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The irritant gases are a heterogeneous group of chemicals that produce toxic effects via a final common pathway: destruction of the integrity of the mucosal barrier of the respiratory tract (Table 124–2).
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In the lung, irritant chemicals damage both the more prevalent type I pneumocytes and the surfactant-producing type II pneumocytes.111 Neutrophil influx, recruited in response to macrophage-derived inflammatory cytokines such as tumor necrosis factor (TNF)-α, releases toxic mediators that disrupt the integrity of the capillary endothelial cells.121,158 This host defense response results in accumulation of cellular debris and plasma exudate in the alveolar sacs, producing the characteristic clinical findings of the acute respiratory distress syndrome (ARDS). The specific mechanisms by which the irritant gases damage the pulmonary endothelial and epithelial cells vary. Many irritant gases require dissolution in lung water to liberate their ultimate toxicant, which often is an acid, as occurs when hydrogen chloride gas produces hydrochloric acid. The exact mechanism by which acids damage cells and induce an inflammatory response remains uncertain. Oxidation of intracellular proteins may result in rapid cytoskeletal shortening, creating spaces between endothelial cells and allowing fluid movement into the alveolar spaces.194 Other gases, such as oxygen and ozone, induce pulmonary damage solely through free radical-mediated oxidative stress on the cellular membranes. Nitrogen dioxide (NO2) and chlorine are characteristic of a group of gases that produce both acid and free radical oxidants. Furthermore, other respirable xenobiotics, such as metals, injure the respiratory tract through oxidant stress and other mechanisms. Because the precise toxicologic and pathophysiologic effects vary widely depending on the physicochemical properties of the xenobiotic, these mechanisms are covered more completely in the following specific discussions.
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By virtue of its use as a war agent, phosgene has received more investigation than the other irritant gases. Although the specific mechanisms of toxicity of the other irritants remain poorly defined, they likely cause injury through a similar process. The acids liberated upon dissolution in the mucosal water react with functional groups on epithelial and endothelial cell membranes and, via cellular messengers, result in a complex inflammatory response.170,145 Phosgene stimulates the synthesis of lipoxygenase-derived leukotrienes and other cytokines such as TNF-α.170 Leukotrienes are important chemotactic factors for neutrophils, which accumulate, liberate oxidants, and produce ARDS.97 ARDS can be prevented in rabbits by tomelukast, a leukotriene receptor antagonist,85 and by methylprednisolone, which blocks leukotriene synthesis; both of which are beneficial postexposure.85 Ibuprofen, an inhibitor of the arachidonic acid cascade, and xenobiotics capable of reducing neutrophil influx, such as colchicine and cyclophosphamide, reduce lung injury and mortality in mice when they are administered shortly after phosgene exposure.77,172 Intratracheal dibutyryl cyclic adenosine monophosphate (DBcAMP), a cAMP analog, and other cAMP amplifiers, such as terbutaline or aminophylline, inhibit the release of leukotrienes and reduce toxicity.102,173 When administered 45 minutes after exposure to phosgene-poisoned rabbits, intratracheal N-acetylcysteine(NAC) decreases the formation of leukotrienes by an undefined means and limits the development of ARDS.174 Presumably, administration via nebulization would prove similarly effective. Intravenous administration of NAC to patients with mild to moderate ARDS, none of whom had phosgene-induced pulmonary damage, improved systemic oxygenation and reduced their need for ventilatory support.190 However, progression to respiratory failure was not altered.
