Acute Responses to Toxic Exposures


This chapter focuses on the acute effects on the lung after exposure to toxic substances. As used in this chapter, acute indicates short-term exposures (minutes to hours), with the initial onset of pulmonary responses within a similarly rapid time period. Generally, the relevant toxicant exposures are of high intensity, far in excess of recommended safety limits for population-wide environmental levels or even workplace-permissible limits. In this chapter, the target organ discussed for the toxicants is the lung. Importantly, target organ does not equate with route of exposure. For most acute exposures, inhalation is the route of delivery leading to the lung injury. Because ingestion may also lead to lung injury, paraquat and hydrocarbon, examples of ingested toxins with severe acute target organ effects on the lung, are included in this chapter. However, in some instances, inhalation may be the route of delivery for the toxicant and yet the primary target organ is not the lung (e.g., solvent inhalation that causes central nervous system depression). Inhalation exposures leading to nonpulmonary illnesses are not addressed here.

Moreover, this chapter does not address brief exposures inducing acute responses mediated by anamnestic (i.e., allergic or other immune-mediated) mechanisms. These responses require prior exposures that have already led to sensitization, such as hypersensitivity pneumonitis (see Chapter 64 ) or occupational asthma (see Chapter 72 ). There are also a number of toxicants causing unusual pulmonary syndromes after subacute (days to months) as opposed to acute exposure. Some of these syndromes have emerged in recent years associated with new technologies or novel toxicants, such as diacetyl-caused popcorn worker’s lung and other flavor industry workers’ diseases linked to this chemical, “flock workers’ lung” caused by short synthetic textile fibers, and “Ardystil lung,” a dye chemical–induced organizing pneumonia. Although beyond the scope of this chapter, some of these syndromes are discussed elsewhere.

Pathogenesis of Lung Injury From Inhaled Toxicants

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).

Table 75-1

Major Clinical Scenarios of Pulmonary Responses Shortly After Acute Toxicant Exposure

Clinical Scenario Exemplar Exposures Additional Comments
Mucous membrane and airway irritation (burning eyes, nose, and throat; laryngospasm and bronchospasm) with or without lower lung injury (pulmonary edema, diffuse alveolar damage) Chlorine, chlorine dioxide, chloramine; bromine; sulfur dioxide; acid aerosols (sulfuric, hydrochloric, hydrofluoric); ammonia; zinc chloride (smoke bombs) At low exposures, mucous membrane irritation may be the sole effect; with heavy exposure, lower lung injury may be seen.
Lower lung injury (pulmonary edema, diffuse alveolar damage) with little or no mucous membrane irritation or airway effects Nitrogen dioxide, phosgene, ozone, cadmium fume, mercury vapor, nickel carbonyl, fluorocarbon (waterproofing) Exposure can be inadvertent or occult with presentation delayed 24–48 hr
Self-limited flulike illness with fever and leukocytosis beginning 6–12 hr after a clear exposure history Zinc oxide fume, heavy organic dust inhalation, polymer fume, endotoxin The presence of hypoxemia or lung injury indicates another diagnosis
Foreign substance ingestion followed by pneumonitis Hydrocarbon aspiration, exogenous lipoid pneumonia, paraquat fibrosis Heavy aerosol inhalation can cause lipoid pneumonia; paraquat can also be absorbed through the skin

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.

General Management Principles

Symptoms and signs of acute inhalation injury can be delayed in onset. Following removal from exposure while safeguarding the rescuing personnel, the next most important management decisions include protection of the airway (i.e., preemptive intubation may be required to prevent precipitous airway obstruction from progressive airway edema) and treatment of hypoxemia. The nasopharynx and larynx may manifest injuries earliest because they are exposed to the highest concentrations of inhaled water-soluble toxicants. The upper airway may also be a primary target organ due to angioedema in selected toxicant ingestions. Within a few hours after exposure, progressive airway edema, mucopurulent sputum production, and bronchorrhea may develop. Bronchoconstriction, peribronchial edema, and bronchial mucosal sloughing may produce atelectasis. In the distal airways and alveoli, epithelial and endothelial injury leads to permeability-induced edema, which can manifest ranging from mild interstitial edema to diffuse alveolar damage. Pulmonary edema may be rapid following high-concentration toxicant exposure or delayed up to 24 to 48 hours. Pneumothorax and pneumomediastinum can be acute complications of respiratory tract injury due to chemical toxicants. Diffuse alveolar damage after severe acute toxic lung injury should be managed consistent with the basic management of acute lung injury due to other causes. This extends to the role of protective ventilation strategies. Concomitant airway injury with acute bronchospasm often warrants treatment with bronchodilators because of the airway obstruction.

