United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-071
October 1980
Ambient
Water Quality
Criteria for
Silver
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AMBIENT WATER QUALITY CRITERIA FOR
SILVER
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in ciny body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. a!. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 19/9).
The term "waiter quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria-presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology
William A. Brungs, ERL-Narragansett David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects
Bonnie Carson (author) Robert M. Bruce, ECAO-RTP
Midwest Research Institute U.S. Environmental Protection Agency
Christopher DeRosa (doc. mgr.), ECAO-Cin Richard Bull, HERL
U.S. Enviromental Protection Agency U.S. Environmental Protection Agency
Bonnie Smith (doc. mgr.), ECAO-Cin Patrick Durkin
U.S. Environmental Protection Agency Syracuse Research Corporation
Ernest Foulkes Alfred Garvin
University of Cincinnati University of Cincinnati
Dinko Kello Terri Laird, ECAO-Cin
Institute for Medical Research U.S. Environmental! Protection Agency
Edward W. Lawless Steven D. Lutkenhoff, ECAO-Cin
Midwest Research Institute U.S. Environmental Protection Agency
Jerry F. Stara, ECAO-Cin
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones., B.J. Bordicks,
B.J. Quesnell, P. Gray, B. Gardiner, R. Swantack.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction
Effects B-3
Acute Toxicity B-3
Chronic Toxicity B-6
Plant Effects B-10
Residues B-11
Miscellaneous B-ll
Summary B-l2
Criteria B-13
References B-34
Mammalian Toxicology and Human Health Effects
Introduction C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-l7
Inhalation C-21
Dermal ^-29
Pharmacokinetics C-33
Absorption C-33
Distribution c"40
Metabolism C-52
Excretion c~56
Effects c'68
Acute, Subacute and Chronic Toxicity C-68
Synergism and/or Antagonism C 94
Teratogenicity C-l02
Mutagenicity c-1°4
Carcinogenicity C-106
Criterion Formulation C-l16
Existing Guidelines and Standards C-116
Current Levels of Exposure C-119
Special Groups at Risk
Basis and Derivation of Criterion
References C-
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CRITERIA DOCUMENT
SILVER
CRITERIA
Aquatic Life
For freshwater aauatic life the concentration (in yg/l) of total
recoverable silver should not exceed the numerical value given by
e(1.72[ln(hardness)]-6.52) at any ^ For ^^ at hardnesse$ Qf 50>
100, and 200 mg/1 as CaC03, the concentration of total recoverable silver
should not exceed 1.2, 4.1, and 13 pg/1, respectively, at any time. The
available data indicate that chronic toxicity to freshwater aauatic life may
occur at concentrations as low as 0.12 wg/1.
For saltwater aauatic life the concentration of total recoverable silver
should not exceed 2.3 yg/1 at any time. No data are available concerning
the chronic toxicity of silver to sensitive saltwater aauatic life.
Human Health
The ambient water auality criterion for silver is recommended to be
identical to the existing water standard which is 50 ug/1. Analysis of the
toxic effects data resulted in a calculated level which is protective of
human health against the ingestion of contaminated water and contaminated
aauatic organisms. The calculated value is comparable to the present stan-
dard. For this reason a selective criterion based on exposure solely from
consumption of 6.5 grams of aauatic organisms was not derived.
VI
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INTRODUCTION
Silver is a white, ductile metal occurring naturally in the pure form
and in ores. Principal uses of silver are in photographic materials, elec-
troplating, as a conductor, in dental alloys, solder and brazing alloys,
paints, jewelry, silverware, coinage, and mirror production. Silver is of
some use as an antibacterial agent and has been shown to be bactericidal
even in concentrations that are not great enough to precipitate proteins;
the assumption is that silver is capable of interfering with essential meta-
bolic processes in the bacterial cell (Goodman and Gilman, 1975).
Silver can exist in two valence states, Ag+ and Ag++. It has an atomic
weight of 107.87. Solubilities of a few common silver salts in water are:
AgCl, 1,930 ug/l; AgN03» 2.5 x 109 wg/l; and Agl, 30 wg/l (Windholz,
1976). Silver occurs primarily in the form of the sulfide (argentite
Ag?S) or intimately associated with other metal sulfides, especially those
of lead and copper. Other common silver minerals include cerargyrite
(AgCl), proustite (3AgS As2S3), pyragyrite (3Ag2S Sb2S3), stepha-
nite (5Ag~S Sb9S-) and native metallic silver. Most lead and copper
L, L. 3
ores are argentiferous, though there are important exceptions. Recovery of
silver and gold from these ores constitutes an important part of their
metallurgical treatment.
Silver is also commonly associated in nature with gold. Not only does
gold occur with silver in copper and lead ores, but native metallic gold
usually contains silver. Gold and silver are mutually soluble in each other
in all proportions in the metallic state.
Silver is usually found in extremely low concentrations in the aquatic
environment, due both to its low crustal abundance and the effectiveness of
A-1
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controls on its mobility in water. In a study of 10 U.S. rivers, Kharkar,
et al. (1968) detected silver in concentrations ranging from 0.092 to 0.55
ug/1. Hem (1970) cites studies of public drinking water supplies and river
waters which report median concentrations of 0.23 and 0.09 vg/1, respec-
tively. The geochemistry of silver has been extensively reviewed by Boyle
(1968).
Sorption and precipitation processes are effective in reducing the con-
centration of dissolved silver and result in higher concentrations in the
bed sediments than in the overlying waters. Sorption by manganese dioxide
and precipitation with halides are probably the dominant controls on the
mobility of silver in the aquatic environment. Some silver is also bioaccu-
mulated, and the remainder is transported in solution to the oceans (U.S.
EPA, 1979).
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REFERENCES
Boyle, R.W. 1968. The geochemistry of silver and its deposits. Geol. Sur-
vey of Canada, Bull. 160, Ottawa, Canada.
Goodman, L.S. and A. Gilman (eds.) 1975. The Pharmacological Basis of
Therapeutics. 5th ed. MacMillan Publishing Co., Inc., New York.
Hem, J.D. 1970. Study and interpretation of the chemical characteristics
of natural waters. U.S. Geol. Survey Paper 1473, Washington, D.C. p. 202.
Kharkar, O.P., et al. 1968. Stream supply of dissolved silver, molybdenum,
antimony, selenium, chromium, cobalt, rabidium and cesium to the oceans.
Geochim. Cosmochim. Acta. 32: 285.
U.S. EPA. 1979. Water-related environmental fate of 129 priority pollut-
ants. EPA 68-01-3852. U.S. Environ. Prot. Agency, Washington, D.C.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
A-3
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Aquatic Life Toxicology*
INTRODUCTION
Silver exhibits oxidation states of 0, +1, +2, and +3, but only the 0
and +1 states occur to any extent in the environment. In natural water, the
monovalent species is the form of environmental concern. In water, silver
may exist as simple hydrated monovalent ions completely dissociated from an-
ions that at one time could have been part of its crystalline salt lattice.
in addition, monovalent silver ions may exist in various degrees of associa-
tion with a large number of inorganic ions, such as sulfate, bicarbonate,
and nitrate, to form numerous compounds with a range of solubilities and po-
tentials for hydrolysis or other reactions. Hem (1970) speculates that
where chloride concentrations exceed 35 mg/1, silver chloride may exert a
major control on solubility of silver.
Sorption appears to be the dominant process leading to partitioning into
sediments. It appears that manganese dioxide, ferric compounds, and clay
minerals all have some degree of adsorptive affinity for silver and are in-
volved in its deposition into sediments (Kharkar, et al. 1968). Dyck (1968)
observed that sorption of silver was strongly dependent on pH. In addition,
silver may be freed from these compounds by reducing conditions in the sedi-
mentary layer and thus may be reduced to metallic silver or may combine with
reduced sulfur to form the extremely insoluble silver sulfide. Finally sil-
ver may exist as metal-organic complexes or may be adsorbed by organic ma-
terials in natural waters.
*The reader is referred to the Guidelines for Deriving Water Quality
Criteria for the Protection of Aquatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
B-l
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Silver is one of the most toxic metals to freshwater aquatic life. Most
of the toxicity studies have been conducted with silver nitrate, which is an
excellent source of free soluble silver ions. Insoluble silver salts are
much less toxic than silver nitrate. Chambers and Proctor (I960) found that
the germicidal action of silver in distilled water was related to the con-
centration of silver ions rather than the physical nature of the silver from
which the ions were originally derived.
Limited information is available concerning the relationship of various
forms of silver and toxicity to aquatic animals. Data indicate that the
acute toxicity of silver to freshwater fishes and Daphnia magna is related
to water hardness, with silver being more toxic in soft water. The acute
toxicity of silver also is related to chloride concentration, but the data
base for this relationship is insufficient to develop criteria on the basis
of chloride concentration. The data base for saltwater organisms is insuf-
ficient to determine the importance of salinity, temperature, and other
water quality factors on the toxicity of silver.
Of the analytical measurements currently available, a water quality cri-
terion for silver is probably best stated in terms of total recoverable sil-
ver, because of the variety of forms of silver that exist in bodies of water
and the various chemical and toxicological properties of these forms. The
forms of silver that are commonly found in bodies of water and are not mea-
sured by the total recoverable procedure, such as the silver that is in
minerals, clays, and sand, probably are forms that are less toxic to aquatic
life and probably will not be converted to the more toxic forms very readily
under natural conditions. On the other hand, forms of silver that are com-
monly found in bodies of water and are measured by the total recoverable
procedure, such as the free ion and the hydroxide, carbonate, and sulfate
B-2
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salts, probably are forms that are more toxic to aquatic life or can be con-
verted to the more toxic forms under natural conditions. Because the cri-
terion is derived on the basis of tests conducted on soluble inorganic salts
of silver, the total silver and total recoverable silver concentrations in
the tests will probably be about the same, and a variety of analytical pro-
cedures will produce about the same results. Except as noted, all concen-
trations reported herein are expected to be essentially equivalent to total
recoverable silver concentrations. All concentrations are expressed as sil-
ver, not as. the compound.
EFFECTS
Acute Toxicity
The data base concerning acute toxicity of silver to freshwater organ-
isms includes 82 acute values for 10 species from nine different taxonomic
families (Table 1). The invertebrate species include a planktonic crusta-
cean, a benthic crustacean that is a detritivor, and a benthic insect among
others, whereas the fish species include a salmonid and five nonsalmonid
species.
For the four invertebrate species, the acute values for silver range
from 0.25 u9/l for Daphnia magna to 4,500 ug/1 for the scud Gammarus pseudo-
limnaeus. both of which were tested in Lake Superior water (Table 1).
Most of the acute values for freshwater fish are for the rainbow trout
and fathead minnow (Table 1). The acute values in flow-through tests ranged
from 3.9 ug/1 for the fathead minnow in soft water to 280 yg/1 for rainbow
trout in hard water. This range of acute values for six fish species was
much less than the range of acute values for four invertebrate species.
Chapman, et al. (Manuscript) examined the acute toxicity of silver to
Daphnia magna with and without food being added to the test solutions. The
B-3
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acute value with food was 9.5 wg/l (Table 6). In a side-by-side test
conducted with no food added (Table 1), the acute value was 0.25 ug/l.
Lemke (Manuscript) also reported the results of side-by-side tests to com-
pare the effect of food on acute toxicity. The result with added food was
43 ug/l (Table 6), and with no added food the results were 8.4 and 15 yg/l
(Table 1). Because this effect is observed with some metals, but not with
others, it appears that this daphnid food, or some component of it, greatly
decreases the acute toxicity of silver.
The results of a study (EG&G Bionomics, 1979) designed to evaluate the
relative toxicity of different forms of silver to the fathead minnow are
given in Tables 1 and 6. Flow-through tests using measured total silver and
free silver (pAg) concentrations were conducted. Silver nitrate with a
96-hour LC5Q value of 16 ug/l (Table 1) was the most toxic silver com-
pound. The 96-hour LC5Q values for silver were 510 and 5,600 ug/l when
the concentration of chloride was increased to 500 and 2,000 mg/1, respec-
tively (Table 6). These test solutions were clear, indicating that silver
was apparently present as a soluble chloride complex. Silver thiosulfate
and both forms of silver sulfide were even less toxic.
The results of a round-robin test in which six laboratories each con-
ducted duplicate static tests with Daphnia magna and duplicate static and
flow-through tests with rainbow trout and fathead minnows (Lemke, Manu-
script) are given in Table 1. The results of all except one test, were
based on measured concentrations. Each laboratory reported that for the
fathead minnow and rainbow trout the results of the flow-through tests were
lower than the results of the static tests. The hardness of the water used
in each laboratory was available, and so a least-squares regression was per-
formed on the natural logarithms of the acute values (the flow-through
B-4
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values for the fish) on the natural logarithms of hardness. The resulting
slopes were 2.29, 1.65, and 1.63 for Daphnia magna, rainbow trout, and fat-
head minnow, respectively, and all were statistically significant (p-0.01).
The concentrations of chloride were 1.2, 32, 8, 11, 13, and 1 mg/1 in the
waters whose hardnesses were 48, 255, 54, 46, 38, and 75 mg/1, respectively.
The regressions on chloride concentrations were not statistically signifi-
cant (p=0.05).
Other data, however, do not show this amount of effect of hardness on
the acute toxicity of silver. Goettl and Davies (1978) tested the acute
toxicity of silver to the fathead minnow, speckled dace, and mottled sculpin
in both soft and hard water. In addition, Davies, et al. (1978) tested the
rainbow trout in soft and hard water. These tests produced slopes of 0.10,
0.50, 0.46, and 0.26, respectively. The last slope is not statistically
significant (p-0.05), but the significance of the first three cannot be
tested because only two points are available.
The apparent lack of effect of chloride is surprising, although the
range of concentrations may be too low. The contradictory evidence con-
cerning the effect of hardness on acute toxicity is also surprising. A com-
parison of all the available data concerning the acute toxicity of silver to
both fathead minnows and rainbow trout suggests the possibility that silver
was unusually toxic in the hard water used by Goettl and Davies (1978) and
Davies, et al. (1978). Therefore, these results were not used in describing
the effect of hardness on the acute toxicity of silver. For the remaining
data, a least-squares regression of the natural logarithms of the acute val-
ues on the natural logarithms of hardness produced slopes of 2.35, 1.30, and
1.50, for Daphnia magna, rainbow trout, and fathead minnows, respectively.
All three slopes were statistically significant (p.0.01). If the data for
B-5
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hard water from Goettl and Davies (1978) and Davies, et al. (1978) are used,
the slopes for rainbow trout and fathead minnow change from 1.30 and 1.50 to
1.00 and 1.14, respectively.
The arithmetic mean slope (1.72) was used with the geometric mean toxic-
ity value and hardness for each species to obtain a logarithmic intercept
for each species, but again the data obtained in hard water by Goettl and
Davies (1978) and Oavies, et al. (1978) were not used. The species mean
acute intercept, calculated as the exponential of the logarithmic intercept,
was used to rank the relative sensitivities of the species (Table 3). A
freshwater Final Acute Intercept of 0.00147 ug/1 was obtained for silver
using the species mean acute intercepts listed in Table 3 and the calcula-
tion procedures described in the Guidelines. Thus the Final Acute Equation
1s e(1.72 [1n(hardness)]-6.52)>
For saltwater animals, acute toxicity data are available for five fish
and five invertebrate species. Fishes were both the most sensitive and most
resistant species tested (Table 3), but invertebrate species as a group were
generally more sensitive to silver than were the fish. Toxicity values
ranged from 4.7 ng/1 for the summer flounder to 1,400 ug/1 for the sheeps-
head minnow. The Saltwater Final Acute Value for silver, derived from the
species mean acute values listed in Table 3 using the calculation procedures
described in the Guidelines, is 2.3 ug/1.
Chronic Toxicity
The results of Daphnia magna renewal life-cycle tests are given in
Table 2. These chronic tests were conducted as part of a round-robin
testing program, similar to that discussed in Lemke (Manuscript), to evalu-
ate methods for acute and chronic toxicity tests using Daphnia magna
(Nebeker, et al. Manuscript b). In contrast to the results of the acute
B-6
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tests, no relationship could be found between hardness and chronic
toxicity. Three of the chronic values (2.6, 13, and 5.2 ug/D are from the
laboratory which reported acute values of 0.6 and 1.1 wg/l. In addition, a
third acute in the same laboratory produced an acute value of 0.25 wg/l
(Nebeker, et al. Manuscript a). The chronic values of 15 and 29 vg/l were
from the same laboratory as the acute values of 15 and 8.4 yg/l, whereas the
chronic value of 5.2 ug/1 corresponds to the acute value of 0.64 yg/1. In
each laboratory the average acute value for silver was lower than the aver-
age chronic value, probably because food was added to the test solutions in
the chronic test, but not in the acute tests.
Special acute tests with Daphnia magna were conducted in two laborator-
ies by adding food to the test solution as is done in the chronic test. In
one laboratory the acute values were 8.4 and 15 yg/1 without food (Table 1)
and 43 ug/1 with food (Table 6). The comparable chronic values were 15 and
29 pg/1, which results in an acute-chronic ratio of less than 1.0 using the
acute without food and 2.0 using the acute with food (Table 2). In the
second laboratory in side-by-side tests, the acute value was 0.25 ug/l with-
out food (Table 1) and 9.5 yg/l with food (Table 6). Because of the varia-
tion in hardness, and probably other water Quality characteristics, and the
results of acute and chronic tests in this laboratory, it seems inappropri-
ate to calculate an acute-chronic ratio for Daphnia magna from these data.
Davies, et al. (1978) conducted an 18-month study to evaluate the ef-
fects of silver nitrate on survival and growth of rainbow trout (Table 2).
The exposure was initiated with eyed embryos which hatched after 26 days.
Premature hatching occurred in silver concentrations of 0.69, 0.34, and 0.17
wg/l. After a 2-month exposure, the length of fish exposed to these three
high test concentrations was significantly (p-0.05) reduced. However, after
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three and one-half months of exposure only the length of the fish in the
high concentration was significantly (p=0.05) less than the length of con-
trol fish. At the termination of the exposure, survival of fish exposed to
0.09 ug/l was similar to the 79.9 percent survival of control fish. Mortal-
ity of fish exposed to 0.17 and 0.34 ug/l was 17.2 and 36.6 percent greater,
respectively, than mortality of control fish. The results of this chronic
test and the comparable acute tests produced an acute-chronic ratio of 54
for silver and rainbow trout.
Davies and Goettl (1978) also investigated the effects of silver iodide
on survival and growth of rainbow trout (Table 6). One toxicity test was
initiated with eyed embryos and lasted for 13 months. These embryos hatched
in eight days, and swim-up was completed in 17 days. Survival through swim-
up was similar in all silver concentrations and ranged from 95.3 to 91.5
percent. Control mortality was not reported because of initial overcrowding
of control tank. Mortality of post swim-up fry was 3.2 percent for the fish
exposed to 0.03 ug/l and was above 18 percent for concentrations of 0.06
ug/l and higher. At the termination of the study the mean length of fish in
all silver concentrations was not significantly (p=0.05) different from the
mean length of control fish. Earlier growth measurements were not reported.
Another toxicity test with silver iodide was initiated with green embry-
os, and the exposure was for 10 months (Table 6). Hatching was completed
after seven weeks and swim-up was completed in 12 weeks. At this time sur-
vival of embryos and sac fry at all test concentrations was similar to sur-
vival of control embryos and sac fry. However, survival after swim-up was
only 73.2 percent in the high concentration of 0.40 ug/l. Survival of fish
in silver concentrations of 0.18 ug/l and lower ranged from 96.4 to 98 per-
cent and was similar to the control fish survival of 97.6 percent. Growth
B-8
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of control fish and fish exposed to silver was not significantly different
(p-0.05) after 8 and 10 months. Earlier growth measurements were not
reported. The difference between the results of the two chronic tests on
silver iodide may have been due to embryonic acclimation to silver with the
longer exposure of the green embryos (Davies and Giettl, 1978). The dif-
ference may also have been just experimental variation.
The chronic values from these three chronic toxicity studies with rain-
bow trout using a similar dilution water and measured concentrations ranged
from 0.04 to 0.27 ,g/l. Two of the three tests were started with eyed em-
bryos, and both of these chronic values were lower than the chronic value
from the test in which fertilized embryos were placed immediately into the
exposure system. The length of exposure of the embryos to silver nitrate
was intermediate between the length of exposure of embryos in the two silver
iodide tests, and the chronic value in the silver nitrate test was interme-
diate between the two chronic values of the silver iodide tests.
Nebeker, et al. (Manuscript c), conducted an early life stage test for
90 days using rainbow (steelhead) trout. The chronic value of 12 ug/1 was
greater than the 96-hour LC5Q value (Table 1) that Nebeker, et al. (1980)
reported for flow-through tests using rainbow trout. In addition, this
chronic value was two orders of magnitude greater than the chronic values
reported by Davies, et al. (1978) and Davies and Goettl (1978) for rainbow
trout. No acute-chronic ratio was calculated from the results of this early
life stage test.
A chronic toxicity value of 18 ug/l for the saltwater mysid shrimp was
determined (Table 2) in a flow-through, life-cycle test (Lussier and Gen-
tile, 1980). In this experiment, groups of 20 juvenile shrimp were reared
in each of five silver concentrations for 58 days at 20°C and 30 g/kg salin-
B-9
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ity. Responses examined included time of appearance of first brood, time of
first spawn, mean brood size (larvae/female), growth of larvae, and survival
of first filial generation. No spawning occurred at 103 wg/l, and time of
spawning was delayed to seven days at 33.3 ug/l. Brood size was statistic-
ally (p<0.05) smaller at 33.3 wg/l as compared to controls. Larval survival
was unimpaired and was at least 95 percent in all treatments, and larval
growth was not retarded at any test concentration. The highest concentra-
tion of silver tested having no statistically significant effect on growth,
reproduction, or survival was 10 ug/l. The 96-hour LC5Q for this species
in the same study was 250 wg/l, and the acute-chronic ratio for this species
was 14.
Because of the variation in the results of chronic tests with rainbow
trout and the problem with determining an acute-chronic ratio for Daphnia
rcagna, neither a Final Acute-Chronic Ratio nor a Freshwater or Saltwater
Final Chronic Value can be determined for silver.
Plant Effects
Data on the toxicity of silver to 13 freshwater plant species are listed
in Table 4. The adverse effect concentrations range from 30 to 7,500 wg/l.
Even though these tests were conducted in various growth media and different
effects were measured, it appears that the adverse effects of silver on
plants are unlikely at concentrations which will not adversely affect fresh-
water animals.
Fitzgerald (1967) studied the effect of halides on the toxicity of sil-
ver. He compared the algistatic activity of silver nitrate on Chlorella py_-
renoidosa in the presence and absence of 12 mg/1 of sodium chloride, sodium
bromide, or sodium iodide. The results indicated that sodium chloride
caused a slight but consistent decrease in the toxicity of silver nitrate.
Sodium iodide caused the greatest decrease in toxicity of silver nitrate.
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This decrease in toxicity was related to the solubility of the silver
halide. The least soluble silver halide, silver iodide, was the least tox-
ic. He a'lso reported that both live and dead algae detoxified silver
nitrate.
Stokes, et al. (1973) found that 30 wg/l of silver inhibited the growth
of ChiorelIIa vulgaris. In addition, two species of green algae isolated
from small lakes which had high concentrations of heavy metals, especially
copper and nickel, had higher tolerances to silver than algae of the same
genus from the laboratory.
information on the sensitivity of saltwater plants to silver is limited
to the resuilts of one test showing a 50 percent reduction in chlorophyll a
production at 170 ug/l and a 50 percent decrease in cell number at 130 ug/l
(Table 4). These EC50 values are intermediate to the range of acute val-
ues for saltwater animals.
Residues
Three insect species have been exposed to silver nitrate (Nehring, 1973)
and bioconcentration factors that range from 15 to 240 were calculated from
the data (Table 5). Bluegills were exposed during a 28-day test, and the
bioconcentration factor was less than one (U.S. EPA, 1978).
No data are available concerning bioconcentration of silver by saltwater
species.
Miscellaneous
Birge, et al. (1978) examined the toxicity of 11 trace metals. Silver
was the most toxic to the embryos and larvae of both rainbow trout and
largemouth bass, with the trout being more sensitive than the bass. Renewal
exposure was maintained from fertilization through four days post-hatch.
The marbled salamander was less sensitive than either fish species.
B-ll
-------
Soyer (1963) reported reduced development in sea urchin embryos at 0.5
uci/1 after a 52-hours exposure (Table 6) and Calabrese, et al. (1973) found
100 percent mortality among American oyster larvae after a 2-day exposure to
10 ug/l. The lower concentration is much lower than the chronic value for
the; mysid shrimp. Also, summer glounder larvae are apparently more sen-
sitive than embryos, but the reverse may be true for winter flounder (Tables
1 aind 6).
Summary
Acute toxicity data for silver are available for 10 specie;; of fresh-
water animals from nine different taxonomic families that perform a wide
variety of community functions. The acute values range from 0.25 wg/l for
Daphnia magna to 4,500 yg/1 for the scud, Gammarus pseudolimnaeus . Fish are
inter-mediate in sensitivity with acute values that range from 3,.9 ug/l for
the fathead minnow in soft water to 280 ug/l for rainbow trout in hard water.
The data base indicates that acute toxicity of silver apparently de-
creases as hardness increases. Silver chloride seems to be much less toxic
than the very toxic silver nitrate. The relatively insoluble salts, silver
thiosulfate and silver sulfide, were the least toxic. On the other hand
silver iodide, when tested chronically at concentrations below its solubili-
ty limit, was as toxic as silver nitrate. Organic materials may also affect
the tcixicity of silver because the acute toxicity of silver nitrcite to Oaph-
rm magna when food was added to the water was much less than whven food was
not added to the water.
Foiur early life stage studies with the rainbow trout Indicate that
chronic toxicity may be influenced by the age of embryos with whiich the test
was started and perhaps by the genetic variety of the rainbow trout.
B-12
-------
Plants appear to be more resistant to silver than some animals, and thus
their well-being is assured if the more sensitive animals are protected.
The bioconcentration factors for silver range from less than one for blue-
gill to 240 for insect larvae.
Acute values for saltwater organisms ranged from 4.7 ug/1 for the summer
flounder to 1,400 ug/1 for the sheepshead minnow. A life-cycle toxicity
test conducted with the mysid shrimp showed that brood size was smaller at
33 ug/1 as compared to controls. The highest concentration tested which had
no statistically significant effect on reproduction and survival was 10
pg/l. One saltwater alga has been tested, and reduced cell numbers were
recorded at 130 vg/l. No information is available showing the influence of
environmental factors such as salinity, on toxicity of silver to saltwater
organisms.
CRITERIA
For freshwater aouatic life the concentration (in wg/l) of total recov-
erable silver should not exceed the numerical value given by
(1.72 [ln(hardness)l-6.52) at any time> For example, at hardnesses of
50, 100, and 200 mg/1 as CaC03, the concentration of total recoverable
silver should not exceed 1.2, 4.1, and 13 ug/l, respectively, at any time.
The available data indicate that chronic toxicity to freshwater aauatic life
may occur at concentrations as low as 0.12 yg/1.
For saltwater aquatic life the concentration of total recoverable silver
should not exceed 2.3 yg/l at any time. No data are available concerning
the chronic toxicity of silver to sensitive saltwater aauatic life.
B-13
-------
Table 1. Acute values for silver
Species
Method*
Hardness
(mg/l as
CaCO,)
Species Mean
LC50/EC50** Acute Value
(V.Q/1) (I1Q/I)
FRESHWATER SPECIES
Rot i f er,
Philodina acutlcornis
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
s.
s,
s,
s,
s.
s.
s.
s.
s.
s,
s.
s,
s,
s.
u
u
u
M
M
M
M
M
M
M
M
M
M
M
25
40
48
48
255
255
54
54
46
46
38
40
47
75
1,400
1.5
0.66
0.39
45
49
2.2
2.9
0.90
1.0
1.1
0.64
0.25
15
Reference
Bulkema, et al. 1974
U.S. EPA, 1978
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Chapman, et al.
Manuscript
Lemke, Manuscript
-------
Table 1. (Continued)
03
I
Species Method*
c. M
Cl adoceran, b« "
Daphnla magna_
FT M
Scud, M> M
Gammarus pseudol Imnaeus
FT M
Midge, M» M
Tanytarsus dlssimi Us
Rainbow trout, FT • M
Salmo qalrdnerl
Rainbow trout, ^ • M
Salmo gal rdner I
Rainbow trout, FT» M
Salmo gal rdner 1
Rainbow trout, FT« M
Salmo gai rdner i
Rainbow trout, n • M
Salmo gairdnerl
Rainbow trout, ^ • M
Salmo gal rdnerj
Rainbow trout, n> M
Salmo galrdnerl
Rainbow trout, s« M
Salmo galrdnerl
Rainbow trout, s»
Salmo gai rdner 1
Rainbow trout, ^ • M
^ajmg^ galrdnerl
Rainbow trout, FT» M
Salmo gal rdner I
Hardness Species Mean
, ° . irsn/FP^O** Acute Value
(2&)S M^ tua/D R«f«r«BC«
Q . _ Lemke, Manuscript
75 8*4
„ c«n - U.S. EPA, 1980a
48 4,500
48 3.200 - U-5' EPA' '98°a
n^ . . i nc fit a 1 • 19 / o
_ -_ ^ IJa V 1 t*5> • **l a i • i ^ • **•
31 5-3
, 0 _ Davies, et al. 1978
20 6-2
0 . _ Davies, et al. 1978
26 8- 1
., _ Davies, et al. 1978
T5Q 13
JJ\J
29 _ Hale, 1977
_ Lemke, Manuscript
48 '8
,, _ Lemke, Manuscript
48 16
on _ Lemke, Manuscript
48 20
_ Lemke, Manuscript
48 32
-.. _ Lemke, Manuscript
255 240
,,n _ Lemke, Manuscript
255 '70
-------
Table 1. (Continued)
03
I
M
cr\
Spec 1 es
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout,
Method*
S, M
S, M
FT, M
FT, M
S, M
S, M
FT, M
FT, M
S, M
S, M
FT, M
FT, M
FT, M
S, M
Hardness
(mg/l as
CaCOx)
255
255
54
54
54
54
46
46
46
46
29
35
42
40
LC50/EC50»*
(lig/l)
240
280
14
12
48
54
6.9
8.4
12
110
7.6
8.5
9.7
73
Species Mean
Acute Value
(ug/l) Reference
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Nebeker, et al.
Manuscript b
Lemke, Manuscript
Lemke, Manuscript
- Lemke. Mannirrln-*-
-------
Table 1. (Continued)
03
I
Species
Rainbow trout,
Salmo qairdnerl
Rainbow trout.
Salmo gairdnerl
Rainbow trout.
Salmo cjairdner 1
Rainbow trout.
Salmo qalrdneri
Rainbow trout.
