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BERYLLIUM COMPOUNDS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Beryllium (divalent cation, m.w.a.) is a metal used in hardening alloys and as a source of neutrons when bombarded with alpha particles. Beryllium poisoning is a somewhat dose-related, work-related illness.

Specific Substances

    A) Beryllium
    1) Berilio
    2) CAS 7440-41-7
    Beryllium Acetate
    1) CAS 543-81-7
    Beryllium Acetate Basic
    1) CAS 19049-40-2
    Beryllium Carbonate
    1) CAS 13106-47-3
    Beryllium Chloride
    1) CAS 7787-47-5
    Beryllium Fluoride
    1) CAS 7787-49-7
    Beryllium Hydroxide
    1) CAS 13327-32-7
    Beryllium Nitrate
    1) Beryllium dinitrate
    2) Nitric acid, beryllium salt
    3) CAS 13597-99-4
    4) Molecular Formula: Be-N2-O6
    Beryllium Oxide
    1) Bromelite
    2) CAS 1304-56-9
    Beryllium Phosphate
    1) CAS 13598-15-7
    Beryllium Silicate
    1) CAS 15191-85-2
    Beryllium Sulfate
    1) CAS 13510-49-1
    Beryllium Sulfate Tetrahydrate
    1) CAS 7787-56-6
    Beryllium Zinc Silicate
    1) CAS 39413-47-3
    Bertrandite
    1) CAS 12161-82-9
    Beryllium-aluminum alloy
    1) CAS 12770-50-2
    Beryllium-copper alloy
    1) CAS 11133-98-5
    Beryllium-copper-cobalt alloy
    1) CAS 55158-44-6
    Beryl ore
    1) CAS 1302-52-9
    Beryllium-nickel alloy
    1) CAS 37227-61-5

Available Forms Sources

    A) FORMS
    1) Beryllium alloys are light and resistant to stress and strain.
    2) Beryllium compounds may contain impurities (IARC, 1980).
    3) Beryllium in concentrations of 0.47, 0.68 and 0.74 mcg/cigarette were found in one study of three cigarette brands (IARC, 1980).
    B) USES
    1) Prior to 1949, beryllium was used as a phosphor in the manufacture of fluorescent lamps and neon signs.
    2) Beryllium is used as a source of neutrons in nuclear reactions.
    3) Beryllium and compounds have been used in the manufacture of electronic and radio tubes, electric heating elements, x-ray tube windows, and in preparing ceramic and crystals for radio use.
    4) Beryllium has been used in the structure of vehicles, guidance systems, radar devices, nose cones, jet plane brakes, and in missiles by military and for space exploration (Harbison, 1998).
    5) Chronic beryllium disease was reported in dental laboratory technicians who were occupationally exposed to beryllium contained in dental alloys used in dental crowns, bridges, and partial denture frameworks (Fireman et al, 2006).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Beryllium (Be) is a divalent alkaline earth metal. Alloys are utilized in automobiles, computers, sports equipment, and dental bridges, while pure beryllium metal is used in nuclear weapons, aircraft, X-ray machines, and mirrors. Exposures often occur in manufacturing, utilizing alloys or pure beryllium. Trace amounts of beryllium are found in air, food, water, and cigarette smoke.
    B) TOXICOLOGY: Beryllium in the ionic form may inhibit various enzymes, including phosphatases, phosphoglucomutase, hexokinase, deoxythymidine kinase, lactate dehydrogenase, and amylase. Ionic beryllium may interfere with DNA synthesis by binding to DNA polymerase. Beryllium is cytotoxic to alveolar macrophages resulting in cell death causing interstitial fibrosis.
    C) EPIDEMIOLOGY: Clinically significant exposure primarily occurs in those who work with beryllium compounds.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Skin effects are common in patients with beryllium toxicity. Exposure may result in papulovesicular dermatitis. A delayed-type hypersensitivity cell-mediated dermatitis may develop in some patients. If materials become embedded in skin, granulomatous lesions may develop. Exposure may also result in conjunctivitis. Mild ocular (conjunctivitis), dermal (dermatitis/ulcers), or pulmonary complaints are most commonly described, but exposure may also cause cough, chest pain, fatigue, headache, nausea, vomiting, nasopharyngitis, fever, tachycardia, enlarged liver and spleen, arthralgias, nephrolithiasis, and lymphadenopathy. Acute beryllium poisoning (duration of less than 1 year) consists of conjunctiva and mucous membrane irritation, and occasionally acute pneumonitis.
    2) SEVERE TOXICITY: Respiratory failure is most common, but seizure, congestive heart failure, and hypoxia have also been described. Inhalation may cause an inflammatory reaction of the entire respiratory tract, including the nasal passages, pharynx, tracheobronchial airways, and alveoli. The most severe cases can cause an acute pneumonitis. This usually occurs immediately after exposure to dusts of soluble beryllium compounds. Exposure is associated with an increased risk of lung cancer.
    3) CHRONIC: Chronic granulomatous disease, berylliosis, results in granulomatous inflammation of the lung, along with dyspnea, cough, chest pain, weight loss, fatigue, and respiratory failure. Diagnosis of chronic beryllium disease requires meeting the standards of the Massachusetts General study group, the patient must exhibit 4 to 6 findings and 1 of the first 2:
    a) Epidemiologic evidence of exposure
    b) Presence of beryllium in lung tissue, lymph nodes, or urine
    c) Consistent lower respiratory tract disease
    d) Radiological findings of a fibronodular interstitial process
    e) Restrictive or obstructive ventilatory defect or diminished CO diffusion
    f) Consistent pathologic changes in lung and/or lymph node tissue
    0.2.5) CARDIOVASCULAR
    A) Chest pain related to dyspnea is a common presenting symptom. Cyanosis, tachycardia, and right sided heart failure may occur in advanced chronic illness.
    0.2.6) RESPIRATORY
    A) ACUTE: Irritation, pneumonitis, dyspnea, pulmonary edema.
    B) CHRONIC: Cough, dyspnea, cyanosis, and fibronodular x-ray changes are commonly seen. Subclinical diminution of pulmonary function occurs.
    0.2.7) NEUROLOGIC
    A) Fatigue, headache, and seizures may occur.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, and a metallic taste may be noted.
    0.2.14) DERMATOLOGIC
    A) ACUTE: Skin irritation, contact dermatitis.
    B) CHRONIC: Granulomas, and skin ulcers indicate imbedded metal.
    0.2.15) MUSCULOSKELETAL
    A) Arthralgia has been reported.
    0.2.20) REPRODUCTIVE
    A) No data were available on embryotoxicity or teratogenicity of beryllium or beryllium compounds.
    B) One case indicates that a woman with a body burden of beryllium may pass beryllium to the fetus. Risk to the infant for developing delayed toxicity is unknown. There may be evidence to suggest that pregnancy may increase susceptibility to the toxicity of beryllium.
    0.2.21) CARCINOGENICITY
    A) Whether beryllium compounds are carcinogenic in humans remains controversial.

