You are here:
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:
DeMarini, D., R. Williams, L. Stankowski, 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. SOT, san antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
The Organization of Economic Cooperation and Development (OECD) and international body of developed countries that establishes guidelines by which various procedures, such and the testing of chemicals and drugs for approval, should be conducted. One of those procedures is OECD Guidelines 471, which stipulates the way by which chemicals and drugs should be tested for mutagenicity in bacteria. Both the EPA and FDA, as well as their counterparts among the OECD nations, comply with the OECD 471 guidelines for bacterial mutagenicity testing prior to granting approval for pesticides and other chemicals (by EPA) or drugs (by FDA). The current OECD 471 guidelines has been in place unchanged for 20 years, and a committee titled the International Workgroup on Genetic Toxicology (IWGT) meets every 4 years to re-evaluate various OECD guidelines relative to genotoxicity testing. In November 2017, this group met in Tokyo to re-evaluated Guidelines 471. The current guidelines requires up to 5 strains of bacteria to be used for mutagenicity testing. However, after much analysis of data, the IWGT has concluded that at least 2 of the strains are redundant and can be eliminated from the testing requirement and, thus, proposes a modification of the OECD 471 guideline. This abstract reflects that conclusion. Such a recommendation, if adopted by the OECD and ultimately by EPA and FDA, would have a significant impact on future genotoxicity testing by reducing the cost, time, and redundancy of the current OECD guidelines. This would reduce the burden on industry as well as the effort on the part of regulators. However, the proposed elimination of 2 of the strains will, as the data analysis shows, provide the same quality assurance that adequate mutagenicity testing in bacteria has been performed.
Description:
Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? An Analysis of Large Mutagenicity Data Sets for the IWGT R. Williams1, D.M. DeMarini2, L.F. Stankowski Jr.3, E. Zeiger4, K.P. Cross5 1Lhasa, LTD, Leeds, UK 2U.S. EPA, RTP, NC 3Charles River Laboratories, Inc., Skokie, IL 4Errol Zeiger Consulting, Chapel Hill, NC 5Leadscope, Columbus, OH 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 the 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 TA97/TA97a detected more unique mutagens than did TA1537. In both cases, the results from these publically available, historical data sets support the removal of the less-sensitive strains TA1535 and TA1537 from the current OECD test guideline. Preliminary results also suggest that E. coli WP2 uvrA pKM101 is more sensitive than E. coli WP2 uvrA and TA102. Additional direct testing to resolve some ambiguities is underway. Adoption of these recommendations would have a significant impact on future bacterial mutagenicity testing by reducing the cost, time, and redundancy of the current OECD 471 guideline. [Abstract does not reflect policies of the U.S. EPA.]