Pathology

In general, the upper airway can be affected by most inhaled toxins, which result in edema of the nasal passage, posterior oropharynx, and larynx. In severe cases, mucous membrane ulceration and hemorrhage ensue. Toxins of low water solubility may reach the lung parenchyma without necessarily producing upper airway lesions. If breath holding, laryngospasm, and normal “scrubbing” activities of the nasopharynx fail to contain the exposure, lesions develop in the trachea and bronchi (e.g., paralysis of cilia, increased mucus production, goblet cell hyperplasia, injury to airway epithelium, epithelial denudation, exudation, submucosal hemorrhage, edema). Pseudomembranes may form along the trachea and bronchi, causing various degrees of bronchiolitis, bronchiolitis obliterans (Figure 56-2), and organizing pneumonia (Figure 56-3). Bronchiolitis has been associated with exposures to oxides of nitrogen—nitric oxide (NO), nitrogen dioxide (NO₂), and nitrogen peroxide (N₂O₄)—as well as sulfur dioxide, ammonia, chlorine (Cl₂), phosgene, fly ash that contains trichloroethylene (C₂HCl₃), ozone (O₃), hydrogen sulfide, hydrogen fluoride (HF), metal oxide fumes, dusts (e.g., asbestos, silica, talc, grain dust), free-base cocaine, tobacco smoke, and fire smoke.

Figure 56-2 Histologic appearance of bronchiolitis obliterans caused by inhalation of oxides of nitrogen in silo filler.

Figure 56-3 Histopathologic features of organizing pneumonia after sulfur dioxide inhalation.

Parenchymal injury is less common than airway damage. When alveolar or interstitial injury occurs, both epithelial damage and endothelial damage are observed, resulting in alveolocapillary leak and the pathologic changes of adult respiratory distress syndrome (ARDS). Diffuse alveolar damage (DAD) is a common histologic pattern in acute interstitial lung disease caused by inhaled toxins. It is characterized by widespread, diffuse edema, epithelial necrosis and cell sloughing (with exudates that fill the alveolar spaces), and formation of hyaline membranes (Figure 56-4). Later, DAD may organize, which leads to proliferation of type II pneumonocytes, resorption of the hyaline membranes and exudates, and fibroblast proliferation. Long-term survivors of such parenchymal injury may fully recover or may have various degrees of permanent interstitial fibrosis.

Figure 56-4 Diffuse alveolar damage caused by anhydrous ammonia inhalation. An agricultural worker inhaled the gas when a hose broke during the transfer of this fertilizing agent.

Pathogenesis

Asphyxiants, such as methane (CH₄) and carbon dioxide (CO₂), displace oxygen (O₂) from the air or, in the case of CO, interfere with normal oxidative metabolism and O₂ transport. Typically, the more soluble gases produce greater injury in the upper airway, whereas less soluble gases injure distal airways and parenchyma. Some of the irritant gases produce direct cellular injury because they are alkalis (e.g., ammonia) or acids (e.g., phosgene). Others, such as ozone and oxides of nitrogen, form oxygen free radicals that cause respiratory tract injury. These gases may also produce smooth muscle bronchoconstriction and stimulate afferent parasympathetic receptors, which explain some of their ability to induce airway hyperreactivity and bronchoconstriction.

Chronic lower-level exposures to various toxic gases (e.g., SO₂, Cl₂) can induce copious mucus secretion, cough, bronchoconstriction, and bronchitis as a physiologic response to the inhalational exposure. Chronic bronchitis is common among workers exposed to relatively low levels of irritants and may increase their risk for development of chronic airflow obstruction and accelerated longitudinal decline in forced expiratory volume in 1 second (FEV₁). In some cases, nonspecific airway hyperreactivity is induced by persistent, nonspecific irritant exposures.

Ammonia

Ammonia is a colorless, water-soluble, alkaline gas with a pungent odor. Because it is usually transported as a liquid, many accidents occur when it is being transferred from tanks to farm equipment. When it comes in contact with the mucosa, NH₃ reacts with H₂O to form a strong alkali, ammonium hydroxide (NH₄OH). Within hours of acute irritation, there may be sloughing of the upper airway mucosa, edema, and obstruction. Laryngeal edema can present without other obvious clinical signs of burns, but if skin burns are present, inhalational injury is likely. Unusual complications include pneumonia and ARDS, which occur within hours to a few days of exposure. Long-term consequences include persistent bronchitis, bronchiectasis, airflow obstruction, interstitial fibrosis, and impaired gas exchange.

Treatment of NH₃ poisoning is supportive: bronchodilators, O₂ therapy, and observation for need for airway protection. Early intubation may be required to protect the airway from acute laryngeal obstruction.

