UKPID MONOGRAPH
COPPER
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.
COPPER
Toxbase summary
Separate toxbase entries exists for:
Copper carbonate
Copper chloride
Copper oxide
Copper sulphate
Type of product
A transition metal used in electrical conductors, alloys (notably
brass and bronze), cooking utensils, coins, corrosion resistant
plumbing pipes, heating and building materials.
Toxicity
Copper toxicity primarily occurs following leaching of copper ions
from copper pipes. No fatalities have been reported among otherwise
healthy individuals following ingestion of water contaminated in this
way. However, renal failure patients have died following copper
intoxication via parenteral exposure to copper contaminated dialysis
water. Childhood cirrhosis is a multifactorial disease which may
become manifest by excess dietary copper intake (Mühlendahl and Lange,
1994).
Inhalation of copper fumes may cause metal fume fever.
Features
Dermal
- Molten copper will burn.
- Leaching of copper from pipes in areas with acidic water has
caused green hair, particularly in fair-haired individuals.
- Copper contact dermatitis is recognized.
Ocular
- Copper foreign bodies can cause serious eye damage.
- Copper deposited in the anterior vitreous may gradually
dissolve over years causing green/brown discolouration of
the lens, cornea and iris with impaired visual acuity.
- Retinal haemorrhage and abscess formation may ensue if
particles reach the posterior vitreous.
- Open angle glaucoma is a rare complication of intraocular
copper dissemination.
Ingestion
- Ingestion of copper-contaminated water causes nausea,
vomiting, abdominal pain and diarrhoea.
- Gastrointestinal mucosal burns with subsequent stricture
formation has followed molten copper ingestion.
- Fatal habitual copper coin ingestion is reported with
extensive hepatic fibrosis at autopsy (Hasan et al, 1995).
Inhalation
- Copper fumes cause pulmonary tract irritation. Metal fume
fever with flu-like symptoms, cough and dyspnoea is also
reported, but is far less common than among workers exposed
to zinc fume.
Injection
- Haemodialysis with copper contaminated water has caused
"copper fever" with headache, fever, myalgia, nausea,
vomiting, abdominal pain and orthostatic hypotension.
Intravascular haemolysis, rhabdomyolysis and pancreatitis
are recognized. Fatalities have occurred (Klein et al,
1972).
Management
Dermal
1. Irrigate with copious lukewarm water.
2. Consider the possibility of systemic copper uptake if there has
been significant or repeated exposure to broken skin.
3. Copper irritant dermatitis and contact sensitivity are managed
most effectively by discontinuing exposure.
Ocular
1. Irrigate immediately with lukewarm water or preferably saline for
at least 10 minutes.
2. Application of local anaesthetic may be required for pain relief
and to overcome blepharospasm to allow thorough decontamination.
3. Ensure no particles remain lodged in the conjunctival recesses.
4. Corneal damage may be detected by the instillation of
fluorescein.
5. Specialist ophthalmological advice is indicated if an intraocular
copper foreign body is suspected.
Ingestion
1. Symptomatic and supportive measures are usually all that are
required following ingestion of copper-contaminated water. The
World Health Organization guideline value for the copper content
of drinking water is 2 mg/L (WHO, 1993).
2. The diagnosis can be confirmed by measurement of the copper
concentration of the water supply.
3. Remove the copper source.
4. Check the full blood count and liver profile if chronic exposure
is suspected.
5. Management of copper coin ingestion is as for other metal objects
with serial X-rays to track transit through the gastrointestinal
tract and a surgical opinion if signs or symptoms suggest
obstruction.
6. The value of chelation therapy in copper poisoning is unproven.
Discussion with an NPIS physician is recommended.
Inhalation
1. Remove from exposure and administer supplemental oxygen by
face-mask if there is evidence of respiratory distress.
2. Arrange a chest X-ray if there are abnormal findings on
respiratory examination.
3. There typically are no long-term sequelae of copper fume fever.
Injection
1. Take a sample of haemodialysis water for copper concentration
determination.
2. Remove copper source from water supply.
3. Measure the whole blood copper concentration.
4. Treat gastrointestinal features symptomatically, replacing fluid
losses as necessary.
5. Monitor biochemical and haematological profiles plus acid-base
status.
6. Intravascular haemolysis is managed conventionally.
References
Bentur T, Koren G, McGuigan M, Spielberg SP.
An unusual skin exposure to copper; clinical and pharmacokinetic
evaluation.
Clin Toxicol 1988; 26: 371-80.
Gleason RP.
Exposure to copper dust.
Am Ind Hyg Assoc J 1968; 29: 461-2.
Hasan N, Emery D, Baithun SI, Dodd S.
Chronic copper intoxication due to ingestion of coins: a report of an
unusual case.
Hum Exp Toxicol 1995; 14: 500-2.
Knobeloch L, Ziarnik M, Howard J, Theis B, Farmer D, Anderson H,
Proctor M.
Gastrointestinal upsets associated with ingestion of
copper-contaminated water.
Environ Health Perspect 1994; 102: 958-61.
Klein Jr WJ, Metz EN, Price AR.
Acute copper intoxication. A hazard of hemodialysis.
Arch Intern Med 1972; 129: 578-82.
Mülendahl KE, Lange H.
Copper and childhood cirrhosis.
Lancet 1994; 344: 1515-6.
Shibuya S, Takase Y, Sharma N.
Esophageal ulcer due to ingestion of melted copper.
Dig Dis Sci 1992; 37: 1785-90.
Spitalny KC, Brondum J, Vogt RL, Sargent HE, Kappel S.
Drinking-water-induced copper intoxication in a Vermont family.
Pediatrics 1984; 74: 1103-6.
Terry RF.
Excess copper in a local water supply.
Med J Aust 1996; 165: 296.
WHO/World Health Organization.
Guidelines for drinking-water quality. 2nd ed. Vol 1. Recommendations.
Geneva: World Health Organization, 1993.
Wyllie J.
Copper poisoning at a cocktail party.
Am J Public Health 1957; 47: 617.
Substance name
Copper
Origin of substance
Copper occurs in pheophytin (an analogue of chlorophyll),
haemocyanin, tyrosinase and caeruloplasmin. It may also be found
in various ores such as cuprite, azurmalachite, malachite,
tetrahedrite, chalcopyrite, covellite, azurite, bornite,
antlerite, chalcocite and enargite
(HAZARDTEXT, 1997; DOSE, 1993).
Synonyms
Allbri natural copper
Anac 110
Arwood copper
Bronze powder
Cuprum
Gold Bronze
Kafar copper
Raney copper (HAZARDTEXT, 1997)
Chemical group
A group 1B transition metal (d block) element.
Reference numbers
CAS 7440-50-8 (DOSE, 1993)
RTECS GL5325000 (RTECS, 1997)
UN 2811 (REPROTEXT, 1997)
HAZCHEM NIF
Physicochemical properties
Chemical structure
Cu
Molecular weight
63.546 (HSDB, 1997)
Physical state at room temperature
Solid (HSDB, 1997)
Colour
Red-brown (MEDITEXT, 1997)
Odour
Odourless (HSDB, 1997)
Viscosity
NIF
pH
NIF
Solubility
Copper is slowly soluble in ammonia water, hot sulphuric acid,
nitric acid and is very slightly soluble in hydrochloric acid and
ammonium hydroxide. (HSDB, 1997; MEDITEXT, 1997)
Autoignition temperature
NIF
Chemical interactions
Zinc, aluminium or iron may cause metallic copper to precipitate
from solution.
Following explosion of copper azide, metallic copper and nitrogen
are formed.
