CADMIUM
EXPLANATION
Cadmium is a contaminant which may enter the food chain from
a number of natural and industrial sources. Cadmium was last
reviewed at the sixteenth meeting of the Committee in 1972 (Annex
1, reference 30) when a provisional tolerable weekly intake of
400-500 µg per person (6.7-8.3 µg/kg bw/week) was allocated.
Since the previous evaluation, additional information has
become available and is summarized and discussed in the following
monograph.
DIETARY EXPOSURE
Cadmium occurs naturally in the environment at low levels
usually with zinc, lead and copper ore deposits. High cadmium
concentrations are often associated with industrial emission
sources, e.g., mining and smelting operations. Major industrial
uses of cadmium are in electroplating, pigments, particularly in
plastics, plastic stabilizers (e.g., cadmium stearate), and nickel-
cadmium rechargeable batteries. Although cadmium is easily
complexed with some organic compounds (e.g., thiocarbamates), and
organometallic compounds have been synthesized, these have not been
found in the general environment since they are rapidly decomposed.
There is, however, some evidence that in certain foods, such as
oysters, cadmium is bound to a metallothionein-like protein
(Friberg et al., 1986; Friberg et al., 1985).
Cadmium concentrations in air relate to the degree of
industrialization and range from less than 1 ng/m3 in remote
uninhabited areas up to 40 ng/m3 in urban environments. In close
vicinity to industrial operations (e.g., zinc smelters), air
concentrations have been found to range as high as 11,000 ng/m3.
For the general population not living in proximity to industrial
operations, cadmium intakes from air are unlikely to exceed 0.8 µg
per day (Friberg et al., 1986; Friberg et al., 1985).
In fresh surface waters and most groundwaters, cadmium levels
are generally less than 1 µg/l. The use of galvanized pipes in
water distribution systems can result in a 5 to 10-fold increase in
cadmium levels in drinking water (i.e. up to 10 µg/l). Similarly,
in areas where there are zinc-bearing mineral formations, cadmium
levels in groundwater may also reach µg/l. Thus, for most
individuals, cadmium intake from drinking water would be less than
about 2 µg/day but for certain persons cadmium intakes from water
could reach as high as 20 µg/day (Friberg et al., 1985; Méranger
et al., 1981).
Results from more recent surveys demonstrate that most foods
contain on average less than 0.02 µg/g cadmium. Exceptions include
certain shellfish (e.g., oysters) and offal. Dietary intake
estimates range from 13-35 µg/day or 0.2 to 0.7 µg/kg bw for an
adult. Some of the variation in reported intakes relates to the use
of the limit of detection. In one instance, for example, using zero
concentration versus detection limit value for samples in which
cadmium could not be detected resulted in estimated intakes of
20 µg/day and 35 g/day, respectively. For infants and children,
cadmium intakes on a body weight basis are generally higher than
that estimated for adults and, in some countries, intakes for the
younger age groups have been reported to exceed 1 µg/kg bw (Friberg
et al., 1986; Friberg et al., 1985; Ministry of Agriculture,
Fisheries and Food, 1985; Dabeka et al., 1987 & FAO/WHO, 1986).
In addition to intake from air, water and food, smoking can
represent a significant source of cadmium exposure. It has been
estimated that a smoker of 20 cigarettes per day would increase
his/her daily intake of cadmium by 2 to 4 µg (Friberg et al.,
1986, Friberg et al., 1985).
In summary, the intake of cadmium from air, excluding
industrial areas, is a minor portion of the total intake from all
sources. Although water is not a major contributor of cadmium
intake for most individuals, elevated cadmium levels in water can
occur and resultant cadmium intakes can be as high as the dietary
contribution. Foods represent the major route of cadmium exposure
by the general public.
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, and excretion
The retention of ingested cadmium varied between 4.7-7.0% in
five adult men (Rahola et al., 1971). Cadmium deficiency
increases the retention of cadmium in rats and this may also be the
case in man (Larsson & Piscator, 1971).
In mammals, cadmium is virtually absent at birth but will
accumulate with time, especially in liver and kidneys. The primary
period of rapid renal concentration may occur during the early
years of life (Henke et al., 1970) and 50-75% of the total body
burden will be found in these two organs.
In various animal studies involving acute and chronic exposure,
10-40% of inhaled cadmium was absorbed (Friberg et al., 1974). It
has been estimated that about 50% of cadmium inhaled in cigarette
smoke is absorbed (Friberg et al., 1985; 1986).
Absorption of cadmium from the gastro-intestinal tract depends
on species, type of cadmium compound, dose size and frequency, age
and interaction with various dietary components (Nomiyama, 1978).
When cadmium chloride was given to rats in drinking water over a
period of 122 months, less than 1% of the total dose ingested was
retained in liver and kidney (Decker et al., 1958).
After single oral doses of cadmium chloride or cadmium
nitrate, absorption varied between 0.5 and 8% in mice, rats and
monkeys (Friberg et al., 1974; Nordberg et al., 1975) and
limited human studies indicate a mean absorption of orally
administered inorganic cadmium of about 5% (Kitamura, 1972; Rahola
et al., 1972; Yamagata et al., 1974; Flanagan et al., 1978;
Shaikh & Smith, 1980).
Metallothionein-bound cadmium in food is absorbed and
distributed differently from inorganic ionic cadmium compounds.
Mice given cadmium-metallothionein had lower blood and liver
cadmium but higher kidney cadmium concentrations than animals given
a similar dose as cadmium chloride (Cherian et al., 1978;
Sullivan et al., 1984). Similarly, cadmium bound to protein in
oysters may be absorbed differently from inorganic cadmium
(McKenzie et al., 1982).
The proportion of an orally-administered dose which is
absorbed varies with age. Young mice retained 10% of an orally
administered dose of cadmium after two weeks whereas adult mice
retained only 1% (Matsusaka et al., 1972) and other studies have
confirmed that neonatal mice and rats absorb cadmium to a greater
extent than older animals (Kello & Kostial, 1977a, b; Engstrom &
Nordberg, 1979b).
Low dietary levels of calcium, iron or protein lead to
enhanced absorption in experimental animals (Friberg et al.,
1985, 1986; Nordberg et al., 1983). Iron deficiency leads to a
higher absorption of cadmium in both animals and humans (Hamilton
& Valberg, 1974; Flanagan et al., 1978). In the latter case,
women with low serum ferritin levels absorbed on average four times
as much (10%) of orally ingested cadmium as a control group, the
highest individual absorption rate being 20% of the dose.
After absorption, cadmium is transported in the blood, mainly
within the erythrocytes. A greater proportion of the blood cadmium
is found in erythrocytes although the concentration is slightly
higher in leucocytes (Friberg, 1952; Friberg et al., 1985; Garty
et al., 1981). Cadmium is intracellularly bound to high molecular
weight and low molecular weight protein fractions (Nordberg, 1972).
The low molecular weight fraction is similar to metallothionein,
which also binds cadmium in plasma.
Erythrocyte cadmium can be released into plasma following
haemolysis (a feature of chronic cadmium intoxication) or when the
erythrocyte lifetime has expired. Plasma metallothionein has an
important role in the transport of cadmium and similar proteins
have been found in various tissues including duodenal mucosa
(Starcher, 1969; Evans et al., 1970). Injected cadmium is
partially dialyzable during the first few minutes (Friberg et
al., 1974) but plasma concentrations decrease rapidly during the
first few hours to less than 1% of the initial value by 24h;
subsequently clearance is much slower. In the fast elimination
phase, cadmium is mainly associated with the high molecular weight
proteins whereas later it is bound also to metallothionein
(Nordberg, 1978).
Metallothionein (mw 6000-7000) can consist of up to 11%
cadmium by weight, bound to sulfhydryl groups (Kagi et al., 1984;
Elinder & Nordberg, 1985) and occurs in large quantities in the
liver of animals exposed to cadmium. Metallothionein occurs in
varying amounts in other tissues, particularly kidney, and its
concentration correlates with that of cadmium in these tissues.
The amount of free metallothionein in plasma is small but its
low molecular weight permits filtration through the glomeruli and
the subsequent reabsorption of cadmium-metallothionein in the
proximal tubules explains the selective accumulation of cadmium in
the renal cortex (Nordberg, 1972). The transport of cadmium bound
to metallothionein from blood to renal tubular cells is rapid and
virtually complete (Nordberg & Nordberg, 1975; Johnson & Foulkes,
1980). Cadmium not bound to metallothionein is not taken up by the
kidneys to a similar degree.
