Toxicological
Profile
for
SILVER
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-24

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TOXIC0LOGICAL PROFILE FOR
SILVER
Prepared by:
Clement International Corporation
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990

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i i
DISCLAIMER
The use of company or product name(s) is Cor identification only and does
not imply endorsement by the Agency for Toxic Substances and Disease Registry

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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the
200 most significant hazardous substances was published in the Federal
Register on April 17, 1987 and on October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list, Each
profile must include the following content:
(A)	An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects,
(B)	A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects, and
(C)	Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The original guidelines were
published in the Federal Register on April 17, 1987. Each profile will
be revised and republished as necessary, but no less often than every
three years, as required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and
reviews the key literature that describes a hazardous substance's
toxicological properties. Other literature is presented but described
in less detail than the key studies. The profile is not intended to be
an exhaustive document; however, more comprehensive sources of specialty
information are referenced.

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iv
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Data needs that are of significance to protection of public health will
be identified by ATSDR, the National Toxicology Program of the Public
Health Service, and EPA. The focus of the profiles is on health and
toxicological information; therefore, we have included this information
in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
William L. Roper, M.D., M.P.H.
Administrator
Agency fof Toxic Substances
and Disease Registry

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V
CONTENTS
FOREWORD	iii
LIST OF FIGURES		ix
LIST OF TABLES		xi
1.	PUBLIC HEALTH STATEMENT 		1
1.1	WHAT IS SILVER?		1
1.2	HOW MIGHT I BE EXPOSED TO SILVER?		2
1.3	HOW CAN SILVER ENTER AND LEAVE MY BODY? 		2
1.4	HOW CAN SILVER AFFECT MY HEALTH? 			3
1.5	WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH
EFFECTS? 		4
1.6	IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO SILVER? 		5
1.7	WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 		5
1.8	WHERE CAN I GET MORE INFORMATION?		10
2.	HEALTH EFFECTS				11
2.1	INTRODUCTION		11
2.2	DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 		11
2.2.1	Inhalation Exposure 		13
2.2.1.1	Death 		13
2.2.1.2	Systemic Effects 		13
2.2.1.3	Immunological Effects 		16
2.2.1.4	Neurological Effects 		16
2.2.1.5	Developmental Effects 		16
2.2.1.6	Reproductive Effects 		16
2.2.1.7	Genotoxic Effects 		16
2.2.1.8	Cancer 		16
2.2.2	Oral Exposure 			16
2.2.2.1	Death			16
2.2.2.2	Systemic Effects 		16
2.2.2.3	Immunological Effects 		20
2.2.2.4	Neurological Effects 		20
2.2.2.5	Developmental Effects 		21
2.2.2.6	Reproductive Effects 		21
2.2.2.7	Genotoxic Effects 		21
2.2.2.8	Cancer 		21
2.2.3	Dermal Exposure		21
2.2.3.1	Death 		21
2.2.3.2	Systemic Effects 		23
2.2.3.3	Immunological Effects 		23
2.2.3.4	Neurological Effects 	 23
2.2.3.5	Developmental Effects 		23

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vi
2.3
2.2.3.6
2.2.3.7
2.2.3.8
TOXICOKINETICS
2.3.1
Reproductive Effects
Genotoxic Effects
Cancer 	
2.4
2.5
2.6
Absorption 	
2.3.1.1	Inhalation Exposure 	
2.3.1.2	Oral Exposure 	
2.3.1.3	Dermal Exposure 	
2.3.2	Distribution 	
2.3.2.1	Inhalation Exposure 	
2.3.2.2	Oral Exposure 	
2.3.2.3	Dermal Exposure 	
2.3.2.4	Other Routes of Exposure 	
2.3.3	Metabolism 	
2.3.4	Excretion 	
2.3.4.1	Inhalation Exposure 	
2.3.4.2	Oral Exposure . 	
2.3.4.3	Dermal Exposure 	
2.3.4.4	Other Routes of Exposure 	
RELEVANCE TO PUBLIC HEALTH 	
BIOMARKERS OF EXPOSURE AND EFFECT 	
2.5.1	Biomarkers Used to Identify or Quantify Exposure to
Silver		 40
2.5.2	Biomarkers Used to Characterize Effects Caused by
Silver	 41
INTERACTIONS WITH OTHER CHEMICALS 	 42
POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 	 43
ADEQUACY OF THE DATABASE 		 43
2.8.1	Existing Information on Health Effects of Silver .... 43
2.8.2	Identification of Data Needs	 44
2.8.3	On-going Studies ..... 	 50
23
23
24
24
24
24
25
25
27
27
27
28
28
30
30
30
31
32
32
32
38
3,
CHEMICAL AND PHYSICAL INFORMATION - .
3.1	CHEMICAL IDENTITY 	
3.2	PHYSICAL AND CHEMICAL PROPERTIES
PRODUCTION, IMPORT, USE AND DISPOSAL
4.1	PRODUCTION ...•¦•••
4.2	IMPORT		
4.3	USE		 • • •
4.4	DISPOSAL		 . . •
5.
POTENTIAL FOR HUMAN EXPOSURE .
5.1	OVERVIEW		
5.2	RELEASES TO THE ENVIRONMENT
5.2.1	Air
5.2.2	Water ...••••
5.2.3	Soil ...••••
5.3	ENVIRONMENTAL FATE . • • •
5.3.1	Transport ind Partitioning
5.3.2	Transforms 'ion and Degradation
51
51
51
65
65
66
66
66
69
69
70
70
70
70
72
72
74