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Free radicals are highly reactive molecular derivatives, typically from oxygen or nitrogen which bind to and destroy tissue near their site of generation. Through initiation of a lipid peroxidative cascade, free radicals destroy lipid membranes and inhibit energy production through the electron transport chain (Chap. 12). Products of lipid peroxidation and cellular damage initiate neutrophilic influx, presumably in an immunologic attempt to combat a pathogen. Ironically, free radicals generated by the invading inflammatory cells contribute to pulmonary damage. Fortunately, the lung has both enzymatic (eg, superoxide dismutase, glutathione peroxidase, catalase) and nonenzymatic (eg, glutathione, ascorbate) antioxidant systems, which detoxify virtually all free radicals present in the lung.154 However, the oxidant burden imposed by oxidant gases can preempt these detoxifying systems and produce cellular damage. For example, nebulization of manganese superoxide dismutase into the airway one hour after smoke inhalation, a form of oxidant lung injury, did not improve lung edema or pulmonary gas exchange.119 However, the observed benefit of NAC may also be related to improved hemodynamic function (Antidotes in Depth: A3).91
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Clinical Manifestations
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Regardless of the mechanism by which the mucosa is damaged, the clinical presentations of patients exposed to irritant gases are similar. Those exposed to gases that result in irritation within seconds generally develop mucosal injury limited to the upper respiratory tract. The rapid onset of symptoms is usually a sufficient signal to the patient to escape the exposure. Patients may present with nasal or oropharyngeal pain in addition to drooling, mucosal edema, cough, or stridor.193 Conjunctival irritation or chemosis, as well as skin irritation, is often noted because concomitant ocular and cutaneous exposure to the gases usually is unavoidable. Gases that are less rapidly irritating may not provide an adequate signal of their presence and may not prompt expeditious escape by the exposed individual. In this case, prolonged breathing allows entry of the toxic gas farther into the bronchopulmonary system, where delayed toxic effects may subsequently be noted. Tracheobronchitis, bronchiolitis, bronchospasm, and ARDS are typical inflammatory responses of the airway and represent the spectrum of acute lower respiratory tract injury.
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Experimental models assessing the water solubility of a gas to predict the location of its associated lesions have largely agreed with the clinical data.105 However, exceptions to this relationship of a gas and its expected toxicity are common. For example, in situations in which escape from ongoing exposure is prevented, patients may develop lower respiratory tract injury after prolonged exposure to acutely irritating gases. Alternatively, rapid onset of upper respiratory irritation may be noted in patients after exposure to concentrated gases that are generally associated with delayed symptomatology. Exposure to exceedingly high concentrations of any irritant gas may produce hypoxemia analogous to that resulting from exposure to a simple asphyxiant gas.
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The most characteristic and serious clinical manifestation of irritant gas exposure is ARDS.13,20,162,163 ARDS consists of the clinical, radiographic, and physiologic abnormalities caused by pulmonary inflammation and alveolar filling that must be both acute in onset and not attributable solely to pulmonary capillary hypertension as occurs in patients with congestive heart failure.13,20,162,163 ARDS is a nonspecific syndrome resulting from diverse physiologic insults such as sepsis or trauma. Patients with ARDS may present with dyspnea, chest tightness, chest pain, cough, frothy sputum, wheezing or crackles, and arterial hypoxemia. Typical radiographic abnormalities include bilateral pulmonary infiltrates with an alveolar filling pattern and a normal cardiac silhouette that differentiate this syndrome from congestive heart failure.
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In 2012, the diagnostic criteria for ARDS was updated as a consensus guideline known as the Berlin Definition.9,10 The draft definition proposed three mutually exclusive strata of ARDS based on the degree of hypoxemia (Table 124–3). Some essential changes of the new definition include: acute was defined as one week or less; the term acute lung injury (ALI) was discontinued; measuring the PaO2/FiO2 ratio now requires a specific amount of positive end-expiratory pressure (PEEP); chest radiograph criteria have been clarified to improve interrater reliability; the pulmonary capillary wedge pressure (PCWP) criterion was removed; and additional clarity was added to improve the ability to exclude cardiac causes of bilateral infiltrates.
