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METAL FUME FEVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Metal fume fever is an illness that is caused primarily by exposure to zinc oxide fumes in the workplace while welding, cutting or brazing galvanized metal. Other elements such as copper or magnesium can cause similar effects.

Specific Substances

    1) Brass chills
    2) Brass-founders ague
    3) Brazier's disease
    4) Copper colic
    5) Copper fever
    6) Foundry fever
    7) Galvanized shakes
    8) Galvanizer's poisoning
    9) Galvo
    10) Giessfieber
    11) Metal ague
    12) Metal malaria
    13) Metal shakes
    14) Monday morning fever
    15) Spelter shakes
    16) The shakes
    17) The smothers
    18) Welders ague
    19) Zinc chills
    20) Zinc-fume fever
    21) Zinc oxide chills
    22) Zinc shakes
    23) ANITMONY ELEMENTAL
    24) ANTIMON (POLISH)
    25) ANTIMONY, METAL
    26) AZADOX
    27) COATED ALUMINUM POWDER
    28) ETAIN
    29) FLORES DE ZINCI (ITALIAN)
    30) FUME FEVER
    31) FUME FEVER (METAL)
    32) MEGLUMINE ANTIMONATE
    33) METAL, ALUMINUM
    34) METALLIC ALUMINUM
    35) OUTMINE
    36) POWDERED ALUMINUM, COATED
    37) POWDERED ALUMINUM, PYROPHORIC
    38) POWDERED ALUMINUM, UNCOATED
    39) SATURDAY NIGHT FUME FEVER
    40) SODIUM STIBOGLUCONATE
    41) UNICHEM ZO
    42) VANDEM VAC
    43) VANDEM VOC
    44) VANDEM VPC
    45) WELDING FUME FEVER
    46) ZINC MONOXIDE
    47) ZINC OXIDE DUST
    48) ZINC OXYDATUM
    49) ZINCI OXYCUM
    50) ZINCI OXYDUM
    51) ZINCI WHITE

Available Forms Sources

    A) SOURCES
    1) Metal fume fever frequently occurs in workers while welding zinc, galvanized iron or steel, smelting zinc or copper alloys, in brass foundries or in welding or cutting metals (Hassaballa et al, 2005; Kaye et al, 2002; Anseline, 1972), or when torch cutting coated/painted objects.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Metal fume fever is an illness produced by the inhalation of metal oxide fumes. These oxides are produced by heating various metals such as cadmium, zinc, magnesium, copper, antimony, nickel, cobalt, manganese, tin, lead, beryllium, silver, chromium, aluminum, selenium, iron, and arsenic. However, the most common metals implicated are zinc and copper. It is an occupational disease among individuals who weld, heat or cut galvanized metals. NOTE: This document deals only with metal fume fever. Please see documents for individual metals and/or metal compounds when necessary to obtain information regarding other toxic effects.
    B) TOXICOLOGY: The exact mechanism of meal fume fever is not known but it is thought to be secondary to a cytokine-mediated immune response. The inhalation of the metal oxide fumes injuring the cell lining of airways is thought to be the precipitating event that leads to a systemic reaction.
    C) EPIDEMIOLOGY: Metal fume fever most often occurs among welders with several hundred cases reported to the United States poison centers every year and thousands of cases that likely occur annually in the US.
    D) WITH POISONING/EXPOSURE
    1) Symptoms of metal fume fever are generally described as a flu-like illness. Complaints include fever, chills, nausea, vomiting, abdominal pain, respiratory difficulties, fatigue, joint pain, and muscle aches. Classically, the onset of metal fume fever symptoms is rapid, occurring within 3 to 10 hours of exposure. Initial symptoms may include a metallic taste associated with throat irritation, dyspnea, and a feeling of thirst. This is then followed by a low-grade fever, chills, myalgias, arthralgias, malaise, fatigue, and a nonproductive cough. These may be accompanied by excessive sweating, shaking chills, nausea, vomiting, and headaches. Symptoms are self-limiting and usually resolve within a day or two (but may take longer). There can be subsequent temporary tolerance to the metal oxide fumes that may go away after 1 to 2 days after last exposure.
    0.2.3) VITAL SIGNS
    A) Abnormalities of temperature regulation (fever, chills, shivering) have been reported in humans and in animal studies.
    0.2.4) HEENT
    A) Flushing, dry throat, blurred vision, and stiff neck have been reported. A sweet or metallic taste is common.
    0.2.5) CARDIOVASCULAR
    A) Myocardial injury was reported in one patient after exposure to zinc oxide fumes during the galvanization of iron. Pericardial infusion has also been reported in one patient.
    0.2.6) RESPIRATORY
    A) The respiratory system is the most likely system to be affected in symptomatic MFF. Shortness of breath, chest tightness, rales in the midzone and basal regions, a non-productive cough, dyspnea, expiratory wheeze, and diffuse rales have all been reported. Long term sequelae or lesions are uncommon.
    0.2.7) NEUROLOGIC
    A) Headache, myalgias, weakness, and paresthesias in both feet have been reported.
    B) Inflammation of the meninges has been reported in case of metal fume fever.
    0.2.8) GASTROINTESTINAL
    A) Non-specific gastrointestinal effects may include anorexia, constipation or diarrhea, nausea, vomiting, and abdominal pain.
    0.2.10) GENITOURINARY
    A) There is no evidence that MFF causes kidney damage, even though several of the metals are nephrotoxic on chronic exposure.
    0.2.13) HEMATOLOGIC
    A) Leukocytosis is almost always present.
    0.2.14) DERMATOLOGIC
    A) Hives may rarely occur.
    0.2.15) MUSCULOSKELETAL
    A) Skeletal muscle injury may occur.
    0.2.19) IMMUNOLOGIC
    A) Transient immunologic reactions including tachyphylaxis and anaphylactoid reactions may occur. Increased polymorphonuclear neutrophils and cytokines have been measured in persons exposed to zinc oxide fumes.
    0.2.22) OTHER
    A) Metal fume fever is often confused with other illnesses, especially viral or infectious syndromes.

