Review of QSAR Models and Software Tools for predicting Developmental and Reproductive Toxicity

This report provides a state-of-the-art review of available computational models for developmental and reproductive toxicity, including Quantitative Structure-Activity Relationship (QSARs) and related estimation methods such as decision tree approaches and expert systems. At present, there are relatively few models for developmental and reproductive toxicity endpoints, and those available have limited applicability domains. This situation is partly due to the biological complexity of the endpoint, which covers many incompletely understood mechanisms of action, and partly due to the paucity and heterogeneity of high quality data suitable for model development. In contrast, there is an extensive and growing range of software and literature models for predicting endocrine-related activities, in particular models for oestrogen and androgen activity. There is a considerable need to further develop and characterise in silico models for developmental and reproductive toxicity, and to explore their applicability in a regulatory setting. LIST OF ABBREVIATIONS AD Applicability Domain AR Androgen Receptor CASE Computer Automated Structure Evaluation CoMFA Comparative Molecular Field Analysis EC European Commission ECHA European Chemicals Agency EAS Endocrine Active Substances ED Endocrine Disruptor EINECS European Inventory of Existing Chemical Substances ER Oestrogen Receptor GRIND GRid INdependent Descriptors HTS High-throughput screening IC50 Half Maximal Inhibitory Concentration ILSI International Life Sciences Institute JRC Joint Research Centre LBD Ligand Binding Domain LD50 Median Lethal Dose NMR Nuclear Magnetic Resonance NR Nuclear receptor MCASE Multi Computer Automated Structure Evaluation MC4PC Multi CASE for Personal Computer OECD Organisation for Economic Cooperation and Development OPS Optimal Predictive Space PASS Prediction of Activity Spectra for Substances PDB Protein Data Bank PPAR Peroxisome Proliferator Activated Receptor PR Progesterone Receptor (Q)SAR (Quantitative) Structure-Activity Relationship REACH Registration, Evaluation, Authorisation and Restriction of Chemicals SDF Structure Data file SERM Selective Estrogen Receptor Modulator TEST Toxicity Estimation Software Tool TIMES Tissue MEtabolism Simulator US EPA United States Environmental Protection Agency WoE Weight of Evidence