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氏病(PD)的职业原因。职业性溶剂暴露的长期神经毒性知之甚少。虽然急性帕金森病很少由意外的大剂量溶剂暴露引起，但这些病例在临床和病理上与帕金森病截然不同。相比之下，职业性暴露与典型帕金森病的流行病学联系是不一致的。2008年，Gash等人报告了一组3名PD患者，他们曾在一家制造厂接触到溶剂三氯乙烯(TCE)。我们的基于人群的分析研究(双胞胎研究)的初步工作发现，与职业性三氯乙烯接触相关的帕金森病风险显著增加6倍。氯化溶剂四氯乙烯(PERC，全氯乙烯)和四氯化碳(CCl4)也被关联。此外，最近的啮齿动物三氯乙烯模型惊人地概括了帕金森病的许多特征，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在帕金森病中的作用的理解。首先，以前很少有研究评估接触特定制剂的情况，而是将溶剂暴露作为一个单一的分类变量。由于溶剂包含大量不同的化合物，因此使用这种方法很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与溶剂有关的毒性的遗传和环境因素的伴随调查。这项研究将重点研究工业溶剂TCE、PERC和CCl4与帕金森病风险的关系，并同时考虑与遗传和环境因素的相互作用。我们将利用来自两个特征良好的帕金森病病例对照研究人群的1250名受试者15年来的现有数据，这两个研究人群共享统一、标准化、高度详细的职业任务特定访谈方法。我们将应用无偏见的暴露估计方法来量化终生接触TCE、PERC和CCl4，并测试与帕金森病的相关性。使用更大的独立队列(搜索)；我们将在双胞胎研究中测试我们的初步发现。为了建立因果关系，这项工作是必不可少的。此外，使用来自双胞胎和Search的现有DNA样本，我们将测试这些溶剂与1)编码参与其新陈代谢的酶的基因变体和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，即使风险略有增加，也可能对工人患帕金森病的频率产生巨大影响。这项工作对于增进我们对溶剂构成的危险的认识是至关重要的，并将为保护劳动力免受这种无法治愈的衰弱疾病的伤害提供合理的基础。

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.