Ensemble QSAR Modeling to Predict Multispecies Fish Toxicity Lethal Concentrations and Points of Departure

QSAR modeling can be used to aid testing prioritization of the thousands of chemical substances for which no ecological toxicity data are available. We drew on the U.S. Environmental Protection Agency's ECOTOX database with additional data from ECHA to build a large data set containing in vivo test data on fish for thousands of chemical substances. This was used to create QSAR models to predict two types of end points: acute LC₅₀ (median lethal concentration) and points of departure similar to the NOEC (no observed effect concentration) for any duration (named the "LC₅₀" and "NOEC" models, respectively). These models used study covariates, such as species and exposure route, as features to facilitate the simultaneous use of varied data types. A novel method of substituting taxonomy groups for species dummy variables was introduced to maximize generalizability to different species. A stacked ensemble of three machine learning methods-random forest, gradient boosted trees, and support vector regression-was implemented to best make use of a large data set with many descriptors. The LC₅₀ and NOEC models predicted end points within 1 order of magnitude 81% and 76% of the time, respectively, and had RMSEs of roughly 0.83 and 0.98 log₁₀(mg/L), respectively. Benchmarks against the existing TEST and ECOSAR tools suggest improved prediction accuracy.