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Acid- or Base-Forming Gases Highly Water-Soluble Xenobiotics
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Ammonia is a common industrial and household chemical used in the synthesis of plastics and explosives, and as a fertilizer, a refrigerant, and a cleaner. The odor is characteristic and may be an effective warning signal of exposure and stimulus to avoid further exposure. Dissolution of NH3 in water to form the base ammonium hydroxide (NH4OH) rapidly produces severe upper airway irritation. Patients with exposures to highly concentrated NH3 or exposures for prolonged periods may develop tracheobronchial or pulmonary inflammation. Experimental inhalation of nebulized high-dose ammonia causes ARDS within 2 minutes of exposure.179 Ultrastructural study of the lungs from two individuals dying acutely of ammonia inhalation revealed marked swelling and edema of type I pneumocytes consistent with ARDS.35 Chronic inhalation of low concentrations of NH3 or repetitive exposure to high concentrations of ammonia may cause pulmonary fibrosis.31
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This series of chlorinated nitrogenous compounds (Fig. 124–1) includes monochloramine (NH2Cl), dichloramine (NHCl2), and trichloramine (NCl3). The chloramines are most commonly generated by the admixture of ammonia with sodium hypochlorite (NaOCl) bleach, often in an effort to potentiate their individual cleaning powers.72 Interestingly, the addition of bleach to septic systems may result in liberation of the chloramines after the reaction of bleach with urinary nitrogenous compounds.129 On dissolution of the chloramines in the epithelial lining fluid, hypochlorous acid (HOCl), ammonia, and oxygen radicals are generated, all of which act as irritants. Although less water soluble than ammonia, the chloramines typically promptly result in symptoms. Because these initial symptoms are often mild, however, they may not prompt immediate escape, resulting in prolonged or recurrent exposure with pulmonary and ocular symptoms predominating.41 Exposure to trichloramine occurs at indoor swimming pools43 and is responsible for inducing permeability changes in the pulmonary epithelium, the consequences of which are not yet understood.38
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Hydrogen chloride (HCl).
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The largest and most important use of hydrogen chloride gas is in the production of hydrochloric acid. Dissolution of hydrogen chloride gas in lung water after inhalation similarly produces hydrochloric acid.34,152 Pyrolysis of polyvinyl chloride (PVC), a plastic commonly used in pipe fabrication, generates HCl and is an occupational hazard for firefighters.141 By adsorbing to respirable carbonaceous particles generated in the fire, HCl may be deposited in the alveoli and produce pulmonary toxicity.
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Hydrogen fluoride and its aqueous form, hydrofluoric acid, are used in the gasoline, glassware, building renovation, and semiconductor industries. Hydrogen fluoride gas dissolves in epithelial lining fluid to form the weak acid hydrofluoric acid. The intact HF molecule is the predominant form in solution, and few free hydronium ions (H3O+) are liberated. Low-dose inhalational exposures may result in irritant symptoms,200,212 and large exposures may cause bronchial and pulmonary parenchymal destruction.30,200 Death after inhalation may result from ARDS, but usually is related to systemic fluoride poisoning independent of the route of exposure because of the resultant calcium binding and subsequent hypocalcemia and hyperkalemia26,59 (Chap. 107).
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Sulfur dioxide and sulfuric acid (SO2 and H2SO4).
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Sulfur dioxide has multiple industrial applications and is a byproduct found in the smelting and oil refinery industries. It may also be generated by the inadvertent mixing of chemicals, such as an acid with sodium bisulfite (NaHSO3). Sulfur dioxide is highly water soluble and has a characteristic pungent odor that provides warning of its presence at concentrations well below those that are irritating. In the presence of catalytic metals (Fe, Mn), environmental sulfur dioxide is readily converted to sulfurous acid (H2SO3) within water droplets. Sulfurous acid is a major environmental concern and the cause of “acid rain.” Exposure to atmospheric sulfur dioxide results in a roughly dose-related bronchospasm, which is most pronounced and difficult to treat in patients with asthma. Inhalation of sulfurous acid or dissolution of sulfur dioxide in epithelial lining fluid produces typical pathologic and clinical findings associated with ARDS.159 In addition to the effect of acid generation upon dissolution, sulfur dioxide may cause oxidative damage to the lungs.127 Large acute exposure to either xenobiotic produces the expected acute irritant response of both the upper and lower respiratory tracts,44 and pulmonary dysfunction (see Asthma and Reactive Airways Dysfunction Syndrome) may persist for several years.149
