UKPID MONOGRAPH ZINC 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. ZINC AND ZINC SALTS Toxbase summary Type of product Used in electroplating, solder fluxes, battery casings, dyes, paints, fungicides and disinfectants. Toxicity Zinc salts are more hazardous than elemental zinc. Zinc chloride is corrosive by ingestion and highly irritant by inhalation. Zinc sulphate is a gastrointestinal irritant but is less toxic after ingestion than zinc chloride. Zinc oxide inhalation is an important cause of metal fume fever. Fatal doses The fatal oral dose of zinc sulphate has been estimated as 10-30 g. Recovery has been reported after the ingestion of 12 g elemental zinc (Murphy, 1970). A 72 year-old female died after the inadvertent intravenous administration of 7.4 g zinc sulphate (Brocks et al, 1977). Features Topical - Zinc contact sensitivity has been described. - Zinc dust is irritant and abrasive to the eye. - Topical zinc chloride causes ulceration and burns and chronic exposure has been associated with anorexia, fatigue and weight loss. Ingestion - Lethargy, light-headedness and ataxia occurred in a male who presented three days after ingesting 12 g elemental zinc. Full recovery ensued (Murphy, 1970). - Zinc chloride is highly corrosive and ingestion of only 10 mL of zinc chloride containing solutions has caused oropharyngeal and gastric burns, epigastric tenderness, pharyngeal oedema, haematemesis and malaena. - Respiratory insufficiency and CNS depression may occur in severe cases. Recovery may be complicated by gastrointestinal stricture formation and/or pancreatic insufficiency. - Hyperglycaemia, hypokalaemia, increased alkaline phosphatase, amylase and liver transaminase activities have been reported. - Zinc sulphate overdose causes gastrointestinal irritation. Headache and dizziness are also described. Features are generally less severe than following zinc chloride ingestion although fatal gastrointestinal haemorrhage has occurred. - Chronic excess zinc sulphate ingestion may induce reversible anaemia and leucopenia, transient irritability, tremor and seizures. These neurological features occurred in a premature infant inadvertently given excess zinc sulphate supplements (Tasic et al, 1982). Inhalation - Zinc oxide fume inhalation causes metal fume fever. Symptoms may occur up to 24 hours post exposure with cough, dyspnoea, sore throat, chest tightness, headache, fever, rigors, myalgia, arthralgia and sometimes a metallic taste, nausea, vomiting and blurred vision. Chest X-ray may show transient iII-defined opacities. - Angioedema and urticaria have occurred rarely following zinc oxide fume inhalation. - Zinc chloride inhalation from smoke screen generators or smoke bombs may cause transient cough, sore throat, hoarseness, a metallic taste and chest pain. - Exposure to high zinc chloride concentrations produces a chemical pneumonitis with marked dyspnoea, a productive cough, fever, chest pain and cyanosis. Pneumothorax and the adult respiratory distress syndrome (ARDS) have been reported. Fatalities have occurred. Injection - Zinc toxicity with nausea and vomiting has occurred in a patient undergoing haemodialysis with contaminated water from a galvanized tank. - Inadvertent excess zinc sulphate in a parenteral nutrition solution has been associated with nausea, vomiting, anaemia, thrombocytopenia and elevated amylase activity. Management Topical - Symptomatic and supportive measures as indicated by the severity of the burn. Ingestion Minor elemental zinc or zinc sulphate ingestions: 1. Patients with features of mild gastrointestinal upset require only supportive care. 2. Gastric lavage or other gut decontamination procedure is unnecessary. Zinc chloride ingestions/substantial elemental zinc or zinc sulphate ingestions: 1. Most patients will vomit spontaneously. Gastric lavage is contraindicated following zinc chloride ingestion as this salt is corrosive. Gastric lavage is unlikely to reduce absorption of other salts significantly. 2. Symptomatic and supportive measures with adequate fluid resuscitation are paramount. 3. Endoscopic examination may be required. 4. Save blood and urine for zinc concentration estimations. 5. Monitor the blood count and biochemical profile including serum amylase activity. 6. The value of chelation therapy following zinc ingestion has not been confirmed. Discuss with NPIS if patient is Inhalation 1. Remove from exposure. 2. Administer supplemental oxygen by face mask. 3. Symptomatic patients and those with abnormal respiratory physical signs should have a chest X-ray. 4. Remember that features of metal fume fever may be delayed for up to 24 hours. 