Laboratory Monitoring

    A) Specific assays for beryllium in lung and granuloma tissue are available.
    B) Peripheral lymphocyte or bronchoalveolar lavage fluid cell transformation tests are useful in diagnosis and monitoring. Beryllium antibody tests may also be useful in monitoring exposed workers.
    C) Chest X-ray is often helpful in diagnosing pulmonary infiltrates, but CT scans of the chest often provide more diagnostic clarity.
    D) Arterial blood gases and pulmonary function testing may be helpful to monitor the severity of disease.
    E) Beryllium in urine indicates exposure has occurred, but levels do not correlate with severity or clinical symptoms.
    F) The beryllium fluoride patch test is often sensitizing and has been replaced with the use of a 1% beryllium sulfate test.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For milder cases of the disease, bed rest, and supportive and symptomatic treatment may be all that is required.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) For severely symptomatic patients, close airway monitoring should be undertaken in an intensive care unit as acute lung injury can often be delayed 24 to 72 hours.
    C) DECONTAMINATION
    1) Patients exposed via inhalation should be removed from exposure
    D) AIRWAY MANAGEMENT
    1) If cough or difficulty breathing develops, treat with oxygen and beta-2 agonists. Perform endotracheal intubation and provide assisted ventilation as required. If acute lung injury develops, use small tidal volumes 6 mL/kg, and to minimize barotrauma use PEEP. Corticosteroids have been utilized with some success. Surfactant use can be entertained in infants, children, and adolescents with acute lung injury.
    E) ANTIDOTE
    1) None. Chelators have NOT been found to be effective in the treatment of beryllium poisoning.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients may be observed at home.
    2) OBSERVATION CRITERIA: Observe symptomatic patients with pulmonary, dermal, or ocular complaints that continue despite treatment.
    3) ADMISSION CRITERIA: Admit all patients with persistent respiratory distress, or complaints. Admit those with severe ocular or dermal injury.
    4) CONSULT CRITERIA: Consult a pulmonologist, poison center or medical toxicologist for assistance in managing patients with acute or chronic toxicity, or in whom the diagnosis is not clear. Consult an ophthalmologist or dermatologist for persistent ocular or dermal complaints. An industrial hygienist should be involved for workplace evaluation and monitoring and an occupational physician for long term management.
    G) PITFALLS
    1) Failure to consider beryllium compounds in the differential. Failing to take a complete occupational history in patients presenting with granulomatous lung disease. Failure to notify regulatory authorities as other workers are likely exposed to excess beryllium and are at risk for chronic lung disease.
    H) TOXICOKINETICS
    1) The primary route of exposure is through the lungs. After lung deposition, beryllium is slowly absorbed into the blood. In patients accidentally exposed to dust containing beryllium, serum levels peaked the day following exposure with a biological half-life of 2 to 8 weeks. Gastrointestinal and dermal absorption is low; however, incidental oral exposure to soluble compounds or through open skin wounds may contribute to body burden. Beryllium circulating in blood is bound to proteins (prealbumins and globulins) and a notable portion is stored in bone and lungs. Beryllium stored in lungs and bone has a biologic half-life over 1 year. More soluble compounds may be distributed to other organs (liver, lymph nodes, spleen, heart, muscle, skin, and kidney). According to animal studies, absorbed beryllium is excreted primarily in the urine; however, unabsorbed beryllium, following inhalational exposure or intratracheal administration, is excreted primarily via the feces.
    I) DIFFERENTIAL DIAGNOSIS
    1) Sarcoidosis, reactive airway disease, other granulomatous disorders of the lung.
    0.4.4) EYE EXPOSURE
    A) Ocular exposure can be irrigated with 0.9% normal saline for 15 minutes. If pain persists, perform a detailed ophthalmologic exam. All foreign bodies containing beryllium should be removed meticulously from the eye.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Dermal exposures can be washed with soap and water. All foreign bodies containing beryllium should be removed meticulously from the skin.

Range Of Toxicity

    A) TOXICITY: In two workers who developed acute beryllium disease, and ultimately chronic beryllium disease, air sampling showed no exposures greater than 100 mcg/m(3) and most samples were below 10 mcg/m(3). ACGIH TLV-TWA: 0.00005 mg/m(3) (as Be); NIOSH IDLH (immediately dangerous to life and health): 4 mg/m(3) (as Be).