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vii
5.3.2.2	Water 		74
5.3.2.3	Soil		74
5.4	LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 		75
5.4.1	Air		75
5.4.2	Water		75
5.4.3	Soil			76
5.4.4	Other Media		77
5.5	GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 		78
5.6	POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 		79
5.7	ADEQUACY OF THE DATABASE		80
5.7.1	Identification of Data Needs		80
5.7.2	On-going Studies 		82
6.	ANALYTICAL METHODS 		85
6.1	BIOLOGICAL MATERIALS 		85
6.2	ENVIRONMENTAL SAMPLES 		91
6.3	ADEQUACY OF THE DATABASE		93
6.3.1	Identification of Data Needs		93
6.3.2	On-Going Studies 		94
7.	REGULATIONS AND ADVISORIES 		95
8.	REFERENCES		99
9.	GLOSSARY	-	141
APPENDIX	145

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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Silver - Oral	 18
2-2 Existing Information on Health Effects of Silver 	 45
5-1 Frequency of Sites with Silver Contamination 	 71

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1
2
3
4
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
6
7
8
9
17
22
26
29
33
39
52
53
54
55
56
57
58
59
60
61
62
63
xi
LIST OF TABLES
Human Health Effects from Breathing Silver 	
Animal Health Effects from Breathing Silver 	
Human Health Effects from Eating or Drinking Silver 	
Animal Health Effects from Eating or Drinking Silver 	
Levels of Significant Exposure to Silver - Oral 	
Levels of Significant Exposure to Silver - Dermal 	
Interspecies Differences in the Oral Absorption of Silver . . . .
Distribution in Rats at Six Days of Intramuscularly Administered
Radioactive Silver Tracer Dose when Administered Alone and when
Coadministered with Additional Silver as Silver Nitrate 	
Interspecies Differences in the Clearance of Silver Compounds . .
Genotoxicity of Silver In Vitro 	
Chemical Identity of Silver 	
Chemical Identity of Silver Nitrate 	
Chemical Identity of Silver (I) Oxide 	
Chemical Identity of Silver (II) Oxide 	
Chemical Identity of Silver Sulfide 	
Chemical Identity of Silver Chloride 	
Physical and Chemical Properties of Silver 	
Physical and Chemical Properties of Silver Nitrate 	
Physical and Chemical Properties of Silver (I) Oxide 	
Physical and Chemical Properties of Silver (II) Oxide 	
Physical and Chemical Properties of Silver Sulfide 	
Physical and Chemical Properties of Silver Chloride 	

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x i :i
6-1 Analytical Methods for Determining Silver in B io ] op, i c.'i I
Materials	 ... 86
6-2	Analytical Methods for Determining Silver in Environmental
Samples	 88
7-1	Regulations and Guidelines Applicable to Silver 	 .... 96

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1
1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about silver and to
emphasize the human health effects that may result from exposure to it. The
Environmental Protection Agency (EPA) has identified 1177 sites on its
National Priorities List (NPL). Silver has been found at 27 of these sites.
However, we do not know how many of the 1177 NPL sites have been evaluated for
silver. As EPA evaluates more sites, the number of sites at which silver is
found may change. The information is important for you because silver may
cause harmful health effects and because these sites are potential or actual
sources of human exposure to silver.
When a chemical is released from a large area, such as an industrial
plant, or from a container, such as a drum or bottle, it enters the
environment as a chemical emission. This emission, which is also called a
release, does not always lead to exposure. You can be exposed to a chemical
only when you come into contact with the chemical. You may be exposed to it
in the environment by breathing, eating, or drinking substances containing the
chemical or from skin contact with it.
If you are exposed to a hazardous substance such as silver, several
factors will determine whether harmful health effects will occur and what the
type and severity of those health effects will be. These factors include the
dose (how much), the duration (how long), the route or pathway by which you
are exposed (breathing, eating, drinking, or skin contact), the other
chemicals to which you are exposed, and your individual characteristics such
as age, sex, nutritional status, family traits, life style, and state of
health.
1.1 WHAT IS SILVER?
Silver is one of the basic elements that make ,up our planet. Silver is
rare, but occurs naturally in the environment as a soft, "silver" colored
metal. Because silver is an element, there are no man-made sources of silver.
People make jewelry, silverware, electronic equipment, and dental fillings
with silver in its metallic form. It also occurs in powdery white (silver
nitrate and silver chloride) or dark-gray to black compounds (silver sulfide
and silver oxide). Silver could be found at hazardous waste sites in the form
of these compounds mixed with soil and/or water. Therefore, these silver
compounds will be the main topic of this profile. Throughout the profile the
various silver compounds will at times be referred to simply as silver.
Photographers use silver compounds to make photographs. Photographic
materials are the major source of the silver that is released into the
environment. Another source is mines that produce silver and other metals.