5. The possibility of delayed onset pulmonary oedema and development of ARDS must be considered if zinc chloride (or zinc phosphide) have been inhaled. 6. The value of chelation therapy following zinc chloride inhalation has not been confirmed. Discuss with NPIS. References Allen MB, Crisp A, Snook N, Page RL. 'Smoke-bomb' pneumonitis. Respir Med 1992; 86: 165-6. Brocks A, Reid H, Glazer G. Acute intravenous zinc poisoning. Br Med J 1977; 212: 1390-1. Burkhart KK, Kulig KW, Rumack B. Whole-bowel irrigation as treatment for zinc sulfate overdose. Ann Emerg Med 1990; 19: 1167-70. Chew LS, Lim HS, Wong CY, Htoo MM, Ong BH. Gastric stricture following zinc chloride ingestion. Singapore Med J 1986; 27: 163-6. Chobanian SJ. Accidental ingestion of liquid zinc chloride: local and systemic effects. Ann Emerg Med 1981; 10: 91-3. Malo J-L, Malo J, Cartier A, Dolovich J. Acute lung reaction due to zinc inhalation. Eur Respir J 1990; 3: 111-4. McKinney PE, Brent J, Kulig K. Acute zinc chloride ingestion in a child: local and systemic effects. Ann Emerg Med 1994; 23:1383-7. Murphy JV. Intoxication following ingestion of elemental zinc. JAMA 1970; 212: 2119-20. Potter JL. Acute zinc chloride ingestion in a young child. Ann Emerg Med 1981; 10: 267-9. Tasic V, Gordova A, Delidzhakova M, Kozhinkova N. Zinc toxicity. Pediatrics 1982; 70: 661. Substance name Zinc Origin of substance Widely distributed in small amounts in igneous rocks. It does not occur free in nature but in ores. (CSDS, 1992) Synonyms Pigment black 16 Blue Powder Rheinzink Emanay zinc dust Granular zinc Jasad Merrillite Pasco Zinc powder Zinc dust (CSDS, 1992) Chemical group A group 2B element Reference numbers CAS 7440-66-6 (CSDS, 1992) RTECS ZG8600000 (RTECS, 1996) UN 1436 (powder or dust) (CSDS, 1992) HAZCHEM CODE NIF Physicochemical properties Chemical structure Zinc, Zn (DOSE, 1994) Molecular weight 65.37 (DOSE, 1994) Physical state at room temperature Solid Colour Bluish white (CSDS, 1992) Odour NIF Viscosity NA pH NA Solubility Insoluble in hot or cold water. Soluble in acetic acid and alkalis. (CSDS, 1992; HSDB, 1996) Autoignition temperature NA Chemical interactions Zinc will react explosively with ammonium sulphide, 2-nitroanisole and sodium hydroxide or peroxyformic acid. Powdered zinc reacts explosively with fused ammonium nitrate below 200°C or chlorinated rubber at 216°C. A mixture of zinc filings and arsenic trioxide will explode. Finely divided zinc reacts explosively with potassium chlorate; and on warming with hydroxylamine. Zinc foil reacts explosively with anhydrous manganese dichloride when heated. Zinc dust will ignite in contact with liquid seleninyl bromide, sodium hydroxide, chlorine trifluoride, bromine pentafluoride, ammonium nitrate, or mixed ammonium nitrate and ammonium chloride (when moistened). Zinc foil ignites in cold chlorine in the presence of moisture. Flash ignition will occur if a drop of water is added to a powdered zinc and iodine mixture. Silver-zinc batteries may combust spontaneously. Zinc powder will react incandescently with carbon disulphide, fluorine, potassium dioxide, titanium dioxide, arsenic, selenium or tellurium (on heating), nitryl fluoride (on mild warming). Molten zinc (419°C) mixed with concentrated nitric acid will produce an incandescent reaction. Zinc powder and zinc peroxide when mixed will burn brilliantly. Zinc reacts violently with hexachloroethane in ethanol; ethyl acetoacetate and tris(bromomethyl) ethanol, or sulphur. Rapid autocatalytic dissolution of zinc in 9:1 methanol-carbon tetrachloride may be hazardous. (CSDS, 1992) Major products of combustion Upon burning, melting or heating zinc to temperatures above 500°C, zinc metal oxide fume of particle diameter less than one micron is formed. (HSDB, 1996) Explosive limits Zinc dust forms explosive mixtures with air. (HSDB, 1996) Flammability Flammable/combustible material - may be ignited by heat, sparks or flames. Bulk dust in a damp state may heat spontaneously and ignite on exposure to air. In the compact form it does not burn readily until it is heated above 500°C. (HSDB, 1996) Boiling point 908°C (CSDS, 1992) Density 7.14 at 20°C (CSDS, 1992) Vapour pressure 133.3 Pa at 487°C (CSDS, 1992) Relative vapour density NA Flash Point NA Reactivity In contact with atmospheric oxygen and water, zinc dust may become incandescent. Hydrogen may be produced, especially under acid or alkaline conditions. Zinc dust explosions have occurred, demonstrating the need for precautions including total enclosure and use of cold zinc. (CSDS, 1992) Uses Zinc is used to galvanize iron and steel, for electroplating, in soldering fluxes, and in the manufacture of alloys (with copper, aluminium and magnesium). Zinc-based alloys are used