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Intermediate Water-Soluble Xenobiotics
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Chlorine gas is a valuable oxidizing agent with various industrial uses, and occupational exposure is common. Chlorine gas was used as a chemical warfare agent by both the French and the Germans in World War I (Chap. 132). Although chlorine gas is not generally available for use in the home, domestic exposure to chlorine gas is common. The admixture of an acid to bleach liberates chlorine gas (Fig. 124–2).80,135 Because the anionic component of the acid is not involved in the reaction, combining hypochlorite with virtually any acid, such as phosphoric, hydrochloric, or sulfuric acid, may result in the release of chlorine gas. As such, inappropriate mixing of cleaning products is the cause of most nonoccupational exposures.135 Rarely, patients have intentionally generated chlorine gas in this manner for purportedly “pleasurable” purposes.155 Concentrated chlorine gas may be generated when aging swimming pool chlorination tablets, such as calcium hypochlorite [Ca(OCl)2] or trichloro-s-triazinetrione (TST), decompose118,213 or are inadvertently introduced to a swimming pool while swimmers are present.15,205 Inadvertent mixture of Ca(OCl)2 and TST results in excessive chlorine gas generation and may also be explosive.118 Acute chlorine toxicity may occur when there is a failure of the system when compressed chlorine gas is used for direct chlorination of public swimming pools15,204 or for drinking water systems. Occasional mass poisoning may occur during scientific, industrial, or transportation incidents.42,198
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Mass exposure has also been reported when a chlorine storage tank was being recycled, and it ruptured.40 The odor threshold for chlorine is low, but distinguishing toxic from permissible air concentrations may be difficult until toxicity is manifest. The intermediate solubility characteristics of chlorine result in only mild initial symptoms after moderate exposure and permit a substantial time delay, typically several hours, before clinical symptoms develop. Chlorine dissolution in lung water generates HCl and hypochlorous (HOCl) acids. Hypochlorous acid rapidly decomposes into HCl and nascent oxygen (O). The unpaired nascent oxygen atom produces additional pulmonary damage by initiating a free radical oxidative cascade. Although the majority of life-threatening chlorine poisonings occur after acute, large exposures, patients with chronic, low-concentration exposure or recurrent, moderate concentration poisonings may manifest increased bronchial responsiveness.5,69,76
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Hydrogen sulfide (H2S).
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Hydrogen sulfide exposures occur most frequently in the waste management, petroleum, and natural gas industries,92 although poisoning occurs in asphalt, synthetic rubber, and nylon industry workers as well. It is also rarely seen in hospital workers using acid cleaners to unclog drains clogged with plaster of Paris sludge.148 Hydrogen sulfide is present in natural sources such as volcanic emission, in caves, and in sulfur springs. It is a decay product of organic material found in sewers or manure pits. Hydrogen sulfide, hydrogen fluoride, and phosphine are differentiated from the other irritant gases by their ability to produce significant systemic toxicity. Hydrogen sulfide inhibits mitochondrial respiration in a fashion similar to that of cyanide (Chap. 126).64,157
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H2S has the distinctive odor of “rotten eggs,” which, although helpful in diagnosis, is not specific. Despite a sensitive odor threshold of several parts per billion,157 rapid olfactory fatigue ensues, providing a misperception that the exposure and its attendant risk have diminished. At low and moderate concentrations (≤500 ppm), upper respiratory tract mucosal irritation occurs and is the principal toxicity.192 The rapidity of death in patients exposed to high H2S concentrations makes it likely that either simple asphyxiation or cytochrome oxidase inhibition is causal in most cases.
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Phosgene (carbonyl chloride {COCl2}).
