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Diseases Caused by Respiratory Irritants and Toxic Chemicals

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The presence of respiratory irritants in the workplace can be unpleasant and distracting, leading to poor morale and decreased productivity. Certain exposures are dangerous, even lethal. In either extreme, the problem of respiratory irritants and inhaled toxic chemicals is common; many workers face a daily threat of exposure. These compounds cause harm by a variety of different mechanisms, and the extent of injury can vary widely, depending on the degree of exposure and on the biochemical properties of the inhalant. However, they all have the characteristic of nonspecificity; that is, above a certain level of exposure virtually all persons experience a threat to their health.

There are other inhaled substances that cause only susceptible individuals to develop respiratory problems; such complaints are most appropriately approached as diseases of allergic and immunological origin. Certain compounds, such as isocyanates, acid anhydrides and epoxy resins, can act not only as non-specific irritants in high concentrations, but can also predispose certain subjects to allergic sensitization. These compounds provoke respiratory symptoms in sensitized individuals at very low concentrations.

Respiratory irritants include substances that cause inflammation of the airways after they are inhaled. Damage may occur in the upper and lower airways. More dangerous is acute inflammation of the pulmonary parenchyma, as in chemical pneumonitis or non-cardiogenic pulmonary oedema. Compounds that can cause parenchymal damage are considered toxic chemicals. Many inhaled toxic chemicals also act as respiratory irritants, warning us of their danger with their noxious odour and symptoms of nose and throat irritation and cough. Most respiratory irritants are also toxic to the lung parenchyma if inhaled in sufficient amount.

Many inhaled substances have systemic toxic effects after being absorbed by inhalation. Inflammatory effects on the lung may be absent, as in the case of lead, carbon monoxide or hydrogen cyanide. Minimal lung inflammation is normally seen in the inhalation fevers (e.g., organic dust toxic syndrome, metal fume fever and polymer fume fever). Severe lung and distal organ damage occurs with significant exposure to toxins such as cadmium and mercury.

The physical properties of inhaled substances predict the site of deposition; irritants will produce symptoms at these sites. Large particles (10 to 20mm) deposit in the nose and upper airways, smaller particles (5 to 10mm) deposit in the trachea and bronchi, and particles less than 5mm in size may reach the alveoli. Particles less than 0.5mm are so small they behave like gases. Toxic gases deposit according to their solubility. A water-soluble gas will be adsorbed by the moist mucosa of the upper airway; less soluble gases will deposit more randomly throughout the respiratory tract.

Respiratory Irritants

Respiratory irritants cause non-specific inflammation of the lung after being inhaled. These substances, their sources of exposure, physical and other properties, and effects on the victim are outlined in Table 1. Irritant gases tend to be more water soluble than gases more toxic to the lung parenchyma. Toxic fumes are more dangerous when they have a high irritant threshold; that is, there is little warning that the fume is being inhaled because there is little irritation.

Table 1. Summary of respiratory irritants


Sources of exposure

Important properties

Injury produced

Dangerous exposure level under 15 min 


Plastics, synthetic rubber industry, combustion products

High vapour pressure; high water solubility

Upper airway injury; rarely causes delayed pulmonary oedema


Acetic acid, organic 

Chemical industry, electronics, combustion products

Water soluble

Ocular and upper airway injury


Acid anhydrides

Chemicals, paints, and plastics 
industries; components of epoxy resins

Water soluble, highly reactive, may cause allergic sensitization

Ocular, upper airway injury, bronchospasm; pulmonary haemorrhage after massive exposure



Plastics, textiles, pharmaceutical manufacturing, combustion products

High vapour pressure, intermediate water solubility, extremely irritating

Diffuse airway and parenchymal injury



Fertilizers, animal feeds, chemicals, and pharmaceuticals manufacturing

Alkaline gas, very high water solubility

Primarily ocular and upper airway burn; massive exposure may cause bronchiectasis


Antimony trichloride, antimony penta-chloride

Alloys, organic catalysts

Poorly soluble, injury likely due to halide ion

Pneumonitis, non-cardiogenic pulmonary oedema



Alloys (with copper), ceramics; electronics, aerospace and nuclear reactor equipment

Irritant metal, also acts as an antigen to promote a long-term granulomatous response

Acute upper airway injury, tracheobronchitis, chemical pneumonitis

25 μg/m3

Boranes (diborane)

