Incident cancer studies in a unique arsenic-exposed area of Chile

描述（由申请人提供）：我们来自智利北部的新生态学证据表明，童年或子宫内的砷暴露可能导致年轻人肺癌增加10倍。这可能是第一次将幼年时期暴露于一种常见的环境因素与人类患成年癌症的高风险联系起来。尽管有有趣的动物数据支持，但这些发现是初步的，需要得到证实。智利北部非常独特的砷暴露情况为开展这项工作提供了极好的难得机会。由于智利北部几乎每个人都从大型市政水源取水，而且所有这些水源过去的砷含量在过去50年或更长时间里都有详细的记录，因此可以利用过去接触砷的数据来研究砷的致癌性，这比世界上任何其他地方获得的数据都要准确得多。此外，这一地区长达14年的高暴露期使得成千上万的人仅在子宫内和儿童早期就受到了高度暴露。因此，这个领域提供了一个独特的机会来研究早期生活致癌物的长期影响，并提供了过去接触的优秀数据。我们建议对675例肺癌和膀胱癌病例进行病例对照研究，使用包括所有当地病理学家在内的快速病例确定系统。控制将从智利选民登记册中获得，其中包括智利94%的人口。我们将获得比以往任何研究都更准确的剂量-反应数据，并可直接应用于美国监管和公共卫生决策。将收集生物样本，并调查与代谢、饮食、遗传和其他因素相关的易感性。我们发现证据表明，产生高水平单甲基化砷（MMA）的人患癌症的风险可能比其他人高2-5倍。这是否是由于很少被研究但毒性很高的三价形式（MMA3）将被探索，并可能提供关于砷致癌的主要毒性物种的新信息。数百万美国人的饮用水中都含有砷。目前的美国砷法规没有纳入潜在易感亚群体的信息，尽管这些群体的癌症风险可能非常高。从这个项目中获得的信息可能有助于确定某些人，如儿童、孕妇、砷代谢不良者或营养不良者，在制定监管标准时是否需要特别考虑。关于生命早期暴露、MMA3、饮食以及我们计划作为该项目一部分的未来遗传和蛋白质组学研究的信息可以进一步深入了解环境致癌的重要辅助因素和机制。

DESCRIPTION (provided by applicant): Our new ecologic evidence from Northern Chile suggests that arsenic exposure in childhood or in utero could cause up to a 10-fold increase in lung cancer in young adults. This may be the first time that early-life exposure to a common environmental agent has been linked to such high risks of an adult cancer in humans. Although supported by intriguing animal data, these findings are preliminary and need to be confirmed. The highly unique arsenic exposure scenario in Northern Chile offers an excellent and rare opportunity to do this. Because almost everyone in Northern Chile obtains their water from large municipal sources, and past arsenic levels in all of these sources are well documented over the past 50 years or more, arsenic carcinogenicity can be studied using data on past exposure that are much more accurate than can be obtained anywhere else in the world. In addition, a very distinct 14-year period of high exposure in this area has created a population where tens of thousands of people were highly exposed only in utero and early childhood. As such, this area provides a unique opportunity to study the long-term impacts of an early-life carcinogen with excellent data on past exposure. We propose a case-control study of 675 lung and bladder cancer cases obtained over a three-year period using a rapid case ascertainment system involving all local pathologists. Controls will be obtained from the Chile electoral register which includes 94% of the Chile population. We will obtain dose-response information with data on past exposure that is more accurate than found in any previous study and that can be directly applied to US regulatory and public health decisions. Biological samples will be collected and susceptibility related to metabolism, diet, genetics, and other factors will also be investigated. We have found evidence that people producing high levels of monomethylated arsenic (MMA) may have 2-5 times higher cancer risks than others. Whether this is due to the rarely studied but highly toxic trivalent form (MMA3) will be explored and could provide new information on the primary toxic species of arsenic carcinogenesis. Millions of people in the US are exposed to drinking water arsenic. Current US arsenic regulations do not incorporate information on potentially susceptible subgroups despite the fact that cancer risks in these groups could be exceedingly high. The information gained from this project may help to determine if some people, such as children, pregnant women, those who metabolize arsenic poorly, or those with poor nutrition, may need special consideration in regulatory standard setting. Information on early-life exposure, MMA3, diet, and the future genetic and proteomic studies we will plan as part of this project could add further insight into the important co-factors and mechanisms of environmental carcinogenesis.