Laboratory Monitoring

    A) There is no specific diagnostic test for metal fume fever, but other basic lab studies may be useful in helping guide management or ruling out other causes of symptoms. These include a chest x-ray, arterial blood gas, CBC, and pulmonary function tests. These tests often appear normal, though in severe cases, one may see findings such as infiltrates on the chest x-ray.
    B) No specific study is needed for most patients as long as a good work history demonstrating exposure to metal fume oxides is obtained. Patients may have elevated serum, urine, or plasma concentrations of specific metals such as zinc, but this does not aid in management of the patient.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The mode of toxicity from metal fume fever is inhalational. Thus, treatment of mild to moderate toxicity includes moving the patient away from exposure of the metal oxide fumes to fresh air. For patients with respiratory symptoms, administer oxygen as needed. Bronchospasm can be treated with inhaled beta2-agonists and oral or parenteral corticosteroids. Analgesics, antiemetics, and antipyretics should be administered as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Management of severe toxicity starts similarly to management of mild to moderate toxicity. Severe toxicity is rare. In patients with severe respiratory symptoms, more aggressive treatment such as assisted ventilation or intubation may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: As toxicity is through inhalation, there is no need for gastrointestinal decontamination. Removing the patient from the exposure into fresh air is the most important prehospital management. Although there may be dermal or ocular exposure, there is no evidence for washing skin or irrigation of eyes.
    2) HOSPITAL: Administer 100% humidified supplemental oxygen. Monitor for respiratory distress. ORAL EXPOSURE: The primary route of exposure is by inhalation. Although very small amounts may reach the gastrointestinal tract, no decontamination is needed.
    D) AIRWAY MANAGEMENT
    1) Some of the most prominent symptoms are respiratory and should be accordingly treated with removal to fresh air, oxygen, beta2 agonists, and corticosteroids. In rare cases, assisted ventilation, and even intubation may be needed.
    E) ANTIDOTE
    1) There is no specific antidote for metal fume fever.
    F) ENHANCED ELIMINATION PROCEDURE
    1) There is no evidence for enhanced elimination via dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: The vast majority of these patients can be managed at home with removal from exposure, symptomatic over-the-counter treatment, and the use of proper protective gear (eg, respirators) in the future.
    2) OBSERVATION CRITERIA: Patients who do not improve with the above home measures and those with more severe symptoms should be sent to a healthcare facility for observation and treatment and should not be sent home until they show symptomatic improvement.
    3) ADMISSION CRITERIA: Patients who do not improve despite initial symptomatic treatments should be admitted. Most patients would do fine on a general ward, but those with severe respiratory symptoms potentially necessitating intubation should be admitted to the ICU. Patients should not be discharged home until they are clearly symptomatically improved.
    4) CONSULT CRITERIA: Poison centers or toxicologists may be contacted to help facilitate care. Industrial cases may necessitate evaluation from workmen's compensation clinics, occupational medicine physicians, and/or the state health departments. Those with underlying lung disease and severe respiratory symptoms may benefit from evaluation from a pulmonologist.
    H) PITFALLS
    1) Due to the nonspecific nature of the symptoms, the diagnosis may be missed unless a careful history of exposure to metal oxide fumes is obtained. Thus, patients may experience recurrent symptoms unless they are removed from the source of exposure or proper protective gear is used.
    I) PREDISPOSING CONDITIONS
    1) Patients with underlying lung disease (eg, smokers) may be more predisposed to more severe respiratory symptoms from metal fume fever.
    J) DIFFERENTIAL DIAGNOSIS
    1) Influenza, carbon monoxide poisoning, viral illnesses, smoke inhalation, asthma exacerbation, acute lung injury.
    0.4.4) EYE EXPOSURE
    A) No serious ocular toxicity has been reported from metal fumes.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Symptoms from metal fume fever should not result from simple dermal exposure and in general, no decontamination is needed.