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During World War I, phosgene was an important weapon of mass destruction that produced countless deaths (Chap. 132). Currently, phosgene is used in the synthesis of various organic compounds, such as isocyanates, and it occasionally produces poisoning. It is a byproduct of heating or combustion of various chlorinated organic compounds.181
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Exposure to phosgene initially may produce limited manifestations, but may result in acute mucosal irritation after intense exposure. In fact, the pleasant odor of fresh hay, rather than prompting escape, ironically may promote deep and prolonged breathing of the toxic gas. The most consequential clinical effect related to phosgene exposure is delayed ARDS.27,169 Because of the accumulation of a significant alveolar burden of phosgene, symptoms generally are severe after they occur. The delay in onset may take up to 24 hours, so prolonged observation of patients thought to be phosgene-poisoned is warranted. The mechanism of phosgene toxicity is dependent on the dissolution of the gas into the fluid of the epithelial lining with resultant liberation of hydrochloric acid and reactive oxygen species (ROS).169
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Rather than acidic or alkaline metabolites, free radicals mediate the pulmonary toxicity of certain irritant gases. Many of the chemicals discussed participate in both acid–base and oxidant types of injury. However, the clinical distinction between acid- or alkali-forming agents and oxidant gases is difficult but ultimately may prove therapeutically relevant.
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Oxygen toxicity is uncommon in the workplace but, ironically, is common in hospitalized patients. Although O2 may produce CNS and retinal toxicity, pulmonary damage is more common.180 Several clinical studies indicate that humans can tolerate 100% O2 at sea level for up to 48 hours without significant acute pulmonary damage.37,56 Under hyperbaric conditions (2.0 atmospheres absolute), such as during compressed-air diving or while inside a pressurized hyperbaric chamber, oxygen toxicity may develop within 3 to 6 hours.47 ARDS occurs in approximately 5% of patients administered hyperbaric oxygen for therapeutic purposes.180 Delayed pulmonary fibrosis, presumably from healing of subclinical injury, may develop in patients breathing lower concentrations of O2 at sea level for shorter periods.
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Although it appears paradoxical that O2, an essential molecule, may be deleterious at elevated concentrations, it is not. In mitochondria, O2 plays a critical role as the ultimate acceptor for electrons completing the electron transport chain. It is this same potent oxidizing activity that allows O2 to remove electrons from other compounds generating the reactive oxygen intermediates.164
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Generation of ROS, including superoxide (
), hydroxyl radical (OH·), hydrogen peroxide (HOOH), singlet oxygen (O·), and nitric oxide (NO), produces cellular necrosis, increases pulmonary capillary permeability, and induces apoptosis.142,164 NO, produced by inducible NO synthase (iNOS) in the setting of oxidative stress, is directly cytotoxic or may combine with superoxide anions to form the more reactive oxidant peroxynitrite (ONOO–).93 Experimental prevention of these effects by administration of either parenteral NAC,165,207 a chemical antioxidant, or superoxide dismutase, an enzymatic antioxidant,37,199 suggests that the mechanism of toxicity relates to the oxidant, or electrophilic, effects of these ROS (Chap. 12). Although several other therapies have shown promise in preventing oxygen-mediated toxicity, none has yet proven to be valuable for patients who already manifest pulmonary toxicity. Current techniques for preventing pulmonary oxygen toxicity emphasize reduction of the inspired oxygen concentration by use of PEEP ventilation, although this approach failed to prove beneficial in at least one clinical trial.14 The potential role of liquid ventilation of the lung with perfluorocarbons to prevent or treat pulmonary oxygen toxicity remains under investigation.14
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Oxides of nitrogen (NOx).
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Oxides of nitrogen are a series of variably oxidized nitrogenous compounds.73 The most important substances included in this series are the stable free radicals nitrogen dioxide (NO2) and nitric oxide (NO), as well as nitrogen tetroxide (dinitrogen tetroxide [N2O4]), nitrogen trioxide (N2O3), and nitrous oxide (N2O). The oxides of nitrogen are of limited value in industrial operations, although they may be generated during welding and brazing. NO2, in addition to hydrogen cyanide, is produced in the pyrolysis of nitrocellulose, which is a substantial component of radiographic film. For example, a fire in the radiology department of the Cleveland Clinic in 1929 resulted in 125 casualties, with virtually all deaths resulting from cyanide or NO2 gas poisoning.82 NO2 toxicity may occur when propane-driven ice-cleaning machines are used in indoor ice skating rinks with poor ventilation, thereby allowing accumulation of the generated NO2.114 Military exposure to high NO2 concentrations may occur during closed-space fires, such as in submarines.120 NO2 also causes silo filler’s disease, in which the toxic gas generated during decomposition of silage accumulates within the silo shortly after grain storage, eliminating rodents that feast on the grains.60,215 In the absence of ventilation, high concentrations of NO2 may accumulate in the silo such that an individual entering the silo is rapidly asphyxiated from the depletion of oxygen.83 Additionally, substantial quantities of NO2 remaining after incomplete ventilation may produce the delayed-onset pulmonary toxicity characteristic of silo filler’s disease. Chronic indoor exposure to NO2, generated during cooking99 or outdoor exposure to photochemical smog, of which the oxides of nitrogen are a component, may predispose individuals to the development or exacerbation of chronic lung diseases.
