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OCR for page 324
9
Silver
Raghupathy Ramanathan, Ph.D.
NASA-]ohnson Space Center Toxicology Group
Habitability ancI Environmental Factors Branch
Houston, Texas
PHYSICAL AND CHEMICAL PROPERTIES
Silver is a white, lustrous, ductile, malleable metal (see Table 9-1 for a list
of properties). It reacts with dilute nitric acid and hot sulfuric acid. Silver
forms several inorganic and a few organic salts, including silver chloride,
silver fluoride, silver iodide, silver nitrate, silver acetate, silver sulfide,
silver perchiorate, silver benzoate, and silver diethy! dithiocarbamate (see
Table 9-2~.
OCCURENCE AND USE
Silver, a transition metal, is a rare element that naturally occurs in the
earth's crust, both in pure form and as an ore with lead and copper. Soil
concentrations vary by geological location. Silver has also been reported in
the air; in sea, well, and surface waters (originating from natural resources
and from industrial waste); and in finished public drinking water supplies
(Durfor and Becker 1964; Kopp and Kroner 1967~. A median concentration
of silver at 2.2 micrograms per liter (vigil) (range 0.3-5 vigil) in finished
water supplies has been reported in the United States (Kopp and Kroner
1967~.
324
OCR for page 325
Silver
TABLE 9-1 Physical and Chemical Properties
325
Formula Ag
Chemical name Silver
Synonyms Argentum, shell silver, silber (German), silver colloi-
dal (Stokinger 1981)
CAS registry no. 7440-22-4
Molecular weight 107.87
Atomic number 47
Melting point 960.5°C
Density 10.5 g/cm3 at 20°C
Units 1 ppm in water = 1 mg/L in water
Solubility Metallic silver is practically insoluble in hot and cold
water; it is soluble in fused alkali hydroxides; most
silver salts have limited solubility in water; low solu-
bility depends on pH and chloride concentrations (0.1-
10 mg/L)
Silver and silver salts have been extensively used in making jewelry,
table silverware, coinage, solder, high capacity batteries and conductors,
and dental alloys. It is used extensively in photographic processing. Silver
also has some use as an antibacterial agent in water treatment (Merck 1989~.
Pharmaceutical preparations used for the treatment of warts end bums con-
tain silver. Silver nitrate has also been used as a prophylaxis against opthal-
mia neonatorum. Silver acetate has been used in chewing gums and loz-
enges as a smoking deterrent. High concentrations of silver were found in
the blood and urine of subjects who consumed silver acetate lozenges
(Macintire et al. 1978; East et al. 1980~. The use of silver in medical equip-
ment and devices has been a major area of research in dentistry and
medicine (e.g., silver amalgam vs mercury amalgam and antimicrobial
efficacy and biocompatibility of silver-coated central venous catheters,
prosthetic valves, and silver impregnated collagen cuffs to decrease infec-
tion in tunneled catheters).
Human exposure to silver usually occurs by inhalation of silver-con-
taining dust in the environment or by dermal contact to jewelry or
photographic materials containing silver. Silver has been the primary agent
used to disinfect potable water processed from humidity condensate in the
Russian Mir space station. Silver will also be used in the humidity-conden-
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326
Spacecraft Water Exposure Guidelines
TABLE 9-2 Physical Properties of Silver Salts
Silver Silver Silver Silver
Nitrate Silver Acetate Lactate Chloride Fluoride
Formula AgNO3 CH3COO.Ag Ag(CH3CH AgC1 AgF
(OH)COO)
Molecular 169.89 166.92 214.97 143.32 126.88
weight
NO Silver 63.5 64.63 54.78 74.65 85.04
(wlw)
Solubility 122 g/100 1 g/100 mL at 1 g/15 mL at 1.93 mg/L 1.82 g/100
in water mL at 0°C 0°C 0°C at 25°C mL at 15°C
Source: Merck 1989.
sate water-processing assembly in the Russian service module (SM) to
support the crew during the early phases of assembly of the International
Space Station (ISS). The Russian and U.S. crew members aboard the early
assembly missions ofthe ISS will consume water containing silver at about
0.5 milligrams (mg)/L. Moreover, silver will be added electrolytically in
the Russian water supplies carried to the ISS via Progress resupply vehicles
during the ISS assembly phase. The concentrations of silver in the archived
water samples from the cold and hot water galleys of various Mir missions
ranged from ~ ~g/L to 670 ~g/L, although the target concentration was 500
~g/L. That probably indicates that the mechanism of silver addition did not
work reliably, or there was a silver demand in the system after it had been
added. During the Mir missions, when U.S. astronauts lived in the Mir
space station for 3-6 months (mo), the fuel-cell water transferred from the
shuttle was deiodinated and silver was added as silver salts to support the
crew drinking water requirements. The residual iodine precipitated some of
the silver, which caused very low silver concentrations in some samples.
The common salts that were used to maintain silver in solution were
formate and fluoride. If the crew uses water recovered from the humidity
condensate, the forms of the silver salts will depend on the salts of calcium
and magnesium added as mineralizing agents to improve the organoleptic
properties. Because that has been proprietary, the exact forms are not
known.
OCR for page 327
Silver
327
PHARMACOKINETICS AND METABOLISM
The bioavailability of silver appears to depend on whether it is metallic
silver or one ofthe various silver salts. The available data on the toxicity of
silver focus primarily on its bioaccumulation in aquatic organisms and its
potential toxicity to humans.
Absorption
In an occupational setting, silver can be absorbed readily through inha-
lation of silver dust or dermal exposure to photographic processing chemi-
cals. It also has been absorbed after ingestion of colloidal forms (Hill and
Pillsbury 1939; Newton and Homes 1966; Dequidt et al. 1974, as cited in
ATSDR 1990~.