Salmo qalrdnerl
Rainbow trout,
Salmo flairdnerl
Fathead minnow.
PImephales promelas
Fathead minnow,
PImephales promelas
Fathead minnow.
PImephales promelas
Fathead minnow.
Pimephales promelas
Fathead minnow,
PImephales promelas
Fathead minnow,
PImephales promelas
Fathead minnow,
PImephales promelas
Fathead minnow,
PImephales promelas
Method*
I_B^_H_H^^_
S, M
S, M
FT, M
FT, M
S, M
S, M
FT, M
FT, M
FT, M
FT, M
FT, M
S, M
S, M
FT, M
Hardness
(mg/l as
CaCCK)
•j-j
37
26
75
75
75
Ij
48
33
274
48
48
48
48
255
Species Mean
LC50/EC50«« Acute Value
(uq/l) Reference
OA - Lemke, Manuscript
OH
tt - Nebeker, et al.
Manuscript b
115 - Lemke, Manuscript
*
10 - Lemke, Manuscript
05 - Lemke, Manuscript
22 5 - Lemke, Manuscript
*
11 - U.S. EPA, 1980a
1 1 *
TQ - Goettl & Davies, 1978
Je y
A o _ Goettl & Davies, 1978
*r« O
,i - Lemke, Manuscript
11 *
10 - Lemke, Manuscript
1 £
30 - Lemke, Manuscript
23 - Lemke, Manuscript
]50 - Lemke, Manuscript
-------
Table 1. (Continued)
01
I
H
oo
Species
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
n i i i__ i
Method*
FT, M
S, M
S, M
FT, M
S, M
S, M
FT, M
FT, M
S, M
S, M
FT, M
FT, M
FT, M
S, M
Hardness
(wg/l as
CaCO})
255
255
255
54
54
54
46
46
46
46
38
40
36
25
LC50/EC50**
(vg/l)
HO
230
270
11
14
20
5.3
3.9
6.7
12
5.8
5.6
7.4
12
Species Mean
Acute Value
(WQ/I) Reference
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Lemke, Manuscript
Nebeker, et al.
Manuscript b
~ Lemke. Mannsnrint
-------
Table 1. (Continued)
DO
I
Species
Fathead minnow.
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow.
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Speckled dace.
Rhlnichthys osculus
Speckled dace,
Rhinichthys osculus
Flagfish,
Jordanel la f lorldae
Bluegi 1 1,
Lepomis macrochlrus
Mottled sculpin,
Cottus bairdl
Mottled sculpin,
Method*
S, M
FT, M
FT, M
S, M
S, M
FT, M
FT, M
FT, M
FT, M
S, U
FT, M
FT, M
Hardness
(mg/l as
CaCOO
39
75
75
75
75
38
30
250
48
40
30
250
Species Mean
LC50/EC50** Acute Value
t^/ii (ua/D Reference
07 - Lemke, Manuscript
y . f *
f. -, - Lemke, Manuscript
O. J '
50 - Lemke, Manuscript
*
,n _ Lemke, Manuscript
B7 _ Lemke, Manuscript
O. / *
,6 _ EG&G Bionomics, 1979
. a - Goettl & Davles, 1978
"• y
14 - Goettl & Davles, 1978
9>6 - U.S. EPA, 1980a
M - U.S. EPA, 1980a
53 _ Goettl i Davies, 1978
,, - Goettl i Davies, 1978
IH
Cottus bairdi
-------
Table 1. (Continued)
03
I
N)
O
Species
Bay scallop (juvenile),
Argopecten Irradlans
American oyster,
Crassostrea vlrglnica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
American oyster,
Crassostrea virginica
Hard she 1 1 clam,
Mercenarla mercenarla
Copepod (adult),
Acartia tonsa
Mysid shrimp (juvenile),
Mysldopsls bah la
At 1 ant Ic s i 1 vers I des
( juveni le),
Men Id! a menidia
Atlantic silvers Ides
(larva),
Menidia menidia
Summer flounder (larva),
Paralichthys dentatus
Sheepshead minnow
Hardness
lag/I as LC50/EC50»«
Method* CaC03)
-------
CO
I
to
Table 1. (Continued)
Species
Fourspine stickleback
(adult),
Apeltes quadracus
Winter flounder (larva),
PseudopIeuronectes
amerIcanus
Hardness
(mg/l as
CaCOQ
s, u
LC50/EC50»»
(ug/D
550
500
Species Mean
Acute Value
Jug/I)
550
500
Reference
U.S. EPA, 1980b
U.S. EPA, 1980b
* S = static, FT = flow-through, U = unmeasured, M = measured
«»AII freshwater and saltwater acute toxlclty data were derived with silver nitrate and all
results are expressed as silver, not as the compound.
Freshwater:
Acute toxlclty vs. hardness (see text)
Daphnla magna; slope = 2.35, Intercept = -8.85. r = 0.89, P = 0.01, N = 14
Rainbow trout: slope = 1.30, Intercept = -2.08, r = 0.75, P = 0.01, N = 30
Fathead minnow: slope = 1.50, Intercept = -3.52, r = 0.83, P = 0.01. N = 28
Arithmetic mean acute slope =1.72
-------
Table 2. Chronic values for silver
Species
Test*
Chemical
Hardness
(mg/l as Units
CaCOQ (ug/l)«»
Chronic Value
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Rainbow trout,
Salmo galrdneri
Rainbow trout,
(steel head).
Salmo galrdneri
Mysid shrimp,
Mysidopsis bah la
FRESHWATER SPECIES
LC Silver nitrate 60 1.6-4.1
LC Silver nitrate 75 8.8-19.4
LC Silver nitrate 180 3.4-8.0
LC Silver nitrate 48 2.7-3.9
LC Silver nitrate 70 10.5-21.2
LC Silver nitrate 70 19.8-41.2
ELS Silver nitrate 28 0.09-0.17
ELS Silver nitrate 37 8.9-15.9
SALTWATER SPECIES
LC Silver nitrate - 10-33
• KM/ t» noinrence
2.6 Nebeker, et al.
Manuscript b
13 Nebeker, et al.
Manuscript b
5.2 Nebeker, et al.
Manuscript b
3.2 Nebeker, et al.
Manuscript a
15 Nebeker, et al.
Manuscript a
29 Nebeker, et al.
Manuscript a
0.12 Davles, et al. 1978
12 Nebeker, et al.
Manuscript c
18 Lussler & Genti le,
1980
LC = life cycle or partial life cycle; ELS = early life stage
**Results are expressed as silver, not as the compound
-------
Table 2. (Continued)
Acute-Chronic Ratios
Acute Value Chronic Value
(Ua/|) (ug/l) Ratio
Cladoceran, 43» 22**
SI Iver Nitrate
43»
Daphnla magna
Rainbow trout, 6.$*** °-12 54
Sal mo galrdnerl
Mysld shrinp, 250 18 M
Mysldopsls bah I a
* Result of acute test with food added to test solutions (Table 6).
** Arithmetic mean of 15 and 29 ug/l (Table 2).
"""Arithmetic mean of 5.3, 6.2 and 8.1 ug/l (Table 1)
-------
ca
i
to
Table 3. Species Mean acute Intercepts, values, and acute-chronic
ratios for si Ivor
Rank* Species
10
Species Mean Species Mean
Acute Intercept Acute-Chronic
(ug/l)
SALTWATER SPECIES
Sheep she ad minnow,
Cyprlnodon varlegatus
1,400
Ratio
10
9
8
7
6
5
4
3
2
1
tank*
FRESHWATER
Scud,
Gammarus pseudol Imnaeus
Rotifer,
Philodina acuticornis
Midge,
Tanytarsus dissimi 1 is
Bluegill,
Lepomis macrochirus
Rainbow trout,
Sal mo galrdneri
Mottled sculpln,
Cottus bairdi
Speckled dace,
Rhlnlchthys osculus
Flagfish,
Jordanella f lor Ida
Fathead minnow,
Plmephales promelas
Cladoceran,
Daphnla magna
Species
SPECIES
5.77
5.52
4.11
0.112
0.0230
0.015
0.014
0.0123
0.0121
0.00192
Species Mean
Acute Value
(ua/l)
54
2.0
Species Mean
Acute-Chronic
Ratio
-------
Table 3. (Continued)
CO
I
ro
un
Rank*
9
8
7
6
5
4
3
2
I
Species Mean Species Mean
Acute Value Acute-Chronic
Species (uq/l) Ratio
Foursplne stickleback,
Apeltes quadracus
Winter flounder,
Pseudop 1 euronectes amer 1 canus
Mysld shrimp,
Mysldopsls bahia
Atlantic sllversldes.
Men id la men id la
Copepod,
Acartla tonsa
Bay seal lop,
Arqopecten Irradlans
Hard she! 1 clam,
Mercenarla mercenarla
American oyster,
Crassostrea virgin lea
Summer flounder,
Parallchthys dentatus
550
500
250 14
210
36
33
21
20
4.7
* Ranked from least sensitive to most sensitive based on species mean
acute Intercept or species mean acute value.
Freshwater:
Final Acute Intercept = 0.00147 ug/l
Natural logarithm of 0.00147 = -6.52
Acute slope = 1.72 (see Table 1)
Final Acute Equation = e< 1.721 In(hardness) 1-6.52)
Saltwater Final Acute Value = 2.28 ug/l
-------
Table 4. Plant values for silver
CD
I
to
Species
Alga (green),
Ch lore! la fusca
Alga (green).
Chloral la fusca
Alga (green),
Chi orel la pyrenoldosa
Alga (green),
Ch 1 ore 1 1 a py reno 1 dosa
Alga (green),
Chi ore Ha variegata
A 1 ga ( green ) ,
Chlorel la vulgar Is
Alga (green),
Chlorel la vulqarls
Alga (green),
Scenedesmus acumlnatus
Alga (green),
Scenedesmus acut 1 formis
Alga (green),
Scenedesmus obi Iquus
Alga (green),
Scenedesmus obi Iquus
Alga (diatom),
Gomphonema parvulum
Effect
FRESHWATER SPECIES
Complete Inhibition
of growth
Inhibition of
growth
Inhibition of
growth
Letha 1
Toxic
Inhibition of
growth
Inhibitor! of
growth
Complete inhibition
of growth
Complete Inhibition
of growth
Toxic
Threshold toxlclty
Toxic
Result*
(ug/l)
100**
50**
100
1,000
420
50**
30**
100**
200**
420
50
420
Reference
Stokes, et al. 1973
Stokes, et al. 1973
Fitzgerald, 1967
Fitzgerald, 1967
Palmer & Maloney,
1955
Hutch inson &
Stokes, 1975
Stokes, et al. 1973
Stokes, et al. 1973
Stokes, et al. 1973
Palmer & Maloney,
1955
Bringman & Kuhn,
1959
Palmer & Maloney,
1955
Alga (diatom),
Nltzschla palea
Toxic
420
Palmer & Maloney,
1955
-------
Table 4. (Continued)
I
to
Species
Alga (blue-green),
Cyl Indrospermum
1 1 chen 1 forme
Alga (blue-green),
Microcystis aeruglnosa
Water weed.
El odea canadensis
Water weed.
El odea canadensis
Duckweed,
Lemna minor
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Effect
Toxic
Toxic
Inhibition of
oxygen evolution
Phytotoxiclty
Phytotoxicity
SALTWATER SPECIES
96-hr EC50,
chlorophyll a
96-hr EC50,
eel 1 numbers
Result*
(iig/l)
420
420
too
7,500
270
170
130
Reference
Palmer & Maloney,
1955
Palmer & Maloney,
1955
Brown & Rattlgan,
1979
Brown & Rattlgan,
1979
Brown & Rattlgan,
1979
U.S. EPA, 1978
U.S. EPA, 1978
* All freshwater and saltwater plant values were derived with silver nitrate
except where Indicated and all results are expressed as silver, not as
the compound.
"•Authors did not specify sliver compound.
-------
03
I
N)
GO
Species TIssue
Table 5. Residues* for silver
Hardness
(mg/l as Bloconcentratlon
CaCOx) factor
FRESHWATER SPECIES
Mayfly, Whole body 62
Ephemerella grand is
Mayfly, Whole body 65
Ephemerella grand Is
Stonefly. Whole body 34
Claasenla sabulosa
StonefIy. Whole body 32
Pteronarcys calIfornica
Stonef ly. Whole body 31
Pteronarcys ca11fornIca
Stonefly, Whole body 30
Pteronarcys calIfornica
Bluegi11, Whole body
Lepomls macrochirus
35**
240**
15**
21**
170**
79**
<1
Duration
(days) Reference
7 Nehrlng, 1973
10 NehrJng, 1973
3 Nehrlng, 1973
6 Nehrlng, 1973
7 Nehrlng, 1973
15 Nehring, 1973
28 U.S. EPA, 1978
* All results were derived with silver nitrate.
**Bioconcentration factors have bean converted from dry weight to wet weight.
-------
Table 6. Other data for si Ivor
Species
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Mayfly,
Ephemerel la grand is
Mayfly,
Ephemerel la grand is
Stonef ly,
m Pteronarcys ca 1 i f orn 1 ica
1
NJ Rainbow trout,
^° Salmo galrdnerl
Rainbow trout
(eyed embryos),
Salmo galrdnerl
Rainbow trout
(green embryos),
Salmo galrdnerl
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
Hardness
(«9/l as
274
47
70
31
30
65
93-105
28
29
38
38
38
Duration
FRESHWATER
24 hrs
48 hrs
48 hrs
7 days
15 days
10 days
28 days
13 mos
10 mos
96 hrs
96 hrs
96 hrs
Effect
SPECIES
LC50
LC50**
LC50**
LC50
LC50
LC50
LC50
Chronic
limits***
Chronic
limits***
100? mortal Ity
(si Iver thlo-
su 1 fate)
No morta 1 i ty
(si Iver sul-
flde gel)
No mortal ity
(si Iver su 1-
fide)
Result*
-------
Table 6. (Continued)
Species
Fathead minnow,
Pltnephales promelas
Fathead minnow,
Plmephales promelas
Fathead minnow.
Plmephales promelas
Fathead minnow,
Plmephales promelas
Bluegl II,
Lepomis macrochirus
Largemouth bass.
Mlcropterus sal mo Ides
Largemouth bass.
'•J3 Mlcropterus sal mo ides
OJ
o Marbled salamander.
Ambystoma opacum
Red alga (sporl Ing),
Plumarla elegans
Bay scallop (juvenile),
Argopecten Irradians
American oyster (larva),
Crassostrea virgin lea
American oyster (larva).
Crassostrea vlrglnica
American oyster,
Crassostrea virginica
Hardness
(mg/l as
CaCOO Duration
38 96 hrs
38 96 hrs
38 96 hrs
131 96 hrs
180 6 mos
93-105 8 days
180 24 hrs
93-105 8 days
SALTWATER
18 hrs
4 days
2 days
12 days
4 days
Effect
LC50 (2,000 mg
cr/D
LC50 (1,000 mg
cr/i)
LC50 (500 mg
Cl~/l)
LC50 (silver
thlosulfate)
To 1 erated
LC50
Letha 1
LC50
SPECIES
98% mortality
15$ Increased
02 uptake
100$ mortal Ity
50$ mortal Ity
Significant
Increase In
Result*
(ug/l)
5,600
510
2,100
> 250, 000
70
110
70
240
1,000
22
10
25
100
Reference
EG&G Bionomics, 1979
EG&G Bionomics, 1979
EG&G Bionomics, 1979
Terhaar, et al. 1972
Co Ionian & Gear ley, 1974
Blrge, et al. 1978
Coleman & Gear ley, 1974
Blrge, et al. 1978
Boney, et al. 1959
Nelson, et al. 1976
Calabrese, et al. 1973
Calabrese, et al. 1977
Thurberg, et al. 1974
oxygen consumpt Ion
-------
Table 6. (Continued)
Hardness
(mg/l as
Species CaCO^)
Hard-she 1 1 clam,
Mercenarla mercenaria
Hard-shell clam,
Mercenarla mercenaria
Hard-shell clam (larva),
Mercenaria mercenaria
Soft-shell clam,
Mya arenaria
Blue mussel,
Mytilus edulis
jp Mud snal 1,
I Nassarius obsoletus
OJ
1-1 Mud snai 1,
Nassarius obsoletus
Surf clam (larva),
Spisula sol Idissima
Surf clam (Juvenile),
Spisu la sol idissima
Surf clam (adult),
Spisula sol idissima
Common barnacle (adult),
Balanus balanoides
Common barnacle (adult).
Duration
2 days
4 days
10 days
4 days
4 days
3 days
3 days
15 days
4 days
4 days
2 days
5 days
Result*
Effect (ug/l)
100* mortality 45
Significant 100
Increase in
oxygen consumption
LC50 32
Significant 100
increase in
oxygen consumption
Significant 100
Increase in
oxygen consumpt Ion
Depression of 500
oxygen consumption
Distressed beha- 250
vior, snail unable
to move
Significant 50
Increase in
oxygen consumption
Significant 10
increase In
oxygen consumpt ion
Significant 50
increase in
oxygen consumption
90* mortality 400
90* mortal ity 200
Reference
Calabrese & Nelson,
1974
Thurberg, et al. 1974
Calabrese, et al. 1977
Thurberg, et al. 1974
Thurberg, et al. 1974
Maclnnes 4 Thurberg,
1973
Maclnnes & Thurberg,
1973
Thurberg, et al. 1975
Thurberg, et al. 1975
Thurberg, et al. 1975
Clarke, 1947
Clarke, 1947
Balanus balanoides
-------
Table 6. (Continued)
Hardness
(mg/l as
Species CaC03)
Sea urch In,
Arbacia llxula
Mummichog (adult),
Fundulus heteroclltus
Mummichog (adult),
Fundulus heteroclltus
Gunner,
Tautogolabrus adspersus
Gunner,
Tautogolabrus adspersus
tn a t
1
U)
K)
Summer flounder (embryo),
Parallchthys dentatus
Summer flounder (embryo),
Para 1 1 chthys dentatus
Summer flounder (embryo),
Parallchthys dentatus
Summer flounder (embryo),
Para 1 1 chthys dentatus
Winter flounder (embryo),
Pseudop leuronectes
Duration
52 hrs
4 days
2 days
4 days
4 days
96 hrs
96 hrs
96 hrs
96 hrs
96 hrs
Effect
Reduced embryo
development
significantly
In vivo Inhlbl-
TTbn of 3 liver
enzymes
Degeneration of
lateral line and
ol factory sensory
structure
Significant
depression of
oxygen consumpt Ion
Decreased oxygen
consumpt Ion
depressed activity
of a 1 1 ver enzyme
LC50
LC50
LC50
LC50
LC50
Result*
(ug/l)
0.5
30
500
120
500
140
8.0
16
48
450
Reference
Soyer, 1963
Jacklm, et al. 1970
Gardner, 1975
Thurberg & Collier,
1977
Gould & Maclnnes, 1977
U.S. EPA, 1980b
U.S. EPA, 1980b
U.S. EPA, 1980b
U.S. EPA, 1980b
U.S. EPA, 1980b
amerlcanus
-------
Table 6. (Continued)
Hardness
(mg/l as
Species CaCO,) Duration Effect
Winter flounder (embryo), - 96 hrs LC50
Pseudop leuronectes
amer i canus
Winter flounder (embryo), - 96 hrs LC50
Pseudop leuronectes
amer I canus
Winter flounder (embryo), - 96 hrs LC50
Pseudop 1 euronectes
amer lean us
Result*
(uq/lj
300
270
200
Reference
U.S. EPA, 1980b
U.S. EPA, 19606
U.S. EPA, 1980b
* All freshwater and saltwater data were derived with silver nitrate except where indicated and all results
are expressed as si Iver, not as the compound.
** Animals were fed during test.
I ***Tests on stiver iodide.
OJ
-------
REFERENCES
Birge, W.J., et al. 1978. Embryo-larval Bioassays on Inorganic Coal Ele-
ments and in situ Biomonitoring of Coal-waste Effluents. In: D.E. Samuel,
et al. (eds.), Surface Mining and Fish/Wildlife Needs in the Eastern United
States. U.S. Dept. Int. Fish Wild!. Serv., FWS/OBS-78/81, Dec. 1978. p. 97.
Boney, A.D., et al. 1959. The effects of various poisons on the growth and
viability of sporelings of the red alga P1umar i a elegans (Bonnem.) Schm.
Biochem. Pharmacol. 2: 37.
Bringmann, G. and R. Kuhn. 1959. Comparative water-toxicology investiga-
tions on bacteria, algae, and daphnids. Ges. Ind. 80: 115.
Bringmann, V.G. and R. Kuhn. 1977. Report on the damaging action of water
pollutants on Daphnia magna. Wass. Abwass-Forsch. 10. 5: 161.
Brown, B.T. and B.M. Rattigan. 1979. Toxicity of soluble copper and other
metal ions to Elodea canadensis. Environ. Pollut. 20: 303.
Buikema, A.L., Jr., et al. 1974. Evaluation of Philodina acuticornis
(Rotifera) as a bioassay organism for heavy metals. Water Res. Bull.
10: 648.
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Calabrese, A. and D.A. Nelson. 1974. Inhibition of embryonic development
of the hard clam Mercenaria mercenaria by heavy metals. Bull. Environ. Con-
tarn. Toxicol. 11: 92.
Calabrese, A., et al. 1973. The toxicity of heavy metals to the embryos of
the American oyster (Crassostrea virginica). Mar. Biol. 18: 162.
Calabrese, A., et al. 1977. Effects of cadmium, mercury and silver on
marine animals. Mar. Fish. Rev. 39: 5.
Chambers, C.W. and C.M. Proctor. 1960. The bacteriological and chemical
behavior of silver in low concentrations. U.S. Dept. Health, Edu. and Wel-
fare. PHS Tech. Rep. W60-4. p. 1.
Chapman, G.A., et al. Effects of water hardness on the toxicity of metals
to Daphnia magna. Status Report. U.S. Environ. Prot. Agency, Corvallis,
Oregon. (Manuscript)
Clarke, G.L. 1947. Poisoning and recovery in barnacles and mussels. Biol.
Bull. 92: 73.
Coleman, R.L. and J. Cearley. 1974. Silver toxicity and accumulation in
largemouth bass and bluegill. Bull. Environ. Contam. Toxicol. 12: 53.
B-35
-------
Davies, P.H. and J.P. Goettl, Jr. 1978. Evaluation of the Potential Im-
pacts of Silver and/or Silver Iodide on Rainbow Trout in Laboratory and High
Mountain Lake Environments. _In_: D.A. Klein (ed.), Environmental Impacts of
Artificial Ice Nucleating Agents. Oowden, Hutchinson and Ross, Inc.,
Stroudsburg, Pennsylvania, p. 149.
Davies, P.M., et al. 1978. Toxicity of silver to rainbow trout (Salmo
gairdneri). Water Res. 12: 113.
Dyck, W. 1968. Adsorption and coprecipitation of silver on hydrous ferric
oxides. Can. Jour. Chem. 46: 1441.
EG&G Bionomics. 1979. The acute toxicity of various silver compounds to
the fathead minnow (Pimephales promelas). Nat!. Assoc. Photo. Manu., Inc.,
Harrison, New York. p. 1, Tables 1-30, Appendix I-IV.
Fitzgerald, G.P. 1967. The algistatic properties of silver. Water Sew.
Works. 114: 185.
Gardner, G.R. 1975. Chemically Induced Lesions in Estuarine or Marine Tel-
eosts. In: W.E. Ribeline and G. Migaki (eds.), The Pathology of Fishes.
Univ. Wisconsin Press, Madison, Wisconsin, p. 657.
Goettl, J.P., Jr. and P.H. Davies. 1978. Water pollution studies. Job 6.
Study of the effects of metallic ions on fish and aquatic organisms. Job
Progress Rep. Fed. Aid Proj. F-33-R-13. Colorado Div. Wild!, p. 6.
B-36
-------
Gould, E. and J.R. Maclnnes. 1977. Short-term effects of two silver salts
on tissue respiration and enzyme activity in the cunner (Tautoqalabrus ad-
spersus). Bull. Environ. Contam. Toxicol. 18: 401.
Hale, J.6. 1977. Toxicity of metal mining wastes. Bull. Environ. Contam.
Toxicol. 17: 66.
Hem, J.D. 1970. Study and interpretation of the chemical characteristics
of natural waters. U.S. Geol. Surv. Water-Supply Pap. 1473. Washington,
D.C. p. 202.
Hutchinson, T.C. and P.M. Stokes. 1975. Heavy metal toxicity and algal bi-
oassays. Water Quality Parameters. ASTM SPT 573: 320.
Jackim, E., et al. 1970. Effects of metal poisoning on five liver enzymes
in the killifish (Fundulus heteroclitus). Jour. Fish. Res. Board Can.
27: 383.
Kharkar, D.P., et al. 1968. Stream supply of dissolved silver, molybdenum,
antimony, selenium, chromium, cobalt, rubidium, and cesium to the oceans.
Geochim. Cosmochim. Acta. 32: 285.
Lemke, A.E. Comprehensive report - Inter!aboratory comparison: acute
testing set. (Manuscript).
R-37
-------
Lussier, S.L. and J.H. Gentile. Chronic toxicity of copper and silver to
the mysid shrimp Mysidopsis bahia. U.S. Environ. Prot Agency, Environ.
Res. Lab., Narragansett, Rhode Island. (Manuscript)
Maclnnes, J.R. and A. Calabrese. 1978. Responses of Embryos of the Ameri-
can Oyster Crassostrea virginica to Heavy Metals at Different Temperatures.
ITK D.S. Mclusky and A.J. Berry (eds.), Physiology and Behavior of Marine
Organisms. Proc. 12th European Symp. on Marine Biol. p. 195.
Maclnnes, J.R. and P.P. Thurberg. 1973. Effects of metals on the behavior
and oxygen consumption of the mud snail. Mar. Pollut. Bull. 4: 185.
Nebeker, A.V., et al. Toxicity of silver and endosulfan to rainbow trout,
fathead minnow, and Daphnia magna. (Manuscript a)
Nebeker, A.V., et al. Daphnia magna static renewal life cycle tests.
Final report of round-robin testing. U.S. Environ. Prot. Agency. (Manu-
script b)
Nebeker, A.V., et al. Sensitivity of steelhead early life stages (embryo-
larval) to silver nitrate. (Manuscript c)
Nehring, R.B. 1973. Heavy metal toxicity in two species of aquatic in-
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Nehring, R.B. 1976. Aquatic insects as biological monitors of heavy metal
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B-38
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Nelson, D.A., et al. 1976. Biological effects of heavy metals on juvenile
bay scallops, Argopecten irradians, in short-term exposures. Bull. Environ.
Contam. Toxicol. 16: 275.
Palmer, C.M. and I.E. Maloney. 1955. Preliminary screening for potential
algicides. Ohio Jour. Sci. 55: 1.
Soyer, J. 1963. Contribution a 1'etude des effects biologiques du mercure
et de 1'argent dans Teau de mer. Vie et Milieu. 14: 1.
Stokes, P.M., et al. 1973. Heavy metal tolerance in algae isolated from
polluted lakes near the Sudbury, Ontario smelters. Water Pollut. Res. Can.
8: 178.
Terhaar, G.J., et al. 1972. Toxicity of photographic processing chemicals
to fish. Photographic Sci. Engr. 16: 370.
Thurberg, P.P. and R.S. Collier. 1977. Respiratory response of cunners to
silver. Mar. Pollut. Bull. 8: 40.
Thurberg, P.P., et al. 1974. Effects of Silver on Oxygen Consumption of
Bivalves at Various Salinities. _In_: F.J. Vernberg and W.B. Vernberg (eds.),
Pollution and Physiology of Marine Organisms. Academic Press, New York.
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B-39
-------
Th'urberg, P.P., et al. 1975. Respiratory Response of Larval, Juvenile, and
Adult Surf Clams, Spisula solidissima, to Silver. _T£: J-J* Cech, Jr., et
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Maine, p. 41.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
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ragansett, Rhode Island.
R-40
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Silver is a frequent contaminant of normal human tissues, gen-
erally at < 1 mg/kg in the ash (Tipton and Cook, 1963). For an
extensive tabulation of silver concentrations in the tissues of
normal individuals, disease victims, and people with argyria, see
Smith and Carson (1977). Anspaugh, et al. (1971) of Lawrence
Livermore Laboratory have also compiled data from the published
literature on the silver content of human tissues. Most reported
values have been based on ash weight or dry weight and are rather
difficult to compare since analytical procedures at such low con-
centrations vary in their accuracies. Data in Table 1, adapted
from Hamilton, et al. (1972/1973), however, seems to be in agree-
ment with most reports.
Silver concentrations in human tissues apparently increase
with age. It has been detected, however, in human placentae (Mis-
chel, 1956) and fetal livers (Robkin, et al. 1973). Absorption
upon exposure or the extent of exposure, itself, may vary consider-
ably among normals as reflected in tissue levels. For example, the
silver content of the hair of school children from 21 school dis-
tricts in Silesia, Poland, ranged from 0.23 to 1.96 mg/kg (average
0.69 mg/kg; analysis by neutron activation) (Dutkiewicz, et al.
1978).
Ingestion from Water
Natural fresh waters contain an average of 0.2 ug/1 silver,
and seawater contains 0.24 ug/1 (Boyle, 1968). Water-analysis data
from many literature sources have been combined in Table 2.
C-l
-------
TABLE 1
Silver Content in Healthy Human Tissues in the United Kingdom*
Blood (U.K. Master Mix)
Blood (U.K.)
Whole brain
Frontal lobe
Basal ganglia
Whole kidney
Cortex
Medulla
Liver
Lung
Lymph nodes
Muscle
Testis
Ovary
Bone (rib) from patient who
lived in:
Hard water area
Soft water area
No.
93
10
2
2
8
8
8
11
11
6
6
5
6
22
22
Ag, ug/g Wet wt.
0.01 + 0.005
0.008 + 0.0008
0.004 + 0.002
0.003 + 0.001
0.004 + 0.002
0.002 + 0.0002
0.001 + 0.0002
0.002 + 0.0002
0.006 + 0.002
0.002 + 0.0001
0.001 + 0.0002
0.002 + 0.0005
0.002 + 0.0004
0.002 + 0.0005
1.1 + 0.2 (ash)
1.1 + 0.2 (ash)
*Source: Hamilton, et al. 1972/1973
C-2
-------
TABLE 2
Silver in Natural U.S. Waters
Detection
Type of Water pH Frequency
Rainfall
Precipitation 0 0
Precipitation
(Agl seeded)
Snowfall
(Agl seeded)
Freshwater -
Springs and surface
freshwaters
Hot springs
SO,, NaCl, 5.3-9.1 0
O HCt>3-, borate, sul-
' fate carbonate
Steam yelh NaCl,
CaCl , KC1
Spring and
well waters - 36 %
Desert well brines - 50 %
Oil well brines
Vadotje mine
waters: SiO2, Acid
Mg, Fe, Al, Ca, Cu,
Mn, SO.
