Abstract
The International Council for Harmonisation of Technical Requirement for Pharmaceuticals for Human Use (ICH) M7 guideline on 'Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk' provides the application of two types of quantitative structure-activity relationship (QSAR) systems (rule- and statistics-based) as an alternative to the Ames test for evaluating the mutagenicity of impurities in pharmaceuticals. M7 guideline also states that the expert reviews can be applied when the outcomes of the two QSAR analyses show any conflicting or inconclusive prediction. However, the guideline does not provide any information of how to conduct expert reviews. Therefore, a conservative approach was chosen in this study, which is based on the intention to capture any mutagenic chemical substances. The 36 chemical substances, which are the model chemical substances in which positive mutagenicity was not observed according to the two types of QSAR analyses (i.e. the results are either conflicting or both negative), were selected from the list of chemical substances with strong mutagenicity known as the reported chemicals under the Industrial Safety and Health Act in Japan. The QSAR Toolbox was used in this study to rationally determine the positive mutagenicity of the 36 model chemical substances by applying a read-across method, a technique to evaluate the endpoint of the model chemical substances using the endpoint information of chemicals that are structurally similar to the model chemical substances. Resulting from the expert review by the read-across method, the 23 model chemical substances (63.8%) were rationally concluded as positive. In addition, 9 out of 11 model chemical substances that were assessed as negative for mutagenicity by both of the QSAR systems had positive analogues, supporting their mutagenicity. These results suggested that the read-across is a useful method, when conducting a conservative approach intended to capture any mutagenic chemical substances.
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