Hydrogen Chloride

Hydrogen chloride (HCl) is highly water-soluble, and injures the mucosa of the upper airways because of its acidity. Typically encountered in the manufacture of fertilizers, textiles, rubber, and dyes, acute HCl exposure causes mucous membrane irritation of the eyes and airways at levels as low as 5 to 10 parts per million (ppm). Higher levels of exposure can cause acute airflow obstruction and gas exchange abnormalities. Meat wrappers become exposed to HCl when they heat polyvinyl chloride film.

Hydrofluoric Acid

Hydrofluoric acid is a highly corrosive chemical primarily causing dermal injury to the hands. Hydrofluoric acid releases free hydrogen ions (H⁺) that penetrate and corrode the skin, potentially down to bone, producing bone demineralization and necrosis. The respiratory effects parallel those of the skin, except effects in the lungs have a rapid onset and patients present with acute respiratory distress. Hydrofluoric acid is water-soluble and thus predominantly exerts its effects on the upper airways, resulting in rapid onset of tissue damage and bronchoconstriction, in some cases even leading to chemical pneumonitis, delayed-onset pulmonary edema, and death.

Sulfur Dioxide

Sulfur dioxide and sulfuric acid (H₂SO₄) aerosols are produced by fossil fuel combustion. These toxic gases are encountered in power plants and in various industrial processes, such as smelting, chemical manufacture, paper manufacture, food preservation, metal and ore refining, and refrigeration. Past SO₂ air pollution catastrophes have increased mortality rates for patients with chronic lung disease and elderly patients.

As little as 0.5 ppm of SO₂ can be detected in air from its characteristic odor. Levels of 6 to 10 ppm may immediately irritate eyes and the nasopharynx. High exposures (≥50 ppm) injure the larynx, trachea, bronchi, and alveoli. A wide range of individual variability in the response to SO₂ is found, but atopic and asthmatic patients show the most susceptibility. Prior exposure to ozone may potentiate the effect of SO₂ in asthmatic subjects. Classically, patients first experience a burning of the eyes, nose, and throat, with associated cough, chest pain, chest tightness, and dyspnea, along with conjunctivitis, corneal burns, and pharyngeal edema, followed hours later by pulmonary edema. Obliterative bronchiolitis (OB; bronchiolitis obliterans) can develop 2 to 3 weeks after exposure. Persistent airflow obstruction has been observed in smelter workers up to 4 years after SO₂ overexposure, probably because of bronchiolitis obliterans.

Symptomatic treatment for acute SO₂ toxicity may include systemic corticosteroids. Bronchospasm in asthmatic patients may reverse spontaneously after removal from SO₂ exposure, or may require administration of bronchodilators and inhaled corticosteroids.

Chlorine

Chlorine is of intermediate solubility and liberates hydrogen chloride and oxygen free radicals when it contacts water. The result is dose-dependent epithelial cell injury. Low levels of Cl₂ exposure cause irritation of the upper airways and eyes. Increasing levels of exposure injure the nasopharynx and larynx. Higher exposures result in pulmonary edema within 6 to 24 hours. Pulmonary function tests typically show airflow obstruction and air trapping. Long-term consequences include persistent airflow obstruction in some survivors. Clinical management of Cl₂ toxicity is supportive. Even symptomatic patients who have negative physical examinations and laboratory tests must be observed for at least 6 hours because of the potential for a delay in the onset of significant airway toxicity. If symptoms persist, corticosteroids may improve outcome.

Oxides of Nitrogen

The oxides of nitrogen (NO, NO₂, N₂O₄) can produce fatal respiratory injury for some of the millions of workers who come into contact with these gases. Occupations at risk include coal miners after firing of explosives, welders who work with acetylene torches in confined spaces, hockey rink workers, and chemical workers exposed to by-product fumes in the manufacture of dyes, lacquers, and nitric acid (HNO₃). Silo filler’s lung (silo filler’s disease) occurs with inhalation of NO₂ formed from fermented corn or alfalfa in silos. The greatest risk occurs in the first few weeks after filling the silo. Because the oxides of nitrogen have low water solubility, the lower respiratory tract can be exposed to these potent oxidizers. NO₂ reacts with H₂O in the lung to form nitric and nitrous (HNO₂) acids. The oxides dissociate into O₂ free radicals, nitrates, and nitrites, which cause tissue inflammation, lipid peroxidation, and impairment of surfactant activity (among other cellular changes). Notably, nitric oxide has a high affinity for hemoglobin and thus causes methemoglobinemia.

