Cadmium
1. NAME
1.1 Substance
Cadmium
1.2 Group
Cadmium (atomic number 48, relative atomic mass 112.40) occurs
in the 0 and +2 oxidation states. It forms many divalent
compounds, mostly inorganic.
1.3 Synonyms
1.4 Identification numbers
1.4.1 CAS number
Cadmium 7440-43-9
Cadmium acetate hydrate 89759-80-8
Cadmium acetate dihydrate 5743-04-4
Cadmium carbonate 515-78-0
Cadmium chloride 10108-64-2
Cadmium chloride hemi-pentahydrate 7790-78-5
Cadmium cyclohexane-butyrate 55700-14-6
Cadmium fluoborate 14486-19-2
Cadmium fluoride 7790-79-6
Cadmium fluosilicate 17010-21-8
Cadmium iodide 7790-80-9
Cadmium lactate 16039-55-7
Cadmium nitrate 10325-94-7
Cadmium nitrate tetrahydrate 10022-68-1
Cadmium oxide 1306-19-0
Cadmium oxide fume 1306-19-0
Cadmium phosphate 13477-1-3
Cadmium selenide 1306-24-7
Cadmium succinate 141-00-4
Cadmium sulfate 10124-36-4
Cadmium sulphate hydrate 7790-84-3
Cadmium sulphate monohydrate 13477-20-8
Cadmium sulphate tetrahydrate 13477-21-9
Cadmium sulphide 1306-23-6
1.4.2 Other numbers
United Nations (UN) Transportation Number Cadmium
compounds 2570 (UN, 1985)
1.5 Main brand names/Main trade names
To be completed by the PCC.
1.6 Main manufacturers/Main importers
To be completed by the PCC.
2. SUMMARY
2.1 Main risks and target organs
The main risks and target organs depend on the form of cadmium
and on the route of entry.
Inhalation of cadmium-containing fumes or dust.
Acute exposure: effects on the respiratory tract and lungs with
bronchitis, pulmonary oedema, interstitial pneumonia.
Chronic exposure: effects on the kidneys and lungs with
proteinuria, impairment of lung function.
Ingestion of cadmium salts
Acute exposure: effects on the gastrointestinal tract, nervous
system, kidneys, liver, cardiovascular system.
Chronic exposure: effects on the kidneys and bone with
proteinuria, renal stones and Itai-itai disease.
2.2 Summary of clinical effects
Acute poisoning
Inhalation of cadmium fumes or dust
There is usually a latent period of 4-12 hours between the
exposure and the onset of symptoms. Initial presentation
simulates metal fume fever: chills fever, headache, weakness,
dryness of the nose and throat, chest pain, dyspnoea, cough,
metallic taste, conjunctivitis, rhinitis, bronchitis. Nausea
and vomiting may also be observed. In severe intoxication,
patients may develop acute pneumonitis and lesional pulmonary
oedema with respiratory failure which can progress to death in
3 - 7 days (Beton et al., 1966; Townshend, 1968; Winston, 1971;
Townshend, 1982; Friberg & Elinder, 1983; Taylor et al., 1984;
Sittig, 1985; Barnhart & Rosenstock, 1984; Ellenhorn &
Barceloux, 1988; Yates & Goldman, 1990).
Ingestion of cadmium salts
Symptoms begin almost immediately after ingestion and include
vomiting, diarrhoea and abdominal pain. In severe poisoning,
facial oedema, hypotension, pulmonary oedema, metabolic
acidosis, oliguria and finally death have been reported
(Buckler et al., 1986; Bernard & Lauwerys, 1986a; Ellenhorn &
Barceloux, 1988).
Chronic poisoning
Inhalation (occupational exposure)
Chronic poisoning may appear after several years of
exposure.
The earliest sign of cadmium-induced nephropathy is increased
proteinuria, in particular 2-microglobulin. ( Friberg, 1948;
Potts, 1965; Tsuchiya, 1967). Increased excretion of calcium
and phosphorus may disturb bone metabolism, and kidney stones
have been found in exposed workers (Friberg & Elinder, 1983).
There may also be a decrease in the ability of the kidneys to
concentrate urine (Friberg et al., 1974). The mortality of
long-term exposure to cadmium is uncertain ( Andersson et al.,
1983; Armstrong & Kazantzis, 1983).
Impairment of lung function has been described in workers
subject to cadmium exposure by inhalation. The changes involve
bronchitis and a mild form of obstructive lung disease with
functional impairment which may progress to emphysema.
Interstitial fibrosis may also be observed (Lauwerys et al.,
1974; Smith et al., 1976; Stanescu et al., 1977; De Silva &
Donnan, 1981; Friberg & Elinder, 1983; Armstrong & Kazantzis,
1983; Sittig, 1985; Goyer,1986).
Ingestion (environmental exposure)
In cadmium-polluted areas of Japan renal damage has also
been observed in the general population (Kjellstrom et al.,
1977b; Shiroishi et al., 1977; Saito et al., 1977; Kojima et
al., 1977). A higher incidence of proteinuria, and ß 2-
microglobinuria has been observed in the Jintzu river basin
in Toyama Prefecture and in other areas where high
concentrations of cadmium have been discovered in rice. The
increased urinary excretion of ß 2-microglobulin was
strongly related to the residence time in that area and to
the cadmium level in urine and blood of the affected
individuals (Kjellstrom et al., 1977b).
Bone effects: Bone lesions are usually a late manifestation
of severe chronic cadmium poisoning. They are characterized
by osteomalacia, osteoporosis and spontaneous fractures.
Signs and symptoms include skeletal deformities, decreased
height, difficulty in walking, duck-like gait, pain in the
back and extremities, and pain resulting from pressure on
the bones (Bernard & Lauwerys, 1986b; Hallenbeck, 1986).
2.3 Diagnosis
Although the total body burden of cadmium is difficult to
assess without a renal biopsy, the blood cadmium level is the
best measure of recent exposure. Levels above 7 µg/L indicate
significant exposure. In case of acute inhalation of cadmium
fumes perform a chest x-ray and monitor arterial blood gases.
In chronic poisoning, renal damage may be evaluated by the
concentration of urinary proteins such as b-2 microglobulin;
the concentration of cadmium in the urine; and/or the
concentration of cadmium in the renal cortex. The urinary
activity of a-N-acetylglucosaminidase is also a sensitive
indicator of excessive absorption of cadmium. In non-
occupationally exposed individuals the urinary excretion of
cadmium is very low (about 2 mg/day or less).
2.4 First-aid measures and management principles
Acute poisoning
By inhalation: The patient should be removed from exposure as
soon as possible. Because the onset of symptoms is delayed the
patient should seek medical attention as soon as possible.
Monitor respiratory function: chest x-ray and blood gases.
By ingestion: If the patient has not already vomited, induce
vomiting with syrup of ipecac or perform gastric lavage.
Local effects from skin exposure: Wash skin immediately with
copious amounts of water for at least 15 minutes. Remove
contaminated clothing. Wash eyes with copious amounts of water
for at least 15 minutes.
The treatment of respiratory or cardiovascular disturbances is
supportive.
Antidotal treatment with EDTA has been proposed in acute
poisoning.
Chronic poisoning: Treatment is supportive.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Cadmium metal does not occur naturally. The only cadmium
mineral is greenockite (CdS), which exists as a coating on the
zinc sulphide ore sphalerite and is very rare.
Small amounts of cadmium are found in zinc, copper and lead
ores. It is generally produced as a by-product from the
smelting of these metals, particularly zinc.
It is obtained by precipitation from zinc electrolyte in
electrolytic zinc refining; recovery from the fumes of zinc
calcine sintering plants; the fumes of lead and copper
smelters; and during the distillation and refining of zinc. It
may be in the form of a chloride, oxide or sulphate which is
then leached, electrolysed, precipitated and cast into bars,
balls or anodes for electroplating (Stokinger, 1981; Friberg &
Elinder, 1983; Sittig, 1985).
3.2 Chemical structure (formula, molecular weight)
The chemical structures and molecular weigths of the main
cadmium compounds are as follows:
Name Structure Molecular weight
Cadmium Cd 112.40
Cadmium carbonate CdCO3 172.41
Cadmium chloride CdCl2 183.32
Cadmium fluoride CdF2 150.40
Cadmium iodide CdI2 366.21
Cadmium oxide CdO 128.40
Cadmium selenate CdSeO4 191.36
Cadmium sulphate CdSO4 208.46
Cadmium sulphide CdS 144.46
(Weast, 1976-7)
3.3 Physical properties
Cadmium is a soft, ductile, bluish-white electropositive metal,
which is very resistant to corrosion. It has many chemical and
physical similarities to zinc and occurs together with this
metal in many natural forms (Stokinger, 1981; Friberg &
Elinder, 1983; Sittig, 1985).
