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    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; Hjortsœ 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 (Hjortsœ et al, 1988; Homma
    et al, 1992) and interstitial fibrosis (Milliken et al, 1963; Hjortsœ
    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

    Hjortsœ 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).

    AUTHORS

    SM Bradberry BSc MB MRCP
    ST Beer BSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH
    UK

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Date of last revision
    17/1/97

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