Global (Q)SARs for skin sensitisation: assessment against OECD principles.
As part of a European Chemicals Bureau contract relating to the evaluation of (Q)SARs for toxicological endpoints of regulatory importance, we have reviewed and analysed (Q)SARs for skin sensitisation. Here we consider some recently published global (Q)SAR approaches against the OECD principles and present re-analysis of the data. Our analyses indicate that "statistical" (Q)SARs which aim to be global in their applicability tend to be insufficiently robust mechanistically, leading to an unacceptably high failure rate. Our conclusions are that, for skin sensitisation, the mechanistic chemistry is very important and consequently the best non-animal approach currently applicable to predict skin sensitisation potential is with the help of an expert system. This would assign compounds into mechanistic applicability domains and apply mechanism-based (Q)SARs specific for those domains and, very importantly, recognise when a compound is outside its range of competence. In such situations, it would call for human expert input supported by experimental chemistry studies as necessary.
Roberts
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DW
School of Pharmacy and Chemistry, Liverpool John Moores University, England, UK. d.w.roberts@ljmu.ac.uk
Aptula
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AO
Cronin
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MT
Hulzebos
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Patlewicz
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D005062:European Union; D007509:Irritants / Q000737:chemistry* / Q000633:toxicity; D008956:Models, Chemical; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D023422:Skin Irritancy Tests / Q000379:methods*
D007509:Irritants