UKPID MONOGRAPH
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 28°C.
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
215°C.
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 20°C/4°C (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 Nève 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
(Ågren, 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 (Ågren, 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 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 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 µg (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
(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).
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 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
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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