PRINCIPLES OF TOXICOLOGY

corneum 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, 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 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 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 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 surface of the skin. For
compounds with the same hydrophobicity, the smaller compound will diffuse across the skin fastest
since 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 very potent, and can 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,
and nitroglycerin. 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 of the foot has a higher rate of diffusion than
the skin of the forehead 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 amount of time.
If the skin is wounded, the barrier to chemicals is compromised and a shorter or direct route to the
systemic 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 and
epidermis, but primarily melanin pigmentation, provide protection against UV radiation by
absorbing the energy before it reaches more sensitive cells and causes adverse effects such as
DNA damage. (See Table 8.1.)
Another important aspect of the skin’s barrier function is its ability to metabolize chemicals that
cross the stratum corneum and enter the viable layers of the skin. Even though the metabolic activity
of the skin on a body weight basis is not nearly as great as that of the liver, it does play a crucial role
in determining the ultimate effects of some chemicals. The epidermis and pilosebaceous units of the
skin contain the highest levels of metabolic activity, which includes phase I (e.g., cytochrome
TABLE 8.1 Defense Roles of the Skin
Prevent water loss
Act as a barrier for physical trauma
Retard chemical penetration
Prevent ultraviolet light penetration and damage
Inhibit microorganism growth and penetration
Regulate body temperature and electrolyte homeostasis
8.2 FUNCTIONS 159