Clinical Effects

Summary Of Exposure

    A) USES: Beryllium (Be) is a divalent alkaline earth metal. Alloys are utilized in automobiles, computers, sports equipment, and dental bridges, while pure beryllium metal is used in nuclear weapons, aircraft, X-ray machines, and mirrors. Exposures often occur in manufacturing, utilizing alloys or pure beryllium. Trace amounts of beryllium are found in air, food, water, and cigarette smoke.
    B) TOXICOLOGY: Beryllium in the ionic form may inhibit various enzymes, including phosphatases, phosphoglucomutase, hexokinase, deoxythymidine kinase, lactate dehydrogenase, and amylase. Ionic beryllium may interfere with DNA synthesis by binding to DNA polymerase. Beryllium is cytotoxic to alveolar macrophages resulting in cell death causing interstitial fibrosis.
    C) EPIDEMIOLOGY: Clinically significant exposure primarily occurs in those who work with beryllium compounds.
    D) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Skin effects are common in patients with beryllium toxicity. Exposure may result in papulovesicular dermatitis. A delayed-type hypersensitivity cell-mediated dermatitis may develop in some patients. If materials become embedded in skin, granulomatous lesions may develop. Exposure may also result in conjunctivitis. Mild ocular (conjunctivitis), dermal (dermatitis/ulcers), or pulmonary complaints are most commonly described, but exposure may also cause cough, chest pain, fatigue, headache, nausea, vomiting, nasopharyngitis, fever, tachycardia, enlarged liver and spleen, arthralgias, nephrolithiasis, and lymphadenopathy. Acute beryllium poisoning (duration of less than 1 year) consists of conjunctiva and mucous membrane irritation, and occasionally acute pneumonitis.
    2) SEVERE TOXICITY: Respiratory failure is most common, but seizure, congestive heart failure, and hypoxia have also been described. Inhalation may cause an inflammatory reaction of the entire respiratory tract, including the nasal passages, pharynx, tracheobronchial airways, and alveoli. The most severe cases can cause an acute pneumonitis. This usually occurs immediately after exposure to dusts of soluble beryllium compounds. Exposure is associated with an increased risk of lung cancer.
    3) CHRONIC: Chronic granulomatous disease, berylliosis, results in granulomatous inflammation of the lung, along with dyspnea, cough, chest pain, weight loss, fatigue, and respiratory failure. Diagnosis of chronic beryllium disease requires meeting the standards of the Massachusetts General study group, the patient must exhibit 4 to 6 findings and 1 of the first 2:
    a) Epidemiologic evidence of exposure
    b) Presence of beryllium in lung tissue, lymph nodes, or urine
    c) Consistent lower respiratory tract disease
    d) Radiological findings of a fibronodular interstitial process
    e) Restrictive or obstructive ventilatory defect or diminished CO diffusion
    f) Consistent pathologic changes in lung and/or lymph node tissue

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Exertional dyspnea is a common finding (Hasan & Kazemi, 1974).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER and chills have been reported in exacerbations of chronic beryllium poisoning (VanOrdstrand et al, 1945).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) TACHYCARDIA has been noted (Hooper, 1981).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) BERYLLIUM: Slight clouding of the surrounding cornea was reported when powdered beryllium metal was experimentally introduced into rabbit corneas. The metal was still visible after 2 months but it was tolerated well. There are no reports of reactions in humans (Grant, 1993).
    2) BERYLLIUM SALTS (chloride, fluoride, nitrate, sulfate): Due to their acidic nature, these salts may cause acute eye irritation. Conjunctivitis, edema of the eyelids, hyperemia of the conjunctiva, persistent burning sensation, and photophobia have been reported. Rarely is the cornea involved and recovery is usually complete in 5 to 10 days (Grant, 1993).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) NASOPHARYNGITIS has been reported from exposure to highly soluble beryllium salts (Hathaway et al, 1996; VanOrdstrand et al, 1945). Reversal of this inflammatory process occurs in 3 to 6 weeks if exposure is discontinued (Tabershaw, 1972).
    2) Mild epistaxis may occur (VanOrdstrand et al, 1945).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) NASOPHARYNGITIS has been reported from exposure to highly soluble beryllium salts (Hathaway et al, 1996; VanOrdstrand et al, 1945).
    2) GINGIVITIS in the form of an allergic contact dermatitis of the oral mucosa has been reported from contact with beryllium contained in dental alloys (Haberman et al, 1993).

Cardiovascular

    3.5.1) SUMMARY
    A) Chest pain related to dyspnea is a common presenting symptom. Cyanosis, tachycardia, and right sided heart failure may occur in advanced chronic illness.
    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Chest pain is a common presenting symptom that is usually related to dyspnea (Hasan & Kazemi, 1974).
    B) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) Heart failure was reported in nearly 16% of the 76 patients added to the beryllium registry since 1966 (Hasan & Kazemi, 1974).
    C) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Cyanosis has been reported (Hasan & Kazemi, 1974).

