PERCUTANEOUS ABSORPTION 483 (1, 4, 10, 16-37). The object of the present review is to deal with the principles of percutaneous absorption from a broader view point, bearing in mind the needs of those involved in the biological testing of these compounds. In attempting to delineate these principles we have taken into account lessons learnt from experimental results with a number of compounds of importance to the cosmetic chemist. These include alcohols, soaps, deter- gents and emollients. Although these are not absorbed from the site of topical application to any meaningful extent, they may produce profound local changes which affect the permeability of the skin to other, possibly toxic, compounds. In addition to the experience gained from this source, we have drawn upon the extensive experience of work done in the field of pharmaceuticals, pesticides and basic research, wherever appropriate. THE CUTANEOUS BARRIER Nature of the barrier The passage of water and other substances into or out of the organism is limited by the skin which in mammals consists basically of an acellular layer of keratin and one or more layers of viable cells underneath. This 'barrier' function resides almost entirely in the stratum corneum (38, 39), a thin membranous layer (in the human 600 [tm in the palms and soles, 10-15 pm in other parts) which is mechanically strong and is capable of resisting chemical attack (38). The importance of this layer in maintaining an adequate barrier was demonstrated by Blank (40, 41). He developed a method for stripping the stratum corneum in successive layers and showed that the rate of water loss, under standardized experimental conditions increased from 0.5 mg cm -ø' h -• to 8 mg cm -ø' h -• after complete stripping of the stratum corneum. Removal of the outer layers had little effect on the rate of water loss indicating that the main barrier occurs at the deeper layer which histologically is the stratum lucidum. The stratum lucidum is an equally effective barrier against the penetration of substances from the outside and its stripping considerably increases the penetration of topically applied substances. This was demonstrated by Blank, Griesemer and Gould (42) in their studies on the percutaneous absorption of the organo- phosphorus insecticide 'satin' from the skin. The absorption of satin after six strippings did not differ from that of controls, but after 12 strippings there was a hundred-fold increase. Damage to this layer also results in increased permeability to a variety of chemical agents (43-45).

484 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The effective performance of this 'barrier function' appears to depend on the chemical composition of the stratum corneum. Chemical analysis has shown that this layer is rich in 'solid' matter which consists principally of keratin fibrils and lipid. These components are derived from the stratum spinosum, the layer of living cells immediately beneath the stratum lucidum (33, 46). The investigations of Matolsty, Downes and Sweeney (47) have shown that removal of the lipid or the protein of the stratum corneum results in an increased permeability to water indicating that both are essential to maintain intact the barrier property of this layer. As one would expect, the thicker the stratum corneum, the more im- permeable is the barrier. Marzulli (29), Blank and Scheuplein (33) and McCreesh (48) have shown that the rates of penetration of a wide variety of liquids applied to the epidermal surface in vitro were inversely related to the thickness of the epidermis, so that the soles and palms are much less per- meable than the skin in other parts of the body. It would appear, however, that this rule does not apply in vivo. In a study of the comparative rates of absorption of parathion, malathion and carbaryl from a number of anato- mic sites, the x4C-labelled compounds were absorbed with equal facility from the palm or the hand or from the forearm. The abdomen and dorsum of the hand had twice the penetration of the forearm, whereas follicle-rich sites, including the scalp, angle of the jaw, the area behind the ear and the forehead, had a four-fold greater penetration (49), indicating that the skin appendages may constitute an important pathway for absorption. The role of the appendages The barrier formed by the stratum corneum is broken by the ducts of numerous glands and hair follicles, which, as indicated above, form an additional route by which substances applied to the skin surface might gain access to the circulation. In the human, the density of sweat ducts is 210 and 220 cm -•' in abdomen and forearm respectively (50), while that of the hair follicles is 40 and 100 in these same areas. This density is, however, variable--both between different anatomical areas and between species. The presence of this additional route of percutaneous absorption has been verified by a number of experiments. Applying dyestuffs on the skin in vivo Rein (51) showed that the vicinity of follicles is stained more intensely than the rest of the epithelium. He also found that perifollicular staining does not occur around follicles which have been occluded by waxy plugs. These observations were supported by the work of MacKee, Sulzberger,