Abstract
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).
Highlights
The International Stakeholder Network (ISTNET) on developmental neurotoxicity (DNT) testing is a collaborative effort of groups from academia, industry and regulatory bodies that aims to align the development of alternative testing methods with the needs of regulatory decision-making
3.1 Compilation of readiness criteria The development and application of in vitro test methods is driven by various stakeholders: basic academic researchers, test developers in industry and public institutions, and regulatory decision makers
Tab. 1: Example for ranking parameters for in vitro methods to detect chemicals that disturb the thyroid hormone axis Ranking parameters were established by OECD for thyroid-disrupting chemicals to determine the readiness of tests for validation (OECD, 2014a)
Summary
Why are alternatives needed? At present, there is no regulatory requirement for pesticides or other chemicals to be tested for DNT prior to registration. The US EPA Office of Pesticide Programs (OPP) suggested to include alternative approaches in the testing paradigm to improve DNT hazard identification in the context of analyzing DNT in vivo studies for 72 pesticide active substances (Raffaele et al, 2010) Another reason regulatory bodies and authorities support the development of alternative medium- to high-throughput assays is the need for testing large numbers of chemicals for their DNT potential (Crofton et al, 2012; EFSA, 2013; Bal-Price et al, 2015a; Fritsche et al, 2017a). While focusing on all these positive aspects, it will be important to bear in mind that fundamental issues of in vitro assays need to be kept in mind: for instance, the metabolic capacities that may differ from the in vivo situation, the interaction of different cell types that may largely affect their response pattern (Gantner et al, 1996), and issues of biological barriers (Leist et al, 2014; Kadereit et al, 2012; Aschner et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