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2
1. PUBLIC HEALTH STATKMKNT
The natural wearing down of si 1 ve r - bea r i ng rocks and soil hv i he	.
°	c	a * ih i a net r n i n
also releases large amounts of silver into the environment .
Silver that is released into the environment may be carried j t>1
distances in air and water. Rain washes silver compound.' out. of	r
1	' 1 11.«111V SO lis so
that it eventually moves into the groundwater. Silver i.s .stable -<,,,1	•
.	r-	,	,	,1!Kl 'eiiiains
in the environment in one form or another uhi.l! it. is taken out ajv-iin by
people. Because silver is an element, it. does not break down, |mt it c.
change its form by combining with other substances. Over t. Line j , ,|lav
from the form first released, to metallic- .silver, and then back r r> fi
j-	tlit- .same or
other compounds. The form it is found it; depends on environmental conditions
More information on the chemical and physical properties ol si IV(. i compounds
can be found in Chapter 3, on its production, use, and 
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1. PUBLIC HEALTH STATEMENT
Because many silver compounds dissolve in water and do not evaporate, the
most common way that silver may enter the body of a person near a hazardous
waste site is by drinking water that contains silver or eating food grown near
the site in soil that contains silver. Silver can also enter the body when
soil that has silver in it is eaten. Most of the silver that is eaten or
breathed in leaves the body in the feces within about a week. Very little
passes through the urine. It is not known how much of the silver that enters
the body through the skin leaves the body. Some of the silver that is eaten,
inhaled, or passes through the skin may build up in many places in the body.
More information on how silver enters and leaves the body can be found in
Chapter 2.
1.4 HOW CAN SILVER AFFECT MY HEALTH?
Since at least the early part of this century, doctors have known that
silver compounds can cause some areas of the skin and other body tissues to
turn gray or blue-gray. Doctors call this condition "argyria." Argyria
occurs in people who eat or breathe in silver compounds over a long period
(several months to many years). A single exposure to a silver compound may
also cause silver to be deposited in the skin and in other parts of the body;
however, this is not known to be harmful. It is likely that many exposures to
silver are necessary to develop argyria. Once you have argyria it is
permanent. However, the condition is thought to be only a "cosmetic" problem.
Most doctors and scientists believe that the discoloration of the skin seen in
argyria is the most serious health effect of silver.
Exposure to dust containing relatively high levels of silver compounds
such as silver nitrate or silver oxide may cause breathing problems, lung and
throat irritation and stomach pain. These effects have been seen in workers
in chemical manufacturing facilities that make silver nitrate and silver
oxide. One man developed severe breathing problems shortly after working with
molten silver. Skin contact with silver compounds has been found to cause
mild allergic reactions, such as rash, swelling, and inflammation, in some
people.
Studies of the health effects of silver in animals commonly use silver
nitrate. Doctors and scientists assume that effects seen using silver nitrate
in animals will be very similar to effects in humans caused by any silver
compound. While this Is likely to be true, it is still possible that some
silver compounds will be more harmful, or toxic, than silver nitrate.
One animal study suggests that long-term exposure (125 days) to
moderately high levels of silver nitrate in drinking water may have a slight
effect on the brain because exposed animals were less active than animals
drinking water without silver. Another study found that some of the animals
that drank water containing moderately high levels of silver for most of their
lives (9 months or longer) had hearts that were larger than normal. It is not
yet known whether these effects would occur in humans. There have been

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4
1. PUBLIC HEALTH STATEMENT
suggestions in some occupational studies in humans that silver can cause
kidney problems; however, more people exposed to si Ivor need to be studied to
find out if silver causes these effects.
No studies of cancer or birth defects in animals from eating, drinking,
or breathing in silver compounds were found. Therefore, it is riot known if
these effects would occur in humans. One study of animals drinking silver
compounds mixed with water for most of their life found no effect on
fertility. Another study found that reproductive tissues were damaged in
animals after they received injections of silver nitrate. However, the
tissues recovered even while the animals received more injections of silver
nitrate. Tests in animals show that silver compounds are likely to be life-
threatening for humans only when large amounts (that: is, grains) arc swallowed,
and that skin contact with silver compounds is very unlikely to be life-
threatening.
Silver does have helpful uses. For example, silver nitrate was used for
many years as drops in newborns' eyes to prevent blindness caused by
gonorrhea, and is also used in salves tor burn victims. Some water treatment
methods (including water filters) also use a form of silver to kill bacteria.
More information on the health effects from exposure to silver is presented in
Chapter 2. More information on the helpful uses of silver is presented in
Chapter 4.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Reports of cases of argyr^a su6gest that gram amounts of a silver
compound taken in medication i*» small doses over several months may cause
argyria in some humans. People w^° work in factories that manufacture silver
compounds can also breathe in the compounds. In the past, some of these
workers have become argyric. However, the level of silver in the air and the
length of exposure that caused argyria in these workers is not known. It is
also not known what level of s^ver causes breathing problems, lung and throat
irritation, or stomach pain if1 PeoPle.
Studies in rats show that drinking water containing very large amounts of
silver (2589 parts of silver per million parts of water, or about 2.6 grams
per liter) is likely to be lif'6"threatening.
There is very little iriformation about health effects following skin
contact with silver compounds. Argyria that covers the entire body is not
seen following skin contact w*-t silver compounds, although the skin may
change color where it touches t e silver. However, many people who have used
skin creams containing silver compounds such as silver nitrate and silver
sulphadiazine have not reporte ealth problems from the silver in the
medicine. In one animal study- a strong solution of silver nitrate (about 41
grams of silver nitrate per li-ter of water which is equal to 41 parts of

