WHO Food Additives Series, 1972, No. 4
EVALUATION OF MERCURY, LEAD, CADMIUM
AND THE FOOD ADDITIVES AMARANTH,
DIETHYLPYROCARBONATE, AND OCTYL GALLATE
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Geneva,
4-12 April 19721
World Health Organization
1 Sixteenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 505; FAO
Nutrition Meetings Report Series, 1972, No. 51.
1. Occurrence and main uses
Cadmium is apparently a non-essential metal, occurring together with
zinc in nature. Cadmium to zinc ratios of 1:100 to 1:12 000 have been
found in most minerals and soils (Bowen, 1966; Schroeder et al.,
1967). Pollution of the environment by cadmium has occurred as a
result of the processing of ores, especially zinc ores, and of several
industrial operations. Air pollution may also result from the use of
cadmium in alloys. When cadmium compounds are used as pigments and
stabilizers in many plastics, they may eventually contribute to air
pollution when these plastics are destroyed. The electroplating
industry is another major use of cadmium and may give rise to
considerable water pollution.
2. Agricultural uses
Cadmium is absorbed from the soil and translocated in plants. Certain
staple foods, such as rice and wheat, may accumulate cadmium naturally
by absorption from the soil. It may also occur as a contaminant in
phosphate fertilizers and municipal sludges and thus it contributes to
levels found in food.
The contribution from cadmium-containing pesticides is probably
insignificant because their use has never been extensive and is
thought to have been discontinued in some areas. In addition, crops
may be contaminated with cadmium-containing dusts.
3. Analytical methods
The concentrations of cadmium in food, water, air and most body fluids
and tissues are very low. An evaluation must thus first be made of
the suitability of the analytical methods employed to obtain data,
before these can be used for estimating intakes and other biological
parameters in man.
A recent evaluation by Friberg et al. (1971) concluded that results of
several investigations on cadmium content in food, blood, urine, etc.
were unreliable because of the lack of sensitivity and specificity of
the analytical method. Some of these reports had been based on
results obtained by using atomic absorption spectrophotometry, without
taking into account the effect of interference from other substances,
i.e. sodium chloride or calcium salts.
Such interference may be eliminated if cadmium is first extracted as a
chelate into an organic solvent. When nanogram amounts of cadmium are
to be determined, great care must be taken to avoid either
contamination or losses during the extraction procedure.
There is a need for collaborative studies between different national
laboratories to ensure that data on cadmium concentrations are
4. Sources of intake
Food is the main source of cadmium intake. Table 1 is a compilation of
data which have been obtained using different analytical methods.
TABLE 1. DAILY INTAKE OF CADMIUM FROM FOOD IN DIFFERENT COUNTRIES
Country Cd/µg/day Method References
United States 4-60 Dithizone Schroeder &
of America Balassa, 1961
Western 48 Atomic absorption Essing et al., 1969
Germany after extraction
Romania 38-64 Dithizone Rautu & Sporn, 1970
Czechoslovakia 60 Dithizone or isotope Lener & Bibr, 1970
Japan (four 59-113 Dithizone or atomic Japan Public Health
non-polluted absorption after Association, 1970
Daily intakes appear to be of the order of 50 µg in some European
countries and the United States of America, whereas in unpolluted
areas in Japan the intake is higher. Since the faecal output of
cadmium represents at least 90% of the ingested amount, the accuracy
of these data is supported by reports on the cadmium content of
faeces. Thus, in West Germany, the mean daily faecal output of
cadmium was found to be 31 µg; in three American subjects the mean
faecal output was 42 µg; and in Japanese subjects from an unpolluted
area it was 57 µg.
Since cadmium dissolves in weak organic acids present in many foods,
the use of cadmium-plated utensils in the food industry should be
strongly discouraged. Likewise, leachable cadmium in enamel and
pottery glazes may be a source of cadmium contamination in the food.
Since commercial zinc can contain up to 1% cadmium, galvanized food
utensils may also contribute to cadmium levels in food.
