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Bacterial Reverse-Mutation Assay (Ames Test): Time to Revise OECD Test Guideline 471?
Citation:
Schoeny, R., K. Cross, D. DeMarini, R. Elespuru, A. Hakura, D. Levy, R. Williams, AND E. Zeiger. Bacterial Reverse-Mutation Assay (Ames Test): Time to Revise OECD Test Guideline 471? Society of Risk Analysis, New Orleans, LA, December 02 - 06, 2018.
Impact/Purpose:
The OECD has a standard test guideline (TG471) for evaluating the mutagenicity of agents using bacterial assays that has not been reviewed for 21 years--since 1997. Under the auspices of the International Workshop on Genetic Toxicology (IWGT), which met in Tokyo, Japan, in November 2017, a working group performed analyses of large data bases of bacterial mutagenicity data, and concluded that at least 4 of the 6 strains currently recommended are redundant and could be eliminated. If such a proposal is adopted by the OECD when it next revised TG471, this would reduce the regulatory burden on industry, which is currently required to adhere to this test guideline by the US EPA, US FDA, and many other regulatory organizations in order to gain approval for marketing their product.
Description:
The International Workshop on Genetic Toxicology (IWGT) meets to formulate recommendations on difficult issues in genotoxicity testing (GT); these are based upon practical experience, newly available data, and data analysis. In 2017 and in follow up work through 2018, one IWGT group evaluated the status of the Bacterial Mutagenicity Assay (Ames Test) and the methods used for evaluating test results. The relevant OECD Test Guideline (TG) 471 has not been revised since 1997, while new data and applications (e.g., miniaturized versions) have become available. This IWGT group discussed criteria for positive and negative responses (use of historical control data, consideration of formal and subjective rules); criteria for acceptable assays (measures of toxicity, standardization of methods); and laboratory proficiency. Other major topics were status of in silico SAR tools for prediction of mutagenicity in the Ames test and definition of a minimum strain set for optimized test specificity and sensitivity. Recommendations on the latter topic relied on analyses of large databases of chemicals tested comparably in multiple strains. Results indicated that Salmonella TA1535 added little information to an Ames test battery that included TA100, and that TA97/TA97a detected more unique mutagens than did TA1537. Analyses also suggest that E. coli WP2 uvrA pKM101 is more sensitive than TA102 or E. coli WP2 uvrA without the plasmid. Preliminary results from additional direct comparison testing of ten chemicals failed to confirm previously reported selectivity between related tester strains. The group described three criteria to be met if the test result is to be called “clearly positive,” defined “clearly negative” results, and made recommendations on repeat testing. Other recommendations are made for assay conduct and strain maintenance. Disclaimer: The findings and conclusions in this abstract are those of the authors and do not represent any regulatory policy of US EPA or US FDA.