96 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS though limited and imperfect, often functions with competence. That is, it minimizes entry of topically applied substances into the body and retards the evaporative loss of body fluids, thus helping to maintain the constancy of the internal milieu. Once a topically applied substance traverses the stratum corneum its absorption into the blood stream is assured. The precise route to the blood stream via epidermal pathways is subject to controversy and it varies in relation to chemical and physical properties of the penerrant. Intercellular areas of the stratum corneum may represent a more vulnerable pathway than the cornified cells themselves (3). In support of this is the fact that intercellular sites contain an intercellular cement substance that is more easily dissolved by solvents than the horny cell substance (4). Furthermore, in rats fed a diet deficient in essential fatty acids, the intercellular cement substance deteriorates and is inadequate to bind cells together (5). The stratum corneum then suffers a loss in barrier capacity for water (6). We have implied that skin permeability appears tied to a relatively constant physical process however, biochemical processes may indeed play a role. Certain chemicals, for example, are metabolized as they transit through skin. Steroids such as testosterone and cortisone are among these substances (7-8). Thus, en route to the blood stream topically applied steroids encounter enzymes in skin that chemically alter the penetrant. We do not know at what age these enzymes appear in the skin, nor do we know if they diminish with age. We have imperfect data on how males and females may differ in this metabolic capacity, and we do not know what other substances may also be transformed by metabolically active skin enzymes (8). Detoxification as well as excretory processes are not the same in young and old members of a species (9). This is related to the fact that enzyme systems are inadequately developed in the newborn and the young. The fact that certain topically applied substances may encounter metabolically active substances in skin offers scientists an interesting area for further exploration. STATEMENT OF COMPLEXITIES One of the first problems that one faces in designing experiments aimed at studying the effects of age as it affects a human skin response, be it its capacity for penetration, irritation, sensitization, skin carcinogenesis, etc. is the enormity of the time-frame involved. The response of the premature infant may differ from that of the neonate. The child may differ from the young adult. The mature and the aged may differ from one another. There are therefore six distinct periods in a lifetime that enter into con- sideration. Since skin varies from site to site, each conclusion applies only to the specific site under investigation. Results of a study that is conducted on hairy skin may not apply, if glabrous skin is used. Skin with a thick horny layer such as the palms and soles may produce different results than skin with a thin horny layer. Dorsal skin may differ from ventral and apocrine-bearing sites from eccrine-bearing sites. Specialized skin areas such as the scrotum and eyelids may differ from the ventral forearm, favorite site for some experimentalists. These, then, are some of the more obvious complexities that enter into any discussion of the permeability and reactivity of skin as related to age.

PERMEABILITY AND REACTIVITY OF SKIN 97 ANATOMIC AND PHYSIOLOGIC CHARACTERISTICS OF SKIN THAT MAY AFFECT PERCUTANEOUS PENETRATION Physicochemical characteristics of the horny layer are expected to determine the pen- errability of skin by topically applied substances. Its integrity, its thickness, and its quality are involved. We know that trees that grow rapidly produce poorer quality wood than those that grow slowly. By analogy then, we expect that rapid turnover of cells might result in a diminution of the quality of horny layer. Indeed this is the case in psoriasis where abnormally rapid turnover of cells results in increased skin perme- ability to water but not to hydrocortisone (10). This was confirmed in one study where application of ammoniated mercury to a psoriatic skin site resulted in 4-20 times greater skin penetration than occurred on a control skin site (11). Age-related turnover studies have been conducted by Baker and Blair (12). They used a staining technique with tetrachlorsalicylanilide (TCSA), a fluorescent substance, to measure the transit time of horny cells in the forearm of young and old subjects. They also measured the number of cell layers in the horny layer. Results showed that it took 20 hrs for each cell layer to be replaced at this skin site in young men, but 34 hrs in men aged 60 to 86. The difference between young and old women was not as great, being 20 and 24 hrs/cell layer respectively. Although a rapid turnover might be expected to result in a slightly poorer quality horny layer, this penetration-favoring effect might be counterbalanced by the increased shed- ding rate, so that a somewhat greater loss in the skin's reservoir capacity would occur. The net effect on skin penetration might be negligible. This normal physiologic turn- over process, then, is of a small consequence in comparison with the abnormal skin changes produced in psoriasis. A third qualitative change in the stratum corneum which can be considered is that of the cell size of the horny layer as related to age. Piewig (13) studied nine skin sites in males and females, caucasians and negroes, infants (5 and 6 months) adults (ages 21- 31), and older humans (ages 65-85). He concluded that cells of the stratum corneum increase in size from infancy to old age they are larger in females than in males they are largest in the axilla and smallest in the forehead. If skin penetration is greater in the intercellular spaces, a difference in cell size could conceivably have an effect. This variable has not been evaluated. Changes in skin physiology that accompany the aging process are suggested by obvious age-related changes in texture if we compare soft baby skin with dry skin of the eighth decade. In the intermediate years, the skin is wetter and oilier from increased eccrine and apocrine gland activity. At puberty, in addition to reaching peak apocrine output, the appearance of pubic and underarm hair signals hormonal changes that could affect the skin's biologic capacities. On becoming an adult, a person's skin becomes thinner, mainly because of a decrease in dermal thickness. Females are more advanced in this process, as the dermal thickness is less than that of males. Skin thickness was mentioned as a possible factor in percutaneous penetration. Thick- ness may be due to increased dermal material, increased epidermal material, or a combination of the two. Clearly, dermal thickness is of no consequence whatever, as the significant kinetics of percutaneous absorption are confined to the epidermis. In the human, the epidermis increases in thickness as the newborn infant matures, peaking at around 30-35 years. After this, it gets thinner with advancing age (14).