New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

Front Toxicol. 2024 Apr 26:6:1359507. doi: 10.3389/ftox.2024.1359507. eCollection 2024.

Abstract

In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.

Keywords: DNT-IVB; adult neurotoxicity (ANT); applicability domain; developmental neurotoxicity (DNT); new approach method (NAM); zebrafish.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was carried out in the framework of the European Partnership for the Assessment of Risks from Chemicals (PARC) and has received funding from the European Union’s Horizon Europe research and innovation programme under Grant Agreement No 101057014. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. This work was also supported by a Helmholtz Association W2 award to T. Tal. The views expressed in this document are those of the authors and are not necessarily those of the EU agencies. Any statement made regarding EU regulations is solely intended for information purposes and does not represent the official opinion of the European Chemicals Agency (ECHA). ECHA is not responsible for any use that may be made of the information contained in this document. Statements made or information contained in this publication are without prejudice to any future work that ECHA may initiate. Funding performed in close connection to the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreements No. 964518 (ToxFree), No. 964537 (RISK-HUNT3R), No. 965406 (PrecisionTox) and No. 963845 (ONTOX) in the ASPIS Cluster. Figures were generated using biorender.com.