Silver Safety and Toxicity
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Silver; CASRN 7440-22-4
File On-Line 01/31/1987
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 12/01/1996
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 06/01/1989
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RFD)
Gaul, L.E. and A.H. Staud. 1935. Clinical spectroscopy. Seventy cases of generalized argyrosis following organic and colloidal silver medication. J. Am. Med. Assoc. 104: 1387-1390.
The critical effect in humans ingesting silver is argyria, a medically benign but permanent bluish-gray discoloration of the skin. Argyria results from the deposition of silver in the dermis and also from silver-induced production of melanin. Although silver has been shown to be uniformly deposited in exposed and unexposed areas, the increased pigmentation becomes more pronounced in areas exposed to sunlight due to photoactivated reduction of the metal.
Gaul and Staud (1935) reported 70 cases of generalized argyria following organic and colloidal silver medication, including 13 cases of generalized argyria following intravenous silver arsphenamine injection therapy and a biospectrometric analysis of 10 cases of generalized argyria classified according to the quantity of silver present. In the i.v. study, data were presented for 10 males (23-64 years old) and for two females (23 and 49 years old) who were administered 31-100 i.v. injections of silver arsphenamine (total dose was 4-20 g) over a 2- to 9.75-year period. Argyria developed after a total dose of 4, 7 or 8 g in some patients, while in others, argyria did not develop until after a total dose of 10, 15 or 20 g. In the biospectrometric analysis of skin biopsies from 10 cases of generalized argyria, the authors confirmed that the degree of the discoloration is directly dependent on the amount of silver present. The authors concluded that argyria may become clinically apparent after a total accumulated i.v. Dose of approximately 8 g of silver arsphenamine. The book entitled "Argyria The Pharmacology of Silver" reached the same conclusion, that a total accumulative i.v. Dose of 8 gm silver arsphenamine is the limit beyond which argyria may develop (Hill and Pillsbury, 1939). However, since body accumulates silver throughout life, it is theoretically possible for amounts less than this (for example, 4 g silver arsphenamine) to result in argyria. Therefore, based on cases presented in this study, the lowest i.v. Dose resulting in argyria in one patient, 1 g metallic silver (4 g silver arsphenamine x 0.23, the fraction of silver in silver arsphenamine) is considered to be a minimal effect level for this study.
Blumberg and Carey (1934) reported argyria in an emaciated chronically ill (more than 15 years) 33-year-old female (32.7 kg) who had ingested capsules containing silver nitrate over a period of 1 year. The patient reported ingesting 16 mg silver nitrate three times a day (about 30 mg silver/day) for alternate periods of 2 weeks. Spectrographic analysis of blood samples revealed a blood silver level of 0.5 mg/L 1 week after ingestion of silver nitrate capsules ceased, and there was only a small decrease in this level after 3 months. The authors noted that this marked argyremia was striking because even in cases of documented argyria, blood silver levels are not generally elevated to this extent. Normal levels for argyremic patients were reported to range from not detected to 0.005 mg Ag/l blood. Heavy traces of silver in the skin, moderate amounts in the urine and feces, and trace amounts in the saliva were reported in samples tested 3 months after ingestion of the capsules stopped; however, despite the marked argyremia and detection of silver in the skin, the argyria at 3 months was quite mild. No obvious dark pigmentation was seen other than gingival lines which are considered to be characteristic of the first signs of argyria. The authors suggested that this may have been because the woman was not exposed to strong light during the period of silver treatment. This study is not suitable to serve as the basis for a quantitative risk assessment for silver because it is a clinical report on only one patient of compromised health. Furthermore, the actual amount of silver ingested is based on the patient's recollection and cannot be accurately determined. In a case reported by East et al. (1980), argyria was diagnosed in a 47-year-old woman (58.6 kg) who had taken excessively large oral doses of anti-smoking lozenges containing silver acetate over a period of 2.5 years. No information was provided as to the actual amount of silver ingested. Symptoms of argyria appeared after the first 6 months of exposure. Based on whole body neutron activation analysis, the total body burden of silver in this female was estimated to be 6.4 (plus or minus 2) g. Both the total body burden and concentration of silver in the skin were estimated to be 8000 times higher than normal. In a separate 30-week experiment, the same subject retained 18% of a single dose of orally-administered silver, a retention level much higher than that reported by other investigators. East et al. (1980) cited other studies on this particular anti-smoking formulation (on the market since 1973) which demonstrated that "within the limits of experimental error, no silver is retained after oral administration." However, this may not hold true for excessive intakes like that ingested by this individual. As with the study by Blumberg and Carey (1934), this study is not suitable to serve as the basis for a quantitative risk assessment. It is a clinical report on only one patient and the actual amount of silver ingested can only be estimated.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RFD)
MF -- None
___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RFD)
Humans are exposed to small amounts of silver from dietary sources. The oral intake of silver from a typical diet has been estimated to range from 27 88 ug/day (Hamilton and Minski, 1972/1973; Kehoe et al., 1940). Tipton et al. (1966) estimated a lesser intake of 10-20 ug/day in two subjects during a 30- day observation period. Over a lifetime, a small but measurable amount of silver is accumulated by individuals having no excessive exposure. Gaul and Staud (1935) estimated that a person aged 50 years would have an average retention of 0.23-0.48 g silver (equivalent to 1-2 g silver arsphenamine). Petering et al. (1991) estimated a much lower body burden of 9 mg over a 50-year period based on estimated intake, absorption, and excretion values; however, it is not clear how the final estimate was calculated. Furchner et al. (1968) studied the absorption and retention of ingested silver (as silver nitrate, amount not specified) in mice, rats, monkeys and dogs. In all four species, very little silver was absorbed from the GI tract. Cumulative excretion ranged from 90 to 99% on the second day after ingestion, with <1% of the dose being retained in <1 week in monkeys, rats and mice. Dogs had a slightly greater retention. The authors used the data from the dog to estimate how much silver ingested by a 70 kg human would be retained. An "equilibrium factor" of 4.4% was determined by integrating from zero to infinity a retention equation which assumes a triphasic elimination pattern for silver with the initial elimination of 90% coming from the dog data. The first elimination half-time of 0.5 days was used "arbitrarily"; subsequent half-times of 3.5 days and 41 days were taken from a metabolic study by Polachek et al. (1960). Furchner et al. (1968) considered their calculated equilibrium factor of 4.4% to be a conservative estimate for the amount of silver which would be retained by a 70 kg human. This figure was rounded to 4% and was used in the dose conversion (i.v. Dose converted to oral intake) for the calculation of the RFD.
