60 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS it has also been studied in excised skin and in the intact skin of man and animals during life. The information obtained from these various types of investigation cannot be suitably interpreted until one knows whether data obtained from animals are applicable to man and whether data obtained from excised skin and from the intact skin of living man are comparable. We must keep these considerations continuously in mind. It is now no longer adequate to say simply that the skin is relatively impermeable to warm' because it is able to prevent dehydration of the body. We must not be satisfied with the vague statement that the skin is quite permeable to mustard gas, nerve gas and estrogens simply because we know that dramatic cutaneous or systemic reactions follow topical application of these subs•:ances to normal skin. It is, of course, true that absorption of mustard gas, a nerve gas or an estrogen from the cutaneous surface can be followed by vesicle formation, death of an experimental animal, or en- largement of mammary tissue, respectively--.reactions which are merely evidence that some absorption has taken place. These reactions do not in themselves measure the amount of absorption that has taken place they cannot serve, therefore, as the quantitative measure of permeability that we need for amplification of knowledge. I here deliberately used the words "absorption" and "penetration" interchangeably. It is not necessary in our discussion today to define these words with great precision, as is so often done in print, or to distinguish sharply between their meanings. Attempts to make such fine differentia- tions between terms may defeat the purpose of a symposium such as this. Todaywe are anxious to focus attention on themovement of molecules of var- ious substances into and through the skin, without attempting to establish minutely precise terminology. We want to know how many molecules move into the skin from a unit area of cutaneous surface in a unit of time, and where these molecules go after leaving the cutaneous surface. If we can consistently think in these terms, i.e., on the molecular level, it is not important whether we call this migration of molecules "absorption," "sorption, .... persorption, .... permeation, .... penetration" or any other name. As you have seen on the program, this morning's session is devoted to a discussion of the methods used for studying percutaneous absorption. Sound methodology is the foundation of any investigative work. We shall first consider whether the methods which have been used in studying percutaneous absorption are sound, if they give quantitative data concern- ing penetration of molecules, and if they indicate where these molecules go after they have left the surface of the skin. It is not my intent to present an all-inclusive review of percutaneous absorption. Several thorough reviews (1-3) have been published recently. Rather, I shall propose a classification of the various methods which have been used for the study of

STATEMENT OF PROBLEM AND CRITICAL REVIEW OF PAST METHODS 61 penetration and cite one or more examples of investigative work in which each of the methods has been used. I believe it is possible to fit most of the methods into the following categories: 1. Penetration into"models" 2. Study of changes in the histology of the skin 3. Use of tracers a. Dyes b. Fluorescent compounds c. Radioactive elements 4. Measurement ofphysiologicalreactions 5. Analysis of tissues: sk. in, blood, urine, etc. 6. Loss ofpenetrant from the cutaneous surface PENETRATION INTO "MODELS" One of the "models" which has been used to simulate skin is agar gel. It has been commonly used in studying the release of antibacterial agents from various ointment bases (4). It is often assumed that those ointment bases which best release antibacterial agents to an agar gel will similarly release ' these substances to the skin when the ointments are placed on the skin. The continuous phase in an agar gel is water. If one observes the transfer of a chemical from some vehicle, petrolatum for example, into an agar gel and the subsequent movement of that chemical in the gel, it is equivalent to observing the transfer from the vehicle into water and the ensuing diffusion through water. In subsequent papers in this symposium, the chemical and physical structure of the skin will be discussed. It is much more complex than a single aqueous phase. It seems unsatisfactory, therefore, to assume that data obtained from a study of penetration into agar gel are applicable to penetration into skin. STUDY OF CHANGES IN THE HISTOLOGY OF THE SKIN When salicylic acid in various vehicles is placed on the skin it produces keratolysis. Strakosch (5) has studied penetration of this substance into the skin by taking biopsies of the skin and examins histologic sections for evidence of kerato]ysis. It is difficult to measure keratolysis quantita- tively under these conditions, and certainly this investigator made no claims that this method would permit quantitative measurement of the amount of salicylic acid which had penetrated the skin. Cotty, in a subsequent paper in this symposium, will discuss another method by which penetration of salicylates may be studied. Goldzieher and his associates (6) also have used histologic sections of skin in their study of the penetration of estrogen. We should delay any discus- sion of this work until after Dr. M. A. Goldzieher has told us about it in