Comprehensive Physiology Wiley Online Library

Permeability of the Skin

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Manifestations of Skin Permeability
2 Structure of the Skin
2.1 Relevant Structural Features of the Whole Skin
3 The Stratum Corneum
3.1 Regional Variations in Structure
4 Human Versus Other Mammalian Skin
5 Biophysics of Skin Permeability
5.1 Mathematical Analysis of Skin Permeability
5.2 Steady‐State Permeability of Skin—Fick's Law
5.3 Appendageal Diffusion
5.4 Concentration Levels in the Skin
5.5 Regional Variations in Permeability
6 Effect of Solvents and Surfactants
6.1 Water
6.2 Aprotic Solvents
6.3 Surfactants
6.4 Organic Solvents
Figure 1. Figure 1.

Top: stained cross section of human skin. Stratum corneum has porous appearance typical of histological preparations. Bottom: electron photomicrograph of top part of epidermis showing 10 cell layers of stratum corneum.

From Scheuplein & Blank
Figure 2. Figure 2.

Schematic of human skin. Dimensions and distances pertain to abdominal skin. The essential elements of the composite skin diffusion barrier are indicated.

From Scheuplein & Blank
Figure 3. Figure 3.

Cellular structure of the stratum corneum. A: a fragment of stratum corneum one cell layer thick (phase contrast). Dark bands bordering cells are regions of cell overlap. B: scanning electron photomicrograph of external surface of stratum corneum (washed with carbon tetrachloride prior to gold‐palladium coating.) C: electron photomicrograph of filled intercellular regions in stratum corneum. Adjacent cell boundaries are highly convoluted and interdigitated. D: cross section of stratum corneum showing surprisingly regular vertical stacking of cells. Tissue was swollen in water (pH = 12) and stained with methylene blue.

From Scheuplein & Blank . From Scheuplein & Blank . Courtesy of A. M. Kligman. Courtesy of A. M. Kligman
Figure 4. Figure 4.

Top: idealized representation of intracellular keratin in stratum corneum. Bottom: electron micrograph of intracellular keratin.

Courtesy of I. Brody
Figure 5. Figure 5.

Quantity of diffusing substance entering (Qin), diffusing through (Qout), and being sorbed (Qm) by a simple membrane. Curves are based on Equations .

Figure 6. Figure 6.

Fick's law plot for aqueous butanol penetrating epidermis.

From Scheuplein & Blank
Figure 7. Figure 7.

Permeability data for aqueous alcohol solutions through epidermis. These curves are plotted together to illustrate the validity of the steady‐state permeability relation, Equation . Logarithmic plots are used in order to include in a single curve the wide range of data. The exponents are the same for figures and in order to facilitate comparison.

From Scheuplein & Blank
Figure 8. Figure 8.

Permeability data for the pure liquid alcohols through epidermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank
Figure 9. Figure 9.

Permeability data for aqueous alcohol solutions through dermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank
Figure 10. Figure 10.

Permeability data for the pure liquid alcohols through dermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank
Figure 11. Figure 11.

Effect of solvent (vehicle) on permeability constant of the alcohols.

From Scheuplein & Blank
Figure 12. Figure 12.

Free‐energy diagrams for polar (water‐soluble) and nonpolar (lipid‐soluble) molecules diffusing through stratum corneum. Maxima and minima are scaled according to measured values.

From Blank & Scheuplein
Figure 13. Figure 13.

Comparison of diffusional resistance of dermis and epidermis for aqueous solutions of alcohols. These resistances were added according to Equation to obtain the total diffusional resistance for the whole skin. R, the diffusional resistance is the reciprocal of the permeability constant.

From Scheuplein & Blank
Figure 14. Figure 14.

Approach to steady‐state flow for a membrane with the indicated diffusion constants. (D). Detail near origin (magnified in inset) shows the initial predominance of shunt diffusion.

Figure 15. Figure 15.

The ordinate R = log Qs/QB is the ratio of the shunt to bulk diffusion currents as a function of time. The line R = 0 corresponds to equal currents; the curve above the line corresponds to excess shunt diffusion (Ds), the curves below the line to excess bulk diffusion (DB).

From Scheuplein
Figure 16. Figure 16.

Steady‐state and transient concentration levels in the epidermis. The dotted line at 110 μm corresponds to the location of the basal layer of the epidermis; the solid line at 200 μm corresponds to the location of the edge of the papillary plexus. A semi‐infinite approximation was used to obtain the values for the transient cases.

From Scheuplein
Figure 17. Figure 17.

Steady‐state concentration profiles for finite, composite skin diffusion barrier. The first number is the diffusion constant in the stratum corneum (δ = 10 μm); the second number is the diffusion constant in the epidermis (δ = 200 μm). The various K values are partition coefficients for the stratum corneum.

From Scheuplein
Figure 18. Figure 18.

Approximate transient concentration levels at the site of each type of diffusion shunt at different times (t) after the application of a solution at t = 0. The dotted boundaries represent a concentration level of 10−7 Co, the blackened areas a level of 10−3 Co. (Co is the applied concentration at the surface.) The value of 10−7 corresponds to approximately 10−8 molar when a 1% solution is applied to the skin.

From Scheuplein
Figure 19. Figure 19.

Effect of solvents on permeability. Curve shows the increased water permeability of isolated epidermis during treatment with the pure solvents. The low concentration side of the diffusion cell was filled with the solvent, and the tissue was continuously bathed from one side during the experiment.