Range Of Toxicity

    A) TOXICITY: ZINC OXIDE: Legal workplace limit (OSHA): 5 mg/m(3) averaged over an 8-hour work shift. Permissible exposure limit (NIOSH): 5 mg/m(3) averaged over a work shift up to 10 hours per day, 40 hours per week with a short-term exposure limit of 10 mg/m(3) averaged over a 15 minute period. A time weighted average (ACGIH): 2 mg/m(3) for an 8-hour work day and 40-hour work week. Symptoms have been reported with levels below 5 mg/m(3) but levels of 14 mg/m(3) have been well-tolerated for 8-hour exposures. A level of 45 mg/m(3) was tolerated for 20 minutes but levels above this are generally poorly tolerated.

Clinical Effects

Summary Of Exposure

    A) DESCRIPTION: Metal fume fever is an illness produced by the inhalation of metal oxide fumes. These oxides are produced by heating various metals such as cadmium, zinc, magnesium, copper, antimony, nickel, cobalt, manganese, tin, lead, beryllium, silver, chromium, aluminum, selenium, iron, and arsenic. However, the most common metals implicated are zinc and copper. It is an occupational disease among individuals who weld, heat or cut galvanized metals. NOTE: This document deals only with metal fume fever. Please see documents for individual metals and/or metal compounds when necessary to obtain information regarding other toxic effects.
    B) TOXICOLOGY: The exact mechanism of meal fume fever is not known but it is thought to be secondary to a cytokine-mediated immune response. The inhalation of the metal oxide fumes injuring the cell lining of airways is thought to be the precipitating event that leads to a systemic reaction.
    C) EPIDEMIOLOGY: Metal fume fever most often occurs among welders with several hundred cases reported to the United States poison centers every year and thousands of cases that likely occur annually in the US.
    D) WITH POISONING/EXPOSURE
    1) Symptoms of metal fume fever are generally described as a flu-like illness. Complaints include fever, chills, nausea, vomiting, abdominal pain, respiratory difficulties, fatigue, joint pain, and muscle aches. Classically, the onset of metal fume fever symptoms is rapid, occurring within 3 to 10 hours of exposure. Initial symptoms may include a metallic taste associated with throat irritation, dyspnea, and a feeling of thirst. This is then followed by a low-grade fever, chills, myalgias, arthralgias, malaise, fatigue, and a nonproductive cough. These may be accompanied by excessive sweating, shaking chills, nausea, vomiting, and headaches. Symptoms are self-limiting and usually resolve within a day or two (but may take longer). There can be subsequent temporary tolerance to the metal oxide fumes that may go away after 1 to 2 days after last exposure.

Vital Signs

    3.3.1) SUMMARY
    A) Abnormalities of temperature regulation (fever, chills, shivering) have been reported in humans and in animal studies.
    3.3.3) TEMPERATURE
    A) Abnormalities of temperature regulation (fever, chills, shivering) have been reported in humans and in animal studies (Merchant & Webby, 2001; Kaye et al, 2002; Armstrong et al, 1983; Sferlazza & Beckett, 1991; Hung & Kao, 1995).
    B) FEVER is common and usually mild, but has reached temperatures of 104 degrees F (40 degrees C) (Kaye et al, 2002; Armstrong et al, 1983; Sferlazza & Beckett, 1991; Hung & Kao, 1995).
    C) Chills and shivering are common initial effects (Anseline, 1972) Vogelmeier et al, 1987; (Gordon et al, 1992).

Heent

    3.4.1) SUMMARY
    A) Flushing, dry throat, blurred vision, and stiff neck have been reported. A sweet or metallic taste is common.
    3.4.3) EYES
    A) BLURRED VISION has been reported (Anseline, 1972; Sturgis et al, 1927; McCord, 1960).
    3.4.6) THROAT
    A) SORE THROAT: Sore and dry throat may occur (Van Pee et al, 1998; Anseline, 1972; Sturgis et al, 1927; McCord, 1960; Gordon et al, 1992).
    B) METALLIC TASTE: An unusual sweet or metallic taste is also reported (Armstrong et al, 1983; Sferlazza & Beckett, 1991), most frequently in lead oxide exposure. A sweet taste was reported by a zinc welder (Vogelmeier et al, 1987).

Cardiovascular

    3.5.1) SUMMARY
    A) Myocardial injury was reported in one patient after exposure to zinc oxide fumes during the galvanization of iron. Pericardial infusion has also been reported in one patient.
    3.5.2) CLINICAL EFFECTS
    A) MYOCARDITIS
    1) Myocardial injury occurred in one patient after exposure to zinc oxide fumes during the galvanization of iron. The peak serum creatinine kinase level was 3,146 IU/L, with 12.4 percent MB fraction (Shusterman & Neal, 1986).
    B) PERICARDIAL EFFUSION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old man welder exposed to fumes from galvanized steel became symptomatic and initially developed a headache and neck stiffness followed by difficulty breathing following re-exposure. The clinical diagnosis included aseptic meningitis along with pericarditis, pleuritis, and pneumonitis. A CT of the chest revealed a bilateral pleural effusion, an enlarged heart, and a large pericardial effusion. Symptoms improved following removal from exposure source and supportive care. The pericardial effusion resolved completely within 1 week of exposure (Hassaballa et al, 2005).
    C) TACHYARRHYTHMIA
    1) Sinus tachycardia has been reported (Merchant & Webby, 2001; Kaye et al, 2002; Van Pee et al, 1998).