Aircraft fuel, fungicide manufacturing

Water soluble gas

Upper airway injury, pneumonitis with massive exposure


Hydrogen bromide

Petroleum refining


Upper airway injury, pneumonitis with massive exposure


Methyl bromide

Refrigeration, produce fumigation

Moderately soluble gas

Upper and lower airway injury, pneumonitis, CNS depression and seizures



Alloys with Zn and Pb, electroplating, batteries, insecticides

Acute and chronic respiratory effects

Tracheobronchitis, pulmonary oedema (often delayed onset over 24–48 hours); chronic low level exposure leads to inflammatory changes and emphysema


Calcium oxide, calcium hydroxide

Lime, photography, tanning, insecticides

Moderately caustic, very high doses required for toxicity

Upper and lower airway inflammation, pneumonitis



Bleaching, formation of chlorinated compounds, household cleaners

Intermediate water solubilty

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema



Crowd control agent, “tear gas”

Irritant qualities are used to incapacitate; alkylating agent

Ocular and upper airway inflammation, lower airway and parenchymal injury with masssive exposure



Crowd control agent, “tear gas”

Irritant qualities are used to

Ocular and upper airway inflammation, lower airway injury with massive exposure


Chloromethyl ethers

Solvents, used in manufacture of other organic compounds


Upper and lower airway irritation, also a respiratory tract carcinogen



Chemical manufacturing, fumigant component

Former First World War gas

Upper and lower airway inflammation


Chromic acid (Cr(IV))

Welding, plating

Water soluble irritant, allergic sensitizer

Nasal inflammation and ulceration, rhinitis, pneumonitis with massive exposure



High temperature alloys, permanent magnets, hard metal tools (with tungsten carbide)

Non-specific irritant, also allergic sensitizer

Acute bronchospasm and/or pneumonitis; chronic exposure can cause lung fibrosis



Manufacture of foam insulation, plywood, textiles, paper, fertilizers,
resins; embalming agents; combustion products

Highly water soluble, rapidly metabolized; primarily acts via sensory nerve stimulation; sensitization reported

Ocular and upper airway irritation; bronchospasm in severe exposure; contact dermatitis in sensitized persons


Hydrochloric acid

Metal refining, rubber manufacturing, organic compound manufacture, photographic materials

Highly water soluble

Ocular and upper airway inflammation, lower airway inflammation only with massive exposure


Hydrofluoric acid

Chemical catalyst, pesticides, bleaching, welding, etching

Highly water soluble, powerful and rapid oxidant, lowers serum calcium in massive exposure

Ocular and upper airway inflammation, tracheobronchitis and pneumonitis with massive exposure



Polyurethane production; paints; herbicide and insecticide products; laminating, furniture, enamelling,
resin work

Low molecular weight organic compounds, irritants, cause sensitization in susceptible persons

Ocular, upper and lower inflammation; asthma, hypersensitivity pneumonitis in sensitized persons


Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Low solubility, highly reactive

Pneumonitis, non-cardiogenic pulmonary oedema



Electrolysis, ore and amalgam extraction, electronics manufacture

No respiratory symptoms with low level, chronic exposure

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

1.1 mg/m3

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Potent toxin

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

8 μg/m3

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding, combustion products

Low water solubility, brown gas at
high concentration

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis


Nitrogen mustards;
sulphur mustards

Military gases

Causes severe injury, vesicant

Ocular, upper and lower airway inflammation, pneumonitis

20mg/m3 (N) 
1 mg/m3 (S)

Osmium tetroxide

Copper refining, alloy with iridium, catalyst for steroid synthesis and ammonia formation

