Respiratory tract irritants may damage different lung districts on the basis of their hydro-solubility. Therefore, highly soluble gases—such as ammonia, aldehyde gases, hydrogen chloride, and other acids—are dissolved in watery mucus of
Table I Toxin Classification Based on Site of Action in the Lungs.
Upper airways and bronchi
Terminal bronchioli, alveoli
Systemic absorption (with only slight or no pulmonary toxicity)
Chlorine Ammonia Aldehydes of lower molecular weight (formaldehyde, acetaldehyde) Acrolein Sulfur dioxide Hydrogen chloride Hydrogen fluoride Acetic acid
Nitrogen dioxide Nitrogen oxide Phosgene Ozone
Dusts from hemp, flax, and cotton processing
Carbon dioxide Carbon monoxide Hydrogen cyanide Propane
Table II Examples of Agents Causing Immune-Toxic Reactions.
Immediate hypersensitivity IgE-mediated
Immune-complex-mediated hypersensitivity T-cell mediated hypersensitivity
Bronchial edema, plugging
Noncaseating granuloma Higher incidence of infections
Low molecular weight Nickel Isocyanates
Aldehydes (formaldehyde, acetaldehyde) High molecular weight Detergent enzymes House dust mite Pollens Molds Latex
Interstitial infiltrate, granuloma Farmer's lung
Berylliosis Benzo[a]pyrene Phosgene Nitrogen dioxide the nose, throat, and trachea and have their primary effects there. They can provoke acute painful irritation with sneezing, cough, sore throat, and acute bronchitis. Asphyxiation is possible due to laryngeal spasm and bronchoconstriction. Generally, it is easy to detect the presence of these agents in the environment by their odor and the discomfort evoked.
Gases with lower water solubility—such as phosgene, nitrogen dioxide, chlorine, and isocyanates—evade the first line of defense in the upper airways and have their primary effect on the lower respiratory tract. Their irritative actions appear hours or days after the exposure and may evoke severe inflammatory responses. In most cases it is quite difficult to detect the presence of these gases in the environment.
In addition to their chemical proprieties, the toxicity of irritant agents is related to the intensity of exposure. Therefore, air concentration and duration of exposure can be combined into a cumulative exposure value (concentration x time). These are important parameters to be evaluated in cases of intoxication. Indeed, any irritant gas, at sufficiently high concentration, may be a factor in producing pulmonary edema. The following examples of irritant gases are not exhaustive. We list only the most common irritant agents and their mechanisms of action.
Phosgene gas (carbonyl chloride; carbon oxychloride; chloroformyl chloride) is a toxic inhalant that directly damages the lungs. Although phosgene has not been deployed in warfare since the Geneva Protocol prohibited chemical agent use in 1925, its continued application in common industrial processes, such as dye or plastic manufacturing, makes it an ongoing potential industrial hazard. Phosgene exposure also can occur in fires associated with organochlo-rine compounds (e.g., vinyl chloride), the use of carbon tetrachloride fire extinguishers, and during arc welding procedures.
Phosgene gas has the appearance of a white cloud and the characteristic odor of newly mown hay. Odor alone is insufficient for the detection of phosgene, since toxic exposures may occur at concentrations below the olfactory threshold. Phosgene is one of the most volatile chemical warfare agents, its density is greater than air, and it tends to accumulate in low areas.
Phosgene exerts a direct effect on the respiratory tract, causing extensive cellular damage to the alveolar-capillary membrane. Phosgene reacts with intraalveolar water to form hydrochloric acid. When hydrochloric acid itself is aspirated experimentally there is activation of the alternative pathway of complement leading to deposition of the membrane attack complex and cell injury. It is appealing to believe that phosgene injury follows the same mechanism.
The clinical effects of phosgene are dose dependent. At low concentrations, victims may complain only of a mild cough, dyspnea, and chest tightness. At moderate concentrations, they may also complain of tearing. At high concentrations, victims develop noncardiogenic pulmonary edema within 2 to 6 hours of exposure, producing a clinical picture similar to the acute respiratory distress syndrome (ARDS). Laryngospasm also occurs at higher concentrations, which in turn may cause sudden death. Physical exertion within 72 hours of exposure can trigger dyspnea and pulmonary edema in otherwise asymptomatic patients. Toxic manifestations often are clinically silent at rest, because patients are able to compensate for pulmonary damage in the absence of stress. Death from phosgene inhalation often is caused by latent noncardiogenic pulmonary edema.
