Patterns of Response to Irritant Inhalation

Acute lung toxicity results from a variety of exposures but, nonetheless, is manifest by a narrow repertoire of injury ( Table 75-1 ). Irritant toxic substances can be encountered in various physical states relevant to their inhalational properties. Such states include gases, vapors (i.e., the gaseous form of a substance that is a liquid or a solid at normal temperatures and pressures), and fumes (i.e., solid material, often metals, of small particle size suspended in a gaseous medium (most < 1.0 µm and many < 0.1 µm). Aerosols encompasses a mix of potential states (i.e., liquid droplets or fine particulates dispersed in a gaseous medium; smoke is a subset of aerosol resulting from incomplete combustion).

These various classes of exposures include heterogeneous toxic agents that are capable of causing extensive cell injury throughout the upper and lower respiratory tract. The primary location of respiratory tract injury and the onset of clinical symptoms are partly dependent on the solubility of the gas, vapor, fume, or aerosol involved and, in the case of fumes or aerosols, particle or droplet physical characteristics. Other factors that determine the injury pattern following exposure include (1) amount of the toxic substance inhaled, (2) duration of exposure to the inhalant, (3) concentration of the inhalant in the ambient air, (4) other physical properties (such as pH or chemical reactivity), and (5) a variety of host factors, such as age, use of respiratory protection, and comorbid illness. Overwhelming exposures to any irritant inhalant, however, can cause extensive damage throughout the respiratory tract.

Ammonia and sulfur dioxide are examples of substances that are highly soluble in water. Such highly soluble substances cause immediate irritation of the conjunctival mucosa and upper airways. In contrast, oxides of nitrogen, ozone, and phosgene have relatively low water solubility. For this reason, exposure to one of these agents may not be characterized by immediate symptoms of mucous membrane irritation. This may lead to more prolonged exposure and delay in seeking medical attention. Both more and less soluble irritant exposures can lead to distal lung injury, but in the case of highly soluble materials, a history of severe upper respiratory symptoms should precede the presentation of distal airway and alveolar damage.

Irritants reaching the lower respiratory tract, either because of their inherent physical characteristics or because of exposures that overwhelm the absorptive capacity of the upper airway, can injure both the lung epithelium and its endothelium. Pathophysiologically, irritant injury at this level leads to a nonspecific pattern of diffuse alveolar damage similar to that seen from a variety of different causes (see Chapter 15 ). The pathologic changes in fatal cases of irritant lung injury include focal and confluent areas of edema with protein-rich fluid in the alveolar spaces, hyaline membrane formation, and denudation of the alveolar epithelium. In addition, mucous membranes of the bronchial and bronchiolar walls may be destroyed or denuded. Some pulmonary hemorrhage may be seen in irritant lung injury but is typically not the dominant clinical-pathologic manifestation; prominent pulmonary hemorrhage should raise suspicion of other toxicant- or nontoxicant-mediated syndromes (see Chapter 67 ).

On the cellular level, respiratory tract injury may be mediated through the deposition or formation of an acid, alkali, free radical, or other reactive chemical species. The precise cellular mechanisms of injury from irritant inhalants have not been fully delineated even for relatively common irritants such as chlorine or even the chemical warfare agent phosgene, substances for which a great deal of human and experimental animal data exist.

Other Patterns of Response

Acute irritant inhalation injury is the predominant, but not the only, pathophysiologic mechanism underlying acute toxic lung syndromes. In contrast to the anatomic distribution commonly seen in water-soluble, irritant chemical–related inhalant injury, it may be difficult to delineate a descending, hierarchical pattern from upper airway to lower lung injury following exposure to a diverse group of other agents. Many of these exposures, as with the water-soluble irritants, also lead to acute lung injury via nonimmunologic mechanisms (clinically, acute respiratory distress syndrome; pathologically, diffuse alveolar damage), as detailed subsequently in this chapter. Other toxicant exposures produce various other syndromes of respiratory tract injury, such as heavy metal pneumonitis, hydrocarbon aspiration, or paraquat lung injury. The inhalation fever syndromes are an exception in that they do not involve obvious lung injury; the pathophysiology of this group of self-limited acute lung syndromes appears to be cytokine-mediated.

