PRINCIPLES OF TOXICOLOGY

182 PULMONOTOXICITY: TOXIC EFFECTS IN THE LUNG
Silicosis
Following long-term inhalation of silica-containing dusts, many workers have developed irreversible
lung damage known as silicosis. One-half to two-thirds of the rocks in the crust of the planet contain
silica, so it is to be expected that many industrial processes result in the production of silica-containing
dusts. While some of the inhaled silica dioxide crystals will deposit in the nares and on the mucociliary
escalator, a certain number will reach the alveolar regions of the respiratory system. Unfortunately,
the alveolar macrophages that ingest the silica particles will be damaged by the silicic acid produced
following phagocytosis. Damaged and killed macrophages will release phagocytic enzymes into the
alveolar sacs, which will result in their progressive destruction over time. This eventually results in a
“stiffening” of the lung tissues, which makes breathing more difficult for the affected patient. Over a
long period of time, the body will try to wall off the area, resulting in the development of a silicotic
nodule. Patients with advanced silicosis often have greater susceptibility to respiratory infections such
as tuberculosis. In any one patient, one might find each of these stages located in the same lung. Even
after an individual has been removed from the further inhalation of silica dust, this progressive
deterioration will continue. Another negative aspect of the disease is that it is very difficult to treat,
and currently, clinicians can do little more than alleviate symptomatic suffering.
Asbestosis
The highly effective flame retardant asbestosis has been used for centuries, and in the past few decades,
it has been used in industry for a variety of purposes. Many thousands of workers have received very
high doses of asbestos in the shipbuilding industry. Usually, insulation workers were exposed to
asbestos dust in very enclosed spaces, which tended to increase the concentration of the inhaled fibers.
Countless individuals have been exposed to asbestosis fibers while working with the brake linings of
cars. Chrysotile, or “white” asbestos, accounts for about 90 percent of the asbestos in industrial
applications; the amphiboles account for most of the other potential exposures, in which crocidolite,
or “blue” asbestos, is the most important (and was the first form found to be carcinogenic).
The insidious nature of asbestosis is that major symptoms seldom appear until 5–10 years (or
longer) after the inhalation of the asbestos fibers. As with silicosis, the inability of macrophages to
digest the fibers leads to a progressive fibrosis of the lung tissue. However, with asbestosis there is
also pleural thickening and calcification, which can be picked up by X-ray examination in the relatively
early stages of the disease. Pleural calcification may exist in patients when there are no other symptoms
present. Pulmonary function tests are often useful, in that decreases in compliance and total lung
capacity are observed. A pathologic finding in asbestosis is the appearance of “asbestos bodies,” which
are structures formed by the protein encapsulation of asbestos fibers that resemble a “barbell” in weight
lifting (the protein is thicker on the ends). Asbestosis eventually leads to the development of malignant
neoplasms in the respiratory tract. One form of cancer, mesothelioma, is so rare in situations outside
of asbestos exposure that many physicians consider it a “marker” disease for asbestosis. A higher
incidence (up to an 80-fold increase) of bronchogenic carcinoma is distinctly correlated with tobacco
smoke inhalation and asbestos exposure. These asbestos related cancer deaths generally occur from
25–40 years after the asbestos inhalation.
Excess Lung Collagen
Most types of pulmonary fibrosis involve distinct changes in the proportion of the types of lung collagen
that is produced in the affected lung. Such information is used by pathologists today in determining
the degree of pulmonary fibrosis that has occurred. In most normal lungs, the two most common
collagen types, type I and type III, are observed at a ratio of approximately 2:1. When pulmonary
fibrosis occurs, there is generally an increase in type I collagen in relation to type III collagen.
Mechanistically, the presence of the fibers causes macrophages to release lymphokines and various
growth factors, which leads to an increase in the production of certain collagen types. Since type III