Novel machine learning models to predict endocrine disruption activity for high-throughput chemical screening

Abstract

An area of ongoing concern in toxicology and chemical risk assessment is endocrine disrupting chemicals (EDCs). However, thousands of legacy chemicals lack the toxicity testing required to assess their respective EDC potential, and this is where computational toxicology can play a crucial role. The US (United States) Environmental Protection Agency (EPA) has run two programs, the Collaborative Estrogen Receptor Activity Project (CERAPP) and the Collaborative Modeling Project for Receptor Activity (CoMPARA) which aim to predict estrogen and androgen activity, respectively. The US EPA solicited research groups from around the world to provide endocrine receptor activity Qualitative (or Quantitative) Structure Activity Relationship ([Q]SAR) models and then combined them to create consensus models for different toxicity endpoints. Random Forest (RF) models were developed to cover a broader range of substances with high predictive capabilities using large datasets from CERAPP and CoMPARA for estrogen and androgen activity, respectively. By utilizing simple descriptors from open-source software and large training datasets, RF models were created to expand the domain of applicability for predicting endocrine disrupting activity and help in the screening and prioritization of extensive chemical inventories. In addition, RFs were trained to conservatively predict the activity, meaning models are more likely to make false-positive predictions to minimize the number of False Negatives. This work presents twelve binary and multi-class RF models to predict binding, agonism, and antagonism for estrogen and androgen receptors. The RF models were found to have high predictive capabilities compared to other in silico modes, with some models reaching balanced accuracies of 93% while having coverage of 89%. These models are intended to be incorporated into evolving priority-setting workflows and integrated strategies to support the screening and selection of chemicals for further testing and assessment by identifying potential endocrine-disrupting substances.