Copper is attacked at a very slow rate by dilute sulphuric acid
or cold hydrochloric acid when exposed to the atmosphere. It is
rapidly attacked by acetic and other organic acids, hydrogen
bromide, hot concentrated sulphuric acid, alkalies and dilute
nitric acid.
A brownish-red precipitate of copper ferrocyanide is produced in
the presence of potassium ferrocyanide.
Copper is incompatible with 1-bromo-2-propyne.
Copper and brasses (down to 60 per cent copper) react readily in
the presence of wet acetylene and ammonia to form explosive
acetylides.
When acetylene comes in contact with copper that has been heated
to form a tarnish of copper oxide unstable acetylides are formed.
In the presence of copper, ethylene oxide, ammonium nitrate, lead
azide, acetylenic compounds and 3-bromopropyne form potentially
explosive reactions.
Copper forms an incandescent reaction with potassium dioxide.
(MEDITEXT, 1997)
Major products of combustion
NIF
Explosive limits
NA
Flammability
Copper powder may ignite. (NIOSH, 1997)
Boiling point
2595°C (DOSE, 1993)
Density
8.94 at 20°C (DOSE, 1993)
Vapour pressure
2666.4 at 1970°C (OHM/TADS, 1997)
Relative vapour density
NIF
Flash point
NA
Reactivity
Upon exposure to moist air, copper gradually develops a coating
of green basic carbonate.
On contact with water, liquid copper explodes.
Light friction, heat and percussion may cause combinations of
finely divided copper and bromates of magnesium, sodium, zinc,
potassium, calcium and barium to explode.
A readily explosive peroxide may form upon long standing.
The reacting mixture of copper, platinum, iron, phosphorus or
nickel may become incandescent when heated.
(MEDITEXT, 1997)
Uses
In electrical conductors such as wire and switches.
In applications where high electrical and thermal conductivity
are needed. Copper whiskers are used in thermal and electrical
composites.
In alloys such as bronze and brasses. Other copper alloys include
Monel metal and beryllium-copper.
In electroplated coatings and undercoatings for products made
from nickel, chromium, zinc, and in cooking utensils; also in
corrosion-resistant plumbing pipes, heating, roofing and building
construction materials.
In industrial machinery and automobiles.
In agricultural applications; copper and particularly copper
sulphate are used in insecticides, fungicides, herbicides, and
algicides.
In intrauterine contraceptive devices.
Miscellaneous uses including chemical and pharmaceutical
applications, as a pollution control catalyst, in pigments, dyes,
and anti-fouling paints, in works of art, coinage, fabrics,
textiles, glass, ceramics, cement, nylon, paper products,
printing, photocopying, pyrotechnics and wood preservatives, also
in ammunition, flameproofing, fuel additives and as insulation
for liquid fuels.
(HAZARDTEXT, 1997)
Hazard/risk classification
NIF
INTRODUCTION
Copper plays an important role as a co-factor in several
metalloproteins, including cytochrome oxidase and superoxide dismutase
and is essential for the utilization of iron and haemoglobin
formation. The daily copper intake among the general population is 1-2
mg/day with over 90 per cent in food (IPCS, 1996a).
The richest food sources of copper are shellfish, 'organ' meats,
seeds, nuts and grains where it is bound to specific proteins. Copper
tends to exist in the cupric Cu(II) state in biological systems
including water although it may also be found as Cu(I) (Linder and
Hazegh-Azam, 1996).
Menkes disease (Kinky hair syndrome) is an X-linked inherited copper
deficiency which manifests in the first six months of life with poor
growth, severe learning difficulties and hair abnormality. Copper
deficiency may be seen also as "Swayback" in lambs and calves born to
sheep and cows grazing on copper deficient pastures.
Wilson's disease is an inborn error of metabolism inherited as an
autosomal recessive trait whereby there is reduced biliary copper
excretion associated with decreased or absent circulating
caeruloplasmin (Schilsky, 1996). The disease is characterized by
excessive accumulation of copper in the liver, brain, kidneys and
cornea. Basal ganglia degeneration and cirrhosis are the principle
complications.
Most of the literature regarding copper poisoning relates to acute
ingestion or chronic inhalation of copper salts, notably copper
sulphate. Elemental copper may be a source of toxicity when leached
from copper piping into water supplies or inhaled occupationally as
dust or fumes (almost invariably with copper oxides). Copper fragments
may cause severe penetrating eye injury.
Separate UKPID monographs are available for the following:
Copper carbonate
Copper chloride
Copper oxide
Copper sulphate
EPIDEMIOLOGY
Significant copper contamination of domestic water supplies is rare
and only occurs where water is soft and acidic. A "minor epidemic" of
green hair occurred among college students following the introduction
of fluoride to the town water supply (Cooper and Goodman, 1975).
Acidic water flowing through copper pipes plus frequent hair washing
were likely aetiological factors.
Several cases of severe copper poisoning have occurred among patients
undergoing haemodialysis with copper contaminated water (Klein et al,
1972; Lyle et al, 1976) although copper components are no longer
permitted in haemodialysis systems.
Metal fume fever following occupational inhalation of copper fume is
recognized (Cohen, 1979) but not widely reported. It is a considerably
less significant problem than among zinc workers.
MECHANISM OF TOXICITY
Cellular damage and cell death may result from excess copper
accumulation. This is likely when copper-metallothionein binding and
copper clearance from the cell are blocked.
Metallothionein is a cysteine rich, low molecular weight (6500 Da)
metal-binding protein which is important in heavy metal
detoxification, metal ion storage, and in the regulation of normal
cellular Cu(II) (and Zn(II)) metabolism. It is also thought to be a
free radical scavenger, playing a protective role in oxidative stress.
Metallothionein is found in both intra- and extracellular
compartments. It is known to bind zinc, cadmium, copper, mercury and
silver (in increasing order of affinity) and its gene transcription is
greatly enhanced upon exposure of cells to these metals. High
metallothionein concentrations are also induced in the liver by
physical and chemical stress, infection and glucocorticoids.
It is proposed that free Cu(I) binds to intracellular sulphydryl
groups and inactivates enzymes such as glucose-6-phosphate
dehydrogenase and glutathione reductase (Dash, 1989). In addition
copper may interact with oxygen species (e.g. superoxide anions and
hydrogen peroxide) and catalyze the production of reactive toxic
hydroxyl radicals.
Copper(II) ions can oxidize haem iron to form methaemoglobin.
TOXICOKINETICS
Available toxicokinetic data are derived from studies using water
soluble divalent copper salts (usually the acetate, chloride or
sulphate).
Absorption and distribution
Strickland et al (1972) suggested a mean copper absorption of 57 per
cent (range 40 to 70 per cent) following oral administration of 0.4 -
4.5 mg copper (as copper acetate) to four volunteers. An early human
study suggested a maximum blood copper concentration was reached some
two hours after oral copper chloride administration (1.5 - 12 mg
copper) (Earl et al, 1954).
Copper transport across the intestinal mucosa following ingestion is
facilitated by cytosolic metallothionein. In blood, copper is
initially albumin-bound and transported via the hepatic portal
circulation to the liver where it is incorporated into caeruloplasmin
(an alpha globulin synthesized in hepatic microsomes) (Britton, 1996).
Ninety-eight per cent of copper in the systemic circulation is
caeruloplasmin-bound.