Respiratory

    3.6.1) SUMMARY
    A) The respiratory system is the most likely system to be affected in symptomatic MFF. Shortness of breath, chest tightness, rales in the midzone and basal regions, a non-productive cough, dyspnea, expiratory wheeze, and diffuse rales have all been reported. Long term sequelae or lesions are uncommon.
    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) Shortness of breath, chest tightness, rales in mid-zone and basal regions, a non-productive cough, dyspnea, expiratory wheeze, and diffuse rales have all been reported (Merchant & Webby, 2001; Hassaballa et al, 2005; Kaye et al, 2002; Contreras & Chan-Yeung, 1997; Anseline, 1972; Armstrong et al, 1983; Sferlazza & Beckett, 1991; Langley, 1991).
    2) Dyspnea and wheezing have been reported in workers exposed to fumes of galvanized metal (Kawane et al, 1988; Malo & Cartier, 1987; Langley, 1991; Hung & Kao, 1995).
    3) Chest x-rays are often normal (Perry, 1994; Hung & Kao, 1995).
    B) HYPOXEMIA
    1) Mild hypoxia has been reported (Van Pee et al, 1998; Langley, 1991; Hung & Kao, 1995).
    C) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) There is often a reduction in vital capacity (Drinker et al, 1927; Ameille et al, 1992). Mild obstructive or restrictive patterns may be present upon pulmonary function testing (Parker et al, 1997; (Contreras & Chan-Yeung, 1997; Langley, 1991). Smokers may be more likely to exhibit abnormal pulmonary function tests after exposure to metal fumes than are non-smokers (Rastogi et al, 1991).
    b) CASE REPORT: A 55-year-old plumber presented with malaise, fatigue, cough, fever (39 degrees C), nausea, and dyspnea at rest several hours after using an oxyacetylene torch to remove a steel tank. On admission, he was unable to talk in full sentences, had a respiratory rate of 24/min and a pulse rate of 100/min. Blood gas analysis revealed acute type I respiratory failure with an arterial oxygen partial pressure of 8.8 kPa. A chest radiograph showed patchy opacification in the right perihilar area. Following supportive care he recovered completely and was discharged the following day (Kaye et al, 2002).
    D) PNEUMONITIS
    1) Pulmonary inflammation occurs with metal fume inhalation and its severity tends to be in proportion to the amount of zinc oxide fume inhaled. Typical symptoms of metal fume fever may or may not accompany such inflammation. Frank, severe and delayed pulmonary edema is not a classical feature of metal fume fever (Perry, 1994).
    a) Pulmonary edema produced by ozone and nitrogen oxide exposure has been reported in humans (Dryson & Rogers, 1991). Other metal fumes can cause acute pneumonitis and related pulmonary effects (Perry, 1994) Fuorrtes et al, 1991).
    E) FIBROSIS OF LUNG
    1) WITH POISONING/EXPOSURE
    a) The lung function studies of 15 welders with interstitial pulmonary fibrosis with long-term exposure (mean exposure duration 28 years) to high concentrations of welding fumes (the cumulative dose median concentration of 221 mg/m(3) x years) revealed a pattern of restriction or combined restriction-obstruction, lower diffusion capacity, and reduced blood oxygen tension at exercise. Histological specimens showed patchy interstitial fibrosis. Lung specimens of 8 cases (using energy dispersive x-ray analysis) showed high concentrations of iron particles, and the areas of fibrosis appeared to be related to the presence of welding fume particles (Buerke et al, 2002).
    F) BRONCHITIS
    1) Exposure to metal fumes was associated with chronic bronchitis in one study. Six of 16 welders reported phlegm production each day for up to 3 months per year (Dryson & Rogers, 1991).
    G) SEQUELA
    1) Sequelae are uncommon. Pulmonary lesions and residual effects are extremely rare and are not generally considered classical signs of metal fume fever (Hassaballa et al, 2005).
    2) Upper respiratory infection and rales persisting several days have occurred in metal fume exposures (Anseline, 1972; Rohrs, 1957).
    H) PRIMARY MALIGNANT NEOPLASM OF RESPIRATORY TRACT
    1) Exposure to chromium and nickel fumes has resulted in increased incidences of lung cancer (Dryson & Rogers, 1991).
    I) ACUTE LUNG INJURY
    1) A 43-year-old man developed chills, fever, and malaise after cutting a galvanized metal grate with and oxyacetylene cutting torch. Symptoms progressed to shortness of breath and cough and he developed progressive hypoxia and patchy interstitial infiltrates on chest radiograph. He required mechanical ventilation but recovered with supportive care. Lung biopsy revealed focal mild interstitial pneumonia and extensive diffuse alveolar damage (Banbee & Prina, 1999).
    J) PNEUMONIA
    1) In a study of welders from England and Wales, mortality from pneumococcal and unspecified lobar pneumonia was increased in welders compared with controls (proportional mortality ratios 255, 95% FI 192 to 332). No increase was observed in men above retirement age, suggesting that inhalation of welding fumes reversibly increased the susceptibility to lung infection (Coggon et al, 1994).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PULMONARY EDEMA
    a) Animals exposed to high concentrations of various fumes have developed pulmonary edema and died (Sayers, 1938).

