UKPID MONOGRAPH
ZINC SULPHATE
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
ZINC SULPHATE
Toxbase summary
Type of product
Used in pigments, wood preservatives, catalysts, fertilizers,
corrosion inhibitors and deodorants.
Toxicity
Zinc sulphate is a gastrointestinal irritant. An early report
(Brennan, 1855) described recovery after ingesting 112 g although
fatalities secondary to gastrointestinal haemorrhage could follow
significantly smaller ingestions.
A 72 year-old female died after the inadvertent intravenous
administration of 7.4 g zinc sulphate (Brocks et al, 1977).
Features
Topical
- Zinc sulphate is a skin and eye irritant.
- Zinc contact sensitivity has been described.
Inhalation
- There are no reports of zinc sulphate inhalation although
the salt would irritate the respiratory tract.
Ingestion
- Zinc sulphate ingestion causes gastrointestinal irritation.
Headache and dizziness are also described. Features are
generally less severe than following zinc chloride ingestion
although fatalities have occurred (Mackintosh, 1900).
- Chronic excess zinc sulphate ingestion may induce reversible
anaemia and leucopenia, transient irritability, tremor and
seizures. These neurological features occurred in a
premature infant inadvertently given excess zinc sulphate
supplements (Tasic et al, 1982).
Injection
- Inadvertent excess zinc sulphate in a parenteral nutrition
solution has been associated with nausea, vomiting, anaemia,
thrombocytopenia and elevated amylase activity.
Management
Dermal
1. Decontaminate with soap and water.
2. Symptomatic and supportive measures should be dictated by the
patient's condition.
Ocular
1. Irrigate with copious lukewarm water or 0.9 per cent saline for
at least ten minutes.
2. A topical anaesthetic may be required for pain relief and to
overcome blepharospasm.
3. Ensure removal of particles lodged in the conjunctival recesses.
4. The instillation of fluorescein allows detection of corneal
damage.
5. Seek ophthalmological advice if any significant abnormality is
detected on examination and in those whose symptoms do not
resolve rapidly.
Inhalation
1. Remove from exposure.
2. Institute symptomatic and supportive measures as dictated by the
patient's condition.
3. See zinc oxide monograph for management of "metal fume fever".
Ingestion
Minor ingestions:
1. Patients with features of mild gastrointestinal upset require
only supportive care.
2. Gastric lavage or other gut decontamination procedures are
unnecessary.
Substantial ingestions:
1. Most patients will vomit spontaneously. Gastric lavage or other
gut decontamination procedures are not likely to improve outcome.
2. Symptomatic and supportive measures with adequate fluid
resuscitation are paramount.
3. Endoscopic examination may be required.
4. Save blood and urine for zinc concentration estimations.
5. Monitor the blood count and biochemical profile including serum
amylase activity.
6. The value of chelation therapy following zinc ingestion has not
been confirmed. Discuss with NPIS if patient is symptomatic.
References
Brennan P.
Poisoning by sulphate of zinc.
Lancet 1855; 2: 52-3.
Brocks A, Reid H, Glazer G.
Acute intravenous zinc poisoning.
Br Med J 1977; 212: 1390-1.
Burkhart KK, Kulig KW, Rumack B.
Whole-bowel irrigation as treatment for zinc sulfate overdose.
Ann Emerg Med 1990; 19: 1167-70.
Mackintosh GD.
A fatal case of poisoning with zinc sulphate: necropsy.
Br Med J 1900; 2: 1706-7.
Tasic V, Gordova A, Delidzhakova M, Kozhinkova N.
Zinc toxicity.
Pediatrics 1982; 70: 661.
Substance name
Zinc sulphate
Origin of substance
Treatment of roasted ore concentrates, scrap, leach from flue
dust, or zinc chemical sludges with sulphuric acid to produce
zinc sulphate monohydrate. (HSDB, 1996)
Synonyms
Barazen
Bufopto zinc sulphate
Op-thal - zin
Sulphuric acid, zinc salt (I:I)
Verazinc white copperas
White vitriol
Zinc vitriol (DOSE, 1994)
Chemical group
A compound of zinc, a group II B (d block) transition element.
Reference numbers
CAS 7733-02-0 (DOSE, 1994)
RTECS ZH5260000 (RTECS, 1996)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
ZnSO4 (DOSE, 1994)
Molecular weight
161.43 (DOSE, 1994)
Physical state at room temperature
Solid (MERCK, 1996)
Colour
Colourless (SAX'S, 1996)
Odour
Odourless (MERCK, 1996)
Viscosity
NA
pH
Aqueous solution is acid to litmus; pH about 4.5
(MERCK, 1996)
Solubility
Water: 965 g/L at 20°C (heptahydrate).
Soluble in ethanol, methanol and glycerol.
(DOSE, 1994; HSDB, 1996)
Autoignition temperature
NIF
Chemical interactions
Insoluble sulphates are formed with strontium, calcium, lead and
barium salts. Mercury and silver form slightly soluble salts.
Zinc sulphate has dehydrating action on methylcellulose
suspensions which leads to precipitation of methylcellulose,
tannins, acacia and proteins. (HSDB, 1996)
Major products of combustion
Toxic fumes of zinc oxide and sulphur oxides.