Chlorine, Chloramines, Hydrochloric Acid, and Related Chemicals

Among the toxic agents causing pulmonary responses, chlorine is a common and potent irritant inhalant accounting for substantial human morbidity. Common forms of exposure include industrial leaks, environmental releases primarily during transport, water purification, swimming pool–related events, household cleaning product misadventures, and even homemade chemical bombs or intentional terrorist use. In the form of a yellow-green acrid gas, industrial and environmental releases typically present clear-cut exposure histories. Because the gas is heavier than air, higher contamination can be expected in low-lying areas (hence, its use in trench warfare in World War I). However, other environmental conditions may supervene. Examples include one well-documented case of the gas rising along the heated outside wall of a factory where rooftop workers were exposed. In another case, chlorine initially collected in a basement but then was sucked up into the central heating system of a dormitory.

The history of exposure to chlorine may be less straightforward when the chlorine is generated after de novo generation from chlorine-containing products. Chlorine gas can be generated from liquid bleach containing hypochlorite or from dry powdered bleach containing chlorinated phosphate. In either liquid or powdered bleaches, the chlorine gas is liberated on contact with acids in common household products containing muriatic (i.e., hydrochloric), phosphoric, or hydrofluoric acid or in industrial settings. In contrast, mixing chlorine-containing products with ammonia leads to release of chloramines (monochloramine [NH ₂ Cl] and dichloramine [NHCl ₂ ]) and related chemicals, especially nitrogen trichloride (NCl ₃ ), chemicals whose irritant effects are attributed to in situ pulmonary reactions releasing chlorine, hypochlorous acid, and ammonia. In swimming pools, inadvertent mixing of the chlorinated water with nitrogen donors can also happen, with potential irritant effects attributed to nitrogen trichloride in particular. Chloramines evolved from chlorine and ammonia mixing should not be confused with Chloramine-T (sodium-N-chlorine-p-toluene sulfonamide), a disinfectant that can act as a chemical sensitizer leading to allergic asthma and other anamnestic responses.

Irritant effects after inhalation of hypochlorite aerosols in confined spaces without a history of combining products (not an uncommon scenario when cleaning bathrooms) can also be associated with irritant effects. Similarly, in certain industrial operations, hydrochloric (hydrogen chloride in water) or hypochlorous acid aerosols are also respiratory irritants. Chlorine exposure can also take place in specific industrial processes that use inorganic chlorine derivatives; worthy of particular mention are chlorine dioxide (used in pulp paper processing), chlorinated silanes (gases used in microelectronics), reactive metal halides (e.g., titanium or antimony chlorides), and thionyl chloride (which breaks down to yield hydrogen chloride and sulfur dioxide).

For chlorine and related chemicals, the acute respiratory response corresponds to the effective dose delivered to the lungs. For chlorine, as for irritant gases generally, the dose response has been presumed to be equivalent for any given cross-product of concentration and exposure time (Haber law), although experimental data indicate that this relationship may be more variable. All of these compounds appear to share a final common toxic pathway. As noted in the general discussion of acute toxicant inhalation, water solubility is an important determinant of the dose reaching the lower airways. For chlorine, chlorine dioxide, chloramines, and nitrogen trichloride, their lower solubility favors deeper penetration with a more effective delivered dose compared with an equivalent inhalation of agents with a higher solubility such as acid aerosols. However, exposure to any of these compounds is associated with some degree of immediate mucous membrane and upper airway irritation. In fact, the absence of acute irritant effects is not clinically consistent with chlorine gas or related exposures.

Chlorine inhalation may manifest any of the full spectrum of respiratory tract irritant effects, from minor mucosal responses to upper airway responses to diffuse alveolar damage. Persistent airway hyperresponsiveness after irritant exposure has been associated particularly with chlorine gas and chlorine-containing products, although this association may have more to do with the frequency of exposure to chlorine rather than to any particular effect of chlorine on the airways. Human experimental studies are inconsistent as to whether persons with underlying airway hyperreactivity may be more sensitive to chlorine.

Use of inhaled bronchodilators and inhaled steroids may be indicated for both acute and residual bronchospasm following chlorine inhalation, consistent with general principles of management addressed previously. Although several case reports and series have touted the potential benefits of nebulized sodium bicarbonate inhalation in the acute treatment of chlorine or chloramine inhalation, the efficacy of this intervention has never been assessed in a controlled trial. One small controlled trial administered inhaled bicarbonate 3 months or more after exposure in irritant-induced asthma and described some benefit.

