04239nas a2200553   4500000000100000000000100001008004100002260001500043653004000058653003500098653001700133653004400150653003800194653004400232653005000276653001400326100001700340700002200357700001800379700001900397700001800416700002400434700001800458700001800476700001900494700001900513700002200532700001900554700001900573700001600592700001900608700001900627700001700646700002100663700001900684700002100703700002200724700002200746700001800768700001700786700002200803700002000825700002100845700001700866245014100883856006001024520258701084022001403671       2025                            d  c2025-01-1410aDNT in vitro test battery (DNT-IVB)10aadverse outcome pathways (AOP)10acytotoxicity10akey neurodevelopmental processes (KNDP)10aNew Approach Methodologies (NAMs)10anext generation risk assessement (NGRA)10aphysiologically-based kinetic modelling (PBK)10aScreening1 aEike Cöllen1 aKristina Bartmann1 aJonathan Blum1 aKelly Carstens1 aIvana Celardo1 aNivedita Chatterjee1 aMarco Corvaro1 aNadine Dreser1 aEllen Fritsche1 aThomas Hartung1 aHelena T. Hogberg1 aThomas Knudsen1 aKatharina Koch1 aAnna Kreutz1 aMalene Lislien1 aViktoria Magel1 aSue M. Marty1 aGiorgia Pallocca1 aAnna Bal-Price1 aConstanza Rovida1 aMagdalini Sachana1 aTimothy J. Shafer1 aLena Smirnova1 aIlinca Suciu1 aYaroslav Tanaskov1 aSilvia Tangianu1 aChiara Wolfbeisz1 aMarcel Leist00aMapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing  uhttps://www.altex.org/index.php/altex/article/view/29223 aOn 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.
Plain language summaryA meeting on developmental neurotoxicity (DNT) testing was held in Konstanz, Germany in April 2024 (DNT5 meeting). A major topic of discussion at the conference was the DNT in vitro test battery (DNT-IVB), and how this set of cell-based animal-free test methods may be used in a regulatory context. Opportunities for future developments were addressed in discussion groups: The combination of specific DNT readouts with less specific cytotoxicity data was discussed. Another group of participants addressed opportunities for an immediate or near-future application of the DNT-IVB. One of the discussion groups concluded that a decision framework is required on how to use the DNT-IVB in a regulatory context. Moreover, the use of signalling assays (evaluating the interaction of test compounds with receptors, enzymes and transporters) in combination with the IVB was discussed. Finally, ideas and concepts for the way forward to scientific validation of the DNT-IVB were collected.  a1868-8551