Respiratory

    3.6.1) SUMMARY
    A) ACUTE: Irritation, pneumonitis, dyspnea, pulmonary edema.
    B) CHRONIC: Cough, dyspnea, cyanosis, and fibronodular x-ray changes are commonly seen. Subclinical diminution of pulmonary function occurs.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Beryllium salts (chloride, fluoride, nitrate, sulfate), due to their acidic nature, may cause acute respiratory tract irritation (Grant, 1993).
    B) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Pneumonitis may occur from acute exposures to high concentrations of the oxide or phosphor mixtures, or acid salts. Generalized rales and rhonchi, dyspnea, cyanosis, and chest pain occur.
    C) GRANULOMA
    1) WITH POISONING/EXPOSURE
    a) PULMONARY GRANULOMATOSIS: The onset is delayed for 1 to 25 years after exposure to beryllium (Hathaway et al, 1996).
    b) BERYLLIUM DISEASE: The chronic form is usually characterized by granulomas in the lungs. Onset of symptoms (nasopharyngitis, tracheobronchitis, pneumonitis, cough, dyspnea, weakness, conjunctivitis, periorbital edema, marked weight loss, hepatomegaly, contact dermatitis, skin ulcers, and granulomas of the skin) may be delayed for months or years after final exposure and may persist for a year or more. Other organs may also be affected with time (Cummings et al, 2009; Tarlo et al, 2001; Sharma et al, 2000; Hathaway et al, 1996; Harbison, 1998) Kriebel, 1988a).
    1) BERYLLIUM CASE REGISTRY: Diagnosis of chronic beryllium disease has been made when 4 of the following 6 criteria have been met (Stokes & Rossman, 1991):
    1) Significant beryllium exposure
    2) Presence of beryllium in lung tissue, lymph nodes, or urine
    3) Lower respiratory tract disease and a clinical course consistent with beryllium disease
    4) Radiologic interstitial disease consistent with a fibronodular process
    5) Restrictive or obstructive ventilatory defects of decreased carbon monoxide diffusing capacity
    6) Noncaseating granulomas on lung or lymph node biopsy
    2) DIFFERENTIAL DIAGNOSIS: Chronic beryllium disease has been misdiagnosed as sarcoidosis. In one patient exposed to beryllium in a dental laboratory, sarcoidosis was initially diagnosed. When the history of beryllium exposure was obtained many years later and 9 years since exposure ceased, the peripheral blood lymphocyte transformation and skin sensitization tests were still positive (Muller-Quernheim et al, 1996).
    D) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea is the most frequent presenting complaint (Kriebel, 1988a).
    b) Marked tachypnea due to copper-beryllium alloy has been reported in 2 sisters with chronic beryllium disease (CBD). This report adds clinical support to the role of a genetic predisposition to the development of CBD (Tarlo et al, 2001).
    E) COUGH
    1) WITH POISONING/EXPOSURE
    a) Cough is a frequent presenting complaint (Agency for Toxic Substances and Disease Registry, 2002).
    F) LYMPHADENOPATHY
    1) WITH POISONING/EXPOSURE
    a) About one-half of reported patients have hilar adenopathy. Chronic beryllium disease may appear nodular, granular, or linear. X-rays should be assessed by a certified B-reader using ILO criteria.
    G) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) Dose related diminution of FVC and FEV have been recognized prior to the usual signs and symptoms of chronic berylliosis (Kriebel, 1988a).
    H) EMPHYSEMA
    1) WITH POISONING/EXPOSURE
    a) Emphysema may be a complication as patients survive longer as a result of steroid therapy (Finkel, 1983).
    I) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Cyanosis may occur due to alveolar block from fibrosis (Hasan & Kazemi, 1974).
    J) PNEUMOTHORAX
    1) WITH POISONING/EXPOSURE
    a) Pneumothorax may occur as a consequence of the pulmonary disease (Finkel, 1983).
    K) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema has been reported (Finkel, 1983).
    L) HEMOPTYSIS
    1) WITH POISONING/EXPOSURE
    a) Rarely are symptoms of hemoptysis, hoarseness, or wheezing complaints on presentation (Hasan & Kazemi, 1974).

Neurologic

    3.7.1) SUMMARY
    A) Fatigue, headache, and seizures may occur.
    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) Fatigue is often a common presenting symptom of chronic beryllium disease (Hasan & Kazemi, 1974).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A single patient presented with seizures and on autopsy was shown to have CNS granulomas from beryllium (Hasan & Kazemi, 1974).
    C) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported following an acute exposure (Rees, 1979).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, and a metallic taste may be noted.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) A nonproductive cough in a severe case was violent enough to cause vomiting (Finkel, 1983).
    B) NAUSEA
    1) WITH POISONING/EXPOSURE
    a) Nausea has been reported following an acute exposure (Rees, 1979).
    C) TASTE SENSE ALTERED
    1) WITH POISONING/EXPOSURE
    a) Metallic taste has been reported (VanOrdstrand et al, 1945).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LARGE LIVER
    1) WITH POISONING/EXPOSURE
    a) Liver and spleen enlargement has been reported in patients with chronic beryllium disease. Granulomas may occur in both (Hardy, 1980).
    B) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Abnormal liver function tests have been reported in the chronic form of beryllium disease (Hardy, 1980).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY STONE
    1) WITH POISONING/EXPOSURE
    a) Stone formation in kidneys, salivary glands, and lungs has occurred in chronic beryllium disease (Hardy, 1980).
    B) HYPERCALCIURIA
    1) WITH POISONING/EXPOSURE
    a) Hypercalciuria has been noted in the chronic form of beryllium disease (Hardy, 1980).

Dermatologic

    3.14.1) SUMMARY
    A) ACUTE: Skin irritation, contact dermatitis.
    B) CHRONIC: Granulomas, and skin ulcers indicate imbedded metal.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Beryllium salts (chloride, fluoride, nitrate, sulfate), due to their acidic nature, may cause acute skin irritation (Grant, 1993) in high concentrations and are cutaneous sensitizers (Tabershaw, 1972; Vilaplana et al, 1992).
    b) CASE REPORT: Late positive patch test reactions to beryllium have been reported in two patients. The authors suggested that these late reactions are likely due to active sensitization because retesting with beryllium caused a positive reaction within a few days (LucasCosta et al, 2008).
    c) Onset of dermatitis occurred in two patients approximately 10 days following initial occupational exposure to beryllium (Cummings et al, 2009).
    d) Patients exposed to beryllium alloys in dental prostheses have developed contact dermatitis (gingivitis) (Haberman et al, 1993).
    e) According to a 5-year retrospective study, involving 62 patients who developed allergic contact dermatitis and subsequently underwent patch testing with a metal series, 12 of the 62 patients reported a positive reaction when tested with beryllium chloride. Three of the 12 patients tested positive at the day 4 reading, 6 patients had positive reactions that occurred between day 7 and day 10, and 3 patients reported positive reactions between day 10 and day 20. Only 1 of the 12 patients developed contact dermatitis following occupational exposure to beryllium. The source of exposure to beryllium in 8 patients was due to either dental prostheses, dental braces, or concomitant patch test reactivity to other metals (Toledo et al, 2011).
    B) GRANULOMA
    1) WITH POISONING/EXPOSURE
    a) Beryllium compounds that become implanted in lacerations (Hathaway et al, 1996; VanOrdstrand et al, 1945) lead to granulomas and ulceration. Systemic sensitization may occur. Many cases have concomitant lung disease (Jones Williams, 1988).
    b) PODOCONIOSIS: In areas of the Ethiopian Rift Valley, an non-filarial elephantiasis of the lower extremities has been described. The soil in this region contains high concentrations of several substances including beryllium, as well as high concentrations of abrasive colloidal silica. It has been theorized that continuous exposure of unprotected feet to such soils produces skin abrasions and allows uptake of zirconium and beryllium leading to lymph node granulomas, sclerosis, and elephantiasis (Frommel et al, 1993).
    C) CLUBBING OF NAIL
    1) WITH POISONING/EXPOSURE
    a) CLUBBING was reported in 9.2% of chronic beryllium disease patients reported to the Beryllium Case Registry since 1966 (Hasan & Kazemi, 1974).