Cadmium dust includes various cadmium compounds such as cadmium
chloride. Cadmium fumes consist of minute particles of cadmium
or cadmium oxide formed during combustion (Sittig, 1985).
Cadmium loses its lustre in moist air and is rapidly
corroded by moist ammonia and sulphur dioxide (Stokinger,
1981). The metal is soluble in acids but insoluble in water
(Stokinger, 1981; Sittig, 1985).
Cadmium ions are precipitated from solution by hydroxide ions,
and form insoluble white hydrated compounds with carbonates,
phosphates, arsenates, oxalates and ferrocyanides. All of these
compounds are soluble in ammonium hydroxide with the formation
of complex cations containing cadmium and ammonia.
Solubilities of cadmium compounds (Windholtz et al., 1976)
Name Soluble Insoluble
Cadmium - Water
Cadmium acetate Water, alcohol -
Cadmium bromide Water, alcohol, -
acetone(mod), ether(sl) -
Cadmium carbonate Dil acids Water
Cadmium chloride Water, acetone, Ether
methanol(sl), ethanol(sl) -
Cadmium fluoride Water, acids Alcohol, NH4OH
Name Soluble Insoluble
Cadmium hydroxide NaOH (sl), dil acids, Water
NH4OH, NH4Cl
Cadmium iodide Water, alcohol, ether, -
acetone
Cadmium nitrate Water, alcohol, acetone, Conc HNO3
ethyl acetate
Cadmium oxide Dil acids, NH4 salts Water
Cadmium selenate Water -
Cadmium selenide - Water
Cadmium sulphate Water Alcohol, ethyl
acetate
Cadmium sulphide Conc or warm dil acids Water
conc = concentrated
dil = dilute
mod = moderately
sl = slightly
3.4 Other characteristics
Cadmium dust is reactive with strong oxidizing agents,
elemental sulphur, selenium and tellurium (Sittig, 1985).
Most cadmium compounds are reactive with oxidizing agents,
strong acids and bases, potassium and magnesium (Lenga, 1988).
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
The main use of cadmium is the electroplating of other metals,
mainly steel, iron and copper. Almost 50% of all cadmium is
used for this purpose. Cadmium may also be alloyed with copper,
nickel, gold, silver, bismuth and aluminium to form easily
fusible compounds which can be used as coatings for other
materials, and in welding and in soldering processes (Friberg &
Elinder, 1983; Sittig, 1985).
In addition, cadmium compounds are used in the production of
pigments and dyes (cadmium sulphide, cadmium sulphoselenide),
as stabilizers in plastics (cadmium stearate), and in the
electrodes of nickel-cadmium alkaline batteries.
Cadmium compounds are also used in printing, in textiles, in
television phosphors, photography, lasers, in semiconductors,
pyrotechnics, solar cells, scintillation counters, as a neutron
absorber in nuclear reactors, in dental amalgams, in the
manufacture of fluorescent lamps, in jewellery, in engraving,
in the automobile and aircraft industries, as pesticides,
polymerization catalysts and in paints and glass. Cadmium is
found in superphosphate fertilizers (Stokinger, 1981; Friberg &
Elinder 1983).
Guidance on safe disposal: recover for re-use or recycling,
and bury in a landfill according to local regulations.
4.2 High risk circumstances of poisoning
Inhalation of cadmium fumes and dust by persons employed in the
smelting and refining of cadmium ores, in the electroplating
industry, during heating, grinding, welding and soldering
operations involving cadmium-containing metal products, in the
production of cadmium pigments and in the plastics industry.
(Friberg & Elinder, 1983; Bernard & Lauwerys, 1986a).
The ingestion of food and beverages contaminated with cadmium,
the use of cadmium-plated cooking utensils, and the storage of
acid juice in cadmium-containing earthenware can cause
gastrointestinal toxicity. Acute oral intoxication has also
been observed in workers exposed to cadmium dust who employ
proper hygiene measures (Bernard & Lauwerys, 1986a).
Environmental risks
Increased emissions of cadmium from the production, use and
waste disposal of the metal, combined with its long-term
persistence in the environment and its relatively rapid uptake
and accumulation by food chain crops, contribute to its
potential hazard. Soils may be contaminated with cadmium from
the air, by the application of water, fertilizers or pesticides
which contain cadmium, or by the discharge of cadmium-
containing waste materials. (Page et al., 1986).
Excessive cadmium exposure has also occurred in the general
population through the ingestion of contaminated food and water
(Kjellstrom et al., 1977b; Kojima et al., 1977; Friberg &
Elinder, 1983).
4.3 Occupationally exposed populations
Zinc and lead refiners, welders, solder workers, alloy makers,
battery makers, engravers, textile workers and various
electronics workers (Ellenhorn & Barceloux, 1988).
5. ROUTES OF ENTRY
5.1 Oral
Although cadmium compounds are relatively poorly absorbed from
the gastrointestinal tract (McLellan et al., 1978), the
occurrence of systemic toxicity following ingestion (Buckler et
al., 1986) indicates that the absorption of cadmium from the
gastrointestinal tract does occur and therefore that all
cadmium compounds should be considered potentially harmful if
ingested.
5.2 Inhalation
The occurrence of fulminant acute pneumonitis and pulmonary
oedema as well as neurotoxic effects following exposure to
cadmium-containing dusts and fumes (see e.g. Beton et al.,
1966; Barnhart & Rosenstock, 1984) indicates that inhalation
of cadmium compounds must be considered serious and
potentially fatal (Sittig, 1985; Lenga, 1988).
5.3 Dermal
Although dermal absorption of cadmium is not likely to be
important, skin irritation may be caused by some cadmium
compounds (Sittig, 1985; Lenga, 1988).
5.4 Eye
Exposure to many cadmium compounds as well as cadmium dusts and
fumes is likely to produce severe corrosive damages to the eye
(Lenga, 1988).
5.5 Parenteral
No relevant data available
5.6 Others
No relevant data available.
6. KINETICS
6.1 Absorption by route of exposure
Oral exposure
During chronic background exposure, gastrointestinal absorption
of cadmium is of the order of 2-8% (McLellan et al., 1978;
Friberg & Elinder, 1983; Goyer, 1986). It has been estimated
that a European adult absorbs 1.4 - 8 µg of cadmium per day
(Lauwerys, 1982). Physiological and nutritional factors may
modify this: in people with low body stores of iron the
absorption of cadmium may be significantly higher than in
subjects with normal iron stores (Flanagan et al., 1978).
Cadmium absorption tends to be higher in females than in males.
Animal experiments have shown that a low intake of calcium and
protein may considerably increase the intestinal absorption of
cadmium (Suzuki et al., 1969).
Inhalation
Cadmium concentrations in ambient air are in the order of
0.001-0.005 µg/m3 in rural areas, 0.003-0.05 µg/m3 in urban
areas and up to 0.6 µg/m3 near cadmium-emitting sources
(Bernard & Lauwerys, 1986a).
Much higher concentrations may occur in particular occupational
environments. The rate of absorption of cadmium through the
lungs is a function of the solubility and surface area of the
inhaled particles. 20-30% of the inhaled cadmium is probably
retained in the lungs. Therefore, the amount of cadmium
retained in the respiratory tract would be 0.005-0.025 µg in
rural areas, 0.015-0.250 µg in urban areas and up to about 3 ug
per day in areas near cadmium-emitting sources. On the
assumption that up to about 60% of the retained cadmium is
absorbed (Lauwerys, 1982) the amount of cadmium effectively
absorbed by the lungs is unlikely to be much greater than about
0.2 µg per day (Bernard & Lauwerys, 1986a).
Cigarette smoking adds considerably to cadmium intake.
Friberg et al. (1974) estimated a daily intake of 2-4 µg of
cadmium from the smoking of one packet of cigarettes per
day.
6.2 Distribution by route of exposure
Ingestion and Inhalation: Cadmium is transported in the blood
bound mainly in red cells (more than 90%) or bound to high
molecular weight proteins in the plasma (Bernard & Lauwerys,
1986a; Goyer, 1986).
Cadmium is distributed particularly in the liver and kidneys,
where the production of metallothionein is induced. About 80-
90% of cadmium in the body is bound to metallothionein (Friberg
& Elinder, 1983). At steady state the kidney and liver have
the highest concentrations of cadmium and contain about 30 and
20% of the body burden of the metal, respectively. (Friberg et
al., 1979; Bernard & Lauwerys, 1986a; Goyer, 1986).
The concentration of cadmium in the renal cortex at 40-50 years
of age is between 15 and 50 µg/g (Piscator & Lind, 1972;
Kjellstrom, 1979). In acute exposure most of the cadmium is
distributed to the liver but redistribution to the kidneys
occurs following hepatic production of metallothionein.