Figure 20. Figure 20.

Arrhenius curves for the self‐diffusion of water, water diffusion through stratum corneum (lowest curve), and water diffusion through delipidized stratum corneum (middle curve).

From Scheuplein & Blank


Figure 1.

Top: stained cross section of human skin. Stratum corneum has porous appearance typical of histological preparations. Bottom: electron photomicrograph of top part of epidermis showing 10 cell layers of stratum corneum.

From Scheuplein & Blank


Figure 2.

Schematic of human skin. Dimensions and distances pertain to abdominal skin. The essential elements of the composite skin diffusion barrier are indicated.

From Scheuplein & Blank


Figure 3.

Cellular structure of the stratum corneum. A: a fragment of stratum corneum one cell layer thick (phase contrast). Dark bands bordering cells are regions of cell overlap. B: scanning electron photomicrograph of external surface of stratum corneum (washed with carbon tetrachloride prior to gold‐palladium coating.) C: electron photomicrograph of filled intercellular regions in stratum corneum. Adjacent cell boundaries are highly convoluted and interdigitated. D: cross section of stratum corneum showing surprisingly regular vertical stacking of cells. Tissue was swollen in water (pH = 12) and stained with methylene blue.

From Scheuplein & Blank . From Scheuplein & Blank . Courtesy of A. M. Kligman. Courtesy of A. M. Kligman


Figure 4.

Top: idealized representation of intracellular keratin in stratum corneum. Bottom: electron micrograph of intracellular keratin.

Courtesy of I. Brody


Figure 5.

Quantity of diffusing substance entering (Qin), diffusing through (Qout), and being sorbed (Qm) by a simple membrane. Curves are based on Equations .



Figure 6.

Fick's law plot for aqueous butanol penetrating epidermis.

From Scheuplein & Blank


Figure 7.

Permeability data for aqueous alcohol solutions through epidermis. These curves are plotted together to illustrate the validity of the steady‐state permeability relation, Equation . Logarithmic plots are used in order to include in a single curve the wide range of data. The exponents are the same for figures and in order to facilitate comparison.

From Scheuplein & Blank


Figure 8.

Permeability data for the pure liquid alcohols through epidermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank


Figure 9.

Permeability data for aqueous alcohol solutions through dermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank


Figure 10.

Permeability data for the pure liquid alcohols through dermis as derived from Fick's law, Equation . See legend for Figure .

From Scheuplein & Blank


Figure 11.

Effect of solvent (vehicle) on permeability constant of the alcohols.

From Scheuplein & Blank


Figure 12.

Free‐energy diagrams for polar (water‐soluble) and nonpolar (lipid‐soluble) molecules diffusing through stratum corneum. Maxima and minima are scaled according to measured values.

From Blank & Scheuplein


Figure 13.

Comparison of diffusional resistance of dermis and epidermis for aqueous solutions of alcohols. These resistances were added according to Equation to obtain the total diffusional resistance for the whole skin. R, the diffusional resistance is the reciprocal of the permeability constant.

From Scheuplein & Blank


Figure 14.

Approach to steady‐state flow for a membrane with the indicated diffusion constants. (D). Detail near origin (magnified in inset) shows the initial predominance of shunt diffusion.



Figure 15.

The ordinate R = log Qs/QB is the ratio of the shunt to bulk diffusion currents as a function of time. The line R = 0 corresponds to equal currents; the curve above the line corresponds to excess shunt diffusion (Ds), the curves below the line to excess bulk diffusion (DB).

From Scheuplein


Figure 16.

Steady‐state and transient concentration levels in the epidermis. The dotted line at 110 μm corresponds to the location of the basal layer of the epidermis; the solid line at 200 μm corresponds to the location of the edge of the papillary plexus. A semi‐infinite approximation was used to obtain the values for the transient cases.

From Scheuplein


Figure 17.

Steady‐state concentration profiles for finite, composite skin diffusion barrier. The first number is the diffusion constant in the stratum corneum (δ = 10 μm); the second number is the diffusion constant in the epidermis (δ = 200 μm). The various K values are partition coefficients for the stratum corneum.

From Scheuplein


Figure 18.

Approximate transient concentration levels at the site of each type of diffusion shunt at different times (t) after the application of a solution at t = 0. The dotted boundaries represent a concentration level of 10−7 Co, the blackened areas a level of 10−3 Co. (Co is the applied concentration at the surface.) The value of 10−7 corresponds to approximately 10−8 molar when a 1% solution is applied to the skin.

From Scheuplein


Figure 19.

Effect of solvents on permeability. Curve shows the increased water permeability of isolated epidermis during treatment with the pure solvents. The low concentration side of the diffusion cell was filled with the solvent, and the tissue was continuously bathed from one side during the experiment.



Figure 20.

Arrhenius curves for the self‐diffusion of water, water diffusion through stratum corneum (lowest curve), and water diffusion through delipidized stratum corneum (middle curve).

