Use of New Approach Methodologies for the assessment of Endocrine Disruption within European union regulatory frameworks: Report from the 2024 European partnership for alternative approaches (EPAA) partners’ forum

New Approach Methodologies (NAMs) are increasingly used across industrial sectors to assess chemicals for endocrine activity and support endocrine disruption assessment. The European Partnership for Alternative Approaches to Animal Testing (EPAA) conducted a strategic, cross-sector review of NAM-based frameworks within the EU regulatory context to capture lessons learned, identify scientific gaps, and explore opportunities for collaboration. A key challenge is that most current in vitro NAMs cannot, by design, demonstrate endocrine-mediated adversity in an intact organism. Because evidence of adversity is required to define an endocrine disruptor, this limits the ability of NAMs to replace animal-based endocrine disruptor tests unless clear links between endocrine activity and adverse outcomes are established. Refocusing adverse outcome pathways (AOPs) on improving the predictive capacity of endocrine activity assays, rather than directly demonstrating adversity, could enhance NAM development and application. Additional gaps include limited information on internal exposure, the role of potency, and adequate coverage of sensitive life stages—an issue relevant to both NAMs and in vivo studies. Building regulatory trust in existing and emerging in vitro and in silico methods is essential and will require agreement on acceptable levels of uncertainty and confidence that NAM-based predictions are equivalent to or better than current approaches. Developing robust validation frameworks, enabling cross-sector data sharing, and strengthening dialogue among regulators, academia, and industry are critical to accelerating the regulatory integration of NAMs in endocrine disruption assessment.