Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment
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Project developed under the service level agreement SLA/EFSA-JRC/2009-01
Residues arising from the use of plant protection products (PPPs) on food commodities can consist not only of the active substances but also of their degradation products and metabolites. The toxicological properties of the active substance are normally extensively investigated in toxicological studies, while only very limited experimental data are usually available on the toxicological properties of metabolites and reaction products.
Dietary risk assessment should take into account all compounds contributing to risks but at the same time requests for further toxicological studies should be restricted as much as possible to minimise the use of test animals. In addition to that in many cases a comprehensive assessment with toxicological tests would not be feasible based on the sheer number of metabolites and reaction products. Therefore, the applicability of alternative assessment methods is currently explored. EFSA considered the possible use of Quantitative Structure-Activity Relationships (QSARs) for this task.
The present report describes the outcome of a service level agreement with the Joint Research Centre (JRC) Ispra (Italy) on the “Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment” funded by EFSA. The project addressed the usefulness of different computational estimation methods with an emphasis on QSARs, Structure Activity Relationships (SARs) and expert systems also describing their status in regard to human health hazard assessment and assessment of absorption, distribution, metabolism and excretion (ADME) properties. It also describes how QSAR models and the predictions they generate should be assessed. It contains results from a survey carried out on the current use of computational methods in the assessment of chemicals in food. Finally the results of a research investigation exploring the usefulness of selected computational methods for the prediction of genotoxicity and carcinogenicity are presented. Emphasis was placed on these endpoints since they are of particular relevance when computational methods are combined with the application of the Threshold of Toxicological Concern (TTC) concept. With a view to promoting computational methods in dietary risk assessment, recommendations for further work can be found throughout the report.