Evaluation of the applicability of existing (Q)SAR models for predicting the genotoxicity of pesticides and similarity analysis related with genotoxicity of pesticides for facilitating of grouping and read across

Technical report collection

2019

genotoxicity, QSAR, read-across, plat protection products

Romualdo Benigni,Chiara Laura Battistelli,Cecilia Bossa,Alessandro Giuliani,Elena Fioravanzo,Arianna Bassan,Mojca Fuart Gatnik,James Rathman,Chihae Yang,Olga Tcheremenskaia

To facilitate the practical implementation of the guidance on the residue definition for dietary risk assessment, EFSA has organized an evaluation of applicability of existing in silico models for predicting the genotoxicity of pesticides and their metabolites, including analysis of the impact on genotoxicity of the metabolic structural changes. The prediction ability of (Q)SARs for in vitro and in vivo tests were evaluated. For the Ames test, all (Q)SAR models generated statistically significant predictions, comparable with the experimental variability of the test; instead, the reliability of the (Q)SAR models for assays / endpoints different from in vitro bacterial mutagenicity appears to be quite far from optimality. Secondly, two new Read Across approaches were applied to predict Ames mutagenicity and in vitro Chromosomal Aberrations: Read Across was largely successful for predicting the Ames test results, but much less for in vitro Chromosomal Aberrations. The worse results for endpoints different from Ames may be attributable to the several revisions of experimental protocols and evaluation criteria of results that have made the databases qualitatively non‐homogeneous, and poorly suitable for modelling. A third dimension of this research is the evaluation of the impact of the structural changes‐in result of metabolic or degradation processes‐on the genotoxic potential of the substances. Parent/Metabolite structural differences (beyond the known Structural Alerts) that may, or may not cause changes in the Ames mutagenicity were identified and catalogued. In addition, Structural Alerts analysis applied under human expert supervision permitted the rationalization of the large majority of the changes of patterns of genotoxicity. The findings from this work are suitable for being integrated into Weight‐of‐Evidence and Tiered evaluation schemes. The importance of the human expert knowledge is particularly emphasized.