Paraquat dichloride (commonly referred to as paraquat) is a restricted-use, broad-spectrum herbicide that is commonly used in the United States to control weeds in agricultural and horticultural crops. Because paraquat is not registered for home use, the highest exposures would likely be to those manufacturing and applying paraquat or to those living on or near farms or other areas where paraquat is manufactured or applied. Observational human studies of people who apply pesticides and data from experimental animal studies indicate that long-term, chronic exposure to paraquat might lead to central nervous system toxicity. The National Toxicology Program (NTP) identified paraquat as a potential candidate for systematic review while performing scoping activities to classify environmental exposures associated with Parkinson’s disease. Subsequently, NTP became aware that the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) was also evaluating paraquat as part of registration review activities and collaborated with EPA to avoid duplication of effort.
The objective of these scoping activities was to identify and characterize peer-reviewed, published scientific literature relevant to paraquat exposure and neurobehavioral and neuropathological endpoints associated with Parkinson’s disease in humans and to related models in experimental animals or in vitro studies.
A scoping review was conducted that followed the Office of Health Assessment and Translation (OHAT) method for systematic review through an abbreviated data extraction step. A comprehensive search strategy was used to retrieve original research records from multiple databases (i.e., Embase, PubMed, Scopus, Web of Science, and TOXLINE) through May 24, 2018. Relevant records included reports of exposure to paraquat dichloride and neurobehavioral or neuropathological endpoints relevant to Parkinson’s disease in humans (such as clinical diagnoses, movement abnormalities, and effects on dopaminergic neurons) in epidemiological studies, experimental animal models of parkinsonism, and in vitro model systems. References were screened in duplicate for relevance and categorized by exposure, outcome, species, and cell type, where appropriate. An interactive evidence map was prepared using Tableau software to enable researchers to explore the health outcome data by key feature (e.g., outcome, study type, animal model). Finally, data extraction of quantitative results was performed using the Health Assessment Workspace Collaborative (HAWC) software for those studies that were the most directly relevant to human Parkinson’s disease (e.g., epidemiological studies reporting primary outcomes and studies of mammals exposed to paraquat via exposure routes most representative of human exposures including oral, dermal, and inhalation).
The literature search identified 8,685 references, 458 of which were included after screening as relevant to describing the association between exposure to paraquat and the potential development of Parkinson’s disease with some reports consisting of multiple lines of evidence and measured endpoints. The human epidemiological evidence consisted of 24 studies with the majority conducted in agricultural workers or people living in or near agricultural areas. A total of 143 experimental animal studies reported measurement of primary health endpoints; 11 were found to have high external validity to human exposure by exposing mammals via a route similar to human exposures (i.e., oral, inhalation, dermal). Supporting mechanistic information was reported in 190 experimental animal studies measuring secondary health endpoints and 244 in vitro studies.
Using systematic review methodologies, NTP developed a scoping review and evidence maps of published scientific literature to support potential follow-up systematic review and to identify extant research gaps. The evidence maps are interactive, sortable visualizations of quantitative data from epidemiological studies and experimental study characteristics with links to publications. A considerable body of evidence was identified as relevant to paraquat exposure and Parkinson’s disease that can be used in developing future systematic reviews as were data gaps and scientific challenges that could be addressed by future research.
Boyd WA, Blain RB, Skuce CR, Thayer KA, Rooney AA. 2020. NTP research report on the scoping review of paraquat dichloride exposure and Parkinson’s disease. Research Triangle Park, NC: National Toxicology Program. Research Report 16. https://doi.org/10.22427/NTP-RR-16