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Despite rapid advancements in technology and scientific understanding, genotoxicity testing batteries have remained largely unchanged for years. To modernize genotoxicity assessment and incorporate innovative approaches, the development of Integrated Approaches for Testing and Assessment (IATAs) is essential. These frameworks combine existing knowledge with data from New Approach Methodologies (NAMs) aiming to reduce or eliminate reliance on in\u00a0vivo testing. Genotoxicity is particularly well\u2010suited for IATA development as numerous cutting\u2010edge, non\u2010animal methods have emerged in recent years, including 3D test systems, Prediscreen, MultiFlow, ToxTracker, and transcriptomic\u2010based biomarkers such as GENOMARK and TGx\u2010DDI. However, the integration of NAMs into IATAs must be systematic and scientifically robust. In this process, the Adverse Outcome Pathway (AOP) framework plays a crucial role by linking molecular\u2010level events to adverse health effects, thereby supporting the structured selection of NAMs. This article explores the key challenges and gaps within the current European regulatory frameworks for chemical compound genotoxicity assessment and discusses how an AOP\u2010based IATA can address these issues. Additionally, we present a global AOP network for permanent DNA damage, designed to guide IATA development and improve regulatory decision\u2010making. This integrated approach has the potential to enhance the accuracy, efficiency, and ethical standards of genotoxicity assessment while reducing reliance on animal testing.<\/jats:p>","DOI":"10.1002\/em.70022","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T09:18:02Z","timestamp":1754903882000},"page":"341-366","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Advancing Genotoxicity Assessment by Building a Global <scp>AOP<\/scp> Network"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1531-968X","authenticated-orcid":false,"given":"E.","family":"Demuynck","sequence":"first","affiliation":[{"name":"Scientific Direction of Chemical and Physical Health Risks, Sciensano  Brussels Belgium"},{"name":"Department of In\u00a0Vitro Toxicology and Dermato\u2010Cosmetology Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6685-7299","authenticated-orcid":false,"given":"T.","family":"Vanhaecke","sequence":"additional","affiliation":[{"name":"Department of In\u00a0Vitro Toxicology and Dermato\u2010Cosmetology Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8231-8271","authenticated-orcid":false,"given":"A.","family":"Thienpont","sequence":"additional","affiliation":[{"name":"Scientific Direction of Chemical and Physical Health Risks, Sciensano  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-8797","authenticated-orcid":false,"given":"D.","family":"Cappoen","sequence":"additional","affiliation":[{"name":"Scientific Direction of Chemical and Physical Health Risks, Sciensano  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5672-0048","authenticated-orcid":false,"given":"F.","family":"Van Goethem","sequence":"additional","affiliation":[{"name":"Department of In\u00a0Vitro Toxicology and Dermato\u2010Cosmetology Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9105-7840","authenticated-orcid":false,"given":"L. 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