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Are all bacterial strains required by OECD mutagenicity test guideline TG471 needed?
Citation:
Williams, R., D. DeMarini, L. Stankowski, Jr., P. Escobar, E. Zeiger, J. Howe, R. Elespuru, AND K. Cross. Are all bacterial strains required by OECD mutagenicity test guideline TG471 needed? Mutation Research/Genetic Toxicology and Environmental Mutagenesis . Elsevier Science Ltd, New York, NY, 848:503081, (2019). https://doi.org/10.1016/j.mrgentox.2019.503081
Impact/Purpose:
The current OECD Test Guideline TG471 for genotoxicity testing recommends the use of at least 5 strains of bacteria to evaluate compounds for gene mutation, along with various mammalian cell assays to test for chromosomal mutation. These guidelines are used by EPA, FDA, and most regulatory bodies worldwide. However, these guidelines have not been updated for 20 years, and the present study evaluated a large, 10,000 compound data base to assess whether all 5 bacterial strains are necessary to obtain sufficient determination as to the bacterial mutagenicity of a compound. As determined by this analysis, only 2 bacterial strains appear to be sufficient, when used in combination with the recommended mammalian cell assays for chromosomal mutation, such that 99% of mutagens will be detected. If this modification of the Test Guideline were adopted by OECD, and ultimately by EPA, FDA, and other regulatory bodies, there would be considerable reduction in the cost, time and redundancy to industry to comply with such mutagenicity test guidelines.
Description:
The International Workshop on Genotoxicity Testing (IWGT) meets every four years to seek consensus on difficult or conflicting approaches to genotoxicity testing based upon experience, available data, and analysis techniques. At the 2017 IWGT meeting in Tokyo, one working group addressed the sensitivity and selectivity of the bacterial strains specified in the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471 to recommend possible modification of the test guideline. Three questions were posed: (1) Although TA100 is derived from TA1535, does TA1535 detect any mutagens that are not detected by TA100? (2) Among the options of Salmonella TA1537, TA97 or TA97a, are these strains truly equivalent? (3) Because there is a choice to use one of either E. coli WP2 uvrA, E. coli WP2 uvrA pKM101, or Salmonella TA102, are these strains truly equivalent? To answer these questions, we analyzed published bacterial mutation data in multiple strains from large (>10,000 compound) databases from Leadscope and Lhasa Limited and anonymized data for 53 compounds tested in TA1535 and TA100 provided by a pharmaceutical company. Our analysis involved (1) defining criteria for determining selective responses when using different strains; (2) identifying compounds producing selective responses based upon author calls; (3) confirming selective responses by visually examining dose-response data and considering experimental conditions; (4) using statistical methods to quantify the responses; (5) performing limited additional direct-comparison testing; and (6) determining the chemical classes producing selective responses. We found that few mutagens would fail to be detected if the test battery did not include Salmonella strains TA1535 (8/1167), TA1537 (2/247), TA102 (4/46), and E. coli WP2 uvrA (2/21). Of the mutagens detected by the full TG471 strain battery, 93% were detected using only strains TA98 and TA100; consideration of results from in vitro genotoxicity assays that detect clastogenicity increased this to 99%.
URLs/Downloads:
DOI: Are all bacterial strains required by OECD mutagenicity test guideline TG471 needed?
https://pubmed.ncbi.nlm.nih.gov/31708075/