UKPID MONOGRAPH ZINC OXIDE SM Bradberry BSc MB MRCP 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 OXIDE Toxbase summary Type of product Used in cosmetics, sunscreens, emollient and barrier creams, dental cements and ceramics. Toxicity Topical zinc oxide is relatively non toxic. Zinc oxide inhalation is an important cause of "metal fume fever". Features Topical - Zinc contact sensitivity has been described but zinc oxide is relatively non irritant. Ingestion - A metallic taste, nausea and vomiting have occurred following presumed mucociliary clearance (and swallowing) of inhaled zinc oxide particles. - Nausea, vomiting and abdominal pain have occurred following the consumption of food or drink stored in galvanized vessels. Zinc oxide contributes, in part, to this effect. 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 but there are typically no delayed sequelae. Management Dermal 1. Remove with soap and water. 2. Zinc contact sensitivity is best managed by removal from exposure. Ocular 1. Irrigate with copious lukewarm water or 0.9 per cent saline for at least ten minutes. 2. A topical anaesthetic may be required for pain relief and to overcome blepharospasm. 3. Ensure removal of particles lodged in the conjunctival recesses. 4. The instillation of fluorescein allows detection of corneal damage. 5. Seek ophthalmological advice if any significant abnormality is detected on examination and in those whose symptoms do not resolve rapidly. Ingestion 1. Symptomatic and supportive measures are all that are likely to be required. 2. Measurement of blood and urine zinc concentrations may be indicated following substantial exposure. 3. Check the full blood count and biochemical profile in symptomatic patients. 4. The value of chelation therapy following zinc ingestion has not been confirmed. Discuss with NPIS if patient is symptomatic. 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. Non-steroidal anti-inflammatory drugs are useful for control of pain and fever. 5. The onset of symptoms may be delayed for several hours following exposure but typically resolve within 24-48 hours. References Nemery B. Metal toxicity and the respiratory tract. Eur Respir J 1990; 3: 202-19. Noel NE, Ruthman JC. Elevated serum zinc levels in metal fume fever. Am J Emerg Med 1988; 6: 609-10. Substance name Zinc oxide Origin of substance Occurs as the mineral zincite. Prepared by vapourization of metallic zinc and oxidation of the vapours with preheated air (French process); also from franklinite (American process) or from zinc sulphide. (MERCK, 1996) Synonyms Amalox Azo - 33 Azodox - 55 Chinese White C. I. 77947 C. I. Pigment white 4 Emanay zinc oxide Flowers of zinc Green seal - 8 Hubbuck's white Ozide Permanent white Philosopher's wool Red - seal - 9 Snow white White - seal - 7 Zinc white (DOSE, 1994) Chemical group A compound of zinc, a group II B transition metal (d block) element. Reference numbers CAS 1314-13-2 (DOSE, 1994) RTECS ZH4810000 (RTECS, 1997) UN 2811 (HAZARDTEXT, 1997) HAZCHEM CODE NIF Physicochemical properties Chemical structure ZnO (DOSE, 1994) Molecular weight 81.37 (DOSE, 1994) Physical state at room temperature Solid (MERCK, 1996) Colour White or yellowish-white (MERCK, 1996) Odour Odourless (MERCK, 1996) Viscosity NA pH American process zinc oxide pH 6.95; French process zinc oxide pH 7.37. (MERCK, 1996) Solubility Water: 1.6 g/L at 28°C. Soluble in acetic acid, mineral acids, ammonia, ammonium carbonate, fixed alkali hydroxide solution. Insoluble in alcohol. (DOSE, 1994; HSDB, 1997) Autoignition temperature NIF Chemical interactions Slow addition of zinc oxide to cover the surface of linseed oil varnish resulted in heat generation and ignition. Reacts with hydrochloric acid to produce zinc chloride and with sulphuric acid to produce zinc sulphate. Zinc oxide reacts with hydrogen fluoride to produce zinc fluoride tetrahydrate. It reacts with carbon monoxide or hydrogen to produce elemental zinc. Upon heating with magnesium, zinc oxide is reduced explosively. Zinc oxide powder reacts violently with chlorinated rubber at 215°C. Reacts slowly with fatty acids in fats and oils to produce lumpy masses of zinc oleate and stearate. When mixed with a strong solution of zinc chloride or with phosphoric acid, zinc oxide forms a cement - like product, due to the formation of oxy-salts. (HSDB, 1997) Major products of combustion Fumes of zinc oxide. (SAX'S, 1996) Explosive limits NA Flammability NA Boiling point NIF Density 5.607 at 20°C/4°C (DOSE, 1994) Vapour pressure NIF Relative vapour density NIF Flash point NA Reactivity When heated to decomposition