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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES NO. 12






    The data contained in this document were examined by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Geneva, 18-27 April 1977




    Food and Agriculture Organization of the United Nations
    World Health Organization



    * Twenty-first Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1977, WHO Technical Report Series No. 617

    SILVER

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL  DATA

    BIOCHEMICAL ASPECTS

         Silver does not occur regularly in animal and human tissues but
    is present in man's environment in air, water, soils and food as well
    as in specific products. In some marine species silver tends to
    accumulate in soft tissue. The shells and soft tissues of
    approximately 50 oysters (Crassostrea virginica Gmelin) analysed were
    for silver and other elements. The oysters were collected from
    10 stations of various salinity ranges along the Georgia coast.
    Analysis was carried out by atomic absorption spectrophotometrically.
    The precision of the analysis was about 5. Silver was below
    detectability in the shells (i.e. below 1 ppm) while the soft tissues
    was 28-82 (10-20) ppm (Casarett and Doull, 1975; Windom and Smith,
    1972).

         Silver can be absorbed by the gastrointestinal tract. Retention
    is apparently greatest in the reticulo-endothelial organs. After
    intravenous injection the concentrations were present in decreasing
    order in spleen, liver, bone marrow, lungs, muscle and skin (Browning,
    1969).

         Various studies and clinical observations indicate that silver
    salts can be absorbed from the lungs, gastrointestinal tract and such
    insured epithelia as nasal mucosa, conjunctiva, and skin. Absorbed
    silver is then stored in the reticulo-endothelial cells of the skin,
    mucous membranes, liver, spleen, possibly bone marrow, in basement
    membranes, especially those of the renal glomerulus, and presumably in
    muscles (Ham and Tangue, 1972; Kanai et al., 1976; Bader, 1966;
    Anderson, 1966; Voldrich et al., 1975).

         Radiosilver (110mAg) administration to mice, rats, monkeys and
    dogs by oral intravenous and intraperitoneal routes was excreted for
    more than 90% in the faeces, 90% or more of oral doses were not
    absorbed. Whole body retention in mice, rats and monkeys was less than
    1% of the initial dose after one week. In the same period less than
    10% was retained in dogs (Fnrchner et al., 1968).

         The major route of excretion is via the gastrointestinal tract,
    predominantly through desquamation of silver containing cells of the
    alimentary tract. Urinary excretion has not been reported to occur
    even after intravenous injection (Casarett and Doull, 1975; Kent and

    Mc Cance, 1941). It seems that even mild degrees of liver damage
    considerably impair the ability of the liver to excrete quite small
    doses of silver (Petering, 1976). Unlike lead or mercury there is no
    evidence that silver is a cumulative poison (Petering, 1976).

         No information was obtained on the biotransformation of silver in
    the animal body except that absorbed ionic silver is transformed into
    metallic while being deposited in tissues (Petering, 1976).

         Numerous enzymes were inhibited in vitro by silver ions. High
    affinity to sulfhydryl and histidine imidazole groups was observed.
    Silver ions compete with molecular oxygen as hydrogen acceptor,
    resulting in inhibition of glucose oxydase (Nakamura and Ogura, 1968).

         Protargol, a silver-protein complex containing 8% silver
    inhibited the in vitro prostaglandin E2 synthesis by bull geminal
    vesicles even at concentrations of 10-7M (Deby et al., 1973).

         Glutathione peroxydase activity in the liver of rats treated with
    76 and 751 ppm silver (as silver acetate) for seven weeks was
    respectively 30% and 4% of the control values (Swanson et al., 1974).

         After a single s.c. injection (3 mg silver/kg bw) AgNO3 induced
    the synthesis of a low molecular weight protein in the liver of rats,
    with the characteristics of metallothionein induced by cadmium, zinc
    or mercury salts (Winge et al., 1975).

         Silver ion is a very toxic substance when viewed from the
    standpoint of its action of an inhibitor of enzymes and as a metabolic
    inhibitor of lower forms of life. Biochemically, the silver ion (Ag+)
    can act as potent enzyme inhibitor (Chambers et al., 1974). It has
    been reported (Wagner et al., 1975) that in vitro administration of
    silver dramatically decreased liver glutathione peroxidase in rats fed
    Se-supplemented diets with or without vitamin E. It seems therefore
    that silver acetate exerts its antagonistic effects on Se (silver
    induces Se deficiency signs) through an effect on the activity of
    biosynthesis of glutathione peroxidase.

