Neurotoxicity hazard assessment framework that integrates in silico approaches

This week we are pleased to welcome Dr. Kevin Crofton and Dr. Arianna Bassan as guest contributors to the blog.

Within the in silico toxicology project, a position paper on neurotoxicity is appearing in a special issue of the journal of Computational Toxicology¹.

This paper discusses the need for the development of more informative new approach methodologies (NAM) to assess developmental (DNT) and adult (NT) neurotoxicity induced by xenobiotics. The use of NAMs (including in silico methodologies that predict toxicity from chemical structure such as QSARs and structural alerts) is ideally based on the understanding of the biological mechanism underpinning neurotoxicity (e.g., blocking of GABAA receptors by organochlorines leading to seizures and pyrethroid effects on voltage-gated sodium channels).

In our paper, we discuss the development of a decision assessment framework that builds on the emerging vision of mechanistically informed approaches. Such assessment framework requires the identification of relevant effects/mechanisms and endpoints together with their mutual relationships as it is meant to guide the integration of data from different sources (in vitro data, animal in vivo data, human data) for the assessment of neurotoxicity. The expedited advances in toxicology and the ever-increasing understanding of the biological pathways underlying NT and DNT will impose a continuous adaptation of this framework. However, in our work, we have tried to capture the current knowledge to provide a construct that integrates the use of in silico methods for DNT and NT assessments and that may inform future development of in silico approaches.

The paper also includes overviews on:

• Known mechanisms underlying DNT/NT
• Current state of the art in DNT/NT testing
• In silico approaches for the assessment of neurotoxicity based on knowledge of chemical structure

This work should support the future development of protocols, namely standardized approaches, for the use of in silico methods for the assessments of NT and DNT based on chemical structures ensuring transparent, consistent, and defendable results. Because of the large numbers of chemicals used in all aspects of global commerce, such standardized procedures would be beneficial for compliance across related regulatory programs (e.g., FDA and EFSA, TSCA and REACH).

For more information on this collaboration or related projects, please contact Glenn Myatt (glenn.myatt@instem.com).

References

1. Crofton et al (2022) , Current status and future directions for a neurotoxicity hazard assessment framework that integrates in silico approaches, 22, 100223, https://doi.org/10.1016/j.comtox.2022.100223