500 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS increase was due to an enhancement of percutaneous absorption these authors measured the passage of the •4C-labelled compounds and found that the addition of DMSO increased absorption by a factor of 6.71 in the case of hydrocortisone and 27.4 in the case of hexopyrronium-methyl-•4C. Subsequent studies in vitro showed that DMSO not only enhances percu- taneous absorption but promotes the formation of asteroid reservoir in human skin (132). Comparative studies, in vitro, showed that DMSO is superior to other solvents both in enhancing penetration and in favouring dermal retention. This was clearly demonstrated in a study of the passage of •C-labelled griseofulvin, dissolved in neat DMSO, dimethylacetamide, dimethylform- amide, ethanol or benzene, through human skin in vitro. Taking the rate of penetration of griseofulvin dissolved in benzene as unity, the ratios of penetration when the other compounds were used as solvents were 60, 40, 7 and 3 respectively. The superior property of DMSO to enhance percu- taneous transit is seen even when its concentration is 50•o in water. Thus, the ratios of penetration of •C hydrocortisone dissolved in 50•o DMSO and in neat DMAC, DMFA and 95•o alcohol was 20, 6, 4, 1. The retention of both griseofulvin and hydrocortisone in the excised skin was found to be roughly parallel to their rate of penetration and DMSO, neat or in 60•o aqueous solution, was therefore superior to the other solvents in promoting skin penetration and retention. The retention ratios were approximately 25, 5, 5, 1 when DMSO, DMAC, DMFA or ethanol were used (133). Similar results were obtained using other criteria for percutaneous absorption. After topical application of •sC-labelled hydrocortisone or testosterone, 0.9•o or 11.8•o of the •sC label appears in the urine in 5 days. Presence of 25•o DMSO in the solvent increased the excretion rate of the label approximately four-fold. Dimethylformamide in the same concentra- tion increased the penetration approximately two-fold while propylene glycol and mineral oil in 25•o concentration slightly decreased penetration (134, 135). DMSO was found effective in enhancing the percutaneous absorption of HgCla in vivo in the guinea-pig. Using the 'disappearance measurements' technique, it was found that pretreating the exposure area with 1.0 ml of neat DMSO enhanced the absorption of HgCla from a 0.239 M aqueous solution. No significant change in the rate of absorption was found at lower concentrations. In a similar experiment employing the same concentrations of mercury, the use of 1• soap or alkyl aryl sulphonate were as effective as DMSO (136).

PERCUTANEOUS ABSORPTION 501 The marked acceleration in the rate of percutaneous absorption pro- duced by DMSO prompted a number of investigations into the local changes produced by this compound. This 'accelerant' effect is not thought to be due to increased skin circulation because this can be increased without increasing the penetration rate (115) or the skin 'clearance rate' (137). Furthermore, the accelerant effect can be observed in vitro with isolated non-perfused skin preparations (137). This in vitro effect was studied in detail by Sweeney, Downes and Matoltsy (138). Their results show that there was no significant change in the rate of passage of water through the skin when the epidermis was treated for 30 min with aqueous DMSO in concentrations up to 50•o. At a concentration of 60•o a two-fold increase was observed, at 80•o and 90•o the increase was 10-fold and 90-fold respectively. The changes in permeability in this study were irreversible and the authors concluded that permanent damage to the stratum corneum had resulted from this treatment. The fact that the concentration of DMSO was far more significant than the actual time of exposure in producing this effect was thought to be particularly relevant. The in vivo work indicating a faster rate of absorption of corticosteroids dissolved in 25•o DMSO appear to contradict the results of this in vitro experiment. It would seem possible, however, that the steroids and DMSO may have penetrated the stratum corneum because of a favourable water/ lipid partition coefficient without producing damage. Further in vivo studies failed to support the conclusion of Sweeney et al (138) that the damage produced by DMSO on the stratum corneum was irreversible. Exposure of the flexor aspect of mid-forearm to pure DMSO for 30 min in three volunteers increased the water loss 8-, 11-and 17-fold respectively but the effect was reversed within 6-8 h (139). This discrepancy may be a reflection of the ability of normal skin to repair the damaged stratum corneum. Baker (139) attributed the effect of DMSO to its strongly hygroscopic properties so that its presence in the stratum corneum greatly increases the permeability properties by increasing the water content of this layer. How- ever, the detailed studies of Allenby et al (137) indicate that profound chemical changes occur. DMSO extracted lipoproteins from the stratum corneum, an effect which is likely to disorganize its fibrillar structure. Electron-microscopic studies on the guinea-pig skin treated with neat DMSO show considerable structural damage (62). Compared with the data available on DMSO, information on the mode of action of other 'accelerants' is sparse. Organic solvents, such as benzene,