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
(Michaëlsson 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 (Rodríguez de la Serna and Díaz-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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