Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity

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Anna Bal-Price
Helena T. Hogberg
Kevin M. Crofton
Mardas Daneshian
Rex E. FitzGerald
Ellen Fritsche
Tuula Heinonen
Susanne Hougaard Bennekou
Stefanie Klima
Aldert H. Piersma
Magdalini Sachana
Timothy J. Shafer
Andrea Terron
Florianne Monnet-Tschudi
Barbara Viviani
Tanja Waldmann
Remco H. S. Westerink
Martin F. Wilks
Hilda Witters
Marie-Gabrielle Zurich
Marcel Leist


Multiple non animal-based test methods have never been formally validated. In order to use such new approach methods (NAMs) in a regulatory context, criteria to define their readiness are necessary. The field of developmental neurotoxicity (DNT) testing is used to exemplify the application of readiness criteria. The costs and number of untested chemicals are overwhelming for in vivo DNT testing. Thus, there is a need for inexpensive, high-throughput NAMs, to obtain initial information on potential hazards, and to allow prioritization for further testing. A background on the regulatory and scientific status of DNT testing is provided showing different types of test readiness levels, depending on the intended use of 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 NAMs with respect to various uses (e.g. prioritization/screening, risk assessment). The scoring results suggest that several assays are currently at high readiness levels. Therefore, suggestions are made on how DNT NAMs may be assembled into an integrated approach to testing and assessment (IATA). In parallel, the testing state in these assays was compiled for more than 1000 compounds. Finally, a vision is presented on how further NAM development may be guided by knowledge of signaling pathways necessary for brain development, DNT pathophysiology, and relevant adverse outcome pathways (AOP).

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Bal-Price, A., Hogberg, H. T., Crofton, K. M., Daneshian, M., FitzGerald, R. E., Fritsche, E., Heinonen, T., Hougaard Bennekou, S., Klima, S., Piersma, A. H., Sachana, M., Shafer, T. J., Terron, A., Monnet-Tschudi, F., Viviani, B., Waldmann, T., Westerink, R. H. S., Wilks, M. F., Witters, H., Zurich, M.-G. and Leist, M. (2018) “Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity”, ALTEX - Alternatives to animal experimentation, 35(3), pp. 306–352. doi: 10.14573/altex.1712081.

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