for die-casting, gravity casting and wrought applications. Zinc is a component of brass, battery casings, dyes and paints, fungicides and disinfectants. Zinc is used in chemistry as a reducing agent and an analytical reagent, for deoxidizing bronze, extracting gold and in the manufacture of sodium hydrosulphite and insulin zinc salts. (CSDS, 1992) Hazard/risk classification Index no. 030-001-00-1 Risk phrases F; R15-17 - Highly flammable; Contact with water liberates extremely flammable gases. Spontaneously flammable in air. Safety phrases S(2-) 7/8 - 43 - Keep out of reach of children. Keep container tightly closed and dry. In case of fire, use a class D extinguisher. EEC No: 231-175-3 (CSDS, 1992; CHIP2, 1994) INTRODUCTION Zinc is an essential trace element required for the function of over 200 metallo-enzymes, including alkaline phosphatase and carbonic anhydrase. Zinc also plays a critical role in the regulation of DNA and RNA synthesis (via interaction with DNA binding proteins), in hormone-receptor interactions and in the 'second-messenger' system of cellular signal transduction (Walsh et al, 1994). Oral zinc salts have been advocated in the treatment of acne vulgaris (Michaėlsson et al, 1977), venous leg ulcers (Hallböök and Lanner, 1972), Wilson's disease (Brewer et al, 1994; Gill et al, 1994; Hoogenraad, 1995), leprosy (Mahajan et al, 1994) and in the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal damage (Rodrķguez de la Serna and Dķaz-Rubio, 1994). Eye drops containing zinc sulphate (0.25 per cent) are prescribed in the treatment of excessive lacrimation. EPIDEMIOLOGY In human toxicology the most important zinc salts are zinc chloride, zinc oxide and zinc sulphate (the toxicity of zinc phosphide is due primarily to the release of phosphine). Zinc oxide fumes are emitted in any process involving molten zinc and are the most common cause of metal fume fever. Exposure to zinc chloride occurs in soldering, in the manufacture of dyes, paper and deodorants and on military exercises when it is used as a smoke screen. Accidental or deliberate ingestion of elemental zinc or zinc salts has resulted in poisoning (Murphy, 1970; Burkhart et al, 1990) and fatal intoxication has followed inadvertent intravenous administration (Brocks et al, 1977). MECHANISM OF TOXICITY Excess zinc has been shown to reduce serum free thiol groups and disrupt hepatic enzyme activities (IPCS, 1996). TOXICOKINETICS Absorption Zinc exposure occurs primarily via inhalation and ingestion. Gastrointestinal zinc absorption is a function of intestinal mucosal cell metallothionein which sequesters zinc within enterocytes prior to active transport into plasma (Walsh et al, 1994). Zinc absorption is affected by diet with, for example, less than 15 per cent of dietary zinc absorbed from a high phytate diet compared to 40 per cent from a diet with a high animal protein content (Sandstrom, 1995). Zinc may be absorbed through broken skin when zinc oxide paste is used to treat wounds and burns (Hallmans, 1977). Distribution Intravascular zinc is bound to albumin (approximately 80 per cent) and other proteins (such as 2-macroglobulin) for distribution to tissues while excess zinc is stored as a metallothionein complex, mainly in the liver (Abdel-Mageed and Oehme, 1990; IPCS, 1996). Appreciable amounts of zinc are found also in the kidney, lung, spleen and brain (IPCS, 1996). Excretion Most ingested zinc is eliminated in faeces via bile, pancreatic fluid and intestinal mucosal cells, with up to ten per cent appearing in urine (Abdel-Mageed and Oehme, 1990). Zinc is also eliminated in sweat. The kidneys do not play an important role in regulating total body zinc (IPCS, 1996). The whole-body zinc half-life is some 5-16 months (IPCS, 1996). Zinc freely crosses the placenta and is found in breast milk. CLINICAL FEATURES: ACUTE EXPOSURE Elemental zinc Ingestion A 16 year-old developed lethargy, light-headedness and a staggering gait some three days after ingesting 12 g elemental zinc in an attempt to promote healing of a minor laceration. He was treated with intramuscular dimercaprol (days 8-15) and recovered without sequelae (Murphy, 1970). Injection A patient undergoing haemodialysis with zinc-contaminated water from a galvanized tank developed nausea and vomiting in association with a plasma zinc concentration of 7 mg/L (normal range 0.6-1.1 mg/L) and a red cell zinc concentration of 35 mg/L (normal range 10-14 mg/L). At the time of presentation the patient's haemoglobin concentration was 3.5 g/dL (Gallery et al, 1972). Zinc Oxide Dermal exposure Zinc oxide dust may obstruct the ducts of sebaceous glands giving rise to a pustular eczema (Stokinger, 1981). Inhalation