Copper is distributed to all tissues with the highest concentrations
in liver, heart, brain, kidneys and muscle. Intracellular copper is
predominantly metallothionein-bound. Kurisaki et al (1988) reported
copper in the lungs, liver, kidney, blood, bile and stomach (33.7,
35.1, 41.4, 13.8, 2.8, and 2988 µg/g wet weight respectively)
following ingestion of some 10 g copper sulphate in a 58 year-old
male. Although copper in the liver and kidneys was metallothionein
bound, pulmonary copper was not, probably because copper had entered
the lung via aspiration.
Copper ions can penetrate the erythrocyte membrane. Following acute
copper sulphate ingestion this occurs quite rapidly as indicated by
the markedly higher whole blood than serum copper concentration within
the first few hours of poisoning (Singh and Singh, 1968). In a series
of 40 cases of acute copper sulphate ingestion Singh and Singh (1968)
noted that haemolysis (secondary to erythrocyte copper uptake)
occurred typically 12-24 hours post poisoning, suggesting that red
cell copper accumulation is maximal around this time.
Studies among vineyard sprayers provide evidence of haematogenous
dissemination of inhaled copper (II) ions (Villar, 1974; Pimentel and
Menezes, 1977). Copper ions can also be absorbed through the skin
giving rise to systemic effects (Holtzman et al, 1966; Pande and
Gupta, 1969).
Copper can cross the placenta.
Excretion
Caeruloplasmin renders free copper innocuous with subsequent excretion
via a lysosome-to-bile pathway. This process is essential to normal
copper homeostasis and provides a protective mechanism in acute copper
poisoning. An impaired or overloaded biliary copper excretion system
results in hepatic copper accumulation, as occurs in patients with
Wilson's disease and in copper poisoning.
Renal copper elimination is normally low (Tauxe et al (1966) retrieved
less than one per cent of an injected copper acetate dose in the urine
over 72 hours) but will increase in acute copper poisoning. For
example, a child who ingested 3 grams copper sulphate had increased
urine copper concentrations (maximum 3.0 mg/L) for three weeks post
poisoning (Walsh et al, 1977).
In a series of 40 cases of acute copper sulphate ingestion increased
whole blood copper concentrations were noted up to ten days post
poisoning with values returning to normal over 17 hours to seven days
(Singh and Singh, 1968).
The whole-body half-life of copper has been estimated as approximately
four weeks (Strickland et al, 1972).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Elemental copper is not acutely toxic to intact skin.
Numerous shrapnel fragments penetrated the skin of a 55 year-old
chemist following the explosion of a copper azide solution, yielding
metallic copper and nitrogen (Bentur et al, 1988). Skull and hand
X-rays revealed the presence of multiple soft tissue foreign bodies
believed to be copper-covered glass, metallic copper and copper azide
debris. The patient was otherwise asymptomatic with normal full blood
count, kidney and liver function tests. Skin copper absorption was
estimated as 7.7 mg. Serum copper concentration 12 hours post exposure
was 0.83 mg/L, peaking at 1.24 mg/L four days post exposure (normal
0.7-1.4 mg/L). The copper serum half life was estimated at 167.4 days.
Chelation therapy was not administered and the patient remained
asymptomatic nine weeks later except for traumatic hand motor
dysfunction.
Ocular exposure
Intraocular copper foreign bodies from, for example, exploding brass
cartridges or war-time mines may cause serious injury. The extent of
penetration of the particles determines the nature of subsequent
damage. The smaller the particle and the further from the retina the
copper foreign body is located, the less damage will result (Grant and
Schuman, 1993).
If copper particles penetrate only as far as the anterior vitreous
they may take years to dissolve with gradual dissemination of copper
to the lens, cornea and iris producing green-brown discolouration
(chalcosis) and impaired visual acuity. Removal of the copper source
even years later may allow reversal of these effects (Grant and
Schuman, 1993).
Copper particles which penetrate as far as the retina may lead to
haemorrhage, abscess formation and connective tissue encapsulation.
The vitreous body is destroyed and retinal detachment may ensue.
Subsequently copper may escape its encapsulation and continue to do
damage. Oxidation products of metallic copper are believed to mediate
these effects (Grant and Schuman, 1993).
Open angle glaucoma is a rare complication of intraocular copper
dissemination from foreign bodies (Grant and Schuman, 1993).
Ingestion
Gastrointestinal toxicity
Abdominal pain, diarrhoea, nausea and vomiting have been reported
following ingestion of copper contaminated water (Spitalny et al,
1984; Knobeloch et al, 1994). Contamination of water supplies may
occur when water remains stagnant in a copper main or following
corrosion of copper plumbing materials. Leaching of copper from
plumbing materials is only significant when the water is extremely
soft and acidic. Copper contaminated water is usually first detected
by blue-green staining of laundry, sinks and tubs (at copper
concentrations above 1 mg/L) or an unpleasant smell and bitter taste
(at copper concentrations greater than 5 mg/L) (IPCS, 1996a).
The International Programme on Chemical Safety has suggested
copper(II) ion concentrations of some 30 mg/L are typically required
before acute gastrointestinal upset ensues although this "may vary
with the binding and chemical form of copper present" (IPCS, 1996b).
There are several reports where adverse gastrointestinal effects have
followed the consumption of water containing less than 10 mg/L copper.
In a study in Wisconsin during 1992-3 (Knobeloch et al, 1994), five
separate cases of gastrointestinal upset caused by copper-contaminated
drinking water were investigated. Children were thought to be more
susceptible to the effects of ingested copper in these circumstances
possibly due to a higher copper exposure in relation to body weight or
perhaps a greater sensitivity to the irritant effects of copper. The
authors concluded that water copper concentrations greater than 1.3
mg/L (the "federal action limit" in Wisconsin) commonly caused mild
gastrointestinal features (Knobeloch et al, 1994).
Three members of a family experienced recurrent abdominal pain and
vomiting between five and 20 minutes after ingestion of copper
contaminated water in beverages or with food over a period of some 12
months. Analysis of a sample of the water source revealed a copper
concentration of 7.8 mg/L. Hair and nail copper concentrations of one
of the children were elevated (1200 µg/g and 100 µg/g respectively;
normal range 11-53 µg/g). All symptoms resolved when the family ceased
drinking the water (Spitalny et al, 1984).
Persistent vomiting and diarrhoea resulting in weight loss and
dehydration in a six week-old female were attributed to copper
contaminated drinking water used to dilute her milk (Knobeloch et al,
1994). Analysis of water supplies from her home revealed copper
concentrations of 0.16-7.8 mg/L. Simultaneous elevated methaemoglobin
concentrations were attributed to nitrate contamination of the same
water supply. Her symptoms resolved when bottled water was used.
Similar symptoms were reported in a group of 15 nurses who experienced
nausea, vomiting, abdominal pain and diarrhoea within an hour of
ingesting alcohol which had been refrigerated in a copper-lined flask
at a cocktail party (Wyllie, 1957). Copper intake was estimated to
vary between 5.3 and 32 mg.
Oesophageal and stomach ulcers in association with epigastric pain
were described in a 49 year-old foundry worker one week following the
accidental ingestion of a small amount of melted copper (Shibuya et
al, 1992). Ulcer scars were noted on the tongue and several teeth were
"completely burnt out". Forty days post ingestion the patient could
swallow only liquids due to ulcer-induced oesophageal stricture
confirmed by barium meal. Computed tomography showed circular
oesophageal thickening progressing to occlusion. These injuries
necessitated total gastrectomy and thoracic oesophagus removal some
four months later. Histological findings showed thickened and densely
fibrosed oesophageal and gastric walls with deep ulceration extending
to muscle. The authors concluded that the copper primarily burned the
oesophageal mucosa and was cooled by the gastric juice at the lesser
curvature of the stomach.