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The various oxides of nitrogen may directly oxidize respiratory tract cellular membranes, but more typically generate reactive nitrogen intermediates, or radicals, such as ONOO–, which subsequently damage the pulmonary epithelial cells.146 In addition to generating oxidant cascades, dissolution in respiratory tract water generates nitric acid (HNO3) and NO, which produce injury consistent with other inhaled acids. In fact, inhalation of HNO3 produces the same clinical and pathologic syndrome.86 Antioxidants afford significant protection to human endothelial cells exposed to NO2, indicating an important role of free radicals in the toxicology of these xenobiotics.201
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NO, an endogenous compound important as a neurotransmitter and vasorelaxant, is used clinically as exogenous inhalational therapy for pulmonary hypertension and ARDS.195 In patients with ARDS not resulting from sepsis (although not specifically from inhalational injury), low concentrations of inhaled NO (5 ppm) did not improve the clinical outcome.195 However, one patient with NO2 pulmonary toxicity improved clinically after NO therapy, so further consideration is warranted.112 Furthermore, its use in premature infants with respiratory distress syndrome is well accepted.168 NO is less soluble in the fluid lining the epithelial surfaces than are the other oxides of nitrogen and produces irritant effects after large exposures.88,211 Its pulmonary oxidative toxicity, the manifestations of which are typical of the oxidant gases, is substantially enhanced by conversion to reactive nitrogen intermediates such as ONOO–.19 This radical selectively interacts with tyrosine to produce nitrotyrosine, which may subsequently serve as a marker for oxidant damage.88 NO may be absorbed from the lung and is rapidly bound by hemoglobin to form nitrosylhemoglobin and methemoglobin.
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Ozone is abundant in the stratospheric region found between 5 and 31 miles above the planet. Ozone is formed by the action of ultraviolet light on oxygen molecules, thus reducing the amount of solar ultraviolet irradiation reaching earth. The ozone concentration in passenger aircrafts may at times be above regulatory limits,182 although a specific relationship with the development of clinical effects in airline crew members is elusive.136 Ozone is another important component of photochemical smog and, as such, contributes to chronic lung disease.32,202 It is produced in significant quantities by welding and high-voltage electrical equipment and in more moderate doses by photocopying machines and laser printers. Because of its high electronegativity (only fluorine is higher), ozone is one of the most potent oxidizing agents available. For this reason, it is used as a bleach, particularly as an alternative to chlorine in water purification and sewage treatment.
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The pulmonary toxicity associated with ozone primarily results from its high reactivity toward unsaturated fatty acids and amino acids with sulfhydryl functional groups.21,101 Ozonation and free radical damage to the lipid component of the membrane initiate an inflammatory cascade, with resultant influx of inflammatory cells.22,158 Reactive nitrogen species are also implicated, as NO synthase knockout mice are relatively protected from ozone-induced inflammation and tissue injury.67 Increased permeability of the pulmonary epithelium results in alveolar filling from the transudation of proteins and fluids characteristic of ARDS. Antioxidant agents (eg, vitamin E) that react preferentially with free radicals before membrane damage occurs prevent or limit the pulmonary toxicity of ozone.