Musculoskeletal

    3.15.1) SUMMARY
    A) Arthralgia has been reported.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH POISONING/EXPOSURE
    a) Arthralgia may occur (Hasan & Kazemi, 1974).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Anergy associated with disturbed T-lymphocyte function, depressed helper-suppressor T-cell ratios in the peripheral blood, and massive accumulations of helper T-cells in the lung may occur in chronic beryllium disease (Cullen et al, 1986).
    B) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) Positive lymphocyte transformation (LT) may indicate that the individual has been sensitized to beryllium. LT may be reversible if beryllium exposure is reduced or minimized (Rom et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) No data were available on embryotoxicity or teratogenicity of beryllium or beryllium compounds.
    B) One case indicates that a woman with a body burden of beryllium may pass beryllium to the fetus. Risk to the infant for developing delayed toxicity is unknown. There may be evidence to suggest that pregnancy may increase susceptibility to the toxicity of beryllium.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) No data were available on embryotoxicity or teratogenicity of beryllium or beryllium compounds (IARC, 1980).
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) CASE REPORT - A 25-year-old woman in her second pregnancy had signs and symptoms of beryllium poisoning (weight loss, increasing dyspnea, cough, weakness). She was exposed to beryllium while she worked in a fluorescent tube factory at 17 to 19 years of age. Her first pregnancy was uneventful. She delivered a normal 2.75 kg boy.
    a) Twenty-four hour urine specimens collected from the baby on the second and third day of life contained 0.4 and 0.015 mg of beryllium (Kline et al, 1951). This case indicates that a woman with a body burden of beryllium may pass beryllium to the fetus. Risk to the infant for developing delayed toxicity is unknown. There may be evidence to suggest that pregnancy may increase susceptibility to the toxicity of beryllium (Barlow & Sullivan, 1982).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7440-41-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Beryllium and beryllium compounds
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.2) SUMMARY/HUMAN
    A) Whether beryllium compounds are carcinogenic in humans remains controversial.
    3.21.3) HUMAN STUDIES
    A) PULMONARY CARCINOMA
    1) Beryllium may be associated with an increased risk of lung cancer in humans (Ward et al, 1992). Some reviewers remain skeptical, citing the confounding effects of tobacco smoking (Jones Williams, 1988; MacMahon, 1994). The risk is low at present.
    2) CASE SERIES: Epidemiological studies including about 4300 workers exposed to beryllium have found an excess of lung cancer, on the order of 50 percent, 15 years after onset of exposure (Mancuso, 1970; Mancuso, 1980; Infante et al, 1980; Wagoner et al, 1980). Re-analysis of this data by different researchers showed a significantly smaller excess mortality from lung cancer that could be attributed to tobacco smoking and urban residence of the workers. In addition, these analyses were of workers employed in the early phase of the manufacturing industry, prior to 1949, when occupational exposure standards were first recommended. The workers were exposed to very high levels of beryllium and had a short duration of employment in beryllium manufacturing plants, which may explain the resulting increased risk. No relationship between duration of employment or cumulative exposure and lung cancer risk was determined, although average and maximum exposure were associated with increased risk. No significant increase in lung cancer mortality was detected among workers employed after 1949 and exposed to beryllium. Results from studies evaluating risk of cancers other than lung cancer in manufacturing workers exposed to beryllium and in patients with beryllium disease show no statistically significant increase in risk or mortality from any other cancer (Boffetta et al, 2012).
    3) CASE SERIES: Lung cancer risk was increased in a cohort of 9225 male workers from 7 beryllium processing facilities and was especially associated with a history of very high-level acute exposure and acute beryllium disease (Ward et al, 1992).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Beryllium is a carcinogen in laboratory animals after intratracheal administration (Groth, 1980). Beryllium-induced lung malignancy has occurred in rats, monkeys, and rabbits (Harbison, 1998; Mancuso, 1980; Sky-Peck, 1986; MMWR, 1986).
    B) LACK OF EFFECT
    1) ORAL EXPOSURE: In one study in rats fed 5 mg/liter of beryllium in the drinking water there was no difference in the incidence of malignant tumors in the control versus treatment group (IARC, 1980).