Terry (1996) noted elevated serum copper and caeruloplasmin
concentrations in two females who had consumed copper-contaminated
water (concentration not stated). These abnormalities persisted
despite removal of the contaminating source. Further investigation
revealed they both were receiving hormone replacement therapy which
caused elevated caeruloplasmin, and hence total (but not free), copper
concentrations.
Pulmonary toxicity
Dyspnoea which resolved following three days oxygen therapy was
reported in a worker following melted copper ingestion (Shibuya et al,
1992).
Neurotoxicity
Headaches and dizziness in association with gastrointestinal upset
were reported in a group of nurses within an hour of ingesting an
alcoholic beverage which had been refrigerated in a copper-lined flask
(Wyllie, 1957). Estimated copper intake varied from 5.3-32 mg.
Recurrent headaches were also described in association with
gastrointestinal features in five adults and four children after
drinking copper-contaminated water (Knobeloch et al, 1994).
Inhalation
Occupational exposure to copper fumes may cause upper respiratory
tract irritation and sometimes symptoms of metal fume fever. These
complaints are, however, typically encountered in those working in the
copper industry for prolonged periods (see Chronic exposure).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
Parish (1975) noted that cases of green hair among copper workers have
been reported since 1882. In all cases it generally has been accepted
that copper staining was "from without and not within the hair"
(Parish, 1975).
Cooper and Goodman (1975) reported a "minor epidemic" of green hair in
girls from a state college following the introduction of fluoride to
the town water supply. Low pH water leaching copper from piping was a
possible cause of the discolouration. The authors noted that
individuals with blonde hair were affected mainly, although green
discolouration may not be as apparent in dark haired individuals. In
addition, Goldsmith and Holmes (1975) noted that, independent of any
copper effect, artificial hair bleaching may lead to green hair
discolouration on exposure to chlorinated water.
A hair copper concentration of 466 mg/kg (normal 4-128 mg/kg) was
measured in a six year-old boy who developed green hair following
repeated bathing in a swimming pool (Lampe et al, 1977). In another
case of "green hair" in a five year-old girl (Lampe et al, 1977),
water analysis revealed a copper concentration of only 0.9 mg/L. Hair
returned to normal following daily alternate washing with acidic and
basic shampoos. The source of small amounts of copper in the swimming
pool water was likely to be algicide residue or copper leached from
pipes.
Nordlund et al (1977) described two nursing students who acquired
green discolouration to blonde hair following a four to six week stay
in a university dormitory where they washed their hair daily. Analysis
of one student's hair revealed a copper concentration of 1042 ppm
(normal 17-38 ppm) and the copper concentration of the dormitory water
source was noted to range from 0.41 to 4 ppm (normal 0.25 ppm).
Interference from a faulty electrical connection to the copper water
pipes was thought to have resulted in increased amounts of ionized
copper in the supply.
Despite its widespread use, the sensitizing potential of copper has
been described as "extremely low" (Walton, 1983a). In patch tests
among 354 eczema patients, six tested positive to copper sulphate (5
per cent solution) and 39 to nickel sulphate (2.5 per cent solution)
(Walton, 1983a). All patients positive to copper sulphate were also
nickel sulphate positive. None of the subjects positive to copper
sulphate were occupationally exposed to copper or had a history of
atopy; all were females with hand eczema. The authors postulated
nickel- and copper-containing coins as the source of exposure.
Interpretation of these results was complicated by the possibility
that patients were sensitive to the nickel sulphate trace (0.01 per
cent) in the copper sulphate test solution. The author subsequently
demonstrated (Walton, 1983b) that the six copper sensitive patients
were patch test negative to nickel sulphate (0.01 per cent),
suggesting true copper sensitivity.
Further evidence of true copper allergy was presented by Van Joost et
al (1988) who described two females patch test positive to copper (as
sulphate 5 per cent) and nickel (as sulphate 2.5 per cent) in whom the
possibility of nickel contamination of the copper test solution was
largely excluded by the observation that 11 "control" nickel sensitive
patients each gave no positive reaction to the copper solution.
Epstein (1955) described combined nickel/copper sensitivity in 38 per
cent of 32 patients patch tested, and emphasized that many
nickel-containing alloys also contain copper. The author suggested the
frequency of cross-sensitivity reactions, the close chemical
relationship between copper and nickel (in adjacent positions in the
transition metal series of the periodic table) and evidence for a true
cross-sensitivity between nickel and cobalt as reasons to assume a
true cross-sensitivity between copper and nickel rather than a
coincidental occurrence of separate sensitivities (Epstein, 1955).
In 30 patients known to be contact sensitive to nickel but patch-test
negative to copper, the severity of patch test reaction to a
copper/nickel mixture was greater (p<0.001) than to nickel alone,
suggesting copper ions somehow enhanced the sensitivity reaction to
nickel (Santucci et al, 1993). The authors proposed that the presence
of copper ions facilitated the formation of nickel protein complexes
in the skin although the precise mechanism remains obscure.
In a study by Karlberg et al (1983), 13 of 1190 eczema patients showed
a patch test reaction to two per cent copper sulphate. However, these
patients had concomitant reactions to other known contact allergens
and serial dilution tests with copper sulphate provided no confirmed
cases of copper sulphate contact sensitivity. The authors recommended
a serial dilution test in cases of suspected copper allergy to
eliminate the possibility of an irritant effect and confirm whether
true copper sensitivity is present (Karlberg et al, 1983).
Chronic, low grade gingivitis was reported in an individual with a
copper-containing dental prosthesis. The gingivitis resolved after
replacement of the prosthesis with a non copper-containing device
(Trachtenberg, 1972). Urticarial hypersensitivity to copper-containing
dental cement has also been described (Reid, 1968)
An urticarial rash associated with angioedema and joint pain occurred
in a 24 year-old woman one month after insertion of a
copper-containing intrauterine contraceptive device (IUD) (Barkoff,
1976). She required treatment with adrenaline, systemic steroids and
antihistamines. She showed a positive scratch test reaction to copper
sulphate (one per cent solution) but was patch test negative to
copper. All symptoms resolved when the IUD was removed.
In conclusion, available evidence regarding copper contact sensitivity
suggests that while a true copper contact allergy exists, cross
sensitivity between nickel and copper contributes to many cases.
Copper also may cause an irritant dermatitis or a generalized type 1
hypersensitivity response.
Keratinization of the hands and soles of the feet have been reported
following chronic topical exposure to metallic copper but without
reference to original case data (Sittig, 1985).
Ingestion
Gastrointestinal toxicity
A 15 month-old infant who presented with failure to thrive and
diarrhoea was found to have a serum copper concentration increased to
2.9 mg/L which was attributed to the consumption of contaminated
domestic water (copper concentration 0.8 mg/L) for three months.
Resolution of symptoms and substantial weight gain accompanied removal
from exposure. The child also received a five week course of oral
d-penicillamine 75 mg tds which was associated initially with an
increased urine copper concentration (Salmon and Wright, 1971). The
water copper concentration reported in this case is well below the
provisional guideline value for drinking water of 2 mg/L (WHO, 1993)
which is defined as "the concentration of a constituent that does not
result in any significant risk to health ........ over a lifetime of
consumption" (IPCS, 1996b). This child must have had "abnormal
sensitivity to the metal" as the authors emphasized for copper
intoxication to occur. Wilson's disease was excluded by serum
caeruloplasmin assay and liver biopsy but another defect of copper
metabolism is possible.
A 46 year-old man who habitually ingested coins for several years
presented with a three day history of abdominal distension and
vomiting (Hasan et al, 1995). At laparotomy 700 coins were removed
from a markedly dilated stomach. The patient "became very unwell" post
operatively and died. At autopsy the gastric mucosa was inflamed and
oedematous but most pathological abnormalities were noted in the liver
(see below).