Deep mine
waters: sul- Alkaline
fate, carbonate to neutral
Ag Content (ppb)
0.002-0.216
0.02
0.001-4.5
0.11 (0.13 neutron
activation anal)
0.01-0.7
0.13
0.2
up to 43,000 in
siliceous
100-300 in water
up to 13,000,000
in residue
10
10
0.1
207
3.3
Location
St. Louis, Missouri
-
-
-
—
All
Sbea m boat Springs,
Nevada
Niland, California
Near Salion Sea,
California
California
Comstock Lode,
Nevada
Comstock Lode,
Nevada
Remarks
Typically 0.01-0.3
ppbAg
Widely diffused, marked
regional variations.
Surface waters usually have
less Ag than springs
Geothermal brines have
higher concn. of Ag and
other trace metals than
municipal or industrial waste-
waters. Two of these samples
had Ag content in excess of
drinking water standards.
Temperature,
116-170°F
Reference
Rattonetti, 1974
Cooper & Jolly, 1969
War burton, 1969
Hawkes & Webb, 1962
Bowen, 1966
Boyle, 1968
Boyle, 1968
Boyle, 1968
Bradford, 1971
Boyle, 1968
Boyle, 1968
Boyle, 1968
-------
TABLE 2 (Continued)
Type of Water
Sea water
Detection
pH Frequency Ag Content (ppb) Location
0.15-2.9 (0.29) A31
average
Remarks
Run-off is of minor impor-
tance. Like Ba, Ag concen-
trates with increasing depth
and in areas of high organic
productivity. May be less
concentrated near shores.
Reference
o
I
Sea water
Seawater
Sea water
Seawater
Lakes
Lakes
Lake, ground,
and Ottawa
River water
Agricultural
drainage
Lakes
Lakes, streams,
and rivers
86%
100%
33%
0.3
0.16
0.145
0.15-0.3
0.1-3.5
0.1 (average)
6.0 (maximum)
0.006-0.7
0.8 (1.0 maximum)
10
10-200
(in residues)
Gulf of Mexico
40 miles west of
San Francisco
Maine
California
Near Chalk River
Nuclear Laboratory
Coachella Valley,
California
Near Sudbury,
Ontario
U.S.
Samples collected
from 170 High
Sierra Lakes.
After 60 years of
copper smelting
Lanford, 1969
Bowen, 1966
Boyle, 1968
Boyle, 1968
Boyle, 1968
Bradford, et aL 1968
Merritt, 1971
Bradford, 1971
Stokes, et aL 1973
Boyle, 1968
-------
TABLE 2 (Continued)
n
I
en
Type of Water
Surface waters
Stream water
Rivers
Large rivers
U .S. river basins
Detection
pH Frequency
22.4 %
6.6%
Ag Content (ppb)
0.10-3.0
(0.3 average)
0.00006-0.0062
up to 1.0
0-0.94
2.6 (38 maximum)
Location
California
St. Louis, Missouri
N. America & Norway
North America
U.S.
Remarks
Reference
Myers, et aL 1958
Detection limits for
Klein, 1972
Boyle, 1968
Boyle, 1968
Kopp & Kroner,
Page, 1974
1970
Northeast
River Basin
St. Lawrence River
Hudson River
North Atlantic
River Basin
Delaware River
Delaware River
Susquehanna River
Susquehanna River
Southeast
River Basin
Apalachicola River
Mobile River
Neuse River
Neuse
Neuse
Neuse
Neuse
Neuse
Neuse
River
River
River
River
River
River
14.3% 1.9 (6.0 maximum)
29.6% 2.6 (6.0 maximum)
0.13-0.59
5.3% 0.9 (2.5 maximum)
11.1% 1.1 (8.2 maximum)
7.03% 3
0-0.29
0.39
5.5% 0.4 (0.7 maximum)
0.058-0.11
0.085-0.28
0.52
0.56
0.25
0.86
0.30
0.37 (average)
Northeastern U.S.
Massena, New York
Green Island,
New York
O.S.
Trenton, NJ
Conowingo, MD
U.S.
Near Bloustown,
Florida
Mt. Vemon Landing,
Alabama
North Carolina
Kopp & Kroner were ppb.
Includes New Jersey
North
North
North
North
North
North
Carolina
Carolina
Carolina
Carolina
Carolina
Carolina
Groundwater
lithology:
Slate
Shale
Granite
Shale and schist
Cretaceous sand
Tertiary lime
Standard deviation =
49 based on samples
taken at 25 locations.
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Durum & Haffty, 1961
Kopp & Kroner, 1970
Kopp 8. Kroner, 1970
Kopp {. Kroner, 1967
Durum & Haffty, 1961
Andelman, 1973
Kopp & Kroner, 1970
Durum & Haffty, 1961
Andelman, 1973
Andelman, 1973
Andelman, 1973
Andelman, 1973
Andelman, 1973
Andelman, 1973
Andelman, 1973
-------
TABLE 2 (Continued)
O
Type of Water pH
Tennessee
River Basin
Ohio River Basin
Youghiogheny River
Kiskimintas River
Allegheny River
Monongahela River
Monongahela River
Kanawha River
Ohio River
Great Lakes
Lake Erie Basin
Cuyahoga River
Maumee River
Maumee River
Upper Mississippi
River Basin -
Western Great
Lakes Basin
Detroit River
Missouri River
Basin
Detection
Frequency
0%
5.4%
-
-
5.0%
8.3%
5.0%
12.9%
60%
14 1
6.4%
0
12.5%
12.5%
5.4
9.1%
-
4.1%
Ag Content (ppb)
-
2.1 (8.2 maximum)
0.05-1.0
0.5-1.3
2.0
2.0 (4.7 maximum)
4.0
1.2 (3.0 maximum)
0.6-1
5.3 (9.0 maximum)
NO
5.3 (9.0 maximum)
3.6 (6.0 maximum)
3.4 (6.0 maximum)
1.4
1.0 (3.8 maximum)
1.2 (1.5 maximum)
Location
Tennessee and
adjacent areas
U.S.
West Newton,
Pennsylvania
Apollo, Pennsylvania
Pittsburgh,
Pennsylvania
Pittsburgh,
Pennsylvania
Pittsburgh,
Pennsylvania
W infield Dam, West
Virginia
U.S.
Cleveland, Ohio
Toledo, Ohio
Toledo, Ohio
U.S.
U.S.
Detroit, Michigan
U.S.
Remarks
These primary streams re-
ceive acid mine drainage,
but Ag was not detected
50 miles downstream in
Toronto, Ohio
Receives effluents from
automotive, meat-packaging
and paper industries
Travels from Ft. Wayne,
Indiana through industrial
complexes and receives agri-
cultural, petrochemical and
metal working wastes.
Reference
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1967
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1967
Kopp & Kroner, 1970
Kroner & Kopp, 1965
Kroner & Kopp, 1965
Kopp & Kroner, 1970
Kopp & Kroner, 1967
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
-------
TABLE 2 (Continued)
O
I
Type of Water pH
Southwest-Lower
Mississippi Basin
Mississippi River
Mississippi River
Mississippi River
Missouri River
Atchafalaya River
Colorado
River Basin
A aim as River
Colorado River
Colorado River
Colorado River
Western Gulf Basin
Pacific
Northwest Basin
Columbia River -
Columbia River
Clear water River -
Pend Oreille River
Snake River
Snake River
California Basin
Sacramento River
San Fernando Valley
Great Basin
Alaska ~
Yukon River -
Detection
Frequency
4.5%
_
-
12
57
18%
45%
13.6%
0
4.3%
8.6%
0
0
5.3%
5.6%
Ag Content (ppb)
4.3 (9.0 maximum)
0. 0.22
0.26
0.2-20
ND-0.33
5.8 (38 maximum)
2.9 (7.0 maximum)
16 (38 maximum)
ND
0-1.0
3.5 (6.6 maximum)
0.9 (3.7 maximum)
0.09-0.15
0
0.1
0.2
0.5-1.3
1.4
ND
0-0.16
20
0.3
1.1
0.20-0.31
Location Remarks
U.S.
Baton Rouge,
Louisiana
Krotz Springs,
Louisiana
U.S.
Cedar HilL
New Mexico
Lorn a, Colorado
Yuma, Arizona
U.S.
U.S.
Near The Dalles,
Oregon
Lewiston, Idaho 1 occurrence
Albeni Falls 1 occurrence
Dam, Idaho
Payette, Idaho 2 occurrences
Wawawai, Washington 1 occurrence
California
Sacramento, California
California Estimated in
waste water
Nevada 1 occurrence
Alaska
Mountain Village,
Alaska
Reference
Kopp & Kroner, 1970
Durum & Haffty, 1961
Andelman, 1973
Kroner & Kopp, 1965
Kroner & Kopp, 1965
Durum & Haffty, 1961
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1965
Durum & Haffty, 1961
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Durum & Haffty, 1961
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Kopp i. Kroner. 1970
Kopp & Kroner, 1970
Kopp & Kroner, 1970
Durum & Haffty, 1961
Bargman & Garber, 1973
Kopp, 1969
Kopp, 1969
Durum S, Haffty, 1961
-------
Kopp and Kroner (1970) found silver in 6.6 percent of 1,577
surface water samples collected in the United States. Concentra-
tions in samples containing silver varied from 0.1 to 38 ug/1 with
a mean of 2.6 yg/1. The highest silver concentration was in the
Colorada River at Loma, Colorado. Upstream industries included an
old gold-copper-silver mine; an oil shale extraction plant at
Rifle; uranium plants at Rifle, Grand Junction, and Gunnison; and a
gasoline and coke refinery 1 mile from Loma.
Another striking example of elevated silver concentrations was
found in 280 miles of streams and lakes in the Lower North Canadian
River (LNCR) Basin of Oklahoma. The range of silver concentrations
varied from undetectable to 25 ug/1 in samples collected during all
seasons. Water and sediment samples were collected at eight main-
stream stations, eight tributary stream stations, and four Lake
Eufaula stations. The LNCR also contained extraordinarily high
concentrations of other trace elements and nutrients. The probable
reason for the unusually high silver concentrations was the low
water volume in some of the sampling streams. For example, the
maximum concentration of silver was detected on the Soldier Creek
Tributary (pH 7) which drained wastes from the northeast corner of
Tinker Air Force Base. Silver was never detected at the sampling
station closest to the Henryetta zinc smelter, but even the zinc
concentration was lowest there (Frank, 1969).
_o
Photoprocessing effluents usually contain Ag (820-3) 9 / dis-
-14 -13
sociation constant 3.5 x 10 , AgBr solubility product 4.8 x 10
C-8
-------
at 25°C or Ag2S. Thus, under normal circumstances, they contain no
free silver ions. Municipal biological treatment plants receiving
photoprocessing wastes have not suffered any loss in efficiency
from them. Some photoprocessing plants have even installed bio-
logical treatment plants themselves with up to 5 mg Ag/1 in the
water and 250 mg Ag/1 in the aeration tank sludge. Since silver was
present predominantly as Ag2s with small amounts of metallic sil-
ver, the biological system was not adversely affected. Eastman
Kodak activated sludge plant effluent contained 1 mg Ag/1; no
soluble silver was detected (i.e., * 20 ug/1 or <-20 ppb) .
The Genesee River in New York has received photoprocessing ef-
fluents for approximately 70 years. In 1973, on most sampling
dates from May 31 to October 17, it contained 20 ug/1 silver. How-
ever, levels of 90 to 260 ug/1 were detected in June. Sediments
contained up to 150 mg/kg silver dry weight. Raw Lake Ontario
water at the Eastman Kodak intake pipe contained 1 ug/1 silver
(Bard, et al. 1976).
At 0.04 g Ag/1 and 0.01 g H2s+HS~ per liter, AgSH is the major
silver species normally present in freshwater, being present in
concentrations up to 10-fold greater than the concentration of Ag+
and AgCl. In seawater, there is more AgCl2" than AgSH, and Ag+ con-
centrations are trivial. Other species of minor or negligible
importance in seawater are AgBr, Ag(SH)2", AgF, AgOH, Agl, AgN03,
Ag(N02)2~, and AgS04. The waters are oversaturated with silver by
7 to 12 times what is expected from available thermodynamic data
(Jenne, et al. 1977).
C-9
-------
The silver content of natural precipitates (i.e., stream sedi-
ments, etc.) has been discussed by Boyle (1968). The silver con-
tent of U.S. natural precipitates ranges from nil to 1,160 mg/kg.
Turekian found 0.4 to 15.0 mg/kg silver in the suspended matter of
18 U.S. rivers. The Susquehanna River in Pennsylvania, which con-
tained the highest concentration of silver, was estimated to be
transporting 4.5 tons* of silver per year to the ocean (Turekian
and Scott, 1967).
In the Lower North Canadian River (LNCR), the range of silver
content in the ash of total suspended solids (silt plus micro-
organisms) was from undetected to 0.008 mg/kg, except at the sta-
tion where the highest silver concentration was found in the water.
Here, the silver content ranged from 15 to 50 mg/kg in the ash
(Frank, 1969).
Silver concentrations of 0.05 to 45 ug/1 have been found in
effluents from municipal waste treatment plants. Silver concentra-
tions as high as 900 mg/kg in sewage sludge have been reported
(Smith and Carson, 1977).
Bruland, et al. (1974) studied the extent of metal pollution
in the Southern California Coastal Zone which received Los Angeles
area sewage. The average flux of anthropogenic silver into the
sediments of the California Coastal Basin was estimated to be 50
percent greater than the average flux of natural silver (0.09
*A mathematical error in the calculations lead to the report itself
stating 45 tons.
C-10
-------
versus 0.06 ug/cm2/year). The flux of anthropogenic silver to the
sediments was calculated to be 11 MT/year/12,000 km2, with the
chief source being the municipal wastewaters (15 MT/year/12,000
km2) , rather than the storm water plus dry weather flow or the
washout fluxes (1 and 5 MT/year/12,000 km2, respectively). Extrac-
tion studies indicated that the silver in these sediments occurred
predominantly as sulfides or bound to the organic phase.
The concentrations of silver in the wastewater particulates
were 32 to 130 (average 70) mg/kg compared with about 6 mg/kg for
the sediments in the basins receiving them. (The sediments were
collected at 75 to 890 m from the sewage outfalls.)
High concentrations of mercury, silver, chromium, and zinc
were recently found in the sediments downstream from the Vint Hill
Farms Station military reservation. Although the sediment contami-
nation extends for two miles in South Run in eastern Fauquirer
County, Virginia, which runs into Lake Manassas, the Manassas water
treatment plant is able to remove the metals because of the water
insolubility of the chemical forms present. There is concern, how-
ever, about heavy metal bioaccumulation in fish (Toxic Materials
News, 1978).
The silver concentration in sediments is important because
bottom-feeding mollusks, etc., tend to concentrate silver. Luoma
and Jenne (1977) in laboratory studies determined that the uptake
of silver, bound to various typical sediment species—by the clam
Macoma balthica, depended on the particular sediment species to
which it was bound. The concentration factor for sediment-bound
110mAg (drv ciam tissue/dry sediment) was 3.667 to 6.140 from
C-ll
-------
calcite; 0.395 to 0.850 from MnO • 0.043 to 0.146 from Fe 0 ; 0.034
x y
to 0.076 from biogenic CaC03; and 0.028 to 0.030 from organics.
The percent of mAg in the soft tissues of the clam was 42.6 to
57.0 (average 54.4 percent). In these experiments, the sediment-
bound silver contributed somewhat more silver to the clam tissue
than did solute silver (0.034 to 0.552 mg/kg versus 0.004 to 0.135
mg/kg in soft tissues).
Of 380 finished waters, 6.1 percent were found to contain sil-
ver at concentrations varying from 0.3 to 5 ug/1 (mean 2.2 ug/1) .
Table 3 shows the silver content of water supplies for several U.S.
cities. The silver content of these water supplies did not exceed
the U.S. drinking water limits for maximum allowable concentration
of silver, 0.05 mg/1 (Kopp, 1969). In another study, the maximum
concentration of silver found in 2,595 distribution samples from
959 public water supply systems was 26 ug/1. The average silver
content found in waters having pH < 8 was 0, while for those at pH
_> 8.0, the average silver content was 1 ug/1. Of Chicago water
samples, 15 percent showed increased concentrations of silver after
leaving the water treatment plant (McCabe, 1970).*
In 1935, Braidech and Emery reported 0.010 to 0.200 mg/kg sil-
ver (average 0.080 mg/kg) in the solid residues of all 24 city
water supplies they studied. The highest value was from Denver,
Colorado.
*Silver contents in distribution samples (i.e., tapwater) may be
higher than the finished water from the treatment plant because of
the preferred use of tin-silver solders for joining copper pipes in
the home, office, or factory. In addition, American Standard, Inc.
connects copper pipes for hot and cold water with tin-silver solder
during the assembly of kitchen and bathroom appliances (Silver
Institute, 1976b).
C-12
-------
TABLE 3
Silver in City Water Supplies
Ag Content (ppb)
Location
Remarks
Reference
O
I
M
U>
0.78
0.23 (7.0 maximum)
50 (maximum)
8 (average)
30 (maximum observed)
ND - 0.35
0.09
ND - -< 0.31
^0.53 - ^0.92
ND - -= 0.54
ND - -^0.40
^0.3
^0.4 - ^0.7
0.08
ND - -^0.26
0.29
^0.14 - 0.30
^0.25 - -==.0.28
ND - *c0.49
ND - -=^0.50
ND - r^.0.21
0.55
^0.03 - 0.07
^0.05 - ^=10.26
-^0.26 - -==.0.34
0-9 (100%)
0-1 (74%)
2-5 (22%)
<0.2 - -c:0.27
^.0.29
U.S.
U.S.
Birmingham, AL
Mobile, AL
Montgomery, AL
Phoenix, AZ
Tucson, AZ
Long Beach, CA
Los Angeles, CA
Los Angeles, CA
Oakland, CA
Sacramento, CA
San Diego, CA
San Francisco, CA
San Jose, CA
Denver, CO
Hartford, CT
New Haven, CT
Washington, DC
Jacksonville, FL
Miami, FL
St. Petersburg, FL
Tampa, FL
Atlanta, GA
Savannah, GA
Honolulu, HI
Chicago, IL distribution points
(maximum 2 ppb at the treat-
ment plants)
Chicago, IL
Rockford, IL
Evansville, IN
Maximum allowable Ag con-
tent of drinking water
according to Federal
Water Poll. Con. Admin.
2,595 samples of 956
municipal water supplies.
Cannon & Hopps, 1971
Kopp 6 Kroner, 1970
Taylor, 1971
Durfor 6 Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor fc Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Bargmon «. Garber, 1973
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
McCabe, 1969
Durfor t Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
-------
TABLE 3 (Continued)
O
I
Ag Content (ppb)
0.
2
- <
0.54
^0.24
ND - 0.39
-=i0.24 -^0.48
-^0.30
^0.2 - 0.3
^0.30 - 0.80
«= ~
-=;
0.
0.
0.
0.
:!:
18 -
13 -
18
14-0
06
21-0
•^.0.
«=i"
0.
"^
"<,
0.
*=i
•=;
^.
0.
ND
0.
-^.
0.
-=c
•=c
.u .
68
0.
0.
3
0.
0 .
09
07
23
0.
0.
0. 1'i
-co.
•=;
0.
ND
1.
23
-
1
23 -
17 -
28 -
22 -
41
46
09
- 0
09 -
-==.0
- 0
26
- 0
14 -
19
04 -
17
29
"^0
7.0
0.24
0.74
.49
.22
0.48
•cdO. 34
< 0.56
-------
TABLE 3 (Continued)
O
I
M
cn
Ag Content (ppb)
"^0.23
0.54 - -=;0.76
-CO. 19 - *c.0.20
•^.0.02
-=^0.12 - ^0.19
0.07
ND - -=^.0.24
ND - 0.19
^0.16
ND - ^c.0.29
0.15 - "^0.29
ND - < 0.86
ND - -^ 0.15
ND - 1.5
^0.27 --< 0.54
^0.10 - ^0.15
-=-0.10
0.05 - "=t-0.06
0.26 - 0.53
^0.05
Location
Toledo, OH
Youngs town, OH
Oklahoma City, OK
Tulsa, OK
Portland, OR
Erie PA
Philadelphia, PA
Pittsburgh, PA
Providence, RI
Chattanooga, TN
Memphis, TN
Nashville, TN
Austin, TX
Dallas, TX
El Paso, TX
Houston, TX
Lubbock, TX
Salt Lake City, UT
Norfolk, VA
Richmond, VA
Seattle, HA
Spokane, WA
Tacoma, HA
Madison, HI
Milwaukee, HI
Remarks Reference
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor 6 Becker, 1962
A well Durfor & Becker, 1962
Durfor 6 Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & 'Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
Durfor & Becker, 1962
-------
In a survey of metal concentrations in the drinking (tap)
waters of Canadian communities, silver was found in 0.1 percent of
the 239 sampled waters (detection limit of neutron activation an-
alysis was 0.001 to 0.005 yg/1) (Neri, et al. 1975).
Tapwater in the Boston metropolitan area contained ^ 0.010
mg/1 silver in 896 samples although Cu, Zn, Pb, and Fe were often
present in the soft water of the area due to the corrosion of pipe
materials (Karalekas, et al. 1976).
Silver is used to purify potable water for Swiss ski resorts,
German Breweries, soft drink bottlers, British ships, Shell Oil
Company tankers, drilling rigs, and over half the world's airlines
including Pan Am and American. In the United States, the number of
companies registered by the U.S. EPA to produce silver-containing
water filters grew from 2 to 19 by February, 1978, from 10 only two
years before. At least one water filter has been widely promoted
by television advertising in the United States for home use. The
units of Katadyn Products, Ltd. in Switzerland either produce sil-
ver ions anodically or by the slight dissolution of metallic silver
impregnated on fine-porosity ceramic filters. They have been
approved by the Swiss government for 38 years, requiring less than
200 yg/1 for their antimicrobial action (Silver Institute, 1976a,
1977b, 1978).
The Soviets have found silver ions at concentrations of 100 to
200 ug/1 to be safe, stable, and long-lasting for purification of
polluted water for drinking in the Soviet space ship and orbiting
station program. After animal tests showed these concentrations to
be nondetrimental, year-long human volunteer studies confirmed the
results (Silver Institute, 1973b). Silver sterilizers producing
C-16
-------
100 to 200 ugA silver ions were also used on the Apollo Spacecraft
waste and potable water systems (Albright, et al. 1967).
Ingestion from Food
Silver is a normal trace constituent of many organisms (Boyle,
1968). The ash of higher plants ususally is found to contain -=c 1
ppm silver, while the ash of terrestrial plants, in general, usu-
ally contains about 0.2 ppm silver. Higher values occur in trees,
shrubs, and other terrestrial plants near regions of silver min-
eralization. Seeds, nuts, and fruits generally have higher silver
contents than other plant parts (Smith and Carson, 1977).
Snyder, et al (1975) estimated that the average intake of sil-
ver by humans is 70 ug/day. Kehoe, et al. (1940) had determined
that daily dietary intake of humans in the U.S. was 88 ug/day. Tip-
ton, et al. (1966) found the average daily intake of silver in the
diets of men and women in the U.S. were 35 ug and 40 ug silver,
respectively. Hamilton and Minski (1972/1973) determined that the
average daily human dietary intake of silver in the United Kingdom
was 27 + 17 ug. No consideration was given to intake from water
used for cooking foods, making beverages, or drinking. Clemente,
et al. (1977) reported that the average silver intake in the diets
of three Italian populations was 0.4 yg/day as determined by neu-
tron activation analysis. Five-day fecal samples of the population
which had a silver intake of up to 7 ug/day showed a range of 1.1 to
202 ug/day (average 30 ug/day). Some source of pollution was felt
to be the cause of greater metal intake. The latter population
came from a large town in central Italy, whose major source of pol-
lution was automotive engine exhaust.
C-17
-------
Murthy and Rhea (1968) of the U.S. Public Health Service in
Cincinnati measured, by atomic absorption analysis, 0.027 to 0.054
mg/kg (average) silver in cows milk collected as market samples
from various U.S. cities. The silver content did not vary signifi-
cantly between cities, but there was a significant difference be-
tween quarterly sampling periods in the southeastern states. The
national weighted average was 0.047 + 0.007 mg/kg. Milk from 32
cows on farms serving Cincinnati contained 0.037 to 0.059 mg/kg
silver (average 0.047 + 0.006 mg/kg). Table 4 lists the silver
concentration in several food items.
Ag is an activation product produced during nuclear fis-
sion. The concentration factors* from Lichen to caribou or rein-
deer estimated by Hansen, et al. (1966, cited by Garner, 1972) for
mAg in muscle were 0.3; for liver, 80; for kidney, 1.3; and for
bone, 3. Beattie and Bryant (1970) had estimated that 15 percent
of the total Ag dose from activation products would be received
in a 30-year period starting in infancy by the forage-cow-milk
pathway.
Sewage-sludge amended soils may have 10 times or more silver
than normal and may increase human intake of silver by its incor-
poration into food crops in greater than normal amounts. Silver
uptake by plants appears to be directly related to its soil concen-
tration (Cooper and Jolly, 1969). Addition of phosphate to soil
contaminated with silver, however, reduces its plant availability
(Dawson, 1974).
*Ratio of mAg activity per unit wet weight of tissue activity
per unit wet weight of lichen.
C-18
-------
TABLE 4
Silver in Some Foods
Type of Food
Silver Concentrations, mg/kg
o
i
Beef
Beef liver
(SRM 1577)
Pork
Mutton and lamb
Milk powder
Potato powder
Sugars
Brown (Barbados)
Demerara
Refined
Granulated
Mollusks
Crustaceans
Trout (Lake Cayuga,
New York)
Mushrooms
Wheat (Triticum spp.)
Bran
Flour
Coffee beans
Tea (Camellia sinensis)
0.004-0.024
0.005-0.194 (same sample
by three laboratories)
0.007-0.012
0.006-0.011
0.010 + 0.04
0.015 + 0.005
0.03
0.004
0.001
0.002
0.1-10.0 (dry weight)
2.0 (dry weight)
0.48-0.68 (dry weight)
"Up to several hundred"
(dry weight)
0.5 (dry weight)
1.0 (dry weight)
0.4 (dry weight)
0.02 (dry weight)
0.20-2.00 (dry weight)
Reference
Armour Research
Foundation, 1952;
Mitteldorf and
Landon, 1952
Masironi, 1974
Armour Research
Foundation, 1952
Armour Research
Foundation, 1952
Schelenz, 1977
Schelenz, 1977
Hamilton and
Minski, 1972/1973
Boyle, 1968;
Cooper and Jolly,
1970
Boyle, 1968
Tong, et al. 1974
Cooper and Jolly,
1970
Kent-Jones and
Amos, 1957
Vanselow, 1966
Vanselow, 1966
-------
It is possible that the silver content would be increased in
the meat of animals pastured or fed grains raised on contaminated
soils.* At least one study, however, has indicated that the trans-
fer' of iron, copper, nickel, chromium, zinc, cadmium, and lead from
sewage-sludge amended soils to dairy or beef cattle milk or tissues
is minimal (Nelmes, et al. 1974).
Among aquatic species harvested for food, the heptopancreas
and nephridial organs of brachiopods, molluscs, and arthropods,
particularly crustaceans, accumulate heavy metals. The glandular
tissue of the liver of fish and all other vertebrates concentrates
metals (Vinogradov, 1953). Marine animals accumulate silver in
concentrations which are higher than their environment. Clams and
scallops growing near municipal sewage-sludge dumping sites accumu-
late higher concentrations of silver than do those growing where
the concentrations of silver are lower (Toxic Materials News,
1975). The enrichment factor calculated by Noddack and Noddack
(1939) for silver in marine animals over seawater is 22,000. A
bioconcentration factor is not estimated from the value since these
data are not purported for indigenous species. The dead bodies of
animals in reducing environments will contribute their silver to
sediments, a major factor in the biogeochemical cycle of silver
(Boyle, 1968).
Besides food and drinking water, silver is possibly ingested
from dissolution of silver dental amalgams in the mouth by saliva.
Wyckoff and Hunter (1956) qualitatively detected silver spectro-
*If a 0.25-lb portion of meat contains 0.007 mg/kg, the 0.0065 mg
silver consumed would represent only about 1 to 2 percent of the
low silver dietary intake reported by Tipton, et al. (1966) .
C-20
-------
graphically in the erythrocyte contents and possibly in the plasma
and erythrocyte membrane (ghosts) of two people who had dental
fillings. No silver was detected in a preliminary examination of
another person who did not have any dental fillings. Reynolds and
Warner (1977) concluded that the corrosion product of Ag3Sn amal-
gams after only 30-minute exposure to human saliva in vitro was
SnCl4.
Some silver may be released to soft tissues from silver amal-
gam dental fillings when placed in unlined cavities according to
Leirskar (1974), who found by atomic absorption analysis that there
was definite release of zinc and mercury into a human monolayer
epithelial cell culture (22 yg Zn/ml and 0.0177 to 0.0196 yg
Hg/ml); some silver also appeared to have been released. Silver
amalgam cultures contained 0.02 ug Ag/ml after three days. (The
detection limit for silver, however, was 0.01 ug/ml—much higher
than that for mercury.) Leirskar cited three other studies that
reported diffusion of amalgam constituent metals, including silver,
into adjacent dentin.
Inhalation
Silver is generally a very minor constituent of ambient aero-
sols. Table 5 gives a reasonably representative sample of silver
determinations in air, although it is by no means exhaustive, since
reports of nuclear activation analyses of atmospheric particulates
are proliferating rapidly. Interestingly enough, Chadron,
Nebraska, which has a population of 6,000 in a sparsely inhabited
region, had the same average ambient air concentration of silver in
1973—o.l5 ng/m3—as San Francisco had in 1970. A nonindustrial
C-21
-------
TABLE 5
Silver in Ground-Level Atmospheric Aerosols 6,7
o
i
NJ
Ni
Aerosol Silver Concentration
City
Heidelberg,
Germany
Niles, MI
Northwest IN
East Chicago, IL
Chicago, IL
Oak Ridge, TN
Vicinity:
Walker Branch
Watershed
Chadron, NE
Date
April -
June, 1971
June, 1969
1969
June, 1969
1968
July, 1974
1973
ng/m
4.2
1
1.5
2.4
4.3
0.17
average 0.1
PPb Reference
0.0032 Bogen,
0,00077 Bogen,
Dams,
0.0019 Bogen,
Brar ,
0.00013 Andren
5 .Qt-i-nom
1974
1974
et al.
1974
et al.
