UKPID MONOGRAPH BERYLLIUM SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. BERYLLIUM Toxbase summary Type of product Used in nuclear reactors, electrical insulators and resistors, spark plugs, microwave tubes, the aerospace industry, photographic equipment and many tools. Toxicity The lung is the main target organ of beryllium toxicity. Beryllium lung disease is classified as acute or chronic dependant on the duration of disease rather than the duration of exposure. The acute illness does not persist beyond one year. Chronic beryllium disease is a cell-mediated (delayed) hypersensitivity reaction characterized by granuloma formation and pulmonary fibrosis which may be fatal. Features Topical - Beryllium compounds may cause contact dermatitis. - Beryllium ulcers occur where a beryllium crystal penetrates the skin at a site of previous trauma. - Beryllium chloride, fluoride, nitrate or sulphate are acute eye irritants. Ingestion - Gastrointestinal beryllium absorption is poor and systemic toxicity via this route does not occur. Inhalation Mild inhalation: - Metallic taste, cough, breathlessness. Substantial inhalation: - Cough, chest pain, metallic taste, exertional breathlessness, nasopharyngitis, tracheobronchitis, conjunctivitis, pneumonitis, epistaxis and fever. - Additional features seen in chronic beryllium disease include fever, anorexia, arthralgia, nausea, vomiting, haemoptysis, palpitation, convulsions, renal calculi, corneal calcification, hepatosplenomegaly (secondary to cor pulmonale) and systemic granulomas causing lymphadenopathy and parotid gland enlargement. - Chest X-ray may show upper zone nodules and fibrosis and there may be a restrictive ventilatory defect. Management Topical - Skin nodules from subcutaneous implantation of beryllium metal or its salts are best managed by local excision. Ingestion - Beryllium salt ingestion is not a significant toxicological problem. 1. Management is entirely supportive. 2. Gastrointestinal decontamination is not necessary. Inhalation - Most cases are occupational. 1. Occupational hygiene is paramount. 2. If pulmonary toxicity is suspected remove from exposure. 3. Symptoms of acute and chronic beryllium disease respond well to oral steroids. 4. Experimental studies to assess the value of chelators in beryllium poisoning are underway, but there are insufficient data currently to recommend their use in man.Urine beryllium concentrations allow assessment of beryllium absorption but chronic beryllium disease is not excluded by a low urine beryllium concentration. References Haberman AL, Pratt M, Storrs FJ. Contact dermatitis from beryllium in dental alloys. Contact Dermatitis 1993: 28: 157-62. Hooper WF. Acute beryllium lung disease. N C Med J 1981; 42: 551-3. Izumi T, Kobara Y, Inui S, Tokunaga R, Orita Y, Kitano M, Jones Willams W. The first seven cases of chronic beryllium disease in ceramic factory workers in Japan. Ann NY Acad Sci 1976 ; 278: 636-53. Jones Williams W. Diagnostic criteria for chronic beryllium disease (CBD) based on the UK Registry 1945-1991. Sarcoidosis 1993; 10: 41-3. Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis 1988; 137: 464-73. Monie RDH, Roberts GH. Chronic beryllium pneumonitis: First case accepted by UK register from Scotland. Scott Med J 1991; 36: 185-6. Substance name Beryllium Origin of substance Occurs in the minerals beryl, phenacite, bertrandite, bromellite and chrysoberyl. (DOSE, 1992) Synonyms Beryllium-9 Glucinium (CSDS, 1989) Chemical group A group II A element Reference numbers CAS 7740-41-7 (CSDS, 1989) RTECS DS1750000 (RTECS, 1996) UN 1567 (Be powder) (CSDS, 1989) HAZCHEM CODE NIF Physicochemical properties Chemical structure Beryllium, Be (DOSE, 1992) Molecular weight 9.01 (DOSE, 1992) Physical state at room temperature Solid (CSDS, 1989) Colour Greyish-white (CSDS, 1989) Odour Odourless (HSDB, 1996) Viscosity NA pH NA Solubility Insoluble in cold water (or mercury), slightly soluble in hot water. Soluble in dilute acids and alkalis. (HSDB, 1996) Autoignition temperature NIF Chemical interactions Beryllium reacts readily with some strong acids, producing hydrogen. (NFPA, 1996) Powdered beryllium mixed with carbon tetrachloride or trichloroethylene will flash on heavy impact. (HSDB, 1996) Warm beryllium incandesces in fluorine or chlorine. (HSDB, 1996) Molten lithium at 180°C will attack beryllium severely. (NFPA, 1996) Major products of combustion Combustion yields beryllium oxide fume which is toxic if inhaled. (HSDB, 1996) Explosive limits NIF Flammability Flammable (HSDB, 1996) Boiling point 2970°C (CSDS, 1989) Density 1.85 at 20°C (CSDS, 1989) Vapour pressure NIF