(SAX'S, 1996)
Explosive limits
NA
Flammability
Non combustible. (HSDB, 1996)
Boiling point
The hydrate loses water above 280°C. Decomposes above 500°C.
(MERCK, 1996)
Density
3.74 at 15°C (SAX'S, 1996)
Vapour pressure
7999.32 Pa at 700°C (OHM/TADS, 1997)
Relative vapour density
NIF
Flash point
NA
Reactivity
When heated to decomposition it emits toxic fumes of sulphur
oxides and zinc oxide. (HSDB, 1996)
Uses
Pigments in paints.
In wood preservatives.
Catalyst.
In fertilizers and animal feeds.
Corrosion inhibitor.
Electrolyte.
Deodorant. (DOSE, 1994)
Hazard/risk classification
Index no. 030-006-00-9
Risk phrases
Xi; R36/38. Irritating to eyes and skin.
Safety phrases
S(2-) S22-25. Keep out of reach of children. Do not breathe dust.
Avoid contact with eyes
EEC No: 231-793-3 (CHIP2, 1994)
INTRODUCTION
Zinc is an essential trace element required for the function of over
200 metallo-enzymes, including alkaline phosphatase and carbonic
anhydrase. Zinc also plays a critical role in the regulation of DNA
and RNA synthesis (via interaction with DNA binding proteins), in
hormone-receptor interactions and in the 'second-messenger' system of
cellular signal transduction (Walsh et al, 1994).
Dietary zinc supplements usually are prescribed as zinc sulphate. In
addition zinc sulphate has been advocated in the treatment of acne
vulgaris (Michaëlsson et al, 1977), venous leg ulcers (Hallböök and
Lanner, 1972), Wilson's disease (Gill et al, 1994; Hoogenraad, 1995)
and leprosy (Mahajan et al, 1994). Eye drops containing zinc sulphate
(0.25 per cent) are used in the treatment of excessive lacrimation
(Joint Formulary Committee, 1997).
EPIDEMIOLOGY
Acute zinc sulphate intoxication has occurred in several reports of
deliberate ingestion (Burkhart et al, 1990; Hantson et al, 1996) and
chronic poisoning has resulted from excess oral zinc supplementation
(Hoffman et al, 1988; Ramadurai et al, 1993). Zinc toxicity is also an
occasional complication of parenteral nutrition (Brocks et al, 1977;
Faintuch et al, 1978).
MECHANISM OF TOXICITY
Excess body zinc interacts with free thiol groups on macromolecules,
so blocking the active sites of enzymes, co-enzymes and membrane
receptors. Zinc contributes to normal immunological function and
excess zinc (300 mg daily for six weeks to 11 volunteers) has been
associated with impaired immune and inflammatory responses (Chandra,
1984).
TOXICOKINETICS
Absorption
Zinc sulphate exposure occurs primarily via ingestion.
Gastrointestinal zinc absorption is a function of a cysteine-rich
intestinal protein (CRIP) which sequesters zinc within enterocytes
prior to active transport into plasma (Hempe and Cousins, 1992; Walsh
et al, 1994). Metallothionein contributes to zinc homeostasis at
higher exposures, primarily via retaining excess zinc within mucosal
cells which are subsequently shed into the intestinal lumen (Hempe and
Cousins, 1992). Zinc absorption is affected by diet; it is inhibited
by calcium, phosphorus and phytates and facilitated by dietary protein
(Hunt et al, 1991). In one study less than 15 per cent of dietary zinc
was absorbed from a high phytate diet compared to 40 per cent from a
diet with a high animal protein content (Sandstrom, 1995).
In ten healthy volunteers Nève et al (1991) observed a peak serum zinc
concentration some 2-3 hours after ingestion of 45 mg zinc sulphate.
Zinc salts may be absorbed through the skin, typically as zinc oxide
in medicated dressings (Hallmans, 1977; Agren, 1990).
Distribution
Most intravascular zinc is contained within erythrocytes. Plasma zinc
is bound predominantly to albumin (approximately 80 per cent) and
other proteins (such as alpha2-macroglobulin) for distribution to
tissues. Excess zinc is stored as a metallothionein complex, mainly in
the liver (Abdel-Mageed and Oehme, 1990; IPCS, 1996).
Some 90 per cent of total body zinc is in muscle and bone (Wastney et
al, 1986).
Appreciable amounts of zinc are found also in the kidney, lung, spleen
and brain (IPCS, 1996).
Zinc crosses the placenta slowly and is found in breast milk (Agency
for Toxic Substances and Disease Registry, 1997).
Excretion
Most ingested zinc is eliminated in faeces via bile, pancreatic fluid
and intestinal mucosal cells, with up to ten per cent appearing in
urine (Abdel-Mageed and Oehme, 1990). Zinc is also eliminated in
sweat. The kidneys do not play an important role in regulating total
body zinc (IPCS, 1996).
The whole-body zinc half-life is some 5-16 months (IPCS, 1996).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Zinc sulphate is a skin irritant (Lansdown, 1991) but there are no
human case reports of significant toxicity.
