PRINCIPLES OF TOXICOLOGY

susceptible to alteration by the actions of intestinal microflora, which are important for digestion of
plant materials resistant to the action of mammalian enzymes. Enzyme systems of the intestinal wall
and/or the liver may metabolize chemicals before they reach the systemic circulation, the intestinal
and/or hepatic first-pass effect, which can result in significant reduction in bioavailability. For example,
compared to its 100 percent availability on intravenous injection, the systemic bioavailability in rats
of buprenorphine, an opiate analgesic, was found to be 49 percent when the drug was given
intrahepatoportally and 10 percent when it was given intraduodenally. It can be calculated that after
80 percent of the intraduodenal dose had been inactivated in the intestine, half of the surviving 20
percent was inactivated in the liver.
Another determinant of gastrointestinal absorption is the rate at which foodstuffs pass through the
GI tract. If the rate of passage is slowed, the length of time during which the compound is available
for absorption is increased. Absorption also tends to increase during short periods of fasting but may
fall off after a lengthy fast, probably consequent to a decrease in intestinal blood flow. Other important
influences on absorption include the chemical and physical characteristics of the compound, its
solubility under the conditions present in the GI tract, and its interactions with other compounds. Age
and nutritional status of the individual may also affect absorption from the GI tract.
Skin
The second major pathway for absorption is the skin. The skin is a very effective barrier to absorption,
primarily because of the outermost keratinized layer of thick-walled epidermal cells, the stratum
corneum, which in general is not very permeable to toxicants, although its permeability varies from
location to location. Compared with the total thickness of the epidermis and dermis together, the
thickness of the stratum corneum is relatively slight, but this barrier is rate-limiting in the process of
absorption through the skin. There may be slight absorption through sweat glands or hair follicles, but
these structures represent a very small percentage of the total surface area and are not ordinarily
important in the process of dermal absorption.
All toxicants that penetrate the skin appear to do so by passive diffusion. Lipophilic chemicals are
much better absorbed through the skin than are hydrophilic chemicals, and the ease with which a
compound penetrates the skin is correlated with its partition coefficient.
Dermal absorption can be increased in various ways. An increase in capillary blood flow, as in
response to the demand of a warm environment for efficient heat loss, is associated with increased
percutaneous absorption. Abrasion, which damages or removes the stratum corneum, greatly increases
the permeability of the damaged area. The skin is normally partially hydrated; an increase in the degree
of hydration increases permeability and promotes absorption. Certain solvents, such as dimethyl
sulfoxide (DMSO), also increase skin permeability and facilitate absorption of toxicants.
Lipophilic drugs that would suffer extensive first-pass metabolism if given orally can be administered
dermally. The glyceryl trinitrate patch used in treatment and prevention of angina is a good
example.
Certain toxicants can produce systemic injury by percutaneous absorption. Hydrocarbon solvents,
such as hexane, can produce a peripheral neurotoxicity, and carbon tetrachloride can produce liver
injury. Organophosphate insecticides such as parathion and malathion have caused toxicity and deaths
in industrial and field workers after absorption through the skin.
Lung
2.3 ABSORPTION 43
The third major site of toxicant absorption is the lung. In occupation-linked toxicology, the lung is a
very important route of uptake. Gases and vapors such as carbon monoxide, sulfur dioxide, and volatile
hydrocarbons are absorbed through the lung, and liquid or particulate aerosols, such as sulfuric acid
aerosols or silica dust, are also deposited and/or absorbed in the lung. With solid and liquid particulates,
the site of deposition is critical to the degree of absorption of a compound.