Relative vapour density NA Flash point NA Reactivity NIF Uses Beryllium is an important component of nuclear reactors as a neutron source with low neutron-absorbing capacity. Beryllium oxide is used in the electronics industry in insulators, resistors, spark plugs and microwave tubes. Beryllium-copper alloys are used in the aerospace, electronic, mechanical and other industries as constituents of aircraft engine parts, switches, circuit breakers, fuse clips, springs, bearings, gear parts, camera shutters and many tools and are the major source os occupational beryllium exposure. Other important beryllium alloys are beryllium-aluminium, beryllium-copper-cobalt and beryllium-nickel alloys. (IPCS, 1990; Jones Williams, 1994) Hazard/risk classification Index no. 004-001-00-7 Risk phrases Carc. Cat.2; R49 - May cause cancer by inhalation. T+; R26 - Very toxic by inhalation. T; R25-48/23 - Also toxic if swallowed. Toxic: danger of serious damage to health by prolonged exposure through inhalation. Xi; R36/37/38 - Irritating to eyes, respiratory system and skin. R43 - May cause sensitization by skin contact. Safety phrases S53-45 - Avoid exposure - obtain special instruction before use. In case of accident or if you feel unwell, seek medical advice immediately (show label were possible). EEC no. (CHIP2, 1994) INTRODUCTION Beryllium is a brittle metal which forms compounds in the divalent state. It has a high affinity for oxygen such that a surface film of beryllium oxide forms when the metal is exposed to air. This provides resistance to corrosion which, with low density and high electrical and thermal conductivity, make beryllium an important constituent of many alloys; approximately 72 per cent of all beryllium produced is used in this way (IPCS, 1990). In the general population tobacco smoking is a major source of beryllium exposure but beryllium toxicity is predominantly an occupational disease via exposure to beryllium dust or fumes in the industries listed above. Historically beryllium poisoning occurred also during the production of fluorescent and neon lamps when beryllium was used to coat their inner surface. In these circumstances secondary cases of occupational beryllium poisoning occurred in the families of workers via dust carried home in clothing (Hardy, 1965). Non-occupational beryllium contact-sensitivity has been reported in individuals fitted with beryllium-containing dental prostheses. Table 1 lists the main beryllium salts by solubility. Table 1. Solubility1 of beryllium compounds Soluble beryllium compounds Insoluble beryllium compounds Beryllium chloride Beryllium acetate Beryllium fluoride Beryllium hydroxide Beryllium nitrate Beryllium oxide Beryllium sulphate tetrahydrate2 Beryllium sulphate (after IPCS, 1990) 1 In cold water 2 Formed from beryllium sulphate in hot water MECHANISM OF TOXICITY Beryllium has been shown experimentally to disrupt phosphate and nucleic acid metabolism with subsequent inhibition of enzyme activity and cell replication (IPCS, 1990). Beryllium also impairs reticuloendothelial cell function (Dinsdale et al, 1981). As discussed below beryllium is immunogenic and capable of initiating a type IV hypersensitivity reaction (Vilaplana et al, 1992) via mechanisms which are, at least in part, genetically determined (Barna et al, 1984; McConnochie et al, 1988). TOXICOKINETICS Absorption Beryllium is absorbed mainly by inhalation of dust or fumes; dermal and gastrointestinal absorption are poor. The rate of beryllium absorption from the alveolar space depends on the solubility and particle size of the salt with greater absorption of small particles of soluble salts (IPCS, 1990). Distribution Beryllium is transported in blood and lymph protein-bound or as colloidal beryllium phosphate (Aller, 1990). The small amount of beryllium absorbed following ingestion is deposited primarily in bone. By contrast, the distribution of beryllium following inhalation depends on the solubility of the salt. Beryllium oxide, which is poorly soluble (Table 1), is stored mainly in lung tissue, pulmonary lymph nodes and bone whereas more soluble beryllium compounds (e.g. beryllium chloride; Table 1) will also be found in the liver, abdominal lymph nodes, spleen, muscle, kidney, skin and heart (IPCS, 1990). Beryllium is taken up by cellular lysosomes and may be found subsequently in the nucleus, nucleolus and cytoplasm (Aller, 1990). Excretion Lung clearance of inhaled beryllium is usually rapid during the first few days after exposure, followed by a second slower phase (IPCS, 1990). The initial rapid elimination is explained partly by mucociliary clearance of particulate matter with subsequent gastrointestinal elimination and partly by beryllium uptake by alveolar macrophages. The slow phase may be contributed to by precipitation to a more insoluble form and embedding in pulmonary tissues (Aller, 1990). Beryllium which reaches the systemic circulation is eliminated mainly in the urine, probably via active tubular secretion since most plasma beryllium is colloidally bound and therefore does not pass through the glomerulus (Reeves, 1986). The total body half-life of beryllium in man is approximately 180 days (ICRP, 1960). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Beryllium compounds may cause contact dermatitis. The beryllium source is usually occupational although non-occupational hypersensitivity has occurred in individuals wearing beryllium-containing dental prostheses (Haberman et al, 1993). There is usually a latent period of one to two weeks before the development of erythematous, macular, sometimes blistering lesions which resolve when exposure ceases. Once sensitization has occurred reactivation of the inflammatory response requires only minimal beryllium contact and in this respect beryllium skin disease is a chronic condition (VanOrdstrand et al, 1945) although beryllium contact sensitivity is not usually associated with systemic toxicity (Haberman et al, 1993). Beryllium ulcers occur where a beryllium crystal penetrates the skin at a site of previous trauma (VanOrdstrand et al, 1945; Jones Williams, 1988). Treatment by excision and curettage usually promotes complete healing (VanOrdstrand et al, 1945). Ocular exposure Dust of beryllium chloride, fluoride, nitrate and sulphate are acute eye irritants (Grant and Schuman, 1993). Inhalation This may follow the inhalation of beryllium fluoride, -sulphate, - oxide, -hydroxide or beryllium metal dust (Eisenbud et al, 1948). Clinical features are dose-related and usually occur within days but can be delayed for several weeks. Beryllium lung disease manifests in acute and chronic forms, classified depending on the duration of disease rather than the duration of exposure. Acute beryllium lung disease is a true chemical pneumonitis which may occur during beryllium extraction processes. It is now largely of historical interest due to improved occupational working conditions (Markham, 1996). Pulmonary toxicity A single beryllium salt inhalation may cause irritation of the nose, pharynx and eyes. Depending on the magnitude of exposure there may be a nasal discharge and mild epistaxis (Jones Williams, 1994). More substantial inhalation of soluble bismuth salts (Table 1) will result in rhinitis, tracheitis and bronchitis (Jones Williams, 1994). By contrast, less soluble beryllium salts can reach the alveoli and moderate to severe exposure may precipitate a chemical pneumonitis, usually within 72 hours, with cough, chest pain, exertional breathlessness and possibly fever, hypoxia and inspiratory crackles on auscultation of the lung fields (Kriebel et al, 1988a; Jones Williams, 1994). A subacute presentation is also recognised with more gradual onset of respiratory symptoms, often accompanied by constitutional upset and progression to chronic beryllium lung disease. In patients who develop moderate or severe respiratory symptoms, chest radiographic findings typically lag behind clinical signs for up to three weeks (Jones Williams, 1994). In those with pneumonitis initial diffuse shadowing may progress to widespread, poorly defined opacities which take months to clear (Jones Williams, 1994). There are no characteristic histological features. Restrictive spirometry may be present but usually resolves along with radiological improvement (Hooper, 1981). Most patients recover from acute beryllium lung disease when removed from exposure but fatalities have occurred (VanOrdstrand et al, 1945) and a minority develop late complications including chronic bronchitis, bronchiectasis, emphysema, asthma or progression to chronic beryllium lung disease (Rees, 1979; Jones Williams, 1993). The latter may occur after a symptom free interval of several years (Hardy, 1965; IPCS, 1990). Gastrointestinal toxicity Following acute beryllium inhalation some patients complain of a metallic taste, usually in association with symptoms of constitutional upset including anorexia and fatigue (VanOrdstrand et al, 1945). Diarrhoea has also been reported (Hooper, 1981). CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Beryllium exposure from soil on abraded skin of bare feet has been implicated in the aetiology of non-filarial elephantiasis in Ethiopia (Frommel et al, 1993). Inhalation Chronic beryllium disease