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Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary?
Citation:
Cross, K., D. DeMarini, L. Stankowski Jr, E. Zeiger, AND R. Williams. Are All Ames Strains in the OECD Mutagenicity Test Guideline 471 Useful and Necessary? Environmental Mutagenesis and Genomics Society, San Antonio, TX, September 22 - 26, 2018.
Impact/Purpose:
The OECD test guidelines for mutagenicity testing using bacteria (OECD 471) has not been changed in 20 years. This guideline is used by the US EPA, US FDA, and regulatory agencies around the world for such testing of products for regulatory approval. This abstract describes an analytical reassessment by the International Workshop on Genetic Toxicology that met in November 2017 in Tokyo that shows that 4 out of the 7 bacterial strains the test guideline recommends are probably redundant and unnecessary. If ultimately adopted by OECD, a modified 471 test guideline would reduce the regulatory burden on industry by reducing by nearly half the amount of testing in bacterial assays for mutagenicity that would be required 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. E. coli WP2 uvrA pKM101 may be 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.]