Metallic osmium is inert, tetraoxide forms when heated in air

Severe ocular and upper airway irritation; transient renal damage

1 mg/m3


Arc welding, copy machines, paper bleaching

Sweet smelling gas, moderate water solubility

Upper and lower airway inflammation; asthmatics more susceptible



Pesticide and other chemical manufacture, arc welding, paint removal

Poorly water soluble, does not irritate airways in low doses

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses


Phosphoric sulphides

Production of insecticides, ignition compounds, matches


Ocular and upper airway inflammation


Phosphoric chlorides

Manufacture of chlorinated organic compounds, dyes, gasoline additives

Form phosphoric acid and hydrochloric acid on contact with mucosal surfaces

Ocular and upper airway inflammation

10 mg/m3

Selenium dioxide

Copper or nickel smelting, heating of selenium alloys

Strong vessicant, forms selenious acid (H2SeO3) on mucosal surfaces

Ocular and upper airway inflammation, pulmonary oedema in massive exposure


Hydrogen selenide

Copper refining, sulphuric acid production

Water soluble; exposure to selenium compounds gives rise to garlic odour breath

Ocular and upper airway inflammation, delayed pulmonary oedema



Manufacture of polystyrene and resins, polymers

Highly irritating

Ocular, upper and lower airway inflammation, neurological impairments


Sulphur dioxide

Petroleum refining, pulp mills, refrigeration plants, manufacturing of sodium sulphite

Highly water soluble gas

Upper airway inflammation, bronchoconstriction, pneumonitis on massive exposure


Titanium tetrachloride

Dyes, pigments, sky writing

Chloride ions form HCl on mucosa

Upper airway injury


Uranium hexafluoride

Metal coat removers, floor sealants, spray paints

Toxicity likely from chloride ions

Upper and lower airway injury, bronchospasm, pneumonitis


Vanadium pentoxide

Cleaning oil tanks, metallurgy


Ocular, upper and lower airway symptoms


Zinc chloride

Smoke grenades, artillery

More severe than zinc oxide exposure

Upper and lower airway irritation, fever, delayed onset pneumonitis


Zirconium tetrachloride

Pigments, catalysts

Chloride ion toxicity

Upper and lower airway irritation, pneumonitis



This condition is thought to result from persistent inflammation with reduction of epithelial cell layer permeability or reduced conductance threshold for subepithelial nerve endings.Adapted from Sheppard 1988; Graham 1994; Rom 1992; Blanc and Schwartz 1994; Nemery 1990; Skornik 1988.

The nature and extent of the reaction to an irritant depends on the physical properties of the gas or aerosol, the concentration and time of exposure, and on other variables as well, such as temperature, humidity and the presence of pathogens or other gases (Man and Hulbert 1988). Host factors such as age (Cabral-Anderson, Evans and Freeman 1977; Evans, Cabral-Anderson and Freeman 1977), prior exposure (Tyler, Tyler and Last 1988), level of antioxidants (McMillan and Boyd 1982) and presence of infection may play a role in determining the pathological changes seen. This wide range of factors has made it difficult to study the pathogenic effects of respiratory irritants in a systematic way.

The best understood irritants are those which inflict oxidative injury. The majority of inhaled irritants, including the major pollutants, act by oxidation or give rise to compounds that act in this way. Most metal fumes are actually oxides of the heated metal; these oxides cause oxidative injury. Oxidants damage cells primarily by lipid peroxidation, and there may be other mechanisms. On a cellular level, there is initially a fairly specific loss of ciliated cells of the airway epithelium and of Type I alveolar epithelial cells, with subsequent violation of the tight junction interface between epithelial cells (Man and Hulbert 1988; Gordon, Salano and Kleinerman 1986; Stephens et al. 1974). This leads to subepithelial and submucosal damage, with stimulation of smooth muscle and parasympathetic sensory afferent nerve endings causing bronchoconstriction (Holgate, Beasley and Twentyman 1987; Boucher 1981). An inflammatory response follows (Hogg 1981), and the neutrophils and eosinophils release mediators that cause further oxidative injury (Castleman et al. 1980). Type II pneumocytes and cuboidal cells act as stem cells for repair (Keenan, Combs and McDowell 1982; Keenan, Wilson and McDowell 1983).

Other mechanisms of lung injury eventually involve the oxidative pathway of cellular damage, particularly after damage to the protective epithelial cell layer has occurred and an inflammatory response has been elicited. The most commonly described mechanisms are outlined in table 2.