The thyroid, the pancreas and the salivary glands also
accumulate significant amounts of cadmium.
Placental transfer of cadmium is limited. Cadmium concentration
in newborn blood is on average 50% lower than in maternal blood
(Lauwerys et al., 1978).
6.3 Biological half-life by route of exposure
The half-life of cadmium in the body is not known but estimates
range from 208 - 14 years (Kjellstrom & Nordberg, 1978) to 20 -
40 years (Friberg et al., 1974).
6.4 Metabolism
There is no evidence that the divalent cadmium cation undergoes
biotransformation in man.
6.5 Elimination by route of exposure
Cadmium is eliminated mainly in urine. The amount excreted
daily represents only about 0.005-0.010% of the total body
burden (Friberg et al., 1974). Excretion is proportional to the
body burden (Lauwerys et al., 1974; Roels et al., 1981a) and
increases up to 50-60 years of age (Elinder et al., 1978).
In persons not occupationally exposed to cadmium the urinary
excretion is normally less than 2 µg/day (Bernard & Lauwerys,
1986a).
7. TOXICOLOGY
7.1 Mode of action
The binding of cadmium to metallothionein prevents the free
cadmium ions from exerting their toxic effects. Free cadmium
ions in the cells as a result of the degradation of
metallothionein initiate the synthesis of new metallothionein
which then binds the cadmium thereby protecting the cell from
the highly toxic free cadmium ions. Toxicity may be considered
to occur when the binding capacity of metallothionein is
surpassed.
Renal toxicity
Cadmium induces increased excretion of both low and high
molecular weight proteins. The following mechanisms have been
proposed.
(1) Increased urinary concentrations of low molecular weight
proteins (ß 2-microglobulin) results from a cadmium-induced
defect in the reabsorption of proteins by the proximal tubules
and/or directly by cadmium-induced synthesis of ß 2-
microglobulin.
(2) Altered glomerular function is reflected by increased
urinary concentrations of high molecular weight proteins but
not of low molecular weight proteins.
(3) In the case of mixed-type proteinuria, high molecular
weight proteins may be filtered at the glomerulus and then
incompletely reabsorbed in the proximal tubules.
Pulmonary toxicity
Experimental studies have shown that cadmium-containing
aerosols induce destruction of Type I epithelial cells with
pulmonary oedema, followed by a reparative process.
Interstitial cellular infiltration involves mainly
polymorphonuclear leukocytes and lymphocytes in the initial
phase and the release of alveolar macrophages in the later
stages of the lesion (Palmer et al., 1975; Hayes et al., 1976;
Strauss et al., 1976; Asvardi & Hayes, 1978). Animal studies
have also demonstrated a wide variety of effects of inhaled or
instilled cadmium on pulmonary responses such as collagen
biosynthesis (Chichester et al., 1981; Sampson et al., 1984),
surfactant production (Hayes et al., 1976; Amanuma & Suzuki,
1987), susceptibility to bacterial infection (Bouley et al.,
1977), pulmonary antioxidative systems (Cross et al., 1979;
Grose et al., 1987), mitochondrial and microsomal enzymes
(Fukuhara et al., 1981; Boisset & Boudene, 1981; Palmer et al.,
1983; Prasada Rao & Gardner, 1986), and carcinogenesis (Sanders
& Mahaffey, 1984).
Bone toxicity
Bernard & Lauwerys (1986a) have summarized the following four
possible mechanisms to account for the cadmium-induced
demineralization of bone:
(1) Cadmium-induced renal tubular dysfunction leads to
increased urinary excretion of calcium and phosphorus.
(2) Cadmium-induced inhibition of the activation of vitamin D
in the kidney leads to decreased synthesis of calcium-
binding protein in the intestinal mucosa and decreased
intestinal absorption of calcium (Feldman & Cousins,
1973).
(3) Inhibition of calcium-dependent ATPase and calcium-
binding protein in the intestinal mucosa may lead to
decreased intestinal calcium absorption (Nechay &
Saunders, 1977; Samarawickrama, 1979).
(4) Cadmium may act directly on bone tissue (Kawamura et al.,
1978).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Acute poisoning
Inhalation
Acute exposure to moderately high concentrations of
freshly generated cadmium oxide fumes (200-500 µg
cadmium/m3) may cause symptoms similar to those of
metal fume fever (Bernard & Lauwerys, 1986a).
Concentrations above 1 mg/m3 in air for 8 hours, or
higher concentrations for shorter periods may lead
to acute chemical pneumonitis (Friberg & Elinder,
1983). The lethal concentration of cadmium oxide
fumes for humans has been estimated to be about 5
mg cadmium/m3 for an 8-hour exposure (Friberg et
al., 1974).
Beton et al. (1966) described a case of acute fatal
exposure to cadmium fumes. At autopsy 5 days after
the exposure, tissue cadmium concentrations were:
lungs 2.2 µg/g wet weight, kidneys 5.0 µg/g and
liver 2.8 µg/g.
Lucas et al. (1980) reported the case of a welder
who worked for about 30 minutes with an
oxyacetylene torch and silver solder. The patient
developed acute pneumonitis and died 5 days after
the exposure. Post-autopsy cadmium concentrations
were: urine 224 µg/l, lung 4.7 µg/g wet tissue,
liver 4.8 µg/g and kidney 30.7 µg/g.
Taylor et al. (1984) reported the case of a 36-
year-old man poisoned with cadmium fumes after
smelting lead. The patient developed a pulmonary
oedema and died on the 5th day after exposure. At
48 hours after exposure blood and urine cadmium
concentrations were 3.6 ug/l (normal 1.1 µg/l) and
11 µg/l (normal 1.1 µg/l) respectively. At
autopsy, tissue cadmium concentrations (µg/g) were
considerably elevated, as compared with a control
patient: kidney 67.95 (control, 9.38), liver 1.37
(0.63), lung 0.82 (0.086), skin 0.24 (0.035),
muscle 0.21 (0.058), heart 0.42, brain 0.08
(0.066), stomach 0.43 and small intestine 0.90.
Ingestion
The no-effect level of cadmium administered as a
single oral dose to humans is estimated to be 3 mg
(Bernard & Lauwerys, 1986a). The ingestion of
drinks contaminated with cadmium at concentrations
exceeding 15 mg/l gives rise to gastrointestinal
symptoms (Friberg & Elinder, 1983; Bernard &
Lauwerys, 1986a). The lethal dose has been reported
to range from 350-8,900 mg (Bernard & Lauwerys,
1986a).
Wisniewska-Knypl et al. (1971) reported a case of a
man who ingested 5 g of cadmium iodide and died on
the 7th day. Initial urine cadmium concentration
was 15,600 µg/l and declined to 100 ug/l on the
seventh day. At autopsy the following tissue levels
of cadmium were measured: brain 0.5 µg/g, liver 80
µg/g, kidney 80 µg/g (cortex) and 8.9 µg/g
(medulla), blood 1.1 µg/ml (sampled 3 days after
ingestion).
Buckler et al. (1986) reported the case of a 17
year-old woman with severe acute cadmium
intoxication following the ingestion of 150 g of
cadmium chloride. The patient developed
hypotension, respiratory arrest, metabolic
acidosis, pulmonary oedema, oliguria. and died 30
hours after admission. At autopsy the following
cadmium concentrations were observed: blood 23,000
µg/l, urine 17,000 µg/l, liver 0.4 µg/kg, lung 0.2
µg/kg.
Chronic exposure (occupational)
Renal effects
Several authors have examined the relationship
between the prevalence of kidney dysfunction and
exposure to airborne cadmium. Bernard & Lauwerys
(1986a) concluded that after 10 years of
occupational exposure to 25 ug cadmium/m3, some
workers may have accumulated toxic concentrations
of cadmium in the renal cortex.
Lauwerys et al. (1974) investigated three groups of
workers exposed to cadmium dust together with three
matched control groups. Excessive proteinuria was
found in 15% of workers who had been exposed for
less than 20 years to an average airborne
concentration of cadmium dust of 134 µg/m3. In a
group of workers exposed for more than 20 years to
cadmium dust (average total cadmium concentration
66 µg/m3) nearly 70% had excessive proteinuria.
Kjellstrom et al. (1977a) studied 240 male and
female workers exposed to cadmium oxide and nickel
hydroxide dust in a Swedish battery factory. The
exposure level at the time of the study was about
50 ug cadmium/m3 air. In the group continuously
exposed to cadmium dust in the work environment the
prevalence of increased urinary ß 2-microglobulin
excretion increased with employment time. The
prevalence in smokers was about three times higher
than in nonsmokers.
