A QSAR for Baseline Toxicity: Validation, Domain of Application, and Prediction

The interest in modeling and application of structure−activity relationships has steadily
increased in recent decades. It is generally acknowledged that these empirical relationships
are valid only within the same domain for which they were developed. However, model
validation is sometimes neglected, and the application domain is not always well-defined. The
purpose of this paper is to outline how validation and domain definition can facilitate the
modeling and prediction of baseline toxicity for a large database. A large number of theoretical
descriptors (867) were generated from two-dimensional molecular structures for compounds
present in the U.S. EPA's Fathead Minnow Database (611) and the Syracuse Research
Corporation's PhysProp Database (25 000+). A quantitative structure−activity relationship
model was developed for baseline toxicity (narcosis) toward the fathead minnow (Pimephales
promelas) using a projection-based regression technique, PLSR (partial least squares regression). The PLSR model was subsequently validated with an external test set. The main factors
of variation were related to size/shape and polar interactions. The prediction error was
comparable to, or slightly better than, the ECOSAR procedures. A set of 16 805 compounds,
drawn from the PhysProp Database, was projected onto the PLSR model. More than 90%
(15 597) of the compounds fall within the valid model domain, defined by the residual standard
deviation and the leverage. The predicted baseline toxicity indicates an acute hazard for two-thirds of these compounds, classes I−III in the OECD Globally Harmonized Classification
System (LC50 ≤ 100 mg L-1). Finally, the mode of action assigned in the U.S. EPA Fathead
Minnow Database was investigated. Reclassification to narcosis as the mode of action is
suggested for 92 compounds, mostly from the groups “unsure” and “mixed”. The present
classification into specific modes of action seems to be further strengthened by the findings in
this investigation.