UKPID MONOGRAPH ZINC SULPHATE 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 SULPHATE Toxbase summary Type of product Used in pigments, wood preservatives, catalysts, fertilizers, corrosion inhibitors and deodorants. Toxicity Zinc sulphate is a gastrointestinal irritant. An early report (Brennan, 1855) described recovery after ingesting 112 g although fatalities secondary to gastrointestinal haemorrhage could follow significantly smaller ingestions. A 72 year-old female died after the inadvertent intravenous administration of 7.4 g zinc sulphate (Brocks et al, 1977). Features Topical - Zinc sulphate is a skin and eye irritant. - Zinc contact sensitivity has been described. Inhalation - There are no reports of zinc sulphate inhalation although the salt would irritate the respiratory tract. Ingestion - Zinc sulphate ingestion causes gastrointestinal irritation. Headache and dizziness are also described. Features are generally less severe than following zinc chloride ingestion although fatalities have occurred (Mackintosh, 1900). - 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). Injection - Inadvertent excess zinc sulphate in a parenteral nutrition solution has been associated with nausea, vomiting, anaemia, thrombocytopenia and elevated amylase activity. Management Dermal 1. Decontaminate with soap and water. 2. Symptomatic and supportive measures should be dictated by the patient's condition. 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. Inhalation 1. Remove from exposure. 2. Institute symptomatic and supportive measures as dictated by the patient's condition. 3. See zinc oxide monograph for management of "metal fume fever". Ingestion Minor ingestions: 1. Patients with features of mild gastrointestinal upset require only supportive care. 2. Gastric lavage or other gut decontamination procedures are unnecessary. Substantial ingestions: 1. Most patients will vomit spontaneously. Gastric lavage or other gut decontamination procedures are not likely to improve outcome. 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 symptomatic. References Brennan P. Poisoning by sulphate of zinc. Lancet 1855; 2: 52-3. 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. Mackintosh GD. A fatal case of poisoning with zinc sulphate: necropsy. Br Med J 1900; 2: 1706-7. Tasic V, Gordova A, Delidzhakova M, Kozhinkova N. Zinc toxicity. Pediatrics 1982; 70: 661. Substance name Zinc sulphate Origin of substance Treatment of roasted ore concentrates, scrap, leach from flue dust, or zinc chemical sludges with sulphuric acid to produce zinc sulphate monohydrate. (HSDB, 1996) Synonyms Barazen Bufopto zinc sulphate Op-thal - zin Sulphuric acid, zinc salt (I:I) Verazinc white copperas White vitriol Zinc vitriol (DOSE, 1994) Chemical group A compound of zinc, a group II B (d block) transition element. Reference numbers CAS 7733-02-0 (DOSE, 1994) RTECS ZH5260000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physicochemical properties Chemical structure ZnSO4 (DOSE, 1994) Molecular weight 161.43 (DOSE, 1994) Physical state at room temperature Solid (MERCK, 1996) Colour Colourless (SAX'S, 1996) Odour Odourless (MERCK, 1996) Viscosity NA pH Aqueous solution is acid to litmus; pH about 4.5 (MERCK, 1996) Solubility Water: 965 g/L at 20°C (heptahydrate). Soluble in ethanol, methanol and glycerol. (DOSE, 1994; HSDB, 1996) Autoignition temperature NIF Chemical interactions Insoluble sulphates are formed with strontium, calcium, lead and barium salts. Mercury and silver form slightly soluble salts. Zinc sulphate has dehydrating action on methylcellulose suspensions which leads to precipitation of methylcellulose, tannins, acacia and proteins. (HSDB, 1996) Major products of combustion Toxic fumes of zinc oxide and sulphur oxides. (SAX'S, 1996) Explosive limits NA Flammability Non combustible. (HSDB, 1996) Boiling point The hydrate loses water above 280°C. Decomposes above 500°C. (MERCK, 1996) Density 3.74 at 15°C (SAX'S, 1996) Vapour pressure 7999.32 Pa at 700°C (OHM/TADS, 1997) Relative vapour density NIF Flash point NA Reactivity When heated to decomposition it emits toxic fumes of sulphur oxides and zinc oxide. (HSDB, 1996) Uses Pigments in paints. In wood preservatives. Catalyst. In fertilizers and animal feeds. Corrosion inhibitor. Electrolyte. Deodorant. (DOSE, 1994) Hazard/risk classification Index no. 030-006-00-9 Risk phrases Xi; R36/38. Irritating to eyes and skin. Safety phrases S(2-) S22-25. Keep out of reach of children. Do not breathe dust. Avoid contact with eyes EEC No: 231-793-3 (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). Dietary zinc supplements usually are prescribed as zinc sulphate. In addition zinc sulphate has been advocated in the treatment of acne vulgaris (Michaėlsson et al, 1977), venous leg ulcers (Hallböök and Lanner, 1972), Wilson's disease (Gill et al, 1994; Hoogenraad, 1995) and leprosy (Mahajan et al, 1994). Eye drops containing zinc sulphate (0.25 per cent) are used in the treatment of excessive lacrimation (Joint Formulary Committee, 1997). EPIDEMIOLOGY Acute zinc sulphate intoxication has occurred in several reports of deliberate ingestion (Burkhart et al, 1990; Hantson et al, 1996) and chronic poisoning has resulted from excess oral zinc supplementation (Hoffman et al, 1988; Ramadurai et al, 1993). Zinc toxicity is also an occasional complication of parenteral nutrition (Brocks et al, 1977; Faintuch et al, 1978). 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). TOXICOKINETICS Absorption Zinc sulphate exposure occurs primarily via ingestion. 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 Nčve et al (1991) observed a peak serum zinc concentration some 2-3 hours after ingestion of 45 mg zinc sulphate. Zinc salts may be absorbed through the skin, typically as zinc oxide in medicated dressings (Hallmans, 1977; Agren, 1990). Distribution Most intravascular zinc is contained within erythrocytes. Plasma zinc is bound predominantly to albumin (approximately 80 per cent) and other proteins (such as 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 90 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 Zinc sulphate is a skin irritant (Lansdown, 1991) but there are no human case reports of significant toxicity. Ocular exposure Zinc sulphate (0.25 per cent solution) is used as an astringent in eye drops for the treatment of excessive lacrimation. Adverse effects via this application are not reported although 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. 