Ocular exposure
Zinc sulphate (0.25 per cent solution) is used as an astringent in eye
drops for the treatment of excessive lacrimation. Adverse effects via
this application are not reported although historically the use of 20
per cent zinc sulphate solutions in the treatment of dendritic
keratitis led to the formation of white flecks on the lens
("glaukomflecken") (Grant and Schuman, 1993).
Ingestion
Gastrointestinal toxicity
Zinc sulphate is a gastrointestinal irritant. Brennan (1855) reported
a young man who developed severe diarrhoea, vomiting and abdominal
pain but fully recovered after ingesting 112 g zinc sulphate.
Mackintosh (1900) reported a fatal (not quantified) zinc sulphate
ingestion. Necropsy showed intense haemorrhagic gastrointestinal
inflammation. Another patient suffered acute gastrointestinal
haemorrhage requiring an eight unit blood transfusion after taking 440
mg zinc sulphate daily for one week (Moore, 1978).
A 16 year-old boy vomited several times but developed no other signs
after ingesting 2.5 g (Burkhart et al, 1990).
An 86 year-old woman began coughing and vomiting blue/green liquid
some 15 minutes after ingesting 3g each of zinc sulphate and copper
sulphate (Hantson et al, 1996). An endoscopy less than four hours post
ingestion revealed diffuse gastric inflammation . The initial plasma
zinc concentration was 19.8 mg/L (normal 0.9 - 1.2 mg/L). The
patient's clinical course was complicated by acute renal failure,
cardiac failure and a chemical pneumonitis requiring inotropic support
and mechanical ventilation but she fully recovered over 20 days with
no sequelae. Chelation therapy (intramuscular dimercaprol and oral
d-penicillamine) was given during the first two days although this was
not associated with significantly increased urine zinc elimination
(see Antidotes).
Brown et al (1964) described nausea, vomiting, abdominal pain and
bloody diarrhoea some 20 minutes to ten hours after eating and
drinking foods stored in galvanized containers. Similar symptoms plus
a metallic taste were reported by students who consumed a punch stored
overnight in partially corroded galvanized vessels (Lapham et al,
1983). In these cases elemental zinc and zinc oxide were the original
zinc sources although consumed as soluble zinc salts.
Neurotoxicity
A premature infant with zinc deficiency was inadvertently given excess
zinc sulphate supplements (the route of administration, dose and
duration of therapy were not stated). Irritability, tremor and
seizures accompanied an increased serum zinc concentration to 2.2 mg/L
(normal range 0.8 - 1.3 mg/L) (Tasic et al, 1982).
Headache and dizziness accompanied the gastrointestinal effects caused
by the ingestion of zinc-contaminated punch (Lapham et al, 1983).
Hepatotoxicity
The elderly woman described above (Hantson et al, 1996) who ingested a
mixture of the sulphates of copper and zinc developed a transiently
prolonged prothrombin time (23 seconds) with no associated increase in
hepatic transaminase activities. She fully recovered over 20 days.
Haemotoxicity
Anaemia secondary to gastrointestinal haemorrhage may complicate
significant zinc sulphate ingestion (Moore, 1978).
Endocrine toxicity
Brandao-Neto et al (1990) suggested that zinc may have an inhibitory
effect on the synthesis and secretion of cortisol but this is
unproven.
Pulmonary toxicity
An 86 year-old woman developed a chemical pneumonitis due to partial
aspiration of an ingested mixture of zinc and copper sulphate (3g of
each) (Hantson et al, 1996) (see above). She fully recovered over 20
days.
Injection
Gastrointestinal toxicity
Acute-on-chronic zinc intoxication occurred in seven patients
receiving total parenteral nutrition solutions which accidentally
contained zinc sulphate 100 mg/L (Faintuch et al, 1978). Six patients
developed increased amylase activities (peak activities 557-1850 Klein
units; normal range 130-310) (Faintuch et al, 1978).
Another patient who received excess zinc sulphate (7.4 g) in error
over 60 hours as part of a parenteral nutrition regime (Brocks et al,
1977) developed diarrhoea, vomiting and increased amylase activity
with evidence of cardiovascular, hepatic and renal toxicity (see
below) and died on the 47th day with bronchopneumonia. The peak serum
zinc concentration was 41.8 mg/L.
Haemotoxicity
Following intravenous administration of 7.4 g zinc sulphate, a 72
year-old woman developed anaemia and thrombocytopenia (Brocks et al,
1977). The cause of these features was not completely clear; no bone
marrow or gastrointestinal autopsy findings were included in the
report.
Hepatotoxicity
Cholestatic jaundice was observed in the patient who was inadvertently
administered 7.4 g zinc sulphate intravenously (Brocks et al, 1977).
Nephrotoxicity
A 72 year-old woman developed oliguria immediately following the
inadvertent administration of 7.4 g zinc sulphate via parenteral
nutrition. She remained oliguric despite therapy with frusemide and
intravenous fluids; haemodialysis was instituted when the blood urea
concentration was 61 mmol/L. Acute tubular necrosis was present at
autopsy (Brocks et al, 1977).
Cardiovascular toxicity
Hypotension, pulmonary oedema and cardiac arrhythmias (not specified)
were reported in a 72 year-old woman following intravenous
administration of 7.4 g zinc sulphate over 60 hours (Brocks et al,
1977). She also developed multi-organ failure and sepsis and died on
the 47th day.