Genotoxicity

    A) It is believed that beryllium interacts with DNA and causes gene mutation, chromosomal aberration and sister chromatic exchange in cultured somatic cells (Sharma et al, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Specific assays for beryllium in lung and granuloma tissue are available.
    B) Peripheral lymphocyte or bronchoalveolar lavage fluid cell transformation tests are useful in diagnosis and monitoring. Beryllium antibody tests may also be useful in monitoring exposed workers.
    C) Chest X-ray is often helpful in diagnosing pulmonary infiltrates, but CT scans of the chest often provide more diagnostic clarity.
    D) Arterial blood gases and pulmonary function testing may be helpful to monitor the severity of disease.
    E) Beryllium in urine indicates exposure has occurred, but levels do not correlate with severity or clinical symptoms.
    F) The beryllium fluoride patch test is often sensitizing and has been replaced with the use of a 1% beryllium sulfate test.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Arterial blood gases or pulse oximetry may be useful in monitoring pulmonary function.
    B) HEMATOLOGY
    1) LYMPHOCYTE TRANSFORMATION TEST: Peripheral blood lymphocytes can be cultured in vitro and undergo proliferation in patients with chronic beryllium disease. This test can document sensitization to beryllium better than any other available test and can identify sensitized individuals who do not yet have clinical manifestations (Newman, 1996; Strange et al, 1996) Yoshida et al, 1997).
    2) BERYLLIUM ANTIBODY TEST: A beryllium antibody test has been developed and may be useful in screening exposed workers. Exposure is indicated when the beryllium antibody titer is more than 2 standard deviations higher than those of a control population (Clarke et al, 1995).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Beryllium in the urine indicates exposure has occurred. Quantity does not correlate with severity of exposure or clinical findings (Proctor & Hughes, 1978).
    2) Urine Concentrations (IARC, 1980)
    a) Exposed Humans: 4.8 to 5.8 mcg/liter
    b) Controls: 0.4 to 1 mcg/liter
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Pulmonary function tests (MMWR, 1986). Particularly that of diffusing capacity (CD).
    2) DERMAL
    a) Beryllium skin patch tests have been used but are currently not recommended due to risk of severe reaction and possible sensitization (Rees, 1979).
    b) The beryllium fluoride patch test is often sensitizing and has been replaced with the use of a 1% beryllium sulfate test.
    3) TISSUE
    a) Tissue Concentrations (IARC, 1980)
    1) Nonexposed Humans: 0.04 mcg/kg to 0.06 mg/kg
    2) Exposed Humans: 0.02 mcg/kg to 40 mg/kg
    b) Lung Concentrations (IARC, 1980)
    1) Beryllium Disease Lungs: up to 1 mg/g
    2) Nonexposed Lungs: Lower values were found in general, although some have been as high as those reported for patients with beryllium disease.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray may be of value in detecting pulmonary infiltrates (MMWR, 1986). However, in one study only 15 of 28 patients with biopsy-proven chronic beryllium disease had abnormal chest x-rays (Newman et al, 1994).
    B) CT SCAN
    1) Thin-layer CT scans were more sensitive for finding lung abnormalities and hilar lymphadenopathy than chest x-rays in patients with biopsy-proven chronic beryllium disease, but the absence of CT scan abnormalities does not rule out the diagnosis (Newman et al, 1994).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) LYMPHOBLAST TRANSFORMATION TEST (LTT) has good correlation for clinically diagnosed chronic beryllium disease patients (60 to 70 percent) and may be useful to differentiate this diagnosis from that of idiopathic sarcoidosis or beryllium-exposed healthy controls (Williams & Williams, 1982; (Newman, 1996). This test may prove useful in preventing clinical chronic beryllium disease with early diagnosis in a subclinical phase (Williams & Williams, 1982; (Deodhar & Barna, 1991; Kreiss et al, 1989; Newman, 1996) Strange et al, 1997).
    2) Measurement of Beryllium in microscopic section by laser microscope mass spectrometry (Jones Williams, 1986). This technique appears diagnostic for granuloma tissue.
    3) In vitro proliferation of bronchoalveolar lavage cells to beryllium appears to be extremely sensitive and specific for the diagnosis of chronic beryllium disease (Stokes & Rossman, 1991).
    4) Methods used for beryllium level determinations in the environment include atomic absorption spectrometry, flameless atomic and emission spectrometry, gas chromatography with election captured, and ultra-violet spectrometry (IARC, 1980).
    5) In an animal study, atomic absorption spectrophotometry (AAS) was used following wet acid digestion with concentrated nitric acid to estimate beryllium in liver, kidney and lungs (Sharma et al, 2000).

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) Admit all patients with persistent respiratory distress, or complaints. Admit those with severe ocular or dermal injury.
    B) Hospitalization and observation for 72 hours for delayed onset of pneumonitis is advisable after a significant acute exposure (Proctor & Hughes, 1978).
    6.3.3.2) HOME CRITERIA/INHALATION
    A) Asymptomatic patients may be observed at home.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) Consult a pulmonologist, poison center or medical toxicologist for assistance in managing patients with acute or chronic toxicity, or in whom the diagnosis is not clear. Consult an ophthalmologist or dermatologist for persistent ocular or dermal complaints. An industrial hygienist should be involved for workplace evaluation and monitoring and an occupational physician for long term management.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Observe symptomatic patients with pulmonary, dermal, or ocular complaints that continue despite treatment.

Monitoring

    A) Specific assays for beryllium in lung and granuloma tissue are available.
    B) Peripheral lymphocyte or bronchoalveolar lavage fluid cell transformation tests are useful in diagnosis and monitoring. Beryllium antibody tests may also be useful in monitoring exposed workers.
    C) Chest X-ray is often helpful in diagnosing pulmonary infiltrates, but CT scans of the chest often provide more diagnostic clarity.
    D) Arterial blood gases and pulmonary function testing may be helpful to monitor the severity of disease.
    E) Beryllium in urine indicates exposure has occurred, but levels do not correlate with severity or clinical symptoms.
    F) The beryllium fluoride patch test is often sensitizing and has been replaced with the use of a 1% beryllium sulfate test.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Beryllium is thought to be poorly absorbed from the gut, but some compounds can be irritating. Dilution with 4 to 8 ounces of water or milk may be utilized.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Studies have indicated that beryllium is very poorly absorbed from the gut and that ingestion is not a hazard (Tepper et al, 1961).
    B) IRRITATION
    1) Some beryllium compounds may be irritating to the gut.
    C) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Beryllium is thought to be poorly absorbed from the gut and usually presents no hazard if ingested. Treatment is symptomatic and supportive.

