The potential of mechanistic information organised within the AOP framework to increase regulatory uptake of the developmental neurotoxicity (DNT) in vitro battery of assays

A major challenge in regulatory developmental neurotoxicity (DNT) assessment is lack of toxicological information for many compounds. Therefore, the Test Guidelines programme of the Organisation for Economic Cooperation and Development (OECD) took the initiative to coordinate an international collaboration between diverse stakeholders to consider integration of alternative approaches towards improving and speeding up the current chemical testing for potential DNT effects. During the past few years, a series of workshops was organized during which a consensus was reached that incorporation of a DNT testing battery that relies on in vitro assays anchored to key neurodevelopmental processes should be developed to address regulatory needs. These key processes include neuronal and glial cell proliferation, differentiation, synaptogenesis, and neuronal network function, as well as related common key events identified in the existing Adverse Outcome Pathway (AOP) network. AOPs deliver mechanistic information on the causal links between molecular initiating event, intermediate key events and an adverse outcome of regulatory concern, providing the biological context to facilitate development of Integrated Approaches to Testing and Assessment (IATA) for various regulatory purposes. Developing IATA case studies, using various problem formulations and mechanistic information derived from AOPs, is expected to increase the biological understanding, transparency and communication of biological support for the use of in vitro methods within an IATA, thereby facilitating regulatory uptake, and identification of current gaps of knowledge. This manuscript summarizes the current state of international efforts to enhance DNT testing by using an in vitro battery of assays with particular focus on the role of AOPs in informing the development of IATA for different regulatory purposes, aiming to deliver the OECD guidance document on use of in vitro DNT battery of assays, including in vitro data interpretation.

SACHANA Magdalini;  WILLETT Catherine;  PISTOLLATO Francesca;  PRICE Anna; 

2021-06-29

PERGAMON-ELSEVIER SCIENCE LTD

JRC123786

0890-6238 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC123786,   

10.1016/j.reprotox.2021.06.006 (online),