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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

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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 review current practices in the Ames test. One of the Ames subgroups assessed the sensitivity and selectivity of the standard strains in the Ames test as specified in the OECD test guideline 471, with a view 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 Limited 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:

(i) S. typh TA1535 added little information to an Ames test battery that also included TA100;

(ii) TA97/TA97a is more sensitive to mutagens than TA1537;

(iii) E. coli WP2 uvrA pKM101 is more sensitive than both E. coli WP2 uvrA and TA102.

Additional direct testing to resolve some ambiguities is underway. Recommendations are being agreed, and it is likely that these would have a significant impact on future bacterial mutagenicity testing by reducing the cost, time, and redundancy of the current OECD 471 guideline.



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