The skin is composed of two layers: the outer epidermis and the underlying dermis. The layers are firmly associated and together form a barrier that ranges in thickness from 0.5 to 4 mm or more in different body parts. The epidermis and dermis are separated by a basement membrane, which has an undulating appearance. The uneven interface gives rise to dermal ridges and provides the basis for the fingerprints used in personal identification since the patterns of ridges are unique for each individual. Hair follicles, sebaceous glands, and eccrine and apocrine (i.e., sweat) glands span the epidermis and are embedded in the dermis. A third subcutaneous layer lies below the dermis and is composed mainly of adipocytes. Even though this layer is not technically part of the skin, it plays an integral role by acting as a heat insulator and shock absorber (Figure 9.1).

The epidermis, composed of several layers of cells, some living and some dead, is composed of keratinocytes. These cells undergo keratinization, a process during which they migrate upward from the lower epidermis (basal layer) and accumulate keratin (80%, once fully mature and nonviable). By the time they reach the outer layer, the stratum corneum, the cells are no longer viable. They flatten and lose their aqueous environment, which is replaced by lipids. The stratum corneum superficial cells are continuously lost and must be replaced by new cells migrating from the lowest layers. The lower layers immediately adjacent to the dermis (stratum germinativum and stratum spinosum) are responsible for the continual supply of new keratinocytes and initiation of keratinization. Migration and differentiation of keratinocytes from the lower viable layers to the upper stratum corneum take approximately 2 weeks, with another 2 weeks elapsing before the keratinocytes are shed from the surface. The lowest two layers of the epidermis also contain melanocytes, which produce the pigment melanin. Melanocytes extrude melanin, which is taken up by the surrounding epidermal cells, giving them their characteristic brown color. Langerhans cells are also found in these layers and play a role in the skin’s immune response to foreign agents.

The dermis has a largely supportive function and represents about 90% of the skin in thickness. The predominant cells are fibroblasts, macrophages, and adipocytes. Fibroblasts secrete collagen and elastin, thereby providing the skin with elastic properties. Dermis is well supplied with lymph and blood capillaries. The capillaries terminate in the dermis without extending into the epidermis. A toxicant must penetrate the epidermis and enter the dermis in order to enter the systemic circulation; however, once the stratum corneum is breached, the remaining layers pose little resistance to toxicant penetration. Hair follicles are embedded within the dermis and have a capillary at the bulb of the follicle. In some instances, hair can enhance toxicant absorption across skin by providing a shunt to the blood supply at the base of the follicle. Eccrine glands are embedded deep within the dermis, and coiled sweat ducts wind upward through the epidermis and out through the stratum corneum.

9.2 FUNCTIONS

The skin is an effective barrier to many substances, but is an imperfect barrier to some. This is an important concept because even though relatively small amounts of chemicals cross the skin, they can be sufficient to cause local and/or systemic toxicity. Chemical passage through the skin appears to be by passive diffusion with no evidence so far of active transport. The stratum corneum is the primary layer governing the rate of diffusion, which is slow for most chemicals. This layer also inhibits water loss by diffusion and evaporation from the body except, of course, at the sweat glands, which helps regulate body temperature. The viable layers of the epidermis and the dermis are poor barriers to toxicants, since hydrophilic agents readily diffuse into the intercellular water and hydrophobic agents can embed in cell membranes, eventually reaching the blood supply in the dermis.

Several factors influence the diffusion rate of chemicals across the stratum corneum. In general, hydrophobic agents of low molecular weight can permeate the skin better than those that are hydrophilic and of high molecular weight. This is due to the low water and high lipid content of the stratum corneum, which allows hydrophobic agents to penetrate more readily. However, if the skin becomes hydrated on prolonged exposure to water, its effectiveness as a barrier to hydrophilic substances is reduced. Often, the skin of experimental lab animals is covered with plastic wrap to enhance the hydration of the skin and increase the rate of uptake of agents applied to the skin surface. For compounds with the same hydrophobicity, the smaller compound will diffuse across the skin fastest because its rate of diffusion is quickest. A good example of the diffusion of a class of toxicants across the skin that can cause systemic toxicity is the organophosphate pesticides (e.g., parathion) used in agriculture. These compounds are hydrophobic, are potent, and lead to systemic effects such as peripheral neuropathy (i.e., nerve damage) and lethality after exposure to only the skin.

The property of diffusion of agents across the skin and the reservoir capacity of the skin can be useful in delivering drugs to the systemic circulation over a prolonged period (typically 1–7 days). Transdermal drug delivery using specially designed skin patches is used to deliver nicotine, estradiol, nitroglycerin, and others. This approach provides a steady dose, avoids large peak plasma concentrations from loading doses, and prevents first-pass metabolism by the liver for agents that are sensitive to metabolism such as nitroglycerin.

The rate of diffusion through the epidermis varies among anatomical sites and is not solely a function of skin thickness. In fact, the skin on the sole or palm has a higher rate of diffusion than the skin of the forearm or abdomen, even though it is much thicker. Therefore, skin thickness is not a useful indicator of how much chemical will reach the systemic circulation in a given time. If the skin is wounded, the barrier to chemicals is compromised and a shorter or direct route to the systemic circulation is available because the skin can no longer repel the chemicals. In addition, diseases (e.g., psoriasis) can compromise the ability of the skin to repel chemicals.