Neurologic

    3.7.1) SUMMARY
    A) Headache, myalgias, weakness, and paresthesias in both feet have been reported.
    B) Inflammation of the meninges has been reported in case of metal fume fever.
    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) Weakness and paresthesias of both feet due to exposure to zinc oxide have been reported; psychogenic overlay can occur (Anseline, 1972a).
    B) MUSCLE PAIN
    1) Myalgia has been reported in patients with metal fume fever (Merchant & Webby, 2001; Hung & Kao, 1995; Blanc et al, 1991).
    2) CASE SERIES: Four participants in a study who were exposed to 3.5 g min/m(3) of zinc oxide fumes experienced myalgia during the evening following exposure (Blanc et al, 1991). Generalized myalgia occurred in 3 of 7 pipe cutters exposed to zinc oxide fumes (Hung & Kao, 1995).
    C) ASEPTIC MENINGITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old man welder who was exposed to fumes from galvanized steel developed a headache and stiff neck several hours after exposure. He was re-exposed the next day at work and developed worsening symptoms of myalgia, headache, neck stiffness, and difficulty breathing with pleural effusion. The patient was febrile on admission. A lumbar puncture revealed mild lymphocytic pleocytosis. He also developed pericarditis, pleuritis, and pneumonia. Treatment was supportive and included 50 mg oral indomethacin 3 times daily. Symptoms improved within 16 hours. By day 4, the patient was discharged to home with all cultures negative and no permanent sequelae (Hassaballa et al, 2005).
    D) HEADACHE
    1) Headache and stiff neck have been reported (Merchant & Webby, 2001; Hassaballa et al, 2005; Anseline, 1972; Sturgis et al, 1927; McCord, 1960).
    E) MALAISE
    1) WITH POISONING/EXPOSURE
    a) Malaise and fatigue were reported in workers after using an oxyacetylene torch to remove a steel tank (Kaye et al, 2002).

Gastrointestinal

    3.8.1) SUMMARY
    A) Non-specific gastrointestinal effects may include anorexia, constipation or diarrhea, nausea, vomiting, and abdominal pain.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) Non-specific GI symptoms may include anorexia, constipation or diarrhea, nausea, vomiting, intestinal "colic", and abdominal pain have been reported (Merchant & Webby, 2001; Kaye et al, 2002; McCord, 1960; Rohrs, 1957). A small number of cases have reported excessive salivation (McCord, 1960).

Genitourinary

    3.10.1) SUMMARY
    A) There is no evidence that MFF causes kidney damage, even though several of the metals are nephrotoxic on chronic exposure.
    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) There is no evidence that MFF causes kidney damage, even though several of the metals are nephrotoxic with chronic exposure (Sturgis et al, 1927).
    B) DYSURIA
    1) CASE SERIES: One study reported frequency of urination in 32% of cases and a burning sensation upon urination in 21% of cases (Drinker et al, 1927).

Hematologic

    3.13.1) SUMMARY
    A) Leukocytosis is almost always present.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) Leukocytosis is almost always present. Leukocytosis and left shift were reported in 88% and 83% (respectively) of cases reported by Armstrong et al (1983) (Armstrong et al, 1983a).
    2) CASE REPORT: Neutrophil leukocytosis was noted in a 55-year-old plumber several hours after using an oxyacetylene torch to remove a steel tank (Kaye et al, 2002).
    3) An elevated white blood cell count of 22.8 x 10(9)/L (normal range: 4 to 11 x 10(9)/L) with neutrophilia of 18.7 x 10(9)/L ) was noted in a 26-year-old man after oxycutting zinc-coated steel (galvanized steel) (Merchant & Webby, 2001).

Dermatologic

    3.14.1) SUMMARY
    A) Hives may rarely occur.
    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) CASE REPORT: Urticaria and angioedema occurred in one patient after exposure to zinc oxide fumes (Farrell, 1987).
    B) FLUSHING
    1) Flushing has been reported.
    C) EXCESSIVE SWEATING
    1) Diaphoresis is common (Papp, 1968) Vogelmeier et al, 1987).

Musculoskeletal

    3.15.1) SUMMARY
    A) Skeletal muscle injury may occur.
    3.15.2) CLINICAL EFFECTS
    A) TOXIC MYOPATHY
    1) CASE REPORT: Skeletal muscle and myocardial injury, demonstrated by elevated serum creatine kinase (CK 301 IU/L; normal 15 to 110 IU/L), was reported in a 26-year-old welder with metal fume fever (Shusterman & Neal, 1986).

