A developmental and reproductive toxicity adverse outcome pathway network to support safety assessments

• Published in: Computational toxicology 2024-09, Vol.31, p.100325, Article 100325
• Main Authors: Myden, Alun, Cayley, Alex, Davies, Robert, Jones, Jade, Kane, Steven, Newman, Daniel, Payne, Martin P., Ude, Victor C., Vessey, Jonathan D., White, Emma, Fowkes, Adrian
• Format: Article
• Language: English
• ISSN: 2468-1113; 2468-1113
• DOI: 10.1016/j.comtox.2024.100325

Developmental and reproductive toxicity (DART) are key regulatory endpoints for the protection of human health. DART assessments require large numbers of animals, are expensive and often run at late stages of drug development. Therefore, new approach methodologies (NAMs) are being developed to transition away from animal testing. These NAMs (including in silico models) can be used to screen for DART hazards at the early stages of compound development and may in the future be used for regulatory DART assessments. Due to the implications of a mischaracterised developmental toxicant, both high confidence and understanding of the assessments made using NAMs will be required; it is likely that multiple NAMs will be needed in order to replace the current animal-based assessments. Adverse outcome pathways (AOPs) serve as a pragmatic tool for documenting mechanisms of toxicity. NAMs can be associated to key events (KEs) along an AOP, providing context to their outputs, and therefore increasing confidence in their use. It is likely that networks of pathways will be required for a specific toxicity endpoint in order to confidently apply an AOP-based approach to safety assessments. An insufficient number of DART AOPs are currently described within the public domain; therefore, using a literature-based approach, a network consisting of 340 KEs (including 68 MIEs) was developed. This foundation of pathways was made chemically aware through the association of relevant assays, data and expert rule-based structural alerts to appropriate KEs. The use of the network as a hazard screening tool was assessed, and the application of this to aid an ICH S5 workflow investigated. The knowledge captured within this AOP network can also guide the further development and use of DART-relevant NAMs and integrated approaches to testing and assessments (IATAs).