Quantitative structure-activity relationship to predict acute fish toxicity of organic solvents

REACH regulation requires ecotoxicological data to characterize industrial chemicals. To limit in vivo testing, Quantitative Structure-Activity Relationships (QSARs) are advocated to predict toxicity of a molecule. In this context, the topic of this work was to develop a reliable QSAR explaining the experimental acute toxicity of organic solvents for fish trophic level. Toxicity was expressed as log(LC50), the concentration in mmol.L-1 producing the 50% death of fish. The 141 chemically heterogeneous solvents of the dataset were described by physico-chemical descriptors and quantum theoretical parameters calculated via Density Functional Theory. The best subsets of solvent descriptors for LC50 prediction were chosen both through the Kubinyi function associated with Enhanced Replacement Method and a stepwise forward multiple linear regressions. The 4-parameters selected in the model were the octanol-water partition coefficient, LUMO energy, dielectric constant and surface tension. The predictive power and robustness of the QSAR developed were assessed by internal and external validations. Several techniques for training sets selection were evaluated: a random selection, a LC50-based selection, a balanced selection in terms of toxic and non-toxic solvents, a solvent profile-based selection with a space filling technique and a D-optimality onions-based selection. A comparison with fish LC50 predicted by ECOSAR model validated for neutral organics confirmed the interest of the QSAR developed for the prediction of organic solvent aquatic toxicity regardless of the mechanism of toxic action involved. (C) 2013 Elsevier Ltd. All rights reserved.