From Scheuplein & Blank
References
 1. Abramson, H. A., and M. H. Gorin. Skin reactions. IX. The electrophoretic demonstration of the patent pores of living human skin; its relation to the change on skin. J. Phys. Chem. 44: 1094–1102, 1940.
 2. Adamczyk, B., A. J. H. Boerboom, and J. Kistemaker. A mass spectrometer for continuous analysis of gaseous compounds excreted by human skin. J. Appl. Physiol. 21: 1903–1906, 1966.
 3. Adamczyk, B., A. J. H. Boerboom, and J. Kistemaker. Mass spectrometric study of the dynamics of gas transport through human skin to the lungs. J. Appl. Physiol. 34: 718–721, 1973.
 4. Ainsworth, M. J. Methods for measuring percutaneous absorption. J. Soc. Cosmetic Chemists. 11: 69–78, 1960.
 5. Allenby, A. C., N. H. Creasey, J. A. G. Edginton, J. A. Fletcher, and C. Schock. Mechanism of action of accelerants on skin penetration. Brit. J. Dermatol. 81, Suppl. 4: 47–55, 1969.
 6. Allenby, A. C., J. Fletcher, C. Schock, and T. F. S. Tees. The effect of heat, pH and organic solvents on the electrical impedance and permeability of excised human skin. Brit. J. Dermatol. 81, Suppl. 4: 31–39, 1969.
 7. Arndt, K. A. Cutting fluids and the skin. Cutis. 5: 167–170, 1969.
 8. Baden, H., and L. C. Bonar. The α‐fibrous proteins of epidermis. J. Invest. Dermatol. 51: 478–483, 1968.
 9. Baden, H. P., L. Bonar, and E. Katz. Fibrous proteins of the epidermis. J. Invest. Dermatol. 51: 301–107, 1968.
 10. Baker, H. The effects of dimethylsulfoxide, dimethylformamide and dimethyl acetamide on the cutaneous barrier to water in human skin. J. Invest. Dermatol. 50: 283–288, 1968.
 11. Baker, B. S., R. B. Fountain, J. W. Hadgraft, and I. Sarkany. Comparison of some physical properties of four vehicles used in dermatological preparations. Brit. J. Dermatol. 81: 60–64, 1969.
 12. Baker, H., and A. M. Kligman. Measurement of transepidermal water loss by electrical hygrometry. Arch. Dermatol. 96: 441–452, 1967.
 13. Barnes, G. T., and V. K. LaMer. The evaporation resistances of monolayers of long‐chain acids and alcohols and their mixtures. In: Retardation of Evaporation by Monolayers: Transport Processes, edited by V. K. LaMer. New York: Academic, 1962, p. 9–33.
 14. Batchelor, G. S., and K. C. Walker. Health hazards involved in use of parathion in fruit orchards of north central Washington. Arch. Ind. Hyg. Occup. Med. 10: 522–529, 1954.
 15. Behnke, A. R., and T. L. Willman. Cutaneous diffusion of helium in relation to peripheral blood flow and the absorption of atmospheric nitrogen through the skin. Am. J. Physiol. 131: 627–632, 1941.
 16. Berendsen, H. J. C. Water structure in biological systems. Federation Proc. 25: 971–976, 1966.
 17. Berenson, G. S., and G. E. Burch. Studies of diffusion through dead human skin. Am. J. Trop. Med. Hyg. 31: 842–853, 1951.
 18. Bettley, F. R. Influence of soap on the permeability of the epidermis. Brit. J. Dermatol. 73: 448–454, 1961.
 19. Bettley, F. R. Irritant effect of soap in relation to epidermal permeability. Brit. J. Dermatol. 75: 113–116, 1963.
 20. Bettley, F. R., and E. Donoghue. Effect of soap in the diffusion of water through isolated human epidermis. Nature 185: 17–20, 1960.
 21. Bird, R. B., W. E. Stewart, and E. W. Lightfoot. Transport Phenomena. New York: Wiley, 1960, p. 283–286.
 22. Blank, H., E. W. Rosenber, and D. Taplin. An electrical device for measuring sweating and cutaneous water loss. In: Advances in the Biology of Skin, edited by W. Montagna, R. B. Ellis and A. F. Silver. New York: Pergamon, 1962, vol. 3, p. 97–107.
 23. Blank, I. H. Factors which influence the water content of the stratum corneum. J. Invest. Dermatol. 18: 433–440, 1952.
 24. Blank, I. H. Further observations on factors which influence the water content of the stratum corneum. J. Invest. Dermatol. 21: 259–269, 1953.
 25. Blank, I. H. Penetration of low‐molecular‐weight alcohols into skin. I. The effects of concentration of alcohol and type of vehicle. J. Invest. Dermatol. 43: 415–420, 1964.
 26. Blank, I. H., R. J. Scheuplein, and D. J. MacFarlane. Mechanism of percutaneous absorption. III. The effect of temperature on the transport of non‐electrolytes across the skin. J. Invest. Dermatol. 49: 582–589, 1967.
 27. Blank, I. H., and R. J. Scheuplein. Transport into and within the skin. Brit. J. Dermatol. 81, Suppl. 4: 4–10, 1969.
 28. Blank, I. H., and E. B. Shapiro. The water content of the stratum corneum. III. Effect of previous contact with aqueous solutions of soaps and detergents. J. Invest. Dermatol. 25: 391–398, 1955.