Thun et al. (1989) have assessed the quantitative
relationship between exposure to airborne cadmium
and various markers of renal tubular and glomerular
function in 45 male workers employed at a cadmium
recovery plant. Increasing cadmium dose was
associated with reduced reabsorption of ß 2-
microglobulin, retinol binding protein, calcium and
phosphate; serum creatinine concentration was also
increased. Multiple renal abnormalities became
apparent in subjects with a cumulative exposure of
300 mg/m3.days, corresponding to working for 4.3
years at the current permissible United States
exposure limit for cadmium dust (200 µg/m3).
Respiratory effects
It is not clear whether lung impairment results
from long-term exposure above a critical airborne
cadmium concentration or from several episodes of
exposure leading to permanent changes. Only a
proposal for a long-term no-effect level of cadmium
in air can be formulated. To prevent deleterious
effects on the respiratory system, the time-
weighted average exposure to cadmium oxide fumes or
to cadmium dust should not exceed a cadmium
concentration of 20 µg/m3 for a 40-hour working
week for the entire working life (World Health
Organization, 1980).
Lauwerys et al. (1974) investigated three groups of
workers exposed to cadmium dust. A slight but
significant reduction in forced vital capacity,
one-second forced expiratory volume and in peak
expiratory flow rate was found only in those
workers who had been exposed to mean total cadmium
dust concentrations of 66 µg/m3 for more than 20
years.
Stanescu et al. (1977) studied 18 workers
exposed to elevated concentrations of cadmium
dust and fumes (50 to 356 µg of cadmium oxide)
for 22-40 years in a cadmium production factory.
Dyspnoea was found to be more frequent in the
cadmium-exposed group, but there were no
differences in the prevalence of other
respiratory symptoms.
Edling et al. (1986) examined lung function in 57
male workers previously exposed to cadmium-
containing solders, together with a reference
group. Exposure had been in the order of 50-500 µg
cadmium/m3. Although 42% of the workers had
cadmium-induced renal damage in the form of ß 2-
microglobulinuria, there was no evidence of
pulmonary damage.
Chronic exposure (environmental)
Renal effects
Kjellstrom et al. (1977b) studied 138 farming women
between 51 and 60 years who lived in a cadmium-
exposed area, together with 40 reference women in
the same age group. The average urinary cadmium
concentration was about twice as high in the
exposed group (16.7 µg/g creatinine) as in the
reference group (8.8 µg/g creatinine). Cadmium
levels in blood among exposed persons (26 ng/g,
range 7-62 ng/g) were also considerably elevated.
Urinary ß 2-microglobulin excretion was strongly
related to residence times in the exposed area as
well as to the use of contaminated river water in
the household. There was also a correlation between
cadmium levels in the blood and ß 2-microglobulin
excretion.
Shiroishi et al. (1977) analysed total protein, ß
2-microglobulin and cadmium in urine samples
obtained from people with Itai-itai disease and
tubular kidney disease, as well as in samples from
a reference group. On average, urinary ß 2-
microglobulin excretion among patients suffering
from Itai-itai disease was 100-300 times higher
than among the reference group, whereas total
protein excretion was only 7 - 17 times higher.
Kojima et al. (1977) studied 156 farmers living
in a cadmium-exposed area and 93 farmers in a
reference area. Average cadmium intake in the
reference area was about 40 ug/day and in the
exposed area about 150 µg/day. Average urinary
cadmium excretion in the reference group was 2
ug/l and in the exposed group 7.5 µg/l. The
prevalence rate of tubular proteinuria was 3% in
the reference group and 14% in the exposed
group. Tubular proteinuria increased with age
and with exposure duration.
7.2.1.2 Children
No relevant data available.
7.2.2 Relevant animal data
LD50 of different cadmium compounds in various species.
Species Cadmium oxide Cadmium Cadmium chloride
Inhalation Oral Oral
(mg/m3/min) mg/kg mg/kg
Rats 500 225 88
Mice < 700 636 175
Rabbits 2500 63
Guinea pigs 3500
Dogs 4000
Monkeys 15000
(LD 50 by inhalation of cadmium oxide fume after exposure for
10 - 30 min.)
(Barrett, Irvin and Semmons, 1947)
7.2.3 Relevant in vitro data
No relevant information available.
7.2.4 Workplace standards
Exposure limits.
Cadmium dust
WHO 20 µg/m3 40 hr/week for working life.
TWA OSHA 200 µg/m3 over 8 hr, 600 µg/m3 ceil.
TWA NIOSH 40 µg/m3 over 10 hr, 200 µg/m3 15 min ceil.
TLV ACGIH 50 µg/m3 (including salts, as cadmium).
STEL ACGIH 200 µg/m3 (including salts, as cadmium).
IDLH 40 µg/m3
Cadmium oxide fume
WHO 20 µg/m3 40 hr/week for working life.
TWA OSHA 100 µg/m3, 3 mg/m3 ceil.
TWA NIOSH 40 µg/m3 over 10 hr, 200 µg/m3 15 min ceil.
TLV ACGIH 50 µg/m3 ceil.
IDLH 40 µg/m3
MAC USSR 100 µg/m3
Cadmium oxide production
TLV ACGIH 50 µg/m3.
Permissible concentration in water
US EPA, WHO 10 µg/l
Germany 6 µg/l
South African Bureau of Standards 50 µg/l
(WHO, 1980; Friberg & Elinder, 1983; ACGIH, 1986; Sittig,
1985).
7.2.5 Acceptable daily intake (ADI)
The main source of the human body burden of cadmium is
food. Drinking water and ambient air usually contribute
considerably less to the daily intake.
Total daily intake from food in North America and Europe
varies considerably but is generally less than 100
µg/day, whereas in heavily polluted areas,such as parts
of Japan, cadmium intake from food and water has been
reported to be considerably greater (Friberg et al.,
1979; Bernard & Lauwerys, 1986a).
Concentrations of cadmium in domestic water supplies
rarely exceed a few µg/l (Friberg et al., 1974; Bernard &
Lauwerys, 1986a).
The upper limit of air cadmium concentrations in urban
areas is about 0.05 µg/m3 (Bernard & Lauwerys, 1986a).
Assuming a retention rate of 25% and a daily inhalation
of 20 m3 of air, the amount of cadmium retained in the
respiratory tract would not normally exceed 0.25 µg per
day.
Cigarette smoking, however, adds considerably to cadmium
input via inhalation. Friberg et al. (1974) estimates a
daily intake of 2-4 µg cadmium from smoking one packet of
cigarettes per day.
Kjellstrom & Nordberg (1978) have calculated that a
daily intake of 440 µg of cadmium is necessary for a
European or American population to reach the estimated
critical concentration of about 200 µg of cadmium/g
renal cortex.
7.3 Carcinogenicity
Although experimental studies support the potential
carcinogenicity of cadmium, epidemiological data provide
limited evidence that cadmium is carcinogenic in man. The
International Agency for Research on Cancer (1976) has
classified cadmium as probably carcinogenic in humans.
Currently, cadmium is being assessed by an international
working party (Sullivan & Waterman, 1988).
Human studies
Although cadmium has been linked to prostatic cancer in workers
heavily exposed to cadmium over a number of years, recent
epidemiological studies have shown no evidence of an increased
risk.
Earlier epidemiological studies have shown that workers exposed
to cadmium appeared to have increased lung cancer mortality,
and there was a suggestion that the risk increased with the
length and intensity of occupational exposure. Ades & Kazantzis
(1988) have studied lung cancer mortality in a cohort of 4393
men employed at a zinc-lead-cadmium smelter. Although there was
an excess of lung cancer especially evident in those employed
for more than 20 years, the increasing risk of lung cancer
associated with increasing duration of employment could not be
accounted for by cadmium exposure.
Animal studies
The subcutaneous and intramuscular administration of inorganic
cadmium compounds has resulted in the development of local
sarcomas in rats as well as interstitial tumours of the testes
in rats and mice. There is no definite evidence that cadmium
compounds administered orally or by inhalation cause an
increase in the incidence of malignancies in laboratory animals
(International Agency for Research on Cancer, 1976).
7.4 Teratogenicity
Human studies
Cvetkova (1970) reported that birth weights of newborn infants
of cadmium-exposed mothers were lower than those of unexposed
mothers but no congenital malformations were found. There is no
evidence that cadmium has caused teratogenic effects in humans.
Animal studies
Embryotoxicity and teratogenicity has been demonstrated in
experimental animals treated with cadmium compounds. Ferm &
Carpenter (1967) have shown that the intravenous administration
of cadmium to pregnant golden hamsters during the early stages
of gestation resulted in fetal abnormalities and facial and
skeletal deformities in surviving animals. Nayak et al. (1989)
showed that pregnant mice treated parenterally with cadmium
chloride, had increased embryonic resorption and fetal
lethality as well as reduced placental weight. Webb et al.
