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19 Beryllium Toxicity

Environmental ALERT…

Beryllium produces a range of health effects from sensitization without evidence of disease to clinically apparent pulmonary disease.

Chronic beryllium disease may be misdiagnosed as sarcoidosis.

New immunologic tests promise early detection of beryllium disease and differentiation from other interstitial lung diseases.

This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. See page 17 for further information about continuing medical education credits and continuing education units.

Guest Contributor:

Dennis M.Green, MD

Guest Editor:

Lee S.Newman, MD

Peer Reviewers:

John Ambre, MD, PhD; Charles Becker, MD; Jonathan Borak, MD;

Joseph Cannella, MD; Howard Kipen, MD, MPH;

Richard J.Jackson, MD, MPH; Jonathan Rodnick, MD;

Brian A.Wummer, MD

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry



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Environmental Medicine: Integrating a Missing Element into Medical Education 19 Beryllium Toxicity Environmental ALERT… Beryllium produces a range of health effects from sensitization without evidence of disease to clinically apparent pulmonary disease. Chronic beryllium disease may be misdiagnosed as sarcoidosis. New immunologic tests promise early detection of beryllium disease and differentiation from other interstitial lung diseases. This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. See page 17 for further information about continuing medical education credits and continuing education units. Guest Contributor: Dennis M.Green, MD Guest Editor: Lee S.Newman, MD Peer Reviewers: John Ambre, MD, PhD; Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Howard Kipen, MD, MPH; Richard J.Jackson, MD, MPH; Jonathan Rodnick, MD; Brian A.Wummer, MD U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry

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Environmental Medicine: Integrating a Missing Element into Medical Education Case Study A 14-year-old child, daughter of a dental technician, with cough, wheezing, and low-grade fever A mother brings her 14-year-old daughter to you for consultation. The patient has developed a troublesome cough and sometimes at night cannot catch her breath. The child’s cough has worsened with increase in sputum production and chest discomfort. Last night she had a particularly rough time, but she had no wheezing or fever. Chart review reveals no history of asthma or allergies. The patient’s height and weight are appropriate for her age; her two siblings, aged 12 and 6 years, are in good health. History of previous illness reveals three episodes of otitis media but no other significant illness. There is no history of eczema or food intolerance. In response to your questions, the mother tells you that her husband, a dental technician, has been diagnosed with sarcoidosis. He recently had flu-like symptoms similar to those of his daughter including fatigue, nasal congestion, sneezing, and cough. Although her husband, who smokes cigarettes, has had a cough for several years, the mother states that her daughter developed symptoms a few days after her husband’s latest bout. She wonders if her husband’s sarcoidosis could have been transmitted to their daughter. Examination shows a cheerful girl in no acute distress. Her temperature today is 100°F, respiratory rate is 24 without retractions or audible wheezing, and her pulse is 90 and regular. Significant findings include a mildly inflamed pharynx and anterior cervical lymph nodes that are slightly enlarged and mildly tender. Tympanic membranes are clear. Auscultation of the lungs reveals mild and diffuse expiratory wheezing with occasional rhonchi. Results of cardiac and abdominal examinations are normal. Chest X ray shows minimal peribronchial thickening and is otherwise normal. (a) Construct a problem list and a differential diagnosis for the daughter. ___________________________________________________________________________ (b) What further questions might you ask about the father? ___________________________________________________________________________ (c) What is the most likely diagnosis for the daughter? ___________________________________________________________________________ Answers can be found on page 14 and 15.