Oxides of Nitrogen, Ozone, Sulfur Dioxide, and Acid Aerosols

These inhalants are major air pollutants; the effects of low-level exposure are discussed in detail in Chapter 74 . When they are inhaled in high concentrations, these irritants cause acute lung injury. Because of their lower solubility and thus their lower incidence of upper airway symptoms, ozone and, even more commonly, nitrogen dioxide, may be associated with a longer exposure with a greater predilection for lung injury. Nonetheless, with sulfur dioxide and acid aerosols, despite their high solubility, a sufficient intensity of exposure can also lead to diffuse alveolar damage.

High-intensity exposure to oxides of nitrogen can take place through decomposition of organic matter and other sources. Examples of exposure scenarios include nitrogen dioxide-induced lung injury among farmers (also known as silo filler’s disease), use of internal combustion engines in enclosed spaces (with large outbreaks associated with ice resurfacing equipment used in indoor skating rinks), thermal degradation of polymers (e.g., in structural fires), toxic gas produced by the detonation of explosives, the release of gas through reactions of nitric acid breakdown in air or in reaction with metals or organic materials, welding by-products, particularly when “gas-shielded” techniques are employed (manual inert gas welding or tungsten inert welding), and the release of compressed nitrogen dioxide gas. Historically, the detonation of explosives has been one of the most important sources of exposure to nitrogen oxides. Nitric oxide, an inhalant used therapeutically, breaks down to nitrogen dioxide in the presence of oxygen and, thus, must be monitored with appropriate delivery devices to avoid exposure to the potentially toxic nitrogen dioxide.

High-intensity occupational ozone exposure is unusual, but it can happen with welding conditions similar to those associated with oxides of nitrogen. More recently, ozone in water treatment and in pulp paper bleaching has also emerged as a health issue; in the latter industry, there is often concomitant exposure to chlorine dioxide.

Important sources of high-level sulfur dioxide exposure include mining and ore refining, Portland cement manufacturing, sulfur treatment of fruit, and industrial releases. Historically, sulfur dioxide has been and continues to be important in sulfite process pulp paper processing, where acute gas releases are superimposed on chronic lower-level exposure. In the past, sulfur dioxide was also a common refrigerant.

In ambient air pollution, sulfuric acid is an acid aerosol of primary concern; in various occupations, sulfuric acid can also be encountered at high levels. Workers can be exposed to sulfuric acid through both direct use and the breakdown of a highly toxic industrial chemical, dimethyl sulfate. A number of other inorganic and organic acid vapors and aerosols are also important potential causes of acute lung injury, including chromic, acetic, formic, and hydrofluoric acids. Hydrofluoric acid (hydrogen fluoride) inhalation, in addition to nonspecific irritant effects, can induce clinically significant hypocalcemia, which is thought to result from the formation of insoluble calcium fluoride. People can be exposed to hydrofluoric acid in manufacturing of both microelectronics and phosphate fertilizers, in household use of hydrofluoric acid rust removal agents (the mixture of which with hypochlorite bleach can evolve both chlorine and hydrogen fluoride), and in the incomplete combustion (pyrolysis) of fluorinated polymers. Exposure to hydrogen fluoride is a chronic problem in the aluminum smelting industry. Hydrogen fluoride is also released as a breakdown product of sulfur hexafluoride, an electrical insulating liquid chemical used in equipment.

Military and Crowd Control Agents

Toxic Metals

Metal Fume Fever, Polymer Fume Fever, Organic Dust Toxic Syndrome, and Other Inhalation Fevers

There are a number of febrile flulike pulmonary syndromes reflecting similar clinical responses to a diverse group of acute inhalational exposures. Their hallmark is chills, fever, malaise, and myalgia with onset 4 to 8 hours after intense inhalation of fumes or organic dusts. Common respiratory complaints include cough or mild dyspnea, but findings of chest radiographic opacities or hypoxemia are inconsistent with this disorder. Peripheral leukocytosis usually accompanies the syndrome; bronchoalveolar lavage shows a marked influx of neutrophils. These syndromes all are self-limited, resolving clinically within 12 to 48 hours. Inhalation fevers share a common feature of tachyphylaxis, with a blunted response to daily repeated inhalation (and hence the name “Monday morning fever” among both brass founders and cotton mill workers).

