402 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS subjected to experimental studies. While there may be good reasons for using the rat, guinea pig, rabbit or other animals for preliminary physio- logic, pharmacologic and toxicity studies, etc., I can see no good reason for using these animals for the type of studies I am going to mention, unless it is to establish and become familiar with working technics. The need for work on laboratory animals is particularly little if the non-radioactive form of the ointment has previously been used on man without demon- strable harm and if the amount of radioactivity is known to be within safe limits for both topical application and systemic absorption. It might be well to point out, that before radioactive isotopes may be used on human beings, approval must be granted by the Subcommittee on Human Ap- plication of the Isotope Division of the U.S. Atomic Energy Commission. I doubt that I need to do more than mention some of the differences between the skin of the commonly used laboratory animal and that of man for you to understand why conclusions drawn from animal experimentation cannot be applied specifically to the human skin. In contrast to the human skin, the ordinary experimental animal (1) has a heavy coat of hair, which if clipped, shaved or plucked undoubtedly injures the skin to some degree making for unnatural points of entry for any externally applied preparation and, of course, the animal has many more hair follicles per square area which interrupt the continuity of the skin and afford many more portals of entry (2) does not possess sweat glands as does human skin, thus undoubtedly making for differences in the flow of materials over the surface, the extraction of sweat soluble ingredients from the base, the emulsification of sebaceous secretions, which in turn undoubtedly in- fluence penetration and absorption (3) possesses sebaceous glands whose secretions must be different than those of man in the relative amounts secreted and in their chemical contents--again causing differences in the behavior of topically applied preparations and (4) the ordinary external exposures of animal and man are immensely different--who ever heard of a guinea pig wearing underclothes of silk, rayon or nylon using soap or detergents being exposed to extreme changes in temperature and humid- ity or using estrogen creams, perfumes, colognes, after-shave preparations, deodorants, or bubble baths. Certainly for these reasons alone, the human skin should be used whenever possible for the type of investigations I will mention. When planning studies which are to be done on human skin, in vivo, other considerations become important in the selection of the radioactively tagged compound to be used. For our problem, it is necessary to have a radioactive compound that: (1) chemically, in the concentration used, is not a primary irritant and is not known to have a high sensitizing index when applied topically (2) is not toxic if readily absorbed (3) possesses such radioactive properties (type of radiation emitted), has such a half-life

USES AND LIMITATIONS OF RADIOACTIVE ISOTOPES 403 and is in such a concentration as not to be considered harmful either on external application or if absorbed in large quantities. If all these factors are known to be within safe limits, it is possible that the studies on human volunteers will be approved by the Subcommittee on Human Application of the Isotope Division of the AEC. If the topical preparation is being used with the intention of benefiting the patient, its use on human beings is more likely to be granted. When all of these problems have been worked out and permission for procurement and use of the radioactive isotope has been granted, work may begin, providing of course the necessary laboratory equipment and trained personnel are at hand and the subjects are available. It goes without saying that the combined knowledge and efforts of the cosmetic chemist, the dermatologist, and the nuclear physicist, and when needed the help of other qualified specialists, should be the most sensible and expedient way of tackling such problems. And I think I can correctly add that previous experience in this specialized field will prove particularly useful at the outset. There are innumerable problems which might be studied using an oint- ment containing a radioactively tagged compound applied topically. I will enumerate but a few: Does the particular ingredient being studied penetrate the skin? If so, where does it localize--epidermis, hair follicles, sweat ducts, sweat glands, etc.? Is it present in large or small quantities? Is the penetration and localization affected by rubbing, previous preparation of the skin, different ointment bases, etc. ? Does absorption of the ingredient take place so that its presence may be shown in the body fluids? What percentage of the applied material is absorbed? Can the absorption be affected by rubbing, different bases, permitting longer contact With the skin, etc. ? Is penetration and absorption altered by concentration, thickness of the layer applied, dressings? How long does the ingredient remain on the surface or in the skin? Is its loss influenced by humidity, temperature, sweating, washing? How easily is it rubbed off? What is the best way to remove it, use of creams, ointments, oils? Which ones? Soap and water? Do any of these methods increase penetration and absorption at the same time ? (As an aside, I may add that knowledge concerning some of these facets would almost surely be of incalculable importance in devising methods for the decontamination of the skin following exposure to the atomic and hydrogen bomb fall-out.) What is the correlation between degree of penetration and therapeutic effectiveness? Is it necessary to strive for increased penetration or should attempts be made to localize or limit it? Can bases be developed which will allow penetration but prevent systemic absorption ? And so on.