A beneficial role for systemic corticosteroids in the acute phase of irritant and other chemically mediated forms of acute injury to the lungs has not been established, by either controlled trials in humans or studies using experimental animal models. Inhaled steroids are more likely to have a better risk-benefit ratio in the therapy of acute inhalation injury (e.g., in the context of bronchospasm and concomitant use of bronchodilators, taking acute smoke inhalation injury as a paradigm). Despite the lack of controlled evidence of efficacy, anecdotal reports of benefits from systemic corticosteroid use continue to appear. Prophylactic antibiotic drugs have not proved to be efficacious in toxic lung injury; antibiotics should be reserved for those patients with clinical evidence of infection, including ventilator-associated pneumonia. To date, convincing data do not support the use of other pharmacologic agents, such as antioxidants, in the generic treatment of toxic chemical lung injury, although this is the subject of active experimental research.

There are certain exposure-specific management issues that do occasionally arise. In paraquat-induced lung injury, for example, oxygen toxicity is a particular concern because of the specific mechanism of action of paraquat (i.e., high concentrations of oxygen may lead to more severe lung injury). In paraquat as well, immunosuppressive therapy has been of particular interest and has yielded some promising data but remains to be confirmed in randomized, controlled studies. In the case of certain metal toxins, chelation may have a therapeutic role, as is addressed later in relation to the specific exposures involved. Inhalation fever is self-limited, so the principal clinical management issue is to exclude other exposures with more serious outcomes.

Chronic Sequelae and Residual Effects

Among persons surviving symptomatic exposure to acute irritants, there may be persistent structural and functional effects. Long-term consequences to the upper airways (nose, pharynx, and larynx) can be sequelae of acute inhalational exposures; upper airway complaints including chronic rhinitis ( reactive upper airway dysfunction syndrome [RUDS]), anosmia, and vocal cord dysfunction have been reported.

Follow-up studies of more homogeneous populations evaluated after inhalation injury (with only a minority experiencing severe injury) suggest that airflow obstruction and nonspecific airway hyperresponsiveness are the most common persistent abnormalities of the conducting airways after irritant injury. Even so, epidemiologic data suggest that only a minority of those exposed will experience these outcomes. The term reactive airway dysfunction syndrome (RADS) has been applied to the persistence of airway reactivity after acute exposure to respiratory irritants. The more general term irritant-induced asthma has also been used to describe this condition. Insofar as this syndrome represents a form of work-related asthma, it is addressed in Chapter 72 .

Chronic injury to the lower airways and lung parenchyma are unusual sequelae of acute inhalational exposure. Long-term follow-up evaluation after recovery from acute respiratory distress syndrome due to heterogeneous causes (predominantly associated with sepsis) suggests that residual deficits in lung volumes, airflow, and gas exchange may persist long after recovery. Bronchiolitis obliterans (BO), bronchiectasis, and organizing pneumonia may all develop but are rare complications. Irritants, in particular nitrogen oxide and related exposures, have long been known to cause BO. Yet even with nitrogen dioxide, BO is an infrequent event; for example, only 1 case was found in a series of 20 moderate to severe exposures. Pathologically, irritant-induced BO is usually characterized by intrabronchial granulation tissue (to which the term proliferative bronchiolitis obliterans is sometimes applied), as opposed to constrictive (obliterative) BO. The latter appears to be the pathologic correlate of diacetyl-caused popcorn worker’s lung and has been reported in one case of BO following exposure in the World Trade Center disaster, in a case series of Iraq and Afghanistan military veterans (although no single toxic exposure has been implicated), and in association with styrene-fiberglass boat construction, presumably with indolent rather than acute exposure. In addition to residual obstructive ventilatory deficits, restrictive deficits may also result from severe irritant inhalation injury. There is also some indication that an isolated reduction in residual volume may be noted in the follow-up of such cases. Finally, nonspecific respiratory complaints after acute inhalation events can be a somatic manifestation of psychological processes and can be further complicated by posttraumatic stress disorder (PTSD) comorbidity.