Hepatotoxicity
Indian childhood cirrhosis (ICC) is a frequently fatal disease
affecting children (mean age 18 months) in rural areas of India and is
caused by massive hepatic copper accumulation (Pandit and Bhave, 1983;
Pandit and Bhave, 1996). A high dietary copper intake, due to copper
leaching into milk from brass cooking vessels, is the most important
aetiological factor (Pandit and Bhave, 1983; Pandit and Bhave, 1996).
The milk protein casein has been shown to avidly bind copper and serve
as an effective metal ion carrier from brass to the infant (O'Neill
and Tanner, 1989). Fortunately the previously high incidence of ICC,
accounting for 10 per cent paediatric mortality in some Indian
hospitals (Pandit and Bhave, 1983), has been reduced dramatically by
an effective health education campaign aimed at maximizing breast
feeding and avoiding the use of copper-containing cooking utensils
(Pandit and Bhave, 1996). ICC is now rare in India.
Although a high dietary copper intake is undoubtedly the main cause of
ICC, the observed male preponderance and familial occurrence suggests
an inherited predisposition (Pandit and Bhave, 1996). Further support
for a genetic component in at least some cases of paediatric
copper-induced cirrhosis comes from reports of an ICC-like condition
among children in Western countries who have had a high, but not
massive, dietary copper intake (Mühlendahl and Lange, 1994).
A large-scale epidemiological survey in Massachusetts in 1993
concluded that a moderately increased domestic water copper
concentration alone does not cause liver disease (Scheinberg and
Sternlieb, 1994). In this study none of the 135 deaths occurring
between 1969 and 1991 in children under six years-old in three towns
with the highest tapwater copper concentration (8.5-8.8 mg/L) of any
"medium size" USA town, were attributed to any form of liver disease.
In conclusion it appears that idiopathic childhood cirrhosis is a
multifactorial disease which requires increased copper ingestion
superimposed on an inherited defect of copper metabolism to be
manifest fully.
A 15 month-old infant fed with copper-contaminated water (copper
concentration 0.8 mg/L) for three months developed transiently
increased liver enzyme activities in association with features of
gastrointestinal and neurological toxicity (Salmon and Wright, 1971).
As discussed above this child must have been predisposed to copper
toxicity since the water copper concentration was not particularly
high.
Walker-Smith and Blomfield (1973) described a 14 month-old infant who
died six weeks after presenting with clinical and histopathological
features of cirrhosis. The child had been bottle fed with
copper-contaminated water from an acidic private supply running
through domestic copper pipes (water copper concentration 6.75 mg/L).
A slightly low plasma caeruloplasmin concentration and raised urinary
copper excretion were consistent with Wilson's disease although the
acute presentation at such a young age suggested concomitant
abnormally high copper exposure was aetiologically significant.
Some six litres of ascites were drained during operation and a further
litre at autopsy from a 46 year-old male with a history of ingestion
of at least 700 coins (Hasan et al, 1995). Extensive liver fibrosis
was evident at autopsy. Histological findings included
intracanalicular bile plugs, bile ductule proliferation and lymphocyte
infiltration. Copper associated protein deposits were identified
throughout the hepatic parenchyma.
Neurotoxicity
Hypotonia, photophobia and "behaviour change" were noted in a young
child who presented with failure to thrive and was found to have an
increased serum copper concentration (2.9 mg/L) attributed to chronic
copper intoxication from a domestic water supply (Salmon and Wright,
1971).
Inhalation
Although upper respiratory tract irritation and metal fume fever are
cited as "common complaints" among copper workers (Cohen, 1979)
original case data are scarce. Metal fume fever is associated more
typically with zinc oxide inhalation (see Zinc monograph).
Occupational exposure to dusts and fumes of copper and copper salts
have been reported to cause nasal mucosal congestion and occasionally
nasal septum perforation but no original case data have been
identified (Scheinberg, 1983).
Employees complained of head stuffiness, "common cold" symptoms and
"sensations of chills or warmth" a few weeks after commencing copper
plate polishing (Gleason, 1968). Analysis of settled dust revealed
"major" amounts of copper and "minor" amounts of aluminium; air copper
concentrations ranged from 0.03 - 0.12 mg/m3. Following dust control
via exhaust ventilation air copper concentrations were reduced to less
than 0.008 mg/m3 and symptoms resolved.
A seven year study of 494 long term (21 years ± (SEM) 1) copper
refinery workers in Canada revealed no increased prevalence of chronic
obstructive pulmonary disease or small airways dysfunction (Ostiguy et
al, 1995). The plant workers were exposed to dusts of copper,
selenium, silver, lead, arsenic and "other trace metals" at
concentrations below the threshold limit value (TLV), suggesting TLV
enforcement was likely to have prevented the development of pulmonary
disorders. The authors concluded low concentration chronic exposure to
foundry fumes and metal dusts does not necessarily cause a significant
reduction in forced vital capacity and respiratory dysfunction.
Oral toxicity
Superficial green staining of the teeth was reported in a 21 year-old
brass foundry worker after 10 months exposure to fumes containing
approximately 75 per cent copper (Donoghue and Ferguson, 1996). The
authors suggested the staining was attributed to copper adherence from
the brass fume and its subsequent conversion to copper carbonate.
Neurotoxicity
A recent population based case control study among 144 Parkinsonian
patients and 464 controls in Detroit identified a significant
(p<0.05) association between Parkinson's disease and more than 20
years occupational copper exposure (Gorell et al, 1997). Chronic
manganese exposure was independently significantly associated with
this disorder. The neurological hazards of chronic inhalational metal
exposure require further clarification.
Injection
There are several case reports describing copper-intoxication
following haemodialysis with copper contaminated water; fatalities
have been described. Copper contamination occurs typically when copper
piping is used in the dialysate supply system (Lyle et al, 1976). A
faulty mains water deionizer which feeds acidic water to the
dialysate-making machine is an important cause of increased copper
leaching (Manzler and Schreiner, 1970).
"Copper fever" typically presents as an acute illness although failure
to identify the cause frequently leads to acute-on-chronic (Manzler
and Schreiner, 1970) or chronic (Lyle et al, 1976) copper exposure.
Copper components are no longer permitted in haemodialysis systems.
The clinical picture is likened by some authors to metal fume fever
(Lyle et al, 1976). Headache, myalgia, rigors, fever and
gastrointestinal upset typically occur at the time of dialysis,
improving over several hours when dialysis is stopped. Severe cases
may be complicated by delayed onset haemolytic anaemia as discussed
below.
Neurotoxicity
Dialysis associated headaches, fatigue, "chills" and myalgia resolved
in a nine year-old girl on haemodialysis following removal of a five
metre copper pipe between the softener and dialysate supply system
(Lyle et al, 1976). A 53 year-old male was admitted in coma,
responding only to painful stimuli, two days following his 219th
dialysis (Klein et al, 1972). At the time of dialysis he had developed
headache and diarrhoea, progressing to a stuporous state 36 hours
later, with haematological abnormalities (see below). The patient died
seven days after onset of symptoms despite exchange transfusion,
haemodialysis and peritoneal dialysis.
Gastrointestinal toxicity
Abdominal pain, nausea, vomiting and diarrhoea typically occur as
early features during haemodialysis with copper contaminated dialysate
and persist for up to 24 hours (Klein et al, 1972).
Increased serum amylase activity has been observed in
dialysis-associated copper toxicity (Klein et al, 1972). Autopsy
findings in fatal cases include necrotizing haemorrhagic pancreatitis
(Klein et al, 1972).