Data on absorption was estimated from the excretion kinetics of radio-
active silver after administration by the oral route. Furchner et al. (1968)
determined the body burden (by measuring whole-body radioactivity using
a gamma-ray detector) and retention of silver at various times after adminis-
tering doses of Wag (as the nitrate) via the intravenous and oral routes
in female RF mice, male Sprague-Dawley rats, beagle dogs, and Macacca
mulatto monkeys. It was reported that the body burden (based on whole-
body monitoring) was higher when silver was administered intravenously
rather than orally and was proportionately higher as a function of species
size. One must note that the calculated doses (in milligrams per kilogram
tmg/kg]), which were based on the specific activity of the radioactivity
administered, varied widely from species to species. It is not known how
that would have affected the relative amounts absorbed. On the basis ofthe
cumulative excretion by the second day after oral ingestion, which was
between 90°/O and 99°/O of the orally administered dose, the authors con-
cluded that gut absorption was very low. The dog appeared to retain the
greatest percentage ofthe dose, and the authors explained that the phenome-
non was related to gastrointestinal transit time (S hours th] in mice and rats
and about 24 h in dogs, monkeys, and humans). The much longer intestinal
transit time resulted in higher absorption in dogs compared with the other
species studied. By extrapolating the parabolic relationship between body
weights and estimated equilibrium factors from small animals to humans,
the authors estimated 4°/O retention of silver in humans.
A much higher level of silver retention was estimated from a case his-
tory study of silverpoisoning associated with antismoking lozenges (Respa-
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328
Spacecraft Water Exposure Guidelines
ton) that contain 6 mg of silver acetate (Macintire et al. 1978~. A 47-y-old
woman with a 2-y history of blue-gray discoloration of neck and face
(argyria) reported the onset of discoloration after the use of 32 lozenges per
day for 6 mot The woman was given an oral dose of silver acetate labeled
with silver tracer Wag (4.4 Loci and 10 mg of ammonium chloride, as in
the Respaton formulation). Retentions of silver measured by whole-body
counter at 1, 2, 8, and 30 weeks (wk) were 21%, 20%, 19%, and 18.7% of
the total radioactive count measured 20 minutes (min) after the dose (nor-
malized as 100%) (also see East et al. 1980~. There was almost no excre-
tion after 1 day Gil. The blood level 2 h after administration was very low,
and based on the whole-blood volume, the total amount in blood repre-
sented only 1.~% ofthe administered dose. The effect of ammonium chio-
ride in the formulation on the retention and absorption of silver in this in-
stance is not known. Prior to the tracer dose, the total body burden of silver
was estimated by neutron analysis to be about 6.4 ~ 0.2 grams (g). How-
ever, East et al. ( 1980) reported that such high-level constant retention after
an initial drop was not consistent with the biological half-life of 5 ~ for the
retention of whole-body Wag and the half-lives of 30, 15, and 10 ~ in
bone, liver, and kidneys, respectively, as reported by the International Com-
mission on Radiological Protection. That implies that there should be insig-
nificant retention at 30 wk. In addition, according to East et al. (1980), other
investigations believed that the use of the lozenges did not result in any
significant level of absorption of silver. That indicates that with repetitive
doses, the overall body retention might be higher, perhaps due to the satura-
tion ofthe only biliary excretion pathway, resulting in increased distribution
to tissues and poor excretion. Hence, the high percentage of retention could
be a gross overestimate of what might result from chronic small doses.
This level of retention is much higher than that derived by Furchner et al.
(1968) for humans. It has to be noted that a different silver salt was used in
those reports. A summary of oral absorption is presented in Table 9-3.
In a case of accidental inhalation exposure of one worker to dust con-
taining radioactive ~ Wag from an experimental nuclear reactor, radioactiv-
ity was found in the liver and feces even after 200 d (Newton and Holmes
1966~. This strongly indicates that silver could be absorbed through the
lungs into the systemic circulation. Whole-body radiation monitoring dur-
ing the first 155 d revealed wide areas of radioactivity, and 25% of it was
located in the liver. Silver also was found in measurable concentrations in
the blood of workers in a silver oxide/silver nitrate manufacturing plant,
indicating exposure through inhalation (Rosenman et al. 1979~.
Similarly, Armitage et al. (1996) reported that the blood silver levels
ranged from 0.1 ~g/L to 23 ~g/L in 98 occupationally exposed workers
OCR for page 329
Silver
329
TABLE 9-3 Interspecies Differences in the Retention of Silver After an
Oral Dosea
Species Form Dose Retained Reference
Mouse Silver nitrate <1% Furchner et al. 1968
Rat Silver nitrate <2% Furchneret al. 1968
Monkey Silver nitrate <5°/0 Furchner et al. 1968
Dog Silver nitrate <10% Furchneret al. 1968
Human Silver acetate 18% of initial Macintire et al. 1978;
retentions East et al. 1980
aEstimated from cumulative excretion at day 2. The animal data were obtained
after only tracer doses of silver nitrate. Doses were very small (mg/kg) and were
different for each species.
bData from one argyric human who ingested silver acetate from lozenges for
over 2 y. The formulation also contained ammonium chloride.
involved in bullion production, cutlery manufacture, and silver reclamation.
When colloidal silver was administered to Wistar rats orally at 1.68 g/kg for
4 ~ or 0.42 g/kg for 12 4, about 2-5% ofthe dose was absorbed (Dequidt et
al. l 974, as cited in ATSDR 1990~. In another study by Scott and Hamilton
(1950),itwasfoundthatwhencarrier-freeradioactivesilver(<1 fig; 1 loci)
was intragastrically administered to rats, 99°/O ofthe dose was eliminatedin
the feces and 0.1 SILO was eliminated in the urine within 4 d. The total tissue
distribution of the radioactivity was about 0.84°/O of the dose. The results
indicated very little absorption.
Distribution
Reports strongly indicate that silver is distributed to almost all organs
of the body after exposure. Rats given silver nitrate in drinking water
(0.15% or 8.8 millimolar tmM] of silver) for 5 wk showed deposition of
silver granules in the kidneys (Moffat and Creasey 1972; Creasey and Mof-
fat 1973~. Similarly, in Sprague-Dawley rats that received silver nitrate at
various concentrations (6,12, and24 mM of silver) in drinking water for 60
wk. silver accumulated in the basement membranes of the giomerulus,
colon, liver, thyroid, urinary bladder, and prostatic acini (Walker 1971~.