is a hypersensitivity response to beryllium which occurs in susceptible individuals. There may be a latent period of several weeks or years between exposure (which may have been only a few hours) and the onset of symptoms. Inhalation of poorly soluble or insoluble beryllium compounds (e.g. beryllium oxide; Table 1) or beryllium dust are usually responsible and cases have been reported in fluorescent lamp plants (now historical) (Hardy and Tabershaw, 1946), ceramic factories (Izumi et al, 1976), the electronics and atomic energy industries (Jones Willliams, 1988), those involved in the refining of beryllium or its alloys (Cullen et al, 1987), welders (Monie and Roberts, 1991) or manufacturers of beryllium-containing dental prostheses (Kotloff et al, 1993). Although the lungs are the main target organ in chronic beryllium disease, unlike the acute illness, there are frequently widespread systemic manifestations, many secondary to granuloma formation as discussed below. Pulmonary toxicity Chronic beryllium disease manifests primarily as pneumonitis with exertional dyspnoea, cough (which may be productive), chest pain (Stoeckle et al, 1969; Hasan and Kazemi, 1974; Monie and Roberts, 1991) and possibly fever, haemoptysis, wheeze and hoarseness (Hasan and Kazemi, 1974). Respiratory symptoms are frequently accompanied by systemic upset with general malaise, anorexia and weight loss (see below). The most frequently observed clinical signs in the respiratory system are finger clubbing, central cyanosis and inspiratory crackles on auscultation of the lung fields (Stoeckle et al, 1969; Hasan and Kazemi, 1974; Monie and Roberts, 1991; Jones Williams, 1994). Death has occurred following massive haemoptysis in a patient with bilateral upper lobe mycetomas (probably related to steroid therapy) (O'Brien et al, 1987). In chronic beryllium disease a diffuse reticular pattern, more prominent in the upper zones, is seen on chest x-ray with nodules of varying size and sometimes bilateral (possibly calcified) hilar adenopathy (Andrews et al, 1969; Stoeckle et al, 1969; Hasan and Kazemi, 1974). There may be progression to upper zone fibrosis with relative emphysema in adjacent lobes, pleural thickening, pneumothoraces (usually from ruptured bullae) and evidence of pulmonary hypertension (Stoeckle et al, 1969; Hasan and Kazemi, 1974). Pulmonary function tests typically show a restrictive, or isolated diffusion defect, but obstructive lesions have been reported (Andrews et al, 1969). A probable "dose-related" decrease in FVC and FEV1 without chest x-ray abnormalities has also been described (Kriebel et al, 1988b). Lung biopsy in chronic beryllium disease usually shows a chronic inflammatory response with non-caseating granulomas, diffuse fibrosis and smooth muscle hypertrophy (Andrews et al, 1969; Hasan and Kazemi, 1974). The presence of beryllium in tissue sections can be confirmed using laser microprobe mass spectrometry (LAMMS) analysis (Jones Williams and Wallach, 1989; Monie and Roberts, 1991). In 124 cases of chronic beryllium disease, Freiman and Hardy (1970) found a clear relation between the histological appearance of the lung (at lung biopsy or autopsy) and disease prognosis. Only 26 of 95 patients with histological evidence of diffuse pulmonary cell infiltration were alive at the time of the study with a mean disease duration of 8.3 years for the entire group. Follow-up of 43 patients in the UK Beryllium Case Registry 1945-91 (Jones Williams, 1993) reported 25 deaths, 21 from cor pulmonale, though nearly half had survived more than 20 years from the original diagnosis. Lung damage in chronic beryllium disease may be partly reversible. In a survey of 214 workers at a beryllium plant Sprince et al (1978) demonstrated that beryllium-induced hypoxemia and radiographic abnormalities were reduced over three years following improved workplace ventilation and engineering processes with a significant reduction in the air beryllium concentration. Chronic beryllium disease reflects a cell-mediated (delayed) hypersensitivity reaction as evidenced by the ability of beryllium to activate proliferation of beryllium-specific helper T cells (Deodhar et al, 1973). This property forms the basis of the lymphocyte transformation test (LTT) which was shown by Rossman et al (1988) to have high sensitivity and specificity in the diagnosis of chronic beryllium disease using bronchoalveolar lavage fluid cells. In patients with compatible lung pathology Mroz et al (1991) found that an abnormal LTT in peripheral blood cells also could diagnose chronic beryllium disease reliably. The current diagnostic criteria for