Musculoskeletal toxicity
Myalgia is a typical feature of dialysis-associated "copper fever". A
nine year-old female often experienced facial, back and limb pain
during or shortly after dialysis (Lyle et al, 1976).
Severe myalgia may be associated with copper-induced muscle damage and
the development of rhabdomyolysis with free serum myoglobin and
elevated creatine phosphokinase activity (Klein et al, 1972).
Haemotoxicity
Manzler and Schreiner (1970) described intravascular haemolysis as a
delayed complication of dialysis-associated copper intoxication. In a
typical case "chills", nausea, vomiting, abdominal pain and diarrhoea
occurred at the time of dialysis, improving over three hours but the
patient re-presented 18 hours later with recurrence of
gastrointestinal symptoms, profound postural hypotension and
intravascular haemolysis requiring a four unit blood transfusion.
In a similar case leukocytosis, haemolysis with reticulocytosis, a
decrease in haematocrit (17 per cent), and the presence of free serum
haemoglobin/myoglobin were observed in association with other systemic
features of copper poisoning following haemodialysis. The serum copper
concentration rose from 2.0 mg/L before dialysis to 26.6 mg/L post
dialysis. The patient died seven days later (Klein et al, 1972).
Cardiovascular toxicity
Several authors have observed orthostatic hypotension typically
associated with reflex tachycardia in haemodialysis patients exposed
to copper- contaminated dialysate (Manzler and Schreiner, 1970; Klein
et al, 1972).
Hypotension and cardiac arrhythmias were described in a patient four
days following haemodialysis with copper-contaminated dialysate. The
patient did not respond to therapy and died on the fifth hospital day
(Klein et al, 1972).
Metabolic disturbances
Metabolic acidosis is described in patients with
haemodialysis-associated copper poisoning (Klein et al, 1972).
Genitourinary toxicity
Acute and chronic orchitis were reported at autopsy in two patients
who died following haemodialysis-induced copper poisoning. It is
likely however that this was a complication of chronic haemodialysis
and/or uraemia rather than copper intoxication (Klein et al, 1972).
MANAGEMENT
Dermal exposure
Following acute exposure irrigate the affected area with lukewarm
water. Particular care is required if copper has been in prolonged
contact with broken skin since systemic copper uptake is then
possible.
Copper contact sensitivity or irritant dermatitis are managed most
effectively by discontinuing exposure.
Ocular exposure
Irrigate immediately with lukewarm water or preferably saline for at
least 10 minutes. A local anaesthetic may be indicated 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.
Copper foreign bodies pose a serious hazard to the eye, and if
suspected, an ophthalmological opinion should be obtained promptly.
The non-magnetic properties of copper complicate ocular removal.
Surgical removal often is necessary. Highly specialized techniques
have been established to accurately determine the extent of damage and
the precise intra-ocular location of copper foreign bodies (Grant and
Schuman, 1993).
Ingestion
Elemental copper is radiopaque allowing easy localization following
ingestion. In many circumstances, however, exposure is to ionized
copper.
Effective management of copper ingestion primarily involves
appropriate symptomatic and supportive care. Gastrointestinal
decontamination is most unlikely to favourably influence outcome and
should only be considered within the first hour after a potentially
life threatening ingestion. Liver function assessment is important,
especially in children, if chronic excess copper ingestion is
suspected. In these circumstances the serum copper concentration is
likely to be increased. The role of chelating agents is discussed
below.
Gastrointestinal burns following molten copper ingestion are managed
as a thermal burn with early endoscopy and a surgical opinion if
severe burns are present.
Inhalation
Metal fume fever is managed most effectively by removal from exposure.
Other symptomatic and supportive measures should be instituted
according to the patient's condition. There typically are no permanent
radiological abnormalities although transient ill-defined opacities on
chest X-ray are recognized.
Injection
Suspected copper toxicity in haemodialysis patients requires
confirmation by determination of the copper concentration in the water
supply. Management is essentially supportive following removal of the
copper source. Whole blood copper concentrations give some indication
of the body copper burden. Haematological, biochemical and
immunological profiles should be monitored. Intravascular haemolysis
is managed conventionally.
The use of chelating agents is limited since they primarily serve to
enhance renal copper elimination.
Antidotes
Animal studies
The application of dimercaprol-containing ointments or the injection
of aqueous dimercaprol into the eyes of animals with experimentally
induced penetrating copper injury was of no benefit (Grant and
Schuman, 1993).
d-Penicillamine, triethylenetetramine dihydrochloride (trien) and DMPS
each administered in a dose of 50 µmol/kg intraperitoneally daily for
five days were the most effective chelating agents in increasing
copper excretion in the urine (p<0.01) in copper-poisoned rats fed a
high copper diet for 20 days prior to chelation (Planas-Bohne, 1979).
Faecal copper excretion was unaffected. Other workers have
demonstrated enhanced renal copper elimination following parenteral
DMPS and DMSA (Maehashi et al, 1983).
Rana and Kumar (1983) suggested oral sodium calciumedetate (1g/kg
daily for ten days) could limit histopathological renal damage in rats
fed oral copper sulphate 0.1 g/kg daily for 20 days prior to chelation
therapy. Protection against copper-induced hepatic and renal lesions
was observed also in mice administered intraperitoneal DMPS 132 mg/kg
20 minutes after intraperitoneal copper sulphate 10 mg/kg
(approximately the LD50) (Mitchell et al, 1982).
DMPS was the most effective antidote in protecting against
copper-induced mortality in copper sulphate-intoxicated mice (10 mg/kg
intraperitoneally, LD50 8.7 mg/kg) administered intraperitoneal
antidotes 20 minutes post dosing at a 10:1 molar ratio antidote:
copper sulphate. Mice were observed for two weeks or until death. The
survival ratio following DMPS was 25/30, compared to 7/30, 5/15, 4/15,
3/15, 3/15 for d-penicillamine, triethylene-tetramine, sodium
calciumedetate, DMSA and dimercaprol respectively (p<0.0001 for DMPS
compared to all chelating agents except triethylenetetramine,
p<0.0005) (Jones et al, 1980).
Henderson et al (1985) investigated the effect of single and repeated
doses of chelating agents on copper toxicity. Copper intoxicated mice
(10-130 mg/kg subcutaneously) were given single doses of dimercaprol
10 mg/kg or N-acetylcysteine 200 mg/kg, 30 minutes post dosing. With a
single dose of chelating agent, the calculated LD50 (± SE) was
significantly (p<0.05) increased from 54.7 ± 10 mg/kg in control mice
to 95.2 ± 22 mg/kg and 87 ± 14 mg/kg in mice treated with dimercaprol
or NAC respectively. The chelating agents were even more effective
(p< 0.05) in copper-poisoned mice (40-170 mg/kg subcutaneously)
treated with repeated doses of chelating agent: dimercaprol 10 mg/kg,
N-acetylcysteine 200 mg/kg or d-penicillamine 50 mg/kg every hour for
five hours, with calculated LD50 values of 60.5 ± 12 mg/kg, 150.3 ±
35 mg/kg, 139.4 ± 8 mg/kg and 91.4 ± 16 mg/kg for controls,
dimercaprol, NAC and d-penicillamine treated mice respectively.
d-Penicillamine, 52 mg/kg daily for six days, significantly (p<0.05)
enhanced urinary copper excretion in four copper-poisoned sheep (given
20 mg/kg copper sulphate intraruminally daily for 35 days) (Botha et
al, 1993). Under the same conditions triethylenetetramine failed to
increase urinary copper excretion although the authors suggested this
might have been related to specific features of ruminant metabolism.