(1988) showed that cadmium-metallothionein given to rats on
gestation days 8-14 was teratogenic, as well as nephrotoxic in
the mothers.
7.5 Mutagenicity
Data on the mutagenic effects of cadmium in humans are
conflicting. In one study of Itai-itai patients in Japan,
chromosomal aberrations were seen in peripheral blood
lymphocytes (Shiraishi, 1975) but this was not confirmed in
another study (Bui et al., 1975). A slight increase in
chromosomal aberrations in lymphocytes of cadmium-exposed
workers has also been reported (Deknudt & Leonard, 1975;
Bauchinger et al., 1976) but their observations have not been
confirmed by other researchers.
Cadmium chloride and cadmium acetate have been shown to alter
the fidelity of DNA replication in vitro (Loeb et al., 1974;
Sirover & Loeb, 1976; Mizutani & Temin, 1976). Cadmium chloride
has been shown to be a weak, direct-acting mutagen in the Ames
bacterial mutagenicity assay and a correlation was seen between
its toxicity and mutagenicity (Wong, 1988).
In animal mutagenicity studies, Epstein et al. (1972) and
Gilliavod & Leonard (1975) showed no effect in the dominant
lethal mutation test. Watanabe et al. (1977) have provided some
evidence of cadmium-induced mutations in chromosomes of mouse
ovaries.
In conclusion, although cadmium can be shown to cause point
mutations in bacterial DNA and induce in vitro chromosomal
aberrations in human lymphocytes it has not been shown
conclusively to cause the same effects in in-vivo studies.
7.6 Interactions
Numerous experimental studies have established that cadmium can
interact with several other metals such as zinc, copper,
selenium, calcium and iron (see reviews by Sandstead, 1976;
Foulkes, 1986; Webb, 1986). In most instances however the
studies have been carried out using dose levels of cadmium
which are considerably greater than those encountered in either
occupational or environmental exposures.
In people with low body stores of iron, intestinal absorption
of cadmium may be significantly higher than in subjects with
normal iron stores (Flanagan et al., 1978). Animal experiments
have shown that a low intake of calcium and protein may
considerably increase intestinal absorption of cadmium (Suzuki
et al., 1969).
8. TOXICOLOGICAL AND BIOMEDICAL ANALYSES
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Symptoms begin almost immediately after ingestion and
include vomiting, diarrhoea and abdominal pain. In severe
poisoning, facial oedema, hypotension, pulmonary oedema,
metabolic acidosis, oliguria and finally death have been
reported (Buckler et al., 1986; Bernard & Lauwerys,
1986a; Ellenhorn & Barceloux, 1988).
9.1.2 Inhalation
There is usually a latent period of 4-12 hours between
the exposure and the onset of symptoms. Initial
presentation simulates metal fume fever: chills fever,
headache, weakness, dryness of the nose and throat, chest
pain, dyspnoea, cough, metallic taste, conjunctivitis,
rhinitis, bronchitis. Nausea and vomiting may also be
observed. In severe intoxication, patients may develop
acute pneumonitis and lesional pulmonary oedema with
respiratory failure which can progress to death in 3-7
days (Beton et al., 1966; Townshend, 1968; Winston, 1971;
Townshend, 1982; Friberg & Elinder, 1983; Taylor et al.,
1984; Sittig, 1985; Barnhart & Rosenstock, 1986;
Ellenhorn & Barceloux, 1988; Yates & Goldman, 1990).
9.1.3 Skin exposure
Although dermal absorption of cadmium is not likely to be
important, skin irritation may be caused by some cadmium
compounds (Sittig, 1985; Lenga, 1988).
9.1.4 Eye contact
Exposure to many cadmium compounds as well as cadmium
dusts and fumes is likely to produce corrosive damages of
the eyes (Lenga, 1988).
9.1.5 Parenteral exposure
No relevant data available.
9.1.6 Other
No relevant data available.
9.2 Chronic poisoning
9.2.1 Ingestion
In cadmium-polluted areas of Japan the signs of renal
damage observed in cadmium workers have also been
observed in the general population (Kjellstrom et al.,
1977b; Shiroishi et al., 1977; Saito et al., 1977; Kojima
et al., 1977). A higher incidence of proteinuria,
glycosuria and ß 2-microglobulinuria has been observed
in the Jintzu river basin and in other areas where high
concentrations of cadmium have been discovered in rice.
In the endemic area of Toyama, the increased urinary
excretion of ß 2-microglobulin was strongly related to
the residence time in that area and to the cadmium level
in urine and blood of the affected individuals
(Kjellstrom et al., 1977b).
Bone effects: Bone lesions are usually a late
manifestation of severe chronic cadmium poisoning. They
are characterized by osteomalacia, osteoporosis and
spontaneous fractures. Signs and symptoms include
skeletal deformities, decreased height, difficulty in
walking, duck-like gait, pain in the back and
extremities, and pain resulting from pressure on the
bones (Bernard & Lauwerys, 1986b; Hallenbeck, 1986).
9.2.2 Inhalation
Chronic poisoning may appear after several years of
exposure. The earliest sign of cadmium-induced
nephropathy is increased proteinuria. In particular ß 2-
microglobulin urinary excretion is markedly increased
(Friberg, 1948; Potts, 1965; Tsuchiya, 1967). As kidney
dysfunction progresses, minerals such as calcium and
phosphorus may also be lost into the urine. Increased
excretion of calcium and phosphorus may disturb bone
metabolism, and kidney stones have been found in exposed
workers (Friberg & Elinder, 1983). There may also be a
decrease in the ability of the kidneys to concentrate
urine (Friberg et al., 1974). The significance of
proteinuria in relation to long-term renal dysfunction
remains controversial. Roels et al. (1982), for example,
have shown that once increased proteinuria has occurred
it may be irreversible. Tsuchiya (1976), on the other
hand, has suggested that proteinuria may resolve after
removal of the subject from the cadmium exposure. The
effects of long-term exposure to cadmium on mortality are
uncertain ( Andersson et al., 1983; Armstrong &
Kazantzis, 1983.
Impairment of lung function has been described in workers
subject to cadmium exposure by inhalation. The changes
normally involve bronchitis which may lead to a mild form
of obstructive lung disease with functional impairment.
In some cases this condition may progress to fibrosis of
the lower airways with alveolar damage and, in severe
cases, emphysema (Lauwerys et al., 1974; Smith et al.,
1976; Stanescu et al., 1977; De Silva & Donnan, 1981;
Friberg & Elinder, 1983; Armstrong & Kazantzis, 1983;
Sittig, 1985; Goyer,1986). More recent investigations on
workers currently exposed to cadmium indicate that
because of improved working conditions the pulmonary
changes are mild and occur less frequently and probably
occurs at a later stage than renal damage (Lauwerys et
al., 1974; Stanescu et al., 1977; Edling et al., 1986).
9.2.3 Skin exposure
No relevant data available
9.2.4 Eye contact
No relevant data available.
9.2.5 Parenteral exposure
No relevant data available.
9.2.6 Other
No relevant data available.
9.3 Course, prognosis, cause of death
Acute poisoning following inhalation
There is generally a latent period of a few hours before the
onset of symptoms; warning signs are often absent.
Metal fume fever usually last from 1-2 days. Acute pneumonitis,
pulmonary oedema and respiratory failure may develop as early
as 8 - 12 hours following exposure.
The mortality rate is about 15% with death occurring after 4 -
7 days. If the patient survives, there may be a persistent
restrictive ventilatory defect which may last for several years
(Beton et al., 1966; Townshend, 1968; Winston, 1971; Townshend,
1982; Friberg & Elinder, 1983; Taylor et al., 1984; Sittig,
1985; Barnhart & Rosenstock, 1986; Ellenhorn & Barceloux, 1988;
Yates & Goldman, 1990).
Histology has shown congestion with intra-alveolar hemorrhage,
metaplasia of the alveoli lining cells and fibrinous intra-
alveolar exudates (Beton et al., 1966; Barnhart & Rosenstock,
1984).
Acute poisoning following ingestion
Symptoms (acute gastroenteritis) begin almost immediately
following ingestion. In cases of fatal intoxication the initial
symptoms have been followed by either shock due to fluid loss
and death within 24 hours, or by acute renal failure with
cardiopulmonary depression, liver damage and death in 7-14 days
(Buckler et al., 1986; Bernard & Lauwerys, 1986a; Ellenhorn &
Barceloux, 1988).
Necropsy has shown pulmonary oedema, pleural effusions and
ascites, haemorrhagic necrosis of the stomach and duodenum, and
pancreatic haemorrhage (Buckler et al., 1986).
Chronic poisoning following inhalation
The prominent feature and probably the earliest sign of
cadmium-induced nephropathy is increased proteinuria. Although
the minimum latent period before the onset of proteinuria is
normally at least 1 year (Tsuchiya, 1967) the first sign of
disease may not develop until many years later (Bonnell, 1965).
