Can mutagenicity information be useful in an Integrated Testing Strategy (ITS) for skin sensitization?
Our previous work has investigated the utility of mutagenicity data in the development and application of Integrated Testing Strategies (ITS) for skin sensitization by focusing on the chemical mechanisms at play and substantiating these with experimental data where available. The hybrid expert system TIMES (Tissue Metabolism Simulator) was applied in the identification of the chemical mechanisms since it encodes a comprehensive set of established structure-activity relationships for both skin sensitization and mutagenicity. Based on the evaluation, the experimental determination of mutagenicity was thought to be potentially helpful in the evaluation of skin sensitization potential. This study has evaluated the dataset reported by Wolfreys and Basketter (Cutan. Ocul. Toxicol. 23 (2004), pp. 197-205). Upon an update of the experimental data, the original reported concordance of 68% was found to increase to 88%. There were several compounds that were 'outliers' in the two experimental evaluations which are discussed from a mechanistic basis. The discrepancies were found to be mainly associated with the differences between skin and liver metabolism. Mutagenicity information can play a significant role in evaluating sensitization potential as part of an ITS though careful attention needs to be made to ensure that any information is interpreted in the appropriate context.
DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware, USA. patlewig@hotmail.com
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Patlewicz
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Mekenyan
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Dimitrova
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Kuseva
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Todorov
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Kotov
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Stoeva
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Donner
D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000187:drug effects*; D012882:Skin Tests / Q000379:methods
D009153:Mutagens