Toward a Better Testing Paradigm for Developmental Neurotoxicity: OECD Efforts and Regulatory Considerations.

Abstract

Simple SummaryIt is recognized that the current developmental neurotoxicity (DNT) testing paradigm is not fit-for -purpose for the assessment of a large number of chemicals. In the last two decades there have been scientific advances made for evaluating chemical interactions with the developing nervous system that rely on alternative to animal methods. The Organisation for Economic Co-Operation and Development (OECD) provides a forum to develop internationally harmonised guidance to test and assess chemicals for DNT that is primarily based on cellular models. Given the complexity of the developing nervous system and the availability of a number of non-animal methods to address DNT, integration of data from multiple studies is necessary and an OECD framework for organising existing scientific knowledge can be applied as the canvas of this integration. Herein, we 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 non animal methods in a regulatory context.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.