PRINCIPLES OF TOXICOLOGY

the transfer from liver to bile. If transfer from liver to bile is the rate-limiting step, enhancement of the
rate of bile flow will enhance the rate of excretion.
Excretion in the Lung The third major organ of elimination is the lung, the key organ for the
excretion of volatile chemical compounds. Pulmonary excretion, like pulmonary absorption, is by
passive diffusion. For example, the rate of transfer of chloroform out of pulmonary blood is directly
proportional to its concentration in the blood. Essentially, pulmonary excretion is the reverse of the
uptake process, in that compounds with low solubility in the blood are perfusion-limited in their rate
of excretion, whereas those with high solubility are ventilation-limited. Highly lipophilic chemicals
that have accumulated in lipid depots may be present in expired air for a very long time after exposure.
Other Routes of Excretion Skin, hair, sweat, nails, and milk are other, usually minor routes of
excretion. Hair can be a significant route of excretion for furred animals, and indeed the amount of a
metal in hair, like the amount of a volatile compound in exhaled air, can be used as an index of exposure
in both laboratory animals and humans. Hair is not quantitatively an important route of excretion in
humans, however. Sweat and nails are only rarely of interest as routes of excretion, simply because
loss by these routes is quantitatively so slight.
Milk may be a major route of excretion for some compounds. Milk has a relatively high fat content,
3–5 percent or even higher, and therefore compounds that are lipophilic may be excreted in milk to a
significant extent. Some of the toxicants known to be present in milk are the highly lipid-soluble
chlorinated hydrocarbons: for example, the polychlorinated biphenyls (PCBs) and DDT. Certain heavy
metals may also be excreted in milk. Lead is thought to be secreted into milk by the calcium transport
process.
2.5 SUMMARY
2.5 SUMMARY 53
This chapter has conveyed some of the general biochemical and physiological principles that govern
absorption, distribution, and elimination of toxic agents, in particular
• The importance of lipid solubility, molecular size, and degree of ionization to the rate at
which a molecule moves through a membrane by passive transfer or diffusion.
• The characteristics of other transfer processes such as facilitated diffusion, active transport,
phagocytosis, and pinocytosis.
• Absorption from the gastrointestinal tract with particular emphasis on the importance of pH
as a determinant of absorption of ionizable organic acids and bases as well as on compoundspecific
and host-related factors such as lipid solubility and molecular size, the presence of
villi and microvilli in the intestine, the possibility that the compound can be absorbed by
facilitated or active transport mechanisms, and the action of gastrointestinal enzymes or
intestinal microflora.
• Factors determining the rate of diffusion across the skin.
• Absorption of solid and liquid particulates and of gases and vapors in the lung.
• Simple classical and physiologically based kinetic models describing disposition (distribution,
metabolism, and excretion).
• Excretion from kidney, liver (including enterohepatic circulation), and lung, and by less
general routes such as skin, hair, sweat, nails, or milk.