Although the rats were restored to silver-free water, the deposited silver did
not diminish even 10 wk after silver salt ingestion. Maffat et al. (1973)
reported that when silver nitrate was given to three rabbits and 10 rats as a
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330
Spacecraft Water Exposure Guidelines
0. 15% solution (~.8 mM of silver) in drinking water, silver was found in the
meduliary interstitial tissue and in the interstitial cells (which showed signs
of degeneration) in both species. There was a species difference in the
amount of silver deposited (heavy deposits of silver in the rat and smaller
amounts in the rabbit). Matuk et al. (1981) reported retardation of growth
in rats given silver nitrate at 0.25% (15 mM) in drinking water for 10 wk.
When continued for an additional 12 mo, all rats died. Examination of eyes
showed deposits of silver particles in Bruch's membrane the number and
size ofthe particles increased with continued ingestion, but was found to be
decreased in the group that was continued on silver-free water.
In a study involving biologic monitoring of workers (n = 37) in one of
the silver smelting and refining industries in which the exposure is entirely
by inhalation, silver was found in the blood (0.011 fig per milliliter tmL]),
urine (<0.005 ~g/mL), and feces (15 ~g/g). Control subjects excreted about
1.5 Gag in the feces (n = 35~. The author suggests that human fecal excre-
tion of silver at exposure levels equal to the Threshold Limit Value (TLV)
(0.1 mg per cubic meter tm33) would be about 1 mg of silver per day (Di-
Vincenzo et al. 1985~.
Rungby (1986a) studied the anatomical distribution of silver in the
peripheral nervous system of rats 4 ~ after intraperitoneal (silver lactate) or
oral administration (silver lactate or silver nitrate). Silver was found to be
distributed throughout the peripheral nervous system in dorsal root ganglia,
peripheral nerve, adrenal medulla, and enteric ganglia. The localization of
silver deposits in the orally treated animals was independent of the form of
the salt. In all organs, large amounts were present in connective tissue fibers
and basement membranes (Rungby 1986a).
In postmortem analyses for several metals in the tissues of 150 human
adults who died instantaneously, silver was found to be present in all tissues
(Tipton and Cook 1963) in the order of thyroid > skin > liver > adrenals >
intestine > stomach and other tissues. East et al. (1980) did a detailed study
on the uptake and disposition of silver in a 47-y-old woman who ingested
antismoking lozenges containing 6 mg of silver acetate daily for 2.5 y and
developed argyria in the process. Using radioactive tracer of silver acetate
(4.5 ma; 4.43 loci), they measured silver retention. At the end of first week,
1 8°/O of the ingested radioactivity was retained, and that remained constant
up to 30 wk. The blood levels and the percent of excretion in urine over the
first week were very low. Silver was detected at a high concentration in a
skin biopsy sample (71.3 ~ 3.7 ~g/g). Uptake by the skin was substantial.
In the Newton and Holmes ( 1966) study, whole-body monitoring of a 29-y-
old man who accidentally inhaled an unknown amount of dust containing
OCR for page 331
Silver
331
Wag from an experimental nuclear reactor showed that about 25% ofthe
body burden of Wag (total radioactivity) was found near the liver.
Excretion
It was first demonstrated by Scott and Hamilton (1950) that when bile
ducts were ligated in rats, the percent of silver excreted in the feces was
much lower (by a factor of 10) than in control rats, although renal excretion
increased, clearly demonstrating that silver is excreted primarily via the bile
into feces. In a study on the mechanism of elimination of silver by the liver,
Klaassen ( 1979) concluded that most of the silver excreted in feces was the
result of elimination of silver through bile. When the disappearance of
Wag from plasma and bile was measured 2 h after the intravenous admin-
istration at 0.01, 0.03, 0.1, and 0.3 mg/kg Wag was mixed with silver
nitrate) in rats, the concentration of silver in bile was 20 times greater than
that in plasma. Also, the concentration in liver was much higher than that
in plasma, and 25-45% of the dose was excreted in the bile within 2 h
(Gregus and Klaassen 1986~. The disappearance of silver from the plasma
and its excretion into the bile after intravenous administration of silver at
0.1 mg/kg in rats, rabbits, and dogs indicated marked species variations in
the biliary excretion of silver. Rats excreted silver at the rate of 0.25
~g/min/kg, while rabbits and dogs excreted at rates of 0.05 ~g/min/kg and
0.005 ~g/min/kg, respectively. The species with the slowest excretion rate
had the highest liver concentration. Dogs had the highest silver levels in the
liver, and rats had the lowest, indicating that the transport from liver to bile
is the governing factor (Klaassen 1979~. This difference might also explain
the rentention data obtained by Furchner et al. (1968) (see discussion be-
low).
Scott and Hamilton (1950) studied the distribution of silver after an
intramuscular administration of radioactive metallic silver alone as a tracer
dose and then coadministered with two doses of nickel nitrate (0.4 mg/kg/d
and 4.0 mg/kg/~. They reported that when excretion in the feces was de-
creased, a corresponding increase was noted in the deposition of silver in
the pancreas, gastrointestinal tract, and thyroid. This increase suggested that
the liver elimination pathway might be saturated.
Several studies indicate that the elimination of silver follows a 2- or 3-
exponential profile, one with a short half-life and others with a half-life of
several days. In the Newton and Holmes (1966) study cited above, calcula-
tion ofthe amount of silver excreted in the feces by a man who accidentally
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332
Spacecraft Water Exposure Guidelines
inhaled an unknown amount of radioactive silver dust indicated that elimi-
nation from the body followed a biphasic exponential decay curve the first
phase had a half-life of 1 4, and the second terminal phase had a half-life of
43 d. Matuk (1983) reported similar results after an intraperitoneal injection
of radioactive silver. There was an initial rapid loss of radioactivity from
plasma, liver, end kidneys, which was followedby a slower rate of loss. The
loss was somewhat linear and slower from forebrain and spleen. As shown
above, silver is excreted predominantly in the feces and, to a minor extent,
in the urine following an oral dose. The rate of excretion is rapid in the first
week and then slows, showing biphasic elimination kinetics in humans
given silver acetate orally (East et al. 1980~.