In addition to silver arsphenamine, any silver compound (silver nitrate, silver acetate, argyrol, Neosilvol and Collargol, etc.), at high dose, can cause argyria. Another important factor predisposing to the development of argyria is the exposure of the skin to light.
Argyria, the critical effect upon which the RFD for silver is based, occurs at levels of exposure much lower than those levels associated with other effects of silver. Argyrosis, resulting from the deposition of silver in the eye, has also been documented, but generally involves the use of eye drops or make-up containing silver (Greene and Su, 1987). Silver has been found to be deposited in the cornea and the anterior capsule of the lens. The same deposition pattern was seen in the eyes of male Wistar rats following administration of a 0.66% silver nitrate solution to the eyes for 45 days (Rungby, 1986). No toxicological effects were reported.
Toxic effects of silver have been reported primarily for the cardiovascular and hepatic systems. Olcott (1950) administered 0.1% silver nitrate in drinking water to rats for 218 days. This exposure (about 89 mg/kg/day) resulted in a statistically significant increase in the incidence of ventricular hypertrophy. Upon autopsy, advanced pigmentation was observed in body organs, but the ventricular hypertrophy was not attributed to silver deposition.
Hepatic necrosis and ultrastructural changes of the liver have been induced by silver administration to vitamin E and/or selenium deficient rats (Wagner et al., 1975; Diplock et al., 1967; Bunyan et al., 1968). Investigators have hypothesized that this toxicity is related to a silver-induced selenium deficiency that inhibits the synthesis of the seleno-enzyme glutathione peroxidase. In animals supplemented with selenium and/or vitamin E, exposures of silver as high as 140 mg/kg/day (100 mg Ag/L drinking water) were well-tolerated (Bunyan et al., 1968).
___I.A.5. CONFIDENCE IN THE ORAL RFD
The critical human study rates a medium confidence. It is an old study (1935) which offers fairly specific information regarding the total dose of silver injected over a stated period of time. One shortcoming of the study is that only patients developing argyria are described; no information is presented on patients who received multiple injections of silver arsphenamine without developing argyria. Therefore, it is difficult to establish a NOAEL. Also, the individuals in the study were being treated for syphilis and may have been of compromised health.
Confidence in the data base is considered to be low because the studies used to support the RFD were not controlled studies. For clinical case studies of argyria (such as Blumberg and Carey, 1934; East et al., 1980), it is especially difficult to determine the amount of silver that was ingested.
Confidence in the RFD can be considered low-to-medium because, while the critical effect has been demonstrated in humans following oral administration of silver, the quantitative risk estimate is based on a study utilizing intravenous administration and thus necessitates a dose conversion with inherent uncertainties.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RFD
Other EPA Documentation -- None
Agency Work Group Review -- 10/09/1985, 02/05/1986, 04/18/1990, 02/20/1991, 07/18/1991
Verification Date -- 07/18/1991
___I.A.7. EPA CONTACTS (ORAL RFD)
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Basis -- In animals, local sarcomas have been induced after implantation of foils and discs of silver. However, the interpretation of these findings has been questioned due to the phenomenon of solid-state carcinogenesis in which even insoluble solids such as plastic have been shown to result in local fibrosarcomas.
___II.A.2. HUMAN CARCINOGENICITY DATA
___II.A.3. ANIMAL CARCINOGENICITY DATA
Schmahl and Steinhoff (1960) reported, in a study of silver and of gold, that colloidal silver injected both i.v. And s.c. into rats resulted in tumors in 8 of 26 rats which survived longer than 14 months. In 6 of the 8, the tumor was at the site of the s.c. injection. In about 700 untreated rats the rate of spontaneous tumor formation of any site was 1 to 3%. No vehicle control was reported.
