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    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 28C.
         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
         215C.
         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 20C/4C                       (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 Nve 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
    (gren, 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 (gren, 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 g. Urine zinc excretion was not increased
    by sodium calciumedetate with only 1000 g/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 mol/24h
    on day 20 to 260 mol/24h on day 22 (coinciding with intravenous
    N-acetylcysteine administration) then rose to nearly 300 mol/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 g.

    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 g (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
    (Lonard 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 g/L at supply works, 5000 g/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

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