Regulatory implications of Ames' mutagenicity assay using Salmonella typhimurium

Interpretive difficulties can be expected when molecular biology and modern genetics are applied to the safety evaluation of chemicals. Experience, in a regulatory setting, with evaluating the results of short term tests, such as Ames' mutagenicity assay using Salmonella typhimurium (Ames' assay), shows that the traditional toxicological paradigm for interpreting and evaluating the results of such tests is less than adequate. The considerable importance of a negative test outcome to the public health as well as to the course of the commercial development of a potentially useful chemical places special demands on both the investigator and the regulatory reviewer for an understanding of Ames' assay. The adequate design, conduct, interpretation, and evaluation of the outcomes of this assay require a knowledge of the chemical properties of the test agent, an understanding of the scientific basis of the test, and an appreciation of the extent to which modifications of the assay can alter the outcome. The investigator and the regulatory reviewer use the same considerations to determine the adequacy of the test design and of the test results. However, a fundamental difference exists between how they interpret results and how they view the outcome. Results from a study comparing activation systems from food animal and laboratory animal sources are used to illustrate the complexity of using safety data from a genetic test. A framework is developed to suggest how to accommodate the points of view of the investigator and the regulatory reviewer in evaluating these data.