There is some evidence that polyamines structurally related to
triethylenetetramine (e.g. 2,3,2-tetramine) have a more potent
cupruretic action (Borthwick et al, 1980) but experience with these
agents is limited (Twedt et al, 1988).
Diethyldithiocarbamate (DDC) chelates copper but the lipophilic
chelate accumulates in tissues, especially the brain (Iwata et al,
1970; Jasim et al, 1985), suggesting it may be an unsuitable antidote
in copper poisoning. It has been suggested that DDC modifies the
permeability of cell membranes and the blood brain barrier to copper
(Allain and Krari, 1993).
Clinical studies
Wilson's disease
Wilson's disease, characterized by decreased biliary copper excretion
traditionally has been treated with d-penicillamine which serves to
increase urinary copper elimination (Scheinberg et al, 1987). Adverse
reactions to d-penicillamine are not uncommon and frequently are
immunologically rather than toxicologically-induced including
nephrotic syndrome, systemic lupus erythematosus (Walshe, 1982), white
cell dyscrasias, thrombocytopenia, haemolytic anaemia (Walshe, 1982)
and urticaria (Walshe, 1968). Anorexia, nausea and vomiting are
described (Walshe, 1968). In animal studies penicillamine induces
hepatic metallothionein (Heilmaier et al, 1986) which may disrupt the
body distribution of other trace elements. Adverse effects occur in up
to 10 per cent of patients receiving penicillamine and may necessitate
treatment withdrawal (Walshe, 1982). Thus, in recent years,
alternative agents have been investigated.
Sunderman et al (1963) advocated parenteral and/or oral DDC in the
management of Wilson's disease but evidence that this antidote
enhances cerebral copper uptake limits its usefulness (see above).
Walshe (1982) demonstrated increased urine copper elimination,
symptomatic improvement and resolution of basal-ganglia abnormalities
on CT brain scan among 20 patients with Wilson's disease treated with
triethylenetetramine. These authors suggested triethylenetetramine as
an effective drug for the treatment and maintenance of patients with
Wilson's disease at all stages of the illness. Others concur with this
view (Dubois et al, 1990; Morita et al, 1992) although there are
potential hazards of triethylenetetramine therapy, notably
sideroblastic anaemia (Perry et al, 1996).
Although zinc sulphate has been utilized as alternative therapy to
penicillamine in patients with Wilson's disease (Hoogenraad and Van
den Hamer, 1983; Van Caillie-Bertrand et al, 1985; Veen et al, 1991),
this treatment is unsuitable for acute copper poisoning as the
mechanism of benefit is reduced gastrointestinal copper absorption.
DMPS 200 mg bd increased urine copper elimination in a patient with
Wilson's disease (Walshe, 1985).
Acute poisoning
There are no controlled data regarding the use of any chelating agent
in acute copper poisoning. In severely poisoned patients the presence
of acute renal failure often limits the potential for antidotes which
enhance urinary copper elimination.
d-Penicillamine, the standard therapy for Wilson's disease, has been
utilized in copper poisoning (Holtzman et al, 1966; Jantsch et al,
1984/85; Hantson et al, 1996) but without confirmed evidence of
enhanced urinary copper excretion. Intramuscular dimercaprol
(Fairbanks, 1967; Jantsch et al, 1984/85; Schwartz and Schmidt, 1986;
Hantson et al, 1996) and intravenous sodium calciumedetate (Holleran,
1981; Agarwal et al, 1975) have also been employed but again without
confirmed benefit.
A five year-old child with copper intoxication following repeated
application of copper sulphate crystals to skin burns received a 12
day course of d-penicillamine 250 mg qds (Holtzman et al, 1966). Six
hour urine copper excretion on the first day of chelation was 1000 µg,
with a maximum value of 2000 µg/6h some 24 hours later. No pre- or
post-chelation copper excretion data were given.
Jantsch et al (1984/85) advocated the use of chelation therapy with
dimercaprol and d-penicillamine following their experience with a
patient who survived the alleged ingestion of 250 g copper sulphate. A
single intramuscular dimercaprol dose 4 mg/kg was administered within
the first ten hours (time not specified) followed by oral
d-penicillamine 250 mg qds for at least seven days. The only 24 hour
urine copper excretion measured "after initiation of chelation
therapy" was 8160 µg (time not specified) with no pre- or
post-chelation data presented. This case was unusual in that despite
massive copper sulphate ingestion the patient developed no features of
severe gastrointestinal irritation (save initial vomiting), no
haemolysis or oliguria.
Walsh et al (1977) administered intramuscular dimercaprol 2.5 g/kg
(?2.5 mg/kg) plus 12.5 g/kg (?12.5 mg/kg) "edetic acid" four hourly to
an 18 month-old child, commencing five hours after ingestion of 3 g
copper sulphate. The urine copper concentration from a two hour
collection was 500 µg/L on the second day, increasing to 3000 µg/L on
day 12. The chelating agent was then switched to d-penicillamine 250
mg daily for one month with a gradual fall in urine copper excretion.
Unfortunately urine volumes were not stated and no pre-chelation
measurements were possible.
Hantson et al (1996) recently treated an 86 year-old woman with acute
copper sulphate poisoning with intramuscular dimercaprol 4 mg/kg qds
and oral d-penicillamine 250 mg qds, both commenced within four hours
of poisoning. Urine copper elimination was not enhanced and chelation
was discontinued after 48 hours following onset of renal failure.
These authors concluded that "available clinical and toxicokinetic
data do not support the benefits of chelation in addition to
supportive therapy" in acute copper (and zinc) sulphate poisoning.
Alkaline diuresis
Muthusethupathi et al (1988) advocated forced alkaline diuresis in
copper sulphate poisoning. In 103 copper sulphate-poisoned patients in
whom gastric lavage followed by forced alkaline diuresis were
instituted immediately, the incidence of renal failure was claimed to
be substantially lower (14.6 per cent) than in other similar series.
However, no copper excretion data were reported, and it is possible
that prompt fluid resuscitation with correction of hypovolaemia played
an important role in patient recovery (Muthusethupathi et al, 1988).
Haemodialysis
Haemodialysis for five hours in a 41 year-old female failed to remove
copper when instituted 12 hours after the ingestion of 280 mL
dissolved copper sulphate (Agarwal et al, 1975). The patient had
already undergone gastric lavage, had received intravenous sodium
calciumedetate (1g) and a blood transfusion but died on the sixth
hospital day after developing septicaemia, hepatic and renal failure.
Peritoneal dialysis
Cole and Lirenman (1978) reported a two year old child who had
ingested some 30 mL super-saturated copper sulphate solution and
underwent peritoneal dialysis for the management of renal failure.
Copper extraction into the dialysate was enhanced markedly by the
addition of salt-poor albumin 25 g/L. Over a 40 hour dialysis period
(between 17 and 57 hours post ingestion) 0.7 mg copper was removed in
17 litres dialysate compared to 9.1 mg copper removed in 24 litres
during dialysis with added albumin between 57 and 117 hours. The
authors advocated albumin-enriched peritoneal dialysis in the
management of copper poisoning complicated by acute renal failure. It
should be noted, however, that the child consumed at least 2.7 g
copper so that the amount removed by dialysis, even with albumin, was
small.
Enhancing elimination: Conclusions and recommendations
1. There are no controlled clinical data regarding the use of
chelating agents in copper poisoning.