         Much of the biologic action of silver can be attributed to the
    reaction of silver ion with sulfhydryl groups to produce stable silver
    mercaptide (Petering, 1976).

         Cooper and Jolly (1970) in a review of the ecologic effects of
    silver have pointed out that the current experimental practice of
    seeding clouds with silver iodide to promote rainfall may lead to new
    hazards for both man and natural biologic systems if the practice is
    extended (Petering, 1976).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

         Sarcomas, malignant fibrosarcomas, fibromas, fibro-adenomas and
    invasions of muscle with corrective tissue were observed after
    implantation of foil, platelets and pellets made of silver or dental
    alloy under the skin of mice and rats (Oppenheimer et al., 1956;
    Shubik and Hartwell, 1969).

    Special studies on mutagenicity

         No DNA damaging capacity was observed in a recombination-assay
    with AgCl in a Bacillus Subtilis strain (Nishioka, 1975).

    Acute toxicity studies

         Oral administration of 50 mg AgNO3/kg bw to mice caused death in
    50% of the animals in a 14 day observation period (Goldberg et al.,
    1949).

         Intraperitoneal administration of 2 ml of an aqueous solution
    containing 0.239 M AgNO3 to guinea pigs (0.216 g AgNo3/kg bw) was
    fatal in 6/10 animals after seven days (Wahlberg, 1965).

         Intraperitoneal injection of 20 mg AgNo3/kg bw in rabbits caused
    death accompanied by degeneration of liver parenchyma and kidney
    tubules. Silver granules were observed in these organs (La Torraca,
    1962).

         Subcutaneous injection of 7 mg AgNO3/kg bw to rats affected
    testis histology and spermatogenesis. After 18 hours the peripheral
    tubules were affected and some central tubules were completely
    degenerated. Some tubules recovered but not the duct system (Hoey,
    1966).

         A single dose of 500 mg of colloidal silver was lethal to dogs in
    12 hours (Shouse and Whipple, 1931). Prior to death there was
    anorexia, weakness, loss of weight, and anaemia. Death was due to
    pulmonary congestion and oedema,

    Short-term studies

    Rats

         Rats (90-100 g) were given a 0.25% solution of AgNO3 in
    distilled water as drinking water for a period ranging from 1 to 12
    weeks. Rats were killed at 1, 2, 3, 4, 8 and 12 weeks and at 1, 2, 3,
    6, 10 months and also 16 months after silver administration had

    stopped. Deposition of silver in the glomerular basement membrane was
    noticed one week after the initiation of treatment electron
    microscopically (Ham and Tange, 1972).

         1500 ppm Ag1 (as acetate) in drinking water for two to four
    weeks caused liver necrosis and death in vitamin E deficient rats. The
    effect was prevented by 120 ppm D- -tocophirylacetate and partially by
    1 ppm Se (Diplock et al., 1967).

         Addition of silver acetate to the diet (130-1000 ppm) or drinking
    water (1500 ppm) of weaning rats fed a vitamin E deficient diet,
    precipitated a rapidly fatal hepatocellular necrosis and muscular
    dystrophy on day 14 of the treatment or subsequently. No changes were
    observed in liver of rats given silver acetate and vitamin E
    supplements. The mitochondrial changes possessed some of the features
    seen in rats fed a diet deficient in vitamin E and selenium. A reduced
    availability of selenium by silver in vitamin E deficient rats is
    postulated (Grasso et al., 1969).

         Rats fed a casein-based diet were given 0.76 and 751 ppm silver
    (as acetate) in drinking water for a period of seven weeks. Dietary Se
    (0.5 ppm as Na2SeO3) prevented growth depression observed in rats
    receiving 76 ppm silver and markedly improved growth and survival of
    those given 751 ppm, but increased liver and kidney silver levels.
    Liver glutathione peroxidase activity of the treated groups
    supplemented with selenium was respectively 30% and 4% of the
    controls. Glutathione peroxidase of erythrocytes was not affected
    (Swanson et al., 1974).

         Cyanocabalamine (3 ppm), vitamin E and selenium (0.05 and 1 ppm)
    were found to antagonize silver-induced liver necrosis in rats (Bunyan
    et al., 1968).

         Rats (six per group) were treated with drinking water containing
    0.5, 2 and 20 mg Ag/l for 6-12 months. 2 mg Ag+/l decreased the
    nucleic acid level in brain and liver after one year and 20 mg Ag+/l
    increased RNA and DNA contents of the brain after six months and
    caused dystrophic changes in the brain accompanied by a decrease in
    nucleic acid level after 12 months. The liver was less sensitive
    towards silver than the brain (Kharchenko et al., 1973).