 29. Brody, I. The ultrastructure of the tonofibrils in the keratinization process of normal human epidermis. J. Ultrastruct. Res. 4: 264–297, 1960.
 30. Brody, I. Observations on the fine structure of the horny layer in the normal human epidermis. J. Invest. Dermatol. 42: 27–31, 1964.
 31. Brody, I. Intercellular space in normal human stratum corneum. Nature 209: 472–476, 1966.
 32. Brown, E., and W. Scott. The absorption of methyl salicylate by the human skin. J. Pharmacol. Exptl. Therap. 50: 32–50, 1934.
 33. Brown, V. K. H. Solubility and solvent effects as rate determining factors in the acute percutaneous toxicities of pesticides. Soc. Chem. Ind. London, Monograph 29: 93–105, 1968.
 34. Buettner, K. J. K. Diffusion of water vapour through small areas of human skin in a normal environment. J. Appl. Physiol. 14: 269–275, 1959.
 35. Burch, G. E., and T. Winsor. Diffusion of water through dead plantar, palmar and dorsal human skin and through toe nails. Arch. Dermatol. 53: 39–41, 1944.
 36. Burch, E. E., and T. Winsor. Rate of insensible perspiration locally through living and dead human skin. Arch. Internal Med. 74: 437–444, 1946.
 37. Cahn, M. M., and E. J. Levy. Ultraviolet light factor in Chloropromazine dermatitis. Arch. Dermatol. 75: 38–40, 1957.
 38. Christophers, E., and A. M. Kligman. Visualization of the cell layers of the stratum corneum. J. Invest. Dermatol. 42: 407–409, 1964.
 39. Clendenning, W. E., and R. B. Stroughton. Importance of the aqueous/lipid partition coefficient for percutaneous absorption of weak electrolytes. J. Invest. Dermatol. 39: 47–49, 1962.
 40. Conning, D. M., and M. J. Hayes. Dermal toxicity of phenol; an investigation of the most effective first‐aid measures. Brit. J. Ind. Med. 27: 155–159, 1970.
 41. Crank, J. The Mathematics of Diffusion. London: Oxford Univ. Press, 1957, p. 42–45.
 42. Cronin, E., and R. B. Stroughton. Percutaneous absorption. Regional variations and the effect of hydration and epidermal stripping. Brit. J. Dermatol. 74: 265–272, 1962.
 43. Cronin, E., and R. B. Stroughton. Nicotinic acid and ethyl nicotinate in excised human skin. Arch. Dermatol. 87: 445–449, 1963.
 44. Crow, K. D., E. Alexander, W. H. L. Buck, B. E. Johnson, I. A. Magnus, and A. D. Porter. Photosensitivity due to pitch. Brit. J. Dermatol. 73: 220–232, 1961.
 45. Davies, J. T., and E. K. Rideal. Interfacial Phenomena. New York: Academic, 1963, p. 154–156.
 46. DeLong, C. W., R. C. Thompson, and H. A. Kornberg. Percutaneous absorption of tritium oxide. Am. J. Roentgenol. Radium Therapy, Nucl. Med. 71: 1038–1045, 1954.
 47. Dirnhuber, P., and R. T. Tregear. Equilibration between water vapour and human skin. J. Physiol., London 152: 58–59P, 1960.
 48. Dorn, H. Clinical eczema due to dyes and auxiliary products used in the textile industry. Arch. Klin. Exptl. Dermatol. 211: 291–295, 1960.
 49. Dugard, P. H., and R. J. Scheuplein. Effect of ionic surfactants on the permeability of human epidermis: an electrometric study. J. Invest. Dermatol. 60: 263–269, 1973.
 50. Durham, W. F., H. R. Wolfe, and J. W. Elliot. Adsorption and excretion of parathion by spraymen. Arch. Environ. Health 24: 381–387, 1972.
 51. Duriau, F. Recherches expérimentales sur l'absorption et l'exhalation par le tegument externe. Arch. Gen. Med. T. 7: 161–173, 1856.
 52. Dutkiewicz, T., and J. Piotrowski. Determination of the degree of absorption of certain aromatic compounds by workers. Prom. Toksikol i Klinika Prof. Zabolevanii. Khim. Etiol. (Moscow; Gos. Izd. Med. Lit.) 5: 39–49, 1962.
 53. Elfbaum, S. G., and K. Laden. The effect of dimethyl sulfoxide on percutaneous absorption: a mechanistic study, Part I. J. Soc. Cosmetic Chemists 19: 841–847, 1968.
 54. Feldman, R. J., and H. I. Maibach. Penetration of 14C hydrocortisone through normal skin. Arch. Dermatol. 91: 661–666, 1965.
 55. Feldman, R. J., and H. I. Maibach. Percutaneous penetration of 14C hydrocortisone in man. Arch. Dermatol. 94: 649–651, 1966.
 56. Feldman, R. J., and H. I. Maibach. Regional variation in percutaneous penetration of 14C cortisol in man. J. Invest. Dermatol. 48: 181–183, 1967.
 57. Filskie, B. K., and G. E. Rogers. The fine structure of α keratin. J. Mol. Biol. 3: 784–786, 1961.
 58. Fisher, A. A. Contact Dermatitis (2nd. ed). Philadelphia: Lea & Febiger, 1973, p. 448.
 59. Franz, T. J. On percutaneous absorption: on the relevance of in vitro data. J. Invest. Dermatol. 64: 190–195, 1975.
 60. Fredriksson, T. Studies on the percutaneous absorption of sarin and two allied organophosphoreus cholinesterase inhibitors. Acta Dermato‐Venereol. Suppl. 41: 1–81, 1958.
