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An alternative QSAR-based approach for predicting the bioconcentration factor for regulatory purposes

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Andrea Gissi1, Domenico Gadaleta1, Matteo Floris2, Stefania Olla3, Angelo Carotti1, Ettore Novellino4, Emilio Benfenati5, and Orazio Nicolotti1
1 Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Bari, Italy;
2 Biomedicine Sector, CRS4, Parco Polaris, Loc. Pixinamanna, Pula, Italy;
3 IRGB-CNR, Cittadella Universitaria di Cagliari, Monserrato, Italy;
4 Dipartimento di Farmacia - Università degli Studi di Napoli “Federico II”, Napoli, Italy;
5 IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy

Summary

The REACH (Registration, Evaluation, Authorization and restriction of Chemicals) and BPR (Biocidal Product Regulation) regulations strongly promote the use of non-animal testing techniques to evaluate chemical risk. This has renewed the interest towards alternative methods such as QSAR in the regulatory context. The assessment of bioconcentration factor (BCF) required by these regulations is expensive, in terms of costs, time, and laboratory animal sacrifices. Herein, we present QSAR models based on the ANTARES dataset, which is a large collection of known and verified experimental BCF data. Among the models developed, the best results were obtained from a nine-descriptor highly predictive model. This model was derived from a training set of 608 chemicals and challenged against a validation and blind set containing 152 and 76 chemicals, respectively. The model’s robustness was further controlled through several validation strategies and the implementation of a multi-step approach for the applicability domain. Suitable safety margins were used to increase sensitivity. The easy interpretability of the model is ensured by the use of meaningful biokinetics descriptors. The satisfactory predictive power for external compounds suggests that the new models could represent a reliable alternative to the in vivo assay, helping the regis­trants to fulfill regulatory requirements in compliance with the ethical and economic necessity to reduce animal testing.

 

Keywords: REACH, BPR, QSAR, bioconcentration factor, biokinetics descriptors, applicability domain

 

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ALTEX 31(1), 23–36

DOI: 10.14573/altex.1305221



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