PRINCIPLES OF TOXICOLOGY

9.2 MECHANISMS OF INDUSTRIALLY RELATED PULMONARY DISEASES 183
is considered to be more compliant than type I, this might be the cause of the “stiffening” of the lung
tissue, but this is not known for certain.
Emphysema
Whenever inhaled toxins result in the progressive destruction of the alveolar walls of the lung tissue,
there is an enlargement of the lung air spaces accompanied by a decrease in the surface area of the
lung available for gas exchange. This is commonly referred to as emphysema, and it is a relatively
common pulmonary disease condition in the United States. Although emphysema is due primarily to
tobacco smoke inhalation, a number of inhaled industrial toxins may also be responsible for the
development of emphysematic conditions. For instance, the inhalation of coal dust by miners over
extended periods has been shown to result in both pulmonary fibrosis and emphysema.
Recent research has indicated that a genetically related deficiency in α-1-antiprotease, of a
biochemical inhibitor of elastase, is clinically related to the relatively early onset of emphysema. It is
believed that the breakdown of the alveolar walls is modulated by elastases, which are released by
neutrophils and perhaps alveolar macrophages, and if the α-1-antiprotease enzyme is genetically absent
or decreased, this results in a higher incidence of emphysema. In this scenario, if an inhaled toxin
causes increased migration of the normally protective cells (neutrophils and macrophages) to the site
of the inhaled toxin deposition, then these cells may end up damaging the lung tissue in addition to
eliminating the toxins.
Pulmonary Edema
Many inhaled agents produce sufficient cellular toxicity to cause an increase in the membrane
permeability of the alveocapillary membrane complex of the lung and other airway linings. This results
in an increase in fluid, either in the interstitial space of the alveocapillary membrane complex or on
the surface of the airways or alveolar sacs. This increase in fluid is called edema, and its presence
impedes the exchange of oxygen and carbon dioxide between the alveolar air and the pulmonary blood.
If the decrease in gas exchange proceeds sufficiently, the affected individual can die, literally in their
own fluids.
Among the many agents that result in pulmonary edema are the air pollutant gases, such as nitrogen
dioxide and ozone. These agents typically exert their lung toxicity at relatively low levels of exposure
in air-pollution episodes, but in industrial exposures, workers may be exposed to considerably higher
concentrations. Chlorine and phosgene, two of the more potent inducers of pulmonary edema, were
shown to induce thousands of deaths when used as chemical warfare gases in World War I. Recently,
it was reported that the Iraqi military has used one or both of these agents against the Kurdish minority
in that country. Since chlorine is now the primary chemical used to keep water supplies clean, its
industrial use has soared. Municipalities use chlorine for their drinking water treatment; therefore, its
geographic distribution is widespread. Large-scale releases of chlorine have occurred during transport
to these disparate localities, and there have been a number of fatalities from pulmonary edema
following chlorine inhalation. Phosgene is also used frequently in industry; however, strict industrial
hygiene controls, due to the extreme toxicity of the chemical, has resulted in a low frequency of worker
injury. Other agents known to cause pulmonary edema include nickel oxide, paraquat, cadmium oxide,
and some industrial solvents.
The delayed onset of pulmonary edema in most cases of chemical inhalation results in a significant
hazard for exposed workers. Usually, the edema fluid is not readily detected by the exposed individual
or by clinical examination for at least several hours after the termination of exposure.
In a typical occupational exposure, the worker may experience short-term symptoms involving
irritation of the airway, which influences them to seek immediate medical assistance. Since the
short-term symptoms usually have no immediate cytotoxic sequelae, the medical examination will
result in no revelation of significant morbidity, and the patient will be released. Then, 4–24 h later, the
pulmonary edema rapidly develops, usually while the patient is asleep. Often, when patients awake