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Miscellaneous Pulmonary Irritants
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Methylisocyanate (MIC; Fig. 124–3) is one of a series of compounds sharing a similar isocyanate (N=C=O) moiety. Toluene diisocyanate (TDI) and diphenyl-methane diisocyanate (MDI) are important chemicals in the polymer industry. In those exposed to MIC in Bhopal, ARDS was evident both clinically and radiographically.130 MIC is a significantly more potent respiratory irritant than the other regularly used isocyanate derivatives such as TDI.6 Cyanide poisoning does not occur, and empiric antidotal therapy is not indicated.
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Riot control agents: capsaicin, chlorobenzylidenemalononitrile, and chloroacetophenone.
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Historically, riot control agents (Fig. 132–5), commonly called Mace, consisted primarily of chloroacetophenone (CN) or chlorobenzylidenemalononitrile (CS).24 Both are white solids that are dispersed as aerosols. The dispersion is generally accomplished through mixture with a pyrotechnic agent such as a grenade or with a volatile organic solvent in a personal protection canister. Because the delivery systems of these agents are of limited sophistication and are subject to prevailing environmental conditions, dosing is unpredictable, and unintended self-poisoning is common.24 After low-concentration exposure, ocular discomfort and lacrimation alone are expected, accounting for the common appellation tear gas. The effects are transient, and complete recovery within 30 minutes is typical, although long-lasting pulmonary effects may occur (see Asthma and Reactive Airways Dysfunction Syndrome).161 Closed-space or close-range exposure, as well as physical exertion during exposure, may produce significant ocular toxicity, dermal burns, laryngospasm, ARDS,196 or death.24 Because of their high potential for severe toxicity, CN and CS were replaced for civilian use by oleoresin capsicum (OC), also known as pepper spray or pepper mace. Although capsaicin, its active component, is considerably less toxic, it is occasionally responsible for pneumonitis23 and death.186
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Capsaicin interacts with the vanilloid receptor-1 (VR1), which was recently renamed the transient receptor potential vanilloid-1 (TRPV1).191 Stimulation of this receptor invokes the release of substance P, a neuropeptide involved with transmission of pain impulses. Substance P also induces neurogenic inflammation, which, in the lung, results in ARDS and bronchoconstriction (see Asthma and Reactive Airways Dysfunction Syndrome).191 The severe pulmonary toxicity of CS and CN likely is related to their ability to alkylate tissues in a manner similar to nitrogen mustard.48
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Acute inhalational exposures to certain metal compounds produce clinical effects identical to those of the chemical irritants. For example, zinc chloride (ZnCl2) fume is used as artificial smoke because of the dense white character of the fume, and an aqueous solution is still used as a soldering flux. Exposure to zinc chloride fumes for just a few minutes is associated with ARDS and death66,94,95 (Chap. 103). Cadmium oxide (CdO) is generated during the burning of cadmium metal in an oxygen-containing environment, as occurs during smelting or welding (Chap. 91). The refining of nickel using carbon monoxide (Mond process) produces nickel carbonyl [Ni(CO)4], a volatile pulmonary oxidant175 (Chap. 99). Inhalation of volatilized elemental mercury,134 which occurs during the vacuuming of mercury spills or home extracting of precious metals, may be toxic. Although at sufficient concentrations, many of these metal exposures produce warning symptoms, severe toxicity may occur even in the absence of warning symptoms. The mechanism of toxicity may relate to overwhelming oxidant stress with a pronounced inflammatory response as measured by serum cytokines (eg, TNF-α) concentrations.95 Experimental findings suggest a role for inactivation of natural antioxidant systems.214 Patients with metal-induced pneumonitis present with chest tightness, cough, fever, and signs consistent with ARDS. Metal pneumonitis is distinguishable from other causes of ARDS only by history or, retrospectively, by elevated serum or urine metal concentrations.8 In particular, metal pneumonitis should be differentiated from the more common and substantially less consequential metal fume fever, discussed later in this chapter. In addition to standard supportive measures, patients with acute metal-induced pneumonitis should be hospitalized and receive corticosteroids.95 Chelation therapy has no documented benefit for treatment of patients with ARDS, but should be used based on conventional indications.