, et al
n 1 £i r* 1
— —
1971
1970
. 1974
QTK
Washington, DC
San Francisco, CA
Kellogg, ID
(city hall)
June -
Sept. 1973
June -
Sept. 1974
1974
1970
(range 0.02
to 1.8)
0.14
0.04
1.1
0.15
10.5* (range
0.936 to 36.5)
Trout, 1975 cited by
Greenberg, et al. 1978
John, et al. 1973
cited by Greenberg,
et al. 1978
Ragaini, et al. 1977
n«nn of mercury, antimony, cadmium, zinc, and lead ranged from 113 to
10,800 ng/m The nearby Bunker Hill smelter smelts silver-rich lead concentrates and roasts
ziric concGnti7citGs»
-------
.3 ,
city, Washington, D.C., had a concentration of 1.1 ng/m in 1974.
The very industrialized urban environment of Chicago, Illinois, had
an ambient atmospheric silver concentration only four times higher
(4.3 ng/m3). Even one of the sites having an expectedly high sil-
ver concentration in the silver-rich Coeur d'Alene region of
northern Idaho had only an order of magnitude greater silver con-
centration (average 10.5 ng/m3) than a nonindustrialized large
population center.
Smith and Carson (1977) estimated that total annual atmos-
pheric silver emissions in the United States in the early 1970's
were about 340 short tons or about 310,000 kg. About 60 percent of
this total was distributed equally between iron and steel produc-
tion and cement manufacture, about 12 percent each was due to
fossil fuel burning and nonferrous metal smelting and refining, and
about 7 percent was due to urban refuse incineration. Another
published estimate for total annual silver emissions was 417 short
tons (Dulka and Risby, 1976, citing a personal communication from
V. Duffield, 1975).
Greenburg, et al. (1978) attributed to urban refuse incinera-
tion a much higher share of the total silver content in the urban
particulate load. They estimated that the contribution of silver
from refuse incineration to ambient urban air is 1.7 ng/m .
Steel mills have been implicated as the major source of aero-
sol silver, yet the following data (Harrison, et al. 1971) do not
seem to support this contention. Air particulate samples were col-
lected on June 11 and 12, 1969, at 25 stations in the northwest
Indiana area, including the Hammond-East Chicago-Gary-Whiting
C-23
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metropolitan complex. At that time, the entire sampling area con-
tained three large steel mills, as well as four large petroleum
refineries, foundries, steel fabricators, chemical plants, a large
cement-manufacturing plant, and two large power utilities. The
silver concentrations in the area ranged from 0.5 to 5 ng/m3. The
maximum silver concentration was found at a station downwind from
the steel mills. High silver concentrations did not occur at the
same stations where maximum iron levels occurred. Therefore, steel
manufacturing was not believed to be the major source of silver
found in these samples (Dams, et al. 1971).
At another station, in Gary, near the third steel mill,
secondary maxima for iron and eight other metals were associated
with a silver concentration of 4 ng/m3. The direction of the unus-
ually strong, steady wind prevailing during the sampling was such
that most of the shoreline steel and cement plant emissions (^- 85
percent and 12.5 percent, respectively, of the area's industrial
particulate emissions) may have been swept directly over the lake
so that the observed air concentrations at stations nearest them
were much lower than normal (Dams, et al. 1971). On April 4, 1968,
one day after general rainfall, with wind blowing at 34 km/hr, the
silver concentrations in surface air samples from 22 aerosol-
collecting stations in Chicago, Illinois, ranged from 0.18 to 7.0
3 3
ng/m (average 4.3 ng/m ). Correlation coefficients for silver
with other elements or dust were not determined (Brar, et al.
1970).
Another source of silver to ambient air is from volatile emis-
sion from certain trees. Curtin, et al. (1974/1975) traced the
C-24
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path of elements from the soil and mull (the humus-rich layer of
mixed organic and mineral matter 3 to 8 cm thick beneath individual
trees) into the needles, twigs, and volatile exudates of Lodgepole
pine, Engelmann spruce, and Douglas fir in Idaho Springs, Colorado
and Stibnite, Idaho. Silver was not detected in the soil; but in
Colorado, its highest concentrations were in the mull ash under all
species. in Idaho, the silver concentration was highest in the
twigs of the pine and spruce and in the exudate residue of the Doug-
las fir. Presumably, the metals in the exudate are complexed by
terpenes and appear in the blue haze of forested areas.
Nadkarni and Ehmann (1969) measured 2.61 mg/kg silver in a
reference cigarette tobacco* by neutron activation analysis and
2.87 mg/kg silver in the paper. Nadkarni, et al. (1970) found 0.27
± 0.18 mg/kg silver in a filter cigarette of a popular brand and
0.18 ± 0.03 mg/kg in a nonfilter cigarette of the same brand; there
was 0.48 mg/kg silver in 1.65 g of smoke condensate from 500 filter
cigarettes and 0.30 mg/kg silver in 14.5 g condensate from 500 non-
filter cigarettes. Only 0.60 percent of the silver transferred
into the mainstream smoke condensate of the filter cigarette; 4.4
percent transferred from the nonfilter cigarette. The amount of
silver inhaled into the lungs in the mainstream smoke per cigarette
would be negligible according to these data: 8.7 ng per nonfilter
cigarette and 1.6 ng per filter cigarette.
*A blend of four major tobacco types: flue-cured, Hurley, Oriental,
and Maryland. The nonfilter cigarette dimensions were 85 mm in
length, 25 mm in circumference.
C-25
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Exposure from cloud-seeding operation may be significant only
to a ground-based generator operator.* Standler and Vonnegut
(1972) estimated the concentration of silver (0.1 ym particles) in
air downwind in the target area from a ground-based silver iodide
cloud-seeding generator is 0.1 ng/m3, a factor of 105 below the
maximum allowable concentration in workplace air. At the generator
site itself, however, exposure exceeds the maximum permissible con-
centration within 50 m downwind of the generator. Seven cloud-
seeding operators with extensive exposure to silver iodide knew of
no persons who had experienced any ill effects due to silver
iodide, despite the fact that their hands may remain yellowed for
weeks, vonnegut, however, recalled a technician in New Mexico in
the early 1950's who claimed the aerosol from a ground-based gen-
erator aggravated his respiratory allergy, and Douglas had reported
in 1970 a skin rash developing in an individual who had been within
a few meters of an operating generator for six hours. Inhaling the
acetone vapors from the unignited silver iodide solution is of more
concern to some operators.
The Occupational Safety and Health Administration (OSHA) stan-
dard for silver metal and soluble compounds in the workplace air is
0.01 mg/m for an 8-hour time-weighted average (39 FR 23541).
According to the American Conference of Governmental Indus-
trial Hygienists (ACGIH, 1977), the Threshold Limit Value-Time
Weighted Average (TLV-TWA) for aerosol silver metal or soluble
silver compounds as metal is 0.01 mg/m3. The tentative value for
*Bernard Vonnegut in 1947 in General Electric Laboratory experi-
C- ln
C-26
-------
the Threshold Limit Value-Short Term Exposure Limit (TLV-STEL) is
~0.03 mg/m3. The TLV-TWA is based on a normal 8-hour workday or 40-
hour work week, day-after-day exposure. The TLV-STEL is defined as
the maximum concentration to which a worker may be exposed continu-
ously for as long as 15 minutes without irritation, chronic or
irreversible tissue changes, or sufficient narcosis to increase
accident proneness, self-rescue, or work efficiency. Up to four
such excursions may occur per day provided at least 60 minutes
elapse between such exposures and provided the TLV-TWA was not ex-
ceeded in the time lapses.
The ACGIH (1971) stated that, "If one assumes a 20-year expo-
sure, a 10 m3/day* respiratory volume, and a 50 percent body reten-
tion, a level of silver fivefold the recommended TLV (0.05 mg/m )
will result in an accumulation of 1.2 g or a probable borderline
amount for the production of argyria."** The problem of how ab-
sorption of metallic silver from the lungs might parallel direct
injection of silver compounds into the bloodstream was not dealt
with.
More pertinent information with regard to a TLV for silver in
air was supplied to the ACGIH by Fassett in a personal communication
(undated and unidentified as to organization). After observing
silver workers for many years, he believed that silver concentra-
tions of 0.01 mg/m3 in workroom air are unlikely to cause argyria.
* Presumably, for the work day. Snyder, et al. (1975) estimated a
23 m /day respiratory volume. _
**The reference is somewhat in error in stating that the gradually
accumulated intake of from 1 to 5 g Ag will lead to generalized
argyria. The values given by Hill and Pillsbury (1939) are 0.91 to
7.6 g, given i.v.
C-27
-------
Jindrichova (1962, cited by ACGIH, 1971) had observed 12 cases of
argyria resulting from exposure to workroom air concentrations of 1
to 2 mg/m in the processes of manufacturing silver varnish and its
use in silvering radio-technical parts.
Winell (1975) compared the hygienic standard for chemicals in
the work environment for which both the United States and the USSR
had standards. Since silver was not included, apparently the USSR
does not have a limit for silver. Argentina, Great Britian, Nor-
way, and Peru apply the U.S. standards.
Occupations where silver inhalation is still possible include
silver polishers and occupations involved in melting silver or its
low-melting alloys (e.g., tin-silver solder for copper plumbing).
The silver nitrate manufacturers and packers were the most frequent
victims of generalized argyria according to Barker and Hunter
(1935), but the processes have been obsolete for decades.
Silver polisher's lung was first described in 1945. The dust
inhaled contains both iron oxide (rouge) and metallic silver. The
latter stained the tissue black (Aponte, 1973). Argyria was seen
less often in pourers of molten silver than in silversmiths engaged
in filing, soldering, polishing, engraving, etc. But, according to
Lewin (1896), it was always localized rather than generalized as
would occur from inhalation. Yet Koelsh (1912) (both references
cited by Harker and Hunter, 1935) found that two men whose occupa-
tion involved cutting up thin sheets of silver had generalized pig-
mentation and suggested it was due to inhalation or ingestion of
the workplace dust (300 mg silver/kg dust).
C-28
-------
in the melting area at the San Francisco mint on December 24
to-27, 1972, the Industrial Hygiene Services Branch of the National
institute for Occupational Safety and Health (NIOSH) determined
0.01 to 0.04 mg/m3 of silver fumes in the air (average 0.02 mg/m3;
the threshold limit value of 0.01 mg/m3 was exceeded in seven of
the eight samples). The melting and casting operations caused
smoke and fumes throughout the melting room despite adequate venti-
lation over the melting area (Anania and Seta, 1973). Although
silver is seldom encountered in new U.S. coinage except for the
special silver-containing editions of U.S. Eisenhower dollars made
only at the San Francisco mint from time to time, such information
is probably applicable to the extent of occupational exposure at
firms that make medallions, silver bars, and other commemorative
items of case silver. Sterling silverware and holloware are gener-
ally manufactured without melting operations. Silver platers are
more at risk from cyanide poisoning rather than silver poisoning.
Dermal
Laws in many states still require that a few drops of a 1 or 2
percent silver nitrate solution be applied to the conjunctiva of
the eyes of newborn infants to prevent ophthalmia neonatorum by
transmittal of gonorrhea from the mother (Martin, 1965). Use of
silver nitrate is a legal requirement in Denmark, but it is not
used in Japan or Australia. Elsewhere, there is a free choice
between silver nitrate and antibiotics. Silver nitrate is no
longer used in 20 percent of U.S. hospitals because of the dangers
of chemical conjunctivitis (Shaw, 1977).
C-29
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In the U.S., several silver-containing Pharmaceuticals for use
on skin or mucous membranes can be obtained; some do not need a
prescription. Among the medications are Argyro;© (mild silver pro-
tein) and Protargo® (strong silver protein) , Neo-Silvo:© (col-
loidal silver iodide in a gelatin base), silver nitrate, and Silva-
dendsJ (silver sulfadiazine) (Pariser, 1978).
The risk of argyria from silver-containing topical medicinals
continues today. Marshall and Schneider (1977) reported a case of
systemic argyria which had first begun to appear by November, 1971
in a 46-year-old woman. She had begun using silver-nitrate appli-
cators for bleeding gums from ill-fitting dentures, upon the advice
of her dentist. From April, 1970, she had used three applicators
per week and continued using them even after the first bluish dis-
coloration appeared about her nose and forehead. By July, 1972,
she was already strikingly pigmented, was diagnosed as having
argyria, and was advised to discontinue use of the applicators. In
1973, the pigmentation of her abdominal organs was noted during an
exploratory laparotomy. None of the patient's physical ailments
was attributed to the use of silver nitrate.
Moyer and his associates instituted the use of hypotonic sil-
ver nitrate burn treatment in April, 1964, at Barnes Hospital in
St. Louis, Missouri. It was discontinued there in December, 1967.
Monafo had developed colloidal silver isotonic solutions, and
Margraf and Butcher had developed other silver salts in ointment.
\
In the opinion of Monafo and Moyer (1968) of St. John's Mercy
Hospital in St. Louis, "Because most salts of silver, other than
the nitrate, are insoluble..., it was predicted that due to preci-
C-30
-------
pitation at the wound surface, little or no absorption of silver
would occur through burn wounds. It was, therefore, anticipated
that systemic toxicity would be inconsequential. Moreover, argy-
ria, the slate-gray discoloration of the skin that results from the
ingestion or absorption of silver is,innocuous physiologically and
does not shorten life." No patient had developed argyria, but sil-
ver was detected in plasma and urine. Patients with extensive
burns treated for up to 80 days had 0.05 to 0.30 mg silver per liter
in their plasma.
Hartford and Ziffren (1972) reported on the results of 0.5
percent silver nitrate use on the dressings of 220 burn patients.
Compared with the rate in the 1950-1960 decade, mortality had been
dramatically reduced. By the late 1960's, the search for a less
soluble but effective silver compound lead to the synthesis (by
C.L. Fox, Jr.) and clinical trials of silver sulfadiazine.
Silver sulfadiazine, by 1974, according to Fox (1975), had
been used in the treatment of more than 10,000 burn patients in
many countries for more than seven years. It had been approved by
the regulatory agencies in the United States and the United Kingdom
so that more general use had begun (Silver Institute, 1977a).
Less than 10 percent of the sulfadiazine is absorbed, and far
less of the silver. Daily treatment of 1 m2 of burn surface (a 50
percent burn in an adult) requires 200 g AgN03 (127 g Ag) (40 liters
of 0.5 percent solution) or 4 g silver sulfadiazine (1.2 g Ag) (one
400 g jar of 1 percent cream or lotion). Fewer than 10 of 10,000
patients showed any drug sensitivity (Fox, 1975).
C-31
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A 1 percent silver cream made of silver nitrate, zinc sulfate,
and allantoin has been developed for self-care treatment of cuta-
neous ulcers. In a study of 400 chronic skin ulcers in 264
patients, 84.5 percent were completely healed within 3 to 40 weeks
(10 weeks average) (Silver Institute, 1977c). The compound is
another slow-release form of silver and is less likely to produce
argyria than silver nitrate preparations alone.
Silver nitrate hair dyes have been used regularly since about
1800. Sodium thiosulfate developers are added to the hair first,
followed by 0.5 to 15 percent silver nitrate solutions containing
various amounts of ammonia to give gradations of shade. The 5 per-
cent solution with ammonia is widely used to dye eyebrows and eye-
lashes and is the only colorant commonly used for the purpose in
the U.S. (Wall, 1957, 1972). At least one case of argyrosis has
been reported from such use. An Italian physician who dyed his
eyebrows, moustache, beard, and eyelashes with a silver dye for 25
years developed argyria in the conjunctiva of both eyes (Wall,
1957).
Several swimming pools in the U.S. are equipped with filtering
systems of activated carbon of very high surface area coated with
pure metallic silver. The effective water concentrations of silver
ions are 20 to 40 ug/1 (Silver Institute, 1973a,c, 1974, 1976c).
Dermal absorption of silver from swimming pools is not expected,
although absorption through the conjunctiva is possible. Although
evidence is cited later in this document that mucous membranes and
C-32
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wounds allow absorption of silver compounds to an unknown extent,*
very little, if any, ionic silver is absorbed by intact skin.
PHARMACOKINETICS
Absorption
Silver may enter the body via the respiratory tract, the gas-
trointestinal tract, mucous membranes, or broken skin. Some re-
ports even claim absorption through intact skin. In most cases of
argyria, caused by occupational exposure, absorption has been via
the respiratory tract or the conjunctiva (Hill and Pillsbury,
1939) . Up to 10 percent of a single oral dose of silver is ab-
sorbed. The literature data do not lend themselves to a ready cal-
culation of the degree of absorption after inhalation or dermal
exposure. Absorption from even nonintact skin appears to be much
less than 1 percent.
Rats ingesting 1.68 g/kg of colloidal silver for 4 days or
0.42 g/kg for 12 days showed higher silver concentrations in the
lungs than in the liver. Based on distribution studies described
in the following discussion, the amount found in the lungs is so
high that perhaps the rats aspirated part of the dose. Otherwise,
the total amount of silver recovered in the heart, lungs, kidney,
spleen, liver, and muscles would indicate that at least 2 percent
of the higher dose (if one assumed the average rat weighed 200 g)
was absorbed. Apparently, almost 5 percent of the silver was
absorbed at the lower dose (Dequidt, et al. 1974).
*That is, the percent of the total dose absorbed has not been cal-
culated; however, long-term use of the topical silver medicinals
(generally silver nitrate) for mucous membranes has certainly led
to argyria.
C-33
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Scott and Hamilton (1950) concluded that rats absorbed 0.1
percent of a carrier-free dose of radiosilver upon ingestion.*
Rats were given the doses intragastrically. Four days after the
dosing, 99.0 percent of the original dose had been eliminated in
the feces and 0.18 percent in the urine; yet the tissue distribu-
tion apparently totals 0.835 percent; 0.52 percent in the lungs,
0.025 percent in the blood, 0.11 percent in the G.I. tract, 0.034
percent in the skin, and 0.076 percent was in the balance remaining
after the other internal organs, bones, and muscles revealed no
silver.
Dogs (four male beagles, average 5.5 years, 12 to 16 kg) were
presumed to absorb 10 percent of oral doses of 0.6 yCi 110Ag as the
nitrate since only 90 percent was lost very rapidly (Furchner, et
al. 1966b).
Three rabbits inhaled an aerosol of 10 percent colloidal sil-
ver solution for eight hours (Kondradova, 1968a,b) and were immedi-
ately sacrificed. In the tracheal epithelium, silver had accumu-
lated in the large vacuoles in the cytoplasm of epithelial cells.
In a human who had accidentally inhaled 110mAg, most of the
inhaled silver had a biological half-life of about one day, prob-
ably due to rapid mucociliary clearance, swallowing, and fecal
excretion. By whole-body counting on the second day, silver activ-
ity was seen in the liver, which indicated some absorption although
*Furchner, et al. (1966b) state that the findings of the Scott
and Hamilton report indicate about 4 percent absorption from
the gastrointestinal (G.I.) tract. They found that mice absorbed
less than 1 percent.
034
-------
the published data do not permit a calculation of absorption (New-
ton and Holmes, 1966). Newton and Holmes believed colloidal forms
of silver are the species of silver absorbed in the lungs and that
phagocytosis would account for the localization in the liver. They
cited a study by Hahn and Corrothers (1953) in which the radio-
silver coating of colloidal gold particles administered intrabron-
chially to dogs was gradually leached off in the lungs and appeared
in the liver.
West, et al. (1950) reviewed early investigations into cuta-
neous absorption of silver. Muller, in a privately printed 1936
report cited in Hill and Pillsbury (1939), stated that all of the
silver oxide in a 5 percent oily dispersion was absorbed after
topical application to intact skin, wounds, or mucous membranes.
He found no silver deposits in the skin or underlying tissue, but
he claimed to have accounted for 73.1 to 88.5 percent of the silver
administered to four guinea pigs in their excreta within 31 days of
the inunction of their intact skin. Win (1887) could find no per-
manent deposit of silver granules six weeks after their dermal
injection. Jacobi (1878) could not produce generalized argyria,
however, by s.c. injections of a silver solution in rabbits; yet
Pincussen and Roman (1931) found silver in blood, skin, kidney,
spleen, and liver after s.c. injection of silver sulfate in rats.
West, et al. (1950) citing unpublished data of West, Elliott, and
Hahn, found activity in many organs and feces of albino rats after
s.c. injections of a mixture of Ag and Ag.
C-35
-------
Hill and Pillsbury (1939) reviewed several studies in which
silver was apparently not absorbed from intact skin. The Muller
study was described in a footnote.
The depilated backs of rats were painted daily with a satu-
rated solution of CollargoKV (colloidal silver and silver oxide)
for three months. By atomic absorption spectrometry and colori-
metry, traces of silver were found in the heart and lungs, 1.54
mg/kg in the kidney, 1.50 mg/kg in the spleen, and 0.16 mg/kg in the
liver (Dequidt, et al. 1974).
Wahlberg (1965) determined that the absorption of silver
nitrate from a solution containing 25.8 g Ag/1 by the intact skin
2
(3.1 cm ) of guinea pigs was less than 1 percent five hours after
topical application.
Argyria was relatively common following use of silver prepa-
rations as applications to the mucous membranes according to Hill
and Pillsbury (1939), but the argyria was usually described as
"local" rather than "generalized," which would indicate systemic
absorption.
Marshall and Schneider (1977), however, have described a rare,
present-day case of generalized argyria due to assiduous use of a
silver nitrate stick for bleeding gums due to ill-fitting dentures.
Applications of silver nitrate dressings to open wounds allows
systemic absorption of silver. Constable, et al. (1967) treated
2
open wounds (3.5 x 3.5 cm ) on the backs of guinea pigs with 0.5
percent AgNOo solution for five days. In Table 6, the range of sil-
ver concentrations in the organs of four or five topically treated
guinea pigs are compared with those in one guinea pig drinking the
C-36
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TABLE 6
Comparison of Tissue Distribution after Dermal Gastro-
intestinal Absorption of Silver from a 0.5 Percent AgN03 Solution*
Concentration, mg/kg
Organ Dermal Route Gastrointestinal Route
Skin
Skin by wound
Ulcer
Liver
Bile
Kidney
Lymph node
Stomach
Intestine
3.0-35.5
42.5-3,491.1
2.0-6,649.5
15.2-29.6
0.5-1.8
7.6-152.0
1.8-14.4
2.2-24.9
3.8-38.0
1.
-
-
35.
0
2.
2.
164.
10.
5
3
1
8
8
0
*Source: Constable, et al. 1967.
C-37
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0.5 percent AgNO3 solution (probably not the same amount as re-
ceived by topical treatments). Loss of silver from the liver was
fairly rapid after cessation of treatments. After one week, <:40
percent remained and after two weeks, <<25 percent. Since the AgNCU
contained some Ag (t^,^ = 7 days), radioautographs showed that
silver was concentrated in the Kupffer cells and around the bile
canaliculi with very small amounts in the glomeruli and most in the
kidney in the cells lining the renal tubules.
Bader (1966) analyzed the organs of two burn patients who had
been treated with fresh dressings of silver nitrate continuously
for at least six days or for every 8 hours for 30 days. In the 66-
year-old man, who had died of a brain tumor about 50 days after the
8-hour treatment was initiated, the silver concentrations in the
tissues were slightly above normal: bone, 0.025 mg/kg; heart,
0.040 mg/kg; kidney, 0.140 mg/kg; and skin, 2,800 mg/kg. The
second patient was an 18-year-old male, who died of respiratory
complications on his 7th hospital day. Before death, the silver
concentration in his urine was 0.038 mg/1 and in his blood, 0.12
mg/1. There was no silver detected in his lungs or brain; but the
concentrations in other tissues were: heart, 0.032 mg/kg; kidney,
0.14 mg/kg; spleen, 0.23 mg/kg; liver, 0.44 mg/kg; muscle, 2.0
mg/kg; and skin, 1,250.0 mg/kg. On the basis of information of Fox
(1975), the daily dose of silver from silver nitrate dressings is
127 g. The patient dying on the 7th day was probably treated for at
least six days, receiving 762 g silver. On the assumption that his
body weight and the weight of his organs were those of reference
man (Snyder, et al. 1975) and with the exclusion of the silver
C-38
-------
content of his skin, one can calculate that the organs named con-
tained 57.5 mg silver. Because the silver concentration of his
liver and heart were approximately the same as those of the older
man, we will assume that his bones had the same silver content, 0.9
mg. These values plus his urinary output for at least one day (cer-
tainly no more than 0.04 mg and probably less because of possible
renal impairment), total 58.44 mg or 0.008 percent of the 762 g
dose of silver.
Silver sulfadiazine has very low water solubility and probably
remains in the wound exudate according to Nesbitt and Sandman
(1977). The solubility in distilled water cannot be detected by
any potentiometrie method. At pH 3.851 with a nitric acid buffer,
ionic strength 0.1 M, the solubility of Ag+ was about 6.5 x 10" M;
at pH 2.128, about 60 x 10"5 M. Yet, Wysor (1975a) , citing a Marion
Laboratories brochure on Silvaden<£9 dated March 1, 1972, stated
that very large concentrations of silver sulfadiazine applied topi-
cally has caused silver deposition in the kidney basement membrane.
Wysor (1975a) gave CF. mice, infected with Plasmodium berghei, oral
doses of 1,050 mg/kg of various silver sulfonamides for five days.
Only silver sulfadiazine proved effective in curing the mice of
their malaria; presumably, it was solubilized and absorbed.
Dermal absorption of silver sulfadiazine from wounds is low.
In clinical trials with silver sulfadiazine cream, Fox, et al.
(1969) reported that when 5 to 10 g of the drug was applied to the
burned surface of 31 patients, the levels of sulfadiazine in the
blood were 10 to 20 mg/1 and there was 60 to 300 mg/1 in the urine
(24-hour excretion of 100 to 200 mg). When burned guinea pigs were
C-39
-------
treated with radioactive silver sulfadiazine, Fox, et al. (196.9)
did not detect any radioactivity in the organs or blood.
Moncrief (1974) reported that 10 percent of the sulfadiazine
of silver sulfadiazine applied to burns is absorbed to give blood
levels of 15 to 40 mg/1, peaking 3 to 4 days after initiation of
treatment. The daily absorption rate decreases during the first 10
to 15 days after the initiation of therapy. Radiosilver does not
appear in the blood from silver sulfadiazine; but when silver
nitrate soaks are used, there is 0.05 to 0.3 mg/1 silver in the
plasma.
Burke (1973) compared the excretion of silver by children and
adults, untreated and treated with silver sulfadiazine. His re-
sults are in Table 7.
Distribution
The amount of silver administered, its chemical form, and the
route by which it is administered affect the tissue content and
distribution of silver within the body (Furchner, et al. 1968).
It is retained by all body tissues. The primary sites of deposi-
tion in persons who have never taken silver therapeutically are the
liver, skin, adrenals, lungs, muscle, pancreas, kidney, heart, and
spleen. Silver is also deposited in blood vessel walls, testes,
pituitary, nasal mucous' membrane, maxillary antra, trachea, and
bronchi (Sax, 1963). Although silver does not accumulate in the
lungs with age, it was present in 39 percent of the lungs from
Americans analyzed by Tipton and Cook (1963). Examinations of
accidental death victims indicated that the silver content of the
myocardium, aorta, and pancreas tended to decrease with age (Bala,
C-40
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TABLE 7
Silver Concentrations in Human Blood and Excreta*
(mg/kg)
Subject
Blood
Urine
Feces
Patient with 70 percent 0.75
burns, treated with silver
sulfadiazine for 1 month
Same patient, 2 months 0.13
later, after grafting
Patient with 60 percent 0.09
burns, treated with silver
sulfadiazine for
3 months, off treat-
ment for 1 month
Control adult 0.05
Child with 15 percent
burns, 11-months-old
(length of silver treat-
ment not given)
Control child
0.73
0.12
0.02
0.003
7.0
3.2
19.3
1.0
0.53
6.0
2.0
0.21
*Source: Burke, 1973
041
-------
et al. 1969). Silver accumulates in the body with age, however,
even if none is administered intentionally (Hill and Pillsbury,
1939).
A striking feature of argyria is the regular deposition of
silver in blood vessels and connective tissue, especially around
the face, conjunctiva, hands, and fingernails (Hill and Pillsbury,
1939) . The silverbearing particles in one case of localized argy-
ria of a photoprocessor were found to be silver sulfide (Ag2S),
possibly contained in the mitochondria (Buckley, et al. 1965). The
silver-containing particles were sparsely distributed at the dermo-
epidermal junction of the papillary bodies adjacent to the epi-
dermal portion of the sweat ducts. The silver had entered the skin
via the sweat glands (Buckley, 1963).
In argyria, aside from the blood vessels and connective tis-
sues, the dermis of the skin, glomeruli of the kidney, choroid
plexus, mesenteric glands, and thyroid contain the greatest amounts
of deposited silver. The epithelium is free of silver deposits
(but Buckley, et al. 1965, report that silver ions are present
there).* Other tissues where deposition may occur include: bone
marrow, pancreas, liver, spleen, testes, and ovaries (Hill and
Pillsbury, 1939; Sax, 1963; Van Campen, 1966). The adrenals,
*According to Lever (1961) in the 3rd edition of Histopathology of
the Skin, in argyria, silver is found in the dermis—chiefly out-
side the cells, as uniformly sized particles ("...fine, small
round, brownish...")—but never the epidermis. The particles, ly-
ing singly or in clumps, are -s^ly in diameter. "Under a dark-
field microscope, the silver appears as brilliantly refractile,
white granules against a dark background." Melanin and hemosi-
derin granules are larger, largely intracellular, and nonrefrac-
tile on dark-field illumination.
C-42
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lungs, dura mater, bones, cartilage, muscles, and nervous tissue
are minimally or never involved as deposition sites for silver
(Hill and Pillsbury, 1939). Exposed skin shows greater amounts of
melanin in the dermis and epidermis. Robert and Zurcher (1950,
cited by Lever, 1961), had stated that silver favors melanin forma-
tion by increasing oxidative processes. Silver is especially
deposited in intima of blood vessels and connective tissue of
internal organs. Basement membranes around the acini of the testes
and of the choroid plexis are rich in silver granules (Barker and
Hunter, 1935).
Polachek, et al. (1960) reported the metabolism of radiosilver
in a patient with malignant carcinoid that agreed reasonably well
with the carrier-free silver rat studies of Scott and Hamilton
(1950). The radiosilver was incubated with the patient's own blood
and was first associated most with the erythrocytes and the globu-
lin fraction of the plasma (77 percent in the globulin, 15 percent
in the albumin, and 8 percent in the fibrinogen fractions). Upon
injection (i.v.) into the patient (with 0.002 mg carrier Ag/kg),
the 43 yCi radiosilver was removed rapidly from the blood, presum-
ably by the liver with biologic half-life of 48 days. At seven
minutes after injection, only 30 percent of the injected dose
remained in the blood; at two hours, 10 percent remained; and at 1
to 20 days, 2 percent. Urinary excretion was 5 percent of fecal
excretion. Excretion was much slower than in the rat studies.
Only 0.5 to 3 percent of the original dose was eliminated in each of
seven 24-hour periods in the first 21 days post-administration.
Urinary excretion in these 24-hour periods ranged from 0.03 to 0.29
percent.