Signs or symptoms of pneumonitis should suggest alternative, more serious diagnoses, such as cadmium pneumonitis, hypersensitivity pneumonitis (see Chapter 64 ), active infection (in the case of water-source aerosols), or inhalation of more toxic temperature-dependent fluoropolymer combustion by-products (which include hydrogen fluoride and perfluorisobutulyne [PFIB], which is more toxic than phosgene). Toxic pneumonitis due to fluorocarbon-containing aerosol sprays is an exposure scenario distinct from polymer fume fever from exposure to fluoropolymer combustion by-products or from acute lung injury and are dealt with separately (see later).

Metal fume fever is associated with zinc oxide inhalation from welding galvanized metal or brass working. There is only limited clinical evidence that other metals (magnesium and copper) are capable of causing a similar response, and experimental data further discount magnesium as a potential cause of fume fever. Zinc oxide fume rarely has also been purported to cause an acute lung pattern in case reports of welding-related illness, but the likelihood of cadmium or nitrogen dioxide co-exposures make this uncommon association questionable. Further, controlled experimental human exposure data do not support this as a zinc oxide inhalation effect.

Polymer fume fever is associated with thermal breakdown products of fluoropolymers (e.g., Teflon and related materials). The pathophysiologic mechanisms underlying the metal and polymer fume fever syndromes have not been established, but research suggests that pulmonary cytokines may play a key role.

Organic dust toxic syndrome (ODTS) is associated with inhalation of materials contaminated with thermophilic bacteria and fungal spores, including wood chips, straw, silage, seeds, grains and flour, and textile raw materials. The increasing industrialization of agricultural processes, especially the use of animal confinement techniques or so-called concentrated animal feeding operations (CAFOs), is an additional source of exposure leading to ODTS, although these same settings also can produce irritant gases such as hydrogen sulfide and ammonia. ODTS has gone by various names, including pulmonary mycotoxicosis, silo unloader’s syndrome, and mill fever. One of the best documented historical outbreaks of ODTS was among individuals who worked with contaminated cotton mattresses. Inhalation of aerosols from contaminated water sources produces a self-limited febrile syndrome similar to ODTS. Some of these outbreaks are attributable to inhalation of Legionella species without actual infection (i.e., without clinical evidence of pneumonia) and are referred to as “Pontiac fever.” Contaminated aerosols causing inhalation fever syndromes can originate from saunas or hot tubs, commercial (industrial) humidifying systems, and metal machining cooling fluids. Along with these heterogeneous exposure scenarios, a variety of different names have been used for these syndromes, including humidifier fever, sump bay fever, and bath water fever. As with ODTS, many of the same occupational and environmental conditions can lead to or be concomitant with cases of hypersensitivity pneumonitis and, more specific to waterborne aerosols, active respiratory infection. In addition to its self-limited nature, a key characteristic differentiating an outbreak of inhalation fever from other syndromes is its relatively high attack rate over a fairly short time period. As with metal fume fever and polymer fume fever, cytokines are presumed to be key mediators of the ODTS and water-borne aerosol-related inhalation fevers, with endotoxin and related factors being key exposure variables.

Fluorocarbon Aerosol Spray Pneumonitis

Acute lung injury following inhalation exposure to commercial fluorocarbon-containing aerosol products is an important emerging syndrome first reported in the early 1990s. This syndrome is distinct both from fluoropolymer fume fever as previously discussed and from exposure to irritant by-products from higher-temperature thermal breakdown of such polymers. A key feature of fluorocarbon aerosol pneumonitis is the onset of symptoms within several hours after using a spray product containing fluorocarbon polymers. Exposure can take place in an occupational setting (e.g., construction) or, commonly, from use of over-the-counter products. These exposures can be relatively brief, with varying degrees of ventilation; importantly, exposure need not be in an enclosed space. Victims usually do not recall previous exposure; there is nothing in the condition to suggest a hypersensitivity mechanism. Application of multiple types of fluorocarbon-containing products have been linked to outbreaks; although waterproofing leather and fabric sprays have dominated the reports, other products include floor stain protector, rust-proofing spray, grout sealer, and ski wax. The clinical presentations manifest a range of severity consistent with varying degrees of nonspecific acute lung injury; management is based on standard support care. The various descriptive labels for this condition, such as “horse rug lung” and “hill walkers’ lung,” can obscure the consistent pattern of the syndrome.