2. Animal data suggest DMPS may be the most effective antidote in
copper poisoning, though DMPS was administered within 20 minutes
of copper dosing in these studies. DMPS has a more favourable
adverse effect profile than dimercaprol and d-penicillamine
although these are alternatives if DMPS is not available. DMPS
usually is given orally or parenterally in a dose of 30 mg/kg
body weight per day. Side effects are infrequent but have
included allergic skin reactions, nausea and vertigo (Aposhian,
1983). Discussion of individual cases with an NPIS physician is
recommended.
3. There is insufficient evidence to advocate alkaline diuresis in
the management of acute copper poisoning.
4. The role of haemodialysis and peritoneal dialysis is limited to
the management of renal failure.
Management of copper and caeruloplasmin concentrations in
biological fluids
Although whole blood copper concentrations correlate well with the
severity of poisoning following acute ingestion, they should always be
interpreted in conjunction with the clinical features. Serum copper
concentrations are less useful in acute intoxications (Chuttani et al,
1965). In 20 patients who ingested copper sulphate, mean (± SD) whole
blood copper concentrations were markedly lower (2.9 ± 1.3 mg/L) in
those with only gastrointestinal symptoms compared to those who
developed jaundice, renal failure or shock (mean whole blood copper
8.0 ± 4.0 mg/L). The number of patients in each group was not stated.
Among 65 cases of acute copper sulphate poisoning, Wahal et al (1976)
observed that although patients who developed complications had higher
whole blood, red cell and plasma copper concentrations than
uncomplicated cases, the difference was not statistically significant
(p>0.05). No correlation was found between plasma copper
concentrations and prognosis. However, whole blood copper
concentrations greater than 1.2 mg/L were associated generally with
the development of complications. The four fatalities reported, who
were admitted within 6-8 hours of ingestion, had whole blood
concentrations of at least 2.1 mg/L.
Serum caeruloplasmin concentration estimation has been suggested as a
useful prognostic indicator in cases of acute copper sulphate
poisoning. Wahal et al (1978) observed significantly higher (p<0.001)
serum caeruloplasmin concentrations in uncomplicated cases of copper
sulphate poisoning than in those with complications (gastrointestinal
haemorrhage, jaundice, renal impairment, delirium or coma). Values
less than 35 mg/dL within 24 hours of poisoning or less than 44 mg/dL
beyond 72 hours post ingestion were associated with the development of
complications.
Increased urine copper excretion (preferably as a 24 hour collection)
will be present in any moderate or severe case of copper sulphate
poisoning. The main value of this measurement is to monitor the effect
of chelation therapy.
AT RISK GROUPS
Infants are at increased risk of excess copper accumulation during the
first three months of life since their hepatic copper stores are
significantly higher than in adults. This is due to the presence of
fetal copper-binding protein which enables the fetal liver to
accumulate sufficient copper to maintain body stores despite the
relatively lower copper content of breast milk (Walker-Smith and
Blomfield, 1973).
MEDICAL SURVEILLANCE
Close attention to personal hygiene and the use of appropriate
protective equipment are of primary importance among those
occupationally exposed to copper.
Twenty-four hour urine copper excretion is a useful screening
procedure if copper intoxication is suspected but the source of
exposure is unclear. However, when collected in an occupational
setting great care must be taken to avoid sample contamination. Serum
or whole blood copper concentrations may be useful if exogenous copper
contamination of urine samples is suspected (Cohen, 1979). It should
be remembered that impaired biliary copper excretion from any cause
will lead to increased renal copper elimination.
Pre-employment screening for Wilson's disease may be indicated in
those occupationally exposed to copper.
Normal copper concentrations in biological fluids
Plasma/serum: 0.7 - 1.3 mg/L (Weatherall et al, 1996).
Whole blood: 1.6 - 2.7 mg/L (Chuttani et al, 1965).
Urine: Less than 60 µg/24h (Weatherall et al, 1996).
OCCUPATIONAL DATA
Occupational exposure standard
Copper: Long-term exposure limit (8 hour TWA reference period) fume
0.2 mg/m3; dusts and mists 1 mg/m3 (Health and Safety Executive,
1997).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There is no conclusive evidence that copper is carcinogenic in humans
(Aaseth and Norseth, 1986). Enterline et al (1995) studied the
incidence of cancer in a cohort of 2802 copper smelters employed for
at least one year during the period 1940-64. A significant (p<0.01)
increase in deaths from respiratory cancer (SMR 209.7) was noted
during the follow-up period 1941-86 but were attributed to cumulative
arsenic rather than copper exposure during employment.
Chewing copper-containing Areca nuts, common in the Orient, has been
associated with oral submucous fibrosis and an increased risk of oral
cancer (World Health Organization, 1984). In three volunteers saliva
copper concentrations were significantly (p<0.001) increased during
nut chewing compared to control values (Trivedy et al, 1997). The
authors suggested copper released from the nuts induced lysyl oxidase
activity, upregulating collagen synthesis and facilitating its cross-
linking, resulting in connective tissue accumulation.
Reprotoxicity
In a controlled study Barash et al (1990) investigated the teratogenic
potential of copper releasing intrauterine contraceptive devices (IUD)
on the developing human embryo. No malformations or copper deposits
were observed in the organs/placentae of copper IUD-exposed embryos
(n=11) examined between seven and 12 weeks gestation. The results from
the small study suggest that copper releasing IUDs have no observed
negative effects on the developing embryo.
Genotoxicity
Copper induced sister chromatid exchanges in human peripheral
lymphocytes (DOSE, 1993).
Fish toxicity
Chronic, partial chronic and early life stage toxicity tests were
carried out on bluegill sunfish, bluntnose minnow, king salmon,
fathead minnow and brook trout. The study duration was 30-60 days
post-hatch. Under hard water conditions for fat head minnow the lowest
observed effect concentration (LOEC) - no observed effect
concentration (NOEC) was 33-15 µg/L and for the bluntnose minnow 18-4
µg/L. The reproduction part of the life cycle gave the most sensitive
responses.
In a chronic study (30-60 days post-hatch) with fathead minnow and
bluegill sunfish, in soft water conditions LOEC-NOEC range was 40-11
µg/L, fry survival was the most sensitive response. A partial chronic
study (30-60 days post-hatch) the LOEC-NOEC for brook trout was 17-9
µg/L, fry growth and survival were the most sensitive responses.
LC50 (96 hr) Oreochromis niloticus 1.06 mg/L.
LC50 (96 hr) rainbow trout 0.253 mg/L.
LC50 (48 hr) larvae of flat fish Paralichthys olivaceus 0.36 mg/L
(Cu2+).
The fertilized eggs of Cyprinus carpio (108 hr) were exposed to 10,
50, 70 and 100 ppb copper. Survival of developing eggs, hatchlings,
hatching and hatchability percentage decreased with increasing
concentration. Deformities observed were formation of blisters, curved
tail, stunted growth, circulatory failure, enlargement of the
pericardial sac, deformed head region, underdeveloped fins and
deformed vertebral column.
Rainbow trout exposed to a number of combinations of copper, water
hardness and pH showed reduced growth rate during the first 10 days,
followed by partial or complete recovery. The lethal concentration of
copper to rainbow trout was not affected by alkalinity at 10-50 ppm in
soft water, however, the toxicity doubled by the same alkalinity
change in hard water. Synergism between pH value and copper toxicity
was observed (DOSE, 1993).
EC Directive on Drinking water quality 80/778/EEC
EC advisory level for drinking water, 100 µg/L at source of supply;
3000 µg/L after standing in piping for 12 hours (DOSE, 1993).
WHO Guidelines for Drinking Water quality
Guideline value for drinking water 2 mg/L (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
28/1/98
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