EVALUATION OF CHEMICALS TO ANIMAL SKIN 181 investigators. Rabbit skin can, I think, be said to be somewhat more sensitive to chemical irritation than the average human skin. Guinea pig and rat skin are widely used for irritation studies, however, and so long as the investigator has the background of comparative evaluation between the animal and human, it makes really very little difference which animal is selected. It is quite possible that the use of swine will become much more popular than it has in the past if some of the miniature breed programs now under way turn out successfully. Pharmacologically, irritation is synonymous with stimulation and one should not overlook the fact that a very mild degree of irritation which is controllable and reproducible may be exactly what one is seeking for certain cosmetic applications. Certainly it is the basis for much therapeutic pharamacology. As mentioned earlier, methodology is the big problem in evaluating irri- tation critically. Severe irritation, including necrosis, is of course readily observable but not readily comparable from one chemical to another. Certain types of chemicals, as for example the organic amines, do more subcutaneous damage than would be expected from the appearance of the epidermis. Elaborate methods for conducting and evaluating dermal studies have been published and I am sure that this group is familiar with them. Most of these, however, apply to one objective only and it is of fundamental importance that the biological scientist design and evaluate his program in such a manner that he obtains the answer tb the specific question under study. To be led astray by following methods applicable to other objectives is perhaps the most common mistake that one sees in this field, particularly by those lacking fundamental training and experi- ence to whom skin studies look so simple. While discussing the subject of irritation I should like to digress some- what from the skin and say that we feel the combination of eye and dermal studies is often more revealing than either study alone. This is particu- larly true when one is investigating a series of compounds or various con- centrations and vehicles for the same compound. We have observed that the reactions in the eye and in the skin sometimes correlate and sometimes are quite opposite. Another aspect of comparative testing which I think has not been adequately developed is that employing repeated daily application to both the skin and the eye. This is in effect an evaluation of the skin exhaustion capacity and is revealing in some cases. It is not unusual to find, when running parallel series on different compounds, that one compound or one formulation will cause no more reaction after many days of application than it caused on the first application and the reaction may in fact become more mild. On the other hand, a second material or formulation will cause practically no irritation during the first several days and then either abruptly or gradually, increase in degree of irritation

182 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS produced. Studies such as this can conveniently be conducted only in animals if large numbers of chemicals and multiple conditions are to be evaluated in any type of a mass scale. Time, economics, and availability of almost unlimited subjects militate strongly for the use of animal rather than human panels for investigations such as these. In actual practice the use of animals serves a very important function in screening candidate materials for eventual human tests. While it is true that there is a statistical chance that a valuable candidate may be passed over, this is a calculated risk and certainly the risk is nowhere near as great as would be experienced in human testing only, with all of its multiple limitations. Perhaps the most confusing application of animal testing is in the field of evaluating sensitization. I should like to say at the outset that our staff members have had appreciable experience with the various sensitizing techniques in animals. I should also like to add that we do not believe any technique is completely reliable for the determination of sensitizing potential. From the time of Landsteiner, the literature is replete with discussions of sensitization in animals. Many of these papers cover such aspects as the species of animal, the purity of breed, the Mendelian charac- teristics, the age, the sex, the diet, the method of application, the frequency of application, the number of applications, the interval of challenge ex- posure after sensitizing exposure and countless other variables. It seems to be self-evident that ifsensitization in animals were a reliable phenomenon the attention would be spent on studies involving sensitization as an es- tablished entity rather than to the discussion of the variables which tend to explain away the negative result. The above is not meant to say that true sensitization does not occur in animals. I am sure that most of us in the field have seen true sensitization, but the interpretation from animals to humans is extremely inconsistent and unreliable. Most of us also know of examples, published or unpub- lished, where animals have not reacted as humans have, and vice versa. Here again, objective is an extremely important consideration. We do feel that new materials, particularly new individual chemicals, should be screened for strong sensitizing potentials in animals prior to human exposure. Our final evaluation on this subject is that if animals are sensitized we are extremely cautious with that material in humans. Certainly it is a suspect chemical until proved otherwise. On the other hand, a negative result in animals serves only to indicate that the chemical is probably not a strong inherent sensitizer and that with reasonable caution we should not obtain severe sensitizing reactions in humans. The evaluation of aesthetic benefits on animal skin is obviously a long jump and, by and large, is not correlated with the human results. Ex- perienced operators learn to evaluate subjective appearances such as tone,