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) SUPPORT
    1) For milder cases of the disease, bed rest and symptomatic treatment may be all that is required (Tabershaw, 1972).
    B) OXYGEN
    1) Administer 60% to 100% oxygen by mask or cannula.
    C) AIRWAY MANAGEMENT
    1) If cough or difficulty breathing develops, treat with oxygen and beta-2 agonists. Perform endotracheal intubation and provide assisted ventilation as required. If acute lung injury develops, use small tidal volumes 6 mL/kg, and to minimize barotrauma use PEEP. Corticosteroids have been utilized with some success. Surfactant use can be entertained in infants, children, and adolescents with acute lung injury.
    D) MONITORING OF PATIENT
    1) Specific assays for beryllium in lung and granuloma tissue are available.
    2) Peripheral lymphocyte or bronchoalveolar lavage fluid cell transformation tests are useful in diagnosis and monitoring. Beryllium antibody tests may also be useful in monitoring exposed workers.
    3) Chest X-ray is often helpful in diagnosing pulmonary infiltrates, but CT scans of the chest often provide more diagnostic clarity.
    4) Arterial blood gases and pulmonary function testing may be helpful to monitor the severity of disease.
    5) Beryllium in urine indicates exposure has occurred, but levels do not correlate with severity or clinical symptoms.
    6) The beryllium fluoride patch test is often sensitizing and has been replaced with the use of a 1% beryllium sulfate test.
    E) CHELATION THERAPY
    1) Chelators have not been found to be effective in the treatment of beryllium poisoning.
    a) EXPERIMENTAL ANIMALS
    1) DMPS (2,3-dimercaptopropane 1-sulfonate) did deplete liver, spleen, and kidney beryllium (redistributing it to the blood), marginally increased fecal excretion, and decreased beryllium inhibition of hepatic alkaline phosphatase and adenosine triphosphatase in rats (Flora et al, 1995). DMPS cannot currently be recommended for human therapy.
    2) In one animal study, Tiron (a proprietary name for sodium catechol sulfate, a colorimetric agent) and calcium disodium EDTA were used to treat beryllium intoxication in rats. It was shown that Tiron is a more effective chelator than calcium disodium EDTA in reducing the beryllium concentration in the liver, kidney and lungs (Sharma et al, 2000).
    F) CORTICOSTEROID
    1) Steroids may be beneficial in controlling dyspnea, and in delaying the onset of right heart failure and pulmonary insufficiency (Hardy & Stoeckle, 1959; Harbison, 1998). Every-other-day, single-dose regimens of prednisone 20 to 80 mg for short periods (average dose of 20 to 40 mg over years) has been useful in clinical practice (Finkel, 1983).
    G) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) 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)
    3) 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).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) 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).
    7) 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).
    H) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    I) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Dermal exposures can be cleaned with soap and water.
    B) Beryllium does not penetrate intact skin (Tabershaw, 1972).
    6.9.2) TREATMENT
    A) WOUND CARE
    1) Implanted beryllium particles should be removed from the affected area by curettage or excision to prevent incomplete healing (Tabershaw, 1972). This is curative.
    2) Beryllium does not penetrate intact skin (Tabershaw, 1972).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) Acute beryllium lung disease was reported by Hooper (1981) in an 18-year-old male machinist in a plant that was inspected by OSHA regularly and met or exceeded all existing standards. The patient had a history of childhood extrinsic asthma, which resolved spontaneously. Complaints and symptoms on admission were rhinitis, dyspnea with minimal exertion for 6 weeks, nosebleeds, chest pain, diffuse abdominal pain, and diarrhea. Acute beryllium lung disease was diagnosed on the history of occupational exposure, histologic findings, and increased lung beryllium content (0.028 mcg beryllium/g of dried tissue) (Hooper, 1981a).
    2) Rees (1979) reported 2 workers in the beryllium industry without symptoms of beryllium disease who developed acute disease followed by chronic disease without a latency period following an acute exposure to a large dose of beryllium fume. Mantoux (1:100) and Kveim tests were negative in both patients. Skin patch tests for beryllium were positive. Chest radiograph and lung biopsy were characteristic of beryllium disease (Rees, 1979).
    B) CHRONIC EFFECTS
    1) Chronic beryllium disease producing a granulomatous pneumonitis was diagnosed in a former spot welder. The patient used the Sciacky process for welding, which uses a consumable electrode of a copper alloy containing between 2 and 3 percent beryllium releasing beryllium into the atmosphere.
    a) A chest x-ray revealed reticulonodular shadowing affecting the mid and lower zones of both lung fields. The patient had a long-standing productive cough and some exertional dyspnea and complained of grittiness in his eyes. Pulmonary function tests revealed a restrictive defect and a reduction of the diffusing capacity.
    b) Lung biopsy showed a mild interstitial fibrosis with non-caseating epithelioid cell granulomas, but no arteritis. A Mantoux test was negative and a Kveim antigen biopsy was negative. A Schirmer's test confirmed reduced tear secretion.
    c) Hypersensitivity to beryllium could not be demonstrated, but this may have been due to a trial of steroids given previously to alleviate symptoms (Monie & Roberts, 1991).

Range Of Toxicity

Summary

    A) TOXICITY: In two workers who developed acute beryllium disease, and ultimately chronic beryllium disease, air sampling showed no exposures greater than 100 mcg/m(3) and most samples were below 10 mcg/m(3). ACGIH TLV-TWA: 0.00005 mg/m(3) (as Be); NIOSH IDLH (immediately dangerous to life and health): 4 mg/m(3) (as Be).

Minimum Lethal Exposure

    A) CHRONIC
    1) A poor prognosis is associated with chronic beryllium disease. The reported mortality rate was 30 percent in 1972 (Finkel, 1983).
    2) Beryllium Case Registry data indicate the extent of delay in onset of chronic beryllium disease is highly variable (Hardy et al, 1967):
    TIME AFTER EXPOSURENUMBER OF CASES REPORTED
    10 years or more12
    5 to 10 years56
    1 to 5 years89
    1 month to 1 year27
    1 month126

    3) Exposure to a fume source of beryllium may pose a greater risk for development of adverse effects compared to dust exposures (Cullen et al, 1986).
    4) Rats and mice exposed to an aerosol of 13 micrograms beryllium/Liter developed acute lung injury (Sendelbach et al, 1986).