         Groups of eight rabbits received 0, 0.00025, 0.0023, 0.025 and
    0.25 mg Ag/kg via their drinking water during 11 months. Marked
    effects on immunological capacity (measured as phagocytosis) and
    histopathological changes of nervous, vascular and glial tissue of the
    encephalon and medulla were observed in the groups receiving 0.025 and
    0.25 mg Ag/kg bw.  Treatment had no effects on haemoglobin, R.B.C.,
    differential W.B.C., proteinogenic function of the liver and serum SH
    groups. Rats treated with same amounts of silver showed affected
    conditioned reflexes (Barkov and El piner, 1968).

         Groups of 20 chicks received 0, 10, 25, 50, 100 and 200 ppm
    silver during four weeks in combination with 0, 10 or 25 ppm copper in
    the diet. Silver at 100 ppm reduced growth in the copper deficient but
    not in the control chicks. At 50 ppm mortality was increased in the
    copper deficient group, but not in those receiving copper. 10 ppm
    silver reduced the haemoglobin concentration and the elastin content
    in the aorta in deficient chicks. These effects were completely
    overcome by the addition of copper to the diet (Hill and Matrone,
    1970),

         Turkey poults given dietary silver (900 ppm of added silver
    nitrate) exhibited reduced body weight gain, haemoglobin, packed cell
    volume, and aortic elastin content, as well as significantly increased
    ratio of wet heart weight to body weight. The enlarged hearts were
    attributed to a copper deficiency induced by the dietary silver.
    Adding extra copper offset the silver-induced condition (Peterson et
    al., 1973; Jensen et al., 1974),

    OBSERVATION IN MAN

         Absorption of silver resembles whole body retention. It is
    retained in all body tissues (Hamilton et al., 1972a; Tripton et al.,
    1966). The silver content of the miocardium, aorta and pancreas tends
    to decrease with age (Bala et al., 1969) although the amount of silver
    in the body increases with age (Hill and Pillsbury, 1939). The
    concentration of silver in healthy human tissues from the United
    Kingdom was 1-9 g/kg ash was found. The average silver contents in
    wet tissue of normal Americans was about 0.05 g/kg (Tripton, 1963).

         The intake from the diet is estimated at 27 g/day (Hamilton and
    Minski, 1972) up to 88 g/day (Kehoe et al., 1940).

         Silver toxicity is manifested in a variety of forms, some proven
    others suspected. Proven forms include: argyria, gastrointestinal
    irritation, renal and pulmonary lesions. Suspected forms include,
    among others (ill-defined) arteriosclerosis (Casarett and Doull,
    1975).

         Argyria denotes the slate blue colour observed in parts of the
    body of persons exposed chronically to silver (Anderson, 1966).
    Epidemiologically, two types of argyria are recognized: industrial
    argyria and iatrogenic argyria.

         Regardless of type there are two forms of argyria, local and
    generalized. The local form involves the formation of grey blue
    patches on the skin or may manifest itself in the conjunctiva of the
    eye. In generalized argyria the skin shows widespread pigmentation,
    often spreading from the face to most uncovered parts of the body. In
    some cases the skin may become black with a metallic lustre. Heavy

    pigmentation of the eye structures can interfere with vision (Casarett
    and Doull, 1975). Except for this adverse effect argyria is solely a
    cosmetic problem. The slate blue colour of argyria is not entirely due
    as one might suspect, to the deposition of metallic silver (Petering,
    1976), but largely to an increased deposition of melanin. Silver has a
    melanocyte-stimulating property (Rich et al., 1972). Cases of
    generalized argyria have occurred after ingestion or chronic medicinal
    application of gram quantities of silver. Silver was absorbed during
    prolonged (nine months) nasal application of Targesine (silver
    solution). It was calculated that during this time 7000 ml of solution
    containing 210 g silver had been used (Voldrich et al., 1975).

         After chronic medical and occupational exposure to silver,
    argyria and argyrosis are the most common findings. Although
    intravenous administration of a total of 0.91-7.6 g (average 2.39)
    silver as silver arsphenamine in a period of two to nine years has
    caused argyria, hundreds of patients have received up to 1.7 g Ag
    (as arsphenamine) without developing argyria.

         In argyria silver is regularly deposited in blood vessels,
    connective tissue, skin, glomeruli of the kidney, choroid plexus,
    mesenteric glands and thyroid. Adrenals, lungs, dura mater, bones,
    cartilage muscle and nervous tissue are minimally involved as
    deposition sites for silver.

