Abstract Manganese (Mn) is a well-established neurotoxicant that likely induces neurodegeneration through inflammatory pathways. Millions of people worldwide experience high levels of environmental Mn from point source emissions or associated fugitive dust. In the first five years of the SMELTER (South African Manganese EnvironmentaL NeuroToxic Effects Research) study, we assembled a cohort of >800 Black African residents, including >700 exposed to Mn emissions from one of the world’s largest Mn smelters in Meyerton, South Africa. We developed and validated study assessment tools in the appropriate South African languages, measured environmental Mn in Meyerton and a comparable non-exposed reference community (Ethembalethu), examined participants using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3), and evaluated participants using targeted cognitive and mood assessments. We demonstrated that Meyerton residents had markedly poorer performance in these outcomes as compared to Ethembalethu residents. These neurological health effects were associated with concentrations ~100-200 ng/m3 of Mn as particulate matter (PM) <2.5 µm in diameter (PM2.5-Mn), a level consistent with other point sources throughout the world. In this proposal, we will build on these accomplishments by investigating whether Mn exposure is also associated with progression of the observed motor and cognitive health effects in this same cohort and to estimate longitudinal, in addition to cross-sectional, associations. We successfully employed this approach in our studies of Mn-exposed welders in the U.S. in whom longitudinal studies were required to show dose-response effects. To better characterize Mn exposure and mechanism of neurotoxicity, we will incorporate brain magnetic resonance imaging (MRI), including sequences designed to assess neuroinflammation. We will also expand our air monitoring to explore the contribution of PM size on motor, cognitive, and non-motor health outcomes, as well as neuroinflammation as assessed by brain MRI. Finally, we will implement a dissemination plan to inform community and national stakeholders of study results. Our overarching hypothesis is that environmental Mn exposure two orders of magnitude below contemporary occupational exposure is associated with progression of both parkinsonism and cognitive dysfunction and that neuroinflammation mediates the relationship between environmental Mn exposure and clinical neurotoxicity. We further hypothesize that particle sizes <1µm (i.e., the more inspirable particles within PM2.5) will be more strongly associated with clinical outcomes than larger sizes. Accomplishing these aims will inform international environmental Mn regulations and will address an important environmental justice concern identified by a community of participants typically underrepresented in environmental health research. The proposed aims address the NIEHS strategic theme, “Promoting Translation – Data to Knowledge to Action.”

Project Narrative Manganese (Mn) is a well-established neurotoxicant and millions of people worldwide are exposed to high levels of environmental Mn from point source emissions or associated fugitive dust. In this proposal, we will investigate associations between environmental Mn exposure and motor, cognitive, and brain MRI imaging outcomes in an established African cohort. If successful, accomplishing these aims will inform environmental regulation of Mn exposure worldwide.