Table 2. Mechanisms of lung injury by inhaled substances

Mechanism of injury

Example compounds

Damage that occurs


Ozone, nitrogen dioxide, sulphur dioxide, chlorine, oxides

Patchy airway epithelial damage, with increased permeability and exposure of nerve fibre endings; loss of cilia from ciliated cells; necrosis of type I pneumocytes; free radical formation and subsequent protein binding and lipid peroxidation

Acid formation

Sulphur dioxide, chlorine, halides

Gas dissolves in water to form acid that damages epithelial cells via oxidation; action mainly on upper airway

Alkali formation

Ammonia, calcium oxide, hydroxides

Gas dissolves in water to form alkaline solution that may cause tissue liquefaction; predominant upper airway damage, lower airway in heavy exposures

Protein binding


Reactions with amino acids lead to toxic intermediates with damage to the epithelial cell layer

Afferent nerve stimulation

Ammonia, formaldehyde

Direct nerve ending stimulation provokes symptoms


Platinum, acid anhydrides

Low molecular weight molecules serve as haptens in sensitized persons

Stimulation of host inflammatory response

Copper and zinc oxides, lipoproteins

Stimulation of cytokines and inflammatory mediators without apparent direct cellular damage

Free radical formation


Promotion of formation or retardation of clearance of superoxide radicals, leading to lipid peroxidation and oxidative damage

Delayed particle clearance

Any prolonged inhalation of mineral dust

Overwhelming of mucociliary escalators and alveolar macrophage systems with particles, leading to a non-specific inflammatory response


Workers exposed to low levels of respiratory irritants may have subclinical symptoms traceable to mucous membrane irritation, such as watery eyes, sore throat, runny nose and cough. With significant exposure, the added feeling of shortness of breath will often prompt medical attention. It is important to secure a good medical history in order to determine the likely composition of the exposure, the quantity of exposure, and the period of time during which the exposure took place. Signs of laryngeal oedema, including hoarseness and stridor, should be sought, and the lungs should be examined for signs of lower airway or parenchymal involvement. Assessment of the airway and lung function, together with chest radiography, are important in short-term management. Laryngoscopy may be indicated to evaluate the airway.

If the airway is threatened, the patient should undergo intubation and supportive care. Patients with signs of laryngeal oedema should be observed for at least 12 hours to insure that the process is self-limited. Bronchospasm should be treated with b-agonists and, if refractory, intravenous corticosteroids. Irritated oral and ocular mucosa should be thoroughly irrigated. Patients with crackles on examination or chest radiograph abnormalities should be hospitalized for observation in view of the possibility of pneumonitis or pulmonary oedema. Such patients are at risk of bacterial superinfection; nevertheless, no benefit has been demonstrated by using prophylactic antibiotics.

The overwhelming majority of patients who survive the initial insult recover fully from irritant exposures. The chances for long-term sequelae are more likely with greater initial injury. The term reactive airway dysfunction syndrome (RADS) has been applied to the persistence of asthma-like symptoms following acute exposure to respiratory irritants (Brooks, Weiss and Bernstein 1985).

High-level exposures to alkalis and acids can cause upper and lower respiratory tract burns that lead to chronic disease. Ammonia is known to cause bronchiectasis (Kass et al. 1972); chlorine gas (which becomes HCl in the mucosa) is reported to cause obstructive lung disease (Donelly and Fitzgerald 1990; Das and Blanc 1993). Chronic low-level exposures to irritants may cause continued ocular and upper airway symptoms (Korn, Dockery and Speizer 1987), but deterioration of lung function has not been conclusively documented. Studies of the effects of chronic low-level irritants on airway function are hampered by a lack of long-term follow-up, confounding by cigarette smoking, the “healthy worker effect,” and the minimal, if any, actual clinical effect (Brooks and Kalica 1987).

After a patient recovers from the initial injury, regular follow-up by a physician is needed. Clearly, there should be an effort to investigate the workplace and evaluate respiratory precautions, ventilation and containment of the culprit irritants.

Toxic Chemicals

Chemicals toxic to the lung include most of the respiratory irritants given enough high exposure, but there are many chemicals that cause significant parenchymal lung injury despite possessing low to moderate irritant properties. These compounds work their effects by mechanisms reviewed in Table 3 and discussed above. Pulmonary toxins tend to be less water soluble than upper airway irritants. Examples of lung toxins and their sources of exposure are reviewed in table 3.