C-43
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The patient lived 195 days after the injection. Analysis of
the organs post-mortem showed the highest concentrations (counts
per minute per gram) in: liver, 70.0; skin, 37.7*; kidney (left),
10.0; brain, 9.2; and kidney (right), 7.5. From 4.0 to 5.6 cpm/g
was found in an abdominal lymph node, an adrenal gland, the primary
carcinoid in the ileum, a testis, the aorta, and the pancreas; and
2.2 to 3.8 cpm/g was found in the urinary bladder, prostate, heart,
stomach, rib, and ileum. Smaller concentrations were found in the
carcinoid in the liver (metastatic), a lung, muscle, and the spleen
(Polachek, et al. 1960).
Intramuscular injections of dextrin-protected radiosilver
colloid left much material at the injection site, but an i.v. dose
in albino rats (1 ml contained 1.72 x 10 cpm) was mainly found in
the reticuloendothelial system. The bone content was primarily in
the marrow. The continued presence of activity in the blood sug-
gested that tissue-deposited silver was being translocated. A
gelatin-protected silver colloid injected i.v. into albino mice was
also deposited in highest concentrations in the reticulondothelial
system; 22 hours after i.p. injection of the gelatin-protected sil-
ver colloid into five albino mice, 36.5 percent of the activity was
in the gastrointestinal tract and contents; 16.5 percent in the
liver; 10.2 percent, in muscle; 3.5 percent, in bone; and 0.4 per-
cent, in the skin (except the head) (Gammill, et al. 1950).
Table 8 adapted from Smith and Carson (1977) reviews some
other animal data on early distribution of injected silver com-
pounds.
*Because of its relative weight, the skin had the highest accumula-
tion of silver.
C-44
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TABLE 8
Silver Distribution in Animal Tissues
O
I
Distribution at
Organism
White mice
White mice
Rats
Rats
Organ
Blood
Liver
Spleen
*^L
Stomach
Thyroid
Bone
Blood
Liver
Spleen
Stomach
Thyroid
Bone
Lungs
Kidneys
Heart
Pancreas
Small
intestine
Large
intestine
Bladder
Muscles
Testes
Brain
Blood
Heart
Kidneys
Liver
Spleen
Form of Ag 10 min. 30 in in.
110. 125, 19.7%
Ag l 65.6%
0.35%
0.51%
0
0.42%
Total 86.58%
110. fl2nr 0.82%
Ag Bc 58.7%
0.34%
0.73%
_
0.21%
Total 60.80%
110AgNo,
at pH 5.0
in 0.05 t±
acetate
buffer
AflNO, and
Cu(NO )
injected infe>
in vivo
Egated seg-
ments of the
G.I. tract.
1 hr.
13.5%
48.3%
0.70%
0.92%
0.02%
0.31%
63.75%
1.12%
63.6%
0.18%
0.57%
-
0.14%
65.61%
3 hr. 6 hr.
15.2% 0
40.7% 44.3%
0.60% 0
1.25% 0
0 0
0.51% 0.93%
58.32% 45.25%
2 hr.
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
24 hr. 2 days 7 days
000
30.9% 20.0% 10.11%
000
000
000
0.01% 0 0
30.91% ~20TO% 10.11%
0.56%
26.1%
2.09%
0.41%
-
0.45%
23.61%
Dosage
0.2 mlLv.
of 50-60
ug/mlin
tail vein
0.2 mli-v.
of 50-60
yg/mlin
tail vein
0.01 pmoles
Cu * in 0.4
mldistd.
H,0 with
1.5. 3.0,
and 6.0
pinoles
Ag
Remarks Reference
Ag also found in Anghileri,
lungs, kidneys, small
intestine, intestine,
bladder, muscle,
testesm, and brain.
Results indicate Ag Anghileri,
is released in an in-
soluble form and not
as Ag Radiosilver
is slowly excreted
through bile and
urine.
Anghileri,
1969
1969
1969
Ag had little effect VanCampen, 1966
on uptake of Cu
except that a signifi-
cantly greater propor-
tion of Cu was de-
posited in the liver
and significantly Tp^s
retained by the blood
in Ag-treated rats.
-------
Deposition of carrier-free radiosilver in rats was similar
after i.m. and i.v. injections. The most interesting information
from the studies of Scott and Hamilton (1950) was the distinct dif-
ference in organ accumulation between carrier-free doses and doses
containing stable silver compound added as carrier. Table 9 shows
the difference in distribution six days after i.m. injections when
three rats per group were given carrier-free silver or radiosilver
with 0.1 mg stable silver (0.4 mg/kg) or with 1.0 mg stable silver
(4.0 mg/kg).
Obviously, the liver had difficulty maintaining its efficient
removal of silver at a dose of 0.1 rug/rat, but the dose of 1.0
mg/rat definitely showed the limitation of its capacity so that the
rest of the reticuloendothelial system had to handle much more
silver. At the highest dose compared with the carrier-free dose,
the liver had accumulated 94 times as much of the absorbed dose of
silver; the spleen, 269 times as much; and the skin, 31 times as
much. Other organs, including the kidney, had about 10 times as
much silver. Scott and Hamilton presumed that a dose of 5 mg silver
per kg i.m. would be required to give a tissue distribution similar
to that seen in classical argyria.
West, et al. (1949, 1950), had shown that li:LAg nitrate when
injected i.m. or i.v. "...is taken up by blood leukocytes and
C-46
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TABLE 9
Distribution of Silver in the Rat at Day 6 Following
Intramuscular Injections of Different Doses of
Silver (percent of dose per organ)*
Percent of Dose
Absorbed
Absorbed
Heart and lungs
Spleen
Blood
Liver
Kidney.
G.I. tract
Muscle
Bone
Skin
Urine
Feces
Unabsorbed
Carrier-Free
92.1
0.06
0.01
0.50
0.36
0.07
1.12
0.27
0.18
0.24
0.64
96.56
7.9
Dose
0.1 mg
63.7
0.13
0.13
0.95
2.24
0.92
4.22
0.56
0.35
0.67
0.88
88.95
36.3
1.0 mg
53.5
0.59
2.69
3.03
33.73
0.63
8.21
2.39
2.20
7.39
1.82
37.33
46.5
*Source: Scott and Hamilton, 1950,
C-47
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carried into inflammatory body areas."* Presumably, the Ag-protein
complexes formed were phagocytized. Since insoluble silver com-
pounds would be less corrosive and also phagocytized, West and
Goldie (1956), injected normal and tumor-bearing mice with Ag20
to examine the distribution of the radioactivity by autoradio-
graphs. In normal Swiss albino mice given s.c. injections of 0.1
or 0.2 mCi Ag-O, the activity 24 hours after the injection re-
mained mostly at the injection site with a large fraction in the
liver and minor amounts in the spleen, stomach, colon, kidney, and
lung. In normal mice given the injections i.p., most of the activ-
ity was in the liver; some remained at the injection site, but
absorption was much higher than by s.c. injection. Thus, nigher
activity was seen in each of the organs than with s.c. injections.
However, mice with tumors (Sarcoma 180, Sarcoma McGhee, Carcinoma
C3H/BA, and Carcinoma E0771) showed by far the major activity in
the tumors and intracavity exudates when injected with radiosilver
near the tumor site (s.c. into the tumor periphery, into the
pleural cavity with malignant growth, or into the peritoneal cavity
bearing malignant growth). West and Goldie (1956) explained the
preferential silver absorption by tumors as follows: a s.c. injec-
tion in normal mice remained largely at the injection site, presum-
*West, et al. (1950) found that up to 10 percent of intradermal in-
jections of labeled silver nitrate (108f11 Ag) remained at the in-
jection site after 72 hours. When Staphylococcus aureus was in-
jected simultaneously in the same leg five times as much silver
was found at the injection site after 72 hours. But if injected
in different legs, the activity was preferentially found at the
site of bacterial injection.
C-48
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ably clogging the lymphatics. When adjacent tumors were present,
they apparently absorbed the li:LAg20 into macrophages and inter-
spaces of malignant tissue.
In argyric rats given 0.5 percent silver nitrate in their
drinking water for nine months, silver was especially found in
lysosomes of the liver's Kupffer cells, at the basal membrane of
the capillaries, and the connective tissue cells of the pancreas.
In the parenchymatous cells, Putzke (1967) found silver only as a
lipoid-silver complex or in lipofuchsin-like lysosomes and in
residual bodies. The lysosomes were thought to be responsible for
intracellular transport and the extrusion of silver. In the liver,
there was increased activity of cytochrome oxidase, but marked de-
crease in the activity of succinate dehydrogenase.
Ham and Tange (1972) cited numerous studies wherein silver
nitrate was administered in the drinking water of rats to study
glomerular basement membrane formation. These authors gave drink-
ing water containing 2,500 mg/1 AgN03 for 12 weeks to albino and
hooded female rats, killing pairs of animals at 1 to 12 weeks to
study the tissues by light and electron microscopy. Other pairs of
animals were killed at 1 to 10 months after silver intake. Four of
each strain were also killed for study 16 months after the cessa-
tion of silver intake. As shown in Table 10 the silver content in
the liver was similar in both strains, but varied by strain and in-
dividuals of the same strain in the kidneys. Abnormalities in
glomerular epithelial and endothelial cells were not progressive or
consistent. Bloom, et al. (1959) cited by Ham and Tange (1972) in
C-49
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TABLE 10
Silver in Formalin-Fixed Rat Tissues After Drinking
Silver-Containing Water, mg/kg* **
Hooded Rats
Albino Rats
Liver
Kidney
Liver
Kidney
n
i
Ul
o
3 Months' intake of
silver at 2,500
mg/1 in drink-
ing water
10 Months after
removal of silver
from drinking water
16 Months after
removal of silver
from drinking water
6.8, 7.0
1.4, 2.8
0.8-1.4
6.1, 9.8
3.7, 4.3
2.7-4.1
6.3, 7.0
2.2, 2.5
0.7-1.6
3.7, 7.1
1.8, 3.4
3.0-6.0
* Source: Ham and Tange, 1972.
**Determined by potentiometric titration.
-------
observing the phenomenon of increased formation of basement mem-
brane thought the increase might be greater than normal thickening
due to aging.
Moffat and Creasey (1972) fed 10 adult rats and 3 adult rab-
bits drinking water containing 1,500 mg/1 AgN03 for 4 to 20 weeks
to study the permeability of medullary vessels of the kidney to
protein. Only the rat kidney showed heavy silver deposits in the
glomeruli and outer medulla basement membranes. Both species had
heavy deposits in the inner medulla, but the distribution differed
markedly. In the rat, most of the silver was in the basement mem-
brane of the vessels and loops of Henle, but the heaviest deposits
were around the descending vasa recta. The main deposits in the
rabbits were also in the vessels and loops of Henle, but the dis-
tribution in each vessel or loop was asymmetrical. Most of the
silver was deposited on the side adjacent to the collecting duct.
In the silver-dosed rats, the occurrence of degenerating kidney
cells was more common than in normal rats.
Creasey and Moffat (1973) also cited several studies in which
silver nitrate had been administered in drinking water to experi-
mental animals to study the basement membranes of some (brain, eye,
and renal glomeruli) of the many kinds of tissues in which silver
accumulates. Silver is carried in the blood as a silver-protein
complex, and its deposition in tissues appears to indicate vascular
permeability to protein. Extravasation of protein in the kidneys
occurs in immature rats (younger than three months) much less than
in adults. This was shown by the slower rate of appearance (12 to
14 weeks versus 5 weeks) and finer particulate size (<30 nm versus
C-51
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30 to 90 nm) of silver granules deposited in the kidneys of imma-
ture rats given 1,500 mg/1 AgN03 solution for 4 to 15 weeks after
weaning, as compared with adults on the same regimen. The increas-
ing amount of silver deposited in the rat kidney glomeruli with age
has also been attributed to increasing glomerular filtration rate.
Silver granules were detected by electron microscopy in the
glomerular basement membrane of random-bred adult mice after 12
days of ingesting drinking water containing 6 mM AgN03 (648 mg/1
Ag) . After 14 weeks of silver ingestion, larger aggregates were
observed in the basement membrane and mesangium. Within 21 weeks
after cessation of silver ingestion, the silver deposits did not
change significantly (Day, et al. 1976). Some of the mice were
used in a study of immune complex glomerular disease induced by
i.p. injections of bovine serum albumin. The silver-labeled base-
ment membrane helped determine that the immune deposits were on the
intracapillary aspect of the basement membrane (Hunt, et al.
1976).
Metabolism
Silver is transported in the protein fractions of the plasma,
especially the globulins. The reticuloendothelial system, espe-
cially the liver, handles most of the removal of absorbed silver
from the body at moderate doses (0.4 mg/kg in rats, according to
Scott and Hamilton, 1950). At higher doses, deposits are markedly
increased in the skin. Inhaled silver particles that are not re-
moved from the lungs by the mucociliary reflex and coughing are
probably phagocytized and ultimately removed to the liver, from
C-52
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which they are eventually excreted via the bile. Formation of sil-
ver selenide deposits in the liver may be another method of detox-
ifying silver (the interactions of silver and selenium are dis-
cussed under Synergism and/or Antagonism). Many studies have
focused on elucidating the chemical forms of the silver deposits in
the skin. The most probable forms are metallic silver, silver sul-
fide, or silver complexes with the sulhydryl amino acids in pro-
teins. Since the deposits are so inert, they cannot be removed by
common heavy metal detoxification procedures. These deposits
appear to be another method of detoxification by the organism. In
the kidney, complexation with metallothionein may be another detox-
ification pathway.
Transport of silver in the blood is largely in the globulin
fraction. None of the silver content of blood is dialyzable "to
any extent" through cellophane (Scott and Hamilton, 1948). rn
vitro, the distribution of carrier-free Ag after three days in
heparinized rat blood containing an equal volume of isotonic saline
was: hemoglobin, 8.4 percent; ghosts of the cells, 11.6 percent;
globulin, 64 percent; albumin, 16 percent; and the protein-free
fraction, 0.001 percent. In vivo, the distribution of total amount
of radiosilver activity in rat blood five minutes after i.v. injec-
tion was erythrocytes, 10.2 percent; globulin, 57 percent; albumin,
32 percent; and the protein-free fraction, 0.7 percent; the liver
already contained 86 percent of the injected dose by five minutes
(Scott and Hamilton, 1950).
Lifshits (1965) reported the distribution of endogenous silver
in the blood of 16 healthy humans (in mg/1 whole blood). In the
C-53
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plasma, the fibrinogen fraction contained 0.0018 mg/1; the globu-
lins, 0.0064 mg/1; the albumins, 0.0024 mg/1; and minerals, 0.0014
mg/1. In the erythrocytes, the silver distribution was: stroma,
0.0038 mg/1; nonhemoglobin proteins, 0.0009 mg/1; and erythrocyte
minerals, 0.
Silver iodide is readily broken down by biological tissues.
Anghileri (1968) injected 0.2 ml of Ag131I (0.23 mg Agl/ml and 10
pCi 1 I/ml) into the tail veins of young albino mice (15 to 20 g).
In a similar experiment, the silver portion of the molecule was
labeled ( Ag). Less radioactivity was observed in the liver with
Agl than with Ag ^1 (53 percent versus 70 percent of the in-
jected dose after 10 minutes), but the Ag radioactivity remained
longer in the liver (21 percent versus 4.1 percent at 24 hours).
The concentration of radioactivity was much higher in the stomach
and thyroid with I than with Ag in the injected silver iodide
during the first 24 hours.
Camner, et al. (1974) reported that silver-coated 5 urn
Teflon*-/ particles were phagocytized _iri vitro by rabbit alveolar
macrophages in the presence of serum more slowly than were similar
particles coated with aluminum or chromium and at about the same
rate as were particles coated with manganese or uranium. When
serum was not added, there was less difference in phagocytization
rates. The former case is more comparable with the in vivo situa-
tion. (For silver, the average number of particles phagocytized
per macrophage in the presence of serum after 1.5 hours was 0.58;
C-54
-------
and for alumir. ', 0.72. Without serum, the numbers were 0.38 and
0.40, respectively.) There were fewer than 4 percent nonviable
macrophages after the 1.5-hour exposure of a monolayer of macro-
phages from disease-free rabbits to the particle suspension in 75
percent Parker 199 solution and 25 percent autologous rabbit serum
or in 100 percent Parker 199 solution.
After daily applications of 1 percent silver sulfadiazine
cream to the abraded skin of albino rabbits for 100 days at dosages
of 5.0, 10.0, or 15.0 g/kg/day, the kidney tissues were treated
with various solvents* in an effort to determine the chemical form
of the silver deposit. Sulfadiazine was not detected in chloroform
extracts of acidified tissue homogenates.** Since only the
strongly oxidizing solvent 16M nitric acid dissolved any of the
kidney tissue silver deposits (the range of silver concentrations
in four rabbit kidneys by atomic absorption spectrometry was 172.3
to 247.0 mg/kg), Grabowski and Haney (1972) concluded that the form
of silver was as a silver tissue complex whose dissociation under
normal conditions would be minimal, and whose only physiological
threat would be mechanical interference to kidney function. No
structural damage or impairment had been noted in the kidneys, how-
ever.
* 16M HNO3, 30 percent NH4OH, 50 percent CH3C02Hf 9 percent
H2NCSNH2, 37.5 percent HC1.
**The sulfadiazine probably remained in the acid solution as a
salt: A~ +NH3C6H5S02NHC4N2H3.
C-55
-------
Pariser (1978), using the differential solubility methods*
of Buckley, et al. (1965), found that only cyanide solutions re-
moved the silver from tissue sections of argyric patients (ages 83,
58, and "elderly"). This suggested that the chemical form of
silver was as silver sulfide or some other highly insoluble complex
rather than metallic silver.
Chromatographically purified metallothionein from normal rat
liver contained significant concentrations (by neutron activation
analysis) of Cd, Zn, Cu, Hg, and Ag. Experiments with 110mAg"1"
showed further incorporation into metallothionein (Sabbioni and
Girardi, 1977). Possibly this is the mechanism whereby the kidneys
excrete bound silver.
Excretion
Regardless of route and chemical form administered, fecal
excretion of silver always predominates over urinary excretion.
Most absorbed silver is excreted into the intestines by the liver
via the bile.
Scott and Hamilton (1950) showed that the liver is the chief
organ responsible for elimination of absorbed silver. The silver
content in the liver, feces, and gastrointestinal tract contents
was reduced when bile duct ligation or light chloroform anesthesia
(which produces liver damage) in rats was performed prior to injec-
tion of carrier-free radiosilver. Ordinarily, after i.m. injection
*Tissues were extracted with thiosulfate fixing bath (dissolves
silver mercaptides, oxides, chlorides, bromides, iodides, car-
bonates, and phosphates); ferricyanide-bromide bleach followed by
thiosulfate fixing bath (dissolves metallic silver); and 5 percent
sodium cyanide (which dissolves most insoluble silver salts such
as silver sulfide).
C-56
-------
of 1 uCi radiosilver (0.1 ug) , 60.9 percent of that absorbed was
excreted in the feces on the first day, and 21.4 percent was al-
ready in the gastrointestinal (G.I.) tract. After bile duct liga-
tion, on day 2, 57.6 percent of the activity still remained in the
liver, 5.06 percent was in the G.I. tract, and only 6.85 percent
was in the feces. After light chloroform anesthesia for three
hours, the rats excreted silver at 0.0001 the normal rate.
Urinary excretion of silver is generally very low. At four
days after an intravenous (i.v.) dose of radiosilver, rats had ex-
creted 94.06 percent of the dose in the feces and 0.34 percent in
the urine and at 16 days, 97.8 percent and 1.8 percent, respec-
tively (Scott and Hamilton, 1950). Administration of Ca EDTA, a
common metal chelating agent, reportedly increased urinary excre-
tion of silver. Ligating the bile duct in laboratory animals in-
creased renal excretion while reducing fecal excretion by a factor
of 10, thereby further demonstrating the biliary nature of silver
excretion (Furchner, et al. 1968). Radiosilver ( Ag) iodide was
removed from the blood two hours after i.v. administration and was
slowly excreted through the bile and urine in a nonionic form
(Anghileri, 1971). The ratio of urinary-fecal excretion is 0.001
to 0.258 (Furchner, et al. 1968; Kalistratova, et al. 1966; Anghi-
leri, 1969).
Dequidt, et al. (1974) found significant silver excretion in
the urine after several i.p. injections of different forms of sil-
ver medicinals. Wistar rats given 12.6 mg/kg silver i.p. as the
nitrate daily for five weeks (apparently a 4-day work week) elimi-
nated 10 to 20 ug/rat/day in the urine. At 5 mg/kg/day silver as
C-57
-------
silver nitrate for 24 injections within six weeks the urinary
silver excretion was 3 to 15 ug/rat/day (average 4 ug) . When
injections of 29.6 mg/kg colloidal silver were given to rats 11
times within three weeks, the urinary excretion was 8 to 24 ug/
rat/day (average 12.6 ug). Colloidal silver i.p. injections at 5
mg/kg/day for 24 injections within six weeks gave urine containing
2 to 10 ug/rat/day. Silver proteinate i.p. injections (16 within 4
weeks) at 5 mg/kg gave urinary silver contents of 3 to 15 ug/rat/
day.
In rats, silver is eliminated from the lungs in two or three
phases. The fastest phase (0.3 to 1.7 days) removes most of the
inhaled dose by mucociliary clearance. A second phase and third
phase remove absorbed silver, mostly via the liver, with half-lives
of about 8 to 15 and 40 to 50 days, respectively.
As of 1964, 110mAg had been detected 583 times in 186 dif-
ferent individuals in the nuclear industry. Sill, et al. (1964)
described the inhalation exposure of 50 people to activation prod-
uct Ag when an experimental loop containing silver-soldered
thermocouples in the Engineering Test Reactor was opened. Re-
exposure occurred during cleanup procedures, complicating data
interpretation; but the calculated effective half-life was about
eight days before recontamination. The source of the ^ Ag and
the time of exposure was not the same for all subjects. The indi-
vidual with the highest body burden of 0.93 yCi had an elimination
rate with a half-life of 13 days. Two others had effective half-
lives of 17 and 69 days. (The International Commission on Radio-
logical Protection gives 4.9 days for whole-body elimination half-
life.)
C-58
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In most cases, maximum activity occurred in the nose, mouth,
chest, and lower edge of the rib cage. In almost all the cases,
110mAg could not be detected in 1,500-ml urine samples (Sill, et
al. 1964).
At Harwell, England, a 29-year-old man accidentally inhaled
dust from an experimental hole in a nuclear reactor. The burden of
radionuclides was below the maximum permissible, but the levels of
65Zn and 110mAg allowed prolonged study of their retention and dis-
tribution (Newton and Holmes, 1966). Whole-body gamma-ray spec-
trometry on the second day after the accident showed 197 nCi Ag
(and 330 nCi 65Zn). By day 6, 90 percent of the zinc still re-
mained, but only 40 percent of the silver seen on day 2 remained.
About 25 percent of the total activity appeared to be confined to
the region of the liver. The 110mAg appeared to be more closely
confined to the liver than was the 65Zn on day 16, when individual
measurements were made. For 155 days, after which the silver dis-
tribution studies were abandoned, the liver was the major site of
deposition. The whole-body effective half-life of the 15 percent
retained silver was 43 days (biological half-life 52 days).* Dur-
ing the first 100 days, the content in the liver appeared to
decrease at about the same rate, but there was a longer-lived com-
ponent that may have been an artifact from Cs. There was no sil-
ver in the urine during the first 54 days, but it was present in
fecal samples up to about day 300.
*Polachek, et al. (1960) had reported a value of 48 days for liver
clearance. The International Commission on Radiological Protec-
tion in 1959, however, quoted a value of 15 days.
C-59
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The M.S. theses of Phalen (1966) and Carver (1968) reported
controlled inhalation studies in which rats were exposed, nose
only, to Ag-tagged silver smoke. Clearance from the body was
described in two exponential functions of biological half-lives, 8
days and 20 days, indicating two separate body pools of silver
(Phalen and Morrow, 1973).
The initial rapid clearance from the lung is on the order of
several hours or one or two days (Phalen, 1966; Carver, 1968;
Skolil, et al. 1961; and Newton and Holmes, 1966). In humans, 80
percent was cleared from the lungs with a biological half-life of
one day. The half-life for the remainder in the Skolil, et al.
(1961) report was 15 days (Phalen and Morrow, 1973).
Phalen and Morrow (1973) studied six female beagle dogs who
received single acute inhalation exposures to 110mAg-tagged silver
aerosol via tracheal tubes (for 7 to 15 minutes while anesthe-
tized) . The method of aerosol generation (by wire explosion) in-
sured well-characterized spherical particles, primarily of metal-
lic silver. The activity median aerodynamic diameters were 0.5 y.
Absolute deposition in the lungs was 1 ng/kg (in text; in the
author's abstract the value given is 1 mg/kg).
The solubility rate constants were: in distilled water, 0.1
*N
pg/cm /day at 35 to 37°C; and in simulated interstitial fluid, 10
2
ug/cm /day. One could expect 99 percent of the aerosol mass in the
lung to dissolve in two days.
The activity appeared to clear at about 6 to 8 hours. One dog,
exposed for 15 minutes, was sacrificed six hours post exposure.
There was 96.9 percent of the initial deposit still in the lungs,
C-60
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2.4 percent in the liver, 0.38 percent in the blood, and 0.02 per-
cent in the stomach. The solubility rate constant in the lung was
calculated to be 1 ug/cm2/day. Perhaps some dissolved silver re-
mained in the lung as a tissue complex. By three days, half of the
initial amount deposited was gone. Since only 20 percent appeared
in the excreta during the first five days, most of the silver was
not removed by the mucociliary mechanism. Perhaps 90 percent was
carried by the blood to the liver. For three dogs, the major silver
repositories were the liver, lungs, brain, skin, and muscle; one of
the dogs had larger amounts in bile, liver, and bone (Table 11).
Where larger particles are inhaled, elimination may more
resemble that observed after oral dosing, when much of the lung
deposit has been eventually swallowed.
Camner, et al. (1977) found that inhaled 4-um TefloiW par-
ticles coated with carbon, silver, or beryllium were cleared from
rabbits' lungs (8 to 10 New Zealand rabbits per test) at about the
same rate during the first week, despite differences in their tox-
icity and in the rates of _in vitro phagocytosis that had been
reported. Presumably, intact particles of the size and lung burden
used (aerosol inhaled for only 6 to 8 minutes, resulting in 1 to 10
uCi and 10 to 100 yg deposition) were not actively removed from the
lungs by the alveolar macrophages during the first week after inha-
lation. External measurements of clearance could be made because
all of the particles were tagged with Cr.
The silver-coating remained 50 percent intact in rabbit serum
(replaced daily) at 37°C for 12 days. But in a flow-through system
C-61
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TABLE 11
to
Biological Half -Lives (t^2) in Days for Clearance
in 4 Dogs After Inhalation of Silver Aerosol*
Lung
Pooled Data t±/2 t1/2 t1/2
Dogs 1,3,4, 1.7 8.4 40
and 5
Liver
fcl/2 fcl/2
9.0 40
(97% of
that
excreted)
by
of
(1%
8.4
Body
analysis
excreta
in urine)
-12.9
*Source: Phalan and Morrow, 1973
-------
with 10 percent horse serum in saline at 37°C for eight days, 26
percent of the particles had lost more than half their coatings.
Kent and McCance (1941) followed the excretion of silver for
three separate 7-day periods in a woman with severe generalized
argyria produced by "washing out her nose for many years with an
organic silver preparation." Her negative balances (Table 12) may
have been due to desquamation of the silver-containing cells from
the alimentary canal lining.
Enders and Moench (1956) reported that argyric albino rats
with varying degrees of heavy silver deposits in the liver and very
weak to heavy deposits in the kidney after consumption of a silver
medicinal (Targesin^ for three months, showed progressively less
silver in these organs after the silver feeding had been stopped.
At three months postexposure, the liver deposits in 10 rats were
only very weak or entirely absent; and there were no deposits in
the kidneys and duodenum. After six months on a normal diet, four
of the nine rats showed very weak silver deposits in liver, kidney,
and/or duodenum.
Buckley and Terhaar (1973) reported that the skin is an excre-
tory organ in generalized argyria with gradual translocation of
silver from the general body pool through the dermis and finally
into the epidermis as soluble silver. One worker with generalized
argyria was studied. Silver appeared to be released from melanin-
silver complexes as a soluble ionic form near the surface of the
epidermis.
In rats, mice, and rabbits, 99 percent of a one-time oral dose
of silver is eliminated within 30 days. Dogs, which absorb 10
C-63
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TABLE 12
Silver Balance in a Female With
Severe Generalized Argyria*
Silver, mg/week
Food
Feces
Urine
Balance
Week 1
0.05
1.3
0
-1.25
Week 2
0
1.5
0
-1.5
Week
0.7
2.3
0
-1.6
3
*Source: Kent and McCance, 1941
C-64
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percent of the dose, require more than 28 days. Snyder, et al.
(1975) for the International Commission on Radiological Protection
reviewed the literature pertaining to the silver balance for refer-
ence man and concluded that his intake in food and fluids is 70
Ug/day and his losses include 9 ug/day in urine, 60 ug/day in
feces, 0.4 ug/day in sweat, and 0.6 ug/day in hair.
Tipton and Stewart (1970) reported that the range of silver
found in the ash of food was 0.5 to 75 mg/kg; of feces, 1 to 115
mg/kg; and urine, 0.0 to 15 mg/kg (analysis by spectrographic pro-
cedures).
Kehoe, et al. (1940) found only 0.06 mg/silver/day eliminated
in the feces, which was less than the 0.088 mg/day dietary intake
of silver. Although silver was detected in the blood of Americans,
Frenchmen, Mexicans, and Germans, it was not detected in their
urine. Almost all silver is excreted in the feces of mammals with
only traces in the urine (Gammill, et al. 1950; Scott and Hamilton,
1950). However, silver may be detected in urine in cases of silver
poisoning (Sunderman, 1973). Silver has also been detected in
nasal and vaginal secretions (Barsegyants, 1967).
Analyses for silver were made on diets and excreta of a hus-
band (Subject B) and wife (Subject A) for 30 days. Subject B had a
mean intake of 0.035 mg silver per day and Subject A, 0.04 mg silver
per day, respectively. Subject A drank five cups of coffee (not
analyzed for silver content) per day, had a fecal/urinary silver
excretion ratio of 3, and a positive average silver daily balance
of 0.007 mg/day (2.6 mg/yr). Subject B drank three glasses of milk
per day (analyzed for silver content), had a fecal/urinary excre-
C-65
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tion ratio of 8, and a negative average daily silver balance of
0.054 mg after 30 days (Tipton, et al. 1966).*
Average human intake from the diet is estimated at up to 0.088
mg/day (Kehoe, et al. 1940). At that rate, if 100 percent of the
silver ingested is retained in the body, approximately 31 years
would be required to accumulate 1 g of silver. Based on the data of
Tipton and Cook (1963), the average silver content in wet tissue of
Americans is about 0.05 ppm. The body of a 150-lb human, whose tis-
sue content was 0.05 ppm, would contain only 32 mg silver or 3.2
per cent of a 21-year ingestion total. it would appear that very
little of the silver ingested from nontherapeutic sources is actu-
ally retained in the body.
