Prediction of the Neurotoxic Potential of Chemicals Based on Modelling of Molecular Initiating Events Upstream of the Adverse Outcome Pathways of (Developmental) Neurotoxicity

Abstract

Developmental and adult/ageing neurotoxicity is an area needing alternative methods for chemical risk assessment. The formulation of a strategy to screen large numbers of chemicals is highly relevant due to potential exposure to compounds that may have long-term adverse health consequences on the nervous system, leading to neurodegeneration. Adverse Outcome Pathways (AOPs) provide information on relevant molecular initiating events (MIEs) and key events (KEs) that could inform the development of computational alternatives for these complex effects. We propose a screening method integrating multiple Quantitative Structure–Activity Relationship (QSAR) models. The MIEs of existing AOP networks of developmental and adult/ageing neurotoxicity were modelled to predict neurotoxicity. Random Forests were used to model each MIE. Predictions returned by single models were integrated and evaluated for their capability to predict neurotoxicity. Specifically, MIE predictions were used within various types of classifiers and compared with other reference standards (chemical descriptors and structural fingerprints) to benchmark their predictive capability. Overall, classifiers based on MIE predictions returned predictive performances comparable to those based on chemical descriptors and structural fingerprints. The integrated computational approach described here will be beneficial for large-scale screening and prioritisation of chemicals as a function of their potential to cause long-term neurotoxic effects.