Mercury Debt: Molecular Mechanisms and Exposome Mapping of Persistent Post-Amalgam Exposure

Following EU restrictions on dental amalgam from January 1, 2025, and the Minamata Convention's COP-6 decision to phase out dental amalgam globally by 2034, the era of amalgam restorations is drawing to a close. However, populations with historical mercury exposure may retain persistent, species-dependent tissue mercury burdens, particularly within the kidney and brain. This persistent body burden may prolong internal mercury exposure after cessation or substantial reduction of the external source. We propose "Mercury Debt" as a conceptual construct describing residual, species-specific internal mercury exposure after external exposure has ceased or substantially declined. We hypothesize that Mercury Debt could be operationalized as a species- and organ-specific time-integrated internal exposure metric incorporating empirically derived weighting factors. Framed within the exposome paradigm, this review synthesizes recent mechanistic advances in mercury toxicology. We highlight representative molecular pathways, including oxidative stress, calcium dysregulation involving CaM/CaMKII signaling, DRP1-mediated mitochondrial fission, disruption of selenium-dependent biology and selenoprotein function, and mercury-associated epigenetic alterations characterized by DNA methylation changes. Furthermore, we integrate these molecular mechanisms with emerging physiologically based pharmacokinetic (PBPK) modeling, adverse outcome pathway (AOP) networks, and machine learning toxicity predictors. Finally, we outline a five-stage methodological roadmap encompassing speciation biomonitoring, multiomic exposome mapping, PBPK and AOP coupling, explainable AI risk stratification, and carefully controlled biomarker-guided clinical studies. This framework proposes a testable approach for future quantification of persistent internal mercury exposure, requiring validation through longitudinal biomonitoring, PBPK calibration, and mechanistic endpoint integration.