Excretion of radiosilver (110AgN03) was faster, and a larger
percentage of it was excreted in test animals when it was admin-
istered orally than when it was injected either i.p. or i.v. More
than 90 percent of the carrier-free silver administered by any of
these routes was excreted in the feces with at least 90 percent of
the orally ingested silver not being absorbed.
In beagle dogs (average age 5.5 years, 12 to 16 kg) given oral
doses of 6 uCi 110Ag as the nitrate, about 10 percent of the dose
was absorbed. About 70 percent of the absorbed dose had a bio-
logical half-life of about one month. Dogs retained 1 percent of
the dose for at least four weeks (Furchner, et al. 1968).
*Subject A retained 16 percent of the dietary silver she ingested,
but Subject B excreted 2.5 times more silver than he ingested from
his diet. (Both A and B excreted about the same amounts of silver
in their urine.) Subject B was also in negative balance for cop-
per, barium, and nickel. His medicine intake and occupation were
not mentioned nor was the state of his dental restorations.
C-66
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Female RF mice (eight weeks old, 2 g) , given 110Ag as the
nitrate i.p., i.v. (tail vein or jugular vein), or orally (12 mice
per route) lost half the dose much faster than did the rats of Scott
and Hamilton (1950). The rats required 30 days to eliminate 99
percent of the dose, whereas the mice required only 18 days.
Almost the entire oral dose (given by stomach tube) was lost by the
mice with a biological half-life of 0.125 day. The biological
half-life of the remainder was 1.5 days. "The body burden under
conditions of chronic oral ingestion would be only about one-fifth
of the daily dose" (Furchner, et al. 1966a).
The plots of effective retention versus time of oral doses of
110Ag in 12 mice, 6 rats, 4 monkeys, and 4 dogs showed that within
the first day or so, the rate of elimination decreased in the
order: rats-^dogs-^mice->monkeys; but at 5 days, the order was
rats-^mice-^monkeys-^dogs; and at 15 to 35 days, the order was
mice^rats^>monkeys->dogs. The urinary/fecal ratio on day 1 for
rats and mice was 0.001; for monkeys, 0.02 (Furchner and Drake,
1968) .
When a one-time dose of 110mAgI (1 uCi 110mAg in 0.5 g Agl) was
force-fed to three cottontail rabbits, 99 percent of the dose was
excreted within three days, the elimination half-life being 0.48
day. From 8 to 26 percent of the radiosilver entered the cecum (as
judged in three rabbits prevented from reingesting their cecal pel-
lets) (Jones and Bailey, 1974).
Four rabbits were fed 0.00042 percent silver, in the dry mat-
ter of feed, as silver iodide complexes prepared to simulate cloud-
seeding generator products for 30 days. The concentrations of
C-67
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silver in the dry matter of feces and cecal contents were similar
(4.2 to 5.2 mg/kg). The silver content of the dry matter of their
livers (0.2 mg/kg) was the same as that in four control rabbits fed
a normal diet (0.00001 percent silver); thus, absorption was not
likely (Jones and Bailey, 1974).
Roy and Bailey (1974) concluded that accumulation of silver in
the rumen of any ruminant species upon chronic intake is not
likely. The presence of chloride ions, protein, bacteria, and
other organic matter in the rumen inhibit the antimicrobial action
of silver ions and insure that most of the ingested silver* passes
from the rumen in an insoluble form.
EFFECTS
Acute, Subacute, and Chronic Toxicity
The toxicity of silver compounds could be classified as moder-
ate, although large doses of silver compounds may have serious
effects (Table 13). For example, ingestion of 10 g silver nitrate
is usually fatal. In humans taking large doses of silver nitrate
orally, the patient suffers violent abdominal pain, abdominal
rigidity, vomiting, and convulsions and appears to be in severe
shock. Patients dying after i.v. administration of CollargoiS/
(silver plus silver oxide) showed necrosis and hemorrhages in the
bone marrow, liver, and kidney (Hill and Pillsbury, 1939). In the
body, silver may be precipitated by protein or chloride ion. Table
salt (sodium chloride) is an antidote for silver nitrate poisoning.
*Silver iodide or silver nitrate at levels simulating 0.0001 per-
cent and 0.01 percent, respectively, in the dry feed were inserted
with small amount of feed in nylon bags into fistulas in the ru-
mens of goats.
C-68
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TABLE 13
Acute Toxic Effects of Silver on Humans*
How
Administered
Dosage
Survival
Time
Observed Effects
Remarks
n
i
cr>
VD
i.v. Collargo© 36 cc of 12%
soln.
[RJ
i.v. Collargol^ 32 cc of 5%
soln.
IR)
i.v. CollargoK^ To fill renal
pelvis for
X-ray study
i.v. Collargo.
10 cc of 2%
soln.
Intravaginally 2 cc unknown
concn. of
AgN03
Oral
Oral
8 g AgN03 in
soln.
2-30 g AgN03
Oral metallic 50-260 g
Ag
3-14 days
3-14 days
5 min.
A few hr.
to a few
days
Purpura hemorrhagica on the
4th day. Death. Ag chiefly
in the reticuloendothelial
system.
Extensive necrosis and hemor-
rhage of bone marrow, liver,
and kidney.
Death. Severe hemorrhagic
diathesis with parenchyma-
tous hemorrhages in the stom-
ach, intestines, and body
cavities.
Cyanosis, coma; death due to
pulmonary edema.
Death.
Vomitus contained AgCl.
Usually death at dosages
10 g.
Gastric fullness, anorexia,
gastric pain, and/or diarrhea.
No Ag found in
lungs.
Abortion attempt.
Death possibly not
due to AgNO3.
Patient recovered.
10 g is usually
fatal, but 30 g has
been survived.
*Source: Hill and Pillsbury, 1939.
-------
There is little likelihood of systemic effects in people recovering
from toxic doses, but silver may cause degenerative liver changes
(Dreisbach, 1963).
The most common noticeable effects of chronic and, less fre-
quently, subacute human exposure to silver or silver compounds are
generalized argyria, localized argyria, and argyrosis (argyria of
the eye unless stated otherwise). The two most important causes of
argyria are medicinal application of silver compounds and occupa-
tional exposure. Numerous case histories from Hill and Pillsbury
(1939) are summarized in Table 14. Generalized argyria is a slate
gray pigmentation of the skin, hair, and internal organs caused by
deposition of silver in the tissues. The degree of pigmentation is
highest in areas of the skin most exposed to light, but the concen-
tration of silver in the skin from various parts of the body is the
same. Silver also accumulates in the blood vessels and connective
tissue. Additional manifestations of generalized argyria include:
silver coloration of fingernails and conjunctiva and blue halo
around the cornea. in localized argyria, only limited areas are
pigmented.
Every silver compound in common chemical use has caused gen-
eralized argyria. Of 239 recorded cases of generalized therapeutic
argyria analyzed by Hill and Pillsbury (1939), 118 were caused by
silver nitrate and 28 by ArgyrofS)(mild silver protein), the second
most frequent causative agent. Only 19 were caused by i.v. injec-
tion of silver arsphenamine. Of 178 cases, in which the route was
C-70
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o
I
-J
Observed Effect Ag Compound
Increased densL- Ag particles
tries in lung
X-rays
Localized argyria Ag particLes
Generalized Ag salts
argyria
Argyrosis
TABLE 14
Argyria
Time Until
Length of Appearance Ag Intake Ag
Exposure Conditions Exposure of Argyria or Total Dose Excretion
Silver polishers Long periods
Penetration of fine
particles
Ingestion or inhalation
of Ag salts
1-2 mg Ag/m in air
Remarks
Ag impregnation of
vascular elastic mem-
branes.
11 were affected in
upper respiratory
Reference
ACGIH, 1971
ACGIH, 1971
ACGIH, 1971
ACGIH, 1971
Generalized argy- Ag in air
ria, possibility of
Generalized argyria
Generalized argyria
Argyria - no recognizable
health disturbances
Pulmonary argyria
ticnsin manufacturing
Ag varnish and in slver-
ing radio-tech, parts
passages. 9 in con-
junctiva or cornea.
Breathe 10 m air/
day retention of
50% of Ag (assumed)
20 years
Medication or industrial
exposure
5-fold the
recom mended ,
TLV, 0.05 mg/m ,
would lead to
accumulation of
1.2 g Ag.
Primarily in
Lung and Gi
tract.
ACGIH, 1971
Absorbed via
f eces; only
traces in
urine.
Very slight,
over 3 week-
long periods.
GJ. tractor by
dust inhalation.
possible cause of kid-
ney lesions with con-
sequent dangers of
arteriosclerosis and
lung damage but not
fibrosis.
Often have bronchitis
and emphysema, but
no cause-effect rela-
tionship has been
established.
Browning, 1961
Browning, 1961
Browning, 1961
Gafafer, 1964
-------
TABLE 14 (Continued)
Observed Effect
Lung pigmentation
Generalized
argyria
Generalized
argyria
Generalized
argyria
Generalized
argyria
Generalized
O argyria
1
Ji Generalized
to argyria
Localized argyria
Argyrosis
Industrial
argyrosis
Localized argyria
of gums
Mottled pigmen-
tation
Ag Compound
Ag and Fe2O,
AgNO3
ProtargoP*
AgN03, stick
CollargojS)
Ag arsphen-
amine
Dental alloy
AgC:CH
Exposure Conditions
Hocked as a silver
finisher
j-uuoim.
Administered orally
to treat epilepsy and
GO. symptoms
300-g soln. instilled
into urethra daily
Local application for
sore throat and ton-
gue ulcers
Administered orally
to treat pulmonary
tuberculosis
iv.
During preparation foe
a dental crown
Explosion
Time Until
Length of Appearance Ag Intake Ag
Exposure of Argyria or Total Dose Excretion
Weeks to 20 E.g., 2 years 9-1,000 g
years after taking
600 g foe
1.2 year
2 days 3 days
0.5-20 years E.g., 1 year
(when used for
3 years)
E.G., 5 years 1 year 50-530 g
(260 g Ag)
2-10 years 16 months to 0.91-7.6 g
9 years
Remarks
Due primarily to Fe,
but Ag present
201 cases from
1700 to 1939
17 cases from
1700 to 1939
57 cases from
1700 to 1939
12 cases from
1700 to 1939
Caused blue pig men-
Reference
Johnstone and Miller,
1960
Hill and Pillsbury,
1939
J.7J y
Hill and Pillsbury,
1939
HID. and Pillsbury,
Hill and Pillsbury,
1939
d.yjy
Hill and Pillsbury,
1939
Hill and Pillsbury,
1939
Hill and Pillsbury,
1939
Hill and Pillsbury,
1939
Hill and Pillsbury,
1939
Burton, 1970
Orentreich and Pearlsteii
-------
other than i.v., 89 were caused by oral intake of silver, chiefly
as the nitrate or as colloidal silver plus silver oxide, and an-
other 75 by administration to the nose and throat.
Silver compounds, with the possible exception of silver oxide,
are not absorbed through unbroken skin in significant amounts, but
absorption occurs through wounds and mucous membranes. Localized
argyria of therapeutic origin is relatively rare, usually resulting
from topical administration to the conjunctiva, nasal mucosa, tis-
sues of the mouth, or skin ulcers.
Argyrosis involves all eye tissues except the optic nerve.
Instillation of 0.25 percent silver nitrate for three weeks and in-
stillation of 3 to 5 percent silver colloidal compounds for 5 to 10
weeks have produced argyrosis (Hill and Pillsbury, 1939).
Colloidal silver compounds have been widely used to treat
upper respiratory infections, but the amount of silver absorbed and
permanently retained by the respiratory tract has not been deter-
mined. The total safe period for nasal instillation of colloidal
silver compounds is believed to be 3 to 6 months. Colloidal silver
compounds in the nose interfere with normal ciliary activity (Hill
and Pillsbury, 1939).
Urethral application of ProtargoiS^ for treatment of gonorrhea
resulted in argyria after two days, the most sudden onset of argy-
ria reported. Silver nitrate-impregnated compresses applied to
abraded skin caused argyria 14 days after the treatment. In only
two other cases did argyria result in less than six weeks after
treatment (Hill and Pillsbury, 1939) .
C-73
-------
Generalized argyria as an occupational disease was never com-
mon, it occurred almost exclusively among silver nitrate makers
and is now disappearing due to improved work conditions. Some
workers involved in mirror plating, glass bead silvering, silver
Christmas cracker manufacturing, photographic plate manufacturing,
silver mining, and packaging silver nitrate have developed argyria
as a result of ingestion or inhalation of silver fulminate,
nitrate, albuminate, and cyanide (Schwartz, et al. 1947). Bron-
chitis and emphysema have been described in workers with pulmonary
argyria, but a cause-and-effeet relationship has not been estab-
lished (Gafafer, 1964).
Argyrosis occurred in all cases of argyria caused by occupa-
tional exposure and was generally more pronounced than therapeutic-
ally produced argyrosis. Localized argyria is rare, usually re-
sulting when silver compounds contact broken skin or mucous mem-
branes (Hill and Pillsbury, 1939). It has occurred in workers who
handle metallic silver in filing, drilling, polishing, turning,
engraving, forging, soldering, or smelting operations. Local argy-
rosis has occurred in electroplaters, firecracker makers, silver
mirror manufacturers, etc. Silver polishers, exposed over long
periods, sometimes exhibit increased densities in their lung X-rays
due to silver impregnation of the elastic membranes of the pul-
monary vessels. Pigmentation occurs slowly in workers who develop
localized argyria—50 percent of the workers have been employed 25
years or more. The time of the onset of pigmentation has varied 2
to 38 years (ACGIH, 1971; Hill and Pillsbury, 1939).
C-74
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In three cases, post-mortem examination showed the distribu-
tion of silver in the tissues of persons having argyria resulting
from occupational exposure was the same as the distribution of
silver in tissues of those having therapeutic argyria (Hill and
Pillsbury, 1939).
Several toxic effects, only indirectly attributable to silver,
have been reported from use of silver compounds in treatment of
burn patients. Most of them occur within a few days of initial
treatment and are readily corrected by appropriate treatment; the
duration of silver treatments probably seldom extends into the
chronic range (>13 weeks) .
Because of the hypotonicity of the 0.5 percent silver nitrate
dressings and the tendency to precipitate as silver chloride,
electrolyte imbalance may occur in a few hours (Wood, 1965).
Electrolytic disturbances are also occasionally found in patients
treated with silver sulfadiazine (Burke, 1973). For that reason,
the electrolytes in the patient's blood are closely monitored and
supplemented when necessary. Sevefe electrolyte depletion is
especially common in children during prolonged use of 0.5 percent
silver nitrate in burn therapy (Bondoc, et al. 1966).
Methemoglobinemia is sometimes induced in patients treated
with silver nitrate because of the reduction of the nitrate to
nitrite by bacteria in the patient's skin, not because of the pres-
ence of nitrite in the original solution. Cultures of endobacteria
from a burn patient exhibiting methemoglobinemia readily reduced
C-75
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nitrites (Strauch, et al. 1969a). An absorptive surface, such as a
granulating wound or damaged skin, is also needed (Strauch, et al.
1969b). Strauch, et al. (1969a) recommended that discontinuation
of silver nitrate therapy in patients with up to 30 percent methe-
moglobinemia would return patients' hemoglobin levels to normal
within 24 to 72 hours. However, if the level is greater than 30
percent the patient must be actively treated with methylene blue.
Silver sulfadiazine (Silvaden45) Marion Laboratories, Kansas
City, Missouri) is used increasingly to prevent infections from
Pseudomonas aeruginosa and other bacteria in treatment of burn
patients. It is preferred to silver nitrate treatments because it
does not deplete the body of sodium, chloride, or potassium.
Henderson (1975) stated that the finding of leukopenia in burn
patients being treated with silver sulfadiazine (Silvadene® cream)
was not due to the treatment but to the thermal injury itself.
Daniels, etal. (1975, cited by Henderson, 1975) had found that depressed
white blood cell count and suppressed immune response were often
seen in burn patients. Gayle and Haynes (1976, cited by Kiker, et
al. 1977) had seen marked leukopenia in burn patients treated with
silver sulfadiazine. Kiker, et al. (1977) performed a double-blind
study with a nonantimicrobial placebo in the control group to
determine if the leukopenia was due to the silver sulfadiazine
therapy or to the thermal injury. Thus, 60 juvenile patients with
a mean area burned of 48 percent of the body surface and treated
with the placebo showed a white blood cell count of 11.8 + 2.5 x
103/mm3. The 69 juvenile patients (52 percent mean area burn)
receiving silver sulfadiazine treatment had a white blood cell
C-76
-------
count of 12.2 + 2.1 x 103/mm3. There was no significant difference
in the white blood cell count of the two groups (p > 0.05); six
placebo-treated patients and five silver sulfadiazine-treated
patients developed leukopenia (WBC < 5,000/mm3). In a second
similar study with 175 patients receiving silver sulfadiazine, 5.7
percent developed leukopenia. In all cases, the leukopenia re-
solved itself without discontinuing the therapy.
Valente and Axelrod (1978) maintain that the leukopenia ob-
served during silver sulfadiazine therapy is due to the sulfadia-
zine portion of the drug (most of the silver remains at the wound
bound to tissue and bacterial proteins and DNA) , not the injury.
They aspirated the bone marrow of a burn patient exhibiting leuko-
/R^l
penia on two occasions within 48 hours of treatment with Silvadene^
and noted cell maturation arrest.
Renal injury, sometimes fatal, and sensitivity following sul-
fonamide therapy is well-known. Owens, et al. (1974) reported the
first case of nephrotic syndrome apparently due to topical applica-
tion of silver sulfadiazine. The electron-dense deposits seen in
the glomerular basement membrane suggested an immune-complex mech-
anism. No attempt was made to identify the deposits as silver
since precipitation of crystals has been observed during other sul-
fonamide-induced renal damage.
Fox (1973), when asked to discuss side effects that had
occurred in the five years of use of silver sulfadiazine cream in
burn treatment, remarked that two cases of apparent skin sensi-
tivity had come to his attention.
C-77
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Aside from burn therapy and use of medications applied to
mucous membranes, silver metal has been used in surgery. Silver
points have been used for years to induce apical bone healing in
dental surgery. Because of the recognized cytotoxicity of silver
corrosion products, Weissman (1975) recommended that titanium
points be substituted for silver.
Argyrosis of the cornea in workers who handle silver nitrate
may be accompanied by turbidity of the anterior lens capsule and a
disturbance of dark adaptation. Deposition of silver in the eye
does not usually result in loss of vision (Browning, 1961).
Two silver nitrate workers afflicted with argyrosis of the
lung showed mild chronic bronchitis with silver impregnation in the
walls of the middle and upper region of the nasal mucosa. In a more
severe case, the bronchial mucous membrane also showed basal mem-
brane deposits and some squamous metaplasia. There was less evi-
dence of phagocytosis than in the nasal mucosa and no hazard of
fibrosis. Pigmentation was comparable with that of anthracosis and
siderosis (Browning, 1961).
Grant, et al. (1975) analyzed by atomic absorption spectro-
photometry the lung tissues of 11 mummified subjects from northern
Peru believed to have been involved in hard-rock silver mining
and/or ore refining in the period 1500 to 1600 A.D. High levels of
mercury were found in most tissues, but there was no statistical
correlation between the concentrations of mercury or lead and lung
disease. A moderate correlation between lung disease and
silver was found.
C-78
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Marks (1966) reported the case of a 33-year-old woman, a
radiographer for 10 years, who exhibited contact dermatitis under
her contaminated watch strap. Patch tests showed sensitivity to
the thiosulfate complex of silver iodide, fixing fluid which had
contacted silver (but not unused fixing fluid), and 1 percent sil-
ver nitrate. The sensitivity was assumed, therefore, to be due to
ionic silver. Marks had found only one case in the literature of
contact dermatitis due to silver. Gaul and Underwood (1948, cited
by Marks, 1966) reported a dermatitis in a 27-year-old man who had
sensitized himself by using a silver nitrate solution on his feet.
In sensitivity tests, he reacted to old 10 percent silver nitrate
solution (but curiously not to fresh solution), silver foil, and
silver proteinate. Since lists of allergens for patch tests some-
times included 5 or 10 percent silver nitrate solutions, Marks sug-
gested that allergic contact dermatitis was more prevalent when
silver nitrate topical treatments were more common.
Zech, et al. (1973) attributed a nephrotic syndrome in an
obese, argyric 73-year-old man to silver deposits in the kidney.
The man had used a silver-containing mouthwash or gargle for 10
years (1955 to 1965), presumably corresponding to the absorption of
a total amount of 88 g of silver. The patient showed respiratory
insufficiency and a nephrotic syndrome with proteinuria, elevated
a2 macroglobulins, and glomerular (but not tubular) involvement.
Silver deposits were found in the glomerular basement membrane.
C-79
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The toxicity of silver to species other than mammals and birds
will not be discussed because of its inapplicability to human toxic
effects.
Acute effects from silver in mammals are usually associated
with i.v. administration. For example, silver nitrate has been
used frequently since 1932 to produce acute pulmonary edema for
study. Dogs injected with 0.5 ml of 10 percent AgNO3/kg (-^-32 mg
Ag/kg) into the left ventricular wall or the pulmonary artery
developed the edema, myocardial ischemia and lesion, hypertension,
and swelling and necrosis of wall and endocardium. Genesis of pul-
monary hypertension and edema by silver nitrate depends on its
entering the pulmonary circuit, and the mechanism involved is prob-
ably stimulation of vagal terminations (Sales and Duarte, 1960) .
Intravenous injections of silver nitrate in dogs produced hemo-
dynamic disturbances resulting in pulmonary edema, with circulatory
hypoxia causing death (Mazhbich, 1961).
Hill and Pillsbury (1939) reviewed the early literature on the
toxic effects seen in animals given various medicinal forms of
silver. When inorganic compounds were given i.v., the effects were
chiefly on the central nervous system. The animals receiving
lethal doses showed weakness, rigidity, and contractures in the
legs, loss of voluntary movements, and interference with cardiac
blood supply. LD5Q data apparently were not calculated.
The oral LD5Q for silver sulfadiazine in CF, mice has not
been determined, but the LD90_100 was ;> 1,050 mg (Wysor, 1975b and
1977) .
C-80
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The i.p. LD (30 days) for Ag+ as the nitrate in male Swiss
albino mice (21 + 2 g) is 13.9 rag/kg, indicating that Ag is 345
times more toxic than Na+ (as the chloride) (Bienvenu, et al.
1963).
Rabbits receiving 20 injections on their depilated backs of
a silver salt dissolved in distilled water (0.01 M) showed papules
which had a minimum diameter of 5 mm within 24 hours. Of the Group
I metals tested, only silver and gold produced skin reactions (gold
at 0.1 M concentration) (Muroma, 1961).
Some of the toxic effects of Ag"1" and other heavy metal ions
may be due to their alteration of cyclic adenosine monophosphate
(AMP) metabolism, which would be expected based on In vitro experi-
ments by Nathanson and Bloom (1976): an 8 uM solution of silver
nitrate caused 50 percent inhibition of adenylate cyclase in a rat
cerebellar homogenate, and a 30 yM solution caused 58 percent inhi-
bition of phosphodiesterase, in a 0.1 yM solution of cyclic AMP.
Most of the subacute dosing experiments with silver compounds
are summarized in Table 15. Except for the corrosive nature of low
doses of silver nitrate, most of the other compounds tested were
reasonably tolerated by the animals in periods up to 71 days.
Yoshikawa (1970) reported that mice given pretreatments with
certain heavy metals, including silver, lead, cadmium, and mercury,
developed a tolerance to a lethal dose* of the metal as shown by
*The pretreatment dose was 10 percent of the challenge dose. The
challenge dose was "about 70 to 80 percent lethal doses," presum-
ably the LD70_8Q.
C-81
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TABLE 15
Acute Effects of Silver on Terrestrial Animals
Survival
Time
Animal
How Administered
Dosage
Observed Effects
Remarks
References
Rats
Rats
O
oo
to
S.C. injection
AgNO3
S.C.
Rabbits Lv. CryptargcP)
Rabbits Lp. AgNO}
Guinea pig 2 mlLp. AgNOj
Dogs Lv. CollargoiS'
Dogs
Dogs
Lv.
(1 % emulsion of Ag)
Lv.
7 mgAg body we.
0.35 or 0.7 rag/
100 g body wt.
1-3 ocsoln.
contg. 0.1 g
Ag/cc
20 mgAg in
neutral soln.
0.239 M AgNO3
200-300 rag
500 mg
500 mg
4-48 hr.
2hr.
1-7 days
12 hr.
24 hr.
Affected testis hisbology and
sperraatogenesis. Peripheral
tubules affected and some
central tubules completely
degenerated after IB hr.
Some tubules recover. Duct
system seldom fully recovers.
Decreased threshold of elec-
trical stimulation of
epileptiform convulsions.
Congestion of kidneys, tubular
swelling, and/or glomerular
necrosis.
Death in coma. Degenerative
aspects and Ag granules in
liver parcenchyma and
kidney tubules.
Death.
Well tolerated.
Pulmonary edema, anorexia,
profound anemia, active
hyperplastic bone marrow.
Death, hemolysis, lung edema.
Marked deformation of Hoey, 1966
tubules at head of ept-
didycnis Epithelial cells
appeared swollen. Sper-
matogenesis active.
No clinical symptoms of Fedotov, et aL 1968
intoxication.
HiH and Pillsbury, 1939
No abnormalities in
heart, lungs, brain, or
adrenals.
Also had weight Ices
and weakness.
LaTorraca, 1962
Wahlberg, 1965
Shouse and W hippie, 1931
Browning, 1961
A dog given 2,600 mg Shouse and W hippie, 1931
CoUargol over 4 months
in doses of 20-600 mg
died after the last injec-
tion of 600 mg.
Dogs
Lv. Ag albuminate
0.03 g
0.5 hr.
Death.
Hill and Pillsbury, 1939
-------
TABLE 15 (Continued)
n
I
oo
U)
Animal
Dogs
Dogs
Dogs
Dogs
Dogs
Dogs
Dogs
How Administered
Lv. Ag-^Oj
Lv. AgNO3
Lv. AgNO3
Lv. Argyroi~
Lv. Argyrol-^
Lv. Colloidal Ag
AgNO3 placed
directly in stomach
Dosage
0.2 g in 60 cc
H2P
32 rag
3 ragAg
4-5 mgAg
100 mg
2.3-2.6 g
Survival
Time Observed Effects
Death in convulsive seizures,
pulmonary edema.
Death due to mechanical
asphyxia.
Death.
18 he. Death debits regular
respiration while in coma.
Also had edema of lungs
and intestinal hemorrhages.
Hemolysis.
A few days if Death if vomiting prevented.
vomiting is
impeded.
Remarks
At lower dosages:
anesthesia and paralysis
of hind legs followed
by increased bronchial
secretion and asphyxia!
death.
References
Hill and Pillsbury, 1939
Hill and Pillsbury, 1939
Hill and Pillsbury, 1939
HU1 and Pillsbury, 1939
Bin and Pillsbury, 1939
Hill and Pillsbury, 1939
Hill and Pillsbury, 1939
Horses
Lv. (?)
AgNO3
Death, hemorrhage and
thrombi of heart and kidneys.
Bin and Pillsbury, 1939
-------
TABLE 15 (Continued)
O
I
CO
Animal
Rabbits
Rabbits
Dogs
CF-1 Mice
How Administered
Lv. Cryptargot^
daily
Lv. Ag arsphen-
amine (14.5% Ag)
Lv. CollargofS'
Oral or ac.
silver sulf adiazine
Survival
Dosage Time
0.6 ocsoln.
contg. 0.1 g Ag/cc
66.7 mg/kg for
47-70 days
1,300-1,500 mg
over 3-7 days
1,050 mgAg/day
for 30 days
Observed Effects
No albumin or casts in urine.
More Ag retained by animals
losing weight. Most showed
a gradual increase in hemo-
globin and red blood cells.
No toxic effects or discolor-
ation.
Tolerated.
Cured mice of their infection
by Plasmodium berghei within
Remarks
Administered for 71
days.
Minimum dosage
277 mg in 47 days.
Maximum dosage
2,363 mg in 70
days.
References
Hill and Pillsbury, 1939
Hill and Pillsbury, 1939
Shouse and Whipple, 1931
Wysot, 1977
Wysor, 1975b
Rats
ac. Ag-oonbg.
substance not
identified
3,5-7 mgAg
for 14 days
5 days even after a qSenectomy.
Also effective against systemic
infection by Pseudomonas aerugi-
nosa. The mice did not show
any histakgical pathology,
weight loss, or abnormal behavior.
There was a local granulomatous
lesion at the s.c. injection site.
Decreased threshold of epilep-
togenic effect of electrical
stimulation.
No clinical
symptoms of
intoxication.
Fedotov, et aL 1968
-------
fewer deaths in the pretreated mice compared with mice that were
not pretreated. Thus, when 10 male ICR mice were given an i.p. dose
of 3.5 mg Ag/kg as silver nitrate before the challenge dose of 35
mg/kg 24 hours later, only three of the pretreated mice died within
seven days, compared with eight of the nonpretreated mice.
Dymond, et al. (1970) implanted wires of several metals and
alloys including pure silver into the brains of cats for two
months. Silver produced a toxic effect as shown by a very large
scar with a large component of glial elements. The author cited
other reports wherein silver or silver/silver chloride was toxic as
a brain implant. (Other studies wherein implants were maintained
for longer than two months are described under chronic studies).
Olcott (1950) gave rats either silver nitrate or thiosulfate
in 1:1,000 concentration (635 mg Ag/1 if AgNO3 and 660 mg Ag/1 if
Ag2S203) in their drinking water for up to 30 months. The finding
of hypertrophy of the left ventricle in a statistically significant
number of rats was presumed to indicate that the rats had developed
vascular hypertension, possibly due to thickening of the basement
membranes of the renal glomeruli.
Olcott (1948) had given rats 1:1,000 concentration of silver
nitrate or thiosulfate in their drinking water for their lifetime,
beginning shortly after weaning, without observing any shortening
of the lifespan. Skin pigmentation was not observed, but the in-
ternal organs (the pancreas was especially dark) and the eyes were
darkened by silver deposits. Absorption was apparently via the
small intestine based on the large amount of silver found in its
C-85
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villi. The deposition of silver in internal organs and tissues
usually resembled that seen in humans with argyria.
The following chronic studies are arranged in order of the
lowest chronic dose administered.
Albino rats receiving doses of 0.00025 and 0.0025 mg electro-
lytic silver per kg body weight in their drinking water for 11
months did not show any changes in conditioned-reflex activity.
