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New and Emerging Genetic Toxicity Tests and Approaches to Genetic Toxicology Testing

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Genotoxicity and Carcinogenicity Testing of Pharmaceuticals

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Abstract

Genetic toxicology tests are conducted to determine if a compound (drug) has the potential to cause mutations or chromosomal damage, data that has value in predicting its carcinogenic potential. For new pharmaceuticals, test data from a standard test battery are required prior to administering the compound to humans. This test battery includes in vivo studies of chromosomal damage in the rodent hematopoietic system, traditionally performed in the bone marrow, but in recent years, the in vivo micronucleus assay has been validated for use in peripheral blood. In addition, new regulatory guidelines, like ICH S2R1, allow the use of a second in vivo assay as part of the genotoxicity assessment, and having different in vivo assays to use will benefit understanding the in vivo genotoxicity profile of candidate pharmaceuticals. Three ‘new’ in vivo tests are described—the in vivo Comet assay, the in vivo Pig-a gene mutation assay, and the liver micronucleus (MN) assay. An established test, the transgenic rodent (TGR) gene mutation assay, is presented as a test whose use for regulatory decision-making may increase due to the recent introduction of robust testing protocols and new test guidelines. The chapter also discusses refinements in how the traditional genotoxicity tests are conducted and interpreted, including new ways of following up on their findings. Finally, the chapter discusses what has been described as a paradigm shift—that is, a move away from qualitative categorizations of genotoxic vs. non-genotoxic to the use of quantitative genotoxicity data as an adverse outcome on which regulatory decisions may be made.

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Authors and Affiliations

  1. Merck Research Laboratories, West Point, PA, USA

    Patricia A. Escobar

  2. Litron Laboratories, Rochester, NY, 14623, USA

    Stephen D. Dertinger

  3. Division of Genetic and Molecular Toxicology, National Center for Toxicological Research/U.S. Food and Drug Administration (U.S. FDA/NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA

    Robert H. Heflich

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  1. Vice- President of Drug Safety Evaluation, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Michael J. Graziano

  2. ToxRox Consulting, McLean VA 22101, Virginia, USA

    David Jacobson-Kram

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The information in these materials is not a formal dissemination of information by the U.S. Food and Drug Administration and does not represent agency position or policy. S.D.D. is an employee of Litron Laboratories; Litron holds patents, sells commercial kits, and performs fee-for-service work in the area of flow cytometry-based genotoxicity assessments.

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Escobar, P.A., Dertinger, S.D., Heflich, R.H. (2015). New and Emerging Genetic Toxicity Tests and Approaches to Genetic Toxicology Testing. In: Graziano, M., Jacobson-Kram, D. (eds) Genotoxicity and Carcinogenicity Testing of Pharmaceuticals. Springer, Cham. https://doi.org/10.1007/978-3-319-22084-0_5

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