Hydrocarbon Pneumonitis and “Fire-Eater’s” Lung

Hydrocarbon pneumonitis can follow oral ingestion of hydrocarbons and associated hydrocarbon aspiration. In the pediatric high-risk age group, aspiration can take place during ingestion from non–tamper-proof containers typically involving mineral spirits, mineral seal oil (common in furniture polish), lamp oil, kerosene (paraffin), turpentine (pine oil), gasoline, and lighter fluid. In adults, hydrocarbon aspiration associated with fuel syphoning represents an occupational hazard among diesel-powered heavy equipment and tractor operators. Even though these substances have systemic toxic effects such as central nervous system depression, life-threatening complications of ingestion are predominantly the result of concomitant hydrocarbon aspiration and subsequent pulmonary compromise, making the lung the target organ of concern in hydrocarbon ingestion. Pneumatocele is a recognized complication of hydrocarbon pneumonitis. In contradistinction to aspiration hydrocarbon pneumonitis, the toxicity of hydrocarbon (solvent) vapor inhalation manifests primarily in either central nervous system or cardiac effects. Major pulmonary target organ damage associated with acute hydrocarbon exposure by inhalation is unusual but has been reported. Importantly, the lung also appears to be the target organ for the toxicity of intravenously administered hydrocarbons, an unusual but well-documented suicidal scenario.

“Fire-eater’s lung” is an important variant of hydrocarbon pneumonitis. This syndrome typically involves adolescents or young adults becoming exposed through mishap during flame-blowing performances using a variety of different flammable materials. In addition to kerosene and gasoline, the toxicants include jet fuel and, in France, an aromatic hydrocarbon-enriched petroleum-distillate called “kerdan.” There has also been a case of citronella oil aspiration in a fire-eater. As with hydrocarbon pneumonitis in children, fire-eater’s lung can also be complicated by pneumatocele. Although the term acute lipoid pneumonia has been used to refer to the fire-eater’s lung syndrome, as well as in other acute aspirations, this is a misnomer.

In both childhood and adult pneumonitis, hydrocarbons are aspirated at the time of the initial ingestion or subsequently with vomiting. The low viscosity of an ingested hydrocarbon is considered a major factor promoting aspiration, presumably for mechanical reasons. Although it has been theorized that hydrocarbon toxicity may involve disruption of surfactant, the chemical pneumonitis of the syndrome appears to be nonspecific.

Paraquat

Paraquat is a widely used herbicide and a potent toxin. Ingestion, rather than inhalation, is the typical route of exposure associated with human toxicity. There have been systemic reactions following skin exposure after direct exposure to the skin (e.g., soaking of the skin with paraquat) or when the skin integrity has been breached (e.g., preexisting skin lesions or burn). The theoretical risk of smoking contaminated materials has never been established.

Most paraquat deaths result from suicidal intent. Paraquat ingestion is a relatively uncommon method of suicide in the United States, but its incidence is greater in a number of other countries, perhaps related to patterns of crop utilization and ease of access. Although paraquat ingestion leads to acute gastrointestinal tract necrosis and multiorgan failure, the lung is the target organ for toxicity among those surviving the immediate postingestion period. Diquat, a related dipyridyl herbicide, does not cause the lung injury associated with paraquat, although poisoning can lead to renal failure and cerebral hemorrhage.

The pulmonary toxicity of paraquat, in contrast to its gastrointestinal effects, does not reflect caustic irritant injury. The major lung effect of paraquat toxicity is the development of pulmonary edema, usually observed 24 to 48 hours after ingestion. The pulmonary edema may evolve to a condition resembling acute respiratory distress syndrome, associated with histopathologic findings similar to those of diffuse alveolar damage, which may progress to an accelerated, chemically induced pulmonary fibrosis. After stabilization following acute multiorgan toxic effects, disease progression is marked by rapidly worsening respiratory distress, hypoxemia, and a restrictive ventilatory defect, with decreased lung compliance and diffusing capacity, ending in death from ventilatory failure within days to weeks. Survivors may demonstrate modest and slow improvement in lung function.

The mechanism of paraquat toxicity is attributed to the generation of superoxide radicals that may be partly iron dependent. Consistent with an oxidant mechanism, supplemental oxygen and radiation therapy may worsen the outcome; there are no known antidotes for paraquat poisoning, and enhanced elimination as by hemoperfusion has not demonstrated a clear benefit. Plasma paraquat levels can be determined and may have a use in predicting outcome. Data suggest a possible therapeutic benefit from immunosuppression, but this awaits confirmation through controlled clinical trials. Death results from multiorgan failure, which usually happens within 1 to 2 weeks but may be observed up to 6 weeks after ingestion.