         In workers argyrosis of the cornea may be accompanied by
    turbidity of the anterior lens capsule and disturbance of the dark
    adaptation, usually not resulting in loss of vision.

         Argyria is observed only in connexion with occupational medical
    exposure or after cosmetic application of silver (Hill and Pillsbury,
    1939).

         The systemic effects of silver are not extensive because of the
    poor absorption of silver compounds from the intestinal tract
    (Petering, 1976). It is considered that 10 g of silver nitrate taken
    orally is a lethal dose of man, although recovery from smaller doses
    has been reported (Cooper and Jolly, 1970). The systemic effects of a
    lethal dose are preceded by severe haemorrhagic gastroenteritis and
    shock. According to Goodman and Gilman (1965) the silver ion seems
    first to stimulate and then depress structures in the brain stem.
    Central vasomotor stimulation results in a rise in blood pressure. At
    the same time there is bradycardia due to central vagal stimulation.
    Death eventually results from respiratory depression.

    REFERENCES

    Anderson, W. A.D. (1966) In: Pathology, C. V. Mosby, Saint Louis,
    1, 73

    Bader, K. F. (1966) Organ deposition of silver following silver
    nitrate therapy of burns, Food and Cosmetics Toxicol., 5, 435

    Bala, Yu., Lifshits, V. M., Plotko, S. A., Aksenov, G.I. and Kopylova,
    L.M. (1969) Age levels of trace elements in the human body, Voroneah,
    Gos. Med. Inst., 64, 37-44, cited by Carson and Smith, 1975

    Barkov, G. D. and El 'piner, L. I. (1968) The need for limiting the
    silver content of drinkingwater, Gigiena i Sanit., 33, 16-21

    Browning, E. (1969) Toxicity of industrial metals, 2nd ed.
    Butterworths, London, 296-301

    Bunyan, J., Diplock, A. I., Cawthorne, M. A. and Green, J. (1968)
    Vitamin E and stress, VIII. Nutritional effects of dietary stress with
    silver in Vitamin E-deficient chicks and rats, Brit. J. Nutr., 22,
    165-182

    Casarett, L. J. and Doull, J. (1975) In: Toxicology the basic science
    of poisons, MacMillan, New York, pp. 967-969

    Chambers, J., Krieger, C. G., Kay, L. and Stroud, R. (1974) Silver ion
    inhibition of serine proteases: Crystallographic study of silver-
    trypsin, Biochem. and Biophys. Res. Comm., 59, 70-74

    Cooper, C. F. and Jolly. W. C. (1970) Ecological effects of silver
    iodide and other weather modification agents; A review, Water
    Resources Research, 6, 88-98

    Deby, C., Bacq, Z. M. and Simon, D. (1973) In vitro inhibition of
    the biosynthesis of a prostaglandin by gold and silver, Biochem.
    Pharmacol., 22, 3141-3143

    Diplock, A. T., Green, J., Bunyan, J,, McHale, D. and Muthy, I. R.
    (1967) Brit. J. Nutr., 21, 115

    Furchner, J. E., Richmond, C. R. and Drake, G. A. (1968) Comparative
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    in the mouse, rat, monkey and dog, Health Phys., 15, 505-514

    Goldberg, A. A., Shapero, M. and Wilder, E. (1949) Antibacterial
    colloidal electrolytes: the potentiation of the activities of
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    anion, J. Pharmac. Pharmacol., 2, 20

    Goodman, L. S. and Gilman, A. (1965) In: The pharmacological basis of
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    Grasso, P., Abraham, R., Handy, R., Diplock, A. T., Goldberg, L. and
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    necrosis in Vitamin E-deficient rats, Exp. Mol. Pathol., 11,
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    Ham, K. N. and Tange, J. D. (1972) Silver deposition in rat glomerular
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    Hamilton, E. I., Minski, M. J. and Cleary, J. J. (1972) The
    concentration and distribution of some stable elements in healthy
    human tissues from the United Kingdom, Sci. Total Environ., 1,
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    Hamilton, E. I. and Minski, M. J. (1972) Abundance of chemical
    elements in man's diet and possible relations with environmental
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    Hill, C. H. and Matrone, G. (1970) Chemical parameters in the
    study of in vivo and in vitro interactions of transition elements,
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    Hill, W. R. and Pillsbury, D. M. (1939) Argyria, the pharmacology of
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    Hoey, M. J. (1966) The effects of metallic salts on the histology and
    functioning of the rat testis, J. Reprod. Fort., 12, 461-472

