728 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS sensitive enough to detect biological phenomena associated with many (but not all) so- called chemical carcinogens. I have a favorable attitude toward the Ames system be- cause I have been directly and indirectly associated with the development of mutagenic assay systems ever since the 1960's, even before I came to the Food and Dru. g Administration. The outstanding accomplishments of Drs. Ames and McCann represent considerable progress and improvement on bacterial systems which have also been the subject of research by others, including FDA workers, since the 1960's. FDA's activities in this field have been substantial and have included tests of many compounds, including some on the so-called GRAS list, by various systems as those systems have evolved over the past decade. As we entered the phase of testing in 1970, we encountered problems in interpreting the results from some of the systems. It was not always evident whether or not we were dealing with true positives. We have always encouraged and recommended mutagenesis testing, for we believe that it is helpful to know whether or not "positive findings" are associated with particular compounds, both for developers of products and for those primarily involved in public health. The question then arises, why doesn't FDA require mutagenesis testing now ? This leads to another question: Which test should be required for what effect, and will the results be used any differently than they are now used on a voluntary basis ? The second ques- tion involves many issues. In detecting genetic hazards, it would be helpful to measure the potency of a sample of mutagenic compounds in intact experimental mammals. This would provide a better correlation of in vivo effects inherited by succeeding generations. We could thus improve our assessment of genetic risk and our extrapolations from in vitro mutagenic test systems with high sensitivity such as the Ames system. However, the whole issue of forecasting the risk to future generations from mutagenic substances on the basis of our present testing capabilities is the subject of a "white paper" by a select committee functioning under the auspices of the DHEW Toxicology Coordinating Committee. Their report (2) may well serve as a foundation for the evolution of additional test re- quirements in the future. In deciding whether or not a test such as the Ames test should be required by a Federal regulatory agency for controlling carcinogens, it must be recognized that results of a re- quired test, both positive and negative, will have immediate regulatory significance in decision-making, either alone or in conjunction with other tests. If decisions are to be made on the basis of such tests, those tests must be able to stand up under legal scrutiny by the courts. In court, all relevant evidence will be considered and all relevant testimony by experts qualified by training and experience to assess toxicologic risk to human health is admissable. The following questions are fairly typical of those directed at chemists when they testify in court as to their findings. 1. Is the test sensitive in the sense of being capable of detecting the parameters of concern? 2. Is the test specific for detecting the parameters of concern (or are other qualities also detected as positive responses, necessitating another independent test to confirm the identity of the parameter being detected)? 3. Does the test quantitatively measure the parameters of concern and what is the range of error? 4. Is the test as performed acceptable by the current standards of good scientific practice?

REGULATORY CONSIDERATIONS: MUTAGENESIS 729 My comments on those questions reflect current issues and important considerations, but some of my judgments will undoubtedly change as the data base improves. 1. SENSITIVITY The Ames test is extremely sensitive. It will detect the majority of chemical carcinogens presently identified as such in our current data base, except for hormones, metals, and carcinogens dependent on physicochemical effect, such as asbestos. So far there is a strong statistical association with known carcinogens (3, 4). The test system has been greatly modified to improve its sensitivity to known carcinogens, such as the activation systems and the modification of the bacterial cell wall. It must be recognized that the incidence of cancer in test animals or in man can be af- fected by many other factors that have not been (nor should be) identified as carcinogens. Some of these factors affect susceptibility to cancer, such as nutritional and metabolic factors important to the mammalian body's defense against toxicity, including cancer. Other modifying factors are more appropriately classified as tumor promoters. Examples are hormonally active substances which can stress target receptor cells they may lead directly to adenocarcinomas or to certain epithelial changes, more properly called metaplasia, in which glandular or transitional epithelium is transformed to squamous, and a squamous cell or undifferentiated type of tumor can form. These factors are associated with overall patterns of cancer induction, but are not necessarily involved in causation or mechanism latent viruses and their genomes may play a substantial part in the etiology of some cancers in humans. Thus reducing the number of mutacarcinogens in our environment will generally help to control cancer but will not solve the entire problem. The public cannot be protected against all or even most cancers by using a very sensitive test system to identify all "positive" compounds and then trying to reduce all human exposures to these positives to infinitesimal levels. Other Federal laws also affect regulatory decisions. A relevant statute known as the "Delaney Clause" prohibits the intentional addition to foods of a substance legally classified as a food additive if that substance induces cancer in animals or man or has been shown by appropriate tests to induce cancer. The question of whether the Ames test is an appropriate device to support the Delaney Clause should be considered in the context of statistical association with identified carcinogens. We should likewise ques- tion the relevance of in vivo long-term feeding experiments in rodents to the human situation. 2. SPECIFICITY So far, the test system has been fairly specific for the substances tested in that muta- genic effects have been detected for many carcinogens. Thus the present designation of true positives is acceptable, but the question of false positives has not yet been answered satisfactorily. Most of the substances tested so far have been carcinogens relatively few so-called noncarcinogens have yet been tested. Many more substances commonly accepted as safe for human exposure or consumption should be tested before a judgment is made. I did not say "commonly accepted as being noncarcino- genic," because, under our present in vivo bioassay system and current dosing regimens, some substances will register positive in an animal feeding experiment even though they are not carcinogens. Any factor--carcinogen, promoter, or modifier--can