 61. Fredricksson, T. Studies on the percutaneous absorption of parathion and paraoxon. V. Rate of absorption of parathion. J. Invest. Dermatol. 28: 233–236, 1962.
 62. Fredriksson, T. The rate of percutaneous absorption of parathion. Acta Dermato‐Venereol. 41: 353–362, 1962.
 63. Fredriksson, T. Influence of solvents and surface active agents on the barrier function of the skin towards sarin. I. Development of method. Acta Dermato‐Venereol. 43: 91–101, 1963.
 64. Fredriksson, T. Influence of solvents and surface active agents on the barrier function of the skin towards sarin. III. Restoration of the barrier function. Acta Dermato‐Venereol. 49: 481–483, 1969.
 65. Fritsch, W. C., and R. B. Stoughton. The effect of temperature and humidity on the penetration of C14 acetylsalicylic acid in excised human skin. J. Invest. Dermatol. 41: 307–312, 1963.
 66. Garby, L., and H. Linderholm. The permeability of frog skin to heavy water and to ions, with special reference to the effect of some diuretics. Acta Physiol. Scand. 28: 336–346, 1953.
 67. Glasstone, G., K. J. Laidler, and H. Eyring. The Theory of Rate Processes. New York: McGraw‐Hill, 1941, p. 529.
 68. von Gotte, E. K. Der einfluss von killoidekeltrolyten auf die Quellung isolierter Epidermis. Kolloid Z. 117: 43–47, 1950.
 69. Halprin, K. M., and A. Ohkawara. Glucose entry into the human epidermis. II. The penetration of glucose into the human epidermis in vitro. J. Invest. Dermatol. 49: 561–568, 1967.
 70. Harris, E. J. Factors governing the distribution and movement of water. In: Transport and Accumulation in Biological Systems. London: Butterworths, 1960, p. 39.
 71. Harrold, S. P. Denaturation of epidermal keratin by surface active agents. J. Invest. Dermatol. 32: 581–588, 1959.
 72. Hertzmann, A. B. Some relations between skin temperature and blood flow. Am. J. Phys. Med. 32: 233–251, 1953.
 73. Hertzmann, A. B. Effects of heat on the cutaneous blood flow. In: Advances in Biology of the Skin, edited by W. Montagna and R. A. Ellis. New York: Pergamon, 1961, vol. 2, p. 98–116.
 74. Higuchi, T. Physical chemical analysis of percutaneous absorption process from creams and ointments. J. Soc. Cosmetic Chemists 11: 85–97, 1960.
 75. Higuchi, W. I. Diffusion in ointment bases. Proc. Am. Assoc. Coll. Pharm. Teachers' Seminar 13: 162–173, 1961.
 76. Hodge, H. C., and J. H. Steiner. The skin absorption of triorthocresyl phosphate. J. Pharmacol. Exptl. Therap. 79: 225–234, 1943.
 77. Holmes, A. W. Diffusion processes in human hair. J. Soc. Cosmetic Chemists 15: 595–608, 1964.
 78. Homalle, A. Experiences physiologiques sur l'absorption par le tegument externe chez l'homme dans le bain. Union Med. 7: 462–463, 1953.
 79. Jellson, O. F., and W. L. Curwne. Phototoxicity, photoallergy and photoskin tests. Arch. Dermatol. 80: 678, 1959.
 80. Katz, M., and B. J. Poulsen. Adsorption of drugs through the skin. Handbook of Experimental Pharmacology (1st ed.) New Series, vol. 28/1 edited by B. B. Brodie and J. Gillette. Berlin: Springer‐Verlag, 1971, p. 174.
 81. Kedem, O., and A. Katchaisky. A physical interpretation of the phenomenological coefficients of membrane permeability. J. Gen. Physiol. 45: 143–179, 1961.
 82. Kellum, R. E. Short chain fatty acids (below C12) of human skin surface lipids. J. Invest. Dermatol. 48: 364–371, 1961.
 83. Kligman, A. M. The biology of the stratum corneum. In: The Epidermis, edited by W. Montagna and W. C. Lobitz. New York: Academic, 1964, p. 387–433.
 84. Kligman, A. M. Topical pharmacology and toxicology and dimethyl sulfoxide. Part I. J. Am. Med. Assoc. 193: 796–804, 1965.
 85. Kligman, A. M., and E. Christophers. Preparation of isolated sheets of human stratum corneum. Arch. Dermatol. 88: 702–705, 1963.
 86. Kloche, R. A., G. H. Gurtner, and L. E. Farhe. Gas transfer across skin in man. J. Appl. Physiol. 18: 311–316, 1963.
 87. Kolpakov, F. I. Skin permeability to nickel compounds. Arkh. Patol. 25: 38–45, 1963.
 88. Koizumi, T., and W. I. Higuchi. Analysis of data on drug release from emulsions. Part II. J. Pharm. Sci. 57: 87–92, 1968.
 89. von Kooten, W. J., and J. W. H. Mali. The significance of sweat ducts in permeation experiments on isolated cadaverous human skin. Dermatologica 132: 141–151, 1966.
 90. Kuno, Y. Human Perspiration. Springfield, III.: Thomas, 1956, p. 416.
 91. Laidler, K. J., and K. E. Shuler. The kinetics of membrane processes. I. The mechanism and the kinetic laws for diffusion through membranes. J. Chem. Phys. 17: 851–855, 1948.