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Skin sensitization to zinc sulphate has been reported (BIBRA Working
Group, 1989) but no original case data were identified in the English
literature.
Ingestion
Haemotoxicity
Chronic excess zinc sulphate ingestion may induce reversible anaemia
and leukopenia secondary to a relative copper deficiency (Prasad et
al, 1978; Patterson et al, 1985; Simon et al, 1988). The mechanism is
probably zinc-induced intestinal metallothionein synthesis with
increased metallothionein-copper binding and reduced copper
bioavailability via sequestration in the intestinal mucosa.
Ramadurai et al (1993) reported a 36 year-old lady who presented with
sideroblastic anaemia and neutropenia having taken 600 mg zinc
sulphate daily for three years as a health food supplement. On
admission the serum zinc concentration was 2.2 mg/L (normal range
0.6-1.3 mg/L) but this and the haematological abnormalities returned
to normal within four months of zinc supplement withdrawal.
Similar clinical pictures were observed in two patients prescribed 660
mg zinc sulphate daily in the treatment of intractable coeliac disease
(Porter et al, 1977) and apthous ulcers (Hoffman et al, 1988).
Metabolic effects
Chronic excess zinc supplementation has been associated with adverse
effects on the lipid profile (Hooper et al, 1980). This may be a
further effect of deranged copper metabolism (Fosmire, 1990).
In a review of the effects of zinc supplements on serum lipid
concentrations the Agency for Toxic Substances and Disease Registry
(1997) reported mixed results with limited and inconsistent evidence
of zinc-associated reduced serum HDL cholesterol concentrations and/or
raised serum LDL cholesterol in those taking 1.5-4.3 mg zinc/kg body
weight daily for five to 12 weeks.
MANAGEMENT
Dermal exposure
Decontamination with soap and water is likely to be all that is
required. Chronic skin contact should be avoided.
Ocular exposure
Irrigate with copious amounts of lukewarm water for at least ten
minutes. A topical anaesthetic may be required for pain relief and to
overcome blepharospasm. Ensure removal of any particles lodged in the
conjunctival recesses. The instillation of fluorescein allows
detection of corneal damage. Specialist ophthalmological advice should
be sought if any significant abnormality is detected on examination
and in those whose symptoms do not resolve rapidly.
Inhalation
Symptomatic and supportive measures are the priority. Symptomatic
patients and those with abnormal respiratory signs should have a chest
X-ray, receive supplemental oxygen and bronchodilators if necessary
and be observed until symptoms resolve.
Ingestion
Zinc sulphate is a fairly potent emetic and spontaneous vomiting is
likely to occur following significant ingestion. Gastric lavage has no
role. Supportive measures are the mainstay of management. It is
reasonable, though of unproven benefit, to attempt dilution by the
oral administration of milk or water. Burkhart et al (1990) advocated
whole-bowel irrigation as an effective gut decontamination method
following zinc sulphate ingestion but there are no controlled data to
support this view. Patients in whom significant gastrointestinal
corrosive damage is suspected should be considered for early upper
gastrointestinal endoscopy and managed as for other acid ingestions
(see, for example, zinc chloride monograph).
Antidotes
Animal studies
Domingo et al (1988) investigated the antidotal potential of DTPA
(trisodium calcium diethylene triamine-pentaacetate), CDTA
(cyclohexane diamine tetraacetate), d-penicillamine, sodium
calciumedetate, DMSA (dimercapto-succinic acid) and the sodium salt of
DMPS (dimercaptopropanesulphonate) on reducing mortality in rodents
poisoned with intraperitoneal zinc acetate 66-330 mg/kg. This dose
range was selected to span the previously calculated intraperitoneal
LD50 (108 mg/kg) and LD99 (216 mg/kg) for this zinc salt.
Chelation therapy (or 0.9 per cent saline as control) was administered
intraperitoneally to ten mice ten minutes after dosing with zinc.
Antidote doses and outcome (measured as survival at 14 days) are
summarized in Table 1.
The very high antidote doses employed in this study necessitate
caution in interpreting the results with regard to potential clinical
value. Nevertheless at a zinc acetate dose in excess of the LD99
there was 100 per cent survival following treatment with DTPA,
d-penicillamine and DMPS. DMSA was not an impressive antidote under
these conditions.
The same research group (Llobet et al, 1988) undertook a similar
study. Intraperitoneal zinc acetate 0.49 mmol/kg (a dose approximately
equivalent to its LD50) and 1.15 mmol/kg (approximately the LD99)
was administered immediately before antidote administration to ten
mice. Outcome was measured as survival ratio. Sodium calciumedetate
(2152 mg/kg), DTPA (2262 mg/kg) and d-penicillamine (857 mg/kg),
completely protected against mortality at the LD99 for zinc acetate.
Under exactly the same conditions (each chelating agent at a dose of
5.75 mmol/kg) the survival ratios for CDTA, DMPS and DMSA were 80, 50
and 70 per cent respectively.