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5
]. PUBLIC HEALTH STATEMENT
silver nitrate per thousand parts of water) applied to	the skin of guinea pigs
for 28 days did not cause the animals to die; however,	it did cause the guinea
pigs to stop gaining weight normally. It is not known	if this would happen to
people if they were exposed the same way.
Tables 1-1 through 1-4 present the information that is available
concerning specific levels of exposure and health effects. The amount of
silver that has caused death in rats, and that has caused mice to be less
active are shown in Table 1-4.
1.6	IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
SILVER?
There are reliable and accurate ways of measuring silver in the body.
Silver can be measured in the blood, urine, feces, and body tissues of exposed
individuals. Because urine and blood samples are easy to get, these fluids
are most often used to find out if a person has been exposed to silver in the
last week or so. Silver builds up in the body, and the best way to learn if
past exposure has occurred is to look for silver in samples of skin. Tests
for silver are not commonly done at a doctor's office because they require
special equipment. Although doctors can find out if a person has been exposed
to silver by having blood or skin samples examined, they can not tell whether
any health effects will occur. Information about tests for measuring silver
in the body is in Chapters 2'and 6.
1.7	WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The federal government has developed regulations and guidelines to
protect people from the possible health effects from long-term exposure to
silver in drinking water. The Environmental Protection Agency (EPA) suggests
that the level of silver in drinking water not be more than 0.05 milligrams
per liter of water (mg/L) (which is equal to 50 parts of silver per billion
parts of water or ppb). However, in May, 1989, the EPA announced that this
restriction on silver levels in drinking water might be removed. For short-
term exposures (1-10 days), EPA suggests that drinking water levels of silver
not be more than 1.142 mg/L (which is equal to 1.142 parts of silver per
million parts of water or ppm).
Any release to the environment of more than 1 pound silver nitrate or
1000 pounds of silver alone should be reported to the National Response
Center. To limit the amount silver workers are exposed to during an 8-hour
shift for a 40-hour work week, the Occupational Safety and Health
Administration (0SHA) has set a legal limit (Permissible Exposure Limit or
PEL) of 0.01 milligrams of silver per cubic meter of air (mg/m3) in workroom
air.

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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Silver*
Short-term Exposure
(less than or equal to 14 days)
Levels in Air
T.pnpth of Exposure
	Description of Effects
The. health effects resulting
from short-term exposure of
humans to air containing
specific levels of silver
are not known.
Long-term Exposure
(greater than 14 days)
Levels in Air
T^frth of Exposure
	Description of Effects
The health effects resulting
from long-term exposure of
humans to air containing
specific levels of silver
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.

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7
1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Silver
Short-term Exposure
(less than or equal to 14 days)
Levels in Air	Length of Exposure	Description of Effects
The health effects resulting
from short-term exposure of
animals to air containing
specific levels of silver
are not known.
Long-term Exposure
(greater than 14 days)
Levels in Air	Length of Exposure	Description of Effects
The health effects resulting
from long-term exposure of
animals to air containing
specific levels of silver
are not known.

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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Silver*
Short-term Exposure
(less than or equal to 14 days)
Levels in Food
Tpnpth of Exposure
Description of Effects	
The health effects resulting
from short-term exposure o£
humans to food containing
specific levels of silver
are not known.
Levels in Water
The health effects resulting
from short-term exposure of
humans to water containing
specific levels of silver
are not known.
Long-term Exposure
(greater than 14 days)
Levels in Food
Tofipr.h of Exposurp
Description of Effects
The health effects resulting
from long-term exposure of
humans to food containing
specific levels of silver
are not known.
Levels in Water
The health effects resulting
from long-term exposure of
humans to water containing
specific levels of silver
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.

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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking Silver
Short-term Exposure
(less than or equal to 14 days)
Levels in Food
Lennth of Exposure
Description of Effects*
The health effects resulting
from short-term exposure of
animals to food containing
specific levels of silver
are not known.
Levels in Water fppm)
2589
2 weeks
Death in rats.
Long-1 e rm Expo sure
(greater than 14 days)
Levels in Food
Length of Exposure
Description of Effects*
The health effects resulting
from long-term exposure of
animals to food containing
specific levels of silver
are not known.
Levels in Water
95
1587
(PPm)
125 days
37 weeks
Sluggish behavior in mice.
Decreased weight gain in rats
*These effects are listed at the level at which they were first observed.
They may also be seen at higher levels.

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]()
1. PUBLIC HEALTH S TAT KM F. NT
For more information on criteria and standards for silve.r
Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
exposure, see
If you have any more questions or concerns not covered hc,re pieise
contact your State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
This agency can also give you information on the locatj0n r
... .	>1 oi tile ncflfcgf*
occupational and environmental health ciinics. Such clinics	•
..	,	.11	,	, siictiduze in
recognizing, evaluating, and treating illnesses that result from exposure to
hazardous substances.

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11
2. HEALTH EFFECTS
2.1	INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
silver. Its purpose is to present levels of significant exposure for silver
based on toxicological studies, epidemiological investigations, and
environmental exposure data. This information is presented to provide public
health officials, physicians, toxicologists, and other interested individuals
and groups with (1) an overall perspective of the toxicology of silver and (2)
a depiction of significant exposure levels associated with various adverse
health effects.
Silver occurs naturally in several oxidation states. The most common are
elemental silver (0 oxidation state) and the monovalent silver ion (+1
oxidation state). Most of the toxicological studies of silver have
investigated these chemical forms of the element. Other possible oxidation
states of silver are +2 and +3, however, no toxicological studies were located
that researched the health effects of silver compounds with these oxidation
states. Most occupational exposures to silver occur through inhalation of
silver-containing dusts or dermal exposure to photographic compounds.
Published studies on human inhalation of silver are based predominantly on
exposure to elemental silver, silver nitrate, and silver oxide. Human oral
data come from information on medicines containing silver, such as silver
acetate-containing antismoking lozenges, breath mints coated with silver, and
silver nitrate solutions for treating gum disease. Animal studies usually are
based on exposure to silver nitrate and silver chloride in drinking water.
Humans may be dermally exposed to silver through the use of silver-containing
processing solutions for radiographic and photographic materials, dental
amalgams, and medicines (e.g., silver sulphadiazine cream and solutions for
treating burns).
2.2	DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons living
or working near hazardous waste sites, the data in this section are organized
first by route of exposure -- inhalation, oral, and dermal -- and then by
health effect -- death, systemic, immunological, neurological, developmental,
reproductive, genotoxic, and carcinogenic effects. These data are discussed
in terms of three exposure periods -- acute, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration (for
which data exist) are presented in tables and illustrated in figures. The

