PROBLEMS OF PREDICTIVE TESTING 351 PROBLEMS OF PREDICTIVE TEST PROCEDURES Availability of Test Procedures The existing techniques are widely used, and all ot5 them can help in predicting the safety of cosmetics if they are wisely selected and if the data obtained are properly applied. These procedures can and should be modified or exaggerated to suit the product however, the application of results from a small-scale test to the population at large is statistically dif- ficult (5, 6) and leaves much to be desired, especially in view of the artifi- cial conditions which are employed in testing cosmetics. It is probably worthwhile to mention briefly the various groups of tests that are available. Animal tests may include the guinea pig immersion procedure (7), the "Draize" rabbit eye test (8), the standard "Draize" dermal irritation pro- cedure (8, 9), various guinea pig sensitization tests (8, 10, 11), and others. Human patch tests in a variety of forms have been used for many years. These may include the single (primary irritation) patch test (1, 3), the prophetic patch test (1), modification of the patch test to determine possible phototoxicity or photosensitization (3), repeated insult patch tests to determine sensitization (12-14) and, finally, the maximization test procedure of Kligman (1, 4, 15, 16). In-use tests represent the third group of tests available (17). Although no formal procedures for this type of testing exist, the product is generally used in accordance with the manufacturer's direction after preclinical or clinical patch tests. In some instances, it may be desirable to exaggerate the conditions of use by increasing the amount and frequency of applica- tion. Preferably, the period of intensive use is followed by a rest period and then a "challenging" patch test. Problems of Selection The protocol 15or an effective predictive testing program requires a considerable amount of judgment. One of the most important limita- tions on test procedures is the fact that not all of them are applicable to all products, and the selection of the test is as important as the test itself. To subscribe to the concept that a product must pass a particular test be- [ore it can be considered safe for marketing eliminates all opportunity to modify a standard test. It also precludes the need for interpretation of the results obtained by the clinician and, in effect, voids his expert judg- ment.

352 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS In planning a well-organized safety program each preparation must be individually considered, and the tests employed should be appropriate for the product. Knowledge of the formula, familiarity with the in- tended use of the product, and directions for use of the marketed product are essential requirements for selecting the proper predictive test and any alterations that are needed. We feel that, by themselves, animal tests are of limited predictive value, whether they are negative or positive (18). It is generally agreed that these tests have their principal value in providing confidence to the investigator to proceed further with tests on human subjects (10, 13). In addition, animal testing procedures often offer useful clues to potential adverse reactions in human subjects. Any reaction in animal tests thus becomes a special alert to the clinician. On the other hand, a strong posi- tive reaction will be a warning to the investigator either to proceed with extreme caution or to abandon further testing. Animal test procedures are highly exaggerated and rightfully so. They should be carefully interpreted by the investigator so as to be used primarily for guidance to the formulator and not for the purpose of ab- solute judgment on a go or no-go basis. A typical example is the guinea pig immersion test during which animals are exposed to moderately con- centrated solutions of detergents for a prolonged period of time. This test will almost always result in skin reactions. The fact that damage oc- curs is unimportant, but the degree of damage can be used as a guide for the selection of "safe" detergents for a particular use. Similarly, one would certainly not test a waving lotion or a neutralizing solution via the subacute 20-day derreal irritation test with rabbits. The results of such a test would be meaningless and have no relationship to the frequency of use by humans. Human patch tests too must be selected with great care. For example, any closed patch test technique is exaggerated because both the tempera- ture and the humidity are raised in the occluded area and because evap- oration of any volatile materials is precluded. It is also common to use the same test population on more than one occasion. Actually, repeat exposure of the same test population may appear highly desirable because this group might exhibit cumulative irritation and occasional sensitiza- tion due to exposure in previous tests. On the other hand, such a popu- lation by repeated exposure may have become refractive, thus introduc- ing another limitation. The investigator should be aware of the poten- tial of the test population to react, and his interpretation of positive or