Whereas early in gestation cadmium can reach the embryo/fetus
(Dencker et al., 1983), transfer across the fully developed
placenta is normally low (Ahokas & Dilts, 1979; Sonawane et al.,
1975) found that only 0.02% of an injected dose reached the fetus.
The concentration of cadmium in the organs of an embryo, fetus or
neonate is three orders of magnitude lower than in the
corresponding organs of an adult woman (Chaube et al., 1973;
Henke et al., 1970).
Numerous studies have shown that chronic exposure leads to a
selective accumulation of cadmium in the liver and kidneys (renal
cortex) and in some studies up to 75% of the total body burden was
found in these organs (Friberg et al., 1985). Distribution to the
kidneys is particularly important in view of the chronic
nephrotoxicity of cadmium. However, distribution of cadmium in the
body varies with the dosing protocol.
In various species, after administration of a single dose
per os or parenterally, the highest burden initially occurs in
the liver but kidney levels may increase over several months to
exceed liver levels (Gunn & Gould, 1957); pancreas and spleen also
acquire relatively high concentrations (Nordberg & Nishiyama,
1972). The accumulation of cadmium in the liver and subsequent
redistribution to the kidney is probably due to efficient
metallothionein synthesis in the liver; cadmium-metallothionein may
be slowly released into the plasma, filtered through the glomeruli
and reabsorbed in the tubules as previously mentioned. Thus in high
exposure situations, even after discontinuation of exposure,
concentrations of cadmium in the renal cortex may be maintained for
a prolonged period or may even continue to increase if liver stores
are high.
The fate of cadmium after chronic exposure by various routes
has been reviewed by Friberg et al., (1974, 1975, 1986) and
Nomiyama (1978). Initially, cadmium in liver increases rapidly and
is redistributed slowly to the kidney so that the higher the
intensity of exposure, the higher the ratio of liver to kidney
concentrations. The route of administration can also affect this
ratio (Nomiyama et al., 1976).
The concentration of cadmium in liver and renal cortex may
fall subsequent to renal damage and increased leakage of bound
cadmium into the urine (Bonnel et al., 1959; Nomiyama et al.,
1982b).
In humans, after normal levels of exposure, about 50% of the
body burden is found in kidneys, about 15% in the liver and about
20% in the muscles (Kjellstrom, 1979). As in animals, the
proportion of cadmium in the kidney decreases as liver
concentration increases (Friberg et al., 1985). The lowest
concentrations of cadmium are found in brain, bone and fat (Sumino
et al., 1975; Cherry, 1981). Accumulation in the kidneys
continues up to 50-60 years of age in humans and falls thereafter,
possibly due to age-related changes in kidney integrity and function;
in contrast, cadmium levels in muscle continue to increase throughout
life (Friberg et al., 1985). Differences in population mean renal
cortex cadmium levels in different countries have been attributed
mainly to differences in daily intake via food (Friberg et al.,
1986) and smoking increases renal cortex cadmium concentration by
about 10 mg/kg irrespective of differences in the intake in food
(Vahter, 1982).
Normal urinary excretion of cadmium is low. In chronic
injection studies in mice, average daily urinary cadmium excretion
prior to the onset of tubular proteinuria was about 0.01-0.02% of
the body burden (Nordberg, 1972) and in a second study (Elinder &
Pannone, 1979), one month after repeated sub-cutaneous injection,
daily urinary excretion was only 0.001% of body burden. Similar,
low urinary excretion rates have been found in rabbits and monkeys
(Nomiyama, 1973; Nomiyama & Nomiyama, 1976a, b; Nomiyama et al.,
1979, 1982a). Over a range of doses, there was an increase in
urinary excretion associated with an increase in cadmium content of
the renal cortex (Nomiyama & Nomiyama, 1976a; Suzuki, 1980; Bernard
et al., 1981). Studies in mice, rats and rabbits indicate that
urinary excretion of cadmium increases slowly with increasing body
burden but, as renal dysfunction develops, there is a sharp
increase in excretion and a fall in hepatic and renal cadmium
concentrations (Friberg, 1952; Axelsson & Piscator, 1966a; Nomiyama
& Nomiyama, 1976a; Nordberg & Piscator, 1972; Suzuki, 1974).
In humans not excessively exposed to cadmium, mean urinary
cadmium concentrations range from < 0.5 = 2.0 µg/L, or about 0.01%
of body burden, and urinary excretion increases with age and
increasing body burden (Nordberg et al., 1976; Elinder et al.,
1978; Kowal et al., 1979). Urinary cadmium is mainly bound to
metallothionein (Tohyama et al., 1981; Roels et al., 1983b).
It is difficult to estimate the extent of biliary/gastrointestinal
excretion after oral administration of cadmium since most of the faecal
cadmium is unabsorbed material (approximately 95% of the dose). Animal
studies of gastro-intestinal excretion after parenteral administration
indicate that a few per cent of the dose is excreted in the faeces in
the first few days after dosing and faecal excretion initially exceeds
urinary excretion (Nomiyama, 1978; Friberg et al., 1985). The
mechanism of faecal excretion may involve both sloughed off mucosal
cells and excretion in bile. Biliary excretion of cadmium within 24
hours after parenteral administration is dose-dependent (Cirkt &
Tichy, 1974; Nomiyama, 1974; Klaassen & Kotsonis, 1977) and varies
between 0.3% and 13% of the dose; after the initial rapid phase,
excretion is the bile is about 0.02-0,04% of body burden, mostly
associated with a fraction of molecular weight below 10,000
(Nordberg et al., 1977; Elinder & Pannone, 1979). At low or
moderate doses, faecal excretion is quantitatively about the same
as urinary excretion.
Minor routes of excretion include hair (Anke et al., 1976),
breast milk (Schroeder & Balassa, 1961) and pancreatic fluid
(Friberg et al., 1985) but collectively these make little
contribution to total excretion or biological half-life.
The slow excretion results in an extremely long biological
half-life for cadmium, in mouse and rat, the half-life is about
200-700 days (Friberg et al., 1985) and in squirrel monkey is
more than 2 years (Nordberg, 1972). Estimates of biological half-
lives based on animal experiments in mice, rats, rabbits, dogs and
monkeys are highly variable and range up to 22 years in some
primate species (Friberg et al., 1974; Nomiyama et al., 1978,
1979). The retention functions are multi-phasic and the body
contains several compartments with different half-lives. The half-
time of the slowest compartment usually is greater than 20% of the
lifespan of the animal.
Toxicological studies
Special studies on carcinogenicity
Intramuscular or s.c. injection of cadmium metal of cadmium
compounds caused injection site sarcomas (Heath et al., 1962;
Kazantzis, 1963; Kazantzis & Hanbury, 1966; Haddow et al., 1964;
Gunn et al., 1967; Nazari et al., 1967).
Regeneration of Leydig cells following testicular necrosis
induced by a single parenteral dose of cadmium salts has been
interpreted as Leydig cell tumours (Gunn et al., 1963, 1965;
Favino et al., 1968, Lucis et al., 1972). Other studies by
injection or peroral administration have proved negative for
interstitial testicular tumours (Schroeder et al., 1964, 1965;
Loser, 1980) but the doses were lower than would cause renal damage
and which have been encountered in man.
Rats were exposed to cadmium at a concentration of 5 mg Cd/L
in drinking water for 2 years. There were a total of 7 malignant
tumours among 47 cadmium-exposed male animals compared with 2
tumours in 34 controls but this difference was not statistically
significant and it was concluded that cadmium was not carcinogenic
(Kanisawa & Schroeder, 1969). However, the present reviewer
concludes that this study would not meet modern requirements for an
adequate carcinogenicity study.
Three groups of 40 rats were exposed to cadmium chloride
aerosols continuously for 18 m at concentrations of 12.5, 25 or
50 µg/m3; a control group of 41 animals was also included. The
experiment was terminated after 31 m when the incidence of lung
tumours was 15%, 53% and 71% at the three increasing dose levels
compared with a zero incidence of lung tumours in controls
(Takenaka et al., 1983).
A series of studies were performed to investigate the possible
role of cadmium in the aetiology of cancer of the prostate. Three
groups of rats received weekly s.c. injections of 0.022, 0.044 or
0.087 mg Cd/rat as CdSO4 (average weight 220 g at start and 410 g
at termination) for 2 years. A control group of rats was similarly
injected with water. Although high tissue concentrations of cadmium
were achieved (80 mg Cd/kg in the liver of the high dose group), no
malignant changes were observed in the prostate and no significant
differences in tumour incidence at other sites were found between
exposed and control animals (Levy et al., 1973).
