lung cancer; 46-fold increases in bronchiectasis; 3-6 fold increases in respiratory symptoms; and lung function declines similar to those in heavy smokers. This is the first evidence ever that early-life exposure to a common environmental agent can cause such major increases in lung disease in adults. Currently, the exact pathophysiology of these effects and mechanisms by which an in utero chemical exposure can led to lung disease 40-50 years after the exposure occurred, are unknown. Exhaled breath condensate (EBC) contains hundreds of compounds thought to represent the underlying physiology or pathology of the lung, including several hypothesized to be key mediators of arsenic toxicity. Since EBC can be collected non-invasively it may offer a practical method for studying the mechanisms of arsenic-related lung disease. We propose the first investigation ever on whether EBC may be a useful medium for studying the long- term impacts of an early-life toxic exposure. Inflammation, oxidative stress, and tissue remodeling have all been hypothesized to play a role in arsenic toxicity, and biomarkers of these processes will be measured in the EBC of 75 subjects from our Chile cohort and 75 age, gender, and smoking matched unexposed controls. Subjects will be people from our ongoing study in Chile who were randomly selected from the Chile voter registry which contains 94% of all adults in Chile. Detailed data on smoking, diet, workplaces, illnesses, air pollutants, spirometry, and blood, urine, and saliva samples will also be collected. US EPA and FDA are currently evaluating the need for new regulation for arsenic in water and food. A National Research Council review of this process concluded that new mechanistic data are needed to identify susceptible sub-populations needing stricter regulatory protection and to evaluate the likelihood that toxic mechanisms and disease could occur at common US exposure levels. The advantages of this proposal are the unique cohort and its highly accurate data on past exposure; the availability of a good comparison group with little variation in major confounders; and the leveraging of our already established infrastructure and already recruited research subjects. Other advantages are that EBC contains a number of biomarkers thought to be directly relevant to arsenic toxicity, and the potential for EBC to provide a valuable non-invasive medium for directly evaluating pathology and disease mechanisms in the human lung, a primary site of arsenic toxicity.