Pulmonary toxicity Inhalation of zinc oxide fumes causes a dose-dependent inflammatory response in the lung and is the most common cause of "metal fume fever". Symptoms may occur up to 24 hours after fume exposure and resemble an influenza-like illness with cough, dyspnoea, sore throat and chest tightness in association with headache, fever, rigors, sweating, joint pains, sometimes a metallic taste, nausea, vomiting and blurred vision (Rohrs, 1957; Papp, 1968; Anseline, 1972; Farrell, 1987; Noel and Ruthman, 1988; Nemery, 1990). There may be transient chest X-ray changes (usually ill-defined opacities) (Langham Brown, 1988; Malo et al, 1990), increased blood lactate dehydrogenase activity (pulmonary isoenzyme) (Anseline, 1972) and an elevated serum zinc concentration (Noel and Ruthman, 1988) during the acute illness. The prognosis is usually excellent with complete recovery if exposure ceases although there are occasional reports of on-going symptoms and signs of airways obstruction in individuals with no previous history of asthma (Langley, 1991). Symptoms of metal fume fever may improve towards the end of the working week (possibly due to the development of short-term immunity) but reappear after the weekend giving rise to the term 'Monday morning fever'. Studies of zinc oxide inhalation in volunteers have shown a dose dependent reversible increase in the neutrophil count of bronchoalveolar lavage fluid (Blanc et al, 1991) and a reversible restrictive pulmonary function defect accompanying the typical features of metal fume fever (Vogelmeier et al, 1987). Gastrointestinal toxicity The respiratory symptoms of "metal fume fever" are often accompanied by a metallic taste, nausea and vomiting (see above). Cardiovascular toxicity Myocardial injury with an abnormal ECG (sinus bradycardia and ST elevation) and increased creatine kinase activity (Shusterman and Neal, 1986) have been described following inhalation of zinc oxide fumes. A 34 year-old zinc welder developed metal fume fever, urticaria and angioedema of the face, lips and throat after six months zinc oxide exposure. He required parenteral adrenaline and fully recovered although his symptoms recurred upon re-exposure necessitating relocation to office work. Total serum IgE was slightly raised to 106 U/mL (normal <100 U/mL) (Farrell, 1987). Zinc chloride Ocular exposure Zinc chloride is highly irritant to the eyes causing pain and redness which may be complicated by corneal oedema and ulceration, iritis, glaucoma and cataract formation. Discrete grey spots on the lens ("glaukomflecken") as typically seen in acute glaucoma also have been described (Grant and Schuman, 1993). Dermal exposure Topical exposure to zinc chloride causes ulceration (Beliles, 1994) and burns (Chew et al, 1986). Contact dermatitis also has been described (Poisindex, 1996). Inhalation Pulmonary toxicity Exposure to zinc chloride fumes occurs primarily from smoke screen generators or smoke bombs when equal quantities of zinc oxide and hexachloroethane are burnt together. Following detonation of a smoke bomb participants in an airport disaster drill experienced cough, sore throat, hoarseness and chest pain in association with gastrointestinal upset (Schenker et al, 1981). Most symptoms resolved within 48 hours and none experienced permanent injury. In contrast, exposure to high zinc chloride concentrations produces a chemical pneumonitis with productive cough, dyspnoea, fever, chest pain and cyanosis (Allen et al, 1992). The development of emphysematous bullae (which may be complicated by pneumothorax) has been reported (Matarese and Matthews, 1986). The most severe cases develop non-cardiogenic pulmonary oedema (the adult respiratory distress syndrome) (Evans, 1945; Hjorts et al, 1988) sometimes after several days of apparent clinical stability (Homma et al, 1992). Autopsy findings include diffuse pulmonary microvascular obliteration with widespread pulmonary artery occlusion (Hjorts et al, 1988; Homma et al, 1992) and interstitial fibrosis (Milliken et al, 1963; Hjorts et al, 1988; Homma et al, 1992). Gastrointestinal toxicity A metallic taste, nausea and vomiting have been reported following inhalation of zinc chloride from a smoke bomb (Schenker et al, 1981). Ingestion Gastrointestinal toxicity Substantial zinc chloride ingestion causes erosive pharyngitis, oesophagitis and haematemesis which may be complicated by pancreatitis (Chobanian, 1981; Potter, 1981). A 26 year-old woman who ingested 10 mL of a correction fluid containing zinc chloride (35 per cent) and methanol (0.5 per cent) presented four hours post ingestion with oropharyngeal and gastric burns, epigastric tenderness, dysphagia and diarrhoea. Examination