PBT assessment and prioritization by PBT Index and consensus modeling: Comparison of screening results from structural models

The limited availability of comprehensive data for Persistence, Bioaccumulation and Toxicity (PBT) of chemicals is a serious hindrance to the assignment of compounds to the categories of PBT and vPvB; REACH regulation requires authorization for the use of such chemicals, and additionally plans for safer alternatives. In the context of screening and priority-setting tools for PBT-assessment, the cumulative PBT Index model, implemented in QSARINS (QSAR-INSUBRIA), new software for the development and validation of multiple linear regression QSAR models, offers a new holistic approach to identify chemicals with cumulative PBT properties directly from their molecular structure. In this study the Insubria PBT Index in QSARINS was applied to screen and prioritize various datasets, containing a large variety of chemicals of heterogeneous molecular structure previously screened by various authors by different methods, for their potential PBT behaviour. Particular attention was devoted to the model Applicability Domain, using different approaches such as Descriptors Range, Leverage, and Principal Component Analysis (PCA) of the modeling molecular descriptors, in order to discriminate between interpolated and extrapolated predictions. The results of this screening, which is based only on the molecular structure features and is not dependent on single threshold values for P, B and T, were compared with those obtained by the on-line US-EPA PBT Profiler. Good agreement between the various approaches was found, supporting the utility of a consensus approach in priority-setting studies. The main discrepancies have been highlighted and commented on. Moreover, a priority list containing the most hazardous compounds identified in agreement between the two tools has been drafted. The PBT Index, implemented in QSARINS, which has been demonstrated to be a practical, precautionary and reliable screening tool for PBT-behaviour immediately from the molecular structure, can be usefully applied for focusing experimental studies, and even before chemical synthesis, in a “benign by design” approach of safer alternatives.