IPCS INCHEM Home

    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
    Geneva
    1972





                   

    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.

    CADMIUM

    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
    comparable.

    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/g/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
                                  dilution or
                                  atomic absorption

    Japan (four       59-113      Dithizone or atomic     Japan Public Health
    non-polluted                  absorption after        Association, 1970
    areas)                        extraction
                                                                               
    
    Daily intakes appear to be of the order of 50 g 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 g; in three American subjects the mean
    faecal output was 42 g; and in Japanese subjects from an unpolluted
    area it was 57 g.

    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 g/litre (WHO,
    1971).  However, most municipal water supplies contain less than 1
    g/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 g/litre.  Similar results have
    been obtained in Japan.  The intake from water will usually contribute
    less than 5 g 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 g/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 g of
    cadmium.  Assuming an absorption of 25%, this would add 0.5-1 pg per
    day to the body burden.

    5. Observations in man

    (a) Metabolism

    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 g 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
    human subjects.

    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 (Kjellstrm 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 g/g wet weight in Sweden, 25-50 g/g wet weight in the
    United States of America and 50-100 g/g wet weight in Japan (Friberg
    et al., 1971).  It has been calculated that a daily intake of 62 g
    would be necessary to reach 50 g/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 g to reach the same final level in the
    renal cortex (Kjellstrm 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 g/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 g/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
    g/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.

    Comments

    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 g/g wet weight, compared with the critical level of 20O g/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 g 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 g per day and diet surveys
    indicate that in some areas levels are even higher because of
    environmental pollution.

    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.

    EVALUATION

    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 g/kg body-weight
    per day.  It is therefore proposed a provisional tolerable weekly
    intake of 400-500 g 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.

    REFERENCES

    Bowen, H. J. M. (1966) Trace elements in biochemistry, Academic Press,
    London

    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

    Kjellstrm, 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.
    Phys., 2

    Nordberg, G. F. & Nishiyama, K. (1972) Arch. Environ. Hlth, 24, 209

    Piscator, M. (1966) Proteinuria in chronic cadmium poisoning,
    Stockholm, Beckman's

    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,
    22-26 November

    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
    


    See Also:
       Toxicological Abbreviations
       Cadmium (EHC 134, 1992)
       Cadmium (ICSC)
       Cadmium (WHO Food Additives Series 52)
       Cadmium (WHO Food Additives Series 24)
       Cadmium (WHO Food Additives Series 55)
       CADMIUM (JECFA Evaluation)
       Cadmium (PIM 089)