(Quantitative) Structure-Activity Relationships ((Q)SAR)

Physicochemical and (eco)toxicological data gaps are common features in the lives of hazard and risk assessors, and dossier submitters. Laboratory testing is undesirable in terms of the time, resources and costs required. Testing on vertebrates has ethical concerns across all sectors, and is banned for cosmetics marketed in Europe. Where possible, we strive to help clients fill data gaps without a potentially costly and animal-intensive trip to the testing laboratory. Several approaches are possible, including comprehensive literature searches for existing data on the substance itself and also on structural analogues and metabolites/precursors as part of a read-across approach.

These methods may not always yield adequate data for poorly-studied chemicals, in which case structure-activity relationships (SARs) and quantitative SARs (QSARs) may be appropriate alternatives. Computer models have been developed to examine these relationships, enabling the prediction of the characteristics of an untested compound based on knowledge of the activity of others (i.e. the presence or absence of functional groups associated with particular toxicity endpoints). (Q)SAR modelling is gaining regulatory acceptance. For example, under REACH its use is acceptable for certain physicochemical endpoints (e.g. vapour pressure). It can also help dossier submitters to decide on whether laboratory testing is scientifically justified for some of the less complex toxicological endpoints (e.g. for skin irritation, if the substance is predicted to be corrosive). For more complex toxicological endpoints (e.g. carcinogenicity, repeated dose toxicity, and reproductive and developmental toxicity), the utility of (Q)SARs remains limited.

Our scientists routinely apply (Q)SAR models using the OECD QSAR Toolbox (which comprises a range of models and programs including the US EPA’s EPI Suite). The Toolbox allows direct export of (Q)SAR results in a format that can be input directly into a REACH registration dossier in IUCLID. In addition, we are experienced in applying Toxtree and commissioning and interpreting DEREK analyses to estimate likely areas of toxicological hazard. Bibra is an expert consulting partner of Leadscope, which we use in-house for the evaluation of DNA-reactive compounds (particularly pharmaceutical impurities), in accordance with ICH guidance M7. Our vast experience in applying these models is matched by our expertise in interpreting the results; the limitations of (Q)SAR models must be understood and described, and the results should be applied appropriately. (Q)SAR results should always be interpreted in the context of any literature identified in searches of databases such as bibra’s own TRACE, which has been described in a recent publication as a valuable resource for conducting literature searches for carcinogenicity and mutagenicity data. Our toxicologists perform robust sanity checks on all of the outputs to ensure that predictions are sensible and consistent with our extensive on-the-job knowledge and expectations. Our (Q)SAR expertise has been valuable to clients from multiple sectors including:


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