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Environmental Medicine: Integrating a Missing Element into Medical Education Exposure Pathways ❑ Because of its unique properties, beryllium is used in many high-technology consumer and commercial products. ❑ Burning of coal is probably the greatest source of environmental beryllium contamination. Pure beryllium, one of the lightest metals known, is a hard, grayish material obtained from the mineral rocks bertrandite and beryl. Gem quality beryl is known as either aquamarine or emerald. Although production of beryllium has increased only modestly in the United States in the past 2 decades, the uses of beryllium have expanded. Beryllium has important uses in the defense and electronics industry, especially applications in which fatigue and corrosion resistance, insulation, and nonmagnetic and lightweight qualities are desired. Occupational exposure to beryllium (as a dust or fume) can occur where it is mined, processed, or converted into metal, alloys, and chemicals. The United States is the leading producer and consumer of beryllium and its alloys. Pure beryllium metal is used in aircraft disc brakes, X-ray components, space-vehicle optics and instruments, aircraft/satellite structures, missile parts, nuclear-reactor neutron reflectors, nuclear weapons, fuel containers, precision instruments, rocket propellants, navigational systems, heat shields, and mirrors. Beryllium alloys also have many uses, including electrical connectors and relays, springs, precision instruments, aircraft engine parts, nonsparking and nonmagnetic tools, computers, ceramics, submarine cable housings and pivots, wheels and pinions, and dental castings. Dental prostheses are shaped by grinding the structural elements, which are often made of beryllium alloy. Beryllium oxide is the material of choice for many high-technology applications in which heat resistance is imperative. Applications include ceramics, electronic heat sinks, electrical insulators, microwave oven components, gyroscopes, military vehicle armor, rocket nozzles, crucibles, thermocouple tubing, and laser structural components. Although beryllium is a naturally occurring substance, the major source of its emission into the environment is the combustion of fossil fuels (primarily coal), which releases beryllium-containing particulates and fly ash into the atmosphere. The open pits in Utah, where bertrandite is mined, also cause high airborne levels locally. Mantles of some camping lanterns emit small amounts of beryllium during initial use. Tobacco smoke also is a minor source of beryllium exposure. Beryllium is relatively water insoluble and adsorbs tightly to soils. It has been found in various foodstuffs, but bioaccumulation in the food chain is not significant.

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Environmental Medicine: Integrating a Missing Element into Medical Education Who’s at Risk ❑ Most significant exposures to beryllium occur in the occupational setting. ❑ A small percentage of the population is hypersensitive to beryllium. ❑ Chronic beryllium disease has been reported recently in a household contact of a beryllium worker. There are no accurate estimates of the number of workers exposed to beryllium; however, we know that workers potentially exposed are those engaged in smelting, metal machining, and reclaiming scrap alloys, as well as those in high-technology industries such as aerospace, nuclear, telecommunications, and computer industries. The mining of beryllium ore has not been associated with beryllium disease (acute or chronic); however, the relationship has not been studied systematically. Inhaling metallic beryllium, beryllium oxide, beryllium-copper alloys, or beryllium salts can cause beryllium disease. Beryllium disease was first noted in the 1930s in workers exposed to beryllium-containing phosphors in the fluorescent lamp industry. Industry standards and environmental controls for beryllium were established in the 1950s. Although acute beryllium disease occurs rarely today, chronic beryllium disease (berylliosis) continues to occur in industries where beryllium and its alloys are smelted, fabricated, and machined. The terms acute and chronic, used to describe beryllium disease, refer to disease processes, rather than types of exposure. Acute beryllium disease manifests as pulmonary inflammation, whereas chronic beryllium disease is typically a progressive pulmonary granulomatosis. Low, seemingly trivial exposures to beryllium may be important in causing beryllium disease. Chronic beryllium disease has been found in persons living near a plant using beryllium, although neighborhood cases have decreased considerably since industry control measures were instituted. As recently as 1991, a case of chronic beryllium disease due to secondary contamination was reportedly caused by a family member’s exposure to beryllium from a worker’s clothing. A small percentage of exposed persons (1% to 3%) develop beryllium hypersensitivity and chronic disease. (Hypersensitivity to beryllium can be demonstrated by in vitro proliferative responses of lymphocytes obtained through blood or bronchoalveolar lavage.) Some workers manifest this cellular immune response even if they work in areas where beryllium air concentrations are found to be below the recommended workplace exposure limits. Sensitization has been reported in security guards, secretaries, and custodial staff who work at facilities using beryllium. No correlation has been found between smoking and increased incidence of beryllium disease. However, inhalation of beryllium does appear to alter the ability of the lungs to clear other inhaled agents.