chronic beryllium disease therefore are a positive blood beryllium lymphocyte transformation test in the presence of a history of beryllium exposure, consistent clinical and radiological features plus granulomas and beryllium deposits in tissues (Jones Williams, 1988). It should be remembered that a positive beryllium LTT alone is not diagnostic of chronic beryllium disease; it reflects beryllium exposure but may be reversible when exposure is reduced (Rom et al, 1983). Reports that chronic beryllium disease shows a familial tendency probably reflect the role of histocompatibility antigens in beryllium hypersensitivity (McConnochie et al, 1988; Saltini et al, 1989; Deodhar and Barna 1991). It is also likely that the observed precipitation of chronic beryllium disease by pregnancy or infection (Hardy and Tabershaw, 1946) is related to altered immunological status. The main differential diagnosis in chronic beryllium disease is sarcoidosis although the presence of beryllium in tissues and a positive beryllium lymphocyte transformation test allow clarification (Jones Williams and Wallach, 1989). The Kveim test is negative in beryllium disease (Jones Williams and Wallach, 1989). Dermal toxicity Chronic pulmonary beryllium toxicity may be complicated by cutaneous granulomas (Jones Williams, 1994). Gastrointestinal toxicity Patients with chronic beryllium disease often experience anorexia, weight loss, nausea and vomiting (Hasan and Kazemi, 1974; Jones Williams, 1994). Parotid gland enlargement is due to granuloma formation (Hasan and Kazemi, 1974). Nephrotoxicity Hypercalciuria is common in chronic beryllium disease and renal calculi have been reported (Hardy and Tabershaw, 1946; Stoeckle et al, 1969). Granulomata may be seen on renal biopsy (Jones Williams, 1994) Cardiovascular toxicity Patients with severe untreated chronic beryllium lung disease may develop cor pulmonale with orthopneoa, palpitation (Hasan and Kazemi, 1974), hepatomegaly and/or splenomegaly (Hall et al, 1959; Stoeckle et al, 1969; Jones Williams, 1993). Neurotoxicity Central nervous system granulomas may cause seizures (Hasan and Kazemi, 1974). Haemotoxicity Extrapulmonary lymph node granulomata may cause generalised lymphadenopathy (Hasan and Kazemi, 1974). Granulomas may be found also in the spleen and bone marrow (Stoeckle et al, 1969; Jones Williams, 1994). Musculoskeletal toxicity Arthralgia may be a feature of chronic beryllium disease (Hasan and Kazemi, 1974). Ocular toxicity Corneal calcification and band keratopathy have been described in chronic beryllium disease (Grant and Schuman, 1993). A positive Schirmer's test (indicating reduced tear secretion) is recognized (McConnochie et al, 1988; Monie and Roberts, 1991). MANAGEMENT Dermal exposure Skin nodules developing from subcutaneous implantation of beryllium metal alloy or its salts, particularly in machinists and ceramic workers with skin lacerations, are best managed by local excision. This is usually curative although chronic beryllium disease has developed in isolated cases (Jones Williams, 1988). Inhalation Occupational hygiene Beryllium toxicity is only likely to occur following occupational exposure, usually by inhalation of beryllium containing dusts or powders. In these circumstances cessation of exposure is the priority. Adequate skin protection and hygiene to avoid unnecessary beryllium exposure are essential. Supportive measures Symptoms of acute and chronic beryllium disease respond well to oral prednisolone (20-80 mg daily) and in the chronic form treatment is usually lifelong (Izumi et al, 1976; Jones Williams, 1994). Antidotes DMPS and DMSA In animal studies oral DMPS or DMSA (50 mg/kg bd for five days) increased faecal but not urinary beryllium excretion in rats administered 0.5 mg/kg intraperitoneal beryllium nitrate daily for five days/week for three weeks (Flora et al, 1995). Chelation therapy with both agents reversed the hepatotoxic effect of beryllium as shown by liver alkaline phosphatase activity and DMPS caused a significant reduction in the liver and spleen beryllium content in association with an increased blood beryllium concentration (Flora et al, 1995). There are no data regarding the use of DMPS or DMSA in human beryllium poisoning. HEDTA and EDTA In beryllium-poisoned rats (treated for 18 days with parenteral beryllium nitrate 1 mg/kg daily) the administration of intraperitoneal HEDTA (N-(2-hydroxyethyl)ethylenediamine triacetic acid) or calcium disodium EDTA (ethylenediamine tetraacetic acid) prevented beryllium-induced hepatotoxicity (as indicated by hepatic alkaline phosphatase activity) but neither chelating agent