PRINCIPLES OF TOXICOLOGY - Biology East Borneo

8.2 FUNCTIONS 159corneum is the primary layer governing the rate of diffusion, which is very slow for most chemicals.This layer also prevents water loss by diffusion and evaporation from the body except, of course, atthe sweat glands, which helps regulate body temperature. The viable layers of the epidermis and thedermis are poor barriers to toxicants, since hydrophilic agents readily diffuse into the intercellularwater and hydrophobic agents can embed in cell membranes, eventually reaching the blood supply inthe dermis.Several factors influence the rate of diffusion of chemicals across the stratum corneum. In general,hydrophobic agents of low molecular weight can permeate the skin better than can those that arehydrophilic and of high molecular weight. This is due to the low water and high lipid content of thestratum corneum, which allows hydrophobic agents to penetrate more readily. However, if the skinbecomes hydrated on prolonged exposure to water, its effectiveness as a barrier to hydrophilicsubstances is reduced. Often the skin of lab animals is covered with plastic wrap to enhance thehydration of the skin and increase the rate of uptake of agents applied to the surface of the skin. Forcompounds with the same hydrophobicity, the smaller compound will diffuse across the skin fastestsince its rate of diffusion is quickest. A good example of the diffusion of a class of toxicants acrossthe skin that can cause systemic toxicity is the organophosphate pesticides (e.g., parathion) used inagriculture. These compounds are hydrophobic, are very potent, and can lead to systemic effects suchas 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 beuseful 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,and nitroglycerin. This approach provides a steady dose, avoids large peak plasma concentrations fromloading doses, and prevents first-pass metabolism by the liver for agents that are sensitive to metabolismsuch as nitroglycerin.The rate of diffusion through the epidermis varies among anatomical sites and is not solely afunction of skin thickness. In fact, the skin on the sole of the foot has a higher rate of diffusion thanthe skin of the forehead or abdomen, even though it is much thicker. Therefore, skin thickness is nota useful indicator of how much chemical will reach the systemic circulation in a given amount of time.If the skin is wounded, the barrier to chemicals is compromised and a shorter or direct route to thesystemic circulation is available since the skin can no longer repel the chemicals. In addition, diseases(e.g., psoriasis) can compromise the ability of skin to repel chemicals.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 andepidermis, but primarily melanin pigmentation, provide protection against UV radiation byabsorbing the energy before it reaches more sensitive cells and causes adverse effects such asDNA damage. (See Table 8.1.)Another important aspect of the skin’s barrier function is its ability to metabolize chemicals thatcross the stratum corneum and enter the viable layers of the skin. Even though the metabolic activityof the skin on a body weight basis is not nearly as great as that of the liver, it does play a crucial rolein determining the ultimate effects of some chemicals. The epidermis and pilosebaceous units of theskin contain the highest levels of metabolic activity, which includes phase I (e.g., cytochromeTABLE 8.1 Defense Roles of the SkinPrevent water lossAct as a barrier for physical traumaRetard chemical penetrationPrevent ultraviolet light penetration and damageInhibit microorganism growth and penetrationRegulate body temperature and electrolyte homeostasis