Table 3. Compounds capable of lung toxicity after low to moderate exposure


Sources of exposure



Plastics, textiles, pharmaceutical manufacturing, combustion products

Diffuse airway and parenchymal injury

Antimony trichloride; antimony

Alloys, organic catalysts

Pneumonitis, non-cardiogenic pulmonary oedema


Alloys with zinc and lead, electroplating, batteries, insecticides

Tracheobronchitis, pulmonary oedema (often delayed onset over 24–48 hours), kidney damage: tubule proteinuria


Chemical manufacturing, fumigant components

Upper and lower airway inflammation


Bleaching, formation of chlorinated compounds, household cleaners

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema

Hydrogen sulphide

Natural gas wells, mines, manure

Ocular, upper and lower airway irritation, delayed pulmonary oedema, asphyxiation from systemic tissue hypoxia

Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Pneumonitis, non-cardiogenic pulmonary oedema

Methyl isocyanate

Pesticide synthesis

Upper and lower respiratory tract irritation, pulmonary oedema


Electrolysis, ore and amalgam extraction, electronics manufacture

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding; combustion products

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis

Nitrogen mustards, sulphur

Military agents, vesicants

Ocular and respiratory tract inflammation, pneumonitis


Herbicides (ingested)

Selective damage to type-2 pneumocytes leading to RADS, pulmonary fibrosis; renal failure, GI irritation


Pesticide and other chemical manufacture, arc welding, paint removal

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses

Zinc chloride

Smoke grenades, artillery

Upper and lower airway irritation, fever, delayed onset pneumonitis


One group of inhalable toxins are termed asphyxiants. When present in high enough concentrations, the asphyxiants, carbon dioxide, methane and nitrogen, displace oxygen and in effect suffocate the victim. Hydrogen cyanide, carbon monoxide and hydrogen sulphide act by inhibiting cellular respiration despite adequate delivery of oxygen to the lung. Non-asphyxiant inhaled toxins damage target organs, causing a wide variety of health problems and mortality.

The medical management of inhaled lung toxins is similar to the management of respiratory irritants. These toxins often do not elicit their peak clinical effect for several hours after exposure; overnight monitoring may be indicated for compounds known to cause delayed onset pulmonary oedema. Since the therapy of systemic toxins is beyond the scope of this chapter, the reader is referred to discussions of the individual toxins elsewhere in this Encyclopaedia and in further texts on the subject (Goldfrank et al. 1990; Ellenhorn and Barceloux 1988).

Inhalation Fevers

Certain inhalation exposures occurring in a variety of different occupational settings may result in debilitating flu-like illnesses lasting a few hours. These are collectively referred to as inhalation fevers. Despite the severity of the symptoms, the toxicity seems to be self-limited in most cases, and there are few data to suggest long-term sequelae. Massive exposure to inciting compounds can cause a more severe reaction involving pneumonitis and pulmonary oedema; these uncommon cases are considered more complicated than simple inhalation fever.

The inhalation fevers have in common the feature of nonspecificity: the syndrome can be produced in nearly anyone, given adequate exposure to the inciting agent. Sensitization is not required, and no previous exposure is necessary. Some of the syndromes exhibit the phenomenon of tolerance; that is, with regular repeated exposure the symptoms do not occur. This effect is thought to be related to an increased activity of clearance mechanisms, but has not been adequately studied.

Organic Dust Toxic Syndrome

Organic dust toxic syndrome (ODTS) is a broad term denoting the self-limited flu-like symptoms that occur following heavy exposure to organic dusts. The syndrome encompasses a wide range of acute febrile illnesses that have names derived from the specific tasks that lead to dust exposure. Symptoms occur only after a massive exposure to organic dust, and most individuals so exposed will develop the syndrome.

Organic dust toxic syndrome has previously been called pulmonary mycotoxicosis, owing to its putative aetiology in the action of mould spores and actinomycetes. With some patients, one can culture species of Aspergillus, Penicillium, and mesophilic and thermophilic actinomycetes (Emmanuel, Marx and Ault 1975; Emmanuel, Marx and Ault 1989). More recently, bacterial endotoxins have been proposed to play at least as large a role. The syndrome has been provoked experimentally by inhalation of endotoxin derived from Enterobacter agglomerans, a major component of organic dust (Rylander, Bake and Fischer 1989). Endotoxin levels have been measured in the farm environment, with levels ranging from 0.01 to 100μg/m3. Many samples had a level greater than 0.2μg/m3, which is the level where clinical effects are known to occur (May, Stallones and Darrow 1989). There is speculation that cytokines, such as IL-1, may mediate the systemic effects, given what is already known about the release of IL-1 from alveolar macrophages in the presence of endotoxin (Richerson 1990). Allergic mechanisms are unlikely given the lack of need for sensitization and the requirement for high dust exposure.

