Parkinson's Disease and Exposure to Chlorinated Solvents at Marine Base Camp Lejeune

该项目的目标是描述暴露于以下物质所带来的帕金森病（PD）风险： 海军陆战队基地营饮用水中的三氯乙烯（TCE）和四氯乙烯（PERC）溶剂 勒琼，北卡罗来纳州。职业接触常见工业溶剂三氯乙烯（TCE） 与2008年一家小型制造厂的PD集群有关。我们在一项研究中重复了这一观察结果， 对于不一致的双胞胎，我们发现职业暴露于TCE的风险是6倍，而职业暴露于TCE的风险是10倍。 PERC的风险。使用口服TCE的动物研究强烈支持这些药物的生物相容性。 观察，并忠实地概括了PD的关键病理特征：线粒体损伤， 磷酸化α-突触核蛋白的神经元内聚集，以及磷酸化α-突触核蛋白的区域特异性变性。 黑质纹状体多巴胺能神经元值得注意的是，尽管TCE和PERC在美国1/3的人口中存在， 饮用水供应，并在大多数血液和母乳中检测到，迄今为止还没有人类研究 评估了饮用水中TCE或PERC引起PD的风险。 在美国历史上记录最完整的大规模污染事件中， 北卡罗来纳州海军陆战队基地勒琼营的100万居民受到TCE和PERC污染， 从1953年到1987年有毒物质和疾病登记署（ATSDR）制定了详细的 在这段时间内，前居民的特定时间和特定地址接触估计数。1975年期间- 1985年是污染最严重的时期，饮用水中三氯乙烯的估计中值为366微克/升， 超过EPA最大允许水平的70倍。最高接触水平要高出几百倍。 2017年，经过医学研究所的审查，VA发布了将PD指定为推定PD的指南。 前勒琼退伍军人的服务相关疾病。然而，尽管VA已经指定了 PD作为前Lejeune居民的服务连接，以及由此产生的巨大经济后果， 人类饮用水中TCE和PERC的风险从未被直接研究过。所需要的 建立这种关系，并量化和修改过去、现在和未来接触人群的风险 是对暴露和疾病风险的无偏估计。 在本项目中，我们将把ATSDR客观的特定地点和特定时间的暴露估计与全面的 退伍军人健康管理局（VHA）电子病历中提供的诊断和医疗保健数据 (EMR)和相关数据库，首次确定与口服暴露相关的PD风险 TCE和PERC。VHA EMR包含超过25，000，000名退伍军人的健康和福利数据， 包括详细的临床、药房、实验室、人口统计、服务相关和其他数据 几十年我们将利用特殊的VHA EMR资源来1）检验PD风险为 居住在勒琼勒琼营（存在污染）的海军陆战队员比居住在勒琼军营（存在污染）的海军陆战队员更高 彭德尔顿营（无污染）; 2）检验PD风险与较高的 接触饮用水中的三氯乙烯或全氯乙烯，或在勒琼勒琼营居住更长时间;以及3）测试 假设在勒琼营暴露于三氯乙烯或全氯乙烯的程度较高，或持续时间较长， 更严重的PD表型（例如，早期痴呆、骨折、精神病、运动波动、死亡）。 高质量，客观的环境暴露指标根本不存在晚年疾病，如 警局供应给海军基地的饮用水被污染了35年 勒琼营退伍军人提供了一个独特的机会，明确地描述了TCE的风险程度 和PERC，美国饮用水中最常见的两种污染物。识别和描述风险 的PD将赋予暴露的退伍军人权力，并推动正在进行的努力，以实施疾病预防 治疗策略在那些退伍军人在最高风险。

The goal of this project is to characterize the risk of Parkinson’s disease (PD) conferred by exposure to the solvents trichloroethylene (TCE) and tetrachloroethylene (PERC) in drinking water at Marine Base Camp Lejeune, North Carolina. Occupational exposure to the common industrial solvent trichloroethylene (TCE) was implicated in a cluster of PD in a small manufacturing plant in 2008. We replicated this observation in a study of discordant twins, in which we found a 6-fold risk associated with occupational exposure to TCE and 10-fold risk for PERC. Animal studies using orally-administered TCE strongly support the biological plausibility of these observations, and faithfully recapitulate the key pathologic characteristics of PD: mitochondrial impairment, intra-neuronal aggregation of phosphorylated alpha-synuclein protein, and regionally-specific degeneration of nigrostriatal dopaminergic neurons. Strikingly, despite the fact that TCE and PERC are present in 1/3 of US drinking water supplies and are detectable in most blood and breast milk, no human studies to date have assessed the risk of PD from TCE or PERC in drinking water. In the best documented large-scale contamination in US history, the drinking water supplied to up to 1 million residents of Marine Base Camp Lejeune in North Carolina was contaminated with TCE and PERC from 1953 until 1987. The Agency for Toxic Substances and Disease Registry (ATSDR) has developed detailed time- and address-specific exposure estimates for former residents throughout this time period. During 1975- 1985, the period of maximal contamination, the estimated median TCE level in drinking water was 366 ug/L, more than 70-fold the EPA maximum allowable level. Peak exposure levels were several hundred-fold higher. In 2017, after review by the Institute of Medicine, the VA issued guidelines designating PD as a presumptive service-connected illness for former Lejeune veterans. However, despite the fact that the VA has designated PD as service connected for former Lejeune residents, and the enormous financial consequences thereof, the risk from TCE and PERC in drinking water in humans has never been directly studied. What is needed to establish this relationship and to quantify and modify the risk for past, present and future exposed populations is an unbiased estimate of exposure and disease risk. In this project, we will link ATSDR objective site- and time-specific exposure estimates with comprehensive diagnostic and health care data available in Veterans Health Administration (VHA) electronic medical records (EMR) and associated databases to determine, for the first time, the risk of PD associated with oral exposure to TCE and PERC. The VHA EMR contains health and benefits data on more than 25,000,000 veterans, and includes detailed clinical, pharmacy, laboratory, demographic, service-related and other data going back decades. We will utilize the exceptional VHA EMR resources to 1) test the hypothesis that the risk of PD is greater in Marines who resided at Camp Lejeune (contamination present) than in Marines who resided at Camp Pendleton (contamination absent); 2) test the hypothesis that the risk of PD is associated with higher exposure to TCE or PERC in drinking water, or longer duration of residence at Camp Lejeune; and 3) test the hypothesis that higher exposure to TCE or PERC, or longer duration at Camp Lejeune is associated with a more severe PD phenotype (e.g., earlier onset of dementia, fractures, psychosis, motor fluctuations, death). High quality, objective environmental exposure metrics simply do not exist for late-life disorders such as PD. The unfortunate circumstances of the 35-year contamination of drinking water supplied to Marine Base Camp Lejeune Veterans offers a singular opportunity to definitively characterize the degree of risk from TCE and PERC, two of the most common contaminants in US drinking water. Identifying and characterizing the risk of PD will empower exposed Veterans and advance ongoing efforts to implement disease preventing therapeutic strategies in those Veterans at highest risk.