it emits toxic fumes of zinc oxide. (SAX'S, 1996) Uses Filler for plastics and rubbers. Emollients and barrier creams. Astringent. Cosmetics and sunscreens. Temporary dental filling. In dental cements and ceramics In single incendiary devices. As a pigment. (DOSE, 1994) Hazard/risk classification NIF 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). Zinc oxide is an important constituent of emollient skin preparations used in the treatment of eczema and other scaling disorders. It is a sparingly soluble salt with near neutral pH, properties which render it less toxic than zinc sulphate or zinc chloride. Most toxicological reports involving zinc oxide are of "metal fume fever" following occupational inhalation of zinc oxide dust and/or fume. In the production of smoke screens zinc oxide is burned with hexachloroethane to produce zinc chloride; the latter is responsible for most of the adverse effects of "artificial smoke" inhalation. EPIDEMIOLOGY Zinc oxide fumes are emitted in any process involving molten zinc and are the most common cause of "metal fume fever". In recent years improved environmental control measures have reduced significantly the incidence of this occupational hazard but cases are still cited in the toxicological literature (Langley, 1991). MECHANISM OF TOXICITY Excess body zinc interacts with free thiol groups on macromolecules, so blocking the active sites of enzymes, co-enzymes and membrane receptors. Zinc contributes to normal immunological function and excess zinc (300 mg daily for six weeks to 11 volunteers) has been associated with impaired immune and inflammatory responses (Chandra, 1984). The precise pathogenesis of "metal fume fever" is poorly understood. In an experimental model Blanc et al (1991) demonstrated a dose-dependant increase in the polymorphonuclear leukocyte count in bronchoalveolar lavage fluid obtained 22 hours after exposure in nine welders. A later volunteer study (Kuschner et al, 1995) confirmed these findings and demonstrated a concomitant increase in bronchoalveolar lavage fluid proinflammatory cytokines triggered by zinc oxide inhalation. This supports an underlying immunological process which is likely since the clinical picture is similar to "farmer's lung" and other forms of extrinsic allergic alveolitis. TOXICOKINETICS Absorption Zinc oxide exposure occurs primarily via inhalation and dermal contact. Workers occupationally exposed to zinc fumes may have increased urine zinc concentrations (Hamdi, 1969) as evidence of systemic zinc uptake via the lungs. However, some inhaled zinc is undoubtedly swallowed (and absorbed via the gastrointestinal tract) following clearance via the mucociliary mechanism. Gastrointestinal zinc absorption is a function of a cysteine-rich intestinal protein (CRIP) which sequesters zinc within enterocytes prior to active transport into plasma (Hempe and Cousins, 1992; Walsh et al, 1994). Metallothionein contributes to zinc homeostasis at higher exposures, primarily via retaining excess zinc within mucosal cells which are subsequently shed into the intestinal lumen (Hempe and Cousins, 1992). Zinc absorption is affected by diet; it is inhibited by calcium, phosphorus and phytates and facilitated by dietary protein (Hunt et al, 1991). In one study less than 15 per cent of dietary zinc was absorbed from a high phytate diet compared to 40 per cent from a diet with a high animal protein content (Sandstrom, 1995). In ten healthy volunteers Nève et al (1991) observed a peak serum zinc concentration some 2-3 hours after ingestion of 45 mg zinc (as zinc sulphate). Zinc may be absorbed through broken (Hallmans, 1977) and intact (Ågren, 1990) skin when zinc oxide is used in medicated dressings. Distribution Most intravascular zinc is contained within erythrocytes. Plasma zinc is bound predominantly to albumin, the remainder bound to other proteins, particularly alpha2-macroglobulin, for distribution to tissues. Excess zinc is stored as a metallothionein complex, mainly in the liver (Abdel-Mageed and Oehme, 1990; IPCS, 1996). Some ninety per cent of total body zinc is in muscle and bone (Wastney et al, 1986). Appreciable amounts of zinc are found also in the kidney, lung, spleen and brain (IPCS, 1996). Zinc crosses the placenta slowly and is found in breast milk (Agency for Toxic Substances and Disease Registry, 1997). 