Clinically, the patient will usually present symptoms 2 to 8 hours after exposure to (usually mouldy) grain, hay, cotton, flax, hemp or wood chips, or upon manipulation of pigs (Do Pico 1992). Often symptoms begin with eye and mucous membrane irritation with dry cough, progressing to fever, and malaise, chest tightness, myalgias and headache. The patient appears ill but otherwise normal upon physical examination. Leukocytosis frequently occurs, with levels as high as 25,000 white blood corpuscles (WBC)/mm3. The chest radiograph is almost always normal. Spirometry may reveal a modest obstructive defect. In cases where fibre optic bronchoscopy was performed and bronchial washings were obtained, an elevation of leukocytes was found in the lavage fluid. The percentage of neutrophils was significantly higher than normal (Emmanuel, Marx and Ault 1989; Lecours, Laviolette and Cormier 1986). Bronchoscopy 1 to 4 weeks after the event shows a persistently high cellularity, predominantly lymphocytes.

Depending on the nature of the exposure, the differential diagnosis may include toxic gas (such as nitrogen dioxide or ammonia) exposure, particularly if the episode occurred in a silo. Hypersensitivity pneumonitis should be considered, especially if there are significant chest radiograph or pulmonary function test abnormalities. The distinction between hypersensitivity pneumonitis (HP) and ODTS is important: HP will require strict exposure avoidance and has a worse prognosis, whereas ODTS has a benign and self-limited course. ODTS is also distinguished from HP because it occurs more frequently, requires higher levels of dust exposure, does not induce the release of serum precipitating antibodies, and (initially) does not give rise to the lymphocytic alveolitis that is characteristic of HP.

Cases are managed with antipyretics. A role for steroids has not been advocated given the self-limited nature of the illness. Patients should be educated about massive exposure avoidance. The long-term effect of repeated occurrences is thought to be negligible; however, this question has not been adequately studied.

Metal Fume Fever

Metal fume fever (MFF) is another self-limited, flu-like illness that develops after inhalation exposure, in this instance to metal fumes. The syndrome most commonly develops after zinc oxide inhalation, as occurs in brass foundries, and in smelting or welding galvanized metal. Oxides of copper and iron also cause MFF, and vapours of aluminium, arsenic, cadmium, mercury, cobalt, chromium, silver, manganese, selenium and tin have been occasionally implicated (Rose 1992). Workers develop tachyphalaxis; that is, symptoms appear only when the exposure occurs after several days without exposure, not when there are regular repeated exposures. An eight-hour TLV of 5 mg/m3 for zinc oxide has been established by the US Occupational Safety and Health Administration (OSHA), but symptoms have been elicited experimentally after a two-hour exposure at this concentration (Gordon et al. 1992).

The pathogenesis of MFF remains unclear. The reproducible onset of symptoms regardless of the individual exposed argues against a specific immune or allergic sensitization. The lack of symptoms associated with histamine release (flushing, itching, wheezing, hives) also militates against the likelihood of an allergic mechanism. Paul Blanc and co-workers have developed a model implicating cytokine release (Blanc et al. 1991; Blanc et al.1993). They measured the levels of tumour necrosis factor (TNF), and of the interleukins IL-1, IL-4, IL-6 and IL-8 in the fluid lavaged from the lungs of 23 volunteers experimentally exposed to zinc oxide fumes (Blanc et al. 1993). The volunteers developed elevated levels of TNF in their bronchoalveolar lavage (BAL) fluid 3 hours after exposure. Twenty hours later, high BAL fluid levels of IL-8 (a potent neutrophil attractant) and an impressive neutrophilic alveolitis were observed. TNF, a cytokine capable of causing fever and stimulating immune cells, has been shown to be released from monocytes in culture that are exposed to zinc (Scuderi 1990). Accordingly, the presence of increased TNF in the lung accounts for the onset of symptoms observed in MFF. TNF is known to stimulate the release of both IL-6 and IL-8, in a time period that correlated with the peaks of the cytokines in these volunteers’ BAL fluid. The recruitment of these cytokines may account for the ensuing neutrophil alveolitis and flu-like symptoms that characterize MFF. Why the alveolitis resolves so quickly remains a mystery.