Since World War II, extensive methodology has been developed to quantify the rate and extent of percutaneous penetration—in silico, in vitro, and in vivo—in artificial membranes, animal, and man.

The skin also provides protection against microorganisms and ultraviolet (UV) radiation. Hydrated skin has a greater risk of becoming infected by microorganisms than does dry skin, which is why soldiers in Vietnam often suffered from foot infections. The stratum corneum and epidermis, but primarily melanin pigmentation, provide some protection against UV radiation by absorbing the energy before it reaches more sensitive cells and causes adverse effects such as DNA damage (Table 9.1).

Another important aspect of the skin’s barrier function is its ability to metabolize chemicals that cross the stratum corneum and enter the skin’s viable layers. Even though the metabolic activity of the skin on a body weight basis is less than that of the liver, it plays a crucial role in determining the ultimate effects of some chemicals. The epidermis and pilosebaceous units contain the highest levels of metabolic activity, which includes Phase I (e.g., cytochrome P450–mediated) and Phase II enzymes (e.g., epoxide hydrolase, UDP glucuronosyltransferase, glutathione transferase). Some chemicals that cross the skin are simply degraded and eliminated as innocuous metabolites. For others such as benzo(a)pyrene or crude coal tar (the latter is often used in dermatological therapy), metabolism of the parent compound can produce a metabolite that is a putative carcinogen. In addition to metabolizing foreign agents, the skin also has anabolic and catabolic metabolic activity important to its maintenance.

9.3 TYPES OF DERMAL TOXICITY

Irritant Dermatitis

Irritant contact dermatitis is a common occupational disease. The highest incidence of chronic irritant dermatitis of the hands occurs in food handlers, janitorial workers, construction workers, mechanics, metal workers, horticulturists, and those exposed to wet working environments, such as hairdressers, nurses, and domestic workers. Irritant dermatitis is confined to the area of irritant exposure, and because it is not immunity-related, it can occur in anyone given a sufficient chemical exposure. Previous exposure to the chemical is not required to elicit a response as is needed for allergic contact dermatitis because contact irritant dermatitis is not a hypersensitivity reaction (discussed in Section “Allergic Contact Dermatitis”). A range of responses can occur after exposure to an irritant, including, but not limited to, skin reddening (erythema), vesicles, blistering, eczemas or rashes that weep and ooze, hyperkeratosis (thickening of the skin), pustules, and dryness and roughness. Unlike with corrosive chemicals (e.g., strong acids and bases), the ultimate skin damage from most irritant contact dermatitis is not due to the primary actions of the chemicals but to the secondary inflammatory response elicited by the chemical. Note that even though the ultimate inflammatory response elicited by different chemicals may appear the same, they often occur through different mechanisms.

An array of factors influences the ability of an irritant to elicit an inflammatory response. As noted earlier, factors affecting skin permeability and chemical composition of the irritant determine the rate of percutaneous penetration and how much chemical reaches the viable layers of the skin. Other factors determine whether irritant dermatitis occurs and to what magnitude. Higher concentrations and greater amounts of a given agent contacting the skin surface are more likely to elicit a response than lower concentrations and smaller quantities. The genetic makeup and age of the individual plays a critical role in the irritant sensitivity to a particular agent—the same chemical can cause no response in one individual and a dramatic response in another. However, specific genetic factors influencing sensitivity are unknown. In general, infants appear to be more and the elderly less susceptible to irritants. Concomitant disease may increase or decrease sensitivity to an irritant. Extremes in temperature, humidity, sweating, and occlusion can alter the threshold of irritation for a given compound.

The range of agents that can cause irritant dermatitis is extensive and diverse, and all cannot be covered in this section. Table 9.2 lists some commonly encountered classes. All have the potential of causing irritation on primary exposure; however, in the workplace, exposure to a potential irritant often occurs repeatedly and to relatively low quantities. Since the response is dependent on the amount of irritant to which the individual is exposed, repeated exposure (cumulative irritation) may be required before clinical signs of dermatitis appear. Management of irritant dermatitis is based on reducing or avoiding the amount of irritant exposure. Wearing gloves to provide protection against wetness or chemicals and minimizing wet working conditions and hand washing can be helpful. Complete healing of lesions may take several weeks, and the likelihood of a flare-up is often increased for months. Controlled studies failed to document efficacy of topical corticosteroids and, in fact, they may exacerbate the condition. Tap water compresses are traditionally utilized and were effective in one controlled study.

Agent	Examples
Water	—
Cleansers	Soaps and detergents
Bases	Epoxy resin hardeners, lime, cement, and ammonium
Acids	Hydrochloric acid and citric acid
Organic solvents	Many petroleum-based products
Oxidants	Peroxides, benzoyl peroxide, and cyclohexanone
Reducing agents	Thioglycolates
Plants	Orange peel, asparagus, and cucumbers

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