PERCUTANEOUS ABSORPTION 513 or out of mammalian organisms. The earlier claims by Folk and Peary (181) and Buettner (182) have been questioned by later workers (59, 180) on the grounds that insufficient attention was given to a number of physico- chemical factors which could account for the results observed by the earlier authors. No claims have been made that active transport affects the per- cutaneous absorption of other substances. A striking example of metabolic transformation within the skin was reported by Fredriksson (54, 183) who showed that parathion (E605, diethyl 4-nitrophenylthionophosphate) is metabolized to paraoxon (E600 or diethyl 4-nitrophenylphosphate) which is then degraded to non-toxic metabolites within the skin of the cat. Another example of chemical trans- formation within the skin is the reduction of hexavalent chromium to the trivalent form (125). It is not known whether these examples represent enzymatic activity or are straight-forward chemical interactions. SUMMARY AND CONCLUSION The principal cutaneous barrier to the absorption of substances from the external environment, in man and other mammals, is the stratum corneum. This barrier is broken by the ducts of sweat glands and hair follicles but percutaneous absorption via these appendages forms a small proportion of the total absorbed so that the major pathway for percutaneous absorption is across the stratum corneum. In fact, removal of the stratum corneum by the adhesive-tape stripping techniques results in a 10- to 12- fold increase in the absorption of any particular substance. Damaging the stratum corneum by abrasion or other means has a similar effect. The stratum corneum allows some substances to pass through it more readily than others. The precise physico-chemical factors that determine this performance are imperfectly understood but the evidence accumulated from in vivo and in vitro work allows some broad generalizations to be formed. Lipids and lipid-soluble substances readily pass through the stratum corneum, organic compounds possessing hydrophilic groups do so less readily, while water and water-soluble substances, in particular if these are in an ionized form, traverse the stratum corneum with difficulty. If the compound is applied topically in a vehicle, the rate of its absorption is considerably influenced by that of the vehicle, by the degree of its partition between the vehicle and the stratum corneum, and by its concentration in the vehicle. If the degree of partition is very small, the compound is absorbed along with the vehicle. If it is considerable, percu-

514 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS taneous absorption is probably independent of that of the vehicle. Concen- tration of the compounds in the vehicle appears to be important for aqueous solutions of electrolytes and less so for other types of compounds and vehicles. These features appear to be applicable to compounds in pure solvents or in creams and ointments. The physiological state of the stratum corneum considerably influences percutaneous absorption. An increase in its temperature or in its normal water content considerably increases the rate at which substances, particu- larly water and water-soluble substances, pass across. Alteration of pH affects percutaneous absorption through an alteration of the state of ioniza- tion of the test substance or through damage induced by very high or low pH. Measurement of percutaneous absorption has been made more sensitive and accurate by the employment of radio-isotope techniques. The older techniques employing chemical analysis and histochemical demonstration of topically applied substances are less widely used but may be of value in certain specific investigations. The method of 'disappearance measurement' of a compound, labelled with a suitable isotope, has found a wide applica- tion in experimental studies of percutaneous absorption in vivo but has only a limited application to human studies. This method needs to be com- bined with autoradiographic studies in order to allow for any error arising from stray (v-emitters) or inaccessible ([i-emitters) sources of radiation if the test compound is retained in the skin appendages. Excretion in urine, faeces and expired air of the topically applied compound or its metabolite provide a good qualitative evidence of percutaneous absorption but with few exceptions are a poor guide for quantitative studies. The same comment may be applied to biochemical estimations (such as enzyme levels), measure- ment of storage in internal organs and assessment of the percutaneous LD50. Despite this reservation such tests may provide invaluable information in some fields of toxicity studies, e.g. pesticides. The pharmacological effects chiefly employed in human percutaneous studies are vasomotor effects and inhibition or stimulation of sweat produc- tion under physiological conditions. In vitro studies employ both chemical and isotopic techniques for measuring the transepidermal passage of a particular test compound on skin samples removed from animals or man and mounted on a suitable chamber. These techniques give useful com- parative information on the percutaneous absorption of different chemicals or the same chemical in different solvents. They also provide basic informa- tion on physiological and pathological skin conditions which affect trans-