The significance of proteinuria in relation to long-term renal
dysfunction remains controversial (see section 9.2.2).
Pulmonary changes in patients occupationally exposed to
cadmium appear after several years (see section 9.2.2).
Chronic poisoning following ingestion
In cadmium-polluted areas of Japan, renal damage has also been
observed in the general population. Bone lesions are usually a
late manifestation of severe chronic cadmium poisoning.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute: Hypotension and dysrhythmias have been observed
after inhalation of cadmium fumes. In one case
inflammatory changes of the myocardium were noted (Taylor
et al., 1984).
Hypotension and shock have also been reported after
ingestion of cadmium chloride (Buckler et al., 1986;
Bernard & Lauwerys, 1986a).
Chronic: No data available
9.4.2 Respiratory
Acute: In cases of acute poisoning following inhalation
the earliest symptom is slight irritation of the upper
respiratory tract. This may be followed over the next few
hours by the development of an acute pneumonitis
including cough, chest pain and dyspnoea. After severe
exposure, fulminant pulmonary oedema may occur (Beton et
al., 1966; Townshend, 1968; Taylor et al., 1984; Barnhart
& Rosenstock, 1984; Yates & Goldman, 1990). Buckler et
al. (1986) reported respiratory effects after acute
ingestion of cadmium but no direct effect has been
documented.
Chronic: Respiratory effects can also occur as a result
of long-term occupational exposure to cadmium dusts and
fumes. These effects do not normally precede renal
tubular dysfunction and appear to involve only mild
obstructive lung disease (dyspnoea, reduced vital
capacity, and increased residual volume). In some cases
fibrosis with alveolar damage may occur, and emphysema
has been attributed to excessive exposure to cadmium
(Lauwerys et al., 1974; Stanescu et al., 1977; Edling et
al., 1986).
9.4.3 Neurological
9.4.3.1 CNS
Acute: Insomnia, confusion and restlessness may be
encountered in cases of inhalational poisoning
(Beton et al., 1966; Taylor et al., 1984). Bernard
& Lauwerys (1986a) list headache as one of the main
symptoms associated with the acute ingestion of
toxic doses of cadmium salts. The mechanism is
unknown but hypoxaemia may be responsible for these
effects.
Chronic: No data available.
9.4.3.2 Peripheral nervous system
Acute: No data available.
Chronic: No data available.
9.4.3.3 Autonomic nervous system
Acute: No data available.
Chronic: No data available.
9.4.3.4 Skeletal and smooth muscle
Aching pains in the back and limbs, chills,myalgia
and generalized weakness may be observed in acute
inhalational poisoning (Beton et al., 1966).
9.4.4 Gastrointestinal
Acute: Following the ingestion of cadmium compounds
gastrointestinal manifestations are the first symptoms to
appear. Nausea and vomiting occur, normally without
delay. There may also be salivation, diarrhoea, abdominal
pain and discomfort (Buckler et al., 1986; Bernard &
Lauwerys, 1986a). In the fatal case reported by Buckler
et al. (1986) necropsy revealed haemorrhagic necrosis of
the stomach, duodenum and jejunum.
Metallic taste, nausea, vomiting, diarrhoea and abdominal
pain have also been reported after the inhalation of
cadmium-containing dusts and fumes (Beton et al., 1966;
Taylor et al., 1984).
Chronic: No data available.
9.4.5 Hepatic
Acute: In the case reported by Buckler et al. (1986) in
which a young woman ingested 150 g of cadmium chloride,
focal hepatic necrosis was observed at autopsy. Taylor et
al. (1984) reported evidence of fatty infiltration and
acute centrilobular necrosis of the liver in a patient
who died following the inhalation of cadmium fumes.
Chronic: No data available.
9.4.6 Urinary
9.4.6.1 Renal
Acute: In cases of acute ingestion oliguria and
acute renal failure may occur (Buckler et al.,
1986; Bernard & Lauwerys, 1986a).
Oliguria, anuria and nocturia have been reported
following the inhalation of cadmium fumes (Beton et
al., 1966; Taylor et al., 1984). In the case report
by Beton et al. (1966) the kidneys showed bilateral
cortical necrosis and tubular degeneration on
autopsy.
Chronic: Many studies have established that the
kidney is the critical organ for long-term, low-
level exposure to cadmium from both occupational
(see e.g. Friberg, 1948; Potts, 1965; Tsuchiya,
1967) and environmental sources (Kjellstrom et al.,
1977b; Shiroishi et al., 1977; Saito et al., 1977;
Kojima et al., 1977). The prominent feature and
probably the earliest sign of cadmium-induced
nephropathy is proteinuria. Although the minimum
latent period before the onset of proteinuria is
normally at least 1 year (Tsuchiya, 1967), the
first sign of disease may not develop until many
years later (Bonnell, 1965).
Cadmium-induced proteinuria is considered to occur
at concentrations in the range 100-300 µg cadmium
per gram wet weight of renal cortex (Friberg et
al., 1974). The critical concentration of cadmium
in the renal cortex has recently been estimated by
neutron activation to be between 215 and 385 µg/g.
The critical body burden and urinary cadmium
concentration has been estimated to be about 180 mg
and 10-15 µg cadmium/g creatinine respectively
(Roels et al, 1979, 1981b, 1983).
In cadmium-exposed workers the urinary excretion of
low molecular weight proteins is markedly
increased. This is often accompanied by increased
urinary excretion of high molecular weight
proteins. As the kidney dysfunction progresses,
amino acids, glucose and minerals such as calcium
and phosphorus, as well as cadmium itself are also
eliminated in the urine. Increased excretion of
calcium and phosphorus may disturb bone metabolism,
and kidney stones have been found in exposed
workers (Friberg & Elinder, 1983). There may also
be a decrease in the ability of the kidneys to
concentrate urine (Friberg et al., 1974).
The significance of proteinuria in relation to
long-term renal dysfunction is uncertain. Roels et
al. (1982) have shown that once an increased
proteinuria has occurred it may be irreversible,
whereas Tsuchiya (1976) has suggested that the
proteinuria may disappear after removal of the
subject from the cadmium exposure. It is possible
that slight proteinuria, detectable only by the
determination of urinary ß 2-microglobulin, may be
reversible depending on the past exposure
conditions and on the health status of the worker
(Bernard & Lauwerys, 1986a).
The effects of long-term exposure to cadmium on
mortality are also equivocal. Andersson et al.
(1983), for example, have reported a significant
increase in deaths from nephritis and nephrosis in
a group of 175 workers exposed to cadmium for more
than 15 years, whereas Armstrong & Kazantzis (1983)
found no significant increase in mortality rate
from nephritis and nephrosis in cadmium-exposed
workers.
The signs of renal damage observed in cadmium
workers have also been observed in the general
population living in cadmium-polluted areas of
Japan. A higher incidence of proteinuria,
glycosuria and delta 2-microglobulinuria has been
observed in the Jintzu river basin in Toyama
Prefecture and in other areas where high
concentrations of cadmium have been discovered in
rice. In the endemic area of Toyama the increased
urinary excretion of delta 2-microglobulin was
strongly related to the residence time in that area
and to the cadmium level in urine and blood of the
affected individuals (Kjellstrom et al., 1977b).
Lauwerys et al. (1980), Lauwerys & De Wals (1981)
and Roels et al. (1981a) have studied the effects
of environmental exposure to cadmium on renal
function in elderly subjects living in Belgium.
Renal function of a group of 60 women of 60 years
of age who had spent the major part of their lives
in a cadmium-polluted area was compared with that
of two groups of aged women from areas less
polluted by this heavy metal. The group of women
from the contaminated area had, on average, a
higher cadmium body burden than the groups from the
other areas. The parameters selected for evaluating
renal function (total protein, aminoacids, delta 2-
microglobulin and albumin in the urine) followed
the same trend. A retrospective mortality study
revealed that the standardized mortality ratio from
nephritis and nephrosis was significantly higher in
the cadmium-polluted area than in other areas (see
also Bernard & Lauwerys, 1986b).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Acute: Skin irritation may be expected as a result of
contact with some cadmium compounds (Lenga, 1988).
Chronic: No data available.
9.4.9 Eye, ears, nose, throat: local effects
Acute: The earliest symptom of inhalational exposure is
irritation of the upper respiratory tract, including
dryness of the nose and throat (Beton et al., 1966).
Rhinitis and conjuntivitis may be observed. The severity
and latency of symptoms are a function of dose.
Chronic: No data available.
9.4.10 Haematological
Acute: The ingestion of cadmium chloride has been
reported to produce an elevation in serum haemoglobin
concentration, increased haematocrit and altered
coagulation function (Buckler at al., 1986).