In studies on the prostate carcinogenicity of cadmium sulfate
after gavage, rats were given weekly doses of 0.08 to 0.35 mg/kg bw
and mice received 0.44 - 1.75 mg/kg bw. Due to the low gastro-
intestinal absorption, tissue levels after two years were low
and the highest dose group of rats had average kidney cadmium
concentrations of 5 mg/kg i.e. lower than in normal human adults.
No differences in tumour incidence were seen between controls and
treated rats or mice after two years and 18 months respectively
(Levy et al., 1975; Levy & Clack, 1975).
Special studies on mutagenicity and clastogenicity
Drosophila exposed to various cadmium compounds failed to
display any chromosomal abnormalities (Ramel & Friberg, 1971;
Vorobjeva & Sabalina, 1975) and in vitro studies on cultured
human lymphocytes and fibroblasts were also negative (Paton &
Alison, 1972; Deknudt & Deminatti, 1978; Kogan et al., 1978).
Andersen et al., (1983) found that cadmium chloride (1.1 mg Cd/L)
had a spindle-inhibiting effect on cultured human lymphocytes and
showed that induction of metallothionein synthesis in these cells
had a protective effect.
Cadmium (as sulfate) at a concentration of 62 mg Cd/L in the
culture medium caused a marked increase in the frequency of
chromatid breaks, translocations and discentric chromosomes in
cultured human leucocytes (Shiraishi et al., 1972) and Rohr and
Bauchinger (1976) observed a reduced mitotic index in cultured
hamster fibroblasts at 100 µg Cd/L, with chromosomal aberrations at
concentrations above 500 µg/L. The effects on cultured hamster
fibroblasts appeared to depend on the medium used (Deaven &
Cambell, 1980).
Watanabe et al., (1979) observed aneuploidy in rat oocytes
after exposure to cadmium chloride in vivo. When lambs received
cadmium in feed (60 µg Cd/kg) for 191 days there was a significant
increase in extreme hypodiploidy which may be related to the
spindle-inhibiting effect noted above (Doyle et al., 1974).
After injection of 0.6 - 2.8 mg Cd/kg bw in mice, there was an
increased frequency of chromatid breaks in bone marrow cells after
6 h and chromosome gaps and breaks in spermatocytes (Felten, 1979).
These effects may be associated with the acute effects on
haemopoiesis and the testes.
One cytogenetic study on Itai-Itai patients showed some
chromosomal aberrations (Shiraishi et al., 1972) but another
study was negative (Bui et al., 1975). Studies on cadmium workers
have similarly been equivocal as Bui et al., (1975) found no
chromosomal abnormalities whereas Deknudt & Leonard (1975) reported
a significant increase in chromosomal anomalies in leucocytes from
such workers. Mice examined three months after an i.p. dose of
1.75 mg Cd/kg displayed no chromosomal abnormalities (Gilliavod &
Leonard, 1975).
Special studies on teratogenicity and fetotoxicity
In experiments in a variety of animal species, teratogenic
effects have been observed after single injections of high doses of
cadmium (3 mg/kg bw or more). These effects have been demonstrated
after i.v. injection of cadmium sulfate in hamsters (Ferm &
Carpenter, 1968; Mulvihill et al., 1970; Ferm, 1971, 1972) and
after i.p. or subcutaneous administration of cadmium chloride to
rats or mice (Barr, 1973; Chernoff, 1973; Ishizu et al., 1973).
The effects included cleft lip and palate and limb and tail
abnormalities.
The above teratogenicity studies all involved high parenteral
doses but similar teratogenic effects have been seen after dosing
per os (Scharpf et al., 1972). Pregnant rats were given daily
doses of 20, 40, 60 or 80 mg CdCl2/kg bw by gavage on days 6 - 19
of pregnancy, with simultaneous administration of sodium chloride.
In addition to the skeletal abnormalities, the offspring were
examined for soft tissue defects. These were found to include heart
and kidney anomalies which were treatment but not dose related. At
the lowest dose, heart abnormalities were detected in 19.7% of test
fetuses, compared with 6.6% of controls; caudal ectopia of the
kidney occurred in 15.7% of low-dose fetuses with no such
abnormality in controls (Scharpf et al., 1972).
In a long-term multigeneration study in mice in which cadmium
was administered in drinking water at a concentration of 10 mg
Cd/L, increased fetal mortality and malformations were observed
(Schroeder & Mitchener, 1971). A high neonatal mortality (30.5%)
occurred prior to weaning in the F1 and F2a litters.
The teratogenicity of cadmium has been reviewed by Ferm &
Layton (1981) and Ferm & Hanlon (1983). It has been reported that
pretreatment of the dams with low doses of cadmium protects against
a subsequent dose of cadmium at a level that would normally be
teratogenic, presumably by inducing synthesis of metallothionein.
In addition, protection is afforded by co-administration of zinc
(Ferm & Carpenter, 1968; Daston, 1982) or selenium (Holmberg & Ferm,
1969). Maternal zinc deficiency alone can produce congenital
malformations (Hurley et al., 1971) and administration of cadmium
to zinc-deficient animals further increased the incidence of
malformations (Parzyck et al., 1978).
Support of the hypothesis that cadmium induces a fetal zinc
deficiency was provided by the observation that, after
administration of cadmium at doses of 0.25-1.25 mg Cd/kg bw to
pregnant rats on day 12 of gestation, there was a dose-related
decrease in the fetal uptake of a dose of 65 mg zinc given 4 h
later, and decreased activity of the fetal zinc-dependent thymidine
kinase (Samarawickrama & Webb, 1979).
Interactions with copper have also been observed and when
pregnant goats were given high oral doses of cadmium in the diet
(80-500 mg Cd/kg dry matter in a diet containing 10 mg Cu/kg) fetal
death occurred in half of the offspring with neonatal death of the
remainder (Anke, 1973). Very low copper concentrations were found
in fetal liver and other organs and there were typical signs of
copper deficiency.
High doses of cadmium by injection caused placental damage and
fetal deaths in rats and mice (Parizek, 1964; Parizek et al.,
1986b; Chiquoine, 1965) and fetotoxicity was also seen in rats
exposed by inhalation (Cvetkova, 1970).
In most experiments in which adverse effects on the embryo/
fetus were seen, the doses were very large and administered
parenterally, conditions which are unlikely to occur in pregnant
women. In view of the low placental transfer at realistic levels of
exposure (see metabolic studies above), the protective effect of
prior low-level exposure, and the nutritional complications of
induced zinc and/or copper deficiency, the relevance for humans of
the teratogenicity observed in these studies is doubtful and there
are no reports of teratogenic effects in occupationally exposed
women. In some such cases, however, birth weights of offspring of
exposed mothers were lower than controls and a few cases of rickets
were observed (Cvetkova, 1970).
Other effects on reproductive organs and function
Single injections of cadmium salts, equivalent to 1-3 mg Cd/kg
bw caused dramatic testicular necrosis (Parizek & Zahor, 1956;
Parizek, 1957). Within hours the testes undergo selective and
complete destruction (Gabbiani et al., 1974); at a later stage,
Leydig cells regenerate (Parizek, 1960; Allanson & Deansley, 1962).
Similar doses also induce haemorrage and necrosis in ovaries of
pre-pubertal rats (Parizek et al., 1968a; Kar et al., 1959).
The cadmium induced testicular necrosis generally results in
permanent infertility. Ramaya & Pomerantzeva (1977) found markedly
reduced weights of testes with morphological changes in mice up to
6 months after dosing; the animals were sterile. Krasovskii et
al., (1976) reported decreased sperm motility and lowered
spermatogenic index in rats given cadmium in the diet at doses of
0.5-5.0 mg Cd/kg bw.
The extensive literature in this field has been reviewed by
Barlow & Sullivan (1982). However, the circumstances of
experimental exposure frequently are unrelated to the human chronic
low-dose situation. There are no indications of impaired
reproductive function or testicular atrophy in humans exposed to
cadmium.
Acute toxicity
The LD50 after injection of soluble cadmium compounds is in
the range of 2.5-25 mg/kg bw (Friberg, 1950; Eybl & Sykora, 1966;
Commission of the European Community, 1978). Shortly after
injection, severe endothelial damage occurs in the small vessels of
the peripheral nervous system and testes (Gabbiani, 1966; Parizek,
1957). After some hours, marked liver changes are seen and liver
damage may be the cause of death after acute parenteral
intoxication.