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). A 16 year-old boy vomited several times but developed no other signs after ingesting 2.5 g (Burkhart et al, 1990). An 86 year-old woman began coughing and vomiting blue/green liquid some 15 minutes after ingesting 3g each of zinc sulphate and copper sulphate (Hantson et al, 1996). An endoscopy less than four hours post ingestion revealed diffuse gastric inflammation . The initial plasma zinc concentration was 19.8 mg/L (normal 0.9 - 1.2 mg/L). The patient's clinical course was complicated by acute renal failure, cardiac failure and a chemical pneumonitis requiring inotropic support and mechanical ventilation but she fully recovered over 20 days with no sequelae. Chelation therapy (intramuscular dimercaprol and oral d-penicillamine) was given during the first two days although this was not associated with significantly increased urine zinc elimination (see Antidotes). Brown et al (1964) described nausea, vomiting, abdominal pain and bloody diarrhoea some 20 minutes to ten hours after eating and drinking foods stored in galvanized containers. Similar symptoms plus a metallic taste were reported by students who consumed a punch stored overnight in partially corroded galvanized vessels (Lapham et al, 1983). In these cases elemental zinc and zinc oxide were the original zinc sources although consumed as soluble zinc salts. Neurotoxicity A premature infant with zinc deficiency was inadvertently given excess zinc sulphate supplements (the route of administration, dose and duration of therapy were not stated). Irritability, tremor and seizures accompanied an increased serum zinc concentration to 2.2 mg/L (normal range 0.8 - 1.3 mg/L) (Tasic et al, 1982). Headache and dizziness accompanied the gastrointestinal effects caused by the ingestion of zinc-contaminated punch (Lapham et al, 1983). Hepatotoxicity The elderly woman described above (Hantson et al, 1996) who ingested a mixture of the sulphates of copper and zinc developed a transiently prolonged prothrombin time (23 seconds) with no associated increase in hepatic transaminase activities. She fully recovered over 20 days. Haemotoxicity Anaemia secondary to gastrointestinal haemorrhage may complicate significant zinc sulphate ingestion (Moore, 1978). Endocrine toxicity Brandao-Neto et al (1990) suggested that zinc may have an inhibitory effect on the synthesis and secretion of cortisol but this is unproven. Pulmonary toxicity An 86 year-old woman developed a chemical pneumonitis due to partial aspiration of an ingested mixture of zinc and copper sulphate (3g of each) (Hantson et al, 1996) (see above). She fully recovered over 20 days. 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) developed diarrhoea, vomiting and increased amylase activity with evidence of cardiovascular, hepatic and renal toxicity (see below) and died on the 47th day with bronchopneumonia. 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). The cause of these features was not completely clear; no bone marrow or gastrointestinal autopsy findings were included in the report. Hepatotoxicity Cholestatic jaundice was observed in the 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; haemodialysis was instituted when the blood urea concentration was 61 mmol/L. Acute tubular necrosis was present at autopsy (Brocks et al, 1977). Cardiovascular toxicity Hypotension, pulmonary oedema and cardiac arrhythmias (not specified) were reported in a 72 year-old woman following intravenous administration of 7.4 g zinc sulphate over 60 hours (Brocks et al, 1977). She also developed multi-organ failure and sepsis and died on the 47th day. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Skin sensitization to zinc sulphate has been reported (BIBRA Working Group, 1989) but no original case data were identified in the English literature. 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 concentration was 2.2 mg/L (normal range 0.6-1.3 mg/L) but this 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). Metabolic effects Chronic excess zinc supplementation has been associated with adverse effects on the lipid profile (Hooper et al, 1980). This may be a further effect of deranged copper metabolism (Fosmire, 1990). In a review of the effects of zinc supplements on serum lipid concentrations the Agency for Toxic Substances and Disease Registry (1997) reported mixed results with limited and inconsistent evidence of zinc-associated reduced serum HDL cholesterol concentrations and/or raised serum LDL cholesterol in those taking 1.5-4.3 mg zinc/kg body weight daily for five to 12 weeks. 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. 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. Ingestion Zinc sulphate is a fairly potent emetic and spontaneous vomiting is likely to occur following significant ingestion. Gastric lavage has no role. 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. 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. Patients in whom significant gastrointestinal corrosive damage is suspected should be considered for early upper gastrointestinal endoscopy and managed as for other acid ingestions (see, for example, zinc chloride monograph). 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. 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. 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 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 the iron-induced increased metallothionein concentrations since metallothionein concentrations since metallothionein was a greater affinity for zinc than iron. MEDICAL SURVEILLANCE 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 NIF 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). Reprotoxicity There is no conclusive evidence regarding the reprotoxicity of zinc in humans (Reprotext, 1996). 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. 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 human lymphocytes, unscheduled DNA synthesis positive (DOSE, 1994). Fish toxicity Lethal in fathead minnow at < 10 mg/L as zinc (exposure unspecified). LC50 (96 hr) cichlid 13 ppm (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; Sulphates: Guideline level 25 mg/L (DOSE, 1994). WHO Guidelines for Drinking Water Quality NIF 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. 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