Table 1. Survival (%) following parenteral chelation therapy in mice
after a single zinc acetate injection (after Domingo et al, 1988)
Chelating agent Antidote dose Zinc acetate dose
(mg/kg) (mg/kg)
66 153 241
Control - 40 20 0
Na2CaCDTA 1360 100 90 90
Na2CaEDTA 1644 100 90 90
Na2CaDTPA 1569 100 100 100
d-Penicillamine 857 100 100 100
DMSA 619 80 30 10
DMPS 273 100 100 100
Several antidotes have been investigated for their potential to
enhance zinc elimination. Domingo et al (1988) measured 24 hour faecal
and urinary zinc excretion in mice administered 88 mg/kg
intraperitoneal zinc acetate followed ten minutes later by an
intraperitoneal dose of chelating agent (or saline in the control
group). The same chelating agents and doses were used as in Table 1,
again with ten mice in each treatment group. In the control group
urine zinc elimination was less than half faecal excretion. CDTA
enhanced urine zinc excretion some six fold and DTPA, DMSA and DMPS
each some four fold. d-Penicillamine enhanced 48 hour urine zinc
elimination by some 80 per cent. Sodium calciumedetate did not enhance
urine zinc excretion but was the only antidote to increase 24 hour
faecal zinc elimination (by some 20 per cent).
The effect of increasing the time delay between zinc dosing and DTPA
or CDTA administration was investigated by Llobet et al (1989).
Intraperitoneal zinc acetate 0.4 mmol/kg (LD50 0.49 mmol/kg) was
followed 0-24 hours later by a single intraperitoneal dose of
chelating agent to give a chelating agent: zinc acetate molar ratio of
approximately 10:1.
Urine and faecal zinc elimination were monitored for 48 hours with
five mice in each treatment group. Urine and faecal zinc elimination
were increased significantly (p < 0.05) by both chelating agents when
administered up to two hours after poisoning but only DTPA
significantly enhanced the 48 hour urine and faecal zinc excretion
when the antidotes were given 12 hours after zinc dosing.
When there was a 24 hour delay between zinc acetate injection and
antidote administration, DTPA significantly (p < 0.05) enhanced urine
but not faecal 48 hour zinc elimination (CDTA was not effective).
In summary, animal studies suggest DTPA is the most effective zinc
antidote as judged by improved survival (100 per cent following a zinc
acetate dose in excess of the LD99) and increased zinc elimination.
CDTA produced 90 per cent survival and increased urine zinc excretion
some six fold. d-Penicillamine also gave excellent results in
mortality studies, with 100 per cent survival following administration
of zinc acetate at a dose exceeding the LD99. However,
d-penicillamine did not enhance zinc elimination significantly. Sodium
calciumedetate improved survival (90-100 per cent) and in one study
(Domingo et al, 1988) was the only chelating agent to increase faecal
zinc elimination. DMPS 273 mg/kg completely protected mice against the
lethal effects of zinc acetate at a dose in excess of the LD99 and
the same antidote dose enhanced urine zinc excretion some four fold
following administration of 88 mg/kg zinc acetate. By contrast DMSA
619 mg/kg resulted in only 10 per cent survival following 241 mg/kg
zinc acetate.
Clinical studies
Although increased renal zinc excretion has been noted during
chelation therapy instituted to enhance elimination of other toxic
heavy metals, there is no convincing evidence of benefit in human zinc
poisoning. In health, most zinc is eliminated via the gastrointestinal
tract with only a small contribution made by renal excretion. No data
have been found regarding the effect of chelation therapy on biliary
zinc excretion in man.
Dimercaprol
McKinney et al (1994) reported improved mental status in a patient
with severe zinc chloride poisoning (by ingestion) following
administration of intramuscular dimercaprol 12 mg/kg/day for 24 hours
and intravenous sodium calciumedetate 1 g/m2 for five days. This
treatment was instituted 74 hours post ingestion. Chelation therapy
was not associated with increased urine zinc elimination.
Intramuscular dimercaprol 4 mg/kg qds was instituted less than four
hours after the ingestion of 3 g each of zinc sulphate and copper
sulphate by an 86 year-old woman. This patient also received oral
d-penicillamine (see below) but both antidotes were discontinued after
48 hours due to deteriorating renal function. The patient made a full
recovery over 20 days.
A 16 year-old who ingested 12 g elemental zinc was treated some nine
days later with intramuscular dimercaprol 2.3-9.2 mg/kg daily.
Chelation was associated with clinical improvement and a reduction in
the blood zinc concentration but urine zinc concentrations were not
measured (Murphy, 1970).
Sodium calciumedetate
A 24 year-old man who developed erosive pharyngitis and oesophagitis,
hyperamylasaemia, microscopic haematuria and a serum zinc
concentration of 1.46 mg/L (normal range 0.5-0.9 mg/L) after ingesting
liquid zinc chloride, made an uneventful recovery following supportive
care and intravenous sodium calciumedetate 45 mg/kg in divided doses
over 36 hours. No zinc excretion data were given (Chobanian, 1981).
Potter (1981) utilized intravenous sodium calciumedetate 150 mg in the
management of a 28 month-old child who had ingested a zinc chloride
solution; no urine zinc excretion data were given.
The patient reported by McKinney et al (1994) who was severely
poisoned after ingesting one tablespoon of a zinc chloride-containing
soldering flux was treated with intravenous sodium calciumedetate 1
g/m2 for five days. The urine zinc excretion in the eight hours
preceding chelation was 950 µg. Urine zinc excretion was not increased
by sodium calciumedetate with only 1000 µg/24 h removed on the fourth
day of treatment (no interim data were given).