For most compounds, the oral LD50 is 10-20 times that after
parenteral administration (see Table 3). This is explicable by the
relatively poor absorption of cadmium compounds from the
gastro-intestinal tract.
The acute effects on the gonads have been described above and
probably result from initial endothelial damage in the vessels,
oedema, decreased capillary blood flow, ischaemia and cell necrosis
(Aoki & Hoffer, 1978; Francavilla et al., 1981). After parenteral
administration of doses near the LD50, pronounced histological
changes are seen in the small vessels of several organs/tissues.
Hoffman et al., (1975) observed such changes in the liver of rats
given 6 mg Cd/kg bw and Dudley et al., (1982) concluded that the
liver was the major primary target organ for acute cadmium
toxicity. This conclusion is supported by the fact that cadmium
initially accumulates in the liver prior to translocation to the
kidney. Acute changes in blood pressure have also been reported
(Dalhamn & Friberg, 1954; Perry et al., 1970).
Oral administration of single high doses of cadmium compounds
causes desquamation of the epithelium, necrotic changes in the
gastrointestinal mucosa and dystrophic changes in heart, liver and
kidneys (Tarasenko et al., 1974; Vorobjeva & Sabalina, 1975).
Table 3. Acute toxicity of orally-administered cadmium
Species Chemical form LD50 (mg Cd/kg bw)
Mouse Cd metal 890
CdO 63
CdSO4 47
CdCl2 57
Cd(NO3)2 48
CdI2 51
CdCO3 202
CdS 907
Cd caprylate 85
Cd stearate 98
Cd sulphoselenide 1623
Ba-Cd stearate 258
CdTe > 7500
Rat Cd caprylate 270
Cd stearate 203
Ba-Cd stearate 161
(From: Tarasenko et al., 1974; Vorobjevo & Sabalina, 1975;
Vorobjevo & Bubnova, 1981)
Short-term studies
Numerous short-term studies have been performed, mainly aimed at
investigating the pathogenesis of kidney lesions and the critical levels
of cadmium associated with adverse effects in the renal cortex. However,
the results are not always readily interpretable since renal cadmium
levels fall with the onset of proteinuria.
Renal lesions consequent on the administration of cadmium were
first reported in cats by Prodan (1932) and in rats by Wilson
et al., (1941). In cats, the lesions occurred after oral
administration of 100 mg Cd/day for one month and were characterized by
desquamation in proximal tubular epithelium with no changes in the
glomeruli. Wilson et al., (1941) reported slight renal tubular changes
after administration of a diet containing 62 mg Cd/kg to rats.
A summary of subsequent short-term studies in which the levels of
cadmium in the kidney were determined is given below.
Mice
Mice received daily subcutaneous injections of 0.25 or 0.5 mg Cd/kg
bw for 6 months. Total kidney cadmium concentrations at termination were
110-170 mg/kg in the lower dose group and about 170 mg/kg in the high
dose group. These concentrations correspond to about 138-212 mg Cd/kg in
the renal cortex (assuming kidney cortex concentrations are about 1.25
times whole kidney concentrations). No effects were reported at the
lower dose but tubular proteinuria was observed in the higher dose group
(Nordberg & Piscator, 1972).
Rats
Groups of 3-5 male Sprague Dawley rats, body weight 240 g, were
given s.c. injections of 0.5 mg Cd/kg bw daily for 30, 48 or 54 days.
Urinary protein concentration increased in the 5th week, when the kidney
cadmium concentration was 100 mg/kg (equivalent to 125 mg/kg in renal
cortex). Urine volume increased in the eighth week (kidney cadmium 150
mg/kg) and by the ninth week, urinary protein and urinary cadmium were
markedly elevated (Suzuki, 1974).
A group of Wistar rats, initial bw 250 g, were given s.c. doses of
1 mg Cd/kg bw three times a week; 3-5 animals were sacrificed every four
weeks to measure cadmium in the kidney, and protein and ribonuclease
activity were measured in the urine. Urinary cadmium and protein began
to increase in the eighth week when the kidney cadmium concentration was
170 mg/kg. By the tenth week, kidney cadmium had increased to 200 mg/kg
and urinary ribonuclease levels began to rise (Kishino et al., 1975).
A group of 4 male rats were given i.p. doses of cadmium chloride of
0.75 mg/kg twice weekly for 10 months. In two animals, the cadmium
concentration in kidney was 168 mg/kg and the concentration in urine was
1.58 mg/L; there was marked total proteinuria with histological changes
both in renal tubules and glomeruli (Murakami et al., 1974).
Sprague Dawley rats were given cadmium in drinking water at
concentrations of 10, 50, 100 or 200 mg Cd/L for 8.5 months. No
significant histological changes were seen in the lowest dose group in
which the kidney cadmium concentration was 12 mg/kg (15 mg/kg in renal
cortex). Slight histological changes occurred in the 50 mg/L dose group
in which the kidney cadmium levels was 38 mg/kg (44 mg/kg in cortex) and
became progressively more marked at the two highest dose levels when the
kidney cadmium was 90 and 145 mg/kg (113 and 181 mg/kg in cortex)
respectively (Kawai et al., 1976). This study provides evidence of
treatment-related changes in the kidney at renal cortex levels of
cadmium as low as 44 mg/kg and the no effect level was 15 mg Cd/kg in
the cortex. Kajikawa et al., (1981) also reported morphological
changes in the kidneys of rats given drinking water containing 200 mg
CdCl2/L for 91 weeks. Histologically there were degenerative
changes in the proximal tubule and, at the electron microscope level,
proliferation of smooth endoplasmic reticulum and vacuolization and
coagulative necrosis of the tubular cells. No significant changes were
seen in glomeruli or interstitial tissue.
Three pairs of Sprague Dawley rats received drinking water
containing 0.5, 5 or 50 mg CdCl2/L for 18 m and one animals from each
group was sacrificed. Slight histological changes were seen in the renal
tubules of the rats given 50 mg CdCl2/L and the kidney cadmium
concentration was 100 mg/kg, equivalent to 125 mg/kg in the cortex
(Murakami et al., 1974).
When rats were given cadmium in drinking water at a concentration
of 7.5 mg Cd/L for 12 months, an increase in urinary ribonuclease
activity was seen; the concentration of cadmium in renal cortex was
found to be 90 mg/kg (Piscator & Larsson, 1972). In a similar study in
which female rats were given 200 mg Cd/L in drinking water for 11
months, the average concentration of cadmium in the cortex was 200 mg/kg
and this was accompanied by low molecular weight (tubular) and total
proteinuria (Bernard et al., 1981). Rats given a lower concentration
of 50 mg Cd/L in water for 3 months were reported to have acquired
cadmium levels of 100 mg/kg in whole kidney (125 mg/kg cortex) and to
display functional deficits (decreased inulin clearance and p-amino
hippuric acid secretory Tm); histological abnormalities were also in
evidence (Kawamura et al., 1978). Conversely, rats similarly exposed
for 6 months were reported to have lower renal cortical cadmium levels
of 50 mg/kg but, again, histological changes were apparent (Aughey
et al., 1984).
Rabbits
Groups of rabbits were given sub-cutaneous doses of 0.25 mg Cd/kg
bw for 2.5 and 4 months by which times the renal cortex cadmium
concentrations were 235 and 460 mg Cd/kg, respectively. At the lower
concentration there were slight histological changes in the proximal
tubules which were more severe at the higher level and accompanied by
reduced alkaline phosphatase activity in the renal cortex and total
proteinuria (Axelsson & Piscator, 1966a; Axelsson et al., 1968). In
similar studies by subcutaneous administration, rabbits received 0.5 mg
Cd/kg bw for 0.7 and 2.5 months, leading to renal cortical cadmium
concentrations of 200 and 300 mg/kg, respectively. In both cases,
proteinuria was observed (Nomiyama et al., 1982b; Nomiyama & Nomiyama,
1982). After 0.7 months exposure the rabbits displayed glucosuria and
aminoaciduria, and there was a decrease in inulin clearance and in
TmPAH.
In other studies by subcutaneous administration, rabbits given 0.5
mg Cd/kg for 1 month displayed beta-2-microglobulinuria at a renal
cortex concentration of 120 mg/kg (Nomiyama et al., 1982b) and early
work had revealed decreased tubular reabsorption at 50-200 mg Cd/kg
renal cortex after s.c. administration of 1.5 mg Cd/kg for one month
(Nomiyama, 1973; Nomiyama et al., 1978). However, after administering
cadmium to rabbits s.c. at a dose level of 0.5 mg/kg bw for two months,
Kawai et al., (1976) reported only slight histological changes when
the levels of cadmium in the renal cortex were about 200 mg/kg.