significantly reduced blood or tissue beryllium concentrations (Mathur et al, 1993). Iron In animal studies intraperitoneal ferric ammonium citrate (40 mg/kg body weight daily) commenced three days prior to beryllium exposure and continued until death or recovery, protected against beryllium-induced mortality in rats exposed to intravenous beryllium sulphate (6 mg/kg). (Lindenschmidt et al, 1986) or an aerosol of beryllium sulphate (30 per cent w/v) (Sendelbach and Witschi, 1987) via increased ferritin production with subsequent faecal elimination of ferritin-bound beryllium. There are no human data regarding iron therapy in the management of beryllium poisoning. MEDICAL SURVEILLANCE Health surveillance is necessary for those potentially exposed to beryllium fumes or dust. Pre-employment clinical examination and chest x-ray are recommended. Those with an history of atopy are particularly susceptible to beryllium lung disease (Hooper, 1981). Regular monitoring of the beryllium concentration in workplace air, with provision of protective respiratory equipment if required, is mandatory (Health and Safety Executive, 1994). Urine beryllium concentrations allow assessment of beryllium absorption (Health and Safety Executive, 1994) but chronic beryllium disease is not excluded by a low urine beryllium concentration (IPCS, 1990). The identification of beryllium in affected tissues remains important in establishing the diagnosis (Jones Williams and Wallach, 1989; Jones Williams, 1994). Kreiss et al (1989) demonstrated that subclinical chronic beryllium disease could be detected via a positive lymphocyte proliferation test but recent studies suggest this has a limited role in screening (Stokes and Rossman, 1991). Since there may be a substantial latency period between beryllium exposure and the onset of beryllium disease, retired workers should be kept under medical supervision for up to 20 years. The UK Beryllium Case Registry provides important information on the incidence and clinical course of beryllium disease (Jones Williams et al, 1980). By 1994 it included 59 cases of whom 47 manifest the chronic form (Jones Williams, 1994). OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.002 mg/m3 (Health and Safety Executive, 1995b). OTHER TOXICOLOGICAL DATA Carcinogenicity In a cohort mortality study of 689 patients included in a North American beryllium disease case registry mortality from lung cancer (standardised mortality ratio (SMR) = 2.0) and non malignant beryllium disease were significantly increased, with deaths from lung cancer occurring more frequently in those with acute rather than chronic beryllium disease (Steenland and Ward, 1991). Ward et al (1992) similarly found a significantly increased SMR for lung cancer in workers at two beryllium plants in operation before 1950 although the overall slightly increased SMR for the 9225 cohort of workers from seven plants was not significant. The International Agency for Research on Cancer (IARC) Working Group on the carcinogenicity of beryllium has concluded that there is "sufficient evidence in humans for the carcinogenicity of beryllium and beryllium compounds" (IARC, 1993) although their conclusions have been disputed (MacMahon, 1994; Kotin, 1994a and b). By 1993 there were no known cases of beryllium-associated lung cancer in the UK registry (Jones Williams, 1993). Reprotoxicity There are no data confirming that beryllium is a reprotoxin in man (Reprotox, 1996). Genotoxicity Escherichia coli, HeLa cells and Ehrlich ascites tumour cells, DNA cell binding assays positive Chinese hamster ovary and rat lung epithelial cells, 20 hr exposure, positive cytotoxic effects Oral rat (6 month) in drinking water, caused cytotoxicity at the toxic dose level and induced chromosomal aberrations, but was negative in dominant lethal assays (DOSE, 1992). Fish toxicity Acute toxicity range to fish (24-96 hr) (species unspecified) in fresh water 87-0.97 µg/L LC50 (96 hr) fathead minnow 150 µg/L (DOSE, 1992). EC Directive on Drinking Water Quality 80/778/EEC NIF AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH UK This monograph was produced by the staff of the Birmingham Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Date of last revision 16/7/96 REFERENCES Aller AJ. The clinical significance of beryllium. J Trace Elem Electrolytes Health Dis 1990; 4: 1-6. Andrews JL, Kazemi H, Hardy HL. Patterns of lung dysfunction in chronic beryllium disease. Am Rev Respir Dis 1969; 100: 791-800. Barna BP, Deodhar SD, Chiang T, Gautam S, Edinger M. Experimental beryllium-induced lung disease. I. 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