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). CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure No adverse reactions were observed on the skin of 15 healthy volunteers following application of a 25 per cent w/w zinc oxide dressing for 48 hours (Ågren, 1990). Inhalation Pulmonary toxicity Occupational inhalation of zinc oxide fumes occurs during zinc welding, smelting and galvanizing, and causes a dose-dependent inflammatory response in the lung. It is the most common cause of "metal fume fever". Symptoms may occur up to 24 hours after fume exposure but more typically within the first few hours, and resemble an influenza-like illness with cough, dyspnoea, sore throat and chest tightness in association with headache, fever, rigors, sweating, arthralgia, 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 within one to four days if exposure ceases (Langham Brown, 1988) 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'. Tolerance to the inflammatory effects of inhaled zinc may explain, in part, the occurrence of symptoms at lower concentrations in volunteers compared to those occupationally exposed (Gordon et al, 1992). Several studies have attempted to estimate the zinc concentration associated with the symptoms and signs of "metal fume fever" but the results are difficult to interpret. Occupational exposure to 8-12 mg zinc/m3 for up to three hours (Hammond, 1944) or to a mean zinc concentration of 0.034 mg zinc/m3 for 6-8 hours (Marquart et al, 1989) produced no adverse effects. In another study no symptoms occurred following eight hours occupational exposure to 14 mg zinc/m3 or 20 minutes exposure in an experimental setting to 45 mg zinc/m3 (as zinc oxide) (Drinker et al, 1927a). By contrast, Gordon et al (1992) described at least one "classic" symptom of "metal fume fever" (fever, chills, dry or sore throat, chest tightness and headache) some four to eight hours after a two hour inhalation of 4 mg zinc/m3 (5 mg zinc oxide/m3) in each of four volunteers. These symptoms were not accompanied by lung function changes. Exposure for between one and three hours to 320-580 mg zinc/m3 as zinc oxide produced dyspnoea and chest pain some 2-12 hours later (Hammond, 1944). A single volunteer who was normally also exposed to zinc oxide occupationally developed chest discomfort on deep inspiration the day following exposure to 430 mg zinc/m3 for eight minutes (Drinker et al, 1927b). In another study inhalation for just 10-12 minutes of 600 mg zinc/m3 as zinc oxide caused upper airways irritation with cough, retrosternal chest pain and wheeze and a reduced vital capacity in two volunteers (Sturgis et al, 1927). These features were accompanied by fever, non-specific neurological complaints and mild gastrointestinal upset (see below). Symptoms resolved over 49 hours. Studies of zinc oxide inhalation have shown a dose dependent reversible increase in the neutrophil, lymphocyte and macrophage counts 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). Neurotoxicity Non-specific neurological effects such as headache and malaise are typical of "metal fume fever" (Sturgis et al, 1927). Gastrointestinal toxicity The respiratory symptoms of "metal fume fever" are often accompanied by a metallic or sweet taste, nausea and vomiting (Sturgis et al, 1927). Haemotoxicity A transient leucocytosis is typical of "metal fume fever" and resolves usually within 24-48 hours (Sturgis et al, 1927; Rohrs, 1957; Malo et al, 1990). Cardiovascular toxicity Myocardial injury with an abnormal ECG (sinus bradycardia and ST elevation) and increased creatine kinase activity have been described following zinc oxide fume inhalation (Shusterman and Neal, 1986). Ingestion Mucociliary clearance of inhaled zinc oxide particles inevitably occurs and contributes to the features of gastrointestinal toxicity described above. There are also occasional reports of nausea, vomiting and diarrhoea following ingestion of beverages stored in contact with galvanized metals (Callender and Gentzkow, 1937). In these cases zinc/zinc oxide contribute to toxicity as free zinc ions. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure In an early report repeated skin exposure among 17 employees at a zinc oxide manufacturing plant caused "zinc oxide pox" in 14 cases. The lesions appeared as pruritic, papular and pustular eruptions in areas subject to significant sweating and friction (pubic region, axillae, inner thigh and arms) (Turner, 1921). The authors concluded that dust-blocked sebaceous glands accumulated sebum which subsequently became infected. Ingestion It has been suggested that zinc oxide in dental cements may increase the incidence of non-invasive maxillary sinus aspergillosis if cement extrudes from the tooth root canal (Theaker et al, 1995). Zinc as a growth factor for Aspergillus species is one proposed mechanism for this effect although this has been disputed (Odell and Pertl, 1995a). A recent in vitro study found no evidence of enhanced Aspergillus growth by zinc (Odell and Pertl, 1995b). 