Immunologic

    3.19.1) SUMMARY
    A) Transient immunologic reactions including tachyphylaxis and anaphylactoid reactions may occur. Increased polymorphonuclear neutrophils and cytokines have been measured in persons exposed to zinc oxide fumes.
    3.19.2) CLINICAL EFFECTS
    A) INCREASED TOLERANCE
    1) Patients exposed develop tachyphylaxis, a quickly acquired and lost immunity. This tolerance is acquired and lost over 1 to 2 days (McCord, 1960).
    B) ANAPHYLACTOID REACTION
    1) Anaphylactoid reactions, with angioedema, pruritus, and severe swelling of the throat have rarely occurred (Farrell, 1987).
    2) CASE REPORT: Angioedema has been reported in a patient after exposure to zinc oxide fumes (Farrell, 1987).
    C) DISORDER OF IMMUNE FUNCTION
    1) INFLAMMATORY MEDIATORS: Increased polymorphonuclear leukocytes and concentrations of TNF and IL-8 in bronchoalveolar lavage fluid supernates resulted from inhalation of purified zinc oxide fume in experimental human studies (Kuschner et al, 1995). The zinc oxide fume concentrations were lower than typically generated during welding and did not cause symptoms of metal fume fever.
    2) Increased IL6 levels have been reported in plasma of volunteers exposed to zinc oxide fumes. There was no effect on plasma levels of TNF (Fine et al, 1997).
    3) Current research in-vitro, in animals, and in humans, mainly using zinc, suggests that metal fumes probably cause a direct release of cytokines from immune system cells within the lung. The reported cellular sources and specific cytokine(s) involved vary among available reports (Kushner et al, 1998; (Lindahl et al, 1998)Kushner et al, 1997; (Fine et al, 1997) Kushner et al, 1995).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) There is no specific diagnostic test for metal fume fever, but other basic lab studies may be useful in helping guide management or ruling out other causes of symptoms. These include a chest x-ray, arterial blood gas, CBC, and pulmonary function tests. These tests often appear normal, though in severe cases, one may see findings such as infiltrates on the chest x-ray.
    B) No specific study is needed for most patients as long as a good work history demonstrating exposure to metal fume oxides is obtained. Patients may have elevated serum, urine, or plasma concentrations of specific metals such as zinc, but this does not aid in management of the patient.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitoring LDH, CPK or heavy metals may give an indication of severity exposure or extent of damage.
    a) Elevated lactate dehydrogenase pulmonary isoenzymes have occurred after exposure to zinc oxide fumes (Van Pee et al, 1998; Anseline, 1972; Fishburn & Zenz, 1969).
    b) Serum zinc levels may be elevated but the absence of elevated serum zinc cannot be reliably used to exclude exposure or metal fume fever (Perry, 1994).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Urinary zinc may be elevated (Perry, 1994; Fuortes & Schenck, 2000). The absence of urinary zinc cannot be reliably used to rule out exposure or metal fume fever (Perry, 1994).
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Pulmonary function testing may be useful for documenting the severity and progression or resolution of effects. Decreased vital capacity, decreased diffusion capacity, decreased FEV1, and hyperreactivity in response to histamine or methacholine challenge have been reported (Sjogren et al, 1991; Perry, 1994).
    b) One study reported reproducible pulmonary changes in a 26-year-old man during two exposure tests, done 6 months apart, under working conditions and laboratory control; the patient welded one hour on a zinc-coated tube with an electric torch (Vogelmeier et al, 1987).
    2) BRONCHO-ALVEOLAR LAVAGE
    a) Lymphocytosis and other mild changes in broncho-alveolar lavage specimens have been reported (Ameille et al, 1992; Tojima et al, 1998). This test cannot be recommended for routine diagnostic purposes, but may be useful if there is a need to rule out other conditions.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-rays are seldom diagnostic. Films are usually normal or show only increased bronchovascular markings (Rohrs, 1957; Sturgis et al, 1927; Sferlazza & Beckett, 1991; Langley, 1991; Hung & Kao, 1995). Cases have been reported to have bilateral diffuse infiltrates (Ebran et al, 2000).
    B) COMPUTED TOMOGRAPHY
    1) High resolution chest CT in one case demonstrated only exaggerated bronchioli (Tojima et al, 1998).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Patients who do not improve despite initial symptomatic treatments should be admitted. Most patients would do fine on a general ward, but those with severe respiratory symptoms potentially necessitating intubation should be admitted to the ICU. Patients should not be discharged home until they are clearly symptomatically improved.
    6.3.3.2) HOME CRITERIA/INHALATION
    A) The vast majority of these patients can be managed at home with removal from exposure, symptomatic over-the-counter treatment, and the use of proper protective gear (eg, respirators) in the future.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) Poison centers or toxicologists may be contacted to help facilitate care. Industrial cases may necessitate evaluation from workmen's compensation clinics, occupational medicine physicians, and/or the state health departments. Those with underlying lung disease and severe respiratory symptoms may benefit from evaluation from a pulmonologist.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Patients who do not improve with the above home measures and those with more severe symptoms should be sent to a healthcare facility for observation and treatment and should not be sent home until they show symptomatic improvement.