Furchner et al. (1968) also reported that when radioactive silver nitrate
was administered orally to mice, rats, dogs, and monkeys, 90-98°/0 of the
absorbed dose was eliminated in the feces (within 2-4 d) and only minor
amounts were excreted in urine. They also reported interspecies differences
in the clearance of silver. A 2-exponential component described the elimi-
nation data in mice and monkeys, and a 3-exponential component described
the data from rats and dogs. Differences in the transit time through the gut
has been offered as possible explanation (the transit time is ~ h in mice and
rats and about 24 h in dogs and monkeys) (Furchner et al. 1968~. It might
also be attributed to the interspecies differences in biliary excretion rate
reported by Kalaasen (1979~.
Metabolism
Even though silver salts are not metabolized in the typical sense, silver
salts that are transformed are reduced to metallic silver. It was suggested
(ATSDR 1990) that the deposition of silver in tissues is the result of precip-
itation of insoluble silver chlorides and silver phosphates and that those
silver salts are transformed to silver sulfides by forming complexes with
amino or carboxy! groups in proteins or are reduced to metallic silver by
reduction with ascorbic acid (Danscher 1981~. Buckley et al. (1965) identi-
fied silver particles deposited in the dermis of a woman with argyria as
silver sulfide. Similarly, Berry and Galle (1982) reported that deposits of
silver in the internal organs of rats were identified as silver sulfide. Silver
seems to interact with other metal salts, especially with selenium in the diet
(Berry and Galle 1982, as cited in ATSDR 1990~.
OCR for page 333
Silver
333
TOXICITY SU M M ARY
One of the most commonly reported conditions in humans related to
ingestion of silver is argyria, the blue-gray discoloring of skin resulting
from the accumulation of silver in the dermis. It was mostly associated with
frequent and long-term exposure, such as the use of silver amalgam, and
occupational exposure to silver particles (in mines or in industries involving
smelting, polishing, manufacture, and packaging of silver nitrate products).
Argyria has been the result of exposure to metallic silver or silver com-
pounds not only by the dermal route but also by oral and inhalation routes
of exposure. Because of poor absorption of silver by all routes of expo-
sures, chronic toxicities or physiologic effects at doses capable of causing
argyria have not been documented. Gaul and Stand (1935) analyzed 70
cases of argyria where subjects had been exposed to silver either in a colloi-
dal form or had it injected intravenously as a medication (e.g., silver
arsphenamine for syphilis). Ten males and two females received a total of
31-100 intravenous injections of silver arsphenamine over a period of 2 to
about 10 y. This amounted to a total exposure dose of 4-20 g of silver. No
definite threshold could be identified for the incidence of argyria; some
developed the condition after a total dose of 4 g of silver, while it appeared
in others only after 20 g. Using a biospectrometric analysis of skin biopsies,
the authors concluded that the skin discoloration was proportional to the
amount of silver present. Based on the lowest level 4 g of silver
arsphenamine the EPA working group on silver (EPA 1992) calculated
that argyria might occur at a total body burden approximately equivalent to
1 g or above. There is no functional impairment known to be associated
with argyria. In clinical studies, 30 workers (ofwhom 6 had argyria and 20
had argyrosis Preposition of silver in the eye]) who were exposed to silver
and silver oxide for more than 2 y had significant blood silver levels and
abnormal clinical biochemistry (Rosenman et al. 1979~. The exposed work-
ers had complained of poor night vision, nausea, headache, nervousness,
and tiredness. The authors reported that the presence of abdominal pain in
10 workers correlated with the level of silver in the blood. Rosenman et al.
(1987) also reporteUpossible nephrotoxic effects of silver in exposedwork-
ers in a precious-metal powder manufacturing plant. Workers with elevated
concentrations of silver in the urine and in the blood had corneal deposits
of silver and complained of poor night vision. They had significantly in-
creased urinary levels of N-acetyI-beta-c'7-glucosaminidase (NAG) and a
OCR for page 334
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Spacecraft Water Exposure Guidelines
decreased creatinine clearance (clinical markers of nephrotoxicity). Because
of concurrent exposure to cadmium, also a well-known nephrotoxin, the
effect of silver on nephrotoxicity could not be conclusively established in
this study.
Acute Exposure (<1 d)
Data on the toxicity of silver and its salts in humans come mainly from
case reports and accidental exposures. A considerable amount of data is
available from animal studies. Emphasis will be placed on oral bolus studies
and drinking water studies with silver salts. Tamimi et al. (1998) deter-
mined the acute and subchronic toxicity in rats and rabbits after intra-
peritoneal injection and oral administration of an antismoking mouthwash
containing silver nitrate at 0.5°/O (silver at 3.175 mg/mL) as an active ingre-
dient. An oral LD50 (dose lethal to 50°/O of subjects) was reported at about
430 mg/kg for rats (males end females) end et about 1,300 mg/kg for rabbits
(male and female). Postmortem and histopathologic examinations revealed
congestion, edema, hemorrhage, and mucosal necrosis. It is not clear if
other ingredients in the mouthwash might have been responsible for those
effects.
Death in one human was reported in an accidental ingestion of a large
amount of silver nitrate. Symptoms included abdominal pain, diarrhea,
vomiting, corrosion of the gastrointestinal tract, shock, and convulsions. It
was estimated that silver at 143 mg/kg might be a fatal single dose for hu-
mans (Hill and Pillsbury 1939; EPA 1992~. LD50 studies indicate that in
general, silver salts are acutely toxic to rodents. The toxicity and mortality
also was dependent on the route of administration and the chemical nature
(silver acetate, lactate, nitrate, or chIoride) of the dose.
There are no known reports of hepatotoxicity, nephrotoxicity, or
cardiotoxicity resulting from an acute exposure.
Short-Term Exposure (2-10 d)
Dequidt et al. (1974, as cited in ATSDR 1990) reported deaths in rats
following oral ingestion of silver colloid at 1,680 mg/kg/d for 4 d. When
the silver colloid was injected intraperitoneally at 420 mg/kg, rats died
within 24-48 h. Dequidt et al. also reported that nitrate is 20 times more
toxic than the colloidal form when given intraperitoneally. The actual cause
of death was not reported in either of the above studies.
