First report on Quantitative Structure-Toxicity Relationship modeling approaches for the prediction of acute toxicity of various organic chemicals against rotifer species

Nowadays, organic chemicals are crucial components in virtually every aspect of daily life, serving as indispensable elements for modern society. The ongoing synthesis of chemicals and the various potential harmful effects on living organisms are prompting regulatory bodies to view computational approaches as vital supplements and alternatives to traditional animal testing in assessing chemical risks. In this study, we have developed, for the first time, Quantitative Structure-Toxicity Relationship (QSTR) models based on Multiple Linear Regression (MLR) and five Machine Learning (ML) algorithms to predict organic chemical toxicity against a rotifer species (Brachionus calyciflorus). The most influential descriptors included in the MLR model are (SM6_B (p), B07[Cl–Cl], B05[Cl–Cl], MaxssCH2, F09[N–O], B04[Cl–Cl], and minssO), with positive contributions to the dependent variable (negative decimal logarithm of median lethal concentration at 24 h). The interpretation of the molecular descriptors of the MLR model suggested that substances with high molecular polarizability and
lipophilicity (presence of chlorine atoms) positively influence and increase their toxic potency. The analysis of the application domain, conducted using the leverage approach and the standardized residual method, showcased the extensive applicability of each model. In the cross-validation, the best values are presented by Support Vector Regression (SV_R), a value of Q2 Loo = 0.754 and RMSEcv = 0.652, which are slightly higher than the results of the other linear and nonlinear techniques used. Furthermore, our research exhibited a high degree of
fitness, internal robustness, and external predictive power. These findings suggest that the developed QSTR models are well-suited for the reliable prediction of aquatic toxicity for a wide range of structurally diverse organic chemicals. These models can be valuable for tasks such as screening, prioritizing new compounds, filling data gaps, and mitigating the limitations associated with in vivo and in vitro tests, ultimately contributing to the reduction of the use of dangerous chemicals in the environment.