The goal of this work is to investigate occupational causes of Parkinson's disease (PD). The long-termneurological toxicity of occupational solvent exposure is poorly understood. Although acute parkinsonism mayrarely result from accidental high dose solvent exposures, these cases are clinically and pathologically distinctfrom PD. In contrast, epidemiologic associations of occupational exposures with typical PD are inconsistent. In2008 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 chlorinatedsolvents 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, furthersupporting the biological relevance of these observations. Two major deficiencies limit current understanding of the role of TCE, PERC and CCl4 in PD. First, fewprior studies assessed exposure to specific agents, instead considering solvent exposure as a singlecategorical variable. Because solvents encompass a huge range of disparate compounds, association withany particular agent is likely to be obscured using this approach. A second deficiency in our knowledge is thelack 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 PDrisk, and will simultaneously consider interactions with genetic and environmental factors. We will leverageexisting data derived over 15 years of research in 1,250 subjects from two well-characterized PD case-controlstudy populations that share uniform, standardized, highly detailed occupational-task-specific interviewmethods. 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 testour 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 betweenthese solvents and 1) variants in genes encoding enzymes involved in their metabolism, and 2) PD-associatedgenes. 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 amodest increased risk could have an enormous impact on the frequency of PD in workers. This work isessential to advance our knowledge of the risk posed by solvents, and will provide a rational foundation forprotection of the workforce from this incurable debilitating disease.

Public Health Relevance

The goal of this work is to identify occupational causes of Parkinson's disease (PD). This project will investigate the relationship of occupational exposure to the solvents trichloroethylene (TCE); tetrachloroethylene (PERC) and carbon tetrachloride (CCl4) and the risk of PD in two study populations. Because solvents are extremely common in the industrial environment; this work could have an enormous impact on worker health and safety.

National Institute of Health (NIH)
National Institute for Occupational Safety and Health (NIOSH)
Exploratory/Developmental Grants (R21)
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Safety and Occupational Health Study Section (SOH)
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Frederick, Linda J
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Northern California Institute Research & Education
San Francisco
United States
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