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1?
2. HEALTH EFFECTS
points in the figures showing no-observed-adverse-effect levels (NOAKLst or
lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses'
(levels of exposure) used in the studies. LOAELs- have beta classified jnCo
"less serious" or "serious" effects. These distinctions are intended to help
the users of the document identify the levels of exposure at which adverse
health effects start to appear, determine whether or not the intensity of the
effects varies with dose and/or duration, and place into perspective the
possible significance of these effects to human health.
The significance of the exposure levels shown on the tables and graphs
may differ depending on the user's perspective. For example, physicians
concerned with the interpretation of clinical findings in exposed persons or
with the identification of persons with the potential to develop such disease
may be interested in levels of exposure associated with "serious" effects
Public health officials and project managers concerned with response actions
at Superfund sites may want information on levels of exposure associated with
more subtle effects in humaris or animals (LOAEL) or exposure levels below
which no adverse effects (NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels, MRLs) are of interest to
health professionals and citizens alike.
Estimates of exposure posing minimal risk to humans (MRLs) have been
made, where data were believed reliable, for the most sensitive noncancer end
point for each exposure duration. MRLs include adjustments to reflect human
variability and, where appropriate, the uncertainty of extrapolating from
laboratory animal data to humans. Although methods have been established to
derive these levels (Barnes et al. 1987; EPA 1989a), uncertainties are
associated with the techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of these procedures to derive less
than lifetime MRLs. As an example, acute inhalation MRLs may not be
protective for health effects that are delayed in development or are acquired
following repeated acute insults such as hypersensitivity reactions, asthma
or chronic bronchitis. As these kinds of health effects data become'available
and methods to assess levels of significant human exposure improve, these MRLs
will be revised,
2.2.1 Inhalation Exposure
2.2.1.1	Death
No studies were located regarding death in humans or animals after
inhalation exposure to silver or silver compounds.
2.2.1.2	Systemic Effects
No studies were located ^regarding cardiovascular or musculoskeletal
effects in humans or animals #fter nhalation exposure to silver or silver
compounds.

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13
2. HEALTH EFFECTS
Respiratory Effects. Respiratory effects have been observed infrequently
in humans following inhalation of silver compounds. In one case report of a
worker who had become ill 14 hours after he had been working with molten
silver ingots, symptoms were limited primarily to the respiratory system
(Forycki et al. 1983). Unfortunately, the concentration and chemical
composition of the silver in the work room air were not known, and the history
of exposure to silver prior to this incident was not reported. The initial
symptoms seen in this patient included audible crackles during breathing,
rapid pulse, low oxygen content of capillary blood, and scattered thickening
of the lungs observed in chest radiograms. The patient's symptoms progressed
to acute respiratory failure, from which the patient eventually recovered
fully.
Occupational exposure to silver dusts can also lead to respiratory
irritation (Rosenman et al. 1979, 1987). One occupational study describes a
group of 30 employees of a manufacturing facility involved in the production
of silver nitrate and silver oxide (Rosenman et al. 1979). The average air
level of these silver compounds over the duration of the workers' exposure was
not estimated. However, personal air monitoring conducted 4 months previous
to the study determined an 8 hour time-weighted average (TWA) concentration
range of 0.039 to 0.378 mg silver/m3. Duration of employment ranged from less
than one, to greater than ten years. Twenty-five of the 30 workers complained
of upper respiratory irritation (sneezing, stuffiness, and running nose or
sore throat) at some time during their employment, with 20 out of 30
complaining of cough, wheezing, or chest tightness. Chest radiograms and
results of clinical examination of respiratory function were predominantly
normal, with no demonstrated relationships between abnormalities and duration
of employment. Similar complaints were recorded for workers involved in the
manufacture of silver metal powders, although the workers were concurrently
exposed to acids, hydroquinone, formaldehyde, caustics, solvents, and cadmium
(Rosenman et al. 1987).
Acute (2-8 hours) inhalation of an aerosol containing colloidal silver by
rabbits (whole body exposure, concentrations not given) has been reported to
lead to ultrastructural damage and disruption of cells of the tracheal
epithelium (Konradova 1968).
Gastrointestinal Effects. Abdominal pain has also been reported by
workers exposed to silver nitrate and oxide in the workplace (Rosenman et al.
1979) . The pain was described as "burning in quality and relieved by
antacids" and was reported in 10 out of 30 workers examined. Exposure levels
were estimated to be between 0.039 and 0.378 mg silver/m3. No information on
chemical form or particle size was provided. Duration of employment ranged
from less than one, to greater than ten years. This symptom correlated
significantly with blood silver levels, indicating that those workers exposed
to higher levels of airborne silver nitrate and/or oxide are more likely to
suffer gastrointestinal pain.

