Academic journal article Environmental Health Perspectives

The Salmonella Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century

Academic journal article Environmental Health Perspectives

The Salmonella Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century

Article excerpt

OBJECTIVES: According to the 2007 National Research Council report Toxicology for the Twenty-First Century, modern methods (e.g., "omics," in vitro assays, high-throughput testing, computational methods) will lead to the emergence of a new approach to toxicology. The Salmonella mammalian microsome mutagenicity assay has been central to the field of genetic toxicology since the 1970s. Here we document the paradigm shifts engendered by the assay, the validation and applications of the assay, and how the assay is a model for future in vitro toxicology assays.

DATA SOURCES: We searched PubMed, Scopus, and Web of Knowledge using key words relevant to the Salmonella assay and additional genotoxicity assays.

DATA EXTRACTION: We merged the citations, removing duplicates, and categorized the papers by year and topic.

DATA SYNTHESIS: The Salmonella assay led to two paradigm shifts: that some carcinogens were mutagens and that some environmental samples (e.g., air, water, soil, food, combustion emissions) were mutagenic. Although there are > 10,000 publications on the Salmonella assay, covering tens of thousands of agents, data on even more agents probably exist in unpublished form, largely as proprietary studies by industry. The Salmonella assay is a model for the development of 21st century in vitro toxicology assays in terms of the establishment of standard procedures, ability to test various agents, transferability across laboratories, validation and testing, and structure--activity analysis.

CONCLUSIONS: Similar to a stethoscope as a first-line, inexpensive tool in medicine, the Salmonella assay can serve a similar, indispensable role in the foreseeable future of 21st century toxicology.

KEY WORDS: Ames assay, carcinogenicity, 21st century toxicology, genetic toxicology, high-throughput assays, Salmonella assay, Salmonella mutagenicity assay. Environ Health Perspect 118:1515-1522 (2010). doi: 10.1289/ehp. 1002336 [Online 2 August 2010]

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Every day throughout the world, physicians, nurses, and an array of other health professionals use a stethoscope, which was invented by Rene Laennec in 1816 (Weinberg 1993). It is a relatively simple instrument whose sounds can indicate a myriad of disease states that can then be confirmed by more sophisticated assessments. It is hard to visualize a physician or imagine medicine without the stethoscope. Similarly, the Salmonella mutagenicity assay, which was developed initially as a spot test (Ames 1971), then as a plate-incorporation test (Ames et al. 1972) using strains of Salmonella bacteria derived from studies by B.N. Ames and P.E. Hartman (Hartman et al. 1986) and rodent liver microsomal activation coupled initially to the assay by H.V. Mailing (Mailing 1971), is a deceptively simple tool that can be used to detect the mutagenicity of environmental chemicals, environmental mixtures, body fluids, foods, drugs, and physical agents. More complex tests can be applied to confirm and characterize further the mutagenic activity of the agent. Although neither the stethoscope nor the Salmonella assay provides a definitive diagnosis/detection of a disease or a mutagen, respectively, both are indispensible first-line tools in their fields.

There is much unrest in the field of toxicology today because of a variety of scientific developments, including advances in genomic science (Parsons et al. 2008; Wood et al. 2007), improved knowledge of the molecular and mechanistic basis for biological responses to toxicant exposure (Guyton et al. 2009), legislation mandating reduced numbers of animals for toxicology testing (Pfuhler et al. 2009), and governmental direction to incorporate all of the above into a new paradigm for toxicology for the 21st century (National Research Council 2007).

A strict parallel cannot be drawn between a targeted testing assay such as the Salmonella assay, which is used for hazard identification, and a high-throughput screening (HTS) assay such as either the ToxCast program [U. …

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