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

PROBLEMS OF PREDICTIVE TESTING 353 negative results should be tempered by this knowledge. He must, there- fore, not only select his test but also his test population. Not every product should have to be subjected to all known tests. For example, there is no reason to subject a vaginal deodorant, nor any other product not normally exposed to light, to a phototoxicity test. Similarly, it is extremely doubtful whether or not a closed patch test of a shampoo at full strength has any meaning since shampoos normally remain on the scalp only for two to three minutes, are diluted, and are almost completely removed by subsequent rinsing. Finally, a 24- or 48-hour closed patch test of a depilatory would be out of the question and of no value. Such use-related considerations alone form a solid rationale for the desirability of in-use testing. These procedures are also valuable for the study of topically applied products because protocol automatically in- cludes exposure to the natural elements, such as sun, wind, heat, and cold. The importance of this test will become more apparent when some clini- cal experiences are discussed later. For the moment, it will suffice to in- dicate that in-use tests employ the product at near normal frequency in and over the area of usual application and can also take into account the possible misuse or even abuse of a product. PROBLEMS OF INTERPRETATION Let us assume for a moment that the investigator has established in a series of animal safety tests that he can proceed with human testing of a new cosmetic product. He has then carefully selected the proper human tests and has taken into account specific modifications to suit the product and its intended use. The results of these tests are available, and the in- vestigator is now faced with the responsibility of establishing whether the product can be "safely distributed." It is at this point that our inad- vertent errors and our lack of complete scientific knowledge can impair clinical judgment. An important source of error is the grading of reactions which may depend entirely upon the patch test material (14) and on the observer who grades the reaction. Occasionally, reactions may be due to improper application of the patch, i.e., friction. Inadequate tissue contact of the material and improper placement (which may lead to loosening of the occlusive covering) can reduce the severity of reaction to the patch test. Climatic conditions are also believed to have an influence on the reac- tivity of human skin, and there is some evidence that there is greater re- activity during winter months (19, 20).