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Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? An Analysis of Large Mutagenicity Data Sets for the IWGT
Citation:
Cross, K., D. DeMarini, L. Stankowski, E. Zeiger, AND R. Williams. Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? An Analysis of Large Mutagenicity Data Sets for the IWGT. American College of Toxicology, West Palm Beach, FL, November 04 - 07, 2018.
Impact/Purpose:
This abstract describes an analysis of published literature showing that 4 of the 7 bacterial strains currently described for use by the OECD 471 mutagenicity testing guidelines are redundant and unnecessary. These guidelines have not been modified in 20 years and are used by the US EPA, US FDA, and many regulatory bodies worldwide for regulatory compliance for mutagenicity testing. If the guidelines were modified as suggested by this analysis, it would reduce by nearly half the regulatory burden on industry for mutagenicity testing in bacterial assays for regulatory compliance.
Description:
The International Workshop on Genetic Toxicology (IWGT) meets every four years to reach consensus recommendations on difficult or conflicting approaches to genotoxicity testing based upon practical experience and newly available data and analysis techniques. The IWGT met in Tokyo November 2017 with one working group assessing the sensitivity and selectivity of the standard strains in the Ames test as specified in OECD test guideline 471 and to make recommendations for a minimum viable strain profile. The discussions, based partially on bacterial mutation data in multiple strains from large (>10,000 compound) Leadscope and Lhasa databases, included: (1) defining criteria for determining significant selective responses across different strains; (2) identifying compounds producing selective responses using reported author calls; (3) confirming selective responses by examining dose-response data including metabolic activation and experimental conditions; (4) using statistical methods to objectively verify response differences; and (5) determining the frequency and chemotypes of compounds producing selective responses. Results indicated that Salmonella TA1535 added little information to a battery including TA100, and TA97/TA97a detected more unique mutagens than TA1537. Preliminary results suggest 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. For example, altertoxin I was previously reported to be positive in TA1537 and negative in TA97, but gave clearly positive responses in both tester strains when tested concurrently. [Abstract does not reflect policies of the U.S. EPA.]