PRINCIPLES OF TOXICOLOGY

0.02 µm. Note that deposition also depends on the breathing cycle. Slow, deep breathing was associated
with greater percentage deposition of lead in each particle size range.
After being deposited in the alveolar region, particulates may be dissolved and absorbed into the
bloodstream, reaching the systemic circulation directly. If they are not readily soluble, they may be
phagocytized by alveolar macrophages and then either transferred to the lymphatic system, where they
may remain for a considerable time period, or moved together with the macrophage to the mucociliary
escalator for clearance by that route. They may also occasionally remain in the alveolus for an extended
period of time. Absorption of particulates tends to be slower than absorption of gases and vapors, and
appears to be controlled primarily by the solubility of the particulate. For example, the systemic
bioavailability of chromium(VI) and nickel salts from the lung has been shown to parallel their
solubility.
The absorption of water-soluble chemicals in the lung, and even in the nasal cavity, can be quite
high. For example, aspirin was found to be 100 percent bioavailable from the rat nasal cavity but only
59 percent bioavailable when given orally. Nicotine was fully absorbed from intratracheal, bronchial,
and distal sites in the dog lung, although absorption was not equally rapid from all three sites.
Gases and Vapors Absorption of gases and vapors in the lung depends on their solubility in the blood
perfusing the lung. Very soluble compounds will be almost completely cleared from inhaled air and
transferred to pulmonary blood in a single respiration. For such compounds, increasing the rate of
pulmonary blood flow makes very little difference in absorption rate. The only way to increase
absorption is to increase the rate of respiration; that is, to increase ventilation. Absorption of these
compounds is said to be ventilation-limited. If they are also lipid-soluble, they will find their way
rapidly to the lipid depots of the body.
Chloroform is a good example of such a compound. It is very highly lipid-soluble, and is readily
cleared from inspired air. As the blood circulates through the body, the chloroform is transferred to
fat, so that the blood is also effectively cleared and during its next pass through the lung is able to pick
up more chloroform. The absorption of chloroform is ventilation-limited.
For poorly soluble gases, the capacity for absorption is rather limited. Little of the compound will
be transferred to pulmonary blood in a single respiration. Often these are not compounds that are
readily cleared from the blood. If this is the case, the blood will become saturated quickly, and the only
way to increase absorption then is to increase the rate of pulmonary blood flow. Such compounds are
said to be flow-limited in their absorption characteristics. Of course, there is a range of transition
between these two extremes of pulmonary absorption behavior.
2.4 DISPOSITION: DISTRIBUTION AND ELIMINATION
2.4 DISPOSITION: DISTRIBUTION AND ELIMINATION 45
Unlike absorption, disposition consists not just of one kind of process but, rather, of a number of
different kinds of processes taking place simultaneously. Disposition includes both distribution and
elimination, which occur in parallel in almost all cases (Figure 2.1). Elimination is also made up of
two kinds of processes, excretion and biotransformation, which usually take place simultaneously.
Distribution and elimination are often considered independently of each other. While it is convenient
to separate them for discussion, it is important to remember that they are taking place at the same
time. If a substance is effectively excreted, it will not be distributed into peripheral tissues to any great
extent. On the other hand, wide distribution of the compound may impede its excretion.
Kinetic Models
Before discussing some of the specific mechanisms for distribution, excretion, and biotransformation,
it is useful to consider some simple kinetic disposition models. Rates of distribution are related to
kinetic distribution constants. Rates of metabolism, or biotransformation, and of excretion are related
to kinetic constants of elimination. It is possible to integrate all the essential information about