Fused/non-fused polycyclic aromatic hydrocarbons (FNFPAHs) have a variety of toxic effects on ecosystems and human body, but the acquisition of their toxicity data is greatly limited by the limited resources available. Here, we followed the EU REACH regulation and used Pimephales promelas as a model organism to investigate the quantitative structure-activity relationship (QSAR) between the FNFPAHs and their toxicity for the aquatic environment for the first time. We developed a single QSAR model (SM1) containing five simple and interpretable 2D molecular descriptors, which met the validation of OECD QSAR-related principles, and analyzed their mechanistic relationships with toxicity in detail. The model had good degree of fitting and robustness, and had better external prediction performance (MAEtest = 0.4219) than ECOSAR model (MAEtest = 0.5614). To further enhance its prediction accuracy, the three qualified single models (SMs) were used for constructing consensus models (CMs), the best one CM2 (MAEtest = 0.3954) had a significantly higher prediction accuracy for test compounds than SM1, and also outperformed the T.E.S.T. consensus model (MAEtest = 0.4233). Subsequently, the toxicity of 252 true external FNFPAHs from Pesticide Properties Database (PPDB) was predicted by SM1, the prediction results showed that 94.84 % compounds were reliably predicted within the model\'s application domain (AD). We also applied the best CM2 to predict the untested 252 FNFPAHs. Furthermore, we provided a mechanistic analysis and explanation for pesticides ranked as top 10 most toxic FNFPAHs. In summary, all developed QSAR and consensus models can be used as efficient tools for predicting the acute toxicity of unknown FNFPAHs to Pimephales promelas, thus being important for the risk assessment and regulation of FNFPAHs contamination in aquatic environment.

Fused and non-fused polycyclic aromatic hydrocarbons (FNFPAHs) are a type of organic compounds widely occurring in the environment that pose a potential hazard to ecosystem and public health, and thus receive extensive attention from various regulatory agencies. Here, quantitative structure-activity relationship (QSAR) models were constructed to model the ecotoxicity of FNFPAHs against two aquatic species, Daphnia magna and Oncorhynchus mykiss. According to the stringent OECD guidelines, we used genetic algorithm (GA) plus multiple linear regression (MLR) approach to establish QSAR models of the two aquatic toxicity endpoints: D. magna (48 h LC50) and O. mykiss (96 h LC50). The models were established using simple 2D descriptors with explicit physicochemical significance and evaluated using various internal/external validation metrics. The results clearly show that both models are statistically robust (QLOO2 = 0.7834 for D. magna and QLOO2 = 0.8162 for O. mykiss), have good internal fitness (R2 = 0.8159 for D. magna and R2 = 0.8626 for O. mykiss and external predictive ability (D. magna: Rtest2 = 0.8259, QFn2 = 0.7640∼0.8140, CCCtest = 0.8972; O. mykiss:Rtest2 = 0.8077, QFn2 = 0.7615∼0.7722, CCCtest = 0.8910). To prove the predictive performance of the developed models, an additional comparison with the standard ECOSAR tool obviously shows that our models have lower RMSE values. Subsequently, we utilized the best models to predict the true external set compounds collected from the PPDB database to further fill the toxicity data gap. In addition, consensus models (CMs) that integrate all validated individual models (IMs) were more externally predictive than IMs, of which CM2 has the best prediction performance towards the two aquatic species. Overall, the models presented here could be used to evaluate unknown FNFPAHs inside the domain of applicability (AD), thus being very important for environmental risk assessment under current regulatory frameworks.