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Spacecraft Water Exposure Guidelines
TABLE 9-6 Drinking Water Silver Standards Set by Other Organizations
Organization Standard Concentration(mg/L)
EPAa MCL None
MCLG None
SMCL (final) 0.1
1-10 d HA (child) 0.2
Long-term HA 0.2
RfD 0.005
DWEL 0.2
Lifetime 0.1
Cancer group Group D
Cancer risk NA
ATSDRb 1-14 d MRL None set
15-365 d MRL None set
>365 MRL None set
aThere are no federally regulated standards for silver in drinking water. Only
guideline levels are stated. The long-term HA refers to levels that will not cause
any adverse noncarcinogenic effects up to 7 y (10% of lifetime). The RfD is an
estimate of a daily exposure that is likely to be without appreciable risk of dele-
terious effect over a human lifetime. The DWEL assumes that water contributes
to 100% of the exposure. Group D classification means not classifiable as a car-
cinogen to animals or humans (EPA 1996~.
bATSDR did not set MRLs because "sufficient data do not exist to identify a tar-
get organ or establish an MRL for acute duration or intermediate duration. Gen-
eral lack of quantitative information concerning this effect in humans or animals
precludes the derivation of an MRL for chronic-duration exposure" (ATSDR
1990~.
Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry;
DWEL, drinking water equivalent level; EPA, U.S. Environmental Protection
Agency; HA, health advisory; MCL, maximum contaminant level; MCLG, max-
imum contaminant level goal; MRL, minimal risk level; RfD, reference dose;
SMCL, secondary maximum contaminant level.
mentioned above. The doses in the animal study (Furchner et al. 1968) were
extremely small and very different from each other. In the human study
(Macintire et al. 1978) the subject already had significant body burden of
silver, the test dose preparation had ammonium chloride as one ofthe com-
ponents, and acetate was the salt form of silver. Due to these uncertainties,
OCR for page 345
Silver
345
it was decided to use a factor of 10 to account for the differences between
rodents and humans. No additional factors were applied for differences in
uptake of silver from water or from food due to lack of data. ACs were
calculated assuming a total intake of 2.8 L of water per day. That includes
an average of 0.8 L of water used for reconstitution of food and 2 L for
drinking.
Ingestion for 1 d
A 1-d AC was not calculated because there are no data to support a 1-d
value. Although a few animal studies in which rodents were exposed to
silver (as salts) via drinking water showed decreases in water consumption
for the first 3 4, water consumption returned to normal in the days follow-
ing. The initial phenomenon may have been due to taste aversion. The 1 0-d
value will be applied to protect against any 1-d effects.
Ingestion for 10 d
Water Consumption
Silver nitrate at 12 mM (dose of 130 mg/kg/~) in drinking water was
unacceptable to mice, and water consumption dropped dramatically (Day
et al. 1976~. As early as 12 4, there was uniform deposition of silver within
the gIomerular membrane after exposure to 6 mM silver nitrate (calculated
dose of 65 mg/kg/~), although there was no effect on water consumption.
Hence, 65 mg/kg/d is considered a NOAEL for changes in water consump-
tion. Factors of 10, 10, and 3 were applied for species extrapolation, differ-
ences in absorption between rodents and humans, and spaceflight effects,
respectively. Thus, the 10-d AC for decreased water consumption was
derived as
10-d AC = (65 mg/kg/d x 70 kg) (10 x 10 x 2.S L/d x 3~;
10-d AC = 5.4 mg/L (rounded to 5 mg/L).
In Sprague-Dawley rats exposed to silver (as silver nitrate) in drinking
water at 6, 12, or 24 mM (65, 130, or 260 mg/kg/d), the only effect ob-
served was a decline in the amount of drinking water consumed in the 260
mg/kg group (Walker 1971~. That was found as early as 1 wk. The mid-
dle-dose group exhibited only silver deposits in the kidneys without any
OCR for page 346
346
Spacecraft Water Exposure Guidelines
effects on the volume of ingested drinking water. Hence, for the 10-d AC,
a dose of 130 mg/kg/d was used as the NOAEL for effects on water con-
sumption. A factor of 10/7 was included for time extrapolation. The 10-d
AC for decline in water consumption was derived as
10-d AC = (130 mg/kg/d x 70 kg) (10
10-dAC=7.5mg/L.
Nephrotoxicity
x 10 x 2.8 L/d x 3 x 10/7~;
No human experimental data are available to establish an AC for this
parameter. The industrial worker exposure survey reported by Rosenman
et al. (1987), although strongly indicative of nephrotoxic effects of silver,
is heavily masked by the presence of cadmium, a known nephrotoxin in the
workplace. Hence, an AC for nephrotoxicity was not established.
Ingestion for 100 d
Cardiovascular Effects
There are no human data to indicate that silver causes any cardiovascu-
lar effects. In OIcott's (1950) study, rats administered silver nitrate in drink-
ing water for 21 ~ ~ at a dose of 89 mg/kg/d developed left ventricular hy-
pertrophy. Thickening of the renal gIomerular membrane was also noted.
Although a large number of animals were used in that investigation, the way
the effect was reported (as the weight of the left ventricle per 100 g body
weight) was not reliable enough to derive a 100-d AC for cardiovascular
effects.
Neurotoxicity
Rungby and Danscher (1984) reported that 60-~-old NMRI-strain fe-
male mice (n = 20) receiving silver nitrate at 0.015% in drinking water
(silver at 0.095 mg/mL) for 125 ~ were hypoactive, as measured by open
cage field behavior for 4 ~ after the end of exposure. The authors suggested
that that effect might have been due to intraneuronal accumulation of silver
in motor-control nuclei ofthe brain stem. An estimated dose of 25 mg/kg/d
can be considered a LOAEL for that effect. There were no dose-response
OCR for page 347
Silver
347
or time-response data. A NOAEL was not identified. A factor of 10 was
applied to calculate a NOAEL from the LOAEL; a factor of 10 was applied
for species extrapolation; and a factor of 10 was applied for the differences
in absorption between rodents and humans. No time factor was used be-
cause an AC derived from a 125-d study will be protective for a 100-d
duration. A 100-d AC for neurotoxic effects can be calculated as
100-d AC = (25 mg/kg/d x 70 kg) (10 x
100-d AC = 0.6 mg/L (rounded).
Water Consumption
_ , _
10 x 10 x 2.8L/d);
Day et al. ~ 1976) reported that water consumption dramatical ly dropped
in mice administered silver nitrate at 130 mg/kg/d in drinking water. But,
in another batch of mice exposed to half that dose in drinking water and
studied for 12 d to 14 wk. no reduction in water consumption was observed.