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Environmental Medicine: Integrating a Missing Element into Medical Education Additional information for the case study: Because he is concerned about the care he is receiving from another doctor, the father of the patient in the case study asks you to render a second opinion on his condition. During examination, you perform a local excision to biopsy an ulcer on his hand. The biopsy reveals noncaseating granulomas. The biopsy result and a review of the chest radiograph and patient history lead you to include chronic beryllium disease in the differential diagnosis. (1) How might the father have come in contact with beryllium? ________________________________________________________________________ ________________________________________________________________________ (2) Could the father pass beryllium to other family members by contact or by coughing and sneezing? ________________________________________________________________________ ________________________________________________________________________ Biologic Fate ❑ Inhaled beryllium is solubilized in the lungs and distributed primarily to bone, liver, and kidneys. ❑ Contact of beryllium with broken skin can lead to systemic absorption. ❑ Most beryllium is excreted in the urine. Beryllium exposure occurs primarily by inhalation and contact through broken skin. After inhalation, particles containing beryllium are deposited in the respiratory tract, solubilized upon contact with respiratory epithelium, and absorbed into the bloodstream. Solubilized beryllium may bind to the phosphate in plasma proteins, forming a complex that is engulfed by macrophages. The pulmonary half-life of beryllium ranges from several weeks to 6 months, although beryllium has been detected in the lungs of persons with chronic beryllium disease decades after the exposure has ceased. Ingested beryllium is presumed to be solubilized in the acidic milieu of the stomach and absorbed predominantly from the stomach. Beryllium absorption rates vary widely and correspond to gastric emptying time. In the intestinal fluid, a beryllium-protein complex forms and is eliminated. Ingested beryllium is not thought to be associated with disease. Beryllium is not absorbed through intact and uninjured skin. However, significant amounts can be absorbed dermally through burns, abrasions, and open wounds. Local deposition and systemic absorption can result from accidental inoculation by beryllium splinters.

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Environmental Medicine: Integrating a Missing Element into Medical Education Beryllium and its compounds are not biotransformed but remain as Be+2 in the body. The highest levels of beryllium are found in bone; lesser amounts are distributed to the liver and kidneys. Placental crossing occurs only to a small extent. Inhaled or ingested beryllium is excreted slowly. The renal system removes more than 90% of absorbed beryllium, but less than 1% is excreted within the first day. Plasma beryllium does not cross the glomerular membrane and is eliminated through the renal tubules. Levels in the urine are highly variable due to differing compartmental clearance rates; beryllium can take months to years to be removed from pulmonary lymph nodes and bone. The metal has been found in the urine as long as 10 years after cessation of exposure. Physiologic Effects Respiratory Effects ❑ In acute disease, beryllium acts as a chemical irritant. ❑ In chronic disease, beryllium initiates a delayed-type hypersensitivity reaction in the lungs. ❑ The most common histology in chronic beryllium disease is granulomatous interstitial pneumonitis. Two distinct mechanisms of lung injury can result from beryllium exposure. In acute disease, beryllium acts as a direct chemical irritant, causing a nonspecific inflammatory reaction. In chronic disease, which occurs in susceptible persons, a cell-mediated, delayed hypersensitivity reaction is involved. Inflammatory acute disease can progress to granulomatous chronic beryllium disease. Acute beryllium lung disease has been almost completely eliminated in the United States. The U.S. Beryllium Case Registry (maintained by the National Institute for Occupational Safety and Health [NIOSH]) admitted only one case of acute disease from 1975 to 1980. Acute disease manifests as inflammation of the upper or lower respiratory tract or both. Acute and subacute bronchitis may occur, but the most serious complication is chemical pneumonitis. Acute disease can appear suddenly after short exposure to high concentrations or progress slowly after longer exposure to lower concentrations. Pneumonitis or bronchitis induced by inhaling beryllium is histologically identical to these diseases when caused by other pulmonary irritants. A dose-response relationship is suspected in the case of beryllium, but the data are not adequate to allow clarification. Chronic beryllium disease is a granulomatous, interstitial inflammation affecting primarily the lungs, although granulomas also have been found in the liver, spleen, heart, and lymph nodes. The most common manifestation is chronic interstitial pneumonitis with infiltration of lymphocytes, histiocytes, and plasma cells. This interstitial pneumonitis is usually, but not invariably, associated with noncaseating granulomas ranging from indistinct collections of epithelioid cells to well-formed granulomas. Less often, one finds a predominance of well-formed granulomas with only focal, mild interstitial changes. Emphysema is common in chronic disease.