Nitrogen Dioxide (NO2) and Reactive Nitrogen Species (RNS)
The lung can be exposed to a variety of reactive nitrogen intermediates through the inhalation of environmental oxi-dants and those produced during inflammation. Reactive nitrogen species (RNS) include nitrogen dioxide (NO2), and peroxynitrite (ONOO-). Classically known as a major component of both indoor and outdoor air pollution, NO2 is a toxic free radical gas. The gas is formed primarily from burning fuel in motor vehicles, electric power plants, and other industrial, commercial, and residential sources that burn fuel. NO2 can also be formed during inflammation by the decomposition of ONOO- or through peroxidase-catalyzed reactions. Since nitrogen dioxide is a traffic-related pollutant, emissions are generally highest in urban rather than rural areas.
Although NO2 found in outdoor air is a significant source of exposure, the concentration present in indoor air often exceeds that from the outside. Indoor sources of NO2 include kerosene heaters, gas cooking stoves, gas-powered ice scrapers used in hockey rinks, and tobacco smoke. Nitrogen oxides are an important precursor to the formation of ground-level ozone and acid rain and may affect both terrestrial and aquatic systems.
Because of their reactive nature, RNS may play an important role in disease pathology. Depending on the dose and the duration of administration, NO2 has been documented to cause pulmonary injury in both animal and human studies.
The main site of NO2 deposition and injury is at the distal conducting airways at the level of the terminal bronchioles. Injury to the lung epithelial cells following exposure to NO2 is characterized by airway denudation followed by compensatory proliferation. Loss of epithelial cells due to injury causes the proliferation of alveolar type II cells, Clara cells, and/or other bronchiolar cells, which repopulate the injured areas of airway epithelium. The persistent injury and repair process may contribute to airway remodeling, including the development of fibrosis. Furthermore, inhaled NO2 can exacerbate asthma and is associated with an increased susceptibility to respiratory infections.
Ozone (O3) is a secondary pollutant formed in the troposphere through a series of sunlight-driven reactions of atmospheric oxygen with volatile organic compounds and nitrogen oxides, which are produced through combustion. Levels of ozone tend to be higher during hot summer days and in cities with large amounts of traffic and with temperature inversions1 (Los Angeles, Mexico City), but may also be very high in workplaces such as welding plants and paper mills. Ozone is virtually insoluble in water and, therefore, it may be deposited anywhere along the airway, but as it is highly reactive it is thought that very little of the inspired ozone reaches the alveolar epithelium. The majority of the effects of ozone are mediated by a cascade of secondary products derived from free radicals that cause cellular damage when antioxidant defenses have been overwhelmed. Experimental exposure of humans to high concentrations of ozone causes irritation and cough, with decrements in forced vital capacity and forced expiratory volume at first second (FEV1). In healthy subjects ozone induces neutrophilic inflammation of the airway mucosa accompanied by increased levels of inflammatory mediators and proteins in bronchoalveolar lavage (BAL). Albumin, IgG, and a1-antitrypsin are increased in the epithelial lining fluid, indicating increased vascular permeability. Exposure to ozone also induces release of the neutrophil chemoattractant IL-8, as well as GM-CSF, and increases expression of the endothelial adhesion molecule ICAM-1, suggesting a likely mechanism for neutrophil recruitment. Some studies have reported recruitment of eosinophils and mast cells after ozone exposure. In vitro, cultured human epithelial cells exposed to ozone release increased amounts of lipid mediators PGE2, LTC4, LTD4, and LTE4. Fibronectin and the proinflammatory cytokines IL-6 and IL-8 are also released
1 Temperature inversions are defined as a layer of air with negative lapse rate or simply as a region within the troposphere where temperature increases with height.
by epithelial cells in response to ozone exposure. Other in vitro studies carried out using human epithelial cells have shown that both NFkB and AP-1, which regulate the IL-8 gene, increase in response to ozone exposure in respiratory epithelial cells.
Was this article helpful?
This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.