Development of an adverse outcome pathway network for reproductive toxicity endpoints to support identification of endocrine disrupters

Le résumé fourni par la source

Abstract Development of adverse outcome pathways (AOPs) can support the implementation of the EFSA–ECHA Guidance (2018) for identifying endocrine disruptors under EU Regulations 528/2012 and 1107/2009. However, their regulatory utility depends on them being fully developed and OECD‐endorsed, and in many cases their incorporation into more extensive AOP networks (AOPNs). To accelerate this process, EFSA has prioritized the creation of AOPNs spanning estrogenic, androgenic, steroidogenic, and thyroid (EATS) modalities, with an initial focus on mammalian reproductive toxicity driven by estrogenic, androgenic, and steroidogenic (EAS) disruption. In this context, this project developed a foundational AOPN capturing anti‐androgenic mechanisms that converge on key regulatory outcomes, including reduced anogenital distance, nipple retention, hypospadias, and impaired fertility. This AOPN currently includes 10 fully developed AOP. Additional developments under the project includes upstream networks for androgen, estrogen, and steroidogenesis modalties. The work establishes a modular architecture in which upstream molecular signaling pathways feed into shared developmental key events, thereby enabling integration of diverse mechanistic data and supporting transparent tracking of causal evidence. By mapping conserved pathways and identifying mechanistic nodes with high regulatory relevance, the framework also highlights critical knowledge gaps that hinder robust AOP expansion. The project incorporated standardized AOP‐Wiki methodologies to strengthen consistency in reporting and facilitate future network growth, while methodological advances such as refined weight‐of‐evidence procedures, systematic network‐mapping approaches, and strategies for building data‐rich key event relationships enhance reproducibility and evaluative confidence. Together, these developments can increase the practical value of AOPN for chemical evaluation and risk assessment, support alignment with emerging new approach methodologies (NAMs) for endocrine disruptor identification and provide a scalable foundation for future AOP and AOPN development.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.