PRINCIPLES OF TOXICOLOGY

176 PULMONOTOXICITY: TOXIC EFFECTS IN THE LUNG
spherical particle in the time it takes the particles to settle in the air. This calculation is also referred
to as the mass median aerodynamic diameter. If the number of particles is of primary interest (and not
necessarily particle shape), the count median diameter is determined. Of course, the size of particles
may change during the course of traversing the respiratory tract. Since the respiratory tract is highly
humidified, particles that absorb water could be expected to undergo chemical reactions and increase
in size as they descend.
Lung Deposition Mechanisms
Particles tend to deposit in the lung according to size, air velocity, and regional characteristics of the
respiratory system. In the nares, nose hairs tend to block out the very large particles that enter the nose.
Once inside the nares, the abrupt turn in the nasopharyngeal system of humans (from going up to going
down) results in the impact of many of the larger particles on the walls of this region of the respiratory
system.
This mechanism, referred to as impaction, results from the aerodynamic tendency of particles to
travel in a linear direction, even when the respiratory system is turning and branching. An analogy
would be a bifurcating freeway system, in which the safety department will often place barrels at the
point of bifurcation since cars are most likely to strike this location. In a similar manner, particles are
more likely to strike the points of bifurcation in the respiratory system.
A related mechanism of deposition is known as interception. This process occurs when a particle
comes close enough to contact a respiratory surface and, subsequently, deposits there. Interception
does not have to occur at the bifurcations or turns and is mostly a factor in the deposition of fibers,
which are much longer than other forms of particles. It is not uncommon for a fiber to be only a few
µms in diameter and several hundred µms in length, so the probability of contact with the respiratory
surfaces is enhanced.
In the tracheobronchiolar region, the declining airflow allows gravitational influences to result in
the deposition of particles in the 1–5 µm range. This process, referred to as sedimentation, increases
in frequency as the particles in this size range descend lower into the bronchiolar tree. Sedimentation
can also occur in the alveolar region, but the simple process of diffusion will result in the deposition
of particles in the 1-µm range.
Clearance Mechanisms
The respiratory system has an extraordinary design for the clearance of particles and other toxins.
Generally, the clearance mechanism is related to the site of deposition. This respiratory clearance
should not be confused with total body clearance or systemic clearance in the pharmacokinetic sense.
Respiratory clearance removes particles and other toxins from the respiratory tree; ultimate removal
from the body is achieved through the gastrointestinal system, the lymphatics, and the pulmonary
blood.
In the nasopharyngeal and tracheobronchial regions, there is a mucociliary escalator mechanism.
In the respiratory wall, there are pseudostratified columnar epithelial cells together with specialized
goblet cells, which produce a layer of mucous along the wall of epithelial cells. Hundreds of cilia,
which resemble small hairs, protrude from the epithelial cells (Figure 9.7). The mucous itself is in two
layers: the lower layer, known as sol, contains the cilia and is thin and watery so that cilia movement
is not impeded; the upper layer, the gel, is thick and viscous. The cilia beat in unison and move the gel
layer along like a continuous sheet (Figure 9.8). Inhaled particles and other toxins become trapped on
the gel layer. In the tracheobronchial region, the cilia beat upward, and the entrapped particles in the
gel are propelled up toward the mouth. Typically, an individual will solubilize the material in saliva,
which is then eliminated via the gastrointestinal tract. Occasionally the material may be coughed out
of the body. In the nasopharyngeal region, the cilia beat downward toward the mouth and rely on the
same mechanisms of removal. Typically, mucociliary clearance will occur within hours of the
deposition of most particles, and in healthy individuals, the process is usually completed within 48 h.