With oxides of nitrogen, exposures of 15 to 25 ppm result in acute mucous membrane irritation of the eyes and throat. At exposure levels of 25 to 100 ppm, toxic pneumonitis and bronchiolitis can develop, often with a smothering sensation and dyspnea. Exposures above 150 ppm are often fatal, associated with OB, chemical pneumonitis, and pulmonary edema. Symptom onset may be delayed, and patients are cautioned that relapses can occur 3 to 6 weeks after initial exposure, with symptoms of cough, chills, fever, and shortness of breath. In some, persistent obstructive lung disease and chronic bronchitis develop. Case reports suggest improvement after corticosteroids in patients exposed to oxides of nitrogen who manifest bronchiolar inflammation.

Phosgene

Also called carbonyl chloride, phosgene replaced chlorine as the preferred chemical weapon of World War I and resulted in the majority of “gas attack” fatalities. Phosgene is an intermediate product in the manufacture of isocyanates, pesticides, dyes, and pharmaceuticals. It has a low odor threshold at 1 ppm and produces a characteristic smell of musty hay. As a result of its poor water solubility, phosgene causes only mild upper airway and eye irritant symptoms, and deposits distally in the lung where it hydrolyzes to form hydrochloric acid (aqueous HCl) and CO₂. At high levels of exposure, dyspnea, chest tightness, and cough occur. Acute exposure produces necrosis and sloughing of tracheal, bronchial, and bronchiolar mucosa with associated edema, hemorrhage, and atelectasis. Progressive respiratory failure and ARDS may follow.

Mustard Gas

Sulfur mustard gas (dichlorodiethyl sulfide) was first used as a chemical warfare agent in Europe in 1917. Actually, mustard agents are not gases, but liquids at environmental temperatures. These agents are volatile, enter vapor phase at ambient temperatures, and have low water solubility. Exposure to dichlorodiethyl sulfide produces eye irritation and swelling within 2 to 3 hours. With higher exposure, blurred vision, conjunctival edema, and iritis can occur, with potential for corneal ulceration. The skin becomes pruritic and erythematous, and, 4 to 16 hours later, forms blisters. Acute respiratory damage may be evident within a few hours or, more commonly, several days later. Chemical pneumonitis and pulmonary edema can also occur, with upper airway irritation, sneezing, hoarseness, epistaxis, cough, and dyspnea. Acute injury includes edema, inflammation, and destruction of the airway epithelium, with pseudomembranes developing, similar to those seen with diphtheria. Secondary complications include infection and airway stenosis. The long-term effects of mustard gas include death caused by respiratory infections, chronic bronchitis, and accelerated longitudinal decline in airflow. Additional weaponized agents are discussed later.

Ozone

Ozone is a light blue gas with an acrid “electric” odor. O₃ occurs naturally in the stratosphere, produced by the interaction between O₂ and ultraviolet (UV) light. In the troposphere, O₃ is produced from photochemical reactions between oxides of nitrogen and volatile organic compounds. As a major component of environmental air pollution, O₃ remains a serious pollutant for urban populations worldwide. Its low water solubility causes ozone to principally affect the lower respiratory tract. Healthy individuals exposed to low O₃ concentrations experience acute increases in airway resistance, and decreases in FEV₁ and forced vital capacity, probably through a neural reflex mechanism. With acute exposures to low concentrations, patients can experience chest pain, dyspnea, and cough. Exposure to concentrations as low as 0.08 ppm for 6 hours, with intermittent exercise, may cause lung function and inflammatory changes. Exposure to 0.12 ppm for 1 hour is the U.S. Environmental Protection Agency (EPA) Air Quality Standard.

Carbon Monoxide

Carbon monoxide is colorless, tasteless, and odorless, and is the major cause of death by poisoning in the United States and most industrialized countries. Exposure results from incomplete combustion of carbon-containing materials such as gasoline, coal, and wood. Home CO exposures occur from furnace gas leaks or fire smoke inhalation. Methylene chloride (CH₂Cl₂), used in paint strippers and household solvents, metabolizes into CO and can be deadly if handled in poorly ventilated areas.

Severe forms of CO poisoning are characterized by unconsciousness, seizures, syncope, coma, neurologic deficits, pulmonary edema, myocardial ischemia, and metabolic acidosis. Lower exposures produce symptoms of headache, nausea, weakness, giddiness, and tinnitus. Confusion typically occurs at carboxyhemoglobin levels greater than 30%, with coma ensuing at 35% to 45%, and death at 50%. Affected individuals are at risk for delayed neuropsychological effects. Carboxyhemoglobin levels correlate poorly with the clinical severity of neurologic sequelae. CO half-life in individuals at rest is approximately 4 hours and can be reduced to 60 to 90 minutes by breathing 100% O₂ by face mask or to less than 60 minutes with O₂ administered by manual bag-assisted ventilation.