Symptoms begin 3 to 10 hours after exposure. Initially, there may be a sweet metallic taste in the mouth, accompanied by a worsening dry cough and shortness of breath. Fever and shaking chills often develop, and the worker feels ill. The physical examination is otherwise unremarkable. Laboratory evaluation shows a leukocytosis and a normal chest radiograph. Pulmonary function studies may show a slightly reduced FEF25-75 and DLCO levels (Nemery 1990; Rose 1992).

With a good history the diagnosis is readily established and the worker can be treated symptomatically with antipyretics. Symptoms and clinical abnormalities resolve within 24 to 48 hours. Otherwise, bacterial and viral aetiologies of the symptoms must be considered. In cases of extreme exposure, or exposures involving contamination by toxins such as zinc chloride, cadmium or mercury, MFF may be a harbinger of a clinical chemical pneumonitis that will evolve over the next 2 days (Blount 1990). Such cases can exhibit diffuse infiltrates on a chest radiograph and signs of pulmonary oedema and respiratory failure. While this possibility should be considered in the initial evaluation of an exposed patient, such a fulminant course is unusual and not characteristic of uncomplicated MFF.

MFF does not require a specific sensitivity of the individual for the metal fumes; rather, it indicates inadequate environmental control. The exposure problem should be addressed to prevent recurrent symptoms. Although the syndrome is considered benign, the long-term effects of repeated bouts of MFF have not been adequately investigated.

Polymer Fume Fever

Polymer fume fever is a self-limited febrile illness similar to MFF, but caused by inhaled pyrolysis products of fluoropolymers, including polytetrafluoroethane (PTFE; trade names Teflon, Fluon, Halon). PTFE is widely used for its lubricant, thermal stability and electrical insulative properties. It is harmless unless heated above 30°C, when it starts to release degradation products (Shusterman 1993). This situation occurs when welding materials coated with PTFE, heating PTFE with a tool edge during high speed machining, operating moulding or extruding machines (Rose 1992) and rarely during endotracheal laser surgery (Rom 1992a).

A common cause of polymer fume fever was elicited after a period of classic public health detective work in the early 1970s (Wegman and Peters 1974; Kuntz and McCord 1974). Textile workers were developing self-limited febrile illnesses with exposures to formaldehyde, ammonia and nylon fibre; they did not have exposure to fluoropolymer fumes but handled crushed polymer. After finding that exposure levels of the other possible aetiological agents were within acceptable limits, the fluoropolymer work was examined more closely. As it turned out, only cigarette smokers working with the fluoropolymer were symptomatic. It was hypothesized that the cigarettes were being contaminated with fluoropolymer on the worker’s hands, then the product was combusted on the cigarette when it was smoked, exposing the worker to toxic fumes. After banning cigarette smoking in the workplace and setting strict handwashing rules, no further illnesses were reported (Wegman and Peters 1974). Since then, this phenomenon has been reported after working with waterproofing compounds, mould-release compounds (Albrecht and Bryant 1987) and after using certain kinds of ski wax (Strom and Alexandersen 1990).

The pathogenesis of polymer fume fever is not known. It is thought to be similar to the other inhalation fevers owing to its similar presentation and apparently non-specific immune response. There have been no human experimental studies; however, rats and birds both develop severe alveolar epithelial damage on exposure to PTFE pyrolysis products (Wells, Slocombe and Trapp 1982; Blandford et al. 1975). Accurate measurement of pulmonary function or BAL fluid changes has not been done.

Symptoms appear several hours after exposure, and a tolerance or tachyphalaxis effect is not there as seen in MFF. Weakness and myalgias are followed by fever and chills. Often there is chest tightness and cough. Physical examination is usually otherwise normal. Leukocytosis is often seen, and the chest radiograph is usually normal. Symptoms resolve spontaneously in 12 to 48 hours. There have been a few cases of persons developing pulmonary oedema after exposure; in general, PTFE fumes are thought to be more toxic than zinc or copper fumes in causing MFF (Shusterman 1993; Brubaker 1977). Chronic airways dysfunction has been reported in persons who have had multiple episodes of polymer fume fever (Williams, Atkinson and Patchefsky 1974).

The diagnosis of polymer fume fever requires a careful history with high clinical suspicion. After ascertaining the source of the PTFE pyrolysis products, efforts must be made to prevent further exposure. Mandatory handwashing rules and the elimination of smoking in the workplace has effectively eliminated cases related to contaminated cigarettes. Workers who have had multiple episodes of polymer fume fever or associated pulmonary oedema should have long-term medical follow-up.



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