Chronic: No data available.
9.4.11 Immunological
Acute: No data available.
Chronic: Although the effects of cadmium exposure on
immune responses in experimental animals have been
studied extensively, the relevance of the findings for
humans remains to be elucidated.
Most of these studies have examined immune function in
young immunologically competent animals. The most
predominant effects of cadmium have been associated with
reduced T lymphocyte-dependent antibody production as
well as with lowered natural killer (NK) cell activity
and suppressed macrophage activity (Stelzer & Pazdernik,
1983; Cook et al., 1984; Thomas & Imamura, 1986; Blakley
& Tomar, 1986). These effects were considerably less
marked in mature animals (Blakley, 1988).
9.4.12 Metabolic
9.4.12.1 Acid base disturbances
Acute: Buckler et al. (1986) reported a case in
which ingestion of cadmium chloride produced
metabolic acidosis.
Chronic: No data available.
9.4.12.2 Fluid and electrolyte
disturbances
Acute: Electrolyte and fluid imbalance may occur
following fluid losses due to diarrhoea after
poisoning by ingestion.
Chronic: An increase in calcium and phosphorus
urinary elimination may be observed when bone
lesions are present.
9.4.12.3 Others
Townshend (1968) reported slight cyanosis in a
patient more than 3 weeks following an acute
inhalation of cadmium fumes.
A suicidal ingestion of 150 g of cadmium chloride
was associated with glucose intolerance (Buckler et
al., 1986).
9.4.13 Allergic reactions
Acute: No data available.
Chronic: A total of 6 of 56 workers employed in a glass
manufacturing plant (4/32) or in an electroplating
factory (2/24), and who were in frequent and prolonged
contact with either cadmium sulphide or cadmium cyanide,
showed evidence of allergic contact dermatitis. None of
these six workers was positive in patch tests to 1%
cadmium chloride, although they tested positive to other
chemicals with which they were in contact including epoxy
resin, triethylenetetramine, chromium, cobalt and nickel
(Rudzki et al., 1988).
9.4.14 Other clinical effects
Acute: Hypothermia (temperature 30°C) was observed in a
patient following the ingestion of 150 g of cadmium
chloride (Buckler et al., 1986).
Chronic: Bone lesions are usually a late manifestation of
severe chronic cadmium poisoning. They are characterized
by osteomalacia, osteoporosis and spontaneous fractures.
Signs and symptoms include skeletal deformities,
decreased height, difficulty in walking, duck-like gait,
pain in the back and extremities, and pain resulting from
pressure on the bones (Bernard & Lauwerys, 1986b;
Hallenbeck, 1986).
9.4.15 Special risks
Pregnancy: Cvetkova (1970) reported that birth weights
of newborn infants of cadmium-exposed mothers were lower
than those of unexposed mothers, but no congenital
malformations were found.
9.5 Others
No data available.
10. MANAGEMENT
10.1 General principles
The treatment of acute cadmium poisoning should be directed
initially towards decontamination (removal of the patient from
further exposure, or the induction of vomiting).
In cases of inhalation, respiratory symptoms should be
carefully monitored and pulmonary oedema treated.
In cases of ingestion, ipecac/lavage/catharsis should be used
in the usual manner (Ellenhorn & Barceloux, 1988).
Antidotal treatment remains controversial.
For patients with external dust contamination, health care
providers should protect themselves from airborne dust during
decontamination of the patient.
10.2 Relevant laboratory analyses and other investigations
10.2.1 Sample collection
For recent exposure whole blood cadmium concentration is
the best measure of exposure. Whole blood levels above 10
µg/l indicate significant exposure. Blood should be
collected in 10 ml heparinised vacutainers or preferably
in all-plastic syringes, and refrigerated until analysed.
For long-term, low-level exposure, urine cadmium
concentration best reflects the total body burden,
provided renal tubular dysfunction is normal. A 24-hour
urine sample or an early-morning specimen collected into
a clean 120 ml Nalgene bottle should be refrigerated or
frozen until analysed.
10.2.2 Biomedical analysis
In cases of acute poisoning from the inhalation of
cadmium dusts and fumes, monitor cardio-respiratory
function: chest X-ray, ECG and blood gases. Diffusing
capacity may be helpful.
In cases involving the ingestion of cadmium, monitor
cardiovascular parameters (heart rate, blood pressure)
and electrolyte balance.
In chronic poisoning by inhalation or ingestion, the
early nephrotoxic effects of cadmium can be detected on
the basis of the measurement of urinary proteins which
reflect the functional integrity of the tubule or the
glomerulus. Low molecular weight proteins such as ß 2-
microglobulin, retinol-binding protein, or a 1-
microglobulin are currently used for screening for
proximal tubular injury, whereas the analysis of urinary
high molecular weight proteins such as albumin permits
the assessment of glomerular filtration selectivity. The
urinary activity of alpha-N-acetylglucosaminidase is
also a sensitive indicator of excessive absorption of
cadmium.
10.2.3 Toxicological analysis
Several studies (e.g. Lauwerys et al., 1974; Bernard et
al., 1979; Roels et al., 1981b, 1983) have revealed that
in cadmium-exposed populations renal dysfunction is
present when the concentration of urinary cadmium exceeds
10 µg cadmium/g creatinine
10.3 Life support procedures and symptomatic treatment
In cases of inhalational exposure life support measures should
be directed primarily to the treatment of pulmonary oedema.
Emergency treatment may include: oxygen given by mask face,
intubation and artificial ventilation using intermittent
positive-pressure. The efficacy of diuretics and
corticosteroids has not been established.
10.4 Decontamination
In case of poisoning by inhalation of cadmium fumes or dust,
the patient should be rapidly moved to fresh air protecting
health care workers from secondary exposure from dust.
If cadmium-containing substances are ingested, the mouth should
be washed out with water. If vomiting is not prominent, use
ipecac, gastric lavage or catharsis in the usual manner. Oral
activated charcoal is not useful (Friberg & Elinder, 1983;
Lenga, 1988; Ellenhorn & Barceloux, 1988)
In the case of skin exposure, the affected area should be
flooded with water for at least 15 min (Lenga, 1988).
Eye contamination should be managed by continuous irrigation of
the eye with clean water for at least 15 minutes (Lenga, 1988).
10.5 Elimination
The value of forced diuresis or enhanced elimination techniques
has not been established.
10.6 Antidote treatment
10.6.1 Adults
Acute poisoning
The role of EDTA is unclear. Recommendations for its use
are based on the results of many animal studies which
have shown that when administered to cadmium pre-treated
animals, the body burden of cadmium is reduced and the
urinary excretion of cadmium increased. However, thismay
increase the uptake of cadmium by the kidneys and
increase the risk of nephrotoxicity. Friberg & Elinder
(1983) therefore recommend that calcium disodium EDTA is
contraindicated because of its nephrotoxicity when
administered in combination with cadmium.
Conversely, Dreisbach (1983) proposes the following
dosage regimen applicable in cases of acute cadmium
poisoning: 15-25 mg EDTA/kg (0.08-0.125 ml of 20%
solution/kg body weight) in 250-500 ml of 5% dextrose
intravenously over a 1 - 2-hour period twice daily. The
maximum dose should not exceed 50 mg/kg/day. The drug
should be given in 5 day courses with an interval of at
least 2 days between courses. During subsequent courses
urinalysis should be done daily and the dosage reduced if
any unusual urinary findings occur.
Both Friberg & Elinder (1983) and Ellenhorn & Barceloux
(1988) state that dimercaprol (BAL) should not be used in
cases of acute cadmium poisoning.
Cotter (1958) reported the case of three men exposed to
cadmium fumes who were subsequently treated with calcium
disodium EDTA, at a dose of 0.5 g every 2 hours for 1 or
2 weeks. At the end of the treatment period the patients
were either asymptomatic or had made a significant
recovery, as indicated by a reduction in blood urea
nitrogen, blood cadmium and urinary cadmium
concentrations.
Recent studies in rodents have shown that, for acute oral
cadmium intoxication, meso-2,3-dimercaptosuccinic acid
given orally (Basinger et al., 1988; Andersen & Nielsen,
1988; Andersen, 1989) or calcium disodium
diethylenetriaminepentaacetate (DTPA) given parenterally
(Andersen, 1989) are the most effective antidotes,
provided that treatment is started very soon after
cadmium ingestion.
Chronic poisoning
The current consensus appears to be that there is no
recommended chelation treatment for chronic cadmium
exposure (Jones & Cherian, 1990).