Nonrandomized studies show that hyperbaric oxygen reverses the acute effects of CO poisoning and is the most rapid means of reversing acute toxicity. Additional treatments may improve acute neurologic defects. Results of controlled trials are unclear as to the efficacy of hyperbaric oxygen as a treatment for the delayed neuropsychological symptoms. Cardiac monitoring is warranted for patients who have carboxyhemoglobin levels greater than 25% because of the risk of arrhythmias and myocardial infarction.

Hydrogen Cyanide

Individuals exposed to smoke generated by the combustion or pyrolysis of plastics and polyurethanes are at risk of hydrogen cyanide toxicity. The fumes are absorbed through the skin and respiratory tract. By binding to the cytochrome A–cytochrome A₃ subcomplex, hydrogen cyanide blocks oxidative phosphorylation and mitochondrial oxygen utilization, which results in lactic acidosis.

Symptoms produced by exposures to 50 ppm of cyanide gas include headache, tachycardia, tachypnea, and dizziness. Exposures greater than 100 ppm can cause confusion, apnea, and seizures. The patient may emit a bitter almond odor, but this is not a reliable or consistent marker of exposure. Diagnosis rests with the occupational and environmental history. Venous blood appears hyperoxygenated, and the patient may have a distinctive red appearance before respiratory insufficiency, although this also is not a reliable clinical sign. Carboxyhemoglobin levels are measured to differentiate cyanide intoxication from CO poisoning. Treatment focuses on life support measures and detoxification. Early mechanical ventilation, hyperoxygenation, and treatment of metabolic acidosis are critical. Both amyl nitrate and sodium nitrite are recommended.

Hydrogen Sulfide

Hydrogen sulfide is both a respiratory irritant and asphyxiant. As a colorless, naturally occurring gas, H₂S is found in marshes and sulfur springs and as a decay product of organic matter. It is known for its typical “rotten egg” odor. Occupational exposure occurs in the manufacture of chemicals and metals, in petroleum refineries, natural gas plants, coke ovens, paper mills, rubber vulcanization, rayon manufacture, and in tanneries. Heavier than air, H₂S accumulates in low-lying areas; it causes poisoning during oil drilling, wastewater treatment, and natural-gas field leaks. The H₂S reaction with metalloenzymes, such as cytochrome oxidase, accounts for much of its toxicity in humans.

The odor threshold for H₂S is low (0.13 ppm). At concentrations of 50 ppm, H₂S is a mucous membrane irritant. Above 100 ppm, the gas fatigues the sense of olfaction, which makes individuals insensitive to its continued presence. When inhaled, H₂S preferentially affects the lower respiratory tract. At concentrations of 250 ppm, pulmonary edema can occur. At 500 ppm, systemic and neurologic effects develop, with sudden loss of consciousness seen above 700 ppm. Above 1000 ppm, H₂S produces hyperpnea and apnea, which paralyze respiratory drive centers, resulting in death by asphyxia. Prolonged low-level (50 ppm) exposures can cause respiratory tract inflammation and drying; typical symptoms of cough, sore throat, hoarseness, rhinitis, and chest tightness occur between 50 and 250 ppm. At higher acute exposure levels, such symptoms may not manifest because of the rapid absorption of the gas through the lung into the bloodstream.

Management of the patient with H₂S poisoning is generally supportive, with prompt endotracheal intubation and mechanical ventilation for severe cases of intoxication. Oxygen enhances sulfide metabolism and benefits hypoxic tissue. Because the mechanism of H₂S toxicity is similar to that of cyanide, induction of methemoglobinemia with infusion of 3% sodium nitrite or inhalation of amyl nitrate is recommended. Hyperbaric oxygen therapy may be beneficial.

Arsenic

Arsenic is added to metals as a hardener and is also found in pigments, wood preservatives, herbicides, desiccants, and sheep and cattle dips. This metal has many valences, with As(III), As(V), and arsine gas being the most hazardous. Exposure primarily occurs with smelting and pesticide manufacture and application. Acute inhalational exposure causes abdominal pain, diarrhea, vomiting, peripheral neuropathy, seizures, circulatory collapse, and death. Chronic exposure can cause alopecia, paresthesias, and keratoses on the palms and soles of the feet. More serious symptoms include cardiac failure, renal disease, angiosarcoma of the liver, and lung cancer. Chelation with dimercaprol improves excretion of arsenic.