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Environmental Medicine: Integrating a Missing Element into Medical Education Recent immunologic evidence suggests that the key pathogenic event in chronic disease is a beryllium-specific cellular immune response in the lungs, investigators have found elevated helper:suppressor T-cell ratios in the pulmonary lymphocyte population. These helper T cells demonstrate an antigen-like response to beryllium, which is likely to be in the form of a beryllium-protein conjugate. The in vivo sensitization can be detected by the in vitro lymphocyte transformation test in bronchoalveolar lavage and in peripheral blood. Dermal Effects ❑ Skin contact with beryllium can cause ulceration and subcutaneous granulomas. Skin contact with soluble beryllium compounds can induce beryllium sensitization and cause contact dermatitis. Beryllium-containing particles that lodge in a worker’s skin can cause skin ulceration; biopsy reveals noncaseating granulomas at the site of injury. There is no evidence that pulmonary disease can result from isolated dermal contact with beryllium. Carcinogenic Effects ❑ On the basis of animal studies, airborne beryllium is considered a potential human carcinogen. The potential for carcinogenicity due to beryllium depends on the exposure route. Inhalation of beryllium compounds currently is considered by the Environmental Protection Agency (EPA) to be potentially carcinogenic in humans because lung tumors have been induced in experimental animals by this route. Several epidemiologic studies have attempted to clarify the cancer-causing effects in humans, but the published studies have drawn conflicting conclusions. Most recent data suggest that beryllium workers are at increased risk of lung cancer. (3) What organ systems should be evaluated if beryllium exposure is suspected? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Clinical Evaluation History and Physical Examination ❑ If beryllium exposure is suspected, the skin and respiratory tract should be examined carefully. ❑ In chronic beryllium disease, the time between initial exposure and clinical disease can range from months to 30 years. Initial evaluation of a patient with a history of beryllium exposure includes a thorough occupational and environmental history, medical history, physical examination, chest X ray, pulmonary function tests, blood chemistries, and complete blood count. The beryllium-stimulated lymphocyte transformation test (described on page 9) can be used to detect early stages of beryllium disease and to lend specificity to the clinical diagnosis. During the medical history and physical examination, particular attention should be focused on the skin and respiratory tract. The latency between exposure and detectable disease averages 10 to 15 years, with a range of several months to 30 years. Evidence suggests that at least some beryllium disease cases are triggered or exacerbated by physiologic stress such as surgery, pregnancy and lactation, and intercurrent illness. Signs and Symptoms Acute ❑ Acute beryllium toxicity causes a nonspecific inflammatory reaction in the respiratory tract. The onset of pneumonitis due to beryllium exposure can be abrupt or insidious and the progression, rapid or slow. Symptoms include progressive dyspnea, cough, substernal chest pain, anorexia, and fatigue. Common signs are tachycardia, rales, and sometimes cyanosis. Conjunctivitis, periorbital edema, nasopharyngitis, and tracheobronchitis also have been reported. Acute beryllium disease is rarely encountered today. Chronic ❑ Exertional dyspnea is the most common symptom of chronic beryllium disease. There is a wide spectrum of physical findings in patients chronically exposed to beryllium. Some patients are asymptomatic but have an abnormal chest radiograph or positive beryllium-stimulated lymphocyte transformation test. The most common symptom is exertional dyspnea, which is usually progressive. Other complaints may include cough, fatigue, weight loss, chest pain, and arthralgias. Bibasilar rales are detected frequently. Other findings may include lymphadenopathy, skin lesions, hepatosplenomegaly, and clubbing. Signs of pulmonary hypertension, cor pulmonale, and right ventricular failure may be present in end-stage disease. Beryllium can cause contact dermatitis. A single dermal exposure can also sensitize the skin to future exposures. If beryllium becomes embedded in the skin, it can cause delayed healing, ulcers, and

