Untangling the mercury neurotoxicity puzzle in the Amazon: An exposome-based perspective on co-exposure, nutrition, and causality.

For more than four decades, research on Amazonian riverine populations has been shaped by a single dominant narrative: that mercury (Hg) exposure from fish consumption is the primary driver of neurotoxic risk. While this perspective was pivotal in raising global awareness of methylmercury (MeHg) hazards, it has also constrained scientific inquiry, often obscuring the multifactorial vulnerabilities that characterize these communities. This commentary challenges that reductionist framework by integrating evidence demonstrating a far more complex exposure mosaic. In addition to Hg, riverine populations experience substantial co-exposure to lead (Pb) and potentially to cyanogenic compounds released from cassava processing, a plausible but still insufficiently validated pathway. These exposures intersect with chronic malnutrition, micronutrient deficiencies, and infectious disease, converging on shared toxicodynamic pathways such as oxidative stress, calcium dysregulation, mitochondrial injury, and endocrine disruption. Epidemiological data reveal that blood Hg and Pb concentrations strongly covary and increase concurrently with fish and cassava flour intake, reflecting intertwined dietary patterns rather than independent exposure routes. This collinearity raises the possibility that reported associations between Hg biomarkers and neurological outcomes may represent toxicological misattribution, where co-exposures and nutritional deficits, not MeHg alone, account for observed effects. Persisting in a mercury-centric paradigm has simplified Amazonian environmental health and guided policy, funding, and scientific attention toward a single contaminant, often at the expense of urgent health determinants such as anemia, food insecurity, impaired sanitation, and persistent infections. Reframing Amazonian toxicology through an exposome-driven, systems-oriented perspective, integrating multi-exposure biomonitoring, nutritional profiling, and longitudinal omics, offers a more accurate foundation for causal inference and more equitable public health action. This holistic approach is essential to understanding how intertwined environmental, nutritional, and social exposures shape neurodevelopmental and neurological health in Amazonian riverine populations.