N-acetylcysteine
In response to a rising serum zinc concentration, a soldier who
developed adult respiratory distress syndrome following two minutes
inhalation of zinc chloride smoke was administered intravenous (140
mg/kg/day for three days) and nebulized (100 mg qds for 13 days)
N-acetylcysteine between days 19 and 32 in an attempt to enhance zinc
elimination. The urine zinc excretion increased from some 125 µmol/24h
on day 20 to 260 µmol/24h on day 22 (coinciding with intravenous
N-acetylcysteine administration) then rose to nearly 300 µmol/day (the
maximum observed zinc excretion) on day 24. Unfortunately no
pre-chelation zinc excretion measurements were made. There was no
clinical improvement with therapy and the patient died in respiratory
and renal failure on day 32.
d-Penicillamine
An 86 year-old woman who developed chemical pneumonitis, gastritis,
cardiac and renal failure following the ingestion (and partial
aspiration) of 3 g each of zinc and copper sulphate, received 250 mg
oral d-penicillamine qds (in addition to intramuscular dimercaprol 4
mg/kg qds) commenced less than four hours after zinc ingestion
(Hantson et al, 1996). Unfortunately there were no pre-chelation urine
zinc excretion data and treatment was discontinued after 48 hours due
to deteriorating renal function. The maximum 24 hour urine zinc
excretion, achieved on the first day of chelation therapy was some
6000 µg.
Another patient with zinc chloride poisoning by inhalation survived
following treatment with oral penicillamine 125 mg twice daily (Allen
et al, 1992). No blood or urine zinc concentrations were measured.
Antidotes: Conclusions and recommendations
1. There are no controlled clinical data of chelation therapy in
zinc poisoning and animal studies must be interpreted with
caution in view of the extremely high antidote doses employed.
Nevertheless, animal studies suggest that of the antidotes
readily available for clinical use, sodium calciumedetate is the
preferred agent with d-penicillamine or DMPS potential
alternatives.
2. Although case reports claim clinical benefit following parenteral
administration of dimercaprol, sodium calciumedetate and
d-penicillamine, urine and/or faecal zinc excretion data to
support these claims are lacking.
3. Chelation therapy cannot be advocated routinely in the management
of zinc poisoning; symptomatic cases should be discussed with the
NPIS.
AT RISK GROUPS
Patients with haemochromatosis are at greater risk of zinc toxicity
due to the iron-induced increased metallothionein concentrations since
metallothionein concentrations since metallothionein was a greater
affinity for zinc than iron.
MEDICAL SURVEILLANCE
Serum zinc concentrations are increased in acute zinc poisoning. The
24 hour urine zinc excretion is useful when monitoring chronic
exposure although there is no well established relationship between
the extent of exposure and urine zinc concentration. Hair zinc
concentrations are not useful (Agency for Toxic Substances and Disease
Registry, 1997).
Normal zinc concentrations in biological fluids
Plasma and serum: 1.1-1.3 mg/L (IPCS, 1996).
Whole blood: 6.8-10.8 mg/L (IPCS, 1996).
24 hour urine excretion: less than 500 µg (IPCS, 1996).
OCCUPATIONAL DATA
Occupational exposure standard
NIF
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There is no conclusive evidence that zinc is a human carcinogen
(Léonard and Gerber, 1989) and the Environmental Protection Agency has
concluded zinc is not classifiable in this regard (Agency for Toxic
Substances and Disease Registry, 1997).
Reprotoxicity
There is no conclusive evidence regarding the reprotoxicity of zinc in
humans (Reprotext, 1996). There were no adverse effects following the
administration of oral zinc sulphide (providing 20 mg elemental zinc
daily) to 494 women during the last two trimesters of pregnancy
(Mahomed et al, 1989).
A relationship between high amniotic fluid or maternal serum zinc
concentrations and foetal neural tube defects has been proposed, but
evidence for this is inconsistent (Reprotext, 1996; Reprotox, 1996).
There was no association between serum zinc concentrations and the
incidence of neural tube defects in 82 affected pregnancies compared
to 85 controls (Hambidge et al, 1993).
Pre-eclampsia, abnormal deliveries, anencephaly, and an increased
incidence of stillbirths have been associated with low maternal serum
zinc concentrations. Zinc deficiency also has been associated with
delayed sexual maturity.
Low seminal fluid zinc concentrations have been implicated in male
infertility but the use of zinc supplements to treat this condition
remains controversial (Reprotext, 1996; Reprotox, 1996).
Genotoxicity
In vitro human lymphocytes, unscheduled DNA synthesis positive
(DOSE, 1994).
Fish toxicity
Lethal in fathead minnow at < 10 mg/L as zinc (exposure unspecified).
LC50 (96 hr) cichlid 13 ppm (DOSE, 1994).
EC Directive on Drinking Water Quality 80/778/EEC
Zinc: Guide level 100 µg/L at supply works, 5000 µg/L after 12 hour
contact with consumers pipework; Sulphates: Guideline level 25 mg/L
(DOSE, 1994).
WHO Guidelines for Drinking Water Quality
NIF
AUTHORS
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
REFERENCES
Abdel-Mageed AB, Oehme FW.
