Quantitative prediction of toxicological points of departure using two-stage machine learning models: A new approach methodology (NAM) for chemical risk assessment

Abstract

Point of departure (POD) is a concept used in risk assessment to calculate the reference dose of exposure that is likely to have no appreciable risk on health. POD can be directly utilized from no observed adverse effect levels (NOAEL) which is the dose or exposure level at which there is little or no risk of adverse effects. However, NOAEL values are unavailable for most of the chemicals due to inconsistent animal toxicity data. Hence, the current study utilizes a two-stage machine learning (ML) model for predicting NOAEL values, based on data curated from diverse toxicity exposures. In the first stage, a random forest regressor is used for supervised outlier detection and removal addressing any variability in data and poor correlations. The refined data is then used for toxicity prediction using several ML models; random forest and XGBoost show relatively higher performance with an R² value of 0.4 and 0.43, respectively, for predicting NOAEL in chronic toxicity. Similarly, feature combinations with absorption distribution metabolism and excretion (ADME) indicate better NOAEL prediction for acute toxicity. External validation is performed by predicting NOAEL values for cosmetic pigments and calculating reference doses (RfD). Notably, pigments like orange and red show higher RfD values, indicating broader safety margins. This study provides a practical framework for addressing variability and data limitations in toxicity prediction while offering insights into its applicability in risk evaluation.

Keywords: Machine learning; Pigments; Point of departure; Toxicity.