Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach

Abstract

Skin sensitisation is a key endpoint under REACH as it is costly and its assessment currently has a high dependency on animal testing. In order to reduce both the cost and the numbers of animals tested, it is likely that (quantitative) structure–activity relationships ((Q)SAR) and read-across methods will be utilised as part of intelligent testing strategies. The majority of skin sensitisers elicit their effect via covalent bond formation with skin proteins. These reactions have been understood in terms of well defined nucleophilic–electrophilic reaction chemistry. Thus, a first step in (Q)SAR analysis is the assignment of a chemical's potential mechanism of action enabling it to be placed in an appropriate reactivity domain. The aim of this study was to design a series of SMARTS patterns capable of defining these reactivity domains. This was carried out using a large database of local lymph node assay (LLNA) results that had had potential mechanisms of action assigned to them using expert knowledge. A simple algorithm was written enabling the SMARTS patterns to be used to screen a database of SMILES strings. The SMARTS patterns were then evaluated using a second, smaller, test set of LLNA results which had also had potential mechanisms of action assigned by experts. The results showed that the SMARTS patterns provided an excellent method of identifying potential electrophilic mechanisms. The findings are supported, in part, by molecular orbital calculations which confirm assignment of reactive mechanism of action. The ability to define a chemical's potential reaction mechanism is likely to be of significant benefit to regulators and risk assessors as it enables category formation and subsequent read-across to be performed.

Keywords:

• skin sensitisation
• local lymph node assay
• read-across
• QSAR
• reactivity
• SMARTS

Acknowledgements

The funding of the European Union 6th Framework CAESAR Specific Targeted Project (SSPI-022674-CAESAR) and European Union 6th Framework OSIRIS (GOCE-CT-2007-037017) Integrated Project is gratefully acknowledged. Dr Dave Roberts, Dr Nora Aptula and Professor Terry Schultz are gratefully acknowledged for useful and thought provoking insights into chemical reactivity and skin sensitisation.