Maximum Tolerated Exposure

    A) ACUTE
    1) Two workers developed acute beryllium disease, and ultimately chronic beryllium disease. Air sampling showed no exposures greater than 100 mcg/m(3) and most samples were below 10 mcg/m(3) (Cummings et al, 2009).
    B) CHRONIC
    1) Roentgenographic evidence of chronic beryllium disease has persisted for 20 years with no other sign or symptom of illness (Finkel, 1983).
    2) Beryllium Case Registry data indicate the extent of delay in onset of chronic beryllium disease is highly variable (Hardy et al, 1967):
    TIME AFTER EXPOSURENUMBER OF CASES REPORTED
    10 years or more12
    5 to 10 years56
    1 to 5 years89
    1 month to 1 year27
    1 month126

    3) Exposure to a fume source of beryllium may pose a greater risk for development of adverse effects compared to dust exposures (Cullen et al, 1986).
    4) Rats and mice exposed to an aerosol of 13 micrograms beryllium/Liter developed acute lung injury (Sendelbach et al, 1986).
    5) In nuclear facility workers, chronic beryllium disease has developed both among heavily exposed persons (machinists) and those with only inadvertent or bystander exposure (secretaries, security guards) (Kreiss et al, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS7440-41-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Beryllium and compounds, as Be
    a) TLV:
    1) TLV-TWA: 0.00005 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A1
    2) Codes: I, SEN, Skin
    3) Definitions:
    a) A1: Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    b) I: Inhalable fraction; see Appendix C, paragraph A (of TLV booklet).
    c) SEN: The designation SEN refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. The notation does not imply that this is the critical effect or that this is the sole basis for the TLV. Although, for those TLVs that are based on sensitization, the TLV is meant to protect workers from induction of this effect, but cannot protect workers who have already become sensitized. The notation should be used to assist in identifying sensitization hazards and reducing respiratory, dermal, and conjunctival exposures to sensitizing agents in the workplace. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    d) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Beryllium sens; chronic beryllium disease (berylliosis)
    d) Molecular Weight: 9.01
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS7440-41-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Beryllium & beryllium compounds (as Be)
    2) REL:
    a) TWA: Not to exceed 0.0005 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH:
    a) IDLH: 4 mg Be/m3 (as Be)
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS7440-41-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A1 ; Listed as: Beryllium and compounds, as Be
    a) A1 :Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    2) EPA (U.S. Environmental Protection Agency, 2011): B1 ; Listed as: Beryllium and compounds
    a) B1 : Probable human carcinogen - based on limited evidence of carcinogenicity in humans.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Beryllium and beryllium compounds
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Beryllium & beryllium compounds (as Be)
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 2 ; Listed as: Beryllium and its compounds
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): K ; Listed as: Beryllium (See Beryllium and Beryllium Compounds)
    a) K : KNOWN = Known to be a human carcinogen

    D) OSHA PEL Values for CAS7440-41-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Beryllium and beryllium compounds (as Be)
    2) Table Z-1 for Beryllium and beryllium compounds (as Be):
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3:
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Beryllium
    1) TCLo- (INHALATION)HUMAN:
    a) 300 mg/m(3) (Lewis, 1996)
    B) Beryllium Acetate
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 317 mg/kg (IARC, 1980)
    C) Beryllium Carbonate
    D) Beryllium Chloride
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 12 mg/kg (IARC, 1980)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 4.4 mg/kg (IARC, 1980)
    3) LD50- (ORAL)RAT:
    a) 86 mg/kg (IARC, 1980)
    E) Beryllium Fluoride
    1) LD50- (ORAL)MOUSE:
    a) 100 mg/kg (IARC, 1980)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 20 mg/kg (IARC, 1980)
    3) LD50- (ORAL)RAT:
    a) 100 mg/kg (IARC, 1980)
    F) Beryllium Hydroxide
    G) Beryllium Phosphate
    1) LD50- (ORAL)RAT:
    a) 82 mg/kg (IARC, 1980)
    H) Beryllium Sulfate
    1) LD50- (ORAL)MOUSE:
    a) 80 mg/kg (IARC, 1980)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 1.5 mg/kg (IARC, 1980)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 18 mg/kg (IARC, 1980)
    4) LD50- (ORAL)RAT:
    a) 80 mg/kg (IARC, 1980)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 1.5 mg/kg (IARC, 1980)
    I) Beryllium Sulfate Tetrahydrate

Pharmacology Toxicology

Toxicologic Mechanism

    A) Beryllium in the ionic form may inhibit enzymes such as various phosphatases, phosphoglucomutase, hexokinase, deoxythymidine kinase, lactate dehydrogenase and amylase (IARC, 1980).
    B) Ionic beryllium may interfere with DNA synthesis possibly by a non-covalent binding of beryllium to DNA polymerase (IARC, 1980).
    C) Beryllium is cytotoxic to alveolar macrophages resulting in cell death with release of lysosomal enzymes which produces an interstitial fibrosis (Monie & Roberts, 1991).
    D) In patients with chronic beryllium disease, levels of soluble receptors for tumor necrosis factor and interleukin-6 are increased in the serum and bronchoalveolar lavage fluid, while levels of these cytokines in bronchoalveolar lavage cells are stimulated in vitro by exposure to beryllium salts (Tinkle & Newman, 1997).
    E) The alpha subunit of the soluble interleukin-2 receptor might be a biomarker of chronic beryllium disease progression (Tinkle et al, 1997).

Physicochemical

Physical Characteristics

    A) Beryllium is a brittle, hard, grey-white (silver), odorless metal (ITI, 1995; ACGIH, 1991).

Molecular Weight

    A) Beryllium: 9.01 (ITI, 1995)
    B) Beryllium Acetate: 127.10 (IARC, 1980)
    C) Beryllium Acetate, Basic: 406.32 (IARC, 1980)
    D) Beryllium Carbonate: 181.03 (IARC, 1980)
    E) Beryllium Chloride: 79.92 (IARC, 1980)
    F) Beryllium Fluoride: 43.03 (Clayton & Clayton, 1994)
    G) Beryllium Hydroxide: 43.03 (IARC, 1980)
    H) Beryllium Oxide: 25.01 (Clayton & Clayton, 1994)
    I) Beryllium Silicate: 110.11 (IARC, 1980)
    J) Beryllium Sulfate: 105.08 (Clayton & Clayton, 1994)
    K) Beryllium Sulfate Tetrahydrate: 177.14 (IARC, 1980)
    L) Bertrandite: 238.23 (IARC, 1980)
    M) Beryl Ore: 537.51 (IARC, 1980)

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