Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing.

On occasion of the DNT5 meeting in Konstanz, Germany (April-2024), participants brainstormed on future challenges concerning a regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB). The five discussion topics below outline some of the key issues, opportunities and research directions for the next several years: (1) How to contextualize DNT hazard with information on potential maternal toxicity or other toxicity domains (non-DNT)? Several approaches on how to use cytotoxicity data from NAMs were discussed. (2) What opportunities exist for an immediate or near-future application of the DNT-IVB, e.g. as a prioritisation step or add-on to other information? Initial examples are already emerging; the data can be used even if the battery is not converted to a defined approach. (3) How to establish data interpretation procedures for multi-dimensional endpoints that reduce dimensionality and are suitable for classification? A decision framework is required on how to use the DNT-IVB in a regulatory context. Machine-learning (AI-approaches) may provide novel classification models. (4) How can a battery of molecular initiating events (MIEs) be smartly linked to the DNT-IVB? At what tier of an overall strategy would MIEs be evaluated, and how would one optimally balance cost vs information yield. (5) What is the way forward to scientific validation of DNT NAMs and the DNT-IVB? A large set of animal data would be required for conventional approaches, while mechanistic information may establish relevance in other ways