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 In early reports gastrointestinal disturbance with abdominal pain, nausea, anorexia, weakness and peptic ulceration were reported in workers exposed to zinc oxide for several years (McCord et al, 1926; Hamdi, 1969). However, inadequate workplace health and safety conditions plus concomitant exposure to other chemicals (notably zinc chloride, zinc sulphate, other sulphates, sulphides, iron and aluminium oxides, chlorides and arsenicals) undoubtedly contributed to these problems. Hepatotoxicity In a review of zinc oxide toxicity Stokinger (1981) referred to the occurrence of abnormal liver enzyme activities in conjunction with gastrointestinal disturbance following chronic exposure, but there are no original case data in the English literature. Twelve workers exposed to zinc oxide fumes for 4-21 years during brass alloy production had normal liver profiles (Hamdi, 1969). Immunotoxicity A 34 year-old zinc welder developed "metal fume fever", urticaria and angioedema of the face, lips and throat after working with zinc oxide for six months. He required parenteral adrenaline and fully recovered although his symptoms recurred upon re-exposure necessitating relocation to office work. Total serum IgE was raised slightly to 106 U/mL (normal <100 U/mL) (Farrell, 1987). MANAGEMENT Dermal exposure Decontamination with soap and water is likely to be all that is required. Chronic skin contact should be avoided. Ocular exposure Irrigate with copious amounts of lukewarm water for at least ten minutes. A topical anaesthetic may be required for pain relief and to overcome blepharospasm. Ensure removal of any particles lodged in the conjunctival recesses. The instillation of fluorescein allows detection of corneal damage. Specialist ophthalmological advice should be sought if any significant abnormality is detected on examination and in those whose symptoms do not resolve rapidly. Inhalation Symptomatic and supportive measures are the priority in the management of "metal fume fever". Symptomatic patients and those with abnormal respiratory signs should have a chest X-ray, receive supplemental oxygen, bronchodilators and non-steroidal anti-inflammatory agents if necessary and be observed until symptoms resolve. Lung function tests should be performed if a persistent ventilatory defect is suspected. Ingestion Symptomatic and supportive measures are likely to be all that are required. Gastrointestinal decontamination procedures are unlikely to be necessary or useful. Antidotes Animal studies Domingo et al (1988) investigated the antidotal potential of DTPA (trisodium calcium diethylene triamine-pentaacetate), CDTA (cyclohexane diamine tetraacetate), d-penicillamine, sodium calciumedetate, DMSA (dimercapto-succinic acid) and the sodium salt of DMPS (dimercaptopropanesulphonate) on reducing mortality in rodents poisoned with intraperitoneal zinc acetate 66-330 mg/kg. This dose range was selected to span the previously calculated intraperitoneal LD50 (108 mg/kg) and LD99 (216 mg/kg) for this zinc salt. Chelation therapy (or 0.9 per cent saline as control) was administered intraperitoneally to ten mice ten minutes after dosing with zinc. Antidote doses and outcome (measured as survival at 14 days) are summarized in Table 1. Table 1. Survival (%) following parenteral chelation therapy in mice after a single zinc acetate injection (after Domingo et al, 1988) Chelating agent Antidote dose Zinc acetate dose (mg/kg) (mg/kg) 66 153 241 Control - 40 20 0 Na2CaCDTA 1360 100 90 90 Na2CaEDTA 1644 100 90 90 Na2CaDTPA 1569 100 100 100 d-Penicillamine 857 100 100 100 DMSA 619 80 30 10 DMPS 273 100 100 100 The very high antidote doses employed in this study necessitate caution in interpreting the results with regard to potential clinical value. Nevertheless at a zinc acetate dose in excess of the LD99 there was 100 per cent survival following treatment with DTPA, d-penicillamine and DMPS. DMSA was not an impressive antidote under these conditions. The same research group (Llobet et al, 1988) undertook a similar study. Intraperitoneal zinc acetate 0.49 mmol/kg (a dose approximately equivalent to its LD50) and 1.15 mmol/kg (approximately the LD99) was administered immediately before antidote administration to ten mice. Outcome was measured as survival ratio. Sodium calciumedetate (2152 mg/kg), DTPA (2262 mg/kg) and d-penicillamine (857 mg/kg), completely protected against mortality at the LD99 for