The dose 0.0025 mg/kg corresponds to 0.05 mg/1 in the water (Barkov
and El'piner, 1968). Doses of 0.025 (0.5 mg/1) and 0.25 mg Ag+Ag
in rats did affect the conditioned reflex activity. These doses
during 11 months also lowered the immunological activity of rabbits
as judged by increasing phagocytosis by blood leukocytes. Patho-
logical changes were noted in vascular, nerve, brain, and spinal
cord tissues (Barkov and El'piner, 1968).
None of the doses induced changes in the hemoglobin content,
number of erythrocytes, the leukocyte count, the protein-forming
function of the liver, and the content of thiol groups in the blood
(Barkov and El'piner, 1968).
Rats receiving 0.05 mg Ag /I in their drinking water for five
months showed no effect on gastric secretion, blood serum enzymes,
or morphology of the stomach, intestine, liver, and kidney. Patho-
morphological changes in stomach, small intestine, and liver were
noted, however, in rats receiving 20 mg Ag /I. Blood serum aspara-
gine transaminase and alanine transaminase were increased >- 2 and
2.4 times over the level in the control group, respectively, and
growth was depressed 36 percent at the higher concentration (Mas-
lenko, 1976).
C-86
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Pak and Petina (1973) gave 94 white rats of both sexes 0.1,
20, and 50 mg Ag+/l for 4 and/or 6 months while the 20 controls
drank the Moscow water supply. When Ag was supplied as silver
nitrate, after four months there was a small decrease in the -SH
groups in the blood serum (51.2 versus 57.0 uM in the controls) at
50 mg/1. Anodically produced silver of the same concentration did
not produce this effect. But after six months, both forms of Ag at
»
20 mg/1 depleted the -SH groups: ionic silver, 31.2 pM; AgN03,
35.3 uM; and controls, 50.0 uM. At four months, the 0.1 mg/1 con-
centration had actually increased the concentration of -SH groups
in blood serum to 63.0 to 64.0 yM.
Kul'skii, et al. (1973) reported that 0.100 to 0.200 mg Ag+/l
in the drinking water of test animals did not affect the antimi-
crobial and antiviral immunity formation in the animals (Savluk,
1973). There was also no effect on the ratio of the blood-forming
elements (Savluk and Moroz, 1973), the protein content, the func-
tional state of the spleen, or conditioned-reflex development
(Kharchenko and Stepanenko, 1972; and Zapadnyuk, et al. 1973).
The function of the reticuloendothelial system in the manu-
facture of specific protective factors in rats receiving 0.2 and 20
mg Ag+/l in their drinking water for eight months was not altered,
but albino mice receiving the higher dose showed reduced absorptive
capacity of the reticuloendothelial system (Savluk, 1973) .
Kharchenko and Stepanenko (1972) (see also Kul'skii, et al.
1972) found no change in conditioned-reflex activity in male (8
or 15 or 16 per group) albino rats given drinking water with 0.2 to
0.5 mg Ag+/l for six months and insignificant changes in rats given
C-87
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2 mg Ag+/l. However, at 5 to 20 mg/1, intoxication was observed
beginning the 25th to 27th day. At that time, there were no condi-
tioned reflex changes. A dose of 20 mg/1 had inhibited the inten-
sity and prolonged the latent period of the cortical response to
stimuli by the end of the second month. The latent period of the
conditioned reflex was 2.5 times that of the controls. On pro-
longed ingestion, there occurred an increase of excitability, an
increase in the number of intersignal reactions, differentiation
disinhibition, and disturbances in mobility and equilibration of
main nervous processes. After 5 to 6 months at 20 mg/1, the inhi-
bition of the positive conditioned reflexes again occurred, with
increasing intensity.
Male albino rats (five) , drinking water containing 20 mg Ag /I
for eight months, showed a significant decrease in the escape rate
from an aqueous labyrinth as compared to controls. In a 12-month
study the repressing effect on the rate of the first swim to escape
from an aqueous maze was an average 22 percent greater in rats that
had drunk water containing 500 ug/1 and 47 percent in those drink-
ing 2,000 ug/1 (Zapadnyuk, et al. 1973). The repressing effect on
the rate was less at 2 mg/1 and even less at 0.5 mg/1, but those
rats receiving 0.2 mg Ag+/l (0.01 mg Ag/kg body weight) showed no
difference (Zapadnyuk, et al. 1973).
Savluk and Moroz (1973) studied changes in the blood of albino
rats (240 total) receiving electrolytically produced silver ions
for three months in their drinking water at 0.2 mg Ag /I (0.03 mg/
kg/day) and 20 mg Ag /I (3.0 mg/kg). No changes were noted in the
hemoglobin; number, color, and form of the erythrocytes; the color
C-88
-------
index of the blood; and the precipitation reaction of the erythro-
cytes. The increase in the number of leukocytes in the test rats
was statistically insignificant. Upon electrophoretic analysis,
there was no significant difference in the protein fraction ratio
of the blood of the rats receiving 0.2 mg/1 from that of the con-
trols. There seemed to be an increase in gamma and betaglobulin
fractions. At 20 mg Ag+/l, there still was no statistically sig-
nificant difference in the ratio of protein fractions in comparison
with that of the controls; yet the slight increase in the globulin
fractions was accompanied by a lowering of the amount of albumins
and total protein in the blood.
A slight change in protein metabolism shown by changes in the
amount of proteins in each fraction in the serum reverted to normal
by two months after the end of silver intake.
The 0.2 mg/1 animals showed no change in liver function, but
the higher concentration lowered the weight of both the liver and
whole animal. It was concluded neither level was toxic to the
liver.
The higher concentration increased the amounts of almost all
16 free amino acids determined in the blood serum (Savluk and
Moroz, 1973).
The changes in brain nucleic acids of rats after chronic
intake of silver as determined by Kharchenko, et al. (1973b) are
shown in Table 16. Male albino rats (three) , drinking water con-
taining 0.5 mg Ag /I for six months from the time they were three
months old, showed increased body weight compared with the con-
trols, lowered nucleic acid content in the brain, and increased
C-89
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TABLE 16
Quantitative Changes in Nucleic Acids in the Brain of Rats*
Concentration Weight of
of silver, mg/L Animal, g
Weight of
Brain, g
Concentration of
Nucleic Acids in
Brain, mg %
DNA
RNA
Contents of
Nucleic Acids in
Brain, mg
DNA
RNA
Number of
Nuclei in.
Brain, 10
Weight of
Brain/
Nucleus
Content of DNA/ Ratio of the
100 mg Dry RNA/DNA
Weight of Brain Content in Brain
After Intoxication with Silver for 6 Months
Control
0.5
P
? 2°
ya P
o
249 + 20
274 + 23
0.556
278 + 57
0.423
1.93 + 0.07
1.92 + 0.05
0.091
1.95 + 0.14
0.099
13.9 + 1.6
12.0 + 0.7
0.683
19.3 + 0.5
0.95
12.7 + 0.8
8,5 + 1.8
0.920
16.2 + 1.1
0.95
2.75 + 0.36
2.33 + 0.03
0.695
3.79 + 0.26
0.941
2.57 + 0.2
1.73+^0.38
0.90
3.32 + 0.29
0.922
444 + 59
376 + 13
0.695
612 + 30
0.95
4.8 + 0.8
5.1+0.3
0.39
3.2 + 0.1
0.906
0.141 + 0.016
0.119 + 0.021
0.561
0.194 + 0.007
0.95
1.0 + 0.19
0.75 + 0.18
0.478
0.88 + 0.08
0.512
After Intoxication With Silver for 12 Months
Control
0.5
P
2
P
20
P
313 + 42
379 + 28
0.720
326 + 44
0.216
338 + 84
0.195
1.9 + 0.12
2.1 + 0.1
0.806
2.1 + 0.08
0.766
1.9 + 0.1
0.444
15.7 + 0.9
15.5 + 0.8
0.124
18.2 + 0.49
0.892
12 + 1.2
0.921
16.9 + 2
17.7 + 1.2
0.264
18.8 + 1.9
0.466
8+1.2
0.95
3 + 0.2
3.3 + 0.1
0.785
3.9 + 0.1
0.95
2.3 + 0.3
0.859
3.4+0.3
4 + 0.1
0.849
4.1 + 0.5
0.720
1.6 + O.I
0.99
487 + 31
589 + 13
0.785
625 + 13
0.95
374 + 47
0.862
3.9 + 0.13
4 +0.2
0.073
3.4 + 0.1
0.893
5.2 + 0.6
0.859
0.159 + 0.009
0.156 + 0.008
0.181
0.184 + 0.006
0.897
0.121 + 0.011
0.924
1.12 + 0.08
1.19 + 0.02
0.529
1 + 0.1
0.264
0.7 + 0.1
0.95
*Source: Kharchenko, et aL 197 3b
-------
weight of brain per cell nucleus (thus, hypertrophy of the cells).
After 12 months on this regime, both brain and body weights of
three rats were higher than those of the controls, the content of
brain nucleic acids was higher, the weight of brain per nucleus was
about the same as those of the controls, and the RNA/DNA ratio was
higher. These effects were generally more pronounced, but in the
same direction in rats (three) receiving 2 mg Ag /I 12 months.
However, the weight of brain per nucleus and the RNA/DNA ratio was
lowered (that is, DNA content had increased more than the increase
in RNA) (Kharchenko, et al. 1973a,b).
After 20 mg Ag+/l for six months, all of the indices were in-
creased except that the weight of the brain per nucleus and the
RNA/DNA ratio was reduced. After 12 months on this concentration,
all indices were reduced compared with those of the controls except
for increased body weight, identical brain weight (which would in-
dicate dystrophy since brain weight was higher at six months), and
increased weight of brain per nucleus (Kharchenko, et al. 1973b).
Significant changes (p = 0.95) were seen in rats drinking 500 yg of
silver/1 for six months (liver weight 8.7 + 0.3 g versus 7 + 0.6 g
in the controls and RNA content 61.8 + 4.9 mg percent versus 77.9 _+
4.7 mg percent in the controls). The DNA content of the liver was
significantly elevated (39.4 + 2.7 mg versus 25.4 + 4.1 mg in the
controls) in the rats drinking the silver concentration for 12
months.
Apparently, as the animals aged and silver accumulated, the
presumed protective action of increased content of brain nucleic
C-91
-------
acids was weakened. An increase in the number of nuclei in the
brain apparently was also a protective action. Lowering the RNA/
DNA ratio reflected the lowering of metabolic reactions in the
brain tissues. In the controls, the intensity of nucleic acid
metabolism in the intact animal was somewhat increased with growth
(Kharchenko, et al. 1973b) . An increase in brain DNA may well
indicate tissue damage.
Klein (1978) stated that Just and Szniolis (1936) had observed
immunological changes in test animals and had concluded that silver
might be harmful to humans in this regard. There is no indication
in the paper cited of immunological changes. For 100 days, rats
ingested up to 1 mg Ag/1 in their drinking water. At concentra-
tions below 0.4 mg/1, the rats appeared in good health, and dis-
section did not reveal any apparent pathological changes. At 0.4
mg/1, small hemorrhages were detected in the kidney; and there was
blood pigment accumulated in some glomeruli, larger vessels, and
walls of the caniculi in which hemorrhages had occurred. At 0.7
mg/1, there were large amounts of blood pigment in fresh and old
tissue extravasations in the liver; and the changes in the kidney
were more marked. At 1 mg/1, pigment was finally observed in the
spleen and the changes in the liver and kidney were more pro-
nounced.
At a much higher level of silver—60 mg/kg as silver nitrate
or Targesin® (equivalent to 1,200 mg/1 if given in drinking water
to rats) for "several months", silver nitrate-fed animals showed
C-92
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degenerative kidney changes; the Targesin-fed rats did not (Enders
and Moench, 1956).
Bates, et al. (1948, cited by Chusid and Kopeloff, 1962) had
found that silver implants in the brain resulted in formation of a
surrounding fibrous capsule, necrosis, and infiltration of the cor-
tex and meninges. Fischer, et al. (1957, cited by Chusid and
Kopeloff, 1962) had warned that silver or copper wires were unsuit-
able for use in human depth electroencephalography since they had
observed damage and necrosis around such wires in cat brains.
Chusid and Kopeloff (1962) inserted a spheroid pellet (3-5 mm dia-
meter) of silver into the brain of one monkey which survived 21
months. The monkey showed spike and slow changes in the electro-
encephalogram and exhibited a brain lesion classified as a meningo-
cerebral cicatrix in contrast to a necrotizing foreign body reac-
tion, produced by such elements as antimony, cadmium, copper, mer-
cury, and nickel.
To summarize chronic drinking water experiments: rats given
0.05 mg/1 silver in their drinking water for 11 months showed no
changes in conditioned-reflex activity and for five months, no
effect on gastric secretion, blood serum enzymes, liver, or kidney.
A concentration of 0.1 mg/1 or 0.2 mg/1 also appeared to have no
effects; but at _> 0.4 mg/1, hemorrhages were observed in the kid-
neys. At 0.5 mg/liter for 11 months, conditioned reflex activity
and immunological resistance were lowered, and brain nucleic acid
content was increased. A concentration of 2 mg/1 caused similar
effects. By 20 mg/1, numerous physiological changes, including
C-93
-------
growth depression, were evident. Thus, concentrations of silver
ions in drinking water up to 0.2 mg/1 (the maximum allowed by Swiss
authorities for 38 years) caused no deleterious effects within time
periods up to 11 months. Ill effects appeared at 0.4 mg/1, and by
0.5 mg/1, conditioned-reflex activity and immunological activity
were reduced.
Synergism and/or Antagonism
Silver exhibits antagonism to selenium, vitamin E, and copper,
inducing deficiency symptoms in animals fed adequate diets or
aggravating deficiency symptoms when the animals' diet lacks one or
more of the nutrients. The effects have been described in dogs,
sheep, pigs, rats, chicks, turkey poults, and ducklings.
Shaver and Mason (1951) first noted the toxicity of silver to
vitamin E-deficient rats. On 1,500 mg/1 silver as the nitrate in
their drinking water, the animals developed muscular dystrophy,
liver necrosis, and increased mortality. All 23 rats on the low-E
diet died within 18 to 40 days except for one survivor for seven
months. Diplock, et al. (1967) and Grasso, et al. (1969) found the
liver necrosis in rats induced by silver was indistinguishable from
that arising in animals that were deficient in vitamin E and/or
selenium. Grasso, et al. (1969) also noted necrosis in the brain
followed by necrosis of the nuclei, endoplasmic reticulum, and
mitochondria. Bunyan, et al. (1968) reported that 3 mg/kg cyano-
cobalamin in the diet prevented liver necrosis at 0.0130 percent
silver in the drinking water or diet.
C-94
-------
A silver-induced increase in the selenium content of the mito-
chondrial fractions of the liver of vitamin E-deficient rats was
noted by Diplock, et al. (1971). Grasso, et al. (1969) had ob-
served proliferation of lysosomes in the livers of silver-treated
rats deficient in vitamin E. Diplock, et al. (1971) speculated
that Ag2Se accumulation in the lysosomes of the liver mitochondrial
may explain the increased selenium retention in the mitochondria
fraction in silver-treated rats, although the total amount of sele-
nium in the liver was lowered. They further speculated that per-
haps an insoluble silver salt of selenium is formed in the intes-
tine to reduce its absorbability and, therefore, reduce its abso-
lute amount in the liver. Silver-treated rats exhibited greater
fecal excretion of Se from the diet.
Rats fed diets containing 0.00005 percent selenium and 76 or
751 mg/1 silver in their drinking water for 52 days showed liver
glutathione peroxidase levels 30 percent and 4 percent, respec-
tively, of the concentration in control rats given the vitamin E-
deficient diet with 0.00005 percent selenium as sodium selenite but
no silver. The casein-based diet itself contained 0.000002 percent
selenium. However, the selenium dietary supplement did improve the
growth and survival of rats given 751 mg/1 silver (but increased
the silver content of liver and kidney) and entirely prevented the
growth depression seen in rats given 76 mg/1 silver. The silver
metabolism was apparently altered because higher silver concentra-
tions were found in the liver. When the diets were made adequate in
vitamin E (100 lU/kg), as well as selenium, the glutathione
C-95
-------
peroxidase levels in liver, erythrocytes, and kidney of rats given
751 mg/1 silver in water were 5 percent, 37 percent, and 38 per-
cent, respectively, of those of control rats (Wagner, et al. 1975,
and Swanson, et al. 1974).
Whanger (1976b) found that vanadium and zinc apparently pro-
mote the liver necrosis seen in rats deficient in selenium and
vitamin E, but not to the degree that silver does. The effect of
feeding rats nonsupplemented torula yeast diets containing 0.08
percent silver as the acetate was overcome by 40 times (0.004 per-
cent) the required selenium level or by the accepted level of vita-
min E (0.006 percent). Whanger (1976b) speculated that vitamin E
is more critically involved in counteracting silver than selenium.
Both mercury and silver decreased selenium absorption and tissue
content, but mercury did not affect the deficiency-caused liver
necrosis.
In addition to antagonism to selenium and vitamin E, an iso-
lated report (Dodds, et al. 1937) stated that silver reduced the
antidiuretic activity of pituitary extract in rats given 2 yg of
the extract plus 0.2 ml of a 5 percent solution of silver lactate
per 200 g body weight.
Whanger, et al. (1976a) found that feeding ewes low-selenium
diets with 0.005 percent silver as the acetate did not signifi-
cantly affect the incidence of white muscle disease (a selenium-
deficiency syndrome) in their lambs but significantly altered the
concentrations of the enzymes glutamic-oxaloacetic transaminase
(GOT), creatine phosphokinase (CPK), and lactic dehydrogenase (LDH)
in the plasma of the lambs. The relative amounts of plasma GOT for
C-96
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low-selenium, low-selenium plus silver, and low-selenium plus sele-
ni-om diets were 190:616:44; of CPK, 335:216:32; and LDH,
930:2,694:387. Silver gave higher LDH and GOT concentrations than
did arsenic or cobalt.
Higher dietary concentrations of silver were required to pro-
duce selenium-vitamin E deficiency in pigs fed an adquate diet.
Anorexia, diarrhea, and growth depression appeared in four weanling
swine fed a diet adequate in selenium and vitamin E but containing
0.5 percent silver acetate for four weeks. Three of the four pigs
died (at 21, 23, or 28 days of the experiment); all had necrotic
hepatic lesions; and one had the skeletal muscle and cardiac
lesions of selenium-vitamin E deficiency. Pulmonary edema and
excessive fluid in the peritoneal, pleural, and pericardial cavi-
ties were present. Four pigs fed only 0.2 percent silver acetate
for 40 days did not develop any pathological or clinical signs of
the deficiency, but the selenium content of the liver was signifi-
cantly increased (average 0.61 mg/kg wet weight). The lesions and
mortality were prevented in two pigs by adding 100 ID/kg
-------
tained silver. The skeletal muscle and cardiac myopathies and the
hepatic necrosis were generally more severe in pigs given silver
than in those given arsenic or sulfur. The extent of muscular
lesions was indicated in silver-treated pigs by the high serum
glutamic-oxaloacetic transaminase. The ornithine carbamyl trans-
ferase concentration was higher in the pigs treated by silver than
with any other agent.
Dam, et al. (1958, cited by Jensen, et al. 1974) found that
feeding chicks a diet with 0.002 percent (20 mg/kg diet) silver as
the acetate promoted exudative diathesis.
Ganther, et al. (1973) reported that silver at 100 mg/1 in the
drinking water of chicks promoted the liver necrosis characteristic
of vitamin E and selenium deficiency.
Silver acetate at 1,500 mg/1 in the drinking water of vitamin
E-deficient chicks promoted exudative diathesis. Silver was also
found to be a pro-hemorrhagic factor (Bunyan, et al. 1968).
Hill and Matrone (1970) (see also Hill, et al. 1964) found
that silver concentration of 0.01 percent (100 mg/kg) in the diet
of chicks reduced growth when the diet was deficient in copper.
The mortality in the initial 20 chicks was 25 percent after four
weeks on a copper-adequate diet compared with 60 percent on a cop-
per-deficient diet. The hemoglobin content of the blood and the
elastin content of the aorta was reduced in chicks given a diet
with a concentration as low as 0.001 percent (10 mg/kg).
Peterson and Jensen (1975a) obtained results in chicks similar
to those described below in turkey poults. Feeding chicks a diet
containing 0.09 percent (900 mg/kg) silver as the nitrate for four
C-98
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weeks depresse yrowth, enlarged the heart, and increased mor-
tality. The growth depression was not completely corrected by a
concentration of 0.005 percent (50 mg/kg) copper in the diet, but
the cardiac enlargement and mortality were prevented. The 0.09
percent silver in the diet reduced copper concentrations from those
of the controls in blood, liver, spleen, and brain, but did not
significantly affect copper concentrations in the kidney or ex-
creta. (The latter was only a 1-day sample and may not have been
representative.) However, supplementation of the diet with 0.005
percent copper, along with the 0.09 percent silver, brought copper
levels to those of the controls in blood, liver (but not fat-free
liver), and spleen. Again, the copper content in the kidney was
normal, but the concentration in the brain was significantly lower,
and that in the excreta was more than twice as high. Possibly, cop-
per loss through the kidneys was being promoted by silver. Silver
obviously reduced tissue uptake of copper, but the experiments did
not explain whether this was due to interference with copper metab-
olism or with copper absorption.
When Peterson and Jensen (1975b) performed similar 4-week ex-
periments with chicks fed a 0.09 percent silver diet marginal in
vitamin E and selenium, the mortality was mostly due to exudative
diathesis. The growth depression and mortality were prevented by
including 0.0001 percent (1 mg/kg) selenium or 100 IU vitamin E per
kg to the diet. When the silver-containing diet was supplemented
only by 0.15 percent cystine, there were signs of exudative dia-
thesis in 58 percent of the chicks after 15 days and 90 percent mor-
tality after 28 days (49 percent and 83 percent, respectively,
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without added cystine in the diet). Vitamin E was more effective
than selenium in reducing the mortality of the cystine-and-silver-
fed chicks.
Chicks fed an otherwise normal diet containing 0.0005 percent
selenium showed a slower growth rate, and chicks given 0.004 per-
cent selenium for two weeks had increased mortality. Either 0.1
percent silver in the diet as the nitrate or copper as the sulfate
improved the growth rate and prevented mortality. As shown by
experiments with Se, silver interfered with selenium absorption
(when given orally or i.m.) and allowed accumulation of a nontoxic
selenium compound in the tissues, whereas copper provided primarily
the latter effect. Presumably, because of their greater water
insolubility, these nontoxic compounds are the selenides (Jensen,
1975).
Selenium-vitamin E deficiency symptoms were also induced in 20
ducklings fed an adequate diet supplemented with 0.2 percent silver
acetate for three weeks. The birds showed anorexia, retarded
growth, a reluctance to stand, and eventual fatalities (2 of the 18
ducklings affected) with myopathies in the gizzard, intestine,
skeletal muscle, heart, and hydropericardium unless the diet was
supplemented by 200 lU/kg of <^>-tocopherol. Selenium (0.0001 per-
cent) as sodium selenite did not protect against the deficiency
symptoms (Van Vleet, 1977).
Peterson, et al. (1973) fed 21 turkey poults a diet containing
0.09 percent silver as silver nitrate for four weeks, which sig-
C-100
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nificantly reduced body weight gain, hemoglobin, packed cell volume
of the blood, and aortic elastin content while significantly in-
creasing the ratio of wet heart weight to body weight. The heart
enlargement was due to copper deficiency.* (Copper is part of the
enzyme amine oxidase, required for elastin synthesis). Although
six of the poults died (28.6 percent mortality) within the next 18
weeks, during which time they no longer received silver, the
factors affected by silver nitrate had reverted to normal except
for the appearance of the hearts. They were grossly enlarged,
blunt at the apex, and showed marked dilation and thinness of the
right ventricle.
Extending the report of the studies on turkey poults by Peter-
son, et al. (1973), Jensen, et al. (1974) found that there was a
variable incidence of gizzard musculature degeneration, which was
prevented by adding 0.0001 percent selenium or 50 International
Units (IU) vitamin E per kg to the diet. These agents, however, did
not affect the macrocytic hyperchromic anemia; but 0.005 percent
copper in the diet reversed the anemia as was mentioned above.
Hoekstra (1975) enumerated some of the defects related to
selenium deficiency in many animal species: fetal death and
resorption; testicular and liver necroses; degeneration of kidney,
muscle, and vessels; hemorrhage; and erythrocyte hemolysis. He
*Jensen, et al. (1974) later reported that giving the poults 0.005
percent copper in the diet reversed silver's effects on growth
rate, blood, and cardiac tissue.
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proposed a metabolic scheme interrelating the effects of gluta-
thione peroxidase and vitamin E as protectors against sulfur-con-
taining amino acids, oxidant stressors, etc.; but the mechanism
whereby silver interferes with selenium and glutathione peroxidase
was not explained.
Rotruck, et al. (1973) found that there are four selenium
atoms per molecule of the enzyme glutathione peroxidase. Noguchi,
et al. (1973, both reports cited by Peterson and Jensen, 1975b)
advanced the hypothesis that the selenium-containing glutathione
peroxidase destroys peroxides and hydroperoxides within the extra-
mitochondrial water-soluble fraction of the capillary cells and
that lipid-soluble vitamin E prevents auto-oxidation of the lipids
within the membrane* itself. The greater efficiency of vitamin E
rather than selenium in curing selenium-vitamin E deficiency symp-
toms in silver-fed animals may be due to the fact that vitamin E
acts directly, whereas selenium must first be synthesized into glu-
tathione peroxidase or its metabolism and/or absorption are
directly interfered with by silver (Peterson and Jensen, 1975b).
Teratogenicity
Few associations between silver and birth defects have
appeared in the literature, and one is apparently erroneous.
Kukizaki (1975) found only weak cytotoxic effects when silver-
tin alloy powder was incubated in seawater with fertilized eggs or
*Alterations to hepatocyte membranes were consistently seen early
in silver feeding studies producing liver necrosis (Grasso, et al.
1969).
C-102
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early embryos of the sea urchin, Hemicentrotus pulcherrimus.
Metallic mercury, on the other hand, was not only very cytotoxic,
the embryos were deformed. However, five hours after incorporation
with the silver-tin alloy into a dental amalgam, even the cyto-
toxicity almost disappeared.
Silver was among the 54 elements whose salts were tested for
toxicity to 4- and 8-day-old chick embryos, by Ridgway and Karnof-
sky (1952); but it was not among the nine elements (Tl, Cr, Pb, Co,
B, As, Rh, Ba, and Se) whose salts produced abnormalities in embry-
onic development.
Robkin, et al. (1973) reported concentrations of silver
(determined by neutron activation analysis) in dry liver tissue
from 12 anecephalic fetuses (0.75 + 0.15 mg/kg), nine premature
infants (0.68 + 0.22 mg/kg), 12 fetuses from therapeutic abortions
(0.23 + 0.05 mg/kg), and 14 fetuses from spontaneous abortions
(0.21 + 0.05 mg/kg). Mercury concentrations exhibited a similar
pattern. The age of the tissue groups increased in the order of
increasing mercury concentrations. The accumulation of mercury
with age may have accounted for the differences, not a teratogenic
effect. The authors felt more data from large sample sizes were
needed to decide whether the silver anomaly was due to a terato-
genic effect or was also due to accumulation with age.
Barrie (1976) described two rare cases of fibular aplasia in
human infants from mothers whose intrauterine devices had remained
in place during pregnancy. One mother had an intrauterine device
(IUD) of German silver (the Grafenburg ring) the other, an IUD of
polyvinyl acetate containing barium and copper additives (the
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standard Balkan^ shield). Barrie mistakenly stated that the first
"shield is mainly silver. According to Thrush, et al. (1968), Ger-
man silver comprises only nickel, copper, and zinc.
Mutagenicity
Demerec, et al. (1951) studied mutational changes in Escher-
ichia coli by the method of inducing back-mutations from strepto-
mycin dependence to nondependence. Incubation with silver nitrate
solutions of 0.000005 to 0.000100 percent for 3 to 25 hours allowed
4.3 to 84 percent survival of E. coli with 2.1 to 8.2 mutants per
o
10 bacteria after incubation compared with 2.3 to 8.6 mutants per
o
10 bacteria for control plates. Only the lowest concentration
gave more mutants than were in the controls (4.8 versus 2.3 mutants
O
per 10 bacteria). Thus, silver nitrate was deemed nonmutagenic.
Mutations tested for in Micrococcus pyogenes var. aureus
strain FDA209 were resistant to penicillin and/or streptomycin.
Clark (1953) found that a 0.000001 percent solution of silver
nitrate (a concentration that gave the minimum killing action)
apparently was not mutagenic in that the solution did not favor
formation of antibiotic-resistant mutants in Micrococcus aureus.
(In fact, the controls showed more mutants than the test solu-
tions. ) *
Nishioka (1975) used the method reported in 1972 by Kada, et
al. for screening chemical mutagens. The method, named rec-assay,
observes differential growth sensitivities to chemicals in wild and
*90 versus 179 for streptomycin-resistant mutants per million
cells. 9 versus 40 for penicillin-resistant mutants per million
cells.
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recombination-deficient strains of Bacillus subtilis. Chemicals
more inhibitory for Rec~than for Rec+ cells are suspected mutagens
based on their ability to damage DNA. After exposure for 24 hours
to 0.05 ml of a 0.05 M silver chloride solution (sic), both Rec and
Rec~ cultures showed the same degree of inhibition.
Fox, et al. (1969) had suggested that silver sulfadiazine
derived its antimicrobial activity from its ability to react with
cellular DNA. Rosenkranz and co-workers had found that it does in
vitro but not in vivo. McCoy and Rosenkranz (1978) found that sil-
ver sulfadiazine had no mutagenic activity in the Ames test, which
examines the substance's ability to mutate histidine-requiring
strains of Salmonella typhimurium to histidine independence. Al-
though the typhimurium tester strains gave the usual response to
known base substitution and frameshift mutagens in plate assays,
usually fewer than 19 mutants per plate were observed with silver
sulfadiazine. In suspension culture, the antimicrobial activity of
silver sulfadiazine (1 mg/1) was clearly observed; but the relative
number of mutants per 100 million viable cells varied little (7.7
to 10.3) with time, whereas another antimicrobial--2-(2,2-di-
methylhydrazino)-4,5-nitro-2-furylthiazole—showed definite muta-
genic potential, with 394 mutants per 100 million viable cells 80
minutes after addition of 0.5 mg/1.
Apparently, silver is a normal, if minute, constituent of DNA.
Sabbioni and Girardi (1977) found 0.2 mg/kg silver in calf thymus
DNA, but 0.015 mg/kg silver was in the blank. Elements present at
the same level as silver, up to 1.2 mg/kg, were mercury, selenium,
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rubidium, and chromium. Elements present at 2 to 1,450 mg/kg were
barium (8), manganese (16), iron (11.6), strontium (2.2), and zinc
(1,450).
