AMES/QSAR International Collaborative Study


Robust Quantitative Structure–Activity Relationship (QSAR) models defining toxicological endpoints are desirable to enable regulatory authorities to identify chemicals possibly causing adverse effects without performing actual toxicological studies. Much effort has been invested in the development of QSAR models to predict Ames mutagenicity, among many toxicological endpoints, to exploit the large body of Ames data and the strong correlation between chemical structure and Ames mutagenicity. Ames results are important for decisions on the development of chemical products and pharmaceuticals and the assessment of chemical safety, given that a positive result corresponds to increased cancer risk from exposure to the chemical even at a low level. The ICH-M7 guideline (Assessment and control of DNA-reactive impurities in pharmaceuticals to limit potential carcinogenic risk) currently recommends two QSAR models (expert rule-based and statistical) to predict Ames mutagenicity for initially assessing DNA-reactive impurities in pharmaceuticals. This is the first international guideline addressing the use of QSAR in lieu of an actual toxicological study for human health assessment. Thus, QSAR models for Ames mutagenicity now require much greater prediction power to ensure the safety of chemicals. To increase this prediction power, experimental data sets as training data to build the models are important. Large numbers of highly reliable data sets will allow development and improvement of QSAR models with high predictive power.

The Division of Genetics and Mutagenesis, National Institute of Health Sciences (DGM/NIHS) has Ames mutagenicity data for approximately 12,000 new chemicals. The Ames assays were conducted according to the OECD TG471 guideline and Industrial Safety and Health Act in Japan under GLP-compliant conditions. We now provide these Ames data to QSAR builders/vendors to improve their QSAR models for predicting Ames mutagenicity with the permission of the Industrial Safety and Health Department of the Ministry of Health, Labor and Welfare (MHLW), Japan. The Ames/QSAR international collaborative study leaded by DGM/NIHS launched on 2014. Because most of the Ames data are confidential, the QSAR builders/vendors participating in the project must execute a confidentiality agreement. Eleven QSAR builders/vendors are currently participating in this project. A phase I study has already been completed. In this study, we released 4,018 chemicals without their Ames results to the QSAR builders/vendors, who calculated the Ames mutagenicity from their QSAR models. DGM/NIHS evaluated the performance of the QSAR models (sensitivity, specificity, and other criteria) and disclosed the Ames results. The QSAR builders/vendors integrated the Ames results into their QSAR models as training data and entered a phase II trial. We will perform the trials three or four times. Finally, all of the QSAR models will be much improved in prediction of Ames mutagenicity. We believe that the outcome of this project will be of great benefit for QSAR builders/vendors, QSAR users, and regulatory authorities.

The chemicals are classified into three categories according to the Ames results.

> Class A is strongly positive, in which the chemical generally induces more than 1,000 revertants/mg in at least one Ames strains in the presence or absence of rat S9.

> Class B clearly as well as reproducibly induces revertant colonies with dose-dependent manner, but not in class A.

> Class C is negative, which is neither class A nor B.

We disclose class A chemicals. These chemicals must have important alert structures strongly associated with Ames mutagenicity. In the phase I study, the 4,018 chemicals include 187 class A chemicals. We will disclose other class A chemicals depending on the progress of the project.

Masamitsu Honma (

Division of Genetics and Mutagenesis,

National Institute of Health Sciences

Updated 2015.11.19

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