A deep dive into historical Ames study data for N-nitrosamine compounds

Abstract

Mutagenicity data is a core component of the safety assessment data required by regulatory agencies for acceptance of new drug compounds, with the OECD-471 bacterial reverse mutation (Ames) assay most widely used as a primary screen to assess drug impurities for potential mutagenic risk. N-Nitrosamines are highly potent mutagenic carcinogens in rodent bioassays and their recent detection as impurities in pharmaceutical products has sparked increased interest in their safety assessment. Previous literature reports indicated that the Ames test might not be sensitive enough to detect the mutagenic potential of N-nitrosamines in order to accurately predict a risk of carcinogenicity. To explore this hypothesis, public Ames and rodent carcinogenicity data pertaining to the N-nitrosamine class of compounds was collated for analysis. Here we present how variations to the OECD 471-compliant Ames test, including strain, metabolic activation, solvent type and pre-incubation/plate incorporation methods, may impact the predictive performance for carcinogenicity. An understanding of optimal conditions for testing of N-nitrosamines may improve both the accuracy and confidence in the ability of the Ames test to identify potential carcinogens.