Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association

Ames test is used worldwide for detecting the bacterial mutagenicity of chemicals. In silico analyses of bacterial mutagenicity have recently gained acceptance by regulatory agencies; however, current in silico models for prediction remain to be improved. The Japan Pharmaceutical Manufacturers Association (JPMA) organized a task force in 2017 in which eight Japanese pharmaceutical companies had participated. The purpose of this task force was to disclose a piece of pharmaceutical companies' proprietary Ames test data.

Ames test data for 99 chemicals of various chemical classes were collected for disclosure in this study. These chemicals are related to the manufacturing process of pharmaceutical drugs, including reagents, synthetic intermediates, and drug substances. The structure-activity (mutagenicity) relationships are discussed in relation to structural alerts for each chemical class. In addition, in silico analyses of these chemicals were conducted using a knowledge-based model of Derek Nexus (Derek) and a statistics-based model (GT1_BMUT module) of CASE Ultra. To calculate the effectiveness of these models, 89 chemicals for Derek and 54 chemicals for CASE Ultra were selected; major exclusions were the salt form of four chemicals that were tested both in the salt and free forms for both models, and 35 chemicals called "known" positives or negatives for CASE Ultra. For Derek, the sensitivity, specificity, and accuracy were 65% (15/23), 71% (47/66), and 70% (62/89), respectively. The sensitivity, specificity, and accuracy were 50% (6/12), 60% (25/42), and 57% (31/54) for CASE Ultra, respectively. The ratio of overall disagreement between the CASE Ultra "known" positives/negatives and the actual test results was 11% (4/35). In this study, 19 out of 28 mutagens (68%) were detected with TA100 and/or TA98, and 9 out of 28 mutagens (32%) were detected with either TA1535, TA1537, WP2uvrA, or their combination.

The Ames test data presented here will help avoid duplicated Ames testing in some cases, support duplicate testing in other cases, improve in silico models, and enhance our understanding of the mechanisms of mutagenesis.