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14
2. HEALTH KFFKCTS
No studies were located regarding gastrointestinal effects in animals
following inhalation exposure to silver or silver compounds.
Hematological Effects. Blood counts were reported to he normal in all
individuals observed in the occupational study of siIver-exposed workers
conducted by Rosenman et al (1979) with the exception of one individual with
an elevated hemoglobin level. In a study by Piter et al. (1989), silver
reclamation workers chronically exposed to insoluble silver compounds (e.g.,
the silver halides) exhibited a marginal decrease in red blood cell count, as
well as an increase in mean corpuscular volume. However, the toxicological
significance of these findings is unclear.
No studies were located regarding hematological effects in animals
following inhalation exposure to silver or silver compounds. Despite the lack
of supportive animal data, occupational exposure findings suggest that
hematological effects are not a sensitive indicator of silver toxicity.
Hepatic Effects. A study that measured levels of several liver enzymes
(alanine amino transferase, aspartate amino transferase, gamma glutamyl
transferase, and alkaline phosphatase) found no significant differences
between workers exposed to silver and insoluble silver compounds and those
with no history of silver exposure (Pifei et al. 1989).
No studies were located regarding hepatic effects in animals following
inhalation exposure to silver or silver compounds.
Renal Effects. Occupational exposure to silver metal dust has been
associated with increased excretion of a particular renal enzyme (N-acetyl-/3-D
glucosaminidase), and with decreased creatinine clearance (Rosenman et al.
1987) Both of these effects are diagnostic of marginally impaired renal
function. However, the workers in this study were also exposed to cadmium,
which was detected in the urine of 5 of the 27 workers studied. Cadmium is
known to be nephrotoxic; differentiation of the effects of the two metals in
the kidney is not possible with the data presented. Therefore, no conclusion
can be drawn regarding renal effects of silver based on this study.
No studies in animals were located which support the observation of renal
effects in the Rosenman et al (1987) study. Studies in animals have focused
only on the deposition of silver in the kidney following oral exposure (Olcott
1947; 1948) and renal function tests were not conducted.
Dermal/Ocular Effects. Skin and ocular burns, caused by contact with
silver nitrate, have been reported in workers (Moss et al. 1979; Rosenman et
al 1979).
Granular deposits were observed in the conjunctiva and cornea of the eyes
of 20 out of the 30 workers in the occupational study of Rosenman et al.

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15
2. HEALTH EFFECTS
(1979), and subjective determination of the degree of silver deposition in the
conjunctiva correlated with the duration of employment (see also Moss et al.
1979). Furthermore, the amount of deposition in the eyes was found to
correlate significantly with reports of changes in skin color and decreased
night vision. The complaint of decreased night vision was also recorded in a
study of workers involved in the manufacture of metal silver powders (Rosenman
et al. 1987).
An investigation of silver reclamation workers found that 21% and 25%
exhibited conjunctival and corneal argyrosis (silver staining or deposition),
respectively (Pifer et al. 1989). Moreover, lk% of the subjects exhibited
some degree of internal nasal-septal pigmentation. However, no association
was observed between silver deposition and ocular impairment.
In another report describing the same cohort of workers as studied by
Rosenman et al. (1979), Moss et al. (1979) conducted electrophysiological and
psychophysiological studies of the eyes of 7 of the 10 workers who had
complained of decreased night vision. No functional deficits were found in
the vision of these workers.
The relative contributions of dermal/ocular absorption, ingestion, and
inhalation of silver compounds to the development of these ocular deposits and
skin color changes are not known. However, granular deposits containing
silver have been observed to-develop in various ocular tissues of animals
following ingestion of silver compounds, and it is likely that systemic
absorption following inhalation exposure also results in silver deposition
(Matuk et al 1981; Olcott 1947; Rungby 1986). The possibility remains that
the deposits were in some proportion caused by direct exposure of the eyes to
airborne silver compounds.
No studies were located regarding dermal or ocular effects in animals
following inhalation exposure to silver or silver compounds.
No studies were located regarding the following health effects in humans
or animals after inhalation exposure to silver or silver compounds.
2.2.1.3
Immunological Effects
2.2.1.4
Neurological Effects
2.2.1.5
Developmental Effects
2.2.1.6
Reproductive Effects
2.2.1.7
Genotoxic Effects
2.2.1.8
Cancer

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If;
2. HEALTH Kl'l-H TN
2.2.2 Oral Exposure
2.2.2.1	Death
No studies were located regarding death m humans following oral exposure
to silver or silver compounds.
Death has been observed in rats following ingestion of colloidal siLver
and inorganic silver compounds. In each case the level of silvtll- was very
high. For example, death was reported in rats (number nor specified)
following acute oral ingestion of silver col loid (toequi clt et ;11 . 1974), in
another study, Walker (1971) reported deaths in J of 12 rats during a 2-week
exposure to silver nitrate in drinking water. Cause of death was not reported
in either of these studies. However, the rats in the Walker (1971) study were
observed to decrease their water intake "precipitously" beginning on the 1st
day of exposure, and survivors were generally described n.s "poorly groomed and
listless" at the end of the exposure. No lethality occurred in a lower dose
group.
Death was also reported in an unspecified number of rats receiving 222.2
mg silver/kg/day as silver nitrate in drinking water over a longer duration
(Hatuk et al. 1981). The deaths began occurring approximately 23 weeks into a
37-week experiment during which the exposed animals also showed a decreased
weight gain compared to animals receiving only water. The highest NOAEL
values and all reliable LOAEL values for death in each species and duration
are recorded in Table 2-1 and plotted in Figure 2-1.
2.2.2.2	Systemic Effects
No studies were located regarding respiratory, gastrointestinal,
hematological, musculoskeletal, hepatic, or renal effects in humans or animals
after oral exposure to silver or silver compounds.
Cardiovascular Effects. No studies were located regarding cardiovascular
effects in humans following oral exposure to silver or silver compounds.
One study reported enlargement of the left ventricle in rats following 9-
29 months of oral exposure to silver nitrate or silver chloride in drinking
water (Olcott 1950). Left ventricle size (expressed as a ratio of ventricle
weight to body weight) increased with exposure duration, and showed a tendency
to increase with dose of silver. The authors suggest that the increase in
ventricle size could be caused by hypertension, but no blood pressure
measurements were performed. Gross and histopathological examination of the
tissues revealed only a few scattered granular deposits in the heart. The
effect on left ventricle size was seen at a dose of 88.9 mg silver/kg/day;

