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Dermal Route
In contrast to the thin membranes of the respiratory alveoli and the gastrointestinal villi, the skin is a complex, multilayer tissue. For this reason, it is relatively impermeable to most ions as well as aqueous solutions. It thus represents a barrier to most xenobiotics. However, some notable toxicants can gain entry into the body following skin contamination.
For example, certain commonly used organophosphate pesticides have poisoned agricultural workers following dermal exposure. The neurological warfare agent, Sarin, readily passes through the skin and can produce quick death to exposed persons. Several industrial solvents can cause systemic toxicity by penetration through the skin. For example, carbon tetrachloride penetrates the skin and causes liver injury. Hexane can pass through the skin and cause nerve damage.
The skin consists of three main layers of cells as illustrated in the figure:
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|  | epidermis
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| | dermis
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| | subcutaneous tissue
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V. C. Scanlon and T. Sanders, Essentials of
Anatomy and Physiology, 2nd edition. F. A. Davis, 1995. |
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The epidermis (and particularly the stratum corneum) is the only layer that is important in regulating penetration of a skin contaminant. It consists of an outer layer of cells, packed with keratin, known as the stratum corneum layer. The stratum corneum is devoid of blood vessels. The cell walls of the keratinized cells are apparently double in thickness due to the presence of the keratin, which is chemically resistant and an impenetrable material. The blood vessels are usually about 100 µM from the skin surface. To enter a blood vessel, an agent must pass through several layers of cells that are generally resistant to penetration by chemicals.
The thickness of the stratum corneum varies greatly with regions of the body. The stratum corneum of the palms and soles is very thick (400-600 µM) whereas that of the arms, back, legs, and abdomen is much thinner (8-15 µM). The stratum corneum of the axillary (underarm) and inquinal (groin) regions is the thinnest with the scrotum especially thin. As expected, the efficiency of penetration of toxicants is inversely related to the thickness of the epidermis.
Any process that removes or damages the stratum corneum can enhance penetration of a xenobiotic. Abrasion, scratching, or cuts to the skin will make it more penetrable. Some acids, alkalis, and corrosives can injure the stratum corneum and increase penetration to themselves or other agents. The most prevalent skin conditions that enhance dermal absorption are skin burns and dermatitis.
Toxicants move across the stratum corneum by passive diffusion. There are no known active transport mechanisms functioning within the epidermis. Polar and nonpolar toxicants diffuse through the stratum corneum by different mechanisms. Polar compounds (which are water-soluble) appear to diffuse through the outer surface of the hydrated keratinized layer. Nonpolar compounds (which are lipid soluble) dissolve in and diffuse through the lipid material between the keratin filaments.
Water plays an important role in dermal absorption. Normally, the stratum corneum is partially hydrated (~7% by weight). Penetration of polar substances is about 10 times as effective as when the skin is completely dry. Additional hydration can increase penetration by 3-5 times which further increases the ability of a polar compound to penetrate the epidermis.
A solvent sometimes used to promote skin penetration of drugs is dimethyl sulfoxide (DMSO). It facilitates penetration of chemicals by an unknown mechanism. Removal of the lipid material creates holes in the epidermis. This results in a reversible change in protein structure due to substitution of water molecules.
Considerable species differences exist in skin penetration and can influence the selection of species used for safety testing. Penetration of chemicals through the skin of the monkey, pig, and guinea pig is often similar to that of humans. The skin of the rat and rabbit is generally more permeable whereas the skin of the cat is generally less permeable. For practical reasons and to assure adequate safety, the rat and rabbit are normally used for dermal toxicity safety tests.
In addition to the stratum corneum, small amounts of chemicals may be absorbed through the sweat glands, sebaceous glands, and hair follicles. However, since these structures represent only a very small percentage of the total surface area, they are not ordinarily important in dermal absorption.
Once a substance penetrates through the stratum corneum, it enters lower layers of the epidermis, the dermis, and subcutaneous tissue. These layers are far less resistant to further diffusion. They contain a porous, nonselective aqueous diffusion medium, which can be penetrated by simple diffusion. Most toxicants that have passed through the stratum corneum can now readily move on through the remainder of the skin and enter the circulatory system via the large numbers of venous and lymphatic capillaries in the dermis.
 
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