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Environmental Medicine: Integrating a Missing Element into Medical Education granuloma formation. Although rare, cutaneous granulomas can be a manifestation of the systemic process of chronic beryllium disease. They are not necessarily related to direct dermal contamination. Differential Diagnosis ❑ Chronic beryllium disease continues to be misdiagnosed as sarcoidosis. The differential diagnosis for interstitial and granulomatous lung disease is long. Conditions that may resemble chronic beryllium disease include tuberculosis, fungal disease, asbestosis, silicosis, hypersensitivity pneumonitis, pulmonary hemosiderosis, lymphangitic spread of carcinoma, and sarcoidosis. Of these, the clinical features of sarcoidosis are most similar to the characteristics of chronic beryllium disease (Table 1). Although each disease possesses characteristic clinical features, no feature has proved adequately sensitive and specific to be pathognomonic. Chronic beryllium disease tends to have less prominent extrapulmonary manifestations. For example, to date, no patient with chronic beryllium disease has developed uveitis, uveoparotid fever, cranial or peripheral nerve involvement, or cystic bone lesions—conditions that have affected patients with sarcoidosis. Furthermore, chronic beryllium disease is progressive and often requires lifelong corticosteroid therapy to slow its course. Spontaneous remission of chronic beryllium disease has been reported to occur after cessation of exposure, but this is rare. Table 1. Comparison of clinical features— sarcoidosis and chronic beryllium disease Feature Sarcoidosis Chronic beryllium disease Hilar adenopathy Common Less common* Erythema nodosum Common in acute stage Absent Parotid involvement May be present Absent Bone changes Present in chronic stage Absent Response to therapy Good Variable† *About 30% to 40% of patients with chronic beryllium disease exhibit hilar adenopathy. †Chronic beryllium disease is often managed well with corticosteroids, but some patients do not respond to this treatment and experience progressive fibrosis. Laboratory Evaluation ❑ Immunologic tests may assist the clinician in early diagnosis of chronic beryllium disease. Until recently, there was no diagnostic test for beryllium disease. Both atomic absorption spectrophotometry and mass spectrometry, which historically were used to detect and measure beryllium in biopsy specimens, are unsatisfactory. Spectrometric results correlate poorly with severity of pathology and can be within normal limits in some patients with disease. Likewise, elevated blood and urine