The cadmium intake from water is low. The tentative limit set in the
WHO International Standards for Drinking Water is 10 µg/litre (WHO,
1971). However, most municipal water supplies contain less than 1
µg/litre and higher values may be due to contamination either from
industrial sources and piping which may release cadmium. In Sweden,
even near cadmium-emitting industries, cadmium content of
drinking-water was not more than 1 µg/litre. Similar results have
been obtained in Japan. The intake from water will usually contribute
less than 5 µg to the daily intake.
Cadmium in water can influence levels in food: crustacea and shellfish
from contaminated estuaries, and cereals irrigated with
cadmium-containing water may exhibit elevated levels of this
contaminant. High levels of cadmium may also be found in certain
target organs, such as the liver and kidneys of mammals.
The intake from inhaled air is low because the cadmium concentration
is usually below 0.01 µg/m3. However, areas close to
cadmium-emitting industries have significantly higher levels.
Smoking may also contribute to intake. It has been estimated that the
smoking of 20 cigarettes per day may cause the inhalation of 2-4 µg of
cadmium. Assuming an absorption of 25%, this would add 0.5-1 pg per
day to the body burden.
5. Observations in man
The retention of ingested cadmium varied between 4.7-7.0% in five
adult men (Rahola et al., 1971). Calcium deficiency increases the
retention of cadmium in rats and this may also happen in man (Larsson
& Piscator, 1971).
In mammals cadmium is virtually absent at birth but will accumulate,
especially in liver and kidneys with time. The primary period of
rapid renal concentration may occur during the early years of life
(Henke, 1970) - 50-75% of the total body burden will be found in these
two organs. Only a very small proportion of the daily absorbed dose
will be excreted. In time this will result in a considerable
accumulation of cadmium even at relatively low levels of intake.
In the liver and kidneys of man cadmium has been found to be mainly
bound to a low molecular weight protein, metallothionein. Similar
proteins have been found in the red blood cells and plasma of
cadmium-exposed mice (Nordberg et al., 1972), and in the duodenal
mucosa of several species (Starcher, 1969; Evans et al., 1970).
The amount of free metallothionein in plasma is small, but its low
molecular weight (6000-7000) permits filtration through the glomeruli.
The reabsorption of the cadmium metallothionein complex in the
proximal tubules may then explain the selective accumulation of
cadmium in the renal cortex (Nordberg, 1972).
Normal urinary excretion generally amounts to not more than 1-2 µg per
day. Animal experiments indicate that the excretion via the
gastro-intestinal tract may be of the same magnitude. The excretion
in hair is extremely low (Nordberg & Nishiyama, 1972).
The excretion of cadmium depends both on recent exposure and total
body burden. Animal data indicate that the body burden is the most
important factor with regard to urinary excretion. It is not known
which factor is the most important in man. Urinary excretion of
cadmium is considerably increased when renal damage has occurred
following exposure to excessive amounts of cadmium (Friberg at al.,
1971). In exposed mice urinary cadmium was partly found in a protein
of the same molecular size as metallothionein (Nordberg & Piscator,
1972). It is not known in what form cadmium is excreted in normal
The slow excretion results in an extremely long biological half-life
for absorbed cadmium. If 0.005% of the total body burden is excreted
daily, the biological half-life has been calculated to be 33 years.
If 0.01% of the total body burden is excreted daily, it will fall to
about 18 years (Kjellström et al., 1971). Similar calculations by
Tsuchiya & Sugita (1971) indicate that the biological half-life is at
least 16 years.
At present, mean levels of cadmium in renal cortex at age 50 are found
to be about 30 µg/g wet weight in Sweden, 25-50 µg/g wet weight in the
United States of America and 50-100 µg/g wet weight in Japan (Friberg
et al., 1971). It has been calculated that a daily intake of 62 µg
would be necessary to reach 50 µg/g wet weight in the renal cortex at
age 50, assuming an absorption rate of 5%, and that 10% of the daily
absorbed dose is rapidly excreted, and that also 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 (Kjellström et al., 1971).