Hence, 65 mg/kg/d appears to be a NOAEL for decreased water intake.
Factors of 10, 10, 3, and 100/98 were applied for species extrapolation,
differences in absorption between rodents and humans, spaceflight effects,
and time extrapolation, respectively. A 100-d AC for decreased water
consumption can be derived as
100-d AC = (65 mg/kg/d x 70 kg) (10 x 2.8 L/d x 100/98 x 3 x 10);
100-d AC = 5.0 mg/L (rounded).
Ingestion for 1,000 d
The deposition of silver in kidneys as a consequence of argyria has been
reported to be associated with arteriosclerotic changes, and the deposition
of silver in the eyes has been associated with poor night vision (NRC 1977).
Deposition in various tissues, including basement membranes of kidneys,
brain, and spinal cord, has been associated with changes in neuronal func-
tions, such as loss of coordination and convulsions (Reinhardt 1971;
Rosenman et al.1979), EEG changes, and signs of cerebellarataxia (Aaseth
et al.1981). Because these case report studies did not provide enough con-
trolled data to derive an AC, and correlations are only suggestive, argyria
was considered an aesthetic effect. To be conservative, an AC was derived
for this end point using the following sets of data.
OCR for page 348
348
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OCR for page 349
Silver
349
There have been several reports of argyria in humans as a result of
treatment using medications containing silver (Gaul and Stand 1935), after
large doses of lozenges containing silver (East et al. l 980), and after ingest-
ing capsules containing silver nitrate for 15 y (Blumberg and Carey 1934~.
Although these are human cases, there has been a lot of uncertainty about
the exposure levels. In the latter two cases, there had been only one subject.
The Gaul and Stand (1935) study is a report of 70 cases of generalized
argyria in individuals who received several intravenous injections of silver
arsphenamine for syphilis. The disadvantage of that study was that argyria
developed at different total doses, indicating that some individuals were a
lot more sensitive than others. A total dose of 4 g of silver arsphenamine (or
1 g of silver ions) over 1 y could cause argyria (Gaul and Stand 1935; Hill
and Pillsbury 1939~. Extrapolating intravenous exposure to an oral bolus,
using a mean absorption in humans of 10%, that dose would be 10,000 mg
over 365 ~ (accumulated dose over a year). One gram of silver by intrave-
nous injection would correspond to lo gby oral dose (based on the assumed
10% absorption). That would correspond to 27.4 mg/d (10,000 mg/365 d),
giving a dose of 0.39 mg/kg/d for a 70-kg person. Using that as a LOAEL
for argyria, a 1,000-d AC was calculated. Factors of 10 and 1,000/356 were
applied for deriving a NOAEL from the LOAEL and for time extrapolation,
respectively. The AC was calculated as follows:
1,000-d AC = (0.39 mg/kg/d x 70 kg) (10 x 2.8 x 1,000/365~;
1,000-d AC = 0.36 mg/L (rounded to 0.4 mg/L).
NASA also calculated a 1,000-d AC from the only long-term animal
study found in the literature. OIcott (1947) described different levels of
discoloration of eyes in 139 albino rats after administering a solution of
silver nitrate (1:1,000) equivalent to 63 mg/kg/~. Slight gray color in the
eyes was seen after 21 ~ ~ of exposure to silver. The 63 mg/kg/d value was
considered a LOAEL because the coloration was only slight (according to
gradation of colors specified by the authors of the studies). Eye discolor-
ation has been reported in studies in Wistar rats (Rungby 1986b) and in
human cases involving use of eye drops or make-up containing silver
(Greene and Su 1987~. Workers exposed to silver for over 2 y had corneal
deposits of silver, and some complained of poor night vision (Rosenman et
al. 1979~. Factors of 10, 10, 10, and 1,000/21 ~ were applied for species
extrapolation, differences in absorption between rodents end humane, deriv-
OCR for page 350
350
Spacecraft Water Exposure Guidelines
ing a NOAEL from a LOAEL, and time extrapolation, respectively. A
1,000-d secondary AC for this aesthetic effect was calculated as
1,000-d AC = (63 mglkg/d x 70 kg) (10 x 10 x 10 x 2.8 L/d x 1,000/218~;
1,000-d AC = 0.4 mg/L (rounded).
REFERENCES
Alexander, J., and J. Aaseth. 1981. Hepatobiliary transport and organ distribution
of silver in the rat as influenced by selenite. Toxicology 21~3~:179-86.
Aaseth, J., A. Olsen, J. Halse et al. 1981. Argyria-tissue deposition of silver as
selenide. Scand. J. Clin. Lab. Invest. 41:247-251
Armitage, S.A., M.A. White, and H.K. Wilson. 1996. The determination of silver
in whole blood and its application to biological monitoring of occupationally
exposed groups. Ann. Occup. Hyg. 40:331-338
ATSDR (Agency for Toxic Substances and Disease Registry).1990. Toxicological
profile for silver. ATSDRITP-90-24. Agency for Toxic Substances and Disease
Registry, U.S. Public Health Service, U.S. Department of Health and Human
Services, Washington, DC.
Berry, J.P., and P. Galle. 1982. Selenium and kidney deposits in experimental
argyria. Electron microscopy and microanalysis. Pathol. Biol. (Paris) 30~3~:
136-40.
Buckley, W.R., C.F. Oster, and D.W. Fassett.1965. Localized argyria II: chemical
nature of silver containing particles. Acta Dermatol. 92:697-705
Blumberg, H., and T.N. Carey.1934. Detection of unsuspected and obscure argyria
by the spectrographic demonstration of high brood Ag. JAMA 103: 1521-1524.
Bunyan, J., A.T. Diplock, M.A. Cawthorne, and J. Green. 1968. Vitamin E and
stress. Nutritional effects of dietary stress with silver in vitamin E deficient
chicks and rats. Br. J. Nutr. 22: 165-182.
Casto, B.C., J. Meyers, and A. DiPaolo. 1979. Enhancement of viral transforma-
tions for the evaluations of the carcinogenic or mutagenic potential of inor-
ganic metal salts. Cancer Res. 39: 193-198
Creasey, M., and D.B. Moffat. 1973. The deposition of ingested silver in the rat
kidney at different ages. Experentia 29:326-327.
