354 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Cross sensitization and what has been termed skin fatigue or cumula- tive reactions add to the problems already facing the investigator. He must now, for example, consider the possible influence of drugs on the reactivity of the test subject or the ultimate user. The age of the patient influences reactivity due to lack of previous exposure or by virtue of the development of the immunological apparatus. Pre-existing skin condi- tions, such as eczema, may or may not have a direct effect on the final re- sults of the patch test or on the consumer. A further problem is gener- ated by the fact that often patch tests are conducted using more than one and sometimes as many as a dozen products at the same time. The ques- tion then arises whether simultaneous patch testing with different mate- rials could have an influence on the reaction to one or more of the prod- ucts tested. This fact could be an advantage or a disadvantage. Our in- ability to be more specific is, in fact, a limitation in itself. In this con- nection it is noted that racial influences and skin color must also be con- sidered, although to date there is relatively little known about the sensi- tivity of different races to any given chemical (21). It is not surprising that heredity plays an important role in allergic contact dermatitis (22) and this may also apply to reactivity to cosmetics. Finally, the investigator must take into account that the sensitivity potential of a population to a product can change with time. This type of latent sensitivity was studied by Baer et al. (23), who attribute this phenomenon to increased opportunity to exposure to allergic sensitizers. It is conceivable that the safety of chemicals or products established some years ago is no longer applicable today. The relationship of these ob- servations to Agrup's (24) conclusion that patch testing can lead to sen- sitization is by no means clearly established. It must be concluded that the interpretation of predictive human patch testing is made difficult by two factors: (a) possible experimental error and (b) the influence of unknown extraneous factors on the test sub- jects and eventually on the population of potential users. The careful experimenter can usually overcome the limitations due to inadvertent error. He cannot make up for the holes in our knowledge, i.e., the un- known. Some known and some unknown parameters, both of which may in- fluence the results of patch testing or the response during use, are shown in Tables I and II. Many of the questions raised above exert an important influence on the results of a well-conducted in-use test. The results from such a test

PROBLEMS OF PREDICTIVE TESTING 355 Table I Parameters Known to Influence Human Skin Reaction Parameter Response Reference Site of application (in sensitization test) Mode of applica- tion (in sensiti- zation test) Type of patch used Dose Trauma (at site of application) Sex 1. Back abdomen extremities 2. Reapplication to same site new site Epicutaneous intradermal Closed open 1. Response depends on amount deposited per unit area, not total dose 2. One large dose is more sensi- tizing than several small doses Chemical trauma mechani- cal trauma Male female Kligman (21), Magnusson (25) Kligman (1, 21) Kligman (21) Magnusson (14, 25, 26) Kligman (21) Lowney (27) Rebello (28), Kligman (21) Lanman (15) Table II Parameters Which May Influence Human Skin Reaction Parameter Comment Reference Age Trauma to skin (at a remote site) Race and heredity Seasonal variation Pregnancy Diet Effect in sensitization not clearly established Probably increases reaction Probably important 1. Response nfinimum occurs during summer 2. Greater reaction during winter 3. Sweating under patch does not increase reaction Not known Not studied Sipos (29) Kligman (21), Forsbeck (22) Hjorth (30) Justice (20), Kligman (19) Bettley (31)