Background: Parkinson's disease (PD) is a devastating neurological disease that has been repeatedly linked to environmental exposures. Military personnel may be especially susceptible to unique or higher-level exposures. One chemical linked to PD is the organophosphate (OP) insecticide chlorpyrifos. The magnitude of chlorpyrifos use renders it a major exposure to the population as a whole, inclusive of military personnel. Furthermore, chlorpyrifos is of significant importance to the military. Specific to military use, pesticides (containing chlorpyrifos) were sprayed on the outside base of walls or tents, the outside of garbage containers, inside structures in cracks and crevices where walls met the floors and other places to kill indoor pests or fogged to kill primarily outdoor pests such as filth flies, sand flies, and mosquitoes. Some exposure scenarios that are very rare in the public seem to have been common in the military. For example, a significant number of Veterans reported using pet flea and tick collars to protect themselves against insects. These collars typically contain one of several active ingredients, in concentrations from five to twenty percent, including in some cases chlorpyrifos. Military reports have noted that the widespread (and sometimes unconventional) use of OPs, including chlorpyrifos, may cause both acute health effects at the time of exposure and require medical attention, along with elevated rates of neurological or psychiatric symptoms and poorer performance on standardized neuropsychological tests several years after the exposure. Thus, military personnel may have been especially at risk due to widespread exposure from multiple sources and uses and it is critical to understand whether such exposures have influenced PD risk and progression.

Goals and Strategies: The overarching goal is to determine whether military-relevant chlorpyrifos exposure may influence PD. To do so, we will conduct a mix of both human and laboratory studies. The inclusion of both types of studies is critical to determine whether there is a plausible link. Human studies will utilize epidemiological approaches to determine if long-term OP exposure is higher among those with PD, or whether such exposures influence disease onset (are those exposed diagnosed at earlier ages?) and severity. We will examine whether exposure may produce atypical disease or the impact of exposure is influenced by genetics (are some people at higher risk due to genetics?). In laboratory-based studies, we will use a variety of model systems that allow us to test precise doses to determine if exposure reproduces key features of PD. These systems will also allow us to test gene - environment interactions and possible therapeutic approaches.

Key Advances Expected: We expect benefits to current and former military personnel with respect to understanding how chlorpyrifos exposure may influence neurological disease risk.

What types of patients will it help, and how will it help them? Current/former military personnel with likely prior chlorpyrifos exposure. We expect to suggest that those with likely chlorpyrifos exposure should be monitored for PD. Those already diagnosed with PD should be carefully monitored for more rapid development and standard therapy resistance.

What are the potential clinical applications, benefits, and risks? Should we find that military chlorpyrifos exposure influences PD risk, progression, or therapy resistance, these findings would have several implications. First, they would suggest that those with likely exposures should discuss risk and monitoring with their physician (especially neurologist) as soon as possible. Those already diagnosed could potentially benefit from specialized care (movement disorders specialist) earlier after diagnosis if we find that chlorpyrifos alters ages of onset, progression, or resistance to traditional dopamine replacement therapies. Risk for the present study is deemed to be extremely low because we are only examining medical records, conducting interviews, and collecting saliva.

What is the projected time it may take to achieve a patient-related outcome? We expect that at the end of the 3-year grant period we will far better understand the role of military chlorpyrifos in PD. We will convey this information to PD disease support groups, medical professionals, and the scientific community as soon as possible through webinars and both scientific and lay publications.

What is the likely impact of this study on the understanding, prevention, diagnosis, and/or treatment of PD in the context of neurotoxin exposure? First, we expect this study to strongly support efforts to ban chlorpyrifos in the United States. Second, we anticipate suggesting that when serving abroad, care should be taken to limit exposure. Third, we expect that those with likely exposures should discuss risk with their physician and that those already with PD may discuss with their neurologist whether they should more quickly be referred to a movement disorders specialist. Fourth, our gene - environment interaction studies may suggest those with specific genetics may be especially susceptible to chlorpyrifos neurotoxicity. Fifth, our basic science studies may preliminarily identify some new treatment options.