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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:
Williams, R., D. DeMarini, L. Stankowski Jr, AND E. Zeiger. Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? An Analysis of Large Mutagenicity Data Sets for the IWGT. Genetic Toxicology Association, Newark, Delaware, May 03 - 04, 2018.
Impact/Purpose:
The OCED establishes guidelines for various safety testing, and one of those is for the use of bacteria for mutagenicity testing. These guidelines are adopted by the US EPA and US FDA, among many other international regulatory bodies. The work encompassed in this presentation results from a committee of international experts that meets every 4 years to assess these test guidelines, and the committee has recommended the reduction by half of the number of bacterial strains used for the OECD test guidelines for mutagenicity testing using bacteria (essentially the Ames assay). If adopted by OECD and, ultimately, by the US EPA and US FDA, this will reduce the burden on industry for testing requirements for chemical and/or drug approval by these agencies.
Description:
The International Workshop on Genetic Toxicology (IWGT) meets every four years with an objective to reach consensus recommendations on difficult or conflicting approaches to genotoxicity testing based upon practical experience and newly available data and data analysis techniques. The IWGT met in November 2017 in Tokyo with one working group tasked to assess 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, which were 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 when using different strains; (2) identifying compounds producing selective responses based upon reported author calls; (3) confirming selective responses by manually examining dose-response data including metabolic activation and experimental conditions; (4) using statistical methods to objectively verify response differences; and (5) determining the magnitudes and chemotypes of compounds producing selective responses. Results indicated that Salmonella TA1535 added little information to an Ames test battery that also included TA100, and that TA97/TA97a detected more unique mutagens than did TA1537. Preliminary results also suggest that E. coli WP2 uvrA pKM101 is more sensitive than E. coli WP2 uvrA without the plasmid. Additional direct testing to resolve some ambiguities is underway. [Abstract does not reflect policies of the U.S. EPA.]