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TABLE 2-1. Levels of Significant* Exposure to Silver* - Oral
Exposure
Frequency/
LOAEL (Effect)
Figure	Frequency/	NOAEL	Less Serious
Key	Species Route Duration	Effect (mg Ag/kg/day) (mg Ag/kg/day)
Serious
(mg Ag/kg/day)
Reference
ACUTE EXPOSURE
Death
1	Rat
2	Rat
NS
(W)
INTERMEDIATE EXPOSURE
Systemic
3	Rat	(W)
Neurological
4	Mouse (W)
4 d
lx/d
2 wk
7d/wk
37 wk
7d/wk
125 d
7d/wk
Other
181.2
222.2 (< weight gain)
18.lc (hypoactivity)
1680
362.4a (3/12)
Dequidt et al.
1974
Walker 1971
Matuk et al.
1981
Rutigby and
Danscher 1984
"Presented as elemental silver.
as
>
r
H
EC
m
m
o
GO
'Converted to an equivalent concentration of 2,589 ppro in water for presentation in Table 1-4.
bConverted to an equivalent concentration of 1,587 ppm in water for presentation in Table 1-4.
cConverted to an equivalent concentration of 95 ppm in water for presentation in Table 1-4.
mg/kg/day = milligrams per kilogram per day; NS = not specified; d = day; (W) = drinking water; wk = week; x - time(s); < - decreased.

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ACUTE INTERMEDIATE
(¦S.14 Days)	(15 - 364 Days)
(mg/kg'day)
10,000


1.000
100
o*
10
/

A
®3r
3
4m
Key
r Rat	0 LOAEL tor serious effects (animals)
m Mouse	® LOAEL tor less serous effects (animals)
O NOAEL (animals)
The number next to each point corresponds to entries in Table 2-1.
FIGURE 2-1. Levels of Significant Exposure to Silver - Oral

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19
2. HEALTH EFFECTS
however, limitations of the study such as poor experimental design and
inadequate reporting of methods preclude use of these data to predict
equivalent levels of exposure in humans.
Dermal/Ocular Effects. Gray or blue-gray discoloration of the skin has
been observed in individuals that have ingested both metallic silver and
silver compounds in small doses over periods of months to years. Silver
containing granules have been observed during histopathologic examination of
the skin of these individuals. The condition is termed "argyria."
Unfortunately, only rough estimates of the amount of silver ingested were
located, and therefore precise levels of exposure resulting in discoloration
cannot be established.
Case histories of argyria have been published concerning individuals who
had ingested silver through excessive use of antismoking lozenges containing
silver acetate, silver nitrate solutions for the treatment of gum disease,
breath mints coated with metallic silver, and capsules containing silver
nitrate for the relief of gastrointestinal "discomfort" (Aaseth et al. 1981;
Blumberg and Carey 1934; East et al. 1980; Maclntyre et al 1978; Marshall and
Schneider 1977; Shelton and Goulding 1979; Shimamoto and Shimamoto 1987). In
general, quantitative data were nonexistent or unreliable and could not be
used to establish LOAELs. The only common symptom among these cases was the
resulting gray pigmentation of the skin of primarily sun-exposed regions.
Examination of skin biopsies, from these individuals at the light microscopic
level revealed granular deposits in the dermis. The granules were distributed
throughout the dermis, but were particularly concentrated in basement membrane
and elastic fibers surrounding sweat glands. The granules have been observed
to contain silver (Bleehen et al. 1981; Maclntyre et al. 1978).
Ingestion of silver nitrate and silver chloride will also cause
deposition of silver granules in the skin of animals (Olcott 1948; Walker
1971). However, skin discoloration in animals following exposure to these
silver compounds has not been studied specifically, and the level of
deposition that leads to skin discoloration in humans cannot be established
based on existing animal data. Granules are also observed in the eyes of rats
exposed to silver nitrate in drinking water at doses that cause general
deposition in other tissues (Matuk et al. 1981; Olcott 1947; Rungby 1986).
The number of deposits in the eyes is related to the degree of yellow-to-dark-
gray pigmentation observed at gross examination, which in turn is related to
the duration of exposure.
Other Systemic Effects. Rats receiving 222.2 mg silver/kg/day in their
drinking water lost weight over a 37 week exposure period. Weight loss first
appeared about 23 weeks into the experiment, and the authors observed that
several animals that lost weight rapidly died. Body weight in the surviving
experimental animals was an average of 50% less than that of control rats

