Toward a Better Testing Paradigm for Developmental Neurotoxicity: OECD Efforts and Regulatory Considerations
Magdalini Sachana, Timothy J. Shafer, Andrea Terron
Abstract
Characterization of potential chemical-induced developmental neurotoxicity (DNT) hazard is considered for risk assessment purposes by many regulatory sectors. However, due to test complexity, difficulty in interpreting results and need of substantial resources, the use of the in vivo DNT test guidelines has been limited and animal data on DNT are scarce. To address challenging endpoints such as DNT, the Organisation for Economic Co-Operation and Development (OECD) chemical safety program has been working lately toward the development of integrated approaches for testing and assessment (IATA) that rely on a combination of multiple layers of data (e.g., in vitro, in silico and non-mammalian in vivo models) that are supported by mechanistic knowledge organized according to the adverse outcome pathway (AOP) framework. In 2017, the OECD convened a dedicated OECD expert group to develop a guidance document on the application and interpretation of data derived from a DNT testing battery that relies on key neurodevelopmental processes and is complemented by zebrafish assays. This review will provide a brief overview of the OECD DNT project and summarize various achievements of relevance to the project. The review also presents an opportunity to describe considerations for uptake of the DNT in an in vitro battery in a regulatory context.