Prediction of estrogenicity: validation of a classification model

(Q)SAR models can be used to reduce animal testing as well as to minimise the testing costs. In particular, classification models have been widely used for estimating endpoints with binary activity. The aim of the present study was to develop and validate a classification-based quantitative structure-activity relationship (QSAR) model for endocrine disruption, based on interpretable mechanistic descriptors related to estrogenic gene activation. The model predicts the presence or absence of estrogenic activity according to a pre-defined cut-off in activity as determined in a recombinant yeast assay. The experimental data was obtained from the literature. A two-descriptor classification model was developed that has the form of a decision tree. The predictivity of the model was evaluated by using an external test set and by taking into account the limitations associated with the applicability domain (AD) of the model. The AD was determined as coverage of the model descriptor space. After removing the compounds present in the training set and the compounds outside of the AD, the overall accuracy of classification of the test chemicals was used to assess the predictivity of the model. In addition, the model was shown to meet the OECD Principles for (Q)SAR Validation, making it potentially useful for regulatory purposes.