Trichloroethylene and Parkinson's Disease

描述（由申请人提供）：这项工作的目标是调查帕金森病（PD）的职业原因。职业性溶剂暴露的长期神经毒性尚不清楚。虽然急性帕金森病很少由意外的高剂量溶剂暴露引起，但这些病例在临床和病理上与帕金森病不同。相反，职业暴露与典型PD的流行病学关联并不一致。2008年，Gash等人报道了一组3名PD患者，他们在一家生产厂暴露于溶剂三氯乙烯（TCE）。我们基于人群的分析研究（TWINS研究）的初步工作发现，职业性TCE暴露与PD风险显著增加6倍。氯化溶剂四氯乙烯（PERC，过氯乙烯）和四氯化碳（CCl4）也有关联。此外，最近在啮齿动物中建立的TCE模型惊人地概括了PD的许多特征，进一步支持了这些观察结果的生物学相关性。两个主要缺陷限制了目前对TCE、PERC和CCl4在PD中的作用的理解。首先，很少有先前的研究评估暴露于特定的物质，而不是考虑溶剂暴露作为单一的分类变量。由于溶剂包含了大量不同的化合物，因此使用这种方法可能会模糊与任何特定试剂的关联。我们知识的第二个缺陷是缺乏对可能影响溶剂相关毒性的遗传和环境因素的伴随调查。本研究将重点研究工业溶剂TCE、PERC和CCl4与PD风险的关系，并同时考虑遗传和环境因素的相互作用。我们将利用来自两个典型PD病例对照研究人群的超过15年的1250名受试者的现有数据，这些研究人群共享统一、标准化、高度详细的职业任务特定访谈方法。我们将采用无偏暴露估计方法来量化TCE、PERC和CCl4的终生暴露，并测试与PD的关系。使用更大的独立队列（SEARCH）；我们将在TWINS研究中检验我们的初步发现。为了建立因果关系，这项工作至关重要。此外，利用TWINS和SEARCH的现有DNA样本，我们将测试这些溶剂与1)参与其代谢的编码酶的基因变异和2)pd相关基因之间的相互作用。我们还将测试溶剂和环境风险因素的相互作用。这项工作对健康的影响是巨大的。溶剂在工业中无处不在，即使是适度增加的风险也会对工人患帕金森病的频率产生巨大影响。这项工作对于提高我们对溶剂所造成的风险的认识至关重要，并将为保护劳动力免受这种无法治愈的使人衰弱的疾病的侵害提供合理的基础。

DESCRIPTION (provided by applicant): The goal of this work is to investigate occupational causes of Parkinson's disease (PD). The long-term neurological toxicity of occupational solvent exposure is poorly understood. Although acute Parkinsonism may rarely result from accidental high dose solvent exposures, these cases are clinically and pathologically distinct from PD. In contrast, epidemiologic associations of occupational exposures with typical PD are inconsistent. In 2008 Gash et al reported a cluster of 3 PD patients who had been exposed to the solvent trichloroethylene (TCE) in a manufacturing plant. Preliminary work in our population-based analytic study (the TWINS study) found a significant 6-fold increased risk of PD associated with occupational TCE exposure. The chlorinated solvents tetrachloroethylene (PERC, perchloroethylene) and carbon tetrachloride (CCl4) were also associated. In addition, a recent TCE model in rodents strikingly recapitulates many of the features of PD, further supporting the biological relevance of these observations. Two major deficiencies limit current understanding of the role of TCE, PERC and CCl4 in PD. First, few prior studies assessed exposure to specific agents, instead considering solvent exposure as a single categorical variable. Because solvents encompass a huge range of disparate compounds, association with any particular agent is likely to be obscured using this approach. A second deficiency in our knowledge is the lack of concomitant investigation of genetic and environmental factors that may affect solvent-related toxicity. This study will focus on the relationship between the industrial solvents TCE, PERC and CCl4 and PD risk, and will simultaneously consider interactions with genetic and environmental factors. We will leverage existing data derived over 15 years of research in 1,250 subjects from two well-characterized PD case-control study populations that share uniform, standardized, highly detailed occupational-task-specific interview methods. We will apply unbiased exposure estimation methods in order to quantify lifetime exposures to TCE, PERC, and CCl4, and test associations with PD. Using a larger independent cohort (SEARCH); we will test our preliminary findings in the TWINS study. This work is essential in order to establish a causal association. In addition, using existing DNA samples from both TWINS and SEARCH, we will test for interaction between these solvents and 1) variants in genes encoding enzymes involved in their metabolism, and 2) PD-associated genes. We will also test for interaction of solvents and environmental risk factors. The health implications of this work are immense. Solvents are ubiquitous in industry, and even a modest increased risk could have an enormous impact on the frequency of PD in workers. This work is essential to advance our knowledge of the risk posed by solvents, and will provide a rational foundation for protection of the workforce from this incurable debilitating disease.