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This document includes the original commentary by the World Health Organization on toxilogical data of stabilized silver compounds used as food additives.

...Silver in the News...
 

Author: International Promgramme on Chemical Safety, World Health Organization
Original Source Format: http://www.inchem.org/documents/jecfa/jecmono/v12je19.htm

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Commentary

The following document, compiled by the World Health Organization, deals exclusively with stabilized silver compounds ( silver salts and proteins ) many of which have been known to be toxic for quite some time. Some of these referenced studies are single-handedly responsible for much of the misinformation spread, largely through ignorance, about isolated silver as produced via the electrolysis method.

However, the following data actually supports the very real idea that isolated silver products are not handled by the body in the same manner as silver compounds. Needless to say, it is very important to understand the exact nature of any silver product one is using inside the body.

The reader will notice that many of the more extreme experimental data was conducted with rats ( and other animals ) and large amounts of highly concentrated silver compounds. It should be a simple matter to reproduce similiar experiments with colloidal silver produced via the electrolysis method to demonstrate the difference between product types.

In the world of science and medicine, as some of our included comments will show, careful scrutiny must be performed to weed out political slants from otherwise useful data.


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) [ according to a single study done by Roger Altman, almost 75% of orally consumed, isolated silver was eliminated via urine ]. 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) [ we are aware of several individuals with greatly compromised livers ( Hep C. ) who have been using isolated silver products for several years with no signs of silver toxicity ]. 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) [ all of Petering's ionic silver studies were done using large amounts of stabilized ionic silver ].

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 a hydrogen acceptor, resulting in the inhibition of glucose oxydase (Nakamura and Ogura, 1968) [ not likely a real issue unless extremely large amounts of silver are present in the body; this study is useless in that it does not address any of the natural conditions of the body, being a test tube experiment ].

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 [ silver nitrate ] 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 [ interesting correlation, although silver acetate is likely little better than silver nitrate, and we would use neither anywhere near the human body ].

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) [ comparing alloys with pure silver products is certainly out of context in that colloidal silver products and silver in general has been conclusively demonstrated to be non-carcinogenic ].

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 µg/kg ash was found. The average silver contents in wet tissue of normal Americans was about 0.05 µg/kg (Tripton, 1963).

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

Silver toxicity is manifested in a variety of forms, some proven others suspected. Proven forms include: argyria, gastrointestinal irritation [ certainly not experienced with isolated silver products ], 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) [ Imagine that, 210 grams ].

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 metabolism of radionuclides in mammals. IV. Retention of silver 110-m 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 mercuric-, phenylmercuric- and silver ions by a colloidal sulphonic anion, J. Pharmac. Pharmacol., 2, 20

Goodman, L. S. and Gilman, A. (1965) In: The pharmacological basis of therapeutics, MacMillan, New York, 3rd ed., p. 965

Grasso, P., Abraham, R., Handy, R., Diplock, A. T., Goldberg, L. and Green, J. (1969) The role of dietary silver in the production of liver necrosis in Vitamin E-deficient rats, Exp. Mol. Pathol., 11,
186-199

Ham, K. N. and Tange, J. D. (1972) Silver deposition in rat glomerular basement membrane, Aust. J. Biol. Med. Sci., 50, 423-434

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,
341-374

Hamilton, E. I. and Minski, M. J. (1972) Abundance of chemical elements in man's diet and possible relations with environmental factors, Sci. Total Environ., 1, 375-394

Hill, C. H. and Matrone, G. (1970) Chemical parameters in the study of in vivo and in vitro interactions of transition elements, Fed. Proc., 29, 1474-1481

Hill, W. R. and Pillsbury, D. M. (1939) Argyria, the pharmacology of silver, The Williams and Wilkins Co., Baltimore, Maryland, cited by Carson and Smith, 1975

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 electron microscopic study of the corneal and conjunctival deposits of pigments and other substances, Part 2: Conjunctival argyrosis,
Acta Soc. Ophthalmol. Jpn., 80, 385-389

Kent, N. L. and MC Cance, R. A. (1941) The absorption and excretion of "minor" elements by man. I. Silver, gold, lithium, boron and vanadium, 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, 242-25


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EPA Silver Safety Studies ----FDA and Colloidal Silver ----Silver Compound Toxicity ----FAQ: Silver Salts, Proteins and Isolated Silver ----Argyria and Colloidal Silver ----Argyria: Reported Cases ----Cure for Argyria ----Herxheimer Reaction ----Silver Side Effects Poll ----Roger Altman Silver Elimination Study ----World Health Organization Silver Toxicity Data-------Mark Metcalf

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