Specific Exposures ( Table 75-2 )

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.

Table 75-2

Selected Toxic Agents Causing Pulmonary Responses After Acute Exposure

Agent Common Exposure Scenarios References
Acid aerosols Plating; microelectronics; other manufacturing
Acrolein Structural or wildland fires; other combustion
Ammonia Industrial refrigeration leaks; fertilizers
Brevetoxin Aerosolization of “red tide” toxin
Bromine Water treatment; chemical manufacturing
Cadmium fume Flame cutting of soldered or sheet metal materials
Chloramines and nitrogen trichloride Bleach + ammonia mix; chlorination + ammonia
Chlorine gas Gas leak; water treatment; bleach + acid mix
Chlorine dioxide Pulp paper bleaching
Crowd control agents (tear gas) Military and police training and operations
Dimethyl sulfate Industrial chemical yielding sulfuric acid
Fluorocarbon polymers Overheating polymers
Fluorocarbon sprays Waterproofing and related aerosol sprays
Hydrocarbons Aspiration of low-viscosity materials, “fire-eating”
Hydrogen sulfide Sewers and manure pits; fossil fuel and geothermal production
Mercury vapor Gold extraction, heating cinnabar
Methyl bromide Pesticide fumigant
Methyl isocyanate Pesticide manufacturing
Methyl isothiocyanate Breakdown product of metam sodium fumigant
Mustard gas Chemical warfare agent
Nickel carbonyl Nickel processing, metal reclamation
Nitrogen dioxide Silage; combustion; explosives; welding; nitric acid mixes
Organic dusts/aerosols Contaminated dust or bioaerosol generation
Organophosphates Pesticide application; chemical warfare
Ozone Bleaching; water treatment; plasma welding
Paraquat Herbicide skin contamination or ingestion
Phosgene Chlorinated solvent breakdown by-product
Phosphine Fumigation with aluminum or zinc phosphide, microelectronics
Sulfur dioxide Refrigeration; cement manufacture; mining; pulp paper mills
Tributyltin (bis[tributyltin] oxide) Paint additive for mold inhibition
Vanadium Ore processing; fossil fuel by-product, catalyst use
Zinc chloride Smoke bombs (“white smoke”)
Zinc oxide fume Welding galvanized steel; brass casting

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


Unfortunately, chemical warfare agent exposures are not of mere historical interest. Not only can sporadic exposures result from contact with discarded ordinance, but more importantly, exposure can be widespread through the use of chemical warfare agents in acts of terrorism or in conventional military conflicts. Such risks have raised the specter that the diagnosis and management of such toxicants will again become clinically relevant. There have been a number of reviews of the general aspects of this question. The goal of this section is to address individual chemical agents, including other military and crowd control agents that are not warfare chemicals per se, focusing on their respiratory target organ toxicity. Biologic warfare agents of relevance to the respiratory tract are covered elsewhere (see Chapter 40 ).

Sulfur Mustard

Of the major World War I chemical weapons, only sulfur mustard (so called “mustard gas,” although not a true gas in physical state) has been used “militarily” since World War II. Classified as a vesicant because of blistering induced by skin contact, mustard gas inhalation causes severe respiratory injury. Largely on the basis of the Iranian experience of their Iraqi war veterans, sulfur mustard survivors can exhibit residual tracheobronchitis, asthma, bronchiectasis, bronchotracheomalacia, BO, and fibrosis. Nitrogen mustards were sulfur mustard derivatives originally developed for military purposes but later applied medically; nonetheless, occupationally related acute lung injury has been reported through industrial release.


Another World War I toxic gas, phosgene, is currently encountered as a chemical industry process chemical and as a thermal breakdown product or ultraviolet photoreactant of chlorinated solvents (e.g., methylene chloride). An occult cause of exposure can be inadvertent phosgene production from welding metals “degreased” with solvents. Phosgene is the prototypic deeply penetrating inhalant exhibiting a delayed onset of symptoms (12 to 24 hours after exposure).


