Manganese Exposure and Attention-Deficit/Hyperactivity Disorder-Related Neurobehavioral Outcomes in Children: A Systematic Review of Human Studies

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition with multifactorial etiology involving genetic, neurobiological, and environmental determinants. Emerging evidence suggests that environmental exposures may influence neurodevelopmental pathways relevant to ADHD pathophysiology. Manganese is an essential trace element required for normal brain development; however, excessive or dysregulated exposure has been associated with neurotoxic effects. This systematic review aimed to synthesize human evidence on the association between manganese exposure and ADHD or ADHD-related neurobehavioral outcomes in children. METHODS: Four electronic databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Observational studies meeting predefined Population, Exposure, Comparison, Outcomes, and Study Design criteria were included. Methodological quality was assessed using Joanna Briggs Institute appraisal tools, and certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation framework. RESULTS: Thirty studies met the inclusion criteria. Elevated manganese exposure was more frequently associated with increased risk or severity of ADHD or ADHD-related neurobehavioral symptoms, although inverse and nonlinear (U-shaped) associations were also reported. CONCLUSIONS: The available evidence indicates a complex and potentially nonlinear relationship between manganese exposure and child neurobehavioral outcomes. These findings identify manganese exposure as a potentially modifiable environmental factor influencing neurodevelopmental mechanisms relevant to ADHD and highlight the need for longitudinal studies integrating exposure biomarkers with neurobiological and clinical outcomes to clarify causal pathways and therapeutic implications.