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ALTEX. 2018;35(3):306-352. doi: 10.14573/altex.1712081. Epub 2018 Feb 23.

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

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European Commission, Joint Research Centre (EC JRC), Ispra (VA), Italy.
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, Baltimore, MD, USA.
National Centre for Computational Toxicology, US EPA, RTP, Washington, NC, USA.
Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany.
Swiss Centre for Human Applied Toxicology, SCAHT, University of Basle, Switzerland.
IUF - Leibniz Research Institute for Environmental Medicine & Heinrich-Heine-University, Düsseldorf, Germany.
Finnish Centre for Alternative Methods (FICAM), University of Tampere, Tampere, Finland.
Danish Environmental Protection Agency, Copenhagen, Denmark.
In vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Konstanz, Germany.
RIVM, National Institute for Public Health and the Environment, Bilthoven, and Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
Organisation for Economic Co-operation and Development (OECD), Paris, France.
European Food Safety Authority, Parma, Italy.
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
Neurotoxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
VITO, Flemish Institute for Technological Research, Unit Environmental Risk and Health, Mol, Belgium.


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).


developmental in vitro neurotoxicity testing; quality assurance; regulatory toxicology; toxicity screening

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