Danscher, G.1981. Light and electron microscopic localization of silver in biologi-
cal tissue. Histochemistry 71: 177- 186.
Day, W.A., J.S. Hunt, and A.R. McGiven. 1976. Silver deposition in mouse
glomeruli. Pathology 8:201-204.
Dequidt, J., P. Vasseur, and J. Gromez-Potentier.1974. Experimental toxicological
study of some silver derivatives [in French]. Bull. Soc. Pharm. Lille 1 :23-35.
OCR for page 351
Silver
351
Diplock, A.T., J. Green, J. Bunyan, D. McHale, and I.R. Muthy. 1967. Vitamin E
and stress. The metabolism of D-alpha tocopherol in the rat under dietary stress
with Ag. Br. J. Nutr. 21:115-125.
Di Vincenzo, G.D., C. J. Giordano, and L.S. Schrieves.1985. Biologic monitoring
of workers exposed to Ag. Int. Arch. Occup. Environ. Health 56:207-215.
Durfor, C.N., and E. Becker. 1964. Public water supplies of the 100 largest cities
in the United States, 1962. U.S. Geological Survey Paper 1812. Washington,
DC: U.S. Government Printing Office.
East, B.W., K. Boddy, E.D. Williams, D. MacIntyre, and A.L.C. McLay. 1980.
Silver retention, total body silver and tissue silver concentrations in argyria
associated with exposure to an anti-smoking remedy containing silver acetate.
Clin. Exp. Dermatol. 5:305-311.
Eliopoulos, P., and D. Mourelatos. 1998. Lack of genotoxicity of silver iodide in
the SCE assay in vitro, in vivo, and in the Ames/microsome test. Teratog.
Carcinog. Mutagen. 18:303-8.
EPA (U. S. Environmental Protection Agency).1980. Ambient water criteria for Ag.
EPA 440/5-80-071. Office of Environmental Criteria and Assessmen, U.S.
Environmental Protection Agency, Cincinnati, OH.
EPA (U.S. Environmental Protection Agency). 1981. EPA working group. An
exposure and risk assessment for silver. EPA-440-4-81-017. U.S. Environ-
mental Protection Agency, Washington, DC.
EPA (U.S. Environmental Protection Agency).1992. Drinking Water Health Advi-
sory for Silver. NTIS/PB92-135516. U.S. Environmental Protection Agency,
Washington, DC.
Furchner, J.E., G.A. Drake, and C.R. Richmond. 1966. Retention of 110Ag by
mice. U.S. Atomic Energy Commission, Science Laboratory, University of
California, Los Alamos.
Furchner, J.E., C.R. Richmond, and G.A. Drake. 1968. Comparative metabolism
of radionuclides in mammals. IV. Retention of 110Ag in the mouse, rat, mon-
key and dog. Health Phys. 15:505-514.
Furst, A., and M.C. Schlauder.1977. Inactivity oftwo noble metals as carcinogens.
J. Environ. Pathol. Toxicol. 1:51-57.
Furst A. 1981. Bioassay of metals for carcinogenesis: Whole animals. Environ.
Health Perspect. 40:83-91.
Gammill, J.C., B. Wheeler, E.L. Carothers, and P.F. Hahn. 1950. Distribution of
radioactive silver colloids in tissues of rodents following injection by various
routes. Proc. Soc. Exp. Biol. Med. 74:691-695.
Ganther, H.E.1980. Interactions of vitamin E and selenium with mercury and Ag.
Ann. NY Acad. Sci. 355:212-225.
Gaul, L.E., andA.H. Staud.1935. Clinical Spectroscopy. Seventy cases of general-
ized argyrosis following organic and colloidal silver medication, including a
biospectrometric analysis often cases. JAMA 104:1387-1390
OCR for page 352
352
Spacecraft Water Exposure Guidelines
Grasso, P., R. Abraham, R. Hendy, A.T. Diplock, L. Goldberg, and J. Green.1969.
The role of dietary silver in the production of liver necrosis in vitamin
E-deficient rats. Exp. Mol. Pathol. 11:186-199.
Greene, R.M., and W.P. Su. 1987. Argyria. Am. Fam. Physician 36:151-154
Gregus, Z., and C.D. Klaassen.1986. Disposition of metals in rats: A comparative
study of fecal, urinary and biliary excretion and tissue distribution of eighteen
metals. Toxicol. Appl. Pharmacol. 85:24-38.
Hill, W.R., and D.M. Pillsbury.1939. Argyria. The Pharmacology of Silver. Balti-
more, MD: Williams and Wilkins Company.
Jackson, W.F., and B.R. Duling.1983. Toxic effects of Ag-Ag chloride electrodes
on vascular smooth muscles. Circ. Res. 53~1~:105-108.
Klaassen, C.D.1979. Biliary excretion of silver in the rat, rabbit and dog. Toxicol.
Appl. Pharmacol. 50:49-55.
Kopp, J.F., and R.C. Kroner. 1967. Trace metals in waters ofthe United States. A
five-year summary of trace metals in rivers and lakes of the United States
(October 1,1962 to September 30, 1967~. U. S . Department of Interior, Federal
Water Pollution Control Administration, Division of Pollution Surveillance.
Cincinnati, OH.
Landas, S., J. Fischer, L.D. Wilkin, L.D. Mitchell, A.K. Johnson, J.W. Turner, M.
Theriac, andK.C. Moore.1985. Demonstration ofregionalblood-brain barrier
permeability in human brain. Neurosci. Lett. 57~3~:251-256.
Macintire, D., A.L.C. Mclay, B.W. East, E.D. Williams, and K. Boddy. 1978.
Silver poisoning associated with an antismoking lozenge. Br. Med. J. 2:
1749-1750.
Matuk, Y., M. Ghosh, and C. McCulloch. 1981. Distribution of silver in the eyes
and plasma proteins of the albino rat. Can. J. Ophthalmol. 16:145-150.
Matuk, Y. 1983. Distribution of radioactive silver in the subcellular fractions of
various tissues ofthe rat and its binding to low molecular weighs proteins. Can.
