Critical features identification for chemical chronic toxicity based on mechanistic forecast models

Facing billions of tons of pollutants entering the ocean each year, aquatic toxicity is becoming a crucial endpoint for evaluating chemical adverse effects on ecosystems. Notably, huge amount of toxic chemicals at environmental relevant doses can cause potential adverse effects. However, chronic aquatic toxicity effects of chemicals are much scarcer, especially at population level. Rotifers are highly sensitive to toxicants even at chronic low-doses and their communities are usually considered as effective indicators for assessing the status of aquatic ecosystems. Therefore, the no observed effect concentration (NOEC) for population abundance of rotifers were selected as endpoints to develop machine learning models for the prediction of chemical aquatic chronic toxicity. In this study, forty-eight binary models were built by eight types of chemical descriptors combined with six machine learning algorithms. The best binary model was 1D & 2D molecular descriptors - random trees model (RT) with high balanced accuracy (BA) (0.83 for training and 0.83 for validation set), and Matthews correlation coefficient (MCC) (0.72 for training set and 0.67 for validation set). Moreover, the optimal model identified the primary factors (SpMAD_Dzp, AMW, MATS2v) and filtered out three high alerting substructures [c1cc(Cl)cc1, CNCO, CCOP(=S)(OCC)O] influencing the chronic aquatic toxicity. These results showed that the compounds with low molecular volume, high polarity and molecular weight could contribute to adverse effects on rotifers, facilitating the deeper understanding of chronic toxicity mechanisms. In addition, forecast models had better performances than the common models embedded into ECOSAR software. This study provided insights into structural features responsible for the toxicity of different groups of chemicals and thereby allowed for the rational design of green and safer alternatives.