zinc acetate. Under exactly the same conditions (each chelating agent at a dose of 5.75 mmol/kg) the survival ratios for CDTA, DMPS and DMSA were 80, 50 and 70 per cent respectively. Several antidotes have been investigated for their potential to enhance zinc elimination. Domingo et al (1988) measured 24 hour faecal and urinary zinc excretion in mice administered 88 mg/kg intraperitoneal zinc acetate followed ten minutes later by an intraperitoneal dose of chelating agent (or saline in the control group). The same chelating agents and doses were used as in Table 1, again with ten mice in each treatment group. In the control group urine zinc elimination was less than half faecal excretion. CDTA enhanced urine zinc excretion some six fold and DTPA, DMSA and DMPS each some four fold. d-Penicillamine enhanced 48 hour urine zinc elimination by some 80 per cent. Sodium calciumedetate did not enhance urine zinc excretion but was the only antidote to increase 24 hour faecal zinc elimination (by some 20 per cent). The effect of increasing the time delay between zinc dosing and DTPA or CDTA administration was investigated by Llobet et al (1989). Intraperitoneal zinc acetate 0.4 mmol/kg (LD50 0.49 mmol/kg) was followed 0-24 hours later by a single intraperitoneal dose of chelating agent to give a chelating agent: zinc acetate molar ratio of approximately 10:1. Urine and faecal zinc elimination were monitored for 48 hours with five mice in each treatment group. Urine and faecal zinc elimination were increased significantly (p < 0.05) by both chelating agents when administered up to two hours after poisoning but only DTPA significantly enhanced the 48 hour urine and faecal zinc excretion when the antidotes were given 12 hours after zinc dosing. When there was a 24 hour delay between zinc acetate injection and antidote administration, DTPA significantly (p < 0.05) enhanced urine but not faecal 48 hour zinc elimination (CDTA was not effective). In summary, animal studies suggest DTPA is the most effective zinc antidote as judged by improved survival (100 per cent following a zinc acetate dose in excess of the LD99) and increased zinc elimination. CDTA produced 90 per cent survival and increased urine zinc excretion some six fold. d-Penicillamine also gave excellent results in mortality studies, with 100 per cent survival following administration of zinc acetate at a dose exceeding the LD99. However, d-penicillamine did not enhance zinc elimination significantly. Sodium calciumedetate improved survival (90-100 per cent) and in one study (Domingo et al, 1988) was the only chelating agent to increase faecal zinc elimination. DMPS 273 mg/kg completely protected mice against the lethal effects of zinc acetate at a dose in excess of the LD99 and the same antidote dose enhanced urine zinc excretion some four fold following administration of 88 mg/kg zinc acetate. By contrast DMSA 619 mg/kg resulted in only 10 per cent survival following 241 mg/kg zinc acetate. Clinical studies Although increased renal zinc excretion has been noted during chelation therapy instituted to enhance elimination of other toxic heavy metals, there is no convincing evidence of benefit in human zinc poisoning. In health, most zinc is eliminated via the gastrointestinal tract with only a small contribution made by renal excretion. No data have been found regarding the effect of chelation therapy on biliary zinc excretion in man. Dimercaprol McKinney et al (1994) reported improved mental status 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 calciumedetate 1 g/m2 for five days. This treatment was instituted 74 hours post ingestion. Chelation therapy was not associated with increased urine zinc elimination. Intramuscular dimercaprol 4 mg/kg qds was instituted less than four hours after the ingestion of 3 g each of zinc sulphate and copper sulphate by an 86 year-old woman. This patient also received oral d-penicillamine (see below) but both antidotes were discontinued after 48 hours due to deteriorating renal function. The patient made a full recovery over 20 days. 