 92. Lobitz, W. C., and F. Daniels, Jr. Skin. Ann. Rev. Physiol. 23: 207–228, 1961.
 93. Longsworth, L. G. Temperature dependence of diffusion in aqueous solutions. J. Phys. Chem. 58: 770–773, 1954.
 94. Lundgren, H. P., and W. H. Ward. The keratins. In: Ultra‐structure of Protein Fibers, edited by B. Borasky. New York: Academic, 1963, p. 39–122.
 95. MacGregor, W. S. The chemical and physical properties of DMSO. Ann. N.Y Acad. Sci. 141: 3–12, 1967.
 96. Mackee, G. M., M. B. Sulzberger, F. Herrmann, and R. L. Baer. Histologic studies on percutaneous penetration with special reference to the effect of vehicles. J. Invest. Dermatol. 6: 43–61, 1945.
 97. Maibach, H. I., R. H. Feldmann, and T. H. Milby. Regional variation in percutaneous penetration in man. Arch. Environ. Health. 23: 208–211, 1971.
 98. Malaskiewicz, J. G. Effects of surfactants on human skin evaluated by a micromethod. Arch. Klin. Exptl. Dermatol. 237: 652–661, 1970.
 99. Mali, J. W. H. The transport of water through the human epidermis. J. Invest. Dermatol. 27: 451–469, 1956.
 100. Malkinson, F. D. Permeability of the stratum corneum. In: The Epidermis, edited by W. Montagna and W. C. Lobitz. New York: Academic, 1964, p. 435–452.
 101. Malkinson, F. D., and S. Rothman. Percutaneous absorption. In: Handbuch der Haut‐und Geschelecht‐skrakherten, normale und patholgische Physiologie der Haut, edited by J. Jadassohn. Berlin: Springer, 1963, vol. 1, part 3, p. 90–156.
 102. Malten, K. E., D. Spruit, H. G. M. Bolmaars, and M. J. M. de Keizer. Horny layer injury by solvents. Berufdermatosen 16: 135–147, 1968.
 103. Mandelbaum, J., and L. Schessinger. Vitamin A — absorption of through human skin. Arch. Dermatol. 46: 431–442, 1942.
 104. Marzulli, F. N. Barrier to skin penetration. J. Invest. Dermatol. 39: 387–393, 1963.
 105. Matoltsy, A. G., and C. A. Balsamo. A study of the components of the cornified epithelium of human skin. J. Biophys. Biochem. Cytol. 1: 339–360, 1955.
 106. Matoltsy, A. G., M. Matoltsy, and A. Schrogger. Observations on the regenerating skin barrier. J. Invest. Dermatol. 38: 251–253, 1962.
 107. Matoltsy, A. G., and P. F. Parakkal. Membrane‐coating granules of keratinizing epithelia. J. Cell. Biol. 24: 297–307, 1965.
 108. McKenzie, A. W. Percutaneous absorption of steroids. Arch. Dermatol. 86: 611–614, 1962.
 109. McKenzie, A. W., and R. B. Stroughton. Method for comparing percutaneous absorption of steroids. Arch. Dermatol. 86: 608–610, 1962.
 110. Michelfelder, T. T., and S. M. Peck. Absorption of pyrebenzamine through intact and damaged skin. J. Invest. Dermatol. 19: 237–247, 1952.
 111. Middleton, J. D. The mechanism of water binding in stratum corneum. Brit. J. Dermatol. 80: 437–450, 1968.
 112. Monash, S. Location of the superficial barrier to skin penetration. J. Invest. Dermatol. 29: 367–376, 1957.
 113. Monash, S., and H. Balnk. Location and reformation of the epithelial barrier to water vapor. Arch. Dermatol. 78: 710–714, 1958.
 114. Montagna, W. The Structure and Function of Skin (2nd ed.). New York: Academic, 1961, p. 454.
 115. Montes, L. F., J. L. Day, C. J. Wand, and L. Kennedy. Ultrastructural changes in the horny layer following local application of dimethyl sulfoxide. J. Invest. Dermatol. 48: 184–196, 1967.
 116. Morelli, J. V. Cutaneous penetration of dimethyl sulfoxide (DMSO). Arch. Biochem. Cosmetol. 11: 18–20, 1968.
 117. Moyer, C. A., J. S. Dillon, and H. R. Butcher. Function of human skin in relation to its macromolecular structure. Arch. Surg. 92: 222–242, 1966.
 118. Munro, D. D., and R. B. Stoughton. Dimethylacetamide (DMA) and dimethylformanide (DMFA) effect on percutaneous absorption. Arch. Dermatol. 92, 585–586, 1965.
 119. Nemec, S. J., P. L. Adskisson, and H. W. Dorough. Methylparathion adsorbed on the skin and blood cholinesterase levels of persons checking cotton, treated with ultra‐low volume sprays. J. Econ. Entomol. 61: 1740–1742, 1968.
 120. Newell, R. G. D. Photosensitivity caused by promethazene. Brit. Med. J. 2: 359, 1960.
 121. Odland, G. F. The fine structure of the interrelationship of cells in the human epidermis. J. Biophys. Biochem. Cytol. 4: 529–538, 1958.
 122. Onken, H. D., and C. A. Moyer. The water barrier in human epidermis. Physical and chemical nature. Arch. Dermatol. 87: 584–590, 1963.
 123. Oppenheim, M. Beitrage zin Frage der Hautabsorption mit besonderer berucksichtigung de erkrankten Haut. Arch. f. Dermat. Syph. 93: 85–106, 1908.
