In discussing toxic responses of the respiratory system, it is important to make a distinction between the respiratory system as an entryway for toxic substances, referred to as inhalation toxicology, and the respiratory system adversely affected by toxicants, referred to as respiratory tract toxicology. The term pulmonary refers to lungs. Generally, toxicants that adversely affect the respiratory system are those that have been inhaled, including such well-known substances as asbestos, chromate, and silica. However, it is possible for systemic poisons transported from elsewhere in the body to act as respiratory system toxicants. One interesting possibility that has been suggested is lung cancer caused by the diol epoxide of benzo(a)pyrene (see Figure 7.3), which is formed by inhalation of benzo(a)pyrene, converted to the ultimate carcinogen in the liver, and transported back to the lung, where cancer develops.
A highly simplified outline of the respiratory system is shown in Figure 6.4. The function of the respiratory system is to exchange gases with ambient air, taking oxygen from inhaled air into blood and releasing carbon dioxide from respiration back to air that is exhaled. As shown in Figure 6.4, air enters through the nose and travels through the pharynx, trachea, and bronchi, reaching the small sacs in the lung called alveoli, where gas exchange with blood occurs. The alveoli have walls that are as thin as a single cell and highly susceptible to damage; they constitute the alveolar-capillary barrier across which gases are exchanged. A large variety of potentially toxic substances enter with incoming air, including air pollutant particles and gases, disease-causing bacteria and viruses, and airborne allergens, such as pollen. Volatile substances are expelled with exhaled air, and the respiratory tract has mechanisms to eliminate solid and liquid particles and residues from respiratory tract infections.
The respiratory tract may suffer from a variety of ailments that can result from exposure to toxicants. A common one of these is acute or chronic bronchitis, manifested by inflammation of the membrane lining of the bronchial tubes, which can be caused by toxicants or by infections. Emphysema, the bane of aging heavy smokers, is the result of abnormal enlargement and loss of elasticity of pulmonary air spaces, resulting in difficulty in breathing. Interstitial disorders, predominantly pulmonary fibrosis, in which excess fibrous connective tissues develop in the lungs can result from exposure to toxicants. Often indicative of acute lung injury, pulmonary edema is the accumulation of fluid in the lungs; in severe cases, the subject literally drowns from those fluids. And, of course, lung cancer is a major concern with exposure to some kinds of toxicants.
A common toxic effect to the lung is the result of oxidative burden.3 Oxidative burden occurs as the result of active oxidants, especially free radicals that are generated by a variety of toxic agents and the action of lung defense cells. Ozone, O3, the air pollutant most commonly associated with photochemical smog, is a particularly active oxidant in polluted air, and smog contains other oxidants as well. NO2, also associated with photochemical smog and polluted air, contributes to the oxidative burden. Much of the oxidative damage to lungs is probably done by free radicals, such as hydroxyl radical, HO-, and superoxide ion, O-, which initiate and mediate oxidative chain reactions. Lungs of animals exposed to oxidants have shown elevated levels of enzymes that scavenge free radicals, providing evidence for their role in oxidative damage. There is evidence to suggest that lung cells damaged by toxicants release species that convert lung O2 to reactive superoxide anion, O-.
Lungs are subject to both acute and chronic injury from toxicants. A common manifestation of acute injury is pulmonary edema, in which liquid exudes into lung alveoli and other lung cavities, increasing the alveolar-capillary barrier and making breathing more difficult. Among the toxicants that cause pulmonary edema are ozone, phosgene (COCl2), and perchloroethylene (C2Cl4).
There are several major types of chronic lung disorders that can be caused by exposure to toxicants. A common symptom of chronic lung damage is chronic bronchitis. Among the toxicants that cause this condition are ammonia, arsenic, cotton dust (brown lung disease), and iron oxide from exposure to welding fumes.
Lung fibrosis occurs with a buildup of fibrous material inside lung cavities. The fibers are rich in collagen, the tough, fibrous protein that gives strength to bone and connective tissue. Chronic fibrosis can result from pulmonary exposure to aluminum dust, aluminum abrasives, chromium(VI), coal dust, kaolin clay dust, ozone, phosgene, silica, and finely divided mineral talc.
Snider et al. have defined emphysema as "a condition of the lung characterized by abnormal enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of the walls without obvious fibrosis."4 Emphysema is characterized by enlarged lungs that do not expel air adequately and do not exchange gases well. Cigarette smoke is the overwhelming cause of emphysema. Inhalation of aluminum abrasives and cadmium oxide fumes can also cause emphysema.
Lung cancer is the best-known example of cancer caused by exposure to a toxicant, in this case cigarette smoke. As much as 90% of lung cancers are the result of exposure to tobacco smoke. The latency period for the development of lung cancer from this source is usually at least 20 years and may range up to 40 years or longer. Inhalation of other agents can cause lung cancer, although they are usually associated with synergistic effects from cigarette smoke. The most well established of these are asbestos and radon gas, a radioactive alpha particle emitter.
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