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Environmental Medicine: Integrating a Missing Element into Medical Education beryllium levels signify only exposure to beryllium at an indeterminable time; absence of detectable urinary beryllium does not exclude significant exposure. Diagnosis, therefore, has been based traditionally on compatible clinical findings and laboratory results, pulmonary function defect, typical biopsy, and exposure potential. A recently available in vitro assay, the beryllium-stimulated lymphocyte transformation test, may aid in confirming diagnosis and permit screening of patients for subclinical disease. The lymphocyte transformation test, used with beryllium, appears to be both specific and sensitive for beryllium disease. In affected patients, the helper T cells retrieved from bronchoscopic lavage or peripheral blood, when cultured in a bath of beryllium sulfate, yield a growth response that is typical of antigen-stimulated hypersensitivity reactions. Similar cells from patients with sarcoidosis or other pulmonary diseases do not demonstrate a proliferate response. In some patients with chronic beryllium disease, serum chemistry studies show increased total protein due to elevated globulins, hyperuricemia, elevated erythrocyte sedimentation rate, elevated liver enzymes, hypercalcemia, and occasionally, elevated hematocrit. Only a small percentage of patients with beryllium toxicity have elevated serum angiotensin-1-converting enzyme activity. Pulmonary evaluation for chronic beryllium disease, as for all interstitial lung diseases, includes chest X ray, pulmonary function tests, arterial blood gas measurements, and possibly bronchoscopy with tissue biopsy and lavage analysis for cell count, differential, and lymphocyte count. Chest radiograph findings may include diffuse infiltrates and hilar adenopathy, but can be negative. Infiltrates may be granular, diffuse linear, or small nodules. Hilar adenopathy, noted in 30% to 40% of patients, is usually mild, bilateral, and associated with parenchymal infiltrates. Severe disease may show interstitial fibrosis, honeycombing, and formation of conglomerate masses. Pleural thickening and pneumothorax can occur but are unusual. (4) What steps would you take to evaluate the condition of the daughter in the case study? _________________________________________________________________ _________________________________________________________________ (5) What steps will be necessary to evaluate her father’s condition? _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Treatment and Management ❑ Corticosteroid therapy is the primary treatment modality for chronic beryllium disease. ❑ An estimated 30% of patients with chronic beryllium disease die from complications directly attributable to their disease. Although there is little scientific evidence that cessation of exposure alters the course of beryllium disease once it is manifest, exposure cessation should be the first goal of management. For patients with chronic beryllium disease, corticosteroid therapy is the primary treatment modality. Corticosteroids provide symptomatic relief and improve lung function; they are required lifelong for most patients. When symptoms are controlled, an alternate day, single-dose regimen can be tried. Alternate-day doses usually range from 20 mg to 40 mg prednisone; occasionally up to 80 mg is required for short periods. More aggressive disease may require even higher daily doses of corticosteroids. There is no cure, and spontaneous remissions occur rarely. Supplemental oxygen may be necessary to correct hypoxemia associated with chronic beryllium disease. Right ventricular failure and its complications are late-stage sequelae. Severe cough may require restricting physical activity. Pneumothorax can occur. Emphysema and pulmonary fibrosis, which are common in long-term disease, can prove poorly responsive to corticosteroids. As with chronic lung disease of other etiologies, one should be vigilant for bacterial respiratory infections and should treat infections promptly with antibiotics when indicated. Patients should be immunized against pneumococcus and influenza and counseled to avoid exposures to other substances that cause lung injury, including cigarette smoke. Responses to therapy vary. In some cases, the disease symptoms appear mild at diagnosis, progress minimally, and are controlled well with corticosteroids. In others, the course is increasingly severe and controlled poorly by corticosteroids. Reviewers of 130 pathologic specimens obtained from patients in the U.S. Beryllium Case Registry concluded that the greater the degree of interstitial infiltration present, the worse the clinical course and prognosis. Persons demonstrating a predominance of well-formed granulomas and minimal interstitial fibrotic changes had a more benign course and better prognosis. Investigators found no correlation between histology and responsiveness to steroids, nor between length of the latency period and type of histology manifested. It is estimated that 30% of patients with chronic beryllium disease die from complications directly attributable to their disease. Careful irrigation and débridement are recommended for wounds potentially contaminated with beryllium. Complete excision is curative for beryllium-contaminated injury sites that demonstrate delayed healing, ulceration, and granuloma formation. The main treatment for contact dermatitis associated with beryllium salt exposure is cessation of exposure.

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Environmental Medicine: Integrating a Missing Element into Medical Education (6) What treatment will you recommend for the daughter in the case study? _________________________________________________________________ _________________________________________________________________ (7) The father’s beryllium-stimulated lymphocyte transformation test was abnormal and consistent with chronic beryllium disease. How will you treat and manage the father’s condition? _________________________________________________________________ _________________________________________________________________ Standards and Regulations The standards and regulations for beryllium are summarized in Table 2. EPA considers beryllium a probable human carcinogen. Workplace Air The Occupational Safety and Health Administration (OSHA) regulation for beryllium and its compounds is an 8-hour time-weighted average (TWA) of 2 micrograms (as beryllium) per cubic meter of air (2 µg/m3). An employee should not be exposed to a concentration of beryllium and beryllium compounds above 5 µg/m3. The 30-minute maximum peak level is 25 µg/m3. NIOSH recommends that beryllium be treated as a potential human carcinogen and advises a 10-hour TWA not to exceed 0.5 µg/m3.