Administration of cadmium to rabbits in drinking water at a
concentration of 160 mg/l for 6 months resulted in average levels of
cadmium in the kidney of 170 mg/kg (212 mg Cd/kg renal cortex) and this
was associated with marked histological changes and extensive fibrosis
(Stowe et al., 1972).
When cadmium was administered in drinking water to rabbits at
concentrations of 50 or 200 mg/L for 10 months, the resultant levels in
renal cortex were 58 and 200 mg/kg, respectively. At the lower level
there was slight tubular atrophy but at the higher level severe
interstitial and tubular fibrosis were in evidence (Kawai et al.,
1976).
Dietary administration of cadmium to rabbits at a level of 300
mg/kg diet for 4, 10 or 11 months resulted in cadmium levels in the
renal cortex of 200, 300 and 250 mg/kg; at the lowest level
aminoaciduria and elevated urinary enzyme levels were recorded, beta-2-
microglobulinuria was evident at the intermediate level and there was
proteinuria and glucosuria at the highest level (Nomiyama et al.,
1975; 1982b).
Twenty-one male rabbits were divided into three groups; two groups
received cadmium chloride in the diet at a concentration of 300 mg/kg
for 19 and 44 weeks respectively while the third group served as
controls. The treated animals displayed proteinuria and aminoaciduria by
week 19 and it continued to increase in severity when treatment was
continued for 44 weeks. After cessation of treatment, animals which had
received cadmium for 44 weeks showed only slight improvement.
Proteinuria, aminoaciduria and liver function which had not returned to
normal after 24 weeks; anaemia also did not readily recover. Conversely,
animals treated for 19 weeks recovered from the effects of cadmium;
proteinuria and aminoaciduria in most animals disappeared soon after the
end of the cadmium exposure, plasma GTP fell after 1 week and
haemoglobin and haematocrit returned to normal after 6-11 weeks. It was
concluded that the mild cadmium-induced health effects are reversible in
the rabbit but more severe injury is not readily reversible (Nomiyama &
Nomiyama, 1984).
In a study designed to determine the critical level of unbound
cadmium in rabbit renal cortex which causes renal injury, 15 male
rabbits were given single i.v. doses of cadmium chloride of 0, 0.25,
0.5 or 1.0 mg Cd/kg simultaneously with excess mercaptoethanol to
prevent binding to plasma proteins. The critical concentration of
unbound cadmium in the renal cortex at which proteinuria was observed
was 13 mg/kg and it was suggested that the non-metallothionein bound
cadmium concentration was a better index of critical concentration than
total cadmium in the renal cortex (Nomiyama & Nomiyama, 1986).
Pigs
Pigs were given cadmium chloride in the diet at concentrations of
50, 150, 450 and 1350 mg/kg. A decrease in leucine aminopeptidase
activity was observed at a renal cadmium concentration of 78 mg/kg
(equivalent to 100 mg/kg in renal cortex). At the lowest cadmium level
of 12 mg/kg, the only effect was an equimolar increase in zinc in the
kidney (Cousins et al., 1973).
Monkeys
Ten male rhesus monkeys were divided into four groups of 2, 2, 3
and 3 and were fed daily 100 g food containing 0, 3, 30 and 300 mg Cd/kg
respectively. Urine was collected every 2 weeks and blood samples every
4 weeks. One monkey from each of the two top treatment groups was
sacrificed at week 24 for pathological examination and determination of
tissue cadmium levels.
The lowest dose group did not show any effect of treatment over a
period of 55 weeks. The 30 mg/kg group showed no significant changes for
up to 24 weeks although urine levels were up to 18 µg Cd/L and, in the
animal sacrificed at this time, the renal cortex cadmium concentration
was 300 mg/kg. In this group plasma urea nitrogen and urine protein
increased after 30 and 36 weeks. After 55 weeks, qualitative tests were
negative for low molecular weight proteinuria and glycosuria; blood
analyses and liver and kidney function tests were essentially normal
although the cadmium concentrations in the renal cortex of the two
monkeys were 460 and 730 mg/kg and those in the liver were 110 and 160
mg/kg, respectively.
In the highest exposure group, renal dysfunction was observed as
total proteinuria, increased excretion of beta-2-microglobulin and
retinol binding protein, glucosuria, aminoaciduria, decreased
creatinine clearance and decreased tubular reabsorption of phosphate.
Cadmium concentrations in renal cortex and liver of the two monkeys
was 350 and 580 mg/kg, and 410 and 630 mg/kg, respectively. The
critical cadmium concentration in the renal cortex was estimated as
380 mg/kg for low molecular weight proteinuria and 470 mg/kg for
proteinuria, glucosuria and aminoaciduria. The apparent biological
half-life of cadmium at autopsy was calculated to be 22.4, 5.2, 6.4
and 0.66 years for the 0, 3, 30 and 300 mg/kg groups, respectively
(Nomiyama et al., 1979).
In a second experiment, 35 rhesus monkeys were divided into five
groups and each group were fed pelleted food containing 0, 3, 10, 30 or
100 mg/g respectively at a daily dose of 100 g for one month, 150 g for
the next 13 months and 200 g for the following 16 months, urine and
blood samples were examined every 3rd and 6th week respectively. One
animal from each group was sacrificed for tissue cadmium determination
and pathological examination after 60 and 101 weeks; additional animals
were sacrificed from the top dose group after 39 and 50 weeks, and from
the 30 mg/kg group after 77 weeks and similarly examined.
No adverse effects were recorded in the 3 mg/kg group. In the 10
mg/kg group, slight pathological changes were observed in the tubular
epithelium during the 101st week but no other adverse effects were
noted. In the 30 ppm group, slight proteinuria (described as
"negligible") was detected after 58 weeks but no pathological changes
were seen and cadmium concentration in the renal cortex after 60 weeks
was 809 mg/kg. During the 101st, week slight pathological changes were
observed in the tubular epithelium in this dose group when the renal
cortex cadmium concentration was 844 mg/kg. It was concluded that the
critical concentration for proteinuria was 780 mg/kg for proteinuria and
in excess of 840 mg/kg for histopathological changes.
In the 100 mg/kg close group, slight proteinuria, aminoaciduria and
beta-2-microglobulinuria occurred after the 39th-42nd week when the
cadmium concentration in the renal cortex was 635 mg/kg. Subsequently,
marked proteinuria, aminoaciduria and decreases in renal function were
observed during the 48th-54th week when the cadmium concentration in the
cortex was 612 mg/kg. Renal function further deteriorated with time of
exposure and, at termination, marked tubular pathology was evident.
After 101 weeks the cadmium concentration in the renal cortex was 560
mg/kg.
These results were taken to indicate that the critical
concentration for proteinuria, aminoaciduria, beta-2-microglobulinuria,
glycosuria, renal dysfunction and pathological changes were all
approximately 635 mg/kg. However, other changes (elevated plasma enzymes
and anaemia) were detected after 6 and 54 weeks, respectively, in the
100 mg/kg dose group (Nomiyama et al., 1982a).
Forty male and female rhesus monkeys were divided into eight groups
(4-8 per group). Half were given a diet containing cadmium chloride at
a level of 3 mg/kg for one year and then at a level of up to 30 mg/kg
for a further 2 years. The other half were given no additional cadmium
above normal pelleted food. Some animals received diets low in calcium
and/or vitamin D. No proteinuria was noted after 3 years and no
abnormalities in creatinine clearance or phenolsulphophthalein test.
Cadmium concentrations in the renal cortex of monkeys given cadmium and
maintained on a low calcium and vitamin D deficient diet were between
611 and 1017 mg/kg after the third year of the experiment. Biopsy
specimens of renal cortex form 2 monkeys given cadmium in an adequate
diet contained 624 and 1255 mg/kg respectively at the 50th month
(Tertiary Monkey Experiment Team, 1983).
Long term studies
Monkeys
In a long-term study thirty seven male rhesus monkeys, age about 3
years, were divided into five groups and given daily 200 g solid feed
containing added cadmium chloride at concentrations of 0, 3, 10, 30 or
100 mg Cd/kg respectively; the basal diet contained the minimum
requirement of zinc of 6 mg/day (30 mg/kg) in order to avoid the
protective effect of excess zinc and was found to contain 0.27 mg Cd/kg.
The exposure was continued for up to 9 years. Urine and blood specimens
were collected at three and six week intervals respectively and the
animals were examined for haemopoietic, circulatory, liver and renal
functions, calcium and phosphate metabolism and blood and urine metal
levels. Lumbar X-ray examinations were carried out at 12 week intervals
and animals were sacrificed at regular intervals for histopathological
examination and determination of organ metal concentrations.