J. Physiol. Pharmacol. 61:1391-1395.
McCoy, E.C., and H.S. Rosenkranz. 1978. Silver sulfadiazine: Lack of mutagenic
activity. Chemotherapy 24:87-91.
Merck. 1989. The Merck Index, 11th Ed. Rahyway, NJ: Merck and Co.
Moffat, D.B., and M. Creasey. 1972. The distribution of ingested silver in the
kidney of the rat and of the rabbit. Acta Anat (Baser) 83 :346-55.
Newton, D., and A. Holmes . 1966. A case of accidental inhalation of zinc-65 and
110Ag. Radiat. Res. 29:403-412.
Nicogossian, A.E., C.F. Sawin, C.L. Huntoon. 1994. Overall physiological re-
sponse to space flight. Chapter 11 in Space Physiology and Medicine, 3rd Ed.,
A.E. Nicogossian, CL Huntoon, and S.L. Pool, eds. Philadelphia, PA: Lea and
Febiger.
Nishioka, H.1975. Mutagenic activity of metal compounds in bacteria. Mutat. Res.
31 :185-189.
OCR for page 353
Silver
353
NRC (National Research Council).1977. Drinking Water and Health. Washington,
DC: National Academy Press.
Olcott, C.T. 1947. Experimental argyrosis. III. Pigmentation of the eyes of rats
following ingestion of silver during long periods of time. Am. J. Pathol. 23:
783-789.
Olcott, C.T.1948. Experimental argyrosis. IV. Morphologic changes in the experi-
mental animal. Am. J. Pathol. 24:813-833.
Olcott, C.T. 1950. Experimental argyrosis. V. Hypertrophy ofthe left ventricle of
the heart in rats ingesting silver salts. Arch. Pathol. 49:138-149.
Reinhardt, G., Geldmacher-von Mallinck, H. Kittel, O. Opitz. 1971. Acute fatal
poisoning with silver nitrate following an abortion attempt [in German]. Arch.
Kriminol. 148~3~:69-78.
Ridgeway, L.P., and D.A. Karnofsky. 1952. The effects of metals on the chick
embryo: Toxicity end production of abnormalities in development. Ann. N. Y.
Acad. Sci. 55:203-206.
Robison, S.H., O. Cantoni, and M. Costa. 1982. Strand breakage and decreased
molecular weight of DNA induced by specific metal compounds. Carcino-
genesis 3:657-62.
Robkin, M.A ., D.R . Swanson, and T.H. Shepard. 1973. Trace metal concentra-
tions in human fetal livers. Trans. Am. Nucl. Soc. 17:97.
Rosenman, K.D., A. Moss, and S. Kon. 1979. Argyria. Clinical implications of
exposure to silver nitrate and silver oxide. J. Occup. Med 21 :430-435.
Rosenman, K.D., N. Seixas, and I. Jacobs. 1987. Potential nephrotoxic effects of
exposure to silver. Br. J. Ind. Med. 44:267-72
Rossman, T.G., and M. Molina.1986. The genetic toxicology of metal compounds:
l l .Enhancement of ultraviolet light-induced mutagenesis in Escherichia cold
WP2. Environ. Mutagen. 8:263-271.
Rungby, J., and G. Danscher. 1983. Localization of exogenous silver in brain and
spinal cord of silver exposed rats. Acta Neuropathol. (Berl) 60:92-98.
Rungby, J., and G. Danscher. 1984. Hypoactivity in silver exposed mice. Acta
Pharmacol. Toxicol. (Copenh) 55:398-401.
Rungby J.1986a. Exogenous silver in dorsal root ganglia, peripheral nerve, enteric
ganglia, and adrenal medulla. Acta Neuropathol. (Berl) 69~1-2~:45-53.
Rungby, J.1986b. Experimental argyrosis: Ultrastructural localization of silver in
rat eye. Exp. Mol. Pathol. 45:22-30.
Rungby, J.1987. Silver induced lipid peroxidation in mice: Interactions of selenium
end Nicker. Toxicology45:135-142.
Rungby, J., L. Slomianka, G. Danscher, A.H. Andersen, and M.J. West. 1987. A
quantitative evaluation ofthe neurotoxic effect of silver on the volumes ofthe
components of the developing rat hippocampus. Toxicology 43 :261-268.
Schmachl, D., and D. Steinhoff. 1960. Experimental carcinogenesis in rats with
colloidal silver and gold solutions [in German]. Z. Krebsforsch. 63:586-591.
OCR for page 354
354
Spacecraft Water Exposure Guidelines
Scott, K.G., and J.G. Hamilton. 1950. The metabolism of silver in the rat with
radio-silver used as an indicator. Publ. Pharmacol. 2:241-262.
Stokinger, H.E.1981. The metals: Ag. Pp.1881-1894 inPatty's Industrial Hygiene
and Toxicology, 3rd Ed., Vol. 2A, G.D. Clayton and F.E. Clayton, eds. New
York, NY: John Wiley and Sons.
Tichy, P., J. Rosina, K. Blaha Jr., and M. Cikrt. 1986. Biliary excretion of 110Ag
and its kinetics in the isolated perfused liver in rats. J. Hyg. Epidemiol.
Microbiol. Immunol. 30:145-148.
Tamimi, S.O., S.M. Zmeili, M.N. Gharaibeh, M.S. Shubair, andA.S. Salhab.1998.
Toxicity of a new antismoking mouthwash 881010 in rats and rabbits. J.
Toxicol. Environ. Health 53~1~:47-60.
Van Vleet, J.F.1976. Induction of lesions of selenium-vitamin E deficiency in pigs
fed Ag. Am. J. Vet. Res. 37:1415-1420.
Wagner, P.A., W.G. Hoekstro, and H.E. Ganther.1975. Alleviation of silver toxic-
ity by selenite in the rat in relation to tissue glutathione peroxidase. Proc. Soc.
Exp. Biol. Med. 148:1106-1110.
Walker, F. 1971. Experimental argyria: A model for basement membrane studies.
Br. J. Exp. Pathol. 52:589-593.
WHO(WorldHealthOrganization).1984.Pp.141-144inGuidelinesforDrinking
Water Quality, Volume 2. Geneva: WHO.
Representative terms from entire chapter:
drinking water
