Enhancing seizure liability assessment: integrating target-based data and addressing knowledge gaps
Animal models are currently used to predict whether a chemical might cause human neurotoxicity, which can lead to adverse effects such as seizures. However, research suggests that animal models have limited reliability, particularly in predicting drug safety for the central nervous system. The prediction of whether a drug might cause seizures, specifically, is unreliable due to a significant failure rate of novel drugs in human clinical trials caused by unforeseen toxicity, revealing the inadequacy of these models. To address this issue, a collaboration between NIEHS and industry was initiated to identify potential biological targets associated with seizures. By combining targets from established AOPs and drug discovery databases, a seizure-specific AOP network was generated. Resources including NICEATM’s Integrated Chemical Environment and the European Molecular Biology Laboratory’s ChEMBL database were employed to identify new approach methodologies (NAMs) that could measure identified targets. The search identified both compounds likely to induce seizure and compounds that have tested negative for seizure effects. A proof-of-concept evaluation to assess in vitro mechanistic assay data availability across the seizure-relevant targets was conducted. Through this comprehensive approach, the current landscape of seizure risk-informative testing assay availability was assessed, laying the groundwork for future predictive modeling efforts with the ultimate goal of enhancing the ability to anticipate and mitigate seizure-related adverse effects. This project was presented at the 2023 annual meeting of the American College of Toxicology (Behl et al.), and a manuscript is in preparation to be submitted in 2024.