    Jensen, L. S., Peterson, R. P. and Falen, L. (1974) Inducement of
    enlarged hearts and muscular dystrophy in turkey poults with dietary
    silver, Poult. Sci., 53, 57-64

    Kanai, A., Yamaguchi, T. and Nakajima, A. (1976) The analytical
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    Kent, N. L. and MC Cance, R. A. (1941) The absorption and excretion of
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    Bioch. J., 35, 837-

    Kharchenko, P. D., Berdyshew, G. D., Stepanenko, P. Z., and
    Velikoivanenko, A. A. (1973) Change in nucleic acid level in rat
    brain and liver during long-term introduction o silver ions in
    drinking water, Fiziol. Zh (Kiev), 19, 362-368

    Kehoe, R. D., Cholak, J. and Story, R. V. (1940) A spectrochemical
    study of the normal ranges of concentrations of certain trace metals
    in biological materials, J. Nutrit., 19, 579-592

    La Torraca, F. (1962) Anatomic, histopathological and histochemical
    aspects of acute experimental intoxication with silver salts,
    Folia Med. (Naples), 45, 1065-1069, cited by Carson and Smith,
    1975

    Nakamura, S. and Ogura, Y. (1968) Mode of inhibition of glucose
    oxidase by metal ions, J. Biochem. (Tokyo), 64, 439-447, cited by
    Carson and Smith, 1975

    Nishioka, H. (1975) Mutagenic activities of metal compounds in
    bacteria, Met. Res., 31, 185-189

    Oppenheimer, B. S., Oppenheimer, E. I., Danishefsky, I. and Stout, A.
    P. (1956) Carcinogenic effect of metals in rodents, Cancer Res.,
    16 439-441, cited by carson and Smith, 1975

    Petering, H. G. (1976) Pharmacology and toxicology of heavy metals:
    silver, Pharmac. Ther. A., 1, 127-130

    Peterson, R. P., Jensen, L. S. and Harrison, P. C. (1973) Effect of
    silver-induced enlarged hearts during the first four weeks of life on
    subsequent performance of turkeys, Avian Dis., 17, 802-806

    Rich, L. L., Epinette, W. W. and Nasser, W. K. (1972) Argyria
    presenting as cyanatic heart disease, Amer. J. Cardiol., 30,
    290-292

    Shouse, S.S. and Whipple, G. H. (1931) I. Effects of the intravenous
    injection of colloidal silver upon the hematopoietic system in dogs,
    J. Exp. Med., 53, 413-

    Shubik, P. and Hartwell, J. L. (1969) Survey of compounds which have
    been tested for carcinogenic activity, Supplement 2, U.S. Public
    Health Service Publication No. 149

    Swanson, A. B., Wagner, P. A., Ganther, H. E. and Hoekstra, W. G.
    (1974) Antagonistic effects of silver and tri-o-cresylphosphate on
    selenium and glutathione peroxidase in rat liver and erythrocytes,
    Fed. Proc., 33, 639

    Tripton, I. H. and Cook, M. J. (1963) Trace elements in human tissue,
    Part II. Adult subjects from the United States Health Phys., 9,
    103-145

    Tripton, I. H., Stewart, P. L. and Martin, P. G. (1966) Trace elements
    in diets and excreta, Health Phys., 12, 1683-1689

    Voldrich, Z., Holub, M. and Plhon, F. (1975) An isolated case of
    general argyrosis after a long-range administration of Targesine and
    nasal drops, Cs. Otalaryng., 24, 374-376

    Wagner, P. A., Hoekstra, W. G. and Ganther, H. E. (1975) Alleviation
    of silver toxicity by selenite in the rat in relation to tissue
    gluathione peroxidase, Proc. Soc. Exptl. Biol. Med., 148,
    1106-1110

    Wahlberg, J. E. (1965) Percutaneous toxicity of metal compounds,
    Arch. Environ. Health., 11, 201-204

    Windom, H. L. and Smith, R. G. (1972) Distribution of iron,
    magnesium, copper, zinc and silver in oysters along the Georgia
    coast, J. Fisheries Res. Board Canada, 29, 450-452

    Winge, D. R., Premakumar, R. and Kajagopalan, K. V. (1975) Metal
    induced formation of metallothionein in rat liver, Arch. Biochem.
    Biophys., 170, 242-252


    See Also:
       Toxicological Abbreviations
       Silver (ICSC)
       SILVER (JECFA Evaluation)