 124. Parmely, T. H., and A. E. Seeds. Fetal skin permeability to isotopic water (THO) in early pregnancy. Am. J. Obstet. Gynecol. 108: 128–131, 1970.
 125. Peiss, C. N., A. B. Hertzmann, W. C. Randall, and H. E. Ederstrom. Regional rates of cutaneous insensible perspiration. Federation Proc. 10: 103–104, 1951.
 126. Perl, W. An extension of the diffusion equation to include clearance by capillary blood flow. Ann. NY Acad. Sci. 108: 92–105, 1963.
 127. Perl, W., H. Rackow, E. Salanitre, G. L. Wolf, and R. M. Epstein. Intertissue diffusion effect for inert fat‐soluble gases. J. Appl. Physiol. 20: 621–627, 1965.
 128. Petrun, M. M. Percutaneous respiration in children of various ages. Sechenov Physiol J. USSR (English Transl.) 47 (8): 1–3, 1961.
 129. Pinson, E. A. Evaporation from human skin with sweat glands inactivated. Am. J. Physiol. 137: 492–503, 1942.
 130. Plewig, G., and R. R. Marples. Regional differences of cell sizes in the human stratum corneum. Part I. J. Invest. Dermatol. 54: 13–18, 1970.
 131. Possick, P. A. Cement dermatitis. Cutis 5: 167–170, 1969.
 132. Rosenberg, E. W., H. Blank, and S. Resnik. Sweating and water loss through skin. J. Am. Med. Assoc. 179: 809–811, 1962.
 133. Rosendal, T. Concluding studies on the conducting properties of human skin to A. A. Acta Physiol. Scand. 9: 39–49, 1945.
 134. Rothman, S. Physiology and Biochemistry of the Skin. Chicago: University Press, 1954, p. 26–59.
 135. Rushmer, R. F., K. J. K. Buettner, J. M. Short, and G. F. Odland. The skin. Science 154: 343–348, 1966.
 136. Samitz, M. H., S. Katz, and J. D. Shrager. Studies of diffusion of chromium compounds through skin. J. Invest. Dermatol. 48: 514–520, 1967.
 137. Scala, J., D. E. McOsker, and H. H. Reller. The percutaneous absorption of ionic surfactants. J. Invest. Dermatol. 50: 371–379, 1968.
 138. Scheuplein, R. J. Mechanism of percutaneous absorption. I. Routes of penetration and the influence of solubility. J. Invest. Dermatol. 45: 334–346, 1965.
 139. Scheuplein, R. J. Analysis of permeability data for the case of parallel diffusion pathways. Biophys. J. 6: 1–17, 1966.
 140. Scheuplein, R. J. Mechanism of percutaneous absorption. II. Transient diffusion and the relative importance of various routes of skin penetration. J. Invest. Dermatol. 48: 79–88, 1967.
 141. Scheuplein, R. J. On the application of rate theory to complex multibarrier flow co‐ordinates: membrane permeability. J. Theoret. Biol. 18: 72–89, 1968.
 142. Scheuplein, R. J. The Permeability of the Skin to Gases. US Army Res. Office, Life Sci. Div. Ann. Rept. 1, 1970, p. 32.
 143. Scheuplein, R. J., and I. H. Blank. Permeability of the Skin. Physiol. Rev. 51: 702–747, 1971.
 144. Scheuplein, R. J., and I. H. Blank. Mechanism of percutaneous absorption. IV. Penetration of non‐electrolytes (alcohols) from aqueous solutions and from pure liquids. J. Invest. Dermatol. 60: 286–296, 1973.
 145. Scheuplein, R. J., I. H. Blank, G. J. Brauner, and D. J. MacFarlane. Percutaneous absorption of steroids. J. Invest. Dermatol. 52: 63–70, 1969.
 146. Scheuplein, R. J., and L. J. Morgan. “Bound‐water” in keratin membranes measured by a microbalance technique. Nature 214: 456–458, 1967.
 147. Scheuplein, R. J., and L. Ross. Effects of surfactants and solvents on the permeability of epidermis. J. Soc. Cosmetic Chemists 21: 853–873, 1970.
 148. Scheuplein, R. J., and L. Ross. Mechanism of percutaneous absorption. V. Percutaneous Absorption of Solvent Deposited Solids. J. Invest. Dermatol. 62: 353–360, 1974.
 149. Serjsen, P. Epidermal diffusion barrier to 133Xe in man and studies of clearance of 133Xe by sweat. J. Appl. Physiol. 24: 211–216, 1968.
 150. Sekura, D. L., and J. Scala. The percutaneous absorption of alkyl methyl sulfoxides. In: Advances in Biology of Skin. 1972, vol. 12, p. 257–269.
 151. Shelley, W. B., and F. M. Melton. Factors accelerating the penetration of histamine through normal intact human skin. J. Invest. Dermatol. 13: 61–71, 1949.
 152. Shelley, W. B., and P. N. Horvath. Comparative study on the effect of anticholinergic compounds on sweating. J. Invest. Dermatol. 16: 267–274, 1951.
 153. Shugaev, B. B. Comparative toxicity of a series of higher mercaptans. Khim. Seraog. Soedin, Soderzh. Neftyakh Nefteprod [in Russian]. 8: 681–686, 1968.
 154. Smith, H. W., H. A. Clawes, and E. K. Marshall. Mustard gas. IV. The mechanism of absorption by the skin. J. Pharmacol. 13: 1–30, 1919.
 155. Smith, J. G. Jr., R. W. Fischer, and H. Blank. The epidermal barrier: a comparison between scrotal and abdominal skin. J. Invest. Dermatol. 36: 337–341, 1961.