Monitoring

    A) There is no specific diagnostic test for metal fume fever, but other basic lab studies may be useful in helping guide management or ruling out other causes of symptoms. These include a chest x-ray, arterial blood gas, CBC, and pulmonary function tests. These tests often appear normal, though in severe cases, one may see findings such as infiltrates on the chest x-ray.
    B) No specific study is needed for most patients as long as a good work history demonstrating exposure to metal fume oxides is obtained. Patients may have elevated serum, urine, or plasma concentrations of specific metals such as zinc, but this does not aid in management of the patient.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: As toxicity is through inhalation, there is no need for gastrointestinal decontamination. Removing the patient from the exposure into fresh air is the most important prehospital management. Although there may be dermal or ocular exposure, there is no evidence for washing skin or irrigation of eyes.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) MONITORING OF PATIENT
    1) There is no specific diagnostic test for metal fume fever, but other basic lab studies may be useful in helping guide management or ruling out other causes of symptoms. These include a chest x-ray, arterial blood gas, CBC, and pulmonary function tests. These tests often appear normal, though in severe cases, one may see findings such as infiltrates on the chest x-ray.
    2) No specific study is needed for most patients as long as a good work history demonstrating exposure to metal fume oxides is obtained. Patients may have elevated serum, urine, or plasma concentrations of specific metals such as zinc, but this does not aid in management of the patient.
    B) CORTICOSTEROID
    1) Corticosteroids have occasionally been recommended to reduce inflammatory response in patients with serious pulmonary involvement. One study administered 60 mg of prednisone per day which was then tapered over the next week (Anseline, 1972a). Another study administered one dose of methylprednisolone 250 to 500 mg IV to their patients. Controlled studies demonstrating the benefits of corticosteroids have not been performed (Armstrong et al, 1983).
    C) OXYGEN
    1) Nasal oxygen appears to help the shortness of breath and dyspnea (Armstrong et al, 1983).
    D) ACUTE LUNG INJURY
    1) Acute lung injury is an uncommon side effect, and is usually limited to those metal salts which are highly irritating, such as beryllium or zinc chloride. This effect may be delayed for several hours after exposure and may occur without pain or irritation due to lack of sensory receptors in the deep lung.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    E) CHELATION THERAPY
    1) Although several studies have documented elevated zinc or copper levels, chelation has not been considered necessary and is not generally recommended.

Eye Exposure

    6.8.2) TREATMENT
    A) SUPPORT
    1) Although serious eye toxicity has been reported from metal salts placed directly into the eye and imbedded metal particles, no serious ocular toxicity has been reported associated with metal fume fever.

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) A 38-year-old man developed tachypnea, dyspnea, a dry cough, shakes and shivering, and severe leg cramping an estimated two hours after welding on galvanized steel. He was diagnosed as having metal fume fever, and started on a course of amoxicillin/clavulanic acid for a discolored sputum. He eventually made an uneventful recovery (Heydon & Kagan, 1990).
    2) A 29-year-old male developed generalized pruritus and symptoms of metal fume fever after exposure to zinc oxide fumes. The next day, angioedema, urticaria, and severe swelling of the throat occurred, requiring parenteral epinephrine, diphenhydramine, and corticosteroids. Symptoms recurred upon rechallenge. An IgE-mediated anaphylactic (Type I Hypersensitivity) reaction was diagnosed (Farrell, 1987).
    3) A 29-year-old welder experienced pleuritic chest pain, nausea, diarrhea, headache, lightheadedness, weakness, myalgias, shaking chills, and a nonproductive cough after welding galvanized angle iron. Sinus bradycardia and ST elevation were found on admission ECG. Chest pain resolved with sublingual and topical nitroglycerin. Serum creatine kinase peaked at 3,146 International Units/L, with 12.4% as the myocardial fraction. Despite findings consistent with myocardial and skeletal muscle injury, the patient recovered without incident (Shusterman & Neal, 1986).
    4) One welder's inspiratory vital capacity dropped by 40%; his single-breath capacity fell by 60%; and his PCO2 dropped by 10%. However, a chest x-ray and physical examination were normal. Zinc levels in the blood increased; cadmium levels were normal. Lung function was nearly normal after 24 hours, but the cell count on bronchoalveolar lavage increased tenfold to 9.4 x 10(7) cells/mm(3), with a polymorphonuclear leukocytosis (Vogelmeier et al, 1987).
    5) A 29-year-old male experienced continual wheezing lasting at least 3 months after exposure. The welder was working on a dielectric and on galvanized steel and brass pipe. Teflon tape was believed to be present. Initial symptoms also included coughing, shortness of breath, sweating, and a sweet metallic taste in the mouth.
    a) These symptoms subsided after a short time. The wheezing improved but did not subside during the observation period. Exposure to nonspecific irritants such as temperature changes, smoke, and aerosol sprays exacerbated the condition (Langley, 1991).

Range Of Toxicity

Summary

    A) TOXICITY: ZINC OXIDE: Legal workplace limit (OSHA): 5 mg/m(3) averaged over an 8-hour work shift. Permissible exposure limit (NIOSH): 5 mg/m(3) averaged over a work shift up to 10 hours per day, 40 hours per week with a short-term exposure limit of 10 mg/m(3) averaged over a 15 minute period. A time weighted average (ACGIH): 2 mg/m(3) for an 8-hour work day and 40-hour work week. Symptoms have been reported with levels below 5 mg/m(3) but levels of 14 mg/m(3) have been well-tolerated for 8-hour exposures. A level of 45 mg/m(3) was tolerated for 20 minutes but levels above this are generally poorly tolerated.

