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In Vitro-In Vivo Extrapolation of the Mutagenic Potential of NNK

Principal Investigator: Robert Heflich and Berran Yucesoy

Funding Mechanism:  Internal FDA

ID number: E07606.01

Award Date: 10/22/2015

Institution: National Center for Toxicological Research (NCTR)

Standard gene toxicity assays conducted to inform regulatory decision-making, such as the Ames’ bacterial gene mutation assay, provide only qualitative (i.e., positive, negative, equivocal) estimates of gene mutation. These estimates are difficult to translate into relevant human doses and responses, and potency in in vitro assays may or may not reflect potency in animal or human responses. In this study, researchers will "calibrate" responses in the Ames’ assay and the in vitro Pig-a assay to in vivo mutagenicity in the rat Pig-a assay. Researchers will develop mutation dose responses for a tobacco-specific mutagen (nicotine-derived nitrosamine ketone, or NNK) in the in vitro Ames’ and Pig-a assays and in the in vivo rat Pig-a assay. The goal is to assess whether or not animal and human mutagenic responses can be estimated from the Ames’ assay and in vitro Pig-a responses.  This study may provide a new methodology for assessing human gene toxicity associated with tobacco products.

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