revealed gross oral mucosal and pharyngeal oedema with surgical emphysema of the neck and upper chest wall (presumably due to pharyngeal perforation). Serum zinc on the third hospital day was normal (900 µg/L). The patient subsequently experienced haematemesis and malaena necessitating multiple blood transfusions. Recovery was delayed further by formation of a gastric stricture requiring subtotal gastrectomy (Chew et al, 1986). Hedtke et al (1989) reported a 13 month-old child who ingested 9300 mg of a moss killer containing zinc chloride 68 per cent. He presented with vomiting with clinical evidence of gastric mucosal erosions, hyperglycaemia and increased alkaline phosphatase and amylase activities. The peak serum zinc concentration was 14.2 mg/L (normal range 0.68 - 1.36 mg/L) one hour post ingestion. A 16 month-old child who ingested approximately one tablespoon of soldering flux liquid (containing zinc chloride 22.5 per cent and ammonium chloride 5.5 per cent, pH 2) immediately vomited then developed dysphagia with inability to swallow his own saliva (McKinney et al, 1994). Severe gastrointestinal corrosive effects ensued (oropharyngeal, oesophageal and gastric burns). Severe gastric scarring and outlet obstruction necessitated a gastric antrectomy. The peak plasma zinc concentration was 12 mg/L (normal range 0.6 - 1.0 mg/L) 14 hours post ingestion (McKinney et al, 1994). Five months later pancreatic exocrine insufficiency was diagnosed with an on-going requirement for pancreatic enzyme supplements (McKinney et al, 1995). Pulmonary toxicity An asthmatic patient who ingested correction fluid developed an acute episode of bronchospasm and severe oropharyngeal and laryngeal inflammation leading to stridor and dysphonia (Chew et al, 1986). She eventually recovered. A child who immediately started coughing after ingesting a tablespoon of soldering flux (see above) was noted 20 minutes later to have widespread coarse breath sounds and wheezes in addition to features of severe gastrointestinal toxicity. A chest X-ray some five hours later revealed a right pleural effusion with basal atelectasis. The pulmonary features resolved with supportive care although the child had ongoing gastrointestinal problems (McKinney et al, 1994). Nephrotoxicity Microscopic haematuria without associated renal failure (Chobanian, 1981; Chew et al, 1986) and mild albuminuria (Chew et al, 1986) have occurred following zinc chloride ingestion. Neurotoxicity Within 20 minutes of ingesting one tablespoon of solder flux (containing zinc chloride 22.5 per cent and ammonium chloride 5.5 per cent, pH 2) a 16 month-old became comatose and later developed agitation and lethargy which persisted for several days (McKinney et al, 1994). Similar features of somnolence and lethargy occurred in a 13 month-old child following zinc chloride ingestion (Hedtke et al, 1989). Cardiovascular toxicity Premature atrial beats were reported in a 13 month-old child following the supposed ingestion of 9.3 g moss killer containing 68 per cent zinc chloride (Hedtke et al, 1989). Significant hypertension (figure not given) requiring intravenous therapy developed as a late complication in the 16 month-old child described by McKinney et al (1994). This resolved within 24 hours. Hepatotoxicity Severe gastrointestinal corrosive effects following zinc chloride ingestion have been associated with transiently increased liver enzyme activities (McKinney et al, 1994). Haemotoxicity Gastrointestinal ulceration and burns following zinc chloride ingestion may precipitate an acute fall in the haemoglobin concentration. Intravascular haemolysis may occur in severely poisoned patients (McKinney et al, 1994). Zinc sulphate Ocular exposure Eye injury following excessive zinc sulphate exposure is rare though historically the use of 20 per cent zinc sulphate solutions in the treatment of dendritic keratitis led to the formation of white flecks on the lens ("glaukomflecken") (Grant and Schuman, 1993). Ingestion Gastrointestinal toxicity Zinc sulphate is a gastrointestinal irritant. Brennan (1855) reported a young man who developed severe diarrhoea, vomiting and abdominal pain but fully recovered after ingesting 112 g zinc sulphate. A 16 year-old boy vomited several times but developed no other signs after ingesting 2.5 g (Burkhart et al, 1990). Mackintosh (1900) reported a fatal (not quantified) zinc sulphate ingestion. Necropsy showed intense haemorrhagic gastrointestinal inflammation. Another patient suffered acute gastrointestinal haemorrhage requiring an eight unit blood transfusion after taking 440 mg zinc sulphate daily for one week (Moore, 1978). Neurotoxicity A premature infant with zinc