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Environmental Medicine: Integrating a Missing Element into Medical Education Environment Air Beryllium has been designated a hazardous air pollutant under the Clean Air Act. According to EPA regulation, beryllium emissions cannot exceed 10 grams in a 24-hour period. Ambient air concentrations averaged over a 30-day period in the vicinity of stationary sources must not exceed 0.01 µg/m3. Water The EPA advisory for beryllium in water is less than 68 nanograms per liter (ng/L) for consumption of 2 liters (L) of ambient water. Table 2. Standards and regulations for beryllium Agency* Focus Level Comments ACGIH Air-workplace 2µg/m3 Advisory; TLV-TWA† NIOSH Air-workplace 0.5 µg/m3 Advisory; 10-hr TWA OSHA Air-workplace 2 µg/m3 5 µg/m3 25 µg/m3 Regulation; PEL§ as TWA Regulation; Ceiling Regulation; STEL¶ 30-min. maximum peak EPA Drinking water 68 ng/L for consumption of 2L Advisory   Air 10 g 24-hr period Regulation *ACGIH=American Conference of Governmental Industrial Hygienists; EPA=Environmental Protection Agency; NIOSH=National Institute for Occupational Safety and Health; OSHA= Occupational Safety and Health Administration †TLV-TWA (Threshold Limit Value-Time-Weighted Average)=Time-weighted average concentration for a normal workday and a 40-hour workweek to which nearly all workers may be repeatedly exposed. §PEL (Permissible Exposure Limit)=Highest level of beryllium in air to which a worker may be exposed, averaged over an 8-hour workday. ¶STEL (Short-Term Exposure Limit)=usually determined by a 15-minute sampling period.

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Environmental Medicine: Integrating a Missing Element into Medical Education Suggested Reading List Aronchick JM, Rossman MD, Miller WT. Chronic beryllium disease: diagnosis, radiographic findings, and correlation with pulmonary function tests. Radiology 1987;163:677–82. Cullen MR, Cherniak MG, Kominsky JR. Chronic beryllium disease in the United States. Semin Respir Med 1986;7:203–9. Cullen MR, Kominsky JR, Rossman MD, et al. Chronic beryllium disease in a precious metal refinery: clinical epidemiologic and immunologic evidence for continuing risk from exposure to low-level beryllium fume. Am Rev Respir Dis 1987;135:201– 8. Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung disease. Ann Intern Med 1985;102:93–108. Epstein PE, Dauber JH, Rossman MD, Daniele RP. Bronchoalveolar lavage in a patient with chronic berylliosis: evidence for hypersensitivity pneumonitis. Ann Intern Med 1982;97:213–6. Hardy HL Beryllium disease: a clinical perspective. Environ Res 1980;21:1–9. Jones-Williams W. Beryllium disease. Postgrad Med J 1988;64:511–6. Jones-Williams W. On the differential diagnosis of chronic beryllium disease and sarcoidosis [Letter]. Am Rev Respir Dis 1990;142(3):739. Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med 1989;31:603–8. Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis 1988;137:464–73. Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin Immunol 1991;88:54–60. Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease: re-examination of disease definition and natural history. Am Rev Respir Dis 1989;139:1470–86. Rom WN, Lockey JE, Lee JS, et al. Pneumoconiosis and exposures of dental laboratory technicians. Am J Public Health 1984;74:1252–7. Rossman MD, Kern JA, Elias JA, et al. Proliferative response of bronchoalveolar lymphocytes to beryllium: a test for chronic beryllium disease. Ann Intern Med 1988;108:687–93. Saltini C, Winestock K, Kirby M, et al. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells . N Engl J Med 1989;320:1103–9. Government Publications Agency for Toxic Substances and Disease Registry. Toxicological profile for beryllium. Atlanta: US Department of Health and Human Services, Public Health Service, 1988. Report no. ATSDR/TP-88/07. Environmental Protection Agency. Health assessment for beryllium. Washington, DC: US Environmental Protection Agency, 1988. Report no. PB88–179205. Environmental Protection Agency. Health effects assessment for beryllium and compounds. Cincinnati: US Environmental Protection Agency, Environmental Criteria and Assessment Office, 1988. Report no. PB88–179460.