 156. Sodemann, W. A., and G.E. Burch. Regional variations in water loss from skin of diseased subjects living in a subtropical climate. J. Clin. Invest. 23: 37–43, 1944.
 157. Sprott, W. E. Surfactants and percutaneous absorption. Trans. St. John's Hosp. Dermatol. Soc. 51: 56–71, 1965.
 158. Spruit, D., and K. E. Malten. Epidermal water‐barrier formation after stripping of normal skin. J. Invest. Dermatol. 45: 6–14, 1965.
 159. Spruit, D., and K. E. Malten. Estimation of the injury of human skin by alkaline liquids. Berufsdermatosen 16: 11–24, 1968.
 160. Stan, J. H. G., and N. J. Clifford. Absorption of pesticides in a chronic skin disease. Arch. Environ. Health 22: 396–400, 1971.
 161. Steffee, C. H., and A. Baetjer. Histopathologic effects of chromate chemicals. Arch. Environ. Health 11: 66–75, 1965.
 162. Stoughton, R. B. Vasoconstrictor activity and percutaneous absorption of glucocorticosteroids. Arch. Dermatol. 99: 753–756, 1969.
 163. Stoughton, R. B., and W. E. Clendenning. Percutaneous absorption of nicotinic acid and derivatives. J. Invest. Dermatol. 35: 337–341, 1960.
 164. Stoughton, R. B., F. W. Chiu, and D. Nurse. Topical suppression of eccrine sweat delivery with a new anticholinergic agent. J. Invest. Dermatol. 42: 151–155, 1964.
 165. Stoughton, R. B., and W. Fritsch. Influence of dimethyl sulfoxide on human percutaneous absorption. Arch. Dermatol. 90: 512–517, 1964.
 166. Sulzberger, M. D. Dermatitis eczematoza (contact type) due to nickel. Arch. Dermatol. 41: 815, 1940.
 167. Szabo, G. The number of eccrine sweat glands in human skin. In: Advances in Biology of the Skin, edited by W. Montagna, A. R. Ellis, and A. F. Silver. New York: Pergamon, 1962, vol. 3, p. 1–5.
 168. Thompson, T. E. Properties of bimolecular phospholipid membranes. In: Cellular Membranes in Development, edited by M. Locke. New York: Academic, 1964, p. 83.
 169. Tregear, R. T. Relative penetrability of hair follicles and epidermis. J. Physiol. London 156: 303–313, 1961.
 170. Tregear, R. T. The permeability of mammalian skin to ions. J. Invest. Dermatol. 46: 16–23, 1966.
 171. Tregear, R. T. Physical Functions of Skin. London: Academic, 1966, p. 1–52.
 172. Treherne, J. E. The permeability of the skin to some non‐electrolytes. J. Physiol., London 133: 171–180, 1956.
 173. Valette, G., R. Cavier, and J. Savel. Percutaneous absorption and chemical constitution: hydrocarbons, alcohols, and esters. Arch. Intern. Pharmacodyn. 97: 232–240, 1954.
 174. Van Caneghen, P. Penetration of drugs into the skin. Louvain Med. 88: 763–768, 1969.
 175. Vickers, S. F. H. Existence of reservoir in the stratum corneum. Arch. Dermatol. 88: 21–23, 1963.
 176. Wahlberg, J. E. Effect of anionic, cationic and non‐ionic detergents on the percutaneous absorption of sodium chromate 51Cr in the guinea pig. Acta Dermato‐Venereol. 48: 549–555, 1968.
 177. Wahlberg, J. E. Percutaneous absorption of radioactive strontium chloride (89SrCl2). A comparison with 11 other metal compounds. Arch. Dermatol. 97: 336–339, 1968.
 178. Wang, J. H. Self‐diffusion and structure of liquid water. I. Measurements of self‐diffusion of liquid water with deuterium as a chaser. J. Am. Chem. Soc. 73: 510–513, 1951.
 179. Wheatley, V. R. The nature, origin and possible functions of the cutaneous lipids. Proc. Sci. Sect. Toilet Goods Assoc. 39: 25–28, 1963.
 180. Wheatley, V. R., P. Flesch, E. C. J. Esoda, W. M. Coon, and R. Mandol. Studies of the chemical composition of the horny layer lipids. J. Invest. Dermatol. 43: 395–405, 1964.
 181. Wilson, R. H., E. H. Planek, and W. E. McCormick. Allergy in the rubber industry. Ind. Med. 28: 209, 1959.
 182. Wolfe, H. R., W. F. Durham, and J. F. Armstrong. Exposure of workers to pesticides. Arch. Environ. Health 14: 622–633, 1967.
 183. Wolfe, H. R., J. F. Armstrong, D. C. Staiff, and S. W. Comer. Exposure of sprayment to pesticides. Arch. Environ. Health 25: 29–31, 1972.
 184. Wurster, D. E., and S. F. Kramer. Some factors influencing percutaneous absorption. J. Pharm. Sci. 50: 288–293, 1961.
 185. Zener, C. Theory of D0 for atomic diffusion in metals. J. Appl. Physiol. 22: 372–375, 1951.
 186. Zwolinski, B. J., H. Eyring, and C. E. Reese. Diffusion and membrane permeability. J. Phys. Colloid Chem. 53: 1426–1453, 1949.

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Robert J. Scheuplein. Permeability of the Skin. Compr Physiol 2011, Supplement 26: Handbook of Physiology, Reactions to Environmental Agents: 299-322. First published in print 1977. doi: 10.1002/cphy.cp090119