6. Effects of exposure
Workers exposed to high concentrations of cadmium in air have shown
damage to the lungs and the kidneys. A special feature of the renal
damage was the excretion of low molecular weight proteins, so-called
tubular proteinuria (Kazantzis et al., 1963; Piscator, 1966).
Concentrations of cadmium ranging from 20-174 µg/g wet weight in the
kidneys obtained at autopsy of workers exposed to cadmium oxide dust
have been found in cases with long-lasting proteinuria and
morphological kidney changes. In cases without morphological changes
and where there had been no or only slight proteinuria the
concentrations found were 152-446 µg/g wet weight. This paradoxical
result was explained as being due to the result of increased excretion
of cadmium from the more severely damaged kidneys (Friberg et al.,
1971). Similar data have also been obtained from workers exposed to
cadmium oxide fumes and from cases of the Itai-Itai disease in Japan.
From these and animal data it has been estimated that tubular
dysfunction may appear at renal cortex levels of cadmium of about 200
µg/g wet weight. This represents a "critical level" where it can be
expected that the sensitive members of a population may get signs of
renal dysfunction, although not necessarily the majority of the
population exposed will get symptoms.
The Itai-Itai disease in the Toyama district in Japan was probably
caused by the excessive ingestion of cadmium in particularly sensitive
population, deficient in both calcium and vitamin D. River water
polluted by a zinc mine and used for irrigating rice fields
contributed to high levels of cadmium in rice. It was also used as
drinking-water. Almost all reported cases occurred in multiparous
women above 40 years of age. The disease is characterized by severe
osteomalacia leading to multiple painful fractures. Tubular
proteinuria of the same type as in cadmium-exposed workers was found
in all cases.
Itai-Itai disease in Japan is an extreme manifestation of chronic
poisoning, but there is reason to believe that signs of slight tubular
dysfunction, i.e. proteinuria, may be common in certain other areas in
Japan, where there is excessive exposure to cadmium (Friberg et al.,
1971). However, this opinion is not substantiated by extensive
studies reported later (Kojima, 1972).
7. Cardiovascular and testicular lesions
No evidence has yet been found in man that an increased absorption of
cadmium is related to the development of hypertension or to testicular
atrophy as reported in animals.
8. Carcinogenicity studies
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, but the number of
individuals studied was small and no further cases have been reported.
These findings cannot be interpreted with any degree of certainty
unless more information becomes available.
Cadmium is a metal with an extremely long biological half-life in man.
Even low exposure levels may cause in time considerable accumulation
especially in the kidneys.
Since animal data do not provide a satisfactory model for estimating
the threshold level of cadmium, available data on human renal
concentrations and daily intake in different countries have been used
for such estimates. The present mean levels in the renal cortex in 50
year old individuals, not exposed to excessive amounts of cadmium are
25-100 µg/g wet weight, compared with the critical level of 20O µg/g
wet weight. It is therefore obvious that the margin of safety is
small. These levels have probably resulted from daily intakes varying
between 25 and 100 µg of cadmium. Retrospective studies to establish
what changes may have occurred in cadmium concentrations in certain
foodstuffs since 1900 would be useful because such knowledge is
essential for making a prognosis.
At the present time the cadmium intake of many populations is unknown,
and analytical methods, although adequate, require further
standardization. There are uncertainties regarding the absorption and
excretion of cadmium in various nutritional and metabolic states, and
it is not known whether populations with excessive cadmium loads
derived from the diet have developed proteinuria.
Available data indicate that the present intake of cadmium from the
diet varies from below 50 to over 100 µg per day and diet surveys
indicate that in some areas levels are even higher because of
Presently, cadmium inhaled from the urban atmosphere does not
contribute a significant proportion of the total body burden.
However, significant absorption through heavy smoking is possible.
The continuing contamination of the environment from industrial and
other sources is likely to increase the cadmium concentration in food,
and in the future this may lead to hazardous levels. It is
recommended that every effort should be made to limit, and even to
reduce, the existing pollution of the environment with cadmium.