deficiency was inadvertently given excess zinc sulphate supplements (route not stated) and developed transient irritability, tremor and seizures with a serum zinc concentration of 2.2 mg/L (normal range 0.8 - 1.3 mg/L) (Tasic et al, 1982). Zinc poisoning with gastrointestinal symptoms accompanied by headache and dizziness has occurred from acidic foods stored in zinc-galvanized containers, with subsequent formation of soluble zinc salts, including zinc sulphate (Brown et al, 1964; Lapham et al, 1983). Injection Gastrointestinal toxicity Acute-on-chronic zinc intoxication occurred in seven patients receiving total parenteral nutrition solutions which accidentally contained zinc sulphate 100 mg/L (Faintuch et al, 1978). Six patients developed increased amylase activities (peak activities 557-1850 Klein units; normal range 130-310) (Faintuch et al, 1978). Another patient who received excess zinc sulphate (7.4 g) in error over 60 hours as part of a parenteral nutrition regime (Brocks et al, 1977) died on the 47th day following a clinical course complicated by acute gastroenteritis and increased amylase activity. The peak serum zinc concentration was 41.8 mg/L. Haemotoxicity Following intravenous administration of 7.4 g zinc sulphate, a 72 year-old woman developed anaemia and thrombocytopenia (Brocks et al, 1977). Hepatotoxicity Cholestatic jaundice was observed in a patient who was inadvertently administered 7.4 g zinc sulphate intravenously (Brocks et al, 1977). Nephrotoxicity A 72 year-old woman developed oliguria immediately following the inadvertent administration of 7.4 g zinc sulphate via parenteral nutrition. She remained oliguric despite therapy with frusemide and intravenous fluids, and haemodialysis was instituted when the blood urea concentration was 61 mmol/L. At autopsy acute tubular necrosis was present (Brocks et al, 1977). Cardiovascular toxicity Hypotension, pulmonary oedema and cardiac arrhythmias (not specified) were reported in a 72 year-old woman some 60 hours following intravenous administration of 7.4 g zinc sulphate (Brocks et al, 1977). She also developed multi-organ failure and sepsis. CLINICAL FEATURES: CHRONIC EXPOSURE Elemental zinc Ingestion A paranoid schizophrenic with a 12-year history of habitual coin ingestion presented with nausea, vomiting and abdominal pain (Broun et al, 1990). Investigations revealed haematological abnormalities (see below), a raised serum zinc concentration (3.0 mg/L) and a serum copper concentration of 0.2 mg/L. He made a full physical recovery after surgical removal of $22.50. Haemotoxicity Sideroblastic anaemia and evidence of bone marrow suppression in addition to gastrointestinal upset were reported in a patient with a history of coin ingestion (Broun et al, 1990). Iron deficiency anaemia occurred in three children who chewed metal toys containing a zinc alloy. Removal from exposure followed by conventional iron therapy led to resolution of their symptoms (IPCS, 1996). Zinc oxide Inhalation Pulmonary toxicity A 32 year-old man developed exertional dyspnoea, chest pain, persistent nasal congestion and cough after three months exposure to a mixture of zinc oxide, ozone and the oxides of nitrogen whilst welding in a poorly ventilated room (Glass et al, 1994). Lung function tests showed a restrictive defect which did not improve when exposure ceased. Gastrointestinal toxicity Gastrointestinal disturbance with abdominal pain, nausea, anorexia, weakness and peptic ulceration has been reported in workers exposed to zinc oxide for several years (McCord et al, 1926; Hamdi, 1969; Stokinger, 1981). Hepatotoxicity Abnormal liver enzyme activities have been reported in conjunction with gastrointestinal disturbance following chronic occupational zinc oxide exposure (Stokinger, 1981). Zinc chloride Dermal exposure Gastrointestinal toxicity In an early report chronic topical zinc chloride exposure in the pillow manufacturing industry was claimed to result in anorexia and weight loss (du Bray, 1937). Musculoskeletal toxicity The patient described by du Bray (1937) with presumed transcutaneous zinc chloride absorption also complained of fatigue and leg pains. Inhalation Occupational asthma associated with raised serum IgE concentrations occurred in two men after several months working with soldering fluxes containing zinc chloride and ammonium chloride (Weir et al, 1989) although in one patient there was no reduction in FEV1 after exposure to zinc chloride alone. Zinc sulphate Dermal exposure Skin sensitization to zinc sulphate has been reported rarely (BIBRA Working Group, 1989a). Ingestion Haemotoxicity Chronic excess zinc sulphate ingestion may induce reversible anaemia and leukopenia secondary