Maximum Tolerated Exposure

    A) CONCENTRATION LEVEL
    1) The current Occupational Safety and Health Administration (OSHA) standard for workplace for zinc oxide is 5 mg/m(3) averaged over an 8-hour work shift. The National Institute for Occupational Safety and Health (NIOSH) recommends that the permissible exposure limit be 5 mg/m(3) averaged over a work shift up to 10 hours per day, 40 hours per week with a short-term exposure limit of 10 mg/m(3) averaged over a 15 minute period. A time weighted average of 2 mg/m(3), for an 8-hour work day and 40-hour work week, has been provided by the American Conference of Governmental Industrial Hygienists (ACGIH) (Ahsan et al, 2009).
    2) Concentrations of 14 mg/m(3) of zinc oxide was well-tolerated for exposures of 8 hours. Forty-five mg/m(3) was tolerated for 20 minutes. Levels above this are poorly tolerated (McCord, 1960). MMF has been reported to occur from concentrations below 5 mg/m(3) (Anon, 1981).
    3) Industrial monitoring in a zinc foundry revealed no cases of MFF at airborne zinc concentrations as high as 36.3 mg/m(3). However, human experimental MFF has been induced reliably with furnace generated zinc oxide concentrations of 2.5 to 5 mg/m(3) for 2 hours; at or below the current exposure standards for zinc in many countries (Martin et al, 1999).
    4) This apparent discrepancy in reported zinc concentrations suggests that parameters other than concentration alone, such as particulate size or chemical form, may influence the occurrence of clinical MFF.
    B) ANIMAL STUDIES
    1) Zinc oxide levels of 1000 to 2000 mg/m(3) resulted in a drop in body temperature initially and then 6 to 18 hours later a rise. Levels of 2500 mg/m(3) for 3 to 4 hours was fatal in these animals (Turner & Thompson, 1926)

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) SUMMARY - See specific metal agent for "normal" blood concentrations.
    b) ZINC LEVELS
    1) Serum zinc levels may be elevated but the absence of elevated serum zinc cannot be reliably used to exclude exposure or metal fume fever (Perry, 1994).
    2) Armstrong et al (1983) reported levels of 100 to 115 mcg/100 mL (normal is 55 to 150 mcg/100 mL).
    3) Levels of 179 mcg/100 mL and 161 mcg/100 mL, respectively, occurred in a 29-year-old male and a 49-year-old male from cutting galvanized steel for 6 hours in a poorly ventilated room (Noel & Ruthman, 1988).
    4) Blood concentrations of zinc following a controlled one-hour welding experiment were 6.9 to 7 mg/L (normal: 0.5 to 2 mg/L).
    c) COPPER LEVELS
    1) In a study based on a Norwegian copper factory, all exposed workers had copper levels of 126 plus or minus 11 mcg/100 mL (Cohen, 1974).
    d) CADMIUM
    1) Blood concentrations of cadmium in the above experiment were 2.8 to 3.2 mcg/L (normal: less than 3.2 mcg/L) (Vogelmeier et al, 1987).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ZINC OXIDE

Pharmacology Toxicology

Toxicologic Mechanism

    A) MECHANISM - unknown, but some theories include:
    1) ZINC OXIDE - or its alloys heated above 930 deg F produce particles of zinc oxide up to 1 micron in diameter. If under 1 micron, they may cause acute febrile illness when inhaled. Symptoms are due to irritation of the respiratory tract and gastrointestinal tract. Possible mechanism is absorption of zinc oxide and release of modified protein due to alveolar damage (Anseline, 1972).
    2) DIVALENT COPPER - will bind histamine to bovine albumin. Possibly, copper binds histamine to serum proteins and produces a systemic "allergic-like" syndrome (Cohen, 1974; McCord, 1960).
    3) ANTI-ANTIBODY/ANTIGEN COMPLEX may be involved (Mueller & Seger, 1985).
    4) CYTOKINES - Inhalation of zinc oxide fumes caused increased number of polmorphonuclear leukocytes and increased cytokine release in bronchoalveolar lavage fluid of exposed human subjects, animal and in vitro models (Blanc et al, 1991; Blanc et al, 1993; Kuschner et al, 1995) Antonimi et al, 1997; (Kuschner et al, 1998). Cytokines have been associated with fever, flu-like symptoms and other inflammatory responses (Blanc et al, 1993).
    a) Current research in-vitro, in animals, and in humans, mainly using zinc, suggests that metal fumes probably cause a direct release of cytokines from immune system cells within the lung. The reported cellular sources and specific cytokine(s) involved vary among available reports (Kushner et al, 1998; (Lindahl et al, 1998) Kushner et al, 1997; (Fine et al, 1997) Kushner et al, 1995).

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