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). Sodium calciumedetate A 24 year-old man who developed erosive pharyngitis and oesophagitis, hyperamylasaemia, microscopic haematuria and a serum zinc concentration of 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 calciumedetate 45 mg/kg in divided doses over 36 hours. No zinc excretion data were given (Chobanian, 1981). Potter (1981) utilized intravenous sodium calciumedetate 150 mg in the management of a 28 month-old child who had ingested a zinc chloride solution; 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 calciumedetate 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 calciumedetate with only 1000 µg/24 h removed on the fourth day of treatment (no interim data were given). N-acetylcysteine In response to a rising serum zinc concentration, a soldier who developed adult respiratory distress syndrome following two minutes inhalation of zinc chloride smoke was administered intravenous (140 mg/kg/day for three days) and nebulized (100 mg qds for 13 days) N-acetylcysteine between days 19 and 32 in an attempt to enhance zinc elimination. The urine zinc excretion increased from some 125 µmol/24h on day 20 to 260 µmol/24h on day 22 (coinciding with intravenous N-acetylcysteine administration) then rose to nearly 300 µmol/day (the maximum observed zinc excretion) on day 24. Unfortunately no pre-chelation zinc excretion measurements were made. There was no clinical improvement with therapy and the patient died in respiratory and renal failure on day 32. d-Penicillamine An 86 year-old woman who developed chemical pneumonitis, gastritis, cardiac and renal failure following the ingestion (and partial aspiration) of 3 g each of zinc and copper sulphate, received 250 mg oral d-penicillamine qds (in addition to intramuscular dimercaprol 4 mg/kg qds) commenced less than four hours after zinc ingestion (Hantson et al, 1996). Unfortunately there were no pre-chelation urine zinc excretion data and treatment was discontinued after 48 hours due to deteriorating renal function. The maximum 24 hour urine zinc excretion, achieved on the first day of chelation therapy was some 6000 µg. 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: Conclusions and recommendations 1. There are no controlled clinical data of chelation therapy in zinc poisoning and animal studies must be interpreted with caution in view of the extremely high antidote doses employed. Nevertheless, animal studies suggest that of the antidotes readily available for clinical use, sodium calciumedetate is the preferred agent with d-penicillamine or DMPS potential alternatives. 2. Although case reports claim clinical benefit following parenteral administration of dimercaprol, sodium calciumedetate and d-penicillamine, urine and/or faecal 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 the NPIS. AT RISK GROUPS Patients with haemochromatosis are at greater risk of zinc toxicity due to iron-induced increased metallothionein concentrations since metallothionein has a greater affinity for zinc than iron. 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). Attention to personal hygiene and appropriate protective equipment is important to prevent prolonged excess dermal contact. Serum zinc concentrations are increased in acute zinc poisoning. The 24 hour urine zinc excretion is useful when monitoring chronic exposure although there is no well established relationship between the extent of exposure and urine zinc concentration. Hair zinc concentrations are not useful (Agency for Toxic Substances and Disease Registry, 1997). Normal zinc concentrations in biological fluids Plasma and serum: 1.1-1.3 mg/L (IPCS, 1996). Whole blood: 6.8-10.8 mg/L (IPCS, 1996). 24 hour urine excretion: less than 500 µg (IPCS, 1996). OCCUPATIONAL DATA Occupational exposure standard 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 zinc is a human carcinogen (Léonard and Gerber, 1989) and the Environmental Protection Agency has concluded zinc is not classifiable in this regard (Agency for Toxic Substances and Disease Registry, 1997). 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 A Russian study (Voroshilin et al, 1978) reported significantly increased chromosomal aberrations in mice bone marrow following inhalational zinc oxide exposure. There is no evidence regarding the reprotoxicity of zinc oxide in humans (Reprotext, 1996) although other zinc salts have caused chromosomal damage when incubated with human lymphocytes from healthy men (Voroshilin et al, 1978) There were no adverse effects following the administration of oral zinc sulphide (providing 20 mg elemental zinc daily) to 494 women during the last two trimesters of pregnancy (Mahomed et al, 1989). 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 (Reprotext, 1996; Reprotox, 1996). There was no association between serum zinc concentrations and the incidence of neural tube defects in 82 affected pregnancies compared to 85 controls (Hambidge et al, 1993). 