to a relative copper deficiency (Prasad et al, 1978; Patterson et al, 1985; Simon et al, 1988). The mechanism is probably zinc-induced intestinal metallothionein synthesis with increased metallothionein-copper binding and reduced copper bioavailability via sequestration in the intestinal mucosa. Ramadurai et al (1993) reported a 36 year-old lady who presented with sideroblastic anaemia and neutropenia having taken 600 mg zinc sulphate daily for three years as a health food supplement. On admission the serum zinc and copper concentrations were 2.2 mg/L (normal range 0.6-1.3 mg/L) and 44 mg/L (normal range 70-155 mg/L) respectively but these concentrations and the haematological abnormalities returned to normal within four months of zinc supplement withdrawal. Similar clinical pictures were observed in two patients prescribed 660 mg zinc sulphate daily in the treatment of intractable coeliac disease (Porter et al, 1977) and apthous ulcers (Hoffman et al, 1988). Chronic excess zinc supplementation has been associated also with adverse effects on the lipid profile (Hooper et al, 1980). This might be a further effect of deranged copper metabolism (Fosmire, 1990). There is also evidence that excessive zinc intake impairs the immunological response (Chandra, 1984). Other zinc salts Ingestion Sucking zinc gluconate tablets has caused buccal irritation and taste disturbance (Eby et al, 1984). Inhalation The inhalation of talcum powder containing zinc stearate has resulted rarely in death from pulmonary toxicity (BIBRA Working Group, 1989b). MANAGEMENT Ocular exposure Irrigate with copious amounts of lukewarm water. A topical anaesthetic may be required and an ophthalmologic opinion may be necessary. Dermal exposure Decontaminate with soap and water. Treat burns conventionally. Inhalation Symptomatic and supportive measures remain the priority in the management of zinc salt inhalation. Symptomatic patients and those with abnormal respiratory signs should have a chest X-ray, receive supplemental oxygen and bronchodilators if necessary and be observed until symptoms resolve. The possibility of delayed-onset pulmonary oedema and the development of ARDS must be considered if zinc chloride (or zinc phosphide) has been inhaled. In these circumstances high flow oxygen is mandatory but the value of systemic corticosteriods has not been confirmed. Ingestion Supportive measures are the mainstay of management. It is reasonable, though of unproven benefit, to attempt dilution by the oral administration of milk or water. Careful endoscopic examination may be required. Burkhart et al (1990) advocated whole-bowel irrigation as an effective gut decontamination method following zinc sulphate ingestion but there are no controlled data to support this view. Antidotes Animal studies Animal studies suggest that DTPA (trisodium calcium diethylenetriamine-pentaacetate), CDTA (disodium calcium cyclohexanediaminetetraacetate) and sodium calcium edetate are the most effective zinc chelators (Domingo et al, 1988; Llobet et al, 1988; Llobet et al, 1989); DMSA and DMPS were less impressive (Llobet et al, 1988). As discussed below isolated case reports claim chelation therapy is effective in zinc poisoning but there are no controlled data to support this view. Clinical studies Dimercaprol A 16 year-old who ingested 12 g elemental zinc was treated some nine days later with intramuscular dimercaprol 2.3-9.2 mg/kg daily. Chelation was associated with clinical improvement and a reduction in the blood zinc concentration but urine zinc concentrations were not measured (Murphy, 1970). McKinney et al (1994) reported improved mental status and resolution of hypertension in a patient with severe zinc chloride poisoning (by ingestion) following administration of intramuscular dimercaprol 12 mg/kg/day for 24 hours and intravenous sodium calcium edetate 1 g/m2 for five days. This treatment was instituted 74 hours post ingestion. Chelation therapy was not associated with increased urine zinc elimination. Sodium calcium edetate A 24 year-old man who developed erosive pharyngitis and oesophagitis, hyperamylasaemia, microscopic haematuria and a serum zinc concentration increased to 1.46 mg/L (normal range 0.5-0.9 mg/L) after ingesting liquid zinc chloride, made an uneventful recovery following supportive care and intravenous sodium calcium edetate 45 mg/kg in divided doses over 36 hours. No zinc excretion data were given (Chobanian, 1981). Potter (1981) utilized intravenous sodium calcium edetate 150 mg in the successful management of a 28 month-old child who had ingested a zinc chloride solution but again no urine zinc excretion data were given. The patient reported by McKinney et al (1994) who was severely poisoned after ingesting one tablespoon of a zinc chloride-containing soldering flux was treated with intravenous sodium calcium edetate 1 g/m2 for five days. The urine zinc excretion in the eight hours preceding chelation was 950 µg. Urine zinc excretion was not increased by sodium calcium edetate with only 1000 µg/24 h removed on the fourth day of treatment. N-acetylcysteine Hjorts et al (1988) administered intravenous (140 mg/kg/day for three days) and nebulized (100 mg qds for 13 days) N-acetylcysteine between days 19 and 32 to a patient with severe inhalational zinc chloride poisoning. N-acetylcysteine therapy was initially associated with an increased urine zinc excretion but the patient died in respiratory and renal failure on day 32. d-Penicillamine Another patient with zinc chloride poisoning by inhalation survived following treatment with oral penicillamine 125 mg twice daily (Allen et al, 1992). No blood or urine zinc concentrations were measured. Antidotes: Conclusion and recommendations 1. There are no controlled clinical data of chelation therapy in zinc poisoning. However, animal studies suggest that of the readily available antidotes sodium calcium edetate is the preferred agent. 2. Although case reports claim clinical benefit following parenteral administration of dimercaprol, sodium calcium edetate and d-penicillamine, urine zinc excretion data to support these claims are lacking. 3. Chelation therapy cannot be advocated routinely in the management of zinc poisoning; symptomatic cases should be discussed with NPIS staff. MEDICAL SURVEILLANCE Occupational monitoring of workplace air zinc oxide concentrations is important in the prevention of metal fume fever, although recent studies have reported fever, chills, sore throat, chest tightness and headache following only two hours exposure to 5 mg/m3 zinc oxide (Gordon et al, 1992). Serum zinc concentrations are increased in acute zinc poisoning. Plasma and serum zinc concentrations are similar (normal range approximately 1.1-1.3 mg/L) while whole blood zinc concentrations are higher (normal range approximately 6.8-10.8 mg/L) (IPCS, 1996). The 24 hour urine zinc excretion is useful when monitoring chronic exposure. OCCUPATIONAL DATA Occupational exposure standard Zinc chloride, fume: Long-term exposure limit (8 hour TWA reference period) 1 mg/m3. Zinc distearate, total inhalable dust: Long-term exposure limit (8 hour TWA reference period) 10 mg/m3 (respirable dust 5 mg/m3). Zinc oxide, fume: Long-term exposure limit (8 hour TWA reference period) 5 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity There is no conclusive evidence that elemental zinc is a human carcinogen (Léonard and Gerber, 1989). A high incidence of pulmonary carcinoma has been demonstrated in experimental zinc oxide/hexachloroethane smoke poisoning (Marrs et al, 1988), though several potential carcinogens (including hexachloroethane and carbon tetrachloride) are generated in these circumstances. A recent in vitro and in vivo study failed to show a significant genotoxic effect of zinc oxide/hexachloroethane smoke and the authors concluded it was "not .... a major health hazard" (Anderson et al, 1996). Reprotoxicity Evaluation of the role of zinc in reproduction is complex. A relationship between high amniotic fluid or maternal serum zinc concentrations and foetal neural tube defects has been proposed, but evidence for this is inconsistent. Pre-eclampsia, abnormal deliveries, anencephaly, and an increased incidence of stillbirths have been associated with low maternal serum zinc concentrations. Zinc deficiency also has been associated with delayed sexual maturity. Low seminal fluid zinc concentrations have been implicated in male infertility but the use of zinc supplements to treat this condition remains controversial. Zinc freely crosses the placenta and is found in breast milk (Reprotext, 1996; Reprotox, 1996). Genotoxicity Salmonella typhimurium TA98, TA102, TA1535, TA1527 with and without metabolic activation negative. In vivo mouse bone marrow and lymphocytes: Micronucleus assay positive. Maize root meristem: 2-10 fold increase in zinc concentration decreased mitosis and increased chromosomal aberrations (DOSE, 1994). Fish toxicity LC50 (96 hr) brown trout <0.14 mg/L in soft water at pH 8, 3.20 mg/L in hard water at pH 5 (DOSE, 1994). EC Directive on Drinking Water Quality 80/778/EEC Guide level 100 µg/L at supply works, 5000 µg/L after 12 hour contact with consumers' pipework (DOSE, 1994). WHO Guidelines for Drinking Water Quality No health-based guideline value has been proposed for zinc in drinking water (WHO, 1993). 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