Furst and Schlauder (1977) evaluated silver and gold for carcinogenicity in a study designed to avoid solid-state carcinogenesis. Metal powder was suspended in trioctanoin and injected monthly, i.m., Into 50 male and female Fischer 344 rats per group. The dose was 5 mg each for 5 treatments and 10 mg each for 5 more treatments for a total dose of 75 mg silver. The treatment regimen included a vehicle control (a reportedly inert material), and cadmium as a positive control. Injection site sarcomas were found only in vehicle control (1/50), gold (1/50) and cadmium (30/50); no tumors (0/50) appeared at the site of injection in the silver-treated animals. A complete necropsy was performed on all animals. The authors mentioned the existence of spontaneous tumors in Fischer 344 rats, but reported only injection site tumors. They concluded that finely divided silver powder injected i.m. does not induce cancer.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
No evidence of the mutagenicity of silver was shown in two available studies. Demerec et al. (1951) studied silver nitrate for the possible induction of back mutations from streptomycin dependence to nondependence in Eschericha coli. Silver nitrate was considered nonmutagenic in this assay. Nishioka (1975) screened silver chloride with other chemicals for mutagenic effects using a method called the rec-assay. Silver chloride was considered nonmutagenic in this assay.
___II.D.1. EPA DOCUMENTATION
The 1988 Drinking Water Criteria Document for Silver has received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Verification Date -- 09/22/1988
___II.D.3. US EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
As the EPA studies show, the estimated amount of silver intake in order to be at risk for Argyria is 3.8 (to six) grams of silver, although some references site higher than 10 grams.
One teaspoon of 5 ppm colloidal silver contains about 25 micrograms of silver, or .025 milligrams of silver. Six teaspoons, the equivalent of one fluid ounce, therefore contains .15 milligrams of silver. The EPA's critical dose for a 160 lb. adult is 1.09 milligrams daily. Taking one ounce of colloidal silver daily, according to EPA guidelines, is well below the critical daily intake for the development of argyria. Four ounces daily would equal around .6 milligrams.
However, all of this is dependent upon the body's actual retention of colloidal silver in body tissues. There is no existing data which addresses the very real differences between isolated ionic silver ( and particles sized .0003 - .05 microns in diameter), and silver compounds ( silver nitrate, silver arsphenamine , silver proteins, silver salts, silver acetate, etc. ). Can a risk assessment for argyria based on high strength ionic silver compounds be applied to low PPM isolated silver solutions and colloidal silver? This is unknown, but not very likely.
There is accumulating evidence which strongly suggests that neither low PPM isolated ionic silver nor minutely sized silver particles build up in the body at the same rate indicated by the compound study data. Many researchers have traditionally been unable to explain the exact risk elements associated with silver toxicity-- why one individual is at risk for argyria and why another is no, when the amount of silver ingested is the same. As some of the research data shows, however, a selenium deficiency may be a determining factor.
If selenium and other dietary factors are the sole determining factor in the risks associated with argyria ( aside from obvious massive overdoses ), then dose quantities, frequency of use, and actual silver concentration become of paramount importance in gauging risk. If dietary intake and systemic availability of needed substances exceed those required as a part of silver elimination in the body, then the accumulation of silver in the body will not be comparable to the high potency compound products, and thus the risk of argyria will not be equal.
Evidence presented in one study case conducted by Roger Altman lends credence to the idea that silver accumulation via oral use of an isolated colloidal silver product does not always occur. Needless to say, though, much further work needs to be done on the subject for definative answers.
Some researchers believe that build up of silver in the body is caused exclusively by the concentration of silver ingested, irrespective of the actual form of silver. Therefore, it would not likely matter whether one took a silver protein that contained one milligram of silver or one milligram of silver nitrate - the risk for argyria, whatever that may or may not be, would be the same.
However, we do not believe this to be the case. We do not believe that the body itself responds the same to silver compounds as it does to isolated silver. Data inferred from the above studies indicate a wide variance in the amount of silver deposited in those whom have never taken a colloidal silver product. It is extremely unlikely that ANY of the people studied ( outside of silver-rich industrial conditions ) would have ingested large amounts of silver at any given time, and yet the variance in accumulation in body tissues infers that there are other factors involved in accumulation.
While it is our conclusion after four years of study that the risk of Argyria from the use of a quality isolated colloidal silver product is negligable, prudence suggests that actual silver intake be kept below 1.09 milligrams daily until scientific evidence demonstrates otherwise.
This figure is based on the EPA RFD of .005 mg/kg of body weight, based on the average adult.
In the event that greater doses are required for long term treatments, dietary measures to augment the body's elimination system are likely a good idea, including Selenium and Vitamin E supplementation and proper hydration of the body. Measurement of silver accumulation in the body every six months would also be a prudent and revealing measure. Considering the actual silver content per dose, the development of argyria would only occur over a long period of time with unnecessarily large amounts of colloidal silver used daily. Even the most conservative estimates would put the time frame in excess of three years.
times since August 2009
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
Page Last Modified: 08/23/17 06:17