Attempts to determine acceptable levels of exposure to cadmium have
been based on calculations involving the so-called "normal" and
"critical values" of cadmium in the renal cortex and on what is known
of the rate of accumulation of cadmium in this organ. Levels of
cadmium in the renal cortex of adult subjects, without known
occupational exposure to the metal, vary between a mean of about 30
mg/kg wet weight in Sweden, 25-50 mg/kg wet weight in the United
States of America, and 50-100 mg/kg wet weight in japan. In view of
the "critical level" of 200 mg/kg, it was felt that present-day levels
of cadmium in the kidney should not be allowed to rise further. In
order that levels of cadmium in the kidney will not exceed 50 mg/kg,
and assuming an absorption rate of 5% and a daily excretion of only
0.005% of the body load (reflecting the long halflife of cadmium in
the body), total intake should not exceed about 1 µg/kg body-weight
per day. It is therefore proposed a provisional tolerable weekly
intake of 400-500 µg per individual. However, because of many
uncertainties involved, this estimate should be revised when more
precise data and better evidence become available.
Further data on the cadmium concentration in common foodstuffs and in
whole diets are required, and analytical methods need to be
standardized before a more accurate assessment can be made.
Bowen, H. J. M. (1966) Trace elements in biochemistry, Academic Press,
Evans, G. W., Majors, P. F. & Cornatzer, W. E. (1970) Biochem.
biophys. Res. Comun., 40, 1142
Essing, H. G., Schaller, K. H., Szadkowski, D. & Lehnert, G. (1969)
Arch. Hyg., 153, 490
Friberg, L., Piscator, M. & Nordberg, G. (1971) Cadmium in the
environment, The Chemical Rubber Co, Press, Cleveland, Ohio
Henke, G., Sachs. H. W. & Bohn G. (1970) Arch. Toxikol., 26, 8
Japan Public Health Association, 30 March 1970
Kazantzis, G., Flynn, F. V., Spowage, J. S. & Trott, D. G. (1963)
Quart. J. Med., 32, 165
Kipling, M. D. & Waterhouse, J. A. H. (1957) Lancet, i, 730
Kjellström, T., Friberg, L., Nordberg, G. & Piscator, M. (1971) In:
Friberg. L.. Piscator, M. & Nordberg, G. F., eds, Cadmium in the
environment, The Chemical Rubber Co. Press, Cleveland, Ohio
Kojima, K. (1972) Personal communication to WHO
Larsson, S. E. & Piscator, M. (1971) Israel J. med. Sci., 7, 495
Lener, J. & Bibr, B. (1970) Vitalstoffe, 15, 139
Nordberg, G. F. (1972) Cadmium metabolism and toxicity. Doctoral
Thesis, Karolinska Institute, Stockholm
Nordberg, G. F., Nordberg, M., Piscator, M. & Vesterberg, O. (1972)
Biochem. J., 126, 491
Nordberg, G. F. & Piscator, M. (1972) To be published in Environ.
Nordberg, G. F. & Nishiyama, K. (1972) Arch. Environ. Hlth, 24, 209
Piscator, M. (1966) Proteinuria in chronic cadmium poisoning,
Potts, C. L. (1965) Ann. occup. Hyg., 8, 55
Rahola, T., Aran, R. K. & Miettinen, J. K. (1971) IAEA/WHO Symposium
on the Assessment of Radioactive Organ and Body Burdens, Stockholm,
Rautu, R. & Sporn, A. (1970) Die Nahrung, 14, 25
Schroeder, H. A. & Balassa, J. J. (1961) J. chron. Dis., 14, 236
Schroeder, H. A., Nason, A. P., Tipton, I. H. & Balassa, J. J. (1967)
J. chron. Dis., 20, 179
Starcher, B. C. (1969) J. Nutr., 97, 321
Tsuchiya, K. & Sugita, K. (1971) Nord. hyg. T., 53, 105
World Health Organization (1971) International Standards for Drinking
Water, 3rd ed.
Winkelstein, W., jr & Kantor, S. (1969) Amer. J. publ. Hlh, 59, 1134