Dose related decreases in weight and body length were recorded in
the groups given 10 mg Cd/kg diet or more. Over 50% of the 100 mg/kg
showed decreased erythrocyte counts after 120 weeks and a similar effect
occurred after 240 weeks and 360 weeks in the 30 mg/kg group and 10
mg/kg groups respectively. The anaemia was not accompanied by an
increase in reticulocytes. The highest dose group had a higher blood
pressure than other groups during the first 18 months but the age
related increase in the controls was not seen in the test animals. No
change was seen in ECG or pulse rate.
The 100 mg/kg group displayed glucosuria, proteinuria after 48
weeks and plasma creatinine and phosphorous clearance values were
elevated. Plasma uric acid was elevated at 84 weeks and the frequency of
aminoaciduria increased from 91 weeks Urine volume was increased from
101 weeks and beta-2-microglobulin began to rise from 138 weeks and
exceeded 2 mg/L at 172 weeks.
The 30 mg/kg group showed an increase in plasma uric acid at 300
weeks and from 306 weeks there was an increase in urine amino acids and
plasma creatinine. Beta-2-microglobulinuria was noted at 311 weeks and
exceeded 2 mg/L at 426 weeks; total proteinuria was observed at 384
weeks.
The onset of beta-2-microglobulinuria was later than other clinical
indications of renal dysfunction in the 100 mg/kg dose group but these
indicators coincided in the 30 mg/kg group. Despite the early clinical
signs at 48 weeks in the top dose group, there was no marked
aggravation of the condition over the following eight years and no
case of renal failure developed.
No abnormality of renal function was seen in the 3 or 10 mg/kg
dose groups.
In the highest dose group, elevated plasma GOT and GPT were
detected from 6 weeks and increased LDH and decreased plasma A/G ratios
from 18 weeks. No other indications of liver dysfunction were seen in
any dose group. No radiological or clinical biochemical changes in bone
mineral metabolism were seen and serum vitamin D levels and metabolism
in the kidney appeared normal (see also Short-term Studies, Tertiary
Monkey Experiment Team, 1983).
Histologically, dose dependant pathological changes were seen in
the kidneys of the 10, 30 and 100 mg/kg groups but the lesions were only
classified as mild to moderate. Even at the top two dose levels, the
changes were not particularly progressive and only mild renal cortical
fibrosis was evident at completion of the 9 year experiment. No
osteomalacia or osteoporosis was observed in the femur.
Cadmium excretion in the urine showed an exponential relationship
to dose and duration of exposure and did not increase following signs of
renal dysfunction Concentrations in the renal cortex increased to a
maximum of 635 mg/kg at 39 weeks in the 100 mg/kg group, 1170 mg/kg at
257 weeks in the 30 mg/kg groups and 1070 mg/kg at 216 weeks in the 10
mg/kg group, after which there was a decrease irrespective of the
absence or presence of renal dysfunction. Cadmium levels in the liver of
the top dose group reached a maximum of 1040 mg/kg after 101 weeks but
in all other groups it continued to rise until completion of the
experiment when the levels were 106, 430 and 1400 mg/kg in the 3, 10 and
30 mg/kg groups, respectively.
Administration of cadmium caused a dose-dependent increase in
copper and zinc concentrations in blood, plasma, renal cortex and liver.
Organ levels of copper and zinc fell and urinary excretion of these
metals increased following the onset of renal dysfunction.
It was estimated that the critical concentration of cadmium in the
renal cortex was 635 mg/kg in the 100 mg/kg group and 1170 mg/kg in the
30 mg/kg group (Nomiyama et al., 1987).
In a long-term study to investigate whether any difference in
toxicity could be detected between cadmium in contaminated rice and
inorganic cadmium, crab-eating monkeys were given diets containing rice
to a level of 80 µg Cd/day, or cadmium chloride to a level of 190 g
Cd/day. Two animals on standard diets served as controls. The experiment
was conducted over a period of 6 years. Effects due to treatment
included high urinary cadmium (occasionally exceeding 10 µg/L) but no
changes could be detected in urinary beta-2-microglobulin, renal or
hepatic function nor any other haematological or clinical biochemical
index. Cadmium concentrations in the renal cortex and liver increased
proportionally to the dose level and duration of exposure and renal
cortex levels reached a maximal of 570 mg/kg after CdCl2 and 300
mg/kg after contaminated rice (Nomiyama & Nomiyama, 1988).
In the absence of significant treatment-related differences in
organ function and pathology, and in the light of the different doses
used in rice and as inorganic cadmium, it is not possible to reach
conclusions about the relative toxicity of inorganic cadmium and that in
contaminated rice.
Effects on the liver
Friberg et al., (1950) observed fibrosis in the liver of rabbits
given repeated s.c. doses of cadmium and periportal and interlobular
colµgen deposition was found in rabbits after administration of 160 mg
Cd/L in drinking water (Stowe, et al., 1972). In the latter case,
liver cadmium concentration was 188 mg,/kg but liver function tests were
normal. Dystrophic changes were observed after intragastric
administration of cadmium caprylate at a dose corresponding to 47 mg
Cd/kg bw and blood lactate was elevated (Tarasenko et al., 1974).
Decreased glycogen has been recorded in the liver of rats given barium
cadmium laurate in 8-10 daily doses of 169 mg/kg bw by gavage (Larionova
et al., 1974) and glycogen depletion and increased levels of
gluconeogenetic enzymes were reported after cadmium exposure (Merali et
al., 1974; Chapatwala et al., 1982). In long-term studies in rabbits,
amyloid deposition in the liver was associated with administration of
cadmium in the diet at a level of 300 mg/kg diet (Kawai et al., 1976).
In the studies reported above, changes in hepatic enzyme activities have
been reported in rats, rabbits and monkeys.
Effects on calcium metabolism and bone
In view of the manifestations of Itai-Itai disease, considerable
attention has been paid to the effects of cadmium on calcium metabolism
and bone.
Following pregnancy, female rats exposed to cadmium by inhalation
showed radiological evidence of osteoporosis (Tarasenko & Vorobjeva,
1973) and rats exposed subcutaneously showed osteoporosis and
osteosclerosis. Histopathological examination showed an increase in
osteoclasts and "mosaic" bone indicative of osteomalacia.
Rats given 50 mg Cd/L in drinking water showed impaired calcium
absorption (Sugawara & Sugawara, 1974) and histological changes in
duodenal mucosa were seen in these rats and in Japanese quail
(Richardson & Fox, 1974). Dietary cadmium was reported to cause negative
calcium balance in rats and administration with a low protein, low
calcium diet led to reduction in bone calcium and zinc levels.
Impaired calcium absorption may be secondary to effects on the
kidney and renal hydroxylation of 25-hydroxy-cholecalciferol to 1,
25-dihydrocholecalciferol, the active form of vitamin D, was shown to be
inhibited in rats by high dietary cadmium in normal but not in calcium
deficient diets (Feldman & Cousins, 1973; Lorentzon & Larsson, 1977).
Further, rats given cadmium by gastric intubation showed impaired
response to stimulation of calcium absorption by 1-a-hydroxy-vitamin D3
(Ando et al., 1981) and the concentration of calcium-binding protein
in intestinal mucosa is reduced after exposure to cadmium (Fullmer et
al., 1980).
Numerous other studies have reported skeletal changes including
decalcification, osteoporosis and osteomalacia after exposure of rats in
the diet (Kawai et al., 1976; Takashima et al., 1980; Nogawa et
al., 1981), drinking water (Itokawa et al., 1974; Kawamura et al.,
1978), or after s.c. injection (Nogawa et al., 1981). Conversely,
Kajikawa et al., (1981) were unable to detect either osteoporosis or
osteomalacia in a long-term study in rats at 22 mg/L in drinking water.
Monkeys receiving cadmium orally with a diet adequate in calcium
and vitamin D did not develop osteomalacia in the absence of renal
damage (Nomiyama et al., 19791.
Most experiments suggest a direct effect of cadmium on bone
mineralization, causing osteoporosis, and an indirect effect on calcium
absorption via vitamin D hydroxylation.
Effects on Haematopoiesis
Anaemia is a common feature of cadmium intoxication in animals
exposed orally or parenterally (Wilson et al., 1941; Friberg, 1950;
Decker et al., 1958; Prigge et al., 1977). This probably results
from impaired intestinal absorption of iron and may be ameliorated by
dietary supplementation with iron or ascorbic acid (Fox & Fry, 1970; Fox
et al., 1971).