Smoke Inhalation

The generic term smoke inhalation includes potential exposure to a wide array of substances because of the complex chemistry of heat decomposition and pyrolysis. Pyrolysis refers to the thermal decomposition of organic material without the involvement of oxygen and is a common component of burning buildings where oxygen is limited. Pyrolysis produces a variety of gases and a physical product such as charcoal. Although anoxia from carbon monoxide, cyanide, and oxidants represents a major manifestation of toxic insult from acute smoke inhalation, this nonpulmonary target organ effect is not covered here. However, a number of chemical irritants produced as pyrolysis by-products do have significant potential pulmonary toxicity. In contrast to thermal injury to the respiratory tract, which is typically limited to upper airways, with laryngeal edema the major potential medical management problem, inhalation of the smoke from fires can affect the entire respiratory tract through irritant injury.

In certain cases, irritant chemicals from fires are released as preformed substances but, most commonly, the toxins are formed de novo. These irritants are produced by the thermal degradation of both natural and synthetic polymers. The predominant by-products of heat breakdown are determined by the nature of the polymers consumed, temperature of the fire, and availability of oxygen.

Generally, polymers do not break down to their monomer precursors, although residual monomers can be evolved under certain circumstances. For example, when polyvinyl chloride is burned, hydrogen chloride is released rather than the monomer, vinyl chloride. Many of the specific chemical irritants that can be released as common thermal breakdown by-products are addressed elsewhere in this chapter. These include the following: hydrochloric acid (hydrogen chloride), hydrofluoric acid (hydrogen fluoride), and other acids; ammonia; phosgene; and oxides of nitrogen. The zinc chloride “smoke” of smoke bombs (in contrast to the heterogeneous character of “natural smoke”) is also discussed separately.

Aldehydes merit specific attention. They are a common cause of high-intensity irritant lung injury from the smoke from fires. These chemicals include formaldehyde, acetaldehyde, and acrolein. The most severe irritant, acrolein (CH ₂ CHCHO), is least familiar to most health care providers. Acrolein, a highly reactive chemical and key toxicant in smoke inhalation injury, is formed as an important pyrolysis product of both synthetic (e.g., acrylic) and natural polymers. In addition to de novo formation as a combustion by-product, acrolein is also intentionally manufactured and used as a pesticide; its use as an aquatic herbicide to facilitate water flow in irrigation canals can lead to human inhalation exposure with irritant effects.

The general considerations concerning irritant exposure discussed previously, including air concentration and water solubility, come into play in smoke inhalation. These factors are further complicated by the potential interactive effects of multiple simultaneous exposures, as well as the modifying impact of physical cofactors such as airborne respirable particulates (e.g., soot) that may serve as adsorbent carriers facilitating deep lung penetration. In practice, detailed exposure data delineating the irritant contents of a specific smoke exposure are rarely available. Information that may help to elucidate exposure conditions include identity of the products involved (e.g., specific synthetic polymers, if known), history of inhalation within an enclosed or confined space, evidence of thermal injury, and carboxyhemoglobin and methemoglobin levels as markers of inhalation severity based on other concomitant exposures (carbon monoxide and oxidants).

Firefighters (both urban and wildland) and nonoccupationally exposed victims of irritant smoke inhalation have proved to be important groups in which to study acute inhalational syndromes. Large-scale conflagrations (e.g., urban “wildland” fires ) can expose substantial numbers of people to irritant combustion by-products, as can smoke drift from intentional burning of agricultural residue. Studies of such populations after smoke inhalation have demonstrated acute and persistent airflow obstruction and increased nonspecific airway hyperresponsiveness. Bronchiectasis and BO have both been associated with combustion by-product exposure. The acute respiratory effects and potential sequelae of exposure to the plume generated by the destruction of the World Trade Center may relate to other factors such as alkaline (high-pH) dust from concrete, gypsum, and glass fibers, rather than to standard smoke particulate.

