Evaluation of the OECD QSAR Application Toolbox and Toxtree for estimating the mutagenicity of chemicals. Part 1. Aromatic amines

Abstract

The Ames Salmonella typhimurium mutagenicity assay is a short-term bacterial reverse mutation test that was designed to detect mutagens. For several decades, it has been used in research laboratories and by regulatory agencies throughout the world for the detection and characterization of potential mutagens among natural products and man-made chemicals. Faced with the ever-growing number of chemicals available on the market, congeneric and non-congeneric (Q)SAR models have been designed from Ames test results obtained on specific S. typhimurium strains such as TA 100 or TA 98. Such models have great potential for a quick and cheap identification and classification of large numbers of potential chemical mutagens. The OECD QSAR Application Toolbox and Toxtree, which were developed for facilitating the practical use of (Q)SAR approaches in regulatory contexts, include two mechanistic SAR models for predicting the mutagenicity of aromatic amines and α-β unsaturated aliphatic aldehydes. The aim of this study was to estimate the interest and limitations of the former model. The model was first re-computed to check its transparency and to verify its statistical validity. Then, it was tested on about 150 chemicals not previously used for the design of the model but belonging to its domain of application. A critical analysis of the results was performed and proposals were made for increasing the model performances.

Keywords:

• QSAR Toolbox
• Toxtree
• mutagenicity
• aromatic amines
• mechanistic model
• external validation

Acknowledgement

The authors are grateful to the French Ministry of Ecology, Energy, Sustainable Development and Sea (MEEDDM) for financial support.

Note added

During the preparation of the amended version of this paper, a new version of Toxtree was launched (version 2.1.0). We judged interesting to predict the mutagenicity potential of the chemicals listed in Tables 1 and 2 with this new version. Changes were only found in Table 2. They are listed in the table below:

Table

With Toxtree version 2.1.0, the performances of the QSAR6 model on the external test set (Table 2) appear slightly deteriorated.