Jones & Cherian (1990), in a recent review paper, state
that in recent years considerable progress has been made
in the development of a compound which can be given
serious consideration for use in human cases of chronic
cadmium intoxication. They suggest that the reduction of
whole body, renal and hepatic levels of cadmium in mice
treated with recently developed compounds such as sodium
N-(4-methoxylbenzyl)-D-glucamine dithiocarbamate is
comparable or superior to the results obtained with
compounds used clinically with other toxic metals for
which chronic intoxication is considered treatable.
10.6.2 Children
No data available.
10.7 Management discussion
The usefulness of antidotal treatment in cadmium poisoning
remains controversial and has to be assessed by further
studies. There is insufficient convincing scientific evidence
of efficacy for EDTA to recommend its use.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Young adult, acute ingestion (Buckler et al., 1986).
A 17-year-old woman was admitted to hospital with facial
swelling and vomiting. She was too ill to provide any history.
She had facial, pharyngeal and neck swelling and was
hypotensive. Subsequent gastric washout (roughly three hours
after ingestion) produced a white crystalline material
confirmed to be cadmium chloride. She suffered a respiratory
arrest, becoming hypothermic (temperature 30°C),
haemoconcentrated (haemoglobin 222 g/l, packed cell volume
0.52), glucose intolerant (glucose 55.8 mmol/l) and acidotic
(pH 6.9) without ketones. Results of coagulation studies were:
prothrombin time 60 sec (control 13 sec) and partial
thromboplastin time 180 sec (control 39 sec). Over 24 hours she
developed pulmonary and generalized oedema and oliguria. Full
supportive measures including chelation treatment, charcoal
haemoperfusion and positive end expiratory pressure ventilation
were unsuccessful, and she died 30 hours after admission.
Necropsy showed pulmonary oedema, pleural effusion and ascites.
There was haemorrhagic necrosis of the stomach, duodenum and
jejunum, focal hepatic necrosis and slight pancreatic
haemorrhage. The kidneys appeared normal. At autopsy the
following cadmium concentrations were measured: blood 23 mg/l,
urine 17 mg/l, liver 0.4 µg/kg wet tissue, lung, 0.2 µg/kg.
The patient had ingested a massive dose of 150 g of cadmium
chloride, and although the initial diagnosis was delayed, it
seems unlikely that any treatment would have prevented the
membrane dysfunction and destruction of tissue. The case
illustrates the catastrophic effects of ingested cadmium on
organ function.
Adult, acute inhalation (Barnhart & Rosenstock, 1984).
A 34 year-old man had been soldering silver in an enclosed,
unventilated small tank with an opening only large enough to
admit his upper body. At the time of exposure he noted only
diplopia. Later, he developed dyspnoea, cough, abdominal pain
and he felt feverish. Because of persistent cough and dyspnoea
he was seen about two weeks later and told he had metal fume
fever. His cough and dyspnoea resolved in about four weeks.
Chest x-ray films obtained two weeks after his acute exposure
revealed bilateral infiltrates. Four years later they were
normal. Results of pulmonary function tests revealed moderate
restrictive impairment and moderately decreased single breath
diffusing capacity (Dco). His Dco returned to normal within two
months and his total lung capacity had showed continued
improvement but remained below normal nearly four years after
exposure.
Adult, acute inhalation (Lucas et al., 1980).
A previously healthy 34 year-old welder worked for
approximately 30 minutes with an oxyacetylene torch and silver
solder. His workbench was in a large airy building with a high
ceiling. Large doors were open, but there was no specific
ventilation system in operation. He become dyspnoeic with a
persistent non-productive cough within hours of completing the
job. His symptoms worsened steadily and he died 5 days after
exposure. Both lungs showed changes typical of acute
pneumonitis. The source of cadmium was the rod of silver solder
which contained 20% cadmium. The case illustrates the fact
that, unless specific measures are taken, death from cadmium
fume inhalation can occur in an apparently well-ventilated
environment, particularly if the presence of cadmium is not
suspected.
Adult, acute inhalation (Taylor et al., 1984).
A fit 36-year-old man was admitted with a 24-hour history of
vomiting and profuse watery diarrhoea. He had generalised
diffuse, dull, aching abdominal pains, a severe headache and
generalised myalgia with tightness of his chest. He was
slightly confused, restless, and dehydrated but had no fever,
lymphadenopathy, or rash. He had a regular pulse rate of 108
beats/min and blood pressure of 80/40 mm Hg. His chest was
clear. His abdomen was diffusely tender without peritoneal
signs. Severe gastroenteritis was diagnosed, and he was treated
symptomatically.
A chest radiograph was normal. Blood cultures and viral
agglutinin titres yielded negative results. Despite adequate
rehydration he produced only 50 ml of urine over the next 18
hours. He became increasingly dyspnoeic and developed bilateral
fine basal crepitations and radiographic appearances consistent
with gross pulmonary oedema. Electrocardiography showed varying
rhythms of atrial fibrillation, nodal rhythm and sinus
tachycardia. He became feverish and his myalgia worsened.
Twenty four hours after admission it was discovered that he had
been smelting about 182 kg of lead for about 24 hours in an
enclosed environment without wearing adequate protective
clothing. He had felt unwell towards the end of that session.
As he was anuric, chelating agents were not indicated. Although
he was treated with peritoneal dialysis, his condition
deteriorated. He remained dyspnoeic and cyanotic and died 72
hours later. Postmortem examination revealed that his lungs and
gastric mucosa were appreciably congested with moderate
hyperemia throughout the large and small intestines and there
was slight cerebral congestion. Histological investigations
showed mild hepatic fatty infiltration and severe acute
centrilobular necrosis of the liver, acute cellular necrosis in
the loops of Henle, mild interstitial oedema and infiltration
of the myocardium with eosinophils, lymphocytes, and
histiocytes, depletion of lipid content and mild focal
haemorrhage in the adrenals, and congestion and acute
inflammatory cell infiltration of the spleen.
11.2 Internally extracted data on cases
No data available.
11.3 Internal cases
To be completed by the PCC.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes and antisera
To be completed locally.
12.2 Specific preventive measures
Processes releasing cadmium fumes or dust should be designed to
keep concentration levels to a minimum. When adequate
engineering control and ventilation cannot ensure constant safe
air levels, respiratory protection must be used. Eye washing
equipment should be easily accessible if cadmium chloride is
being used. Adequate sanitary facilities should be supplied,
and workers should wash before meals and before leaving work.
Work clothing should be changed daily and washed thoroughly at
work before re-use. Smoking, eating and drinking in work areas
should be prohibited. Cigarettes and food should not even be
stored briefly in cadmium contaminated air.
In the pre-employment physical examination, emphasis should be
given to a history or presence of significant kidney or
respiratory disease. A chest x-ray and baseline pulmonary
function study is recommended (Friberg & Elinder, 1983;
Sitting, 1985).
Medical examination of cadmium-exposed workers should be
carried out at least once every year. These examinations should
emphasize the respiratory system (including pulmonary function
tests) and the kidneys. Cadmium levels in blood and in urine
should be checked regularly. Cadmium levels in urine can be
used to estimate the cadmium body burden. The concentration
should not be allowed to reach 5-10 µg cadmium/g urinary
creatinine. In workers exposed to cadmium for longer periods
quantitative measurements of ß 2-microglobulin and for retinol
binding protein in urine should be made regularly.
Concentrations of ß 2-microglobulin in urine should normally
not exceed 0.5 mg/l (Friberg & Elinder, 1983).
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), DATE (INCLUDING EACH UPDATE)
Author(s): R.W. Mason
National Toxicology Group
University of Otago Medical School,
PO Box 913
Dunedin
New Zealand
Tel: (64) (03) 4797-254
Fax: (64) (03) 4770-509
Tlx: 5706 HOSBORD
G.S. Elliott(Sections 7.3, 7.4, 7.5, 9.4.11 & 9.4.13)
National Toxicology Group
University of Otago Medical School,
PO Box 913
Dunedin
New Zealand
Tel: (64) (03) 4797-254
Fax: (64) (03) 4770-509
Tlx: 5706 HOSBORD
S.D. Jones (Co-author)
National Toxicology Group
University of Otago Medical School,
PO Box 913
Dunedin
New Zealand
Tel: (64) (03) 4797-254
Fax: (64) (03) 4770-509
Tlx: 5706 HOSBORD
Date: 20 October 1990
Reviewers: A. Jaeger, J. Kopferschmitt, Ph. Sauder, F. Flesch
Service de Réanimation Médicale et Centre Anti-Poisons
Hôpitaux Universitaires de Strasbourg
Hôpital Civil
67091 Strasbourg Cedex
France
Tel: 33 88 16 11 44
Fax: 33 88 16 13 30
Date: 26 Janvier 1992
Peer review:Newcastle-upon-Tyne, United Kingdom, February 1992
(Group members: P. Edelman, A. Jaeger, O. Kasilo,
P. Myrenfors, J. Szajewski)