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

在美国，数百万人暴露在食物和饮用水中的砷中。摄入砷是一种既定的 恶性和非恶性肺部疾病的病因，发展中的肺似乎特别 易受影响。我们一直在调查智利的一起独特情况，涉及10万名成年人，他们受到了 在子宫内或幼儿时期饮用水中砷浓度高的时期是有充分记录的， 但不是晚些时候。这种情况，以其庞大的人口和关于过去风险敞口的出色数据，在 环境流行病学，并为我们提供了一个难得的机会来调查早期- 生活曝光率。到目前为止，我们发现肺癌的发病率增加了5倍；支气管扩张症的发病率增加了46倍； 呼吸道症状成倍增加；肺功能下降，与重度吸烟者相似。这是 首次有证据表明，早期接触普通环境制剂会导致如此显著的增加 在成人的肺部疾病中。目前，这些影响和机制的确切病理生理学 子宫内化学物质暴露可导致肺部疾病，暴露后40-50年内发生，目前尚不清楚。呼出 呼气冷凝液(EBC)含有数百种化合物，被认为代表潜在的生理或 肺的病理，包括几个被假设为砷中毒的关键介体。由于EBC可以 无创性采集，为研究砷肺的发病机制提供了一种实用的方法。 疾病。我们建议进行有史以来第一次调查，以确定EBC是否可以作为一种有用的媒介来研究长期的 早期接触有毒物质的长期影响。炎症、氧化应激和组织重塑都是 假设在砷毒性中发挥作用，这些过程的生物标记物将在EBC中进行测量 来自我们智利队列的75名受试者和75名年龄、性别和吸烟的受试者与未接触过的对照组相匹配。科目 将是我们在智利正在进行的研究中随机从智利选民登记中挑选出来的人 占智利所有成年人的94%。关于吸烟、饮食、工作场所、疾病、空气污染物、 还将收集肺活量、血液、尿液和唾液样本。美国环保局和FDA目前正在评估 需要对水和食物中的砷进行新的监管。国家研究委员会对这一过程的审查 结论是需要新的机械数据来识别需要更严格的易感亚群 监管保护，并评估有毒机制和疾病可能共同发生的可能性 美国的暴露水平。这项建议的优点是独特的队列和过去高度准确的数据 暴露；主要混杂因素变化不大的良好对照组的可用性；以及 利用我们已经建立的基础设施和已经招募的研究对象。其他优势 EBC包含许多被认为与砷毒性直接相关的生物标志物，以及潜在的 EBC为直接评估病理和疾病机制提供了有价值的非侵入性媒介 在人类肺部，砷中毒的主要部位。

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.