Chloropicrin, another World War I gas, is a low-threshold irritant currently encountered in chemical manufacturing and as a component of fumigants.


The modern chemical warfare armamentarium is dominated by systemic toxicants developed from organophosphate pesticides (which are discussed later in “Pharmacologic Syndromes”); the nerve agent “VX” is prototypical. These highly lethal neurotoxins have important respiratory effects, including manifestations of both muscarinic receptor stimulation (bronchorrhea and bronchospasm) and nicotinic receptor depolarization blockade (respiratory muscle paralysis); treatment is based on reversing enzyme inhibition and countering the effects of acetyl cholinesterase excess.

Chloroacetophenone (Mace), Other Tear Gas Agents, and Zinc Chloride

Crowd control agents (“tear gases”), as opposed to the war gases, are intended to incapacitate persons via immediate mucous membrane irritation. The agents in greatest use worldwide are chloroacetophenone (“mace”) and orthochlorobenzamalonitrile. In addition to their mucous membrane effects, these agents have also been implicated in lower respiratory injury and even in persistent effects following high-intensity exposures (e.g., in enclosed buildings). Unlike tear gas, exposure to smoke bomb releases (sometimes referred to as “white smoke”) can cause severe lower respiratory injury by exposure to the potent respiratory irritant, zinc chloride fume, created through a pyrotechnic reaction between hexachloroethane and zinc oxide. Military, police, and others who are exposed, often during ill-conceived training exercises, are at risk.

Toxic Metals


Inhalation of certain metal fumes or metal vapors can cause an acute pneumonitis. Dangerous exposures to toxic metal fumes arise, in part, because these agents are not immediately irritating, analogous to the delayed symptoms after phosgene or nitrogen oxide gas inhalation. Patients typically present in respiratory distress 12 to 48 hours after exposure. Indeed, the exposure history often remains occult unless aggressively pursued. Metal pneumonitis from these materials also can include fever as a clinical manifestation of this toxic syndrome. However, the term metal fume fever should not be used in this context. The toxic mechanism generalizable in heavy metal pneumonitis is presumed to be inhibition of enzymatic and other critical cellular functions.

Cadmium, Mercury, and Nickel

The three metals most important clinically in lung injury are cadmium, mercury, and nickel (the latter in the form of nickel carbonyl). For cadmium, exposure typically takes place through welding, brazing (high-temperature soldering) or flame-cutting metal, or working with molten metal under conditions of inadequate ventilation. In welding, brazing, and flame-cutting, the usual source of cadmium is the welding rod, brazing solder, or a metal coating, rather than the base metal itself. In areas of the world where jewelry is made at a cottage industry level, cadmium use in silver-working can present a particular exposure risk.

High levels of the relatively volatile metal mercury can be generated effectively from many nonenclosed operations, most notably through heated metal reclamation processes (e.g., home refining of mercury-gold amalgams or even reclaiming of mercury from electronic equipment). Exposure has also been reported after burning mercury sulfide (Chinese red cinnabar) and mercuric oxide for medicinal purposes. Chelation treatment has not been shown to be effective in heavy metal pneumonitis due to mercury.

Nickel carbonyl is an organic metal derivative and potent pulmonary toxicant, with exposure during nickel refining, during manufacturing processes in which it is used as a catalyst or intermediate, or during metal recycling or reclaiming operations. A case report of fatal nickel fume inhalation from a metal spraying operation that was nickel carbonyl free suggests that under certain conditions inorganic nickel can also cause acute lung injury. Although specific metal chelators have been advocated in nickel-related lung injury, the evidence in support of this in clinical practice (i.e., after illness is manifest) is equivocal. The agent dithiocarb (diethyldithiocarbamate) has been used as a chelating antidote for nickel carbonyl pneumonitis, on the basis of supportive animal data, although its benefits are most clear-cut when administered soon after exposure (e.g., before the time clinical illness would be manifested); disulfiram has been suggested as a potential alternative treatment, although experimental data to support this practice are weak as well.

Other Metals

Other metals, including antimony, manganese, and beryllium, are sometimes cited as causes of acute lung injury consistent with metal pneumonitis, but there are few reports in the past 50 years providing documentation of such disorders. A recent case report implicated copper dust inhalation with acute lung injury. Osmium tetroxide is a potent respiratory irritant with terrorist weapon potential; fortunately, to date experience with human inhalation exposure has been limited. Cerium oxide is another metallic exposure of theoretical concern because of its potential use as a fuel additive and its capacity to cause acute inhalation injury experimentally.