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 (Reprotext, 1996; Reprotox, 1996). Low seminal fluid zinc concentrations have been implicated in male infertility but the use of zinc supplements to treat this condition remains controversial (Reprotext, 1996; Reprotox, 1996). Genotoxicity In vitro Syrian hamster embryo cells, morphological transformations, unscheduled DNA synthesis and sister chromatid exchanges positive (DOSE, 1994). Fish toxicity (Zinc) 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 (Zinc) 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). AUTHORS SM Bradberry BSc MB MRCP 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 28/1/98 REFERENCES Abdel-Mageed AB, Oehme FW. A review of the biochemical roles, toxicity and interactions of zinc, copper and iron: I. Zinc. Vet Hum Toxicol 1990; 32: 34-9. Agency for Toxic Substances and Disease Registry (ATSDR). Zinc. In: ATSDR Toxicological Profiles. Atlanta: CRC Press, Inc., 1997. Agren MS. Percutaneous absorption of zinc from zinc oxide applied topically to intact skin in man. Dermatologica 1990; 180: 36-9. Allen MB, Crisp A, Snook N, Page RL. 'Smoke-bomb' pneumonitis. Respir Med 1992; 86: 165-6. Anderson D, Blowers SD, Marrs TC, Rice P. An in vitro and an in vivo unscheduled DNA synthesis assay with a zinc oxide/hexachloroethane (Zn/HCE) smoke. Hum Exp Toxicol 1996; 15: 38-44. Anseline P. Zinc-fume fever. Med J Aust 1972; 2: 316-8. Blanc P, Wong H, Bernstein MS, Boushey HA. An experimental human model of metal fume fever. Ann Intern Med 1991; 114: 930-6. Callender GR, Gentzkow CJ, Acute poisoning by the zinc and antimony content of limeade prepared in a galvanized iron can. Mil Surgeon 1937; 80: 67-71. Chandra RK. Excessive intake of zinc impairs immune responses. JAMA 1984; 252: 1443-6. Chobanian SJ. Accidental ingestion of liquid zinc chloride: local and systemic effects. Ann Emerg Med 1981; 10: 91-3. Domingo JL, Llobet JM, Paternain JL, Corbella J. Acute zinc intoxication: comparison of the antidotal efficacy of several chelating agents. Vet Hum Toxicol 1988; 30: 224-8. DOSE/Dictionary of substances and their effects. Vol 7. Cambridge: Royal Society of Chemistry, 1994. Drinker P, Thomson RM, Finn JL. Metal fume fever: IV. Threshold doses of zinc oxide, preventative measures, and the chronic effects of repeated exposures. J Ind Hyg 1927a; 9: 331-45. Drinker P, Thomson RM, Finn JL. Metal fume fever: II. Resistance acquired by inhalation of zinc oxide on two successive days. J Ind Hyg 1927b; 9: 98-105. Farrell FJ. Angioedema and urticaria as acute and late phase reactions to zinc fume exposure, with associated metal fume fever-like symptoms. Am J Ind Med 1987; 12: 331-7. Glass WI, Taylor DR, Donoghue AM. Chronic interstitial lung disease in a welder of galvanized steel. Occup Med 1994; 44: 158-60. Gordon T, Chen LC, Fine JM, Schlesinger RB, Su WY, Kimmel TA, Amdur MO. Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits. Am Ind Hyg Assoc J 1992; 53: 503-9. Hallmans G. Treatment of burns with zinc-tape. Scand J Plast Reconstr Surg Hand Surg 1977: 11: 155-61. Hambidge M, Hackshaw A, Wald N. Neural tube defects and serum zinc. Br J Obstet Gynaecol 1993; 100: 746-9. Hamdi EA. Chronic exposure to zinc of furnace operators in a brass foundry. Br J Ind Med 1969; 26: 126-34. Hammond JW. Metal fume fever in the crushed stone industry. J Ind Hyg Toxicol 1944; 26: 117-9. Hazardtext. In: Tomes plus. Environmental Health and Safety Series 1. Vol 33. Colorado: Micromedex, Inc., 1997. Health and Safety Executive. EH40/95. Occupational Exposure Limits 1995. Sudbury: Health and Safety Executive, 1995. Hempe JM, Cousins RJ. Cysteine-rich intestinal protein and intestinal metallothionein: An inverse relationship as a conceptual model for zinc absorption in rats. J Nutr 1992; 122: 89-95. Hjortsœ E, Qvist J, Bud MI, Thomsen JL, Andersen JB, Wiberg-Jœgensen F, Jensen NK, Jones R, Reid LM, Zapol WM. ARDS after accidental inhalation of zinc chloride smoke. Intensive Care Med 1988; 14: 17-24. HSDB/Hazardous Substances Data Bank. In: Tomes plus. Environmental Health and Safety Series I. Vol 31. National Library of Medicine, 1997. Hunt JR, Lykken GI, Mullen LK. Moderate and high amounts of protein from casein enhance human absorption of zinc from whole wheat or white rolls. Nutr Res 1991; 11: 413-8. IPCS/International Programme on Chemical Safety. IPCS Chemical information CD-Rom (Inchem). Geneva: IPCS/Canadian Centre for Occupational Health and Safety (CCOHS), 1996. Kuschner WG, D'Alessandro A, Wintermeyer SF, Wong H, Boushey HA, Blanc PD. Pulmonary responses to purified zinc oxide fume. J Invest Med 1995; 43: 371-8. Langham Brown JJ. Zinc fume fever. Br J Radiol 1988; 61: 327-9. Langley RL. Fume fever and reactive airways dysfunction syndrome in a welder. South