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t4 Workshop Report Recommendation on test readiness criteria for new approach methods in toxicology: exemplified for developmental neurotoxicity

Multiple non animal-based test methods have never been formally validated. In order to use such new approach methods (NAM) in a regulatory context, a process and criteria to define the readiness of the NAM would be useful. The field of neurodevelopmental toxicity (DNT) testing has been chosen here to exemplify the application of readiness criteria. The number of chemicals not tested, and the testing cost per chemical are overwhelming for DNT. Thus, there is a need for low-cost, high-throughput NAM approaches, to obtain initial information on potential hazard, and to allow prioritization for further testing. We give here a background on the regulatory and scientific status of DNT testing, to show that different types of test readiness levels are required, depending on the intended use of the data from NAMs. Readiness criteria, compiled during a stakeholder workshop, uniting scientists from academia, industry and regulatory authorities are presented. An important step beyond the listing of criteria, was the suggestion for a preliminary scoring scheme. On this basis a (semi)-quantitative analysis process was assembled on test readiness of 17 NAM with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggested that several assays reached high readiness levels. Therefore, suggestions were made on how DNT NAM may be assembled to an integrated approach to testing and assessment (IATA). In parallel, an overview of the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision was presented on how further NAM development may be guided by knowledge of signaling pathways necessary for normal brain development, DNT pathophysiology, and relevant adverse outcome pathways.