EXPERIENCES WITH HUMAN PATCH TEST METHOD 329 strong primary irritant. However, the sensitizing substance on second application, even if there has been a mild reaction or no reaction on the first application, will elicit a severe reaction. In the case where it is a primary irritant, a high dilution of this material will elicit as severe a reaction as the concentrated ma- terial in the first application. We have thus far considered merely the concentration of thesema- terials. Now the time factor enters. In order to definitely rule out a substance as being a sensitizer, observations must be made of the skin of the subject for many days after the skin patch is removed. In our own experience we have seen sensitizing reactions appear imme- diately, within several hours after the second application and we have seen them with some substances delayed so that they did not appear for approximately three weeks. At the end of three weeks after the second series of patches had been removed, the site of the second application became inflamed and a severe reaction set in. With some materials the primrose reac- tion is apparent. In this reaction, if the sensitizer is placed on one arm on first application and on the other arm on second application, the sensitizing reaction obtained will appear not only at the second site of application but will produce a flare-up on the original site of application. The patch method of Dr. Schwartz should be, by his own admission, called the "human skin test method." This method as outlined above involves initial application of a substance, a period of layoff, and a second application of the substance. The number of subjects which should be studied again depends on the information which is desired. Primary irritation may be deter- mined on a few subjects. Ten subjects to 25 subjects should give all the information necessary as to whether a material is a primary irritant or not. It is only where it is important to determine whether a material is a sensitizer or not that the group of 200 subjects (unselected subjects, males and females approxi- mately equally divided as to sex and preferably those which are not patients in a clinic where they are being treated for some dermatitis or dermatological condition) is re- quired. It is only when a material or a substance shows up negatively, that it does not tend to appear to be a sensitizer on 200 subjects, that the prophetic patch test issues its prophecy that it is now probably safe to have the material come in contact with a larger group of sub- jects. It must always be remem- bered, however, that regardless of large numbers of cases where a substance has been used safely there is always a possibility that some individual may be allergic to that substance. This, however, does not incriminate the substance itself as being a sensitizing sub- stance. It is only the idiosyncrasy of that person who has that individ- ual allergy or sensitivity that makes him react to this material.

330 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The above method is a widely accepted method. We would at this time like to present another method which is to be used as a supplementary method for the patch test method and which, we might say, our experience has shown to be a more accurate method for deter- mining sensitizing materials. The method is one developed by Dr. John H. Draize, of the Division of Pharmacology of the Food and Drug Administration and the author. It was during a discussion with Dr. A. J. Lehman, Chief of the Division of Pharmacology, of the Food and Drug Administration and his group, that Dr. Draize's method was pre- sented to us as a suggested method on human subjects. The method which has been called the "repeated insult method" is as follows: The material to be studied is placed in contact with the skin of the subject. It is kept in contact with the skin for a period of four to twenty-four hours every other day until ten such applications have been made. At the end of this period there is permitted to elapse a space of three weeks, then the sub- stance is again placed in contact with the skin for a period of twenty- four to forty-eight hours. We have been able to pick up sensitizing substances much more rapidly with this method than we have with a second application on the patch test method. But since this method is fairly involved, it is suggested that it be used on as large a number of subjects as possible and if possible 200 subjects but, where this is im- possible, to get this information on at least a group of 25 to $0 subjects. We feel this method is capable of de- tecting sensitizing substances which have a lower threshold of sensi- tivity than that which might be detected by the other patch test method. We are often asked to study a material and compare it with a second material designed for similar use. We are often asked which is less irritating? Is "ours" less irri- tating? This can be determined by running a series of concentrations of both substances and determining at which concentration the irrita- tion appears. If one material ir- ritates at higher concentration than another material it may be said to be less irritating than the material that irritates at a lower concentration. This data, while it may be factual, does not necessarily mean anything in practice since it is quite possible that the substances will never be used in the concentrations which were tested. In other words, in the "inuse" concentrations, neither one of the substances may be irritating. In conclusion, I wish to point out that the human skin test method of Schwartz may be regarded as a basic technique which must be used intelligently, with several things in mind. Length of time of contact, concentration of material, and use of material and body surface cover- age are the most important factors concerning the modification of the test method. The method of de- termining sensitization as suggested by Dr. Draize is an important con-