WATER AND THE SKIN 199 There is little to no correlation of age and water loss. However, in a studv of human fetal skin it was found that in the early stages of pregnancy the skin is very permeable to tritiated water. During this time the skin may serve as a major pathway for solute and water exchange between amniotic fluid and the fetus. However. as the fetus increases in age a large decrease in skin permea- bility to tritiated water occurs (54). Regardless of the increase in permeability, the highly hydrated horny layer remains quite water-imperlneable and represents a stable and extremely cctive diffusion barrier in comparison with the viable skin layers (28). Hy- drated stratum corncure has a diffusional resistance almost 10,000 times great- er than an equivalent layer of water (55). The activation energy and en- tropy of diffusion show that the mobility of water within the tissue is orders of magnitude less than in liquid water and suggest that the diffusing unit is larger than a single water molecule (28, 56). Measurements of the evaporation rates from stripped and nonstripped skin may be used to calculate the resistance of the stratum corncure to water per- meation (57). The resistance of normal human forearm skin to water trans- port is in the range of 150-600 see/cm. The resistance of the same "stripped" skin was in the range of 0.4-1.25 sec/cm (57). The water transmission rate of fish and frog skins approximates free evaporation of water and is 6-20 times greater than mammalian skins (58). The resistance of hydrated stratum corncure is illustrated by a comparison of the diffusion coefficients of drugs in water and in human stratum corncure. Diffusion coefficients ranging from 10 -'• to 10 -•a cm2/sec could be expected for drugs penetrating hydrated stratum corneum. The diffusion coefficient in water for most drug molecules would be expected to range from 10 -• to 10 -ø cm2/sec (55). Hence, the diffusion of water and low-molecular-weight, water-soluble molecules through hydrated keratin is much more difficult than the corresponding h'ee diffusion in aqueous solution. The filament-matrix ul- trastructure is preserved under hydration and the water appears first to enter between the filaments and only later to diffuse within them (59). The trans- epidermal water loss by passive diffusion varies between 0.2-0.6 mg/cm2/hr dependent on the conditions of temperature, humidity, air flow, and body site measured (7, 11, 12, 14, 53, 57, 60-63). With regard to body sites, Bettley and Grice (61) found a h'ansepidermal water loss of 0.35 mg/cm2/hr on the front of the abdomen as compared with 0.6 on the thigh. Diseased skin in which the process of keratinization is disturbed becomes more permeable to water loss (53, 64, 65). Skin affected by eczema and psoriasis could be 8 to 10 times more permeable than normal (64). Even the apparently normal skin of eczematous subjects shows a higher rate of water loss than normal. When large areas of the body surface are so affected, the whole-body skin water loss may reach as much as 2 1. daily. Comparative studies showed that when compared to the normal, ichthyotic skin showed

9.00 JOUBNAL OF THE SOCIETY OF COSMETIC CHEMISTS twice the normal loss. In erythroderma the water loss was 14 times the normal (53). This is quite apart from sweating and is essentially outside the control of body mechanisms. Apart from its effect on water and salt metabolism, the evaporation of this amount of water from the skin surface requires over 1000 calories, a formidable daily energy requirement of patients who are ill (60). The state of hydration of the stratum corneum has been accepted for quite some time as of major importance in influencing percutaneous absorption. Wurster and Kramer (16) measured the rate of penetration of esters of sali- cylic acid through skin with dry and hydrated stratum corneum. They found that when the tissue was hydrated the rate of penetration of the most water- soluble ester increased more than that of the other esters studied. Working with aspirin in a temperature-humidity chamber, Fritsch and Stoughton (27) showed the dual importance of these factors on the penetration of excised skin. Full hydration of the keratin, accomplished by layering water over acetylsalicyclic acid on the epidermal surface, dramatically increased the penetration when compared to conditions of lower humidity at the same temperature. The importance of hydration can also be found in those investi- gations employing occlusive plastic film in steroid therapy. Here, the preven- tion of water loss from the stratum corneum and the subsequent increased water concentration in this skin layer enhances the penetration of the steroid (23, 29-32). McKenzie and Stoughton (29) have shown that penetration of corticosteroids may be increased 100-fold by occluding the site of application and thus hydrating the stratum corneum. It is also quite probable that some drugs increase the degree of hydration of the skin. This is most likely to occur with substances that readily penetrate the skin, and thus reach sufficiently high concentrations to produce an osmotic effect. A few steroids, such as es- trogens and pregnenolone, have been reported to produce a beneficial effect on aging skin by hydrating the skin (66, 67). Topically applied vehicles have the potential to either increase or decrease the quantity of water in the horny laver. The efficiency of varied type vehicles in aiding penetration can be reasonably predicted on the basis of their effect on hydration of the stratum corneum or how the vehicle alters the activity of water in the stratum corneum and influences the stratum corneum/vehiele partition coefficient. Water-insoluble, oily materials such as petrolatum, lano- lin, and isopropyl myristate significantly retard the rate of loss of water from the skin surface. On the other hand, certain emulsifiers and humectants in- crease the rate of moisturc loss (7, 68-70). Skin keratin has an isoelectric point of 3.7-4.5. Hence, it would appear that hydration would be affected by changes in pt. Yet, there are litfie data to support the idea that the pH of vehicles within the range tolerated without immediate irritation or skin damage affects the hydration state of skin greatly (16). Studies of stratum cornea from varied species (13, 15, 71) showed very little change in the swelling or hydration characterishcs of skin between pH