New approach methodologies for human-relevant toxicology: from mechanistic evidence to regulatory decision-making

New Approach Methodologies (NAMs) are transforming toxicology from a predominantly animal-based, apical endpoint paradigm toward a human relevant, mechanistically informed, exposure driven and data integrated framework for risk assessment. Rather than serving as simple one-to-one replacements for conventional animal studies, NAMs comprise a broad toolbox of in silico, in chemico, in vitro, ex vivo, omics-based, exposure and kinetic modelling approaches that can be combined within Integrated Approaches to Testing and Assessment (IATA), Adverse Outcome Pathway (AOP) frameworks and next generation risk assessment (NGRA). This review critically evaluates the scientific basis, technological platforms, translational applications, advantages, limitations and regulatory readiness of NAMs in modern toxicology. Particular emphasis is placed on the integration of human cell-based systems, microphysiological systems, organoids, transcriptomics, metabolomics, physiologically based kinetic (PBK) modelling, in vitro to in vivo extrapolation (IVIVE), exposure bioactivity relationships and scientific confidence frameworks. Current developments from the European Food Safety Authority (EFSA), European Chemicals Agency (ECHA), European Medicines Agency (EMA), Organisation for Economic Co-operation and Development (OECD), United States Food and Drug Administration (FDA), Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), Health Canada and the European Commission are discussed to highlight the increasing regulatory momentum toward fit-for-purpose qualification and reduced animal use. The review concludes that successful implementation of NAMs will require clear problem formulation, standardized reporting, robust quality control, uncertainty characterization, interoperable data infrastructures and international harmonization.