The Salmonella mutagenicity assay: the stethoscope of genetic toxicology for the 21st century

Abstract

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publications on the Salmonella assay, covering tens of thousands of agents, data on even more agents probably exist in unpublished form, largely as proprietary studies by industry.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.

Figure 1

Peer-reviewed journal articles published per year for genetic toxicology bioassays. (A) Publications for the classical gene mutation assays [Salmonella assay, E. coli mutagenicity assays (E. coli WP2), Hprt assays in V79 and CHO cells or HPRT in TK6 cells (HPRT), and the mouse lymphoma Tk^+/− assay. (B ) Publications for all micronucleus (MN) assays, bone-marrow MN, and comet assays. (C) Publications for the Salmonella assay involving environmental substances (air, water, natural products, soil, and sediments). (D) Publications for the Salmonella assay involving various categories of studies (mechanisms and metabolism, environmental samples, personal exposure studies, commerce, and chemistry). The reference database is available in Supplemental Material (doi:10.1289/ehp.1002336).