Parenteral cadmium caused destruction of erythrocytes (Berlin &
Friberg, 1960) but there was no indication of either effects on
haemoglobin synthesis or haemolytic anaemia having been reported in
rabbits (Axelsson & Piscator, 1966b).
Effects on blood pressure and the cardiovascular system
Chronic exposure of rats to cadmium can induce hypertension
(Schroeder & Vinton, 1962; Schroeder, 1964; Perry & Erlanger, 1974) but
the effect appears to depend on the dose. Low doses (1-5 mg Cd/L in
drinking water) for 1 year caused elevation of blood pressure but at
higher doses (10-25 mg/L) a transient rise was observed which returned
to normal by 1 year while at still higher levels of 50 mg Cd/L a
decrease in blood pressure was observed after 12 months. Generally
similar results were obtained by Perry et al., (1977) with the
greatest increases in blood pressure being seen after prolonged exposure
to low doses of cadmium and hypotension being associated with high
doses.
The mechanisms by which cadmium affects blood pressure have been
reviewed by Perry & Kopp (1983). At doses causing hypertension,
increased circulatory renin activity was detected (Perry & Erlanger,
1973) and both parenteral and chronic oral exposure was reported to
increase sodium retention (Vander, 1962; Perry et al., 1971; Lener &
Musil, 1971).
Effects on the immune system
Effects on the immune system have been reported after both acute
and chronic exposure to cadmium. A decrease in antibody production and
of antibody-forming cells in the spleen was seen in mice given cadmium
in drinking water (Koller et al., 1975) and an inhibition of the cell-
mediated immune response was seen in mice after repeated injections i.p,
(Bozelka & Burkholder, 1982). There is no evidence of increased
susceptibility to infections or other secondary effects of compromised
immune surveillance.
Observations in man
As indicated above (see metabolic studies), absorption and
retention of orally ingested cadmium in man typically is about 5% of the
dose e.g., 4.7-7.0% in five adult men (Rahola et al., 1971) but may be
influenced by other dietary components, and by iron and cadmium status,
and there is considerable individual variation. Absorption of inhaled
cadmium is greater than after oral ingestion.
The slow excretion of cadmium results in an extremely long
biological half-life for absorbed cadmium and this has variously been
estimated at 10-33 years or 15-40% of the lifespan (Nordberg et al.,
1985).
In humans, the longest half-lives are observed in muscle, liver and
renal cortex (Kjellstrom, 1979; Friberg et al., 1974). Based on an
eight-comportment model, the half-lives in liver and kidney were
estimated to be 7.5 and 12 years, respectively (Kjellstrom & Nordberg,
1978). Estimates based on a single compartment model range from 10 to
30+ years (Kjellstrom, 1971; Tsuchiya & Sugita, 1971; Nordberg
et al., 1985). Experimental studies using radioactive cadmium have
variously shown biological half-lives of 26 years (Shaikh & Smith, 1980)
and 93-202 days (Rahola et al., 1972; Flanagan et al., 1978;
McLellan et al., 1978); the confidence limits in the study by Rahola
et al., (1972) were given as 130 days to infinity.
The biological half-life is shorter if there is renal tubular
dysfunction. In three subjects with proteinuria, the average half-life
in the liver, determined by neutron activation analysis, was 2 years
whereas in nine other subjects without proteinuria, the half-life was
13.5 years (Fletcher et al., 1982).
Because of the long half-life in the kidney and probable continuing
transfer from other tissues, accumulation will continue in the renal
cortex. Mean levels of cadmium in renal cortex at mean age 50 found in
various countries are shown in table 4.
In summary, the average cadmium concentration in the renal cortex
of a non-occupationally exposed person aged 50 years varies between
11 - 100 mg/kg in different regions and the 90th percentile is about
twice the median value in those groups studied.
It has been calculated that a daily intake of 62 µg would be
required to reach a concentration of 50 mg/kg in the renal cortex at age
50, assuming an absorption rate of 5%, that 10% of the absorbed daily
dose is rapidly excreted and also that 0.005% of the total body burden
is excreted and also that 0.005% of the total body burden is excreted
daily. A similar calculation assuming that 0.01% of the total body
burden is excreted daily showed that the daily intake would have to be
88 µg to reach the same final level in the renal cortex (Kjellstrom,
1971). Essentially similar conclusions were reached later by Kjellstrom
(1986c).
Using data gathered from the literature, a statistically
significant relationship was established between average cadmium intake
and average kidney cadmium concentration in various countries (Morgan &
Sherlock, 1984). Using this relationship, it was concluded that a
regular dietary intake of 175 µg Cd/day would cause the concentration of
cadmium in the renal cortex to reach a level of 200 mg/kg in 50 years.
Taking the maximum dietary intake recorded in a U.K. one week duplicate
diet study of 150 µg Cd/day (Sherlock et al., 1983), it was
calculated that levels in the renal cortex would reach 200 mg/kg in 60
years.
Table 4. mean renal cortex cadmium concentrations at age 50
Country Renal cortex Cd Reference
(mg/kg wet
weight)
Australia 40 Miller et al., 1976
Belgium (Liege) 46 Vahter, 1982
Canada 55 Le Baron et al., 1977
China 18 Vahter, 1982
Denmark 40 Miljoministeriet, 1980
Finland 20 - 25 Vuori et al., 1979
France 19 Gretz & Laugel, 1982
FRG 10 Fischer & Weigert, 1975
GDR 11 - 22 Anke & Schneider, 1974
India 24 Vahter, 1982
Japan (Akita) 135 Kobayashi, 1983
(Kobe) 54 Kitamura et al., 1970
(Kanazawa) 95 Ishizaki, 1972
(Tokyo) 99 Tsuchiya et al., 1972
(Tokyo) 59 (men)
55 (women)
Norway 30 Syverson et al., 1976
Sweden 11 - 23 Elinder et al., 1976
U.K. 21 Curry & Knott, 1970
U.S.A. (Dallas) 13 - 29 Kowal et al., 1979
(N. Carolina) 14 - 28 Hammer et al., 1973
Yugoslavia 38 Vahter, 1982
Effects of exposure
Acute intoxication in man has been reported following inhalation or
oral ingestion. Acute effects after inhalation include chemical
pneumonitis and sometimes pulmonary oedema (Elinder, 1985) and the onset
of symptoms may be delayed for up to 24 hr. In severe cases, there may
be respiratory insufficiency, shock and death.
Acute oral intoxication has been recorded following the use of
Cadmium-plated utensils and vessels in contact with acidic foods (U.S.
Public Health Service, 1942; Cole & Baer, 1944; Lufkin & Hodges, 1944),
and after consumption of drinks from a vending machine in which cadmium-
containing solder had been used in construction of the water cooling
tank (Nordberg et al., 1973). In the latter case the cadmium
concentration was approximately 16 mg/L. The symptoms were rapid in
onset and included nausea, vomiting, abdominal cramps and headache; in
more severe cases diarrhoea and shock ensued.
There is no evidence of the extreme effects on the gonads which is
a feature of acute intoxication in animals.
In relation to general population exposure, the cumulative chronic
toxicity is more relevant than acute toxicity provided that the use of
cadmium is food-contact materials is avoided. Much of the information on
the chronic effects of cadmium in man has come from occupational
exposure and excessive intake in the diet has been limited to only a few
localities.
After occupational exposure by inhalation, the kidney is most
frequently the critical organ although, under some conditions, the
target organ may be the lung (Bonnel, 1955). After chronic oral
exposure, the kidney is the critical organ. Fully developed intoxication
among industrial workers may present the major features of emphysema and
renal dysfunction similar to that described in animals. In addition,
anaemia, impaired liver function and changes in bone mineralization may
be seen.
The metallothionein-bound cadmium is filtered by the glomeruli and
reabsorbed and selectively concentrated in the proximal tubules. An
early feature of the renal effects in man is impairment of the
reabsorption functions of the tubules with an increase in urinary
excretion of low-molecular weight proteins (tubular proteinuria; beta-2-
microglobulinuria) (Friberg, 1950; Kazantzis et al., 1963; Piscator,
1966). Renal injury may progress and, in severe cases, involve
glomerular damage with proteinuria, aminoaciduria, glucosuria and
phosphaturia. Deranged mineral metabolism in the kidney may cause
resorption of calcium and phosphate from bone and signs of kidney stones
and nephrocalcinosis have been reported in Swedish workers (Axelsson,
1963) and osteomalacia has been seen in French (Gervais & Delpech, 1963)
and English (Kazantzis. 1979) workers. Similar signs of renal
dysfunction have been encountered in cadmium polluted areas in one such
region. Ishizaki (1969) reported a high incidence of proteinuria and
glucosuria. Comparisons of the effects of general environmental and
industrial exposure to cadmium have confirmed that tubular proteinuria,
aminoaciduria and other signs of tubular damage (Saito et al., 1977)
occur in both situations.