Pharmacologic Syndromes

Certain natural and synthetic chemical exposures affect the lung by specific mechanisms consistent with known pharmacologic actions. These chemicals are site-specific for key cellular functions leading to adverse respiratory effects. As noted previously, the most potent chemical warfare agents act through acetyl cholinesterase inhibition, with profound impacts on respiratory function. Similar, albeit less potent, agents have widespread use as agricultural chemicals. Both organophosphate and carbamate pesticides lead to respiratory compromise as a principal toxic effect. For example, in one case series, a considerable number of poisonings from these pesticides led to respiratory failure, accompanied by a high case-fatality rate; in contrast, all the patients without concomitant respiratory failure survived.

Inhaled capsaicin, of interest as a research tool to study substance P–mediated effects, is associated with cough in occupational settings (e.g., in chili pepper processing). When used as a “personal defense spray,” respiratory irritation has been reported, although ocular problems are more common. Brevetoxin is a toxin produced by dinoflagellates associated with “red tides.” Environmental inhalation exposure from airborne aerosols of red tide due to wind and surf action causes cough, sneeze, and wheeze. For lifeguards, brevetoxin health effects represent a source of occupational respiratory morbidity, including work loss. The toxin appears to act by stimulating sodium channels in the lung. Respiratory irritation may also be a manifestation of Pfiesteria dinoflagellate toxin inhalation (although potential neurotoxicologic effects have been of more concern).

Other Inhalant Exposures

Miscellaneous Exposures

A number of other occupational and environmental agents result in acute pulmonary syndromes. Examples of such exposures include diethylaminoethanol and cyclohexylamine (both anticorrosive boiler additives) ; amitrole and glyphosphate (both common herbicides) ; sodium azide (used in a variety of chemical applications but important as a potential inhalant through automobile airbag deployment) ; diazomethane, which is explosive but also highly toxic to the lung with a delayed onset similar to that of nitrogen dioxide ; diborane (an irritant gas used in manufacturing microelectronic equipment) ; barium (inhalation can cause bronchospasm and respiratory muscle weakness in addition to life-threatening hypokalemia) ; and hydrogen selenide (an irritant gas used in several industrial processes, as well as being a potential metal processing by-product). A recent outbreak of severe lung injury in Korea was linked to the room humidifier water being treated with two biocides: polyhexamethyleneguanidine (PHMG) and oligo(2-(2-ethoxy)ethoxyethyl) guanidinium chloride.

Phosphine is an important agricultural fumigant with pulmonary and systemic toxicity that is generated on site as a gas given off by moisture coming in contact with solid form aluminum or zinc phosphide (e.g., in grain storage facilities or railway grain transport cars, where bystanders can be exposed). Ingestion of the parent material by animals can also lead to exposure among treating veterinary personnel. Phosphine also has industrial applications, particularly in the production of microelectronics. Acetic anhydride (used in making epoxy and other resins) has also been associated with acute lung injury following acute inhalation. A distinctly different pattern of injury is associated with a related epoxy chemical, trimellitic anhydride, which causes severe pulmonary hemorrhage after subacute exposure. Carbon dioxide, although a bulk asphyxiant and not a respiratory irritant, causes shortness of breath and induces tachypnea; people can be exposed through natural geologic sources and dry ice sublimation in an enclosed space. Baby (talcum) powder inhalation can cause a pediatric acute pneumonitis within hours of heavy exposure; infant inhalation of nontalcum powders has also led to pneumonitis. Paraphenylenediamine is a dye used to color hair and can also be admixed with henna as a temporary tattooing agent; its ingestion as an agent of self-harm is common in Asia and Africa. In addition to rhabdomyolysis and renal damage, this chemical has a particular propensity to cause angioedema leading to airway obstruction.

Naturally occurring sources of exposure can also be associated with acute and subacute lung responses, although these syndromes are poorly characterized. Epidemiologically, Stachybotrys chartarum (atra) mold growth in water-damaged residential structures was initially linked to a cluster of cases of pulmonary hemorrhage in infants, although the association was later retracted in a follow-up review by the U.S. Centers for Disease Control and Prevention. Other case reports have occasionally linked other molds or mold by-products with lung injury (as opposed to self-limited ODTS, discussed previously).

Lycoperdonosis is a potentially severe, acute pulmonary syndrome following intentional inhalation (sometimes as a natural medicinal treatment) of puffball mushroom (Lycoperdon) spores; in addition to human illness, fatal inhalation in pet dogs is a well-characterized veterinary syndrome. The pathophysiology of the syndrome is not understood, but its high attack rate with heavy exposure suggests a toxic rather than an allergic or infective mechanism.

Key Points

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