Beryllium

The light metal beryllium is used as an alloy for its high tensile strength and is found in industries involving nuclear weapons production, aerospace, ceramics, and electronics. Processes that generate beryllium dust and fumes may lead to acute pneumonitis that can largely be avoided through protective measures. Chronic beryllium disease (CBD) occurs after seemingly small and short-term exposure to the metal, as a result of a hypersensitivity immune response. Some individuals are genetically predisposed to CBD if exposed. Symptoms include dyspnea, dry cough, and fatigue, with rales (crackles) the most common finding on lung auscultation. The disease is diagnosed through the beryllium lymphocyte proliferation test (BeLPT), which can be performed on blood or bronchoalveolar lavage (BAL). This test distinguishes CBD from sarcoidosis and other similar diseases. Noncaseating granuloma formation and lung fibrosis are pathologic consequences. Immunosuppressant therapy (e.g., corticosteroids) is required as the CBD progresses.

Cadmium

Cadmium is used for electroplating, as a pigment in paint to prevent corrosion, and in batteries. It is also a by-product of smelting and refining. Inhaled cadmium accumulates in the liver and kidneys and can cause headache, myalgia, nausea, fever, cough, dyspnea, and chest tightness. Long-term exposure causes pulmonary fibrosis, emphysema, lung cancer, and prostate cancer. Severe poisoning can be treated with calcium disodium edetate (CaNa₂EDTA) to increase excretion.

Chromium

Chromium provides corrosion resistance for electroplating appliances, automotive parts, machinery, and tools. It may be encountered in mining, welding, and cement workers. Chromium (VI) is the most hazardous of the forms of chromium, known to cause eye and respiratory system irritation, ulceration and erosion of the nasal septum, and lung cancer. Acute exposure can be treated with oxygen and bronchodilators while nasal ulcerations should be treated with 10% CaNa₂EDTA ointment.

Cobalt

Cobalt imparts hardness to alloys and is used as a pigment in glass, paint, and ceramics. Cobalt-related lung disease has been well described in diamond polishers and those working with tungsten carbide grinders. Occupational exposures can cause asthma and several forms of interstitial lung disease, including hard metal disease (cobalt lung, tungsten carbide disease), giant cell pneumonitis, and pulmonary fibrosis, as well as cardiomyopathy and possibly lung cancer. Removal from exposure can help in the management of asthma, hard metal disease, and giant cell pneumonitis.

Nickel

Nickel provides durability and prevents corrosion in alloys. Occupational exposure occurs through mining, milling, and refining. Insoluble nickel accumulates in the respiratory tract and can cause rhinitis, sinusitis, anosmia, asthma, interstitial pneumonitis, and lung cancer. Nonoccupational exposures through skin contact with nickel-containing jewelry are a common cause of nickel allergy and increase the risk for asthma in those occupationally exposed. Exposure can be monitored through excess urine nickel excretion.

Inhalational Fume Fever

A variety of clinically similar conditions are caused by inhalation of metal fumes or dust. Metal fumes of copper, magnesium, and most often zinc are formed during activities such as welding and cause metal fume fever. Similarly, the combustion products of polytetrafluoroethylene (PTFE, Teflon) resins may be inhaled and cause polymer fume fever. Organic dust toxic syndrome occurs through the inhalation of bioaerosols (e.g., moldy silage, wood chips, sewage sludge, cotton, grain dust) that are contaminated with bacteria, endotoxins, or fungi.

These inflammatory conditions are characterized by flulike symptoms, including chills, myalgia, headache, fever, malaise, cough, and chest discomfort. On physical examination, crackles may be heard. Diagnosis is made by history and clinical evaluation. Laboratory values may show a leukocytosis with a left shift and elevated serum lactate dehydrogenase. The pathophysiology is not completely understood, but stimulation of the immune system may lead to symptoms, based on studies of cytokine production in BAL fluid and blood of affected individuals.

Treatment is symptomatic, and inhalational fume fever is self-limited, generally peaking at 18 hours and lasting 24 hours. Removal from further exposure is necessary. These conditions share some clinical overlap with hypersensitivity pneumonitis, a lung condition caused by bioaerosols and certain chemicals that induce specific cellular and humoral immune responses.

Biochemical Toxins and Weaponized Agents

A variety of agents have been developed and used to cause mass injury or disruption. Table 56-3 provides an overview of pulmonary effects and treatment of these toxicities. With all chemical exposures, individuals should be removed from exposure and given supportive care.

Table 56-3 Categories of Biochemical Poisons and Weapons: Specific Agents, Pulmonary Effects, and Treatment