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Environmental Medicine: Integrating a Missing Element into Medical Education Answers to Pretest and Challenge Questions Pretest Pretest questions are found on page 1. Challenge questions begin on page 4. The patient’s problem list includes productive cough, wheeze, and low-grade fever. The most likely causes to consider for this patient’s condition are reactive airway disease (asthma, rhinitis, or postnasal drip), an infectious process (viral or bacterial bronchitis or pneumonia), and chemical irritation (cigarette smoke or air pollution). Psychogenic etiology should also be considered. Less likely considerations include bronchiectasis, congenital abnormalities, foreign-body aspiration or other aspiration syndromes, cystic fibrosis, or tracheomalacia- bronchomalacia. Initially, you would want to know the father’s general state of health, his full work history, habits of cigarette smoking, and history of respiratory problems. You may also wish to explore his hobbies and home environment. As a dental laboratory technician, the father may be at risk of exposure to beryllium (casting and grinding alloys used in dental prostheses), as well as to mercury (mixing dental amalgams). Chronic cough is a common symptom of chronic beryllium disease, which can be misdiagnosed as sarcoidosis unless specifically tested for. The most likely diagnosis for the patient is bronchitis. Wheezing, if present, could be a complication of bronchitis, or it could be a new onset of asthma triggered by infection or exacerbated by cigarette smoke from her father’s cigarettes. Workers casting or grinding beryllium can expose members of their households to beryllium dust brought home on workers’ hair, skin, and clothes. These household members have developed chronic beryllium disease. On the basis of her signs and symptoms, it is unlikely that the patient has a beryllium-related disease. However, if she visits her father’s workplace or if he does not change workclothes before leaving the workplace, she should be considered at risk. Challenge Answers Beryllium alloy is used in some dental prostheses. If the father or his laboratory coworkers cast or machine-grind these prostheses, it is possible that beryllium from the workplace contaminated his hand wound. He should be carefully questioned about possible sources of beryllium exposure. There is no evidence to suggest that beryllium toxicity or disease can be passed by body fluids, coughing, or sneezing. To ensure that beryllium is not brought home from the workplace through beryllium-contaminated clothes and skin, you should discuss with the father proper workplace hygiene including changing clothes and showering before leaving the workplace. You should also take steps to determine if others in the workplace are exposed to beryllium. Chronic beryllium disease manifests almost solely in the lungs. If beryllium becomes embedded in skin, ulceration and poor wound healing can ensue.

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Environmental Medicine: Integrating a Missing Element into Medical Education For the daughter, initial evaluation includes a careful history, thorough physical examination, and a chest X-ray. The history suggests an infectious process and, given the clinical picture, no other laboratory tests are recommended at this time. If her respiratory symptoms become chronic, she should be reevaluated. Asthma should be considered and, if her revaluation suggests an interstitial lung disease, the blood beryllium-stimulated lymphocyte transformation test may be used for screening. Due to proven beryllium exposure, the father is a candidate for a more complete evaluation for beryllium toxicity. An abnormal blood beryllium-stimulated lymphocyte transformation test would indicate an increased probability that both the cutaneous and pulmonary abnormalities are due to beryllium exposure. A negative blood test, however, would not exclude the diagnosis of chronic beryllium disease. If the blood test is negative, consideration should be given to a bronchoscopy for lung tissue biopsy and bronchoalveolar lavage lymphocyte transformation test. (Note: The presence of macrophages in the lavage specimen of smokers can render the lavage test inconclusive.) The treatment for bronchitis is supportive care and should include rest, air humidification, and avoidance of noxious stimuli such as cigarette smoke. Antibiotics should be used if bacterial bronchitis is strongly suggested by the clinical course or is proven by reliable laboratory techniques. Given the sleep disturbance experienced by this patient, consideration may be given to bronchodilator therapy such as an inhaled β2 agonist. If the patient’s clinical course suggests asthma, treatment should be tailored to her needs. The father has chronic beryllium disease and a beryllium-induced skin ulceration. The first therapeutic effort should be to remove him from further exposure to beryllium. Values should be obtained for the following baseline tests: pulmonary function tests, carbon monoxide diffusion, and arterial blood gases. Corticosteroid therapy should be instituted. The father should be reevaluated periodically to assess whether he has responded to corticosteroids, and to taper the dose to the minimum needed to control symptoms and maintain physiologic improvement. He should also be monitored for potential long-term steroid side effects. Excision of the cutaneous lesion should prove curative for the skin condition, but lifelong corticosteroid therapy will most likely be required for the lung condition. Because the father may represent a sentinel case, the local health department should be notified. To prevent further exposures, the patient’s workplace should be evaluated. Notification of OSHA or a request for a NIOSH health hazard survey may be warranted. Sources of Information More information on the adverse effects of beryllium and treating and managing cases of exposure to beryllium can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Beryllium Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.