It has generally been found that tubular proteinuria, once
manifest, persists even when exposure ceases (Piscator, 1966; Nogawa et
al., 1979; Roels et al., 1982) although it has been claimed that mild
renal effects may be responsible if exposure ceases (Tsuchiya, 1976) and
this has been supported by animal experiments in rabbits (Nomiyama &
Nomiyama, 1984) and monkeys (Akahori et al., 1983).
Anaemia has been a common feature in cadmium-exposed workers
(Bernard et al., 1979) but this is reversible and independent of renal
damage. It appears that cadmium impairs absorption of iron (Fox et
al., 1971) and does not directly affect haemopoiesis; an increased
destruction of erythrocytes has also been reported in animal experiments
(Elinder, 1985).
The hypertension which has been observed in chronic animal studies
at low doses has not been a consistent feature of human intoxication
(Elinder, 1986). The prevalence of hypertension in polluted areas of
Japan has not been found to be noticeably increased (Shigematsu et
al., 1982) although Nogawa et al., (1975) found an increased
mortality from cardio- and cerebrovascular disease among Japanese
farmers with cadmium-induced proteinuria.
As previously indicated, the renal damage caused by cadmium leads
to deranged mineral metabolism due to effects on vitamin D hydroxylation
which impairs absorption of calcium and bone mineralization; in
addition, increased losses of calcium and phosphate occur in urine.
Itai-Itai disease is an extreme manifestation of this which was first
reported in Toyama, Japan (Kohno et al., 1956) and has since been
reported from three other cadmium contaminated areas (Nogawa et al.,
1975; Takabayashi, 1980); 132 cases with 94 deaths were officially
recorded between 1967 and 1982 (Kato, 1983). The pathogenesis of Itai-
Itai is not totally clear but in a particularly sensitive population of
mainly post-menopausal, multiparous women, who were deficient in both
calcium and vitamin D, cadmium appears to have played a role. The
disease is characterized by severe osteomalacia and sufferers displayed
tubular proteinuria of a similar type to that seen in workers
occupationally exposed to cadmium. Cadmium alone may not be sufficient
cause and a low cadmium and vitamin D intake were accompanying factors
in both occupational and general environmental cases (Friberg et al.,
1985; Kjellstrom, 1985).
Human carcinogenicity
Some epidemiological studies (Potts, 1965; Kipling & Waterhouse,
1967; Winkelstein & Kantor, 1969) indicated an increased risk of cancer
of the prostate in workers exposed to cadmium and an enhanced incidence
of lung cancer was also indicated (Lemen et al., 1976; Kjellstrom et
al., 1979). Subsequent studies (Armstrong & Kazantzis, 1983; Sorahan &
Waterhouse, 1983; Andersson et al., 1984) have not provided good
evidence for a casual association between industrial cadmium exposure
and cancer of the prostate or lung and a study of mortality in Japanese
cadmium-polluted areas revealed no definite increase in prostatic cancer
(Shigematsu et al., 1982). IARC (1976) considered that "available
studies indicate that occupational exposure to cadmium in some form
(possibly the oxide) increases the risk of prostate cancer in man. In
addition, one of these studies suggests an increased risk of respiratory
tract cancer". IARC updated this evaluation in 1982 and concluded that
cadmium and its components should be classified as carcinogenic group
2B i.e. "probably carcinogenic to humans" with "sufficient evidence in
animals and inadequate data in humans".
COMMENTS AND EVALUATION
Since the previous evaluation a large number of reviews have been
carried out and these have been considered by the present Committee.
Cadmium is a pollutant which affects many environmental sectors.
The general population is exposed to cadmium principally from food and
water. Although water is not a major contributor to cadmium intake for
most individuals, elevated natural cadmium levels in water can occur and
resultant cadmium intakes can be as large as the dietary contribution.
Food normally represents the major source of cadmium exposure and
available data indicate that the current intake of cadmium from the diet
is most commonly 10-35 µg/day. Non-food sources may also be a source of
cadmium, e.g., smoking 20 cigarettes per day may contribute a further
1-4 µg/day.
Cadmium is a metal with an extremely long biological half-life in
man. Even low exposure levels may, in time, cause considerable
accumulation, especially in the kidneys.
The kidney has been identified as the critical organ in relation to
chronic exposure to relatively low levels of cadmium (Task Group on
Metal Toxicity, 1976) and in particular the renal cortex. The critical
tissue concentration of cadmium at which renal injury occurs is subject
to inter-individual variation and the Population Critical Concentration
(PCC) has been applied in relation to a specific response rate (e.g.,
PCC50 = the concentration at which 50% of the human population studied
have reached their individual critical concentration). In relation to
cadmium, the first adverse functional change is usually a low molecular
weight (LMW) proteinuria, and intakes in the range of 140-255 µg/day
have been associated with increased LMW proteinuria in the elderly. LMW
proteinuria is not accompanied by any specific histological changes and
the pathological significance of this finding is unclear. However, it
can be used as an indicator of the threshold of a possible toxic effect
and it is appropriate to set the PTWI on the basis of the dose-response
data for this end-point.
Using the concept of PCC, there are limited data on which to base
an evaluation, particularly since the concentrations of cadmium in the
renal cortex may fall when proteinuria occurs. Evidence of renal
dysfunction in animal studies generally has been seen at renal cortex
concentrations of 200-400 mg/kg, but there is evidence of effects at
even lower concentrations. In humans with no, or only slight, changes in
renal tubular function, cadmium levels in the renal cortex have varied,
with few exceptions, between 100 and 450 mg Cd/kg and studies aimed at
determining critical concentrations in the renal cortex have yielded
estimates of about 200 mg Cd/kg for the PCC10. This, of course, does not
represent a no-effect-level.
Using dose-response analysis for individual critical
concentrations, a 10% prevalence rate for LMW proteinuria would be
estimated to occur after 45 years exposure to dietary intakes of 200 µg
Cd/day for a 70 kg person. From regression analysis of cadmium intake
and mean kidney cadmium concentration in various countries, essentially
similar estimates result i.e. the PCC10 of 200 mg Cd/kg renal cortex
would be attained after a dietary intake of 175 µg Cd/day for 50 years.
As LMW proteinuria can be demonstrated among people over 50 at a daily
intake of 140-255 µg/day, this confirms that these estimates are
reasonable and that there is only a relatively small safety margin
between exposure in the normal diet and those which produce effects.
In view of estimates that daily intake of 100 µg Cd/day would lead
to about 2% of the population exceeding their individual critical
concentration, levels of cadmium in foods and total diet should continue
to be monitored and should not rise further. The Committee reiterated
its previously stated position that the use of cadmium-plated utensils
in food processing or preparation should be discouraged and galvanized
equipment should be avoided where possible. Likewise, leachable cadmium
in enamel and pottery glazes may be a source of contamination and
cadmium-based pigments and stabilizers should not be used in food
contact plastics. The use of phosphate fertilizers and sewage sludge on
agricultural land may be a significant source of cadmium and, in some
circumstances this use could lead to elevated levels in crops. Attempts
should be made to minimize accumulation in the crops from such
agricultural sources of cadmium.
In order that levels of cadmium do not exceed 50 µg/g in renal
cortex, assuming an absorption rate of 5% and a daily excretion of
0.005% of body burden, total intake should not exceed about 1 g/kg
bw/day continuously for 50 years. The provisional tolerable weekly
intake for cadmium was therefore set at 7 µg/kg bw.
Since the PTWI is derived from estimated accumulation of cadmium
over a period of 50 years at an exposure rate equivalent to 1 µ/kg
bw/day for adults, excursions above this figure may be tolerated
provided that they are not sustained for a long period of time and do
not produce a significant increase in integrated lifetime dose. In
particular, it is recognized that this exposure will not be uniform with
age. The Committee noted that the estimate of the PTWI does, in fact,
take into account the higher cadmium intake on a body weight basis by
infants and children.
It is recommended that biological monitoring of groups exposed to
relatively high levels of cadmium should be carried out with a view to
providing supplementary data to that obtained from estimates of dietary
intake.
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