Von Rosen (1954) exposed germinated Pisum seeds with 1 cm
rootlets to solutions of heavy metal compounds at 20°C and observed
that the chromosome-breaking ability of the very active metal ions
were in the following (decreasing) order: Tl, Cd, Cu, Os, Hg, Ag,
Ti, Ta, Au, Pt, Cr, and Co. The concentration of the silver ions
(probably as the nitrate as in Von Rosen, 1957) was of the order
0.0001 M. The ions of silver and gold produced swollen prophase
cells, where the chromosomes were visible as long threads but were
often greatly fragmented. Von Rosen (1957) remarked that the ele-
ments that were radiomimetically active in producing chromosome
disturbances were those that can form strong complexes with protein
constituents.
Carcinogenicity
Implanted foils and disks and injected colloidal suspensions
of metallic silver have been found to produce tumors or hyperplasia
in several studies. Yet the investigators almost always qualify
their findings by suggesting the effect is due to the particular
physical form of the metal, to its being an exogenous irritant, or
to its lowering resistance because of the presence of some solu-
bilized silver ions. Some of the literature data are summarized in
Table 17. The data included are of uneven quality because a few of
the original references have not been located and some listings are
C-106
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TABLE 17
Silver Tested for Carcinogenlcity
Investigators Animal Strain or Type Sex
Preparation and Dose
Site and Route
Animals with
Tumors Survival
Duration of
Experiment
SUver Nitrate
O
1
o
^j
Saffiotti & Shubik, 20 mice3 Swiss M
1963
Saffiotti & Shubik, 20 mice3 Swiss M
1963
Frei & Stephens, 30 mice Swiss inbred M
1968
10% in distd water
2/week for 43 weeks
starting 1 week after
topical application
of 1.5% DMBA (7,12-
dimethylbenz(a)anthra-
cene) in mineral oil
Same as above, except
crobon oil was sub-
stituted for the first
silver nitrate treatment
10% in distd. water,
2/week for 50 days
Hair-free skin,
topical
Hair-free skin,
topical
Top ears, topical
3 with 8 papillo- 18 at 10 weeks
mas (average 13 at 20 weeks
latent period 19
weeks)
0 carcinomas
6 with 14 tumors 19 at 10 weeks
(1 was a car- 15 at 20 weeks
cinoma) (average
latent period 21
weeks)
O° 25 survivors
44 weeks.
44 weeks
50 days
Metallic Silver
McDonald & Huffman, 1.3 rats Long Evans
1955 cited in
Shubik & HartweU,
1969
Nothdurft, 1955 Mice
Nothdurft, 1955 Rats Wistar
Nothdurft, 1956 84 rats
cited in Shubik &
Hartwell, 1969
Disks 12 x 0.02 mm
12/animal
Disks 17 x 0.02 m m
12/animal
T>-mm disk implanted
(8/anim al)
Implanted in
bladder
Implanted 6 s.c.
on back, 4 Lp.,
2 s.c. on abdomen
Implanted 6 s.c.
on back, 4 i.p.,
2 s.c. on abdomen
S.C.
2 sarcomas
65 sarcomas
8 weeks
9 to 12 months
9 to 12 months
23 months
-------
TABLE 17 (Continued)
O
M
O
00
Investigators Animal
Oppenheimer, et aL 25 rats
1956
Nothdurft, 1958 35 rats
Strain or Type Sex Preparation and Dose
Wistar M 2 pieces of foil.
1.5-cm wide
Wistar M &F Fragments I x 1 x
0.02 mm
Site and Route
Imbedded, S.C.,
abdominal wall
S.C.
Animals with
Tumors
14(32%)(£ibro-
sarcomas at site
of imbedding)
0
Survival
24 at 18th
month, 31
at 1 2th nronth
Duration of
Experiment
275 to 625 days
At most 33 months
Schmahl & Steinhoff, 31 rats
1960
BD
Becker, et aL
1967
Rats
Furst 6 Schlauder, Rats
1977
Fischer-144
Colloidal silver sus-
pension 1.75 rag.
4/week for 10 months
then 2.5 mg/week for
7 months. Total dose
65 mg/rat
Platelets 11 m m x
3mm thick
Fine powder (-300
mesh) in suspension
in trioctanoin
Lv. or S.C.
injections
Implant
One spindle-cell
sarcoma at in-
jection site at 16
months. Later 8/26
(31%): 6 sarcomas,
leukemia and a lami-
nar epithelial car-
cinoma. (Average
latent period 695
+ 150 days.)
M alignancies at
295 days
(31 %)v
17 months
295 days
S.C.
aFifty female mice given only a similar initiating treating lived 20 to 140 weeks without developing tumors. Among control groups from the same colony, one of 240
females observed for their lifespan developed a papilloma that regressed; and of 240 males, there developed one skin papflloma and a carcinoma of skin appendages. Other
control groups totalling 400 mice of both sexes did not develop any tumors within 100 weeks.
The investigators judged silver nitrate to be an agent causing marked epidermal hyperplasia.
°John I Thompson and Company (1969), reported that the treatment induced 100% epithelial hyperplasia. It did not. It was therefore, not used in further studies of tumor
promotion wherein 1.50 % DMBA was used as the carcinogen. In the test described above, the only untoward effect reported was the presence of 17 inQam matory cells after
10 days in a standard area of ear epidermis, compared with three in the controls while the known tumor promoter 50% croton oil caused 176 inQam matory cells.
The rate of spontaneous malignant tumor formation was 1 to 3 % in 700 untreated rats.
eRats injected with the vehicle or a suspension of gold powder developed one fibrosarcoma per group. By contrast, 60% of rats injected with cadmium powder developed
fibrosarcomas at the injection site.
-------
from "Substances Which Have Been Tested for Carcinogenicity"*
(Hartwell, 1951; Thompson and Co., 1969; Shubik and Hartwell,
1969).
Furst (Chemical and Engineering News, 1975), in an address to
orthopedic surgeons in West Germany, stated that the metals he and
others had tested for carcinogenicity, silver, gold, copper, iron,
and lead, were "benign."
Nothdurft (1958) found no difference in the incidence of sar-
coma formation initiated by s.c. or i.p. injections of silver (17-
mm diameter round disks) in rats and mice and that initiated by
gold, platinum, or ivory. Wistar rats of both sexes were treated
with pieces of cut-up silver foil (8 s.c. implants in each of 31 to
35 animals) ; largest particle size (1x1 mm) was observed for
periods up to a lifetime. Similar implants of gold and platinum
were made. After 12 months, there were 31 survivors in the silver
group, 28 in the gold group, and 26 in the platinum group. The
\
number of survivors after 18 months were 24, 19, and 20, respec-
tively. One rat from each group was observed for 29 months. The
last animal to die (at 33 months) had been treated with silver.
None of the rats developed sarcomas.
*Some of the studies that have been listed in "Substances Which
Have Been Tested for Carcinogenicity" were not really carcinogen
assays at all. For example, Hanzlik and Presho (1923) inserted
0.53, 0.621, and 1.56 g silver granules in the gizzards of three
pigeons and observed weight loss and sickness in the two pigeons
receiving the lower doses. They recovered within 18 and 48 days,
respectively. There was no histopathological examination of tis-
sues. In another inappropriately included study, O'Connor (1954) ,
supported by the British Empire Cancer Campaign, induced deep
necrosis of the colon tissues by anal insertion into mice of silver
nitrate crystals. The mucous membranes and muscle were examined
for the extent of regeneration.
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Oppenheiraer, et al. (1956) imbedded two 1.5 cm circles or
squares of silver foil s.c. into the abdominal wall of each of 25
male Wistar rats immediately ventral to the fascia on either side.
The latent period of tumor formation (all fibrosarcomas) in 14 of
the rats (32 percent) was 275 to 625 days. The authors had earlier
shown that the physical form of plastics played a role in carcino-
gencity, implants of plain plastics causing many more tumors than
perforated film, fibers, or powders. The effect of smoothness may
be operative also with metal implants since flexible steel, tan-
talum, and vitallium foils also produced tumors, in identical
experiments, and crumbly tin foil did not. (There were no
controls.)
Silver alloys were not considered in Table 17 because of the
uncertainty of attributing any effect solely to silver. Fujita
2
(1971) imbedded a solid 1 cm plate of a dental silver-palladium-
gold alloy s.c. in rats and found tumors (fibrosarcomas, fibro-
adenomas, and fibromas) in 7 of 14 animals. The incidence of
tumors was only 1 in 13 when the plate was perforated.
However, in another study, implanted smooth pellets of a
silver-based dental alloy* or pure gold for 5 to 90 days in the oral
submucous membranes of rabbits and in the liver, testes, and
femoral muscles of rats, were judged to be rather innocuous. The
implants produced proliferation of connective tissue and a release
of neutrocytes, monocytes, and histiocytes as the primary effects
and secondarily produced fibroblasts. The effects of the implants
*70.02 percent silver, 24.70 percent palladium, 5.23 percent gold,
and 0.03 percent copper.
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in the rabbits were judged to be mild. Spermatogenesis was noted
in the degenerative seminiferous tubules among the proliferated
fibrotic stroma surrounding the alloy pellets. In the muscle, new
connective tissue invaded the fiber bundles (Habu, 1968).
Both colloidal silver and silver nitrate have been reported to
promote tumor growth. Intratumoral injections of colloidal silver
in 40 rats appeared to stimulate cancer growth rather than inhibit
it as did similar injections of colloidal platinum. In only one of
the treated rats (2.5 percent) did the tumor heal compared with 5
of the 30 control rats (16.6 percent). (Colloidal platinum injec-
tions in 342 rats had given 14.0 to 50.0 percent healing compared
with 0 to 38.0 percent healing in the controls) (Guyer and Mohs,
1933) .
Four rats were given s.c. injections of colloidal silver on
one side and colloidal platinum on the other. After two hours, the
metals in the subcutaneous tissues were surrounded by profuse
serous exudates and beginning leukocyte invasion. At 24 hours,
both metals had initiated fibroblastic proliferation, which re-
placed the leukocytic exudation almost completely by 48 hours.
Colloidal platinum induced a thicker, denser fibroblastic capsule,
which may explain its inhibitive effect on cancers by walling them
off and diminishing the oxygen supply. Irritant ionic silver was
probably present because of the presence of a discoloration in the
nearby tissue fluids by 24 hours, and degeneration of the adjacent
striated muscle. The foreign body reaction around platinum par-
ticles was not accompanied by injury to normal tissue. Possibly,
the promotion, by silver, of cancer growth is due to the production
C-lll
-------
of an area of lowered tissue resistance that allows resistant can-
cer cells to grow freely (Guyer and Mohs, 1933).
Schmahl and Steinhoff (1960) induced tumors in rats with i.v.
and s.c. injections of colloidal gold* or colloidal silver. (The
LD5Q for i.v. administration of colloidal silver in rats is 67
mg/kg. (The animals died within 20 to 24 hours with severe pul-
monary edema). They administered 1.75 mg silver to 31 BD-strain
rats for the first dose, which was followed at weekly intervals by
2.45 mg s.c. doses, so that the total dose per animal over the 10-
month period was 44 mg. The group was then given 2.5 mg weekly
doses i.v. for seven months for an additional total dose of 65 mg Ag
per rat. Argyria was noticeable in the skin and mucous membranes
after 6 to 8 weeks, but their health and growth were not affected.
^Sixteen months after the start of the injections, one rat developed
a spindle-cell sarcoma at the injection site. There were only 26
survivors at this time. Seven others later developed malignant
tumors. Altogether, six sarcomas occurred at the injection site.
Leukemia and lamellar epithelial carcinoma at the maxillary angle
were also observed. The frequency of occurrence of malignancies in
the survivors was 8/26 or 31 percent; 23 percent for the local
malignancies. The average latent period was 695 + 150 days. In 700
untreated rats, the rate of spontaneous malignant tumor formation
was 1 to 3 percent.
Saffiotti and Shubik (1963) treated the hair-free skin of 20
male mice with a 1.5 percent solution of the carcinogen DMBA (7,12-
*Found to be noncarcinogenic.
C-112
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dime thy IbenzU) anthracene) in mineral oil. One week later, the
mice were treated with a 10 percent aqueous solution of silver
nitrate to determine its promoting activity. The silver nitrate
solution was applied twice weekly throughout the rest of the 44-
week experiment. At 10 weeks, there were 18 survivors; at 20
weeks, 13. Three mice developed eight papillomas (but no carcino-
mas) with an average latent period of 19 weeks. Silver nitrate was
judged to be an agent causing marked epidermal hyperplasia. In
another 44-week series, where croton oil was substituted for the
first silver nitrate treatment, there were 19 survivors at 10
weeks; 15, at 20 weeks. Six mice of 20 developed tumors, one of
which was a carcinoma. The average latent period was 21 weeks.
Fifty female mice given only a similar initiating treatment lived
at least 20 weeks (the test extended for 140 weeks). None of the
animals bore tumors. Among control groups from the same colony,
one of 240 females observed for their life span developed a papil-
loma that regressed; and of 240 males, there developed one skin
papilloma and a carcinoma of skin appendages. Other control groups
totaling 400 mice of both sexes did not develop any tumors within
100 weeks.
On the other hand, silver nitrate has been found in at least
one study to be a tumor inhibitor. Taylor and Carmichael (1953)
studied the effect of metallic salts (mainly chlorides) on the
embryo and tumor (C3H mouse mammary adenocarcinoma) of tumor-
bearing eggs and on dba mouse sarcoma transplants in dba mice.
When 0.3 mg aqueous AgNO3 was injected into the egg membrane (46
eggs), survival (at 3 days) was 91 percent that of the controls;
C-113
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tumor weight, 79 percent; and embryo weight, 98 percent. Five con-
secutive daily subdermal injections of 1.0 mg silver nitrate in
saline given to 14 dba mice bearing sarcomas in the inguinal area
reduced the tumor size to 65 percent that of the controls (given
only saline injections) at seven days, but reduced the body weight
of the mice to only 96 percent. Silver nitrate was one of the more
effective tumor growth inhibitors (along with the chlorides of Co,
Cu, Hg, Ni, Rh, Ti, and Zn).
Although the literature is replete with clinical reports of
cases of argyria, the connections between human cancers and silver
as a causal agent are very tenuous. The following reports reflect
the difficulty of finding even tenuous connections in the litera-
ture.
Schulze and Bingas (1968) attributed the formation of a men-
ingioma surrounding a silver clip left from an operation two years
before to remove an ependymoma in the brain of an 11-year-old girl
to its action as a chronic exogenous stimulus. Hormonal changes
during puberty caused the frequent recurrences of the ependymoma.
Some cases of esophageal cancer in certain areas of Brazil
have been related to the assiduous habit of "drinking mate tea
without sugar, in a gourd through a silver straw, at very hot tem-
perature." According to Dantas (1975), the high temperature may be
at least partly the cause of the esophageal cancer.
Bell, et al. (1952) reported that accidental incorporation of
pieces of silver amalgam into the alveolus or gingiva during dental
procedures appear as a grayish-blue macule in the oral mucous mem-
brane. Unless subjected to stress, as when under a denture, they
C-114
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are not tender nor inflammatory. "They closely resemble a blue
nevus and have been removed in some cases on suspicion of neo-
plasm." Under the microscope (low-power), "They at first glance
give a strong impression of blue nevus." There was silver pigment
in the blood vessels and a sparse sprinkle of histiocytes. "No
giant cells, inflammatory infiltrates, or other tissue reactions
have been seen."
C-115
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CRITERION FORMULATION
Existing Guidelines and Standards
Both of the U.S. standards for silver in drinking water and in
workplace air have been based on a presumed 1 g minimum dose of sil-
ver that has caused argyria (Table 18). It should be pointed out
how the minimum 1 g silver needed to produce argyria was deter-
mined. In their book, Hill and Pillsbury (1939) stated that only
intravenous doses of silver could be used to determine accurately
the amount of silver actually taken into the body since the extent
of gastrointestinal or mucous membrane absorption was unknown.
Silver arsphenamine had been administered i.v. to human patients
suffering from syphilis; 19 of them (14 had advanced symptoms of
syphilis; 11 had received other heavy metal treatment*) developed
argyria. Those patients developing argyria had received total
doses of silver ranging from 0.91 g to 7.6 g within 2 to 10 years.
The average total dose was 2.3 g silver. (Fourteen of the patients
developing argyria were males.) The total number of patients that
had been treated with silver arsphenamine was not estimated, but
they were probably quite numerous.*
Until the U.S. Public Health Service Drinking Water Standards
of 1962 [U.S. Department of Health, Education and Welfare (DHEW),
1962], there were no restrictions on silver in drinking water.
*Hill and Pillsbury (1939) had pointed out that, "Generalized pig-
mentation of the skin resembling that of argyria may be seen fol-
lowing the introduction of various metals, in particular bismuth,
arsenic, and gold." Eight of the 19 people had also received
bismuth.
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TABLE 18
Existing Standards Regarding Silver
o
i
Medium
Drinking water
Drinking water
Drinking water
Workplace air, threshold
limit value, 8-hour
time-weighted
Short-term exposure
limit (15 minutes
4 times per day)
Silver
Concentration
50 yg/1
0.5 ug/1
10 ug/1
0.01 mg/m"
0.03 mg/nf
Authority
U.S. EPA, 1976; NAS, 1977
State of Illinois (cited
in NAS, 1977)
State of California (cited
in NAS, 1977)
OSHA, 1974
(40 CFR 1910.1000)
ACGIH, 1977
-------
Neither the World Health Organization International Standards of
1958 nor the European Standards of 1961 set a limit for silver in
drinking water (McKee and Wolf, 1963).
The 1976 National Interim Primary Drinking Water Regulations
(U.S. EPA, 1976) included a section on silver that is practically
identical to the 1962 Drinking Water Standards (DHEW, 1962). Both
begin, "The need to set a water standard for silver (Ag) arises
from its intentional addition to waters for disinfection." Both
state, "... the amount of silver from injected Ag-arsphenamine,
which produces argyria, is precisely known. This value is any
amount greater than 1 g of silver, 8 g Ag-arsphenamine." The con-
dition to be avoided was argyria. The phraseology "any amount" is
misleading, since probably hundreds of patients over at least two
decades of this treatment for syphilis had received total doses of
silver greater than 0.91 g (Hill and Pillsbury, 1939). The two
documents acknowledge, however, that there is "considerable vari-
ability in predisposition to argyria," which is clearly seen upon
examination of Hill and Pillsbury's report of a few hundred case
histories from the literature.
The 1976 document omits the calculations from the 1962 docu-
ment: "Assuming that all silver ingested is deposited in the
integument, it is readily calculated that 10 ug/1 could be ingested
for a lifetime before 1 g silver is attained from 2 liters water
intake per day; 50 yg/1 silver could be ingested approximately 27
years without exceeding silver deposition of 1 g." Yet, both also
consider that intake from foods is "60 to 80 yg/day," based on the
balance study of Kehoe, et al. (1940), and that silver would be
C-118
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increased in sulfur-containing foods by combination with silver in
the cooking water.
The National Academy of Sciences (NAS, 1977) in Drinking Water
and Health made a somewhat different calculation: "The interim
drinking water level of 50 ug/1 would be equivalent to a retention
of 50 ug of silver per day (on the assumption that 50 percent of the
intake is retained in the body), and would result in an accumula-
tion of 1 g in 55 years, to give a probable borderline argyria."
The U.S. National Aeronautics and Space Administration recom-
mended silver at 100 ug/1 for safely providing pure drinking water
on space flights; Swiss health officials, 200 ug/1; and German
health officials, 100 ug/1 (Silver Institute, 1975).
Maximum contaminant levels for inorganic chemicals in the 1975
National Interim Primary Drinking Water Regulations (40 FR 59565)
are based on an average consumption of 2 liters of water per day.
Current Levels of Exposure
Estimates of silver in human diets have varied widely — from
an average of 0.4 ug/day for three Italian populations (Clemente,
et al. 1977) to 27 + 17 ug/day (excluding water) in the United King-
dom (Hamilton and Minski, 1972) to 35 ug/day (man) and 40 ug/day
(woman) (Tipton, et al. 1966), and 88 ug/day (Kehoe, et al. 1940).
Snyder, et al. (1975) estimated the average intake of silver by man
to be 70 ug/day based on a review of the literature. Some of these
estimates were based on intake of both food and water. An estimate
of 30 ug/day for the average human intake in food is reasonable.
C-119
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Ambient air levels of silver up to 10.5 ng/m would lead to
intake of up to 0.24 ug silver per day (at 23 m respired air per
24-hour period). Exposure from cigarettes is negligible.
An average value for silver ingestion by water intake cannot
be made. Silver was detected in only 6.1 percent of 380 finished
waters (and in only 6.6 percent of U.S. surface waters). Because
of the recent increase of interest in water purification by silver
in the United States, many people are probably ingesting water from
nonpublic potable water sources at the 1962 drinking water limit of
0.05 mg/1. Shorter exposure of the U.S. population to European
limits might occur during travel by plane or ship.
A diet high in seafood taken from silver-polluted water may
increase daily silver consumption. Organisms serving as food for
high trophic level aquatic species concentrate silver by a factor
of about 200 (brown algae, 240; diatoms, 210). Other concentration
factors in higher organisms of the food chain are mussels, 330;
scallops, 2,300; oysters, 18,700; and North Sea marine organisms,
average 22,000 (Cooper and Jolly, 1969). Thus, regular ingestion
of fish, etc., from contaminated water might significantly increase
silver dietary intake.
In the workplace, daily intake in the United States is limited
to 100 ug/day (0.01 mg/nr x 10 m/ per workday). Ground-based
cloud-seeding generator operators, however, are exposed to air con-
centrations exceeding the maximum permissible concentration for
several hours at a time.
C-120
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Special Groups at Risk
People treated with silver-containing medicinals are most at
risk of developing argyria, as demonstrated by Hill and Pillsbury
(1939) who summarized 357 recorded cases of argyria, 89 percent of
which were due to therapeutic use of silver. In the period 1931 to
1939, when more people were exposed to therapeutic forms of silver
than in any previous period, 92 percent of the cases were due to
medicinals. Cases of occupationally-caused argyria are seldom
encountered in the recent literature and were usually diagnosed at
least 30 years ago. Hobbyists (e.g., jewelry makers, photograph
developers) may not be aware of the precautions needed with silver
and may be more at risk of argyria.
There are large individual variations in silver absorption,
retention, eliminations, and/or susceptibility to argyria. Al-
though intravenous administration of a total of 0.91 to 7.6 g
(average 2.3 g) silver as silver arsphenamine for 2 to 10 years has
caused argyria, hundreds of patients have received up to 1.7 g
silver i.v. as silver arsphenamine without developing argyria
(Cooper and Jolly, 1969; Hill and Pillsbury, 1939).
Over 10,000 cases of burn and leg ulcer patients have been
treated with silver medicinals. No cases of argyria have been
reported, even when 0.5 percent silver nitrate was used and sys-
temic absorption was shown.
Aside from argyria, more subtle effects may be due to silver
ingestion. On the basis of animal experiments, people marginally
deficient or deficient in copper, selenium, or Vitamin E may have
their deficiency symptoms exacerbated. But rat studies did not
C-121
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support this suggestion. The possibility that silver might render
iodine unavailable in regions that otherwise might have just enough
iodine to prevent goiter is another suggested consequence of silver
in drinking water (Boissevain and Drea, 1936) . To support the con-
tention, however, elevated silver concentrations had been found in
the water of endemic goiter regions, such as the western slopes of
the Colorado mountains (Boissevain and Drea, 1936).
Basis and Derivation of Criterion
The carcinogenic effect data reviewed in the document are not
sufficiently conclusive to provide a quantitative carcinogenic risk
assessment. No study demonstrating carcinogenicity of silver has
met all of the criteria described in 40 CFR 162.11 (a) ii, A or 43
FR 163.83-2bc regarding appropriate route, chemical form, number of
animals, histologic examination of organs, concurrently run control
group, and all other quantitative parameters.
A review of the animal data showed that in 10 toxicologic
experiments on chronic ingestion of drinking water by rats (rabbits
included in one study), containing 50 to 20,000 ug/1 ionic silver,
no effects were observed in rats ingesting silver at 200 ug/1
(Table 19), and further no significant toxic effects were observed
at a dose level below 400 ug/1 (Table 19). Initial physiological
effects were suggested at doses of 400 to 500 yg/1 of silver. If
the no-observable-effect level (NOEL) of 200 yg/1 (Just and
Szniolis, 1936) is used in developing a criterion for silver, the
following calculation could be made:
C-122
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TABLE 19
Toxic Effects in Rats Chronically Exposed to Silver in Their Drinking Water
Silver
Concentration
(pg/liter)
Duration
(months)
Effect
Reference
500
2,000
6-12
12
o
1
CO
20,000
200
2,000
200
20,000
200
400
6
12
8
8
12
12
3.3
3.3
Increase in brain nucleic acids but
not statistically significant.
Significant increase in liver weight
and RNA concentration at 6 months.
Increase in brain nucleic acids
(statistically significant for DNA).
Significant increase in liver RNA
concentration.
Significant increase in brain nucleic
acids. Significant decrease in brain
RNA at 12 months.
Depression of absorption function of
retinculoendothelial system.
0
Changes in serum protein fractions
and the composition of free amino
acids.
Kharchenko, et al,
1973a,b
Savluk, 1973
Savluk and Moroz,
1973
Just and Snziolis,
1936
Kidney hemorrhage.
-------
TABLE 19 (Continued)
O
i
M
ro
Silver
Concentration
(pg/liter)
700
1,000
50
20,000
Duration
(months)
3.3
3.3
5
5
Effect
More pronounced kidney changes.
Kidney, spleen, and liver changes.
No change in digestive organs.
Liver enzyme function changes. Growth
Reference
Maslenko, 1976
100
20,000
50,000
4
4
logical changes in stomach, small
intestine, and liver.
Insignificant serum SH group depletion
Decreased serum SH.
Pak and Petina,
1973
-------
(0.2 mq/kg) (0.035 I/day)* = Q>023 mg/kg/day
0.3 kg**
0.023 mg/kg/day x 70 kg/adult human male =1.6 mg/day
* Estimated volume of water consumed by rats.
** Estimated weight of one rat.
In accordance with The National Academy of Sciences guidelines
(NAS, 1977), a safety factor of 100 would be applied to the NOEL to
yield a concentration of 8 vg/1, i.e.:
1.6 mg/day = 0.016 mg/day = Q>008 mg/1 = 8 yg/1
(100) 21 21
A bioconcentration factor (BCF) has not been used in this deriva-
tion since the measured BCF for bluegill fish (U.S. EPA, 1978) is
less than the concentration of silver in ambient water. It should
be noted, however, that higher values have been reported for non-
indigenous shellfish (Cooper and Jolly, 1969). A BCF relates the
concentration of a chemical in aquatic animals to the concentration
in the water in which they live. An appropriate BCF can be used
with data concerning food intake to calculate the amount of silver
which might be ingested from the consumption of fish and shellfish.
An analysis (U.S. EPA, 1980) of data from a food survey was used to
estimate that the per capita consumption of freshwater and estua-
rine fish and shellfish is 6.5 g/day (Stephan, 1980). A measured
BCF of less than 1.0 was obtained for silver using bluegills (U.S.
EPA, 1978). For lack of other information, a value of 0.5 can be
used as the weighted average BCF for silver and the edible portion
of all freshwater and estuarine aquatic organisms consumed by
Americans.
Although a theoretical "safe" level for ambient water would be
derived from the animal data, the available reports from the
C-125
-------
literature are difficult to interpret due to a number of deficien-
cies, including the reported study by Just and Szniolis (1936).
Histological details of the lesions are not described adequately.
Experimental details, such as the number of animals used, are also
not given. Therefore, the animal data do not provide sufficient
grounds to formulate a sound criterion.
Ingestion of silver by humans results in the additive deposi-
tion (with no apparent elimination) of silver in skin and mucous
membranes causing argyria. The current drinking water standard
(USPHS) of 50 ug/1 has been derived to protect against argyria.
This standard assumes an accumulation of 1.0 g for the lowest
effect over an exposure period of 55 years. The data used to derive
this standard is obtained from the results of clinical studies
reviewed by Hill and Pillsbury (1939) (see Table 14). Even though
the NAS estimate is based on a somewhat shorter exposure period
than the lifetime exposure used in the derivation of a criterion
for ambient water quality, the NAS (1977) derived standard repre-
sents the best scientific judgement in extrapolating the shorter
term human clinical and occupational evidence into long term (55
years) low level exposure from drinking water. The differences
between the NAS standard and the ambient water quality criterion
calculations is in the standard set of assumptions used in the
extrapolation process from shorter term data to life span expo-
sures. Since the NAS derived standard purports to protect the U.S.
population against argyria through past experience, the 50 ug/1
should be considered as the upper limit level for deriving the
ambient water quality criterion, even though the calculated value
C-126
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based on the Hill and Pillsbury data for 70 years of human exposure
would be somewhat lower (s~20 ug/1). This criterion intends to
protect humans against manifestation of argyria during lifetime
exposure. It is fundamentally identical to that of NAS (1977)
except that it considers exposure over a longer period of time.
To compare observed environmental level with the proposed cri-
terion, silver has been detected at levels as low as 0.1 ug/1 in 104
of 1,577 samples taken from 130 points in well and surface waters
of the United States. The concentration in positive samples ranged
from 0.1 to 38 ug/1 with a median of 2.6 ug/1 (Kopp, 1969). Silver
concentrations in finished water from public water supplies have
been found to be about 2.3 ug/1 (Durfor and Becker, 1962; Kopp,
1969) with a maximum of about 6.0 ug/1, while the maximum detected
in tap water supplies (2,595 samples) has been reported to be 30
ug/1 (Taylor, 1971). Silver has been added in special applications
to drinking water supplies at higher concentrations (up to 200
ug/1) as a disinfectant, but this method is not economically com-
petitive for large public water supplies.
The animal toxicity data do not present compelling evidence to
warrant changing the present standard of 50 ug/1 accepted by NAS.
This standard appears, through past experience, to be satisfactory
to protect against argyria in humans. Given the limited precision
of the 0.9 g argyria-inducing dose in humans, the adjustment of the
NAS standard by correcting for lifetime (70 year exposure) does not
seem to offer, in itself, a compelling reason to recommend a lower
criterion. The maximum detectable silver concentration reported in
water samples was 38 ug/1- (The median concentration reported,
C-127
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however, is 2.6 ug/1.) Assuming that 50 percent of the intake at
this concentration is retained in the body (NAS, 1977) , then it
would require 65.6 years to retain the quantity believed to produce
argyria, which is a conservative estimate. There have been no
reported cases of argyria through ingestion at this level, and the
current NAS standard appears to be protective. Therefore, the cur-
rent NAS standard of 50 ug/1, which appears to be protective, is
recommended as the ambient water quality criteria.
C-128
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