A review of the biochemical roles, toxicity and interactions of zinc,
copper and iron: I. Zinc.
Vet Hum Toxicol 1990; 32: 34-9.
Agency for Toxic Substances and Disease Registry (ATSDR).
Zinc. In: ATSDR Toxicological Profiles.
Atlanta: CRC Press, Inc., 1997.
Agren MS.
Percutaneous absorption of zinc from zinc oxide applied topically to
intact skin in man.
Dermatologica 1990; 180: 36-9.
Allen MB, Crisp A, Snook N, Page RL.
'Smoke-bomb' pneumonitis.
Respir Med 1992; 86: 165-6.
BIBRA Working Group.
Zinc sulphate. Toxicity profile. United Kingdom:
The British Industrial Biological Research Association, 1989.
Brandao-Neto J, Vieira JGH, Shuhama T, Russo EMK, Piesco RV, Curi PR.
Interrelationships of zinc with glucose and insulin metabolism in
humans.
Biol Trace Elem Res 1990; 24: 73-82.
Brennan P.
Poisoning by sulphate of zinc.
Lancet 1855; 2: 52-3.
Brocks A, Reid H, Glazer G.
Acute intravenous zinc poisoning.
Br Med J 1977; 212: 1390-1.
Brown MA, Thom JV, Orth GL, Cova P, Juarez J.
Food poisoning involving zinc contamination.
Arch Environ Health 1964; 8: 657-60.
Burkhart KK, Kulig KW, Rumack B.
Whole-bowel irrigation as treatment for zinc sulfate overdose.
Ann Emerg Med 1990; 19: 1167-70.
Chandra RK.
Excessive intake of zinc impairs immune responses.
JAMA 1984; 252: 1443-6.
CHIP2/Chemicals (Hazard Information and Packaging for Supply)
Regulations 1994.
Health and Safety Commission.
Sudbury: Health and Safety Executive, 1994.
Chobanian SJ.
Accidental ingestion of liquid zinc chloride: local and systemic
effects.
Ann Emerg Med 1981; 10: 91-3.
Domingo JL, Llobet JM, Paternain JL, Corbella J.
Acute zinc intoxication: comparison of the antidotal efficacy of
several chelating agents.
Vet Hum Toxicol 1988; 30: 224-8.
DOSE/Dictionary of substances and their effects. Vol 7.
Cambridge: Royal Society of Chemistry, 1994.
Faintuch J, Faintuch JJ, Toledo M, Nazario G, Machado MCC, Raia AA.
Hyperamylasemia associated with zinc overdose during parenteral
nutrition.
J Parenter Enteral Nutr 1978; 2: 640-5.
Fosmire GJ.
Zinc toxicity.
Am J Clin Nutr 1990; 51: 225-7.
Gill HH, Shankaran K, Desai HG.
Wilson's disease: varied hepatic presentations.
Indian J Gastroenterol 1994; 13: 95-8.
Grant WM, Schuman JS.
Toxicology of the eye. 4th ed.
Illinois: Charles C Thomas, 1993.
Hallböök T, Lanner E.
Serum-zinc and healing of venous leg ulcers.
Lancet 1972; 2: 780-2.
Hallmans G.
Treatment of burns with zinc-tape.
Scand J Plast Reconstr Surg Hand Surg 1977: 11: 155-61.
Hambidge M, Hackshaw A, Wald N.
Neural tube defects and serum zinc.
Br J Obstet Gynaecol 1993; 100: 746-9.
Hantson P, Lievens M, Mahieu P.
Accidental ingestion of a zinc and copper sulfate preparation.
Clin Toxicol 1996; 34: 725-30.
Hempe JM, Cousins RJ.
Cysteine-rich intestinal protein and intestinal metallothionein: An
inverse relationship as a conceptual model for zinc absorption in
rats.
J Nutr 1992; 122: 89-95.
Hjortsœ E, Qvist J, Bud MI, Thomsen JL, Andersen JB, Wiberg-Jœgensen
F,
Jensen NK, Jones R, Reid LM, Zapol WM.
ARDS after accidental inhalation of zinc chloride smoke.
Intensive Care Med 1988; 14: 17-24.
Hoffman HN, Phyliky RL, Fleming CR.
Zinc-induced copper deficiency.
Gastroenterology 1988; 94: 508-12.
Hoogenraad TU.
Zinc therapy: an advance in the treatment of Wilson's disease. In:
Sarkar B, ed. Genetic response to metals. 1st ed.
New York: Marcel Dekker, Inc., 1995; 361-78.
Hooper PL, Visconti L, Garry PJ, Johnson GE.
Zinc lowers high-density lipoprotein-cholesterol levels.
JAMA 1980; 244: 1960-1.
HSDB/Hazardous Substances Data Bank.
In: Tomes plus. Environmental Health and Safety Series I. Vol 31.
National Library of Medicine, 1996.
Hunt JR, Lykken GI, Mullen LK.
Moderate and high amounts of protein from casein enhance human
absorption of zinc from whole wheat or white rolls.
Nutr Res 1991; 11: 413-8.
IPCS/International Programme on Chemical Safety.
IPCS Chemical information CD-Rom (Inchem).
