REGULATORY CONSIDERATIONS: MUTAGENESIS 731 mechanisms that tend to operate on classical dose response curves. Others believe that any exposure to a carcinogen, however small, presents a substantial risk to human health. The Ames test is sensitive enough to detect activities that may be involved in the causation of cancer, but it does not measure penetrability of the substance nor se- lective parameters such as biological resistance, which are important to evaluation of toxicity, including carcinogenicity. 4. SCIENTIFIC ACCEPTABILITY OF THE TEST The Ames test is very acceptable at present for limited purposes, namely, decision- making on a voluntary basis with considerable latitude for exercising judgment. However, regulatory decision-making requires stricter criteria for applying judgment, and the answer ultimately must be a simple yes or no. At present there still is considerable controversy over the use of in vitro test systems for assessing risk to human health. Some of the controversy is legitimate. If the Ames test is to be used as a screening test, then what is the definitive test--in vivo carcinogenic bioassay? What happens if the latter test is negative? In how many rodent species and strains? How re- liable is this assay system? How much evidence will be needed to make the chemical acceptable if such should be the true and correct response of society? Should the Ames test then be the definitive test? That would be a major decision that would also invoke consideration of changes in how the Delaney Clause is applied. Many issues are involved that should be settled concurrently to the best of our ability as we continue to evaluate the potential utility of the Ames test for regulatory pur- poses. At present, if results of a carcinogenic bioassay were equivocal but selected mutagenicity tests were positive, I would consider that observation to be of regulatory importance. The Ames type of test has some regulatory use for evaluating which me- tabolites of a drug given to humans or to food-producing animals should receive atten- tion if we are to protect the public against carcinogens. However, a decision-tree approach to regulation based solely on positive versus negative results of any single short-term test may cause confusion. For example, what happens if positive results are obtained with natural constituents of foods, spices and flavors? My major recom- mendation is that we devote more effort to expanding the number of substances tested during the next few years before making a final decision. We need further insight into the specificity of the test system to detect mutacarcinogens. It has been said that most chemical carcinogens have mutagenic activity. With some exceptions, I agree. However, a more relevant question is whether or not most mutagenically positive com- pounds are also carcinogenic in the sense of posing a substantial hazard to public health. What regulatory decision should be made about weak mutagens or weak carcinogens? We could, of course, make these decisions on a day-to-day basis, but it would be better to answer some of the pressing questions before we settle on such tests for regulatory decision-making. Otherwise the distinction between a screening test and a definitive test will rapidly disappear. The Ames test and other similar tests have great utility for voluntary decision-making and may be directly useful for regulatory decision-making in the not too distant future. But a premature rush to regulatory judgment may create unanticipated regulatory difficulties and lead to a controversy with connotations similar to the Delaney Clause.

732 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Moreover, a premature confrontation in a judicial setting may create legal decisions adverse to the appropriate regulatory significance of such test systems as the Ames test. We in FDA recommend using mutagenic tests, including Ames-type tests, to evaluate products. These test systems have many advantages, and further experience with them may demonstrate direct regulatory utility. At present, some of the disadvantages, including the larger questions relating to society's policies about mutacarcinogens, should be addressed and resolved. REFERENCES (1) B. N. Ames, J. McCann and E. Yamasaki, Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test, Mutat. Res., 31,347-364 (1975). (2) W. G. Flamm, Approaches to determining the mutagenic properties of chemicals: risk to future genera- tions, J. Environ. PathoL Toxicol., 1,301-352 (1977). (3) J. McCann, E. Choi, E. Yamasaki and B. N. Ames, Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals, Proc. Nat. Acad. Sci. USA, 72, 5135-5139 (1975). (4) J. McCann and B. N. Ames, Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals: discussion, Proc. Nat. Acad. Sci. USA, 73,950-954 (1976). (5) Federal Food, Drug, and Cosmetic Act As Amended, August 1972, Section 409(c)(3)(A), 21 U.S. Code 348.