Two other metal compounds are well-documented bronchial irritants in humans. Vanadium (typically as a metal oxide), which is encountered in metal processing and, in lower concentrations, as a fossil fuel by-product, causes acute bronchitis. Among boilermakers, vanadium-rich fuel oil ash is suspected to be a key exposure related to acute respiratory symptoms. In a single case report, high-intensity exposure to ash from an oil-burning furnace was associated with diffuse alveolar damage; although vanadium was detectable in the residue, the toxic mechanism in this case was unclear. In another case report, vanadium (as vanadyl pyrophosphate) was linked to pneumonitis. Tributyltin (bis[tributyltin] oxide) is an organotin compound, which is an organic compound with one or more molecules of tin. Tributyltin, which is employed as a mildew and mold retardant, is also an acute airway irritant.

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 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


Anhydrous ammonia is a gas at room temperature and ambient pressure, although ammonia is more commonly encountered in aqueous form, as in cleaning solutions. Potential sources of ammonia gas exposure include incidents in the chemical industry and in hazardous transportation, commercial refrigeration systems, and farming (e.g., fertilizer). Anhydrous ammonia has also been released from illicit methamphetamine laboratory operations, although such exposures are often in the context of conflagrations with concomitant thermal burns and other coexposures. Ammonia has prominent irritant warning properties (such as burning eyes). It is linked with lung injury chiefly in settings of overwhelming exposure or where immediate escape has not been possible. Both asthma and bronchiectasis have been documented after ammonia exposure. Acute ammonia exposure has also been reported to have residual upper airway effects, including decreased olfactory acuity. Death may result from laryngeal edema and airway obstruction, acute pulmonary edema, or complications of the pneumonic process (e.g., bacterial superinfection). A case of lung transplantation within a year after ammonia inhalation has been reported.

Bromine and Methyl Bromide

Bromine is an irritant halogen. It is usually handled as a liquid rather than as a gas, but it vaporizes readily. Sources of bromine exposure other than environmental releases include chemical synthesis and water purification. Bromine is a more potent irritant than chlorine and approximately 100 times more irritating than ammonia. Methyl bromide is a major industrial fumigant with far-greater potential for public exposure. Methyl bromide is also a potent respiratory irritant, but the central nervous system may represent the more important target organ in typical exposures.

Hydrogen Sulfide

Hydrogen sulfide is a common by-product of petroleum extraction and refining, as well as a potential hazard from the breakdown of organic materials (hence, its common name, “sewer gas”); overexposure can result from work in confined spaces, submersion in manure pits, or proximity to geothermal and volcanic sources. Hydrogen sulfide is a respiratory irritant, but it is an even more potent cytotoxic asphyxiant, impairing cytochrome oxidase and cellular respiration. Therefore, in cases of severe hydrogen sulfide exposure, rapid cardiovascular collapse and death often overshadow any pulmonary organ effects, although an acute lung injury pattern can be present in those surviving long enough to receive intensive supportive care; irritant symptoms as a predominant feature may be of greater relevance in lower-intensity exposures.

Methyl Isocyanate and Methyl Isothiocyanate

Methyl isocyanate (MIC) use is restricted to a narrow industrial application in the synthesis of pesticides. The mass fatalities at Bhopal, India, make MIC an important toxin for historical reasons. The toxicity of MIC was the result of its severe irritant properties leading to pulmonary edema. No cyanide-mediated mechanism was involved. Methyl isothiocyanate, a breakdown product of the soil fumigant metam sodium, is an irritant chemically related to MIC that was also involved in a mass exposure episode, although less severe than the MIC release at Bhopal, and has also been associated with respiratory symptoms following agricultural application. The isocyanates associated with urethane, such as toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), and hexamethylene diisocyanate (HDI), are pulmonary irritants but are primarily of concern because of their induced sensitization (see Chapter 72 ).

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.

Jul 21, 2019 | Posted by in CARDIOLOGY | Comments Off on Acute Responses to Toxic Exposures

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