Geneva: IPCS/Canadian Centre for Occupational Health and Safety
(CCOHS), 1996.
Joint Formulary Committee.
British National Formulary.
London: British Medical Association and Wallingford: The
Pharmaceutical Press, 1997.
Lansdown ABG.
Interspecies variations in response to topical application of selected
zinc compounds.
Food Chem Toxicol 1991; 29: 57-64.
Lapham S, Vanderly R, Brackbill R, Tikkanen M.
Illness associated with elevated levels of zinc in fruit punch - New
Mexico.
Morb Mortal Wkly Rep 1983; 32: 257-8.
Léonard A, Gerber GB.
Zinc toxicity: does it exist?
J Am Coll Toxicol 1989; 8: 1285-1290.
Llobet JM, Domingo JL, Corbella J.
Antidotes for zinc intoxication in mice.
Arch Toxicol 1988; 61: 321-3.
Llobet JM, Domingo JL, Corbella J.
Comparison of the antidotal efficacy of polyamincarboxylic acids (CDTA
and DTPA) with time after acute zinc poisoning.
Vet Hum Toxicol 1989; 31: 25-8.
Mackintosh GD.
A fatal case of poisoning with zinc sulphate: necropsy.
Br Med J 1900; 2: 1706-7.
Mahajan PM, Jadhav VH, Patki AH, Jogaikar DG, Mehta JM.
Oral zinc therapy in recurrent erythema nodosum leprosum: a clinical
study.
Indian J Lepr 1994; 66: 51-7.
Mahomed K, James DK, Golding J, McCabe R.
Zinc supplementation during pregnancy: a double blind randomised
controlled trial.
Br Med J 1989; 299: 826-30.
McKinney PE, Brent J, Kulig K.
Acute zinc chloride ingestion in a child: local and systemic effects.
Ann Emerg Med 1994; 23:1383-7.
MERCK/The Merck Index.
Zinc sulphate. In: Budavari S, ed. An encyclopedia of chemicals,
drugs, and biologicals. 12th ed.
New Jersey: Merck and Co., Inc., 1996, 1735-6.
Michaëlsson G, Juhlin L, Vahlquist A.
Effects of oral zinc and vitamin A in acne.
Arch Dermatol 1977; 113: 31-6.
Moore R.
Bleeding gastric erosion after oral zinc sulphate.
Br Med J 1978; 1: 754.
Murphy JV.
Intoxication following ingestion of elemental zinc.
JAMA 1970; 212: 2119-20.
Nève J, Hanocq M, Peretz A, Abi Khalil F, Pelen F, Famaey JP.
Pharmacokinetic study of orally administered zinc in humans. Evidence
for an enteral recirculation.
Eur J Drug Metab Pharmacokinet 1991; 16: 315-23.
OHM/TADS-Oil and hazardous Materials/Technical Assistance Data System.
In: Tomes plus. Environmental Health and Safety Series 1. Vol 32.
United States Environmental Protection Agency, 1997.
Patterson WP, Winkelmann M, Perry MC.
Zinc-induced copper deficiency: Megamineral sideroblastic anemia.
Ann Intern Med 1985; 103: 385-6.
Porter KG, McMaster D, Elmes ME, Love AHG.
Anæmia and low serum-copper during zinc therapy.
Lancet 1977; 2: 774.
Potter JL.
Acute zinc chloride ingestion in a young child.
Ann Emerg Med 1981; 10: 267-9.
Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P.
Hypocupremia induced by zinc therapy in adults.
JAMA 1978; 240: 2166-8.
Ramadurai J, Shapiro C, Kozloff M, Telfer M.
Zinc abuse and sideroblastic anemia.
Am J Hematol 1993; 42: 227-8.
Reprotext.
In: Tomes plus. Environmental Health and Safety Series I. Vol 31.
Colorado: Micromedex, Inc., 1996.
Reprotox.
In: Tomes plus. Environmental Health and Safety Series I. Vol 31.
Washington DC: Fabro S, Scialli AR. Reproductive Toxicology Center,
Columbia Hospital for Women, 1996.
RTECS/Registry of Toxic Effects of Chemical Substances.
In: Tomes plus. Environmental Health and Safety Series I. Vol 31.
National Institute for Occupational Safety and Health (NIOSH), 1996.
Sandstrom B.
Consideration in estimates of requirements and critical intake of
zinc. Adaption, availability and interactions.
Analyst 1995; 120: 913-5.
SAX'S/Lewis RJ.
Sax's dangerous properties of industrial materials. 9th ed. Vol 3.
New York: Van Nostrand Reinhold, 1996
Simon SR, Branda RF, Tindle BH, Burns SL.
Copper deficiency and sideroblastic anemia associated with zinc
ingestion.
Am J Hematol 1988; 28: 181-3.
Tasic V, Gordova A, Delidzhakova M, Kozhinkova N.
Zinc toxicity.
Pediatrics 1982; 70: 661.
Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ.
Zinc: health effects and research priorities for the 1990s.
Environ Health Perspect 1994; 102: 5-46.
Wastney ME, Aamodt RL, Rumble WF, Henkin RI.
Kinetic analysis of zinc metabolism and its regulation in normal
humans.
Am J Physiol 1986; 251: 398-408.