Med J 1991; 84: 1034-6. Léonard A, Gerber GB. Zinc toxicity: does it exist? J Am Coll Toxicol 1989; 8: 1285-1290. Llobet JM, Domingo JL, Corbella J. Antidotes for zinc intoxication in mice. Arch Toxicol 1988; 61: 321-3. Llobet JM, Domingo JL, Corbella J. Comparison of the antidotal efficacy of polyamincarboxylic acids (CDTA and DTPA) with time after acute zinc poisoning. Vet Hum Toxicol 1989; 31: 25-8. Mahomed K, James DK, Golding J, McCabe R. Zinc supplementation during pregnancy: a double blind randomised controlled trial. Br Med J 1989; 299: 826-30. Malo J-L, Malo J, Cartier A, Dolovich J. Acute lung reaction due to zinc inhalation. Eur Respir J 1990; 3: 111-4. Marrs TC, Colgrave HF, Edginton JAG, Brown RFR, Cross NL. The repeated dose toxicity of a zinc oxide/hexachloroethane smoke. Arch Toxicol 1988; 62: 123-32. Marquart H, Smid T, Heederik D, Visschers M. Lung function of welders of zinc-coated mild steel: Cross-sectional analysis and changes over five consecutive work shifts. Am J Ind Med 1989; 16: 289-96. McCord CP, Friedlander A, Brown WE, Minster DK. An occupational disease among zinc workers. Arch Intern Med 1926; 37: 641-59. McKinney PE, Brent J, Kulig K. Acute zinc chloride ingestion in a child: local and systemic effects. Ann Emerg Med 1994; 23:1383-7. MERCK/The Merck Index. Zinc Oxide. In: Budavari S, ed. An encyclopedia of chemicals, drugs, and biologicals. 12th ed. New Jersey: Merck and Co., Inc., 1996; 1734-5. Murphy JV. Intoxication following ingestion of elemental zinc. JAMA 1970; 212: 2119-20. Nemery B. Metal toxicity and the respiratory tract. Eur Respir J 1990; 3: 202-19. Nève J, Hanocq M, Peretz A, Abi Khalil F, Pelen F, Famaey JP. Pharmacokinetic study of orally administered zinc in humans. Evidence for an enteral recirculation. Eur J Drug Metab Pharmacokinet 1991; 16: 315-23. Noel NE, Ruthman JC. Elevated serum zinc levels in metal fume fever. Am J Emerg Med 1988; 6: 609-10. Odell E, Pertl C. Chronic sinusitis. Br Dent J 1995a; 179: 327. Odell E, Pertl C. Zinc as a growth factor for Aspergillus sp. and the antifungal effects of root canal sealants. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995b; 79: 82-7. Papp JP. Metal fume fever. Postgrad Med 1968; 43: 160-3. Potter JL. Acute zinc chloride ingestion in a young child. Ann Emerg Med 1981; 10: 267-9. Reprotext. In: Tomes plus. Environmental Health and Safety Series I. Vol 31. Colorado: Micromedex, Inc., 1996. Reprotox. In: Tomes plus. Environmental Health and Safety Series I. Vol 31. Washington DC: Fabro S, Scialli AR. Reproductive Toxicology Center, Columbia Hospital for Women, 1996. Rohrs LC. Metal-fume fever from inhaling zinc oxide. AMA Arch Ind Health 1957; 16: 42-7. RTECS/Registry of Toxic Effects of Chemical Substances. In: Tomes plus. Environmental Health and Safety Series I. Vol 33. National Institute for Occupational Safety and Health (NIOSH), 1997. Sandstrom B. Consideration in estimates of requirements and critical intake of zinc. Adaption, availability and interactions. Analyst 1995; 120: 913-5. SAX'S/Lewis RJ. Sax's dangerous properties of industrial materials. 9th ed. Vol 3. New York: Van Nostrand Reinhold, 1996. Shusterman D, Neal E. Skeletal muscle and myocardial injury associated with metal fume fever. J Fam Pract 1986; 23: 159-60. Stokinger HE. The metals: Zinc. In: Clayton GD , Clayton FE, eds. Patty's industrial hygiene and toxicology. Vol 2a. 3rd ed. New York: John Wiley & Sons, Inc., 1981; 2033-49. Sturgis CC, Drinker P, Thomson RM. Metal fume fever: I. Clinical observations on the effect of the experimental inhalation of zinc oxide by two apparently normal persons. J Ind Hyg 1927; 9: 88-97. Theaker ED, Rushton VE, Corcoran JP, Hatton P. Chronic sinusitis and zinc-containing endodontic obturating pastes. Br Dent J 1995; 179: 64-8. Turner JA An occupational dermatoconiosis among zinc oxide workers. Public Health Rep 1921; 36: 2727-32. Vogelmeier C, Konig G, Bencze K, Fruhmann G. Pulmonary involvement in zinc fume fever. Chest 1987; 92: 946-8. Voroshilin SI, Plotko EG, Fink TV, Nikiforova VY. Cytogenetic action of inorganic compounds of tungsten, zinc, cadmium, and cobalt on human and animal somatic cells.] Cytol Genet 1978; 12: 46-8. Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ. Zinc: health effects and research priorities for the 1990s. Environ Health Perspect 1994; 102: 5-46. Wastney ME, Aamodt RL, Rumble WF, Henkin RI. Kinetic analysis of zinc metabolism and its regulation in normal humans. Am J Physiol 1986; 251: 398-408. WHO. Guidelines for drinking-water quality. 2nd ed. Vol 1. Recommendations. Geneva: World Health Organization, 1993.