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20
2. HEALTH KFFKGTS
drinking only distilled water over the same exposure period (Matuk et al.
1981) .
2.2.2.3	Immunological Effects
No studies were located regarding immunological effects in humans or
animals following oral exposure to silver or silver compounds.
2.2.2.4	Neurological Effects
Several reports describe the deposition of what are assumed to be silver-
containing granules in tissues of the central nervous system. One report
describes such granules in certain areas of the brain of an argyric woman at
autopsy (Landas et al. 1985) who had used nose drops containing silver nitrate
(concentration not specified) for an unspecified duration. The areas of the
brain described as containing silver in the Landas et al (I98'i) study are
known to have more direct exposure to blood-borne agents than other areas
(e.g., the "circumventricular organs", and the paraventricular and supraoptic
nuclei of the hypothalamus). Unfortunately, the study examines only these
specialized areas, and so does not provide complete information on the
distribution of silver throughout the brain. There is no evidence that
clearly relates the existence or deposition of these granules to a neurotoxic
effect of silver exposure.
However, one study has found that 20 female mice exposed to silver
nitrate in drinking water for h months, and observed to have such deposits in
the central nervous system, were less active (hypoactive) than unexposed
controls (Rungby and Danscher 1984). Activity was measured using a blind
assay. The highest concentration of granular deposits occurred in certain
areas involved in motor control (i.e., red nucleus, deep cerebellar nuclei,
and motor nuclei of the brainstem), with lesser amounts observed in the basal
ganglia, the anterior olfactory nucleus, and in the cortex in general. A
specific relationship between the deposition of granules in these brain areas
following silver ingestion and the decrease in gross activity has not been
established. The highest NOAEL values and all reliable LOAEL values for
neurological effects in each species and duration are recorded in Table 2-1
and plotted in Figure 2-1.
2.2.2.5	Developmental Effects
No studies were located regarding developmental effects in humans or
animals after oral exposure to silver or silver compounds.
2.2.2.6	Reproductive Effects
No studies were located regarding reproductive effects in humans after
oral exposure to silver or silver compounds.

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21
2. HEALTH EFFECTS
No diminution of fertility was observed in male rats exposed,, for up to
2 years, to 88.9 mg silver/kg/day as silver nitrate or silver chloride in
drinking water (Olcott 1948). Appearance of spermatozoa was normal, and no
silver deposits were observed in the testes. Unfortunately, poor experimental
design and reporting of methods preclude use of these data in determining a no
effect level for male reproductive effects.
2.2.2.7	Genotoxic Effects
No studies were located regarding genotoxic effects in humans or animals
after oral exposure to silver or silver compounds.
2.2.2.8	Cancer
No studies were located regarding cancer in humans or animals after oral
exposure to silver or silver compounds.
2.2.3 Dermal Exposure
2.2.3.1	Death
No studies were located regarding death in humans following dermal
exposure to silver or silver compounds.
Mortality following dermal application of silver nitrate has been
investigated in guinea pigs (Wahlberg 1965). The investigators applied 2.0 mL
of a 0.239 molar solution of silver nitrate in water by skin depot to 3.1 cm2
of skin for 8 weeks. No deaths were recorded; however, during the exposure
period the guinea pigs ceased to gain weight. In concurrent investigations of
equimolar amounts of other metal salts using the same methods, mercuric
chloride and cobalt chloride caused the death of more than half of the test
animals.
The NOAEL value for death is recorded in Table 2-2.
2.2.3.2	Systemic Effects
No studies were located regarding respiratory, cardiovascular,
gastrointestinal, hematological, musculoskeletal, hepatic, renal, or ocular
effects in humans or animals after dermal exposure to silver or silver
compounds.
Dermal. Medical case histories indicate that dermal exposure to silver
or silver compounds for extended periods of time can lead to local skin
discoloration similar in nature to the generalized pigmentation seen after
repeated oral exposure. However, the amount of silver and the duration of
time required to produce this effect cannot be established with the existing

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TABLE 2 2. Levels of Significant Exposure to Silver* - Dermal
Exposure	LOAEL (Effect)
Figure	Frequency/	NOAEL	Less Serious	Serious
"sy	Species	Duration	Effect (mg Ag/kg/day) (mg Ag/kg/day)	(mg Ag/kg/day)	Reference
INTERMEDIATE EXPOSURE
Death
Systemic
Gn pig	8 »*	137.13	Wahlbers 1965
7d/wk
(skin depot)
2	Gn pig	8 wk	Other	137.13 (< weight gain)	Wahlberg 1965
7d/wk.	ro
(skin depot)
*	m
Presented as elemental silver.	>
mg/kg/day — milligrams per kilogram per day; Gn pig " guinea pig; wk = week; d - day; < - decreased.
>-~j r-o
o
H

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23
2. HEALTH EFFECTS
information (Buckley 1963; McMahon and Bergfeld 1983). Moreover, adverse
effects such as argyria have not been associated with the use of silver
sulphadiazine as a bactericidal agent (Fox et al. 1969). No studies were
located regarding dermal effects in animals after dermal exposure to silver or
silver compounds.
Other Systemic Effects. Decreased body weight gain was observed in
guinea pigs following application of 81 mg silver nitrate (2 mL of a 0.239 M
solution) to 3.1 cm2 of skin. At the end of 8 weeks, the silver nitrate-
exposed guinea pigs weighed approximately 10-20% less than unexposed controls
and controls exposed to distilled water (Wahlberg 1965).
2.2.3.3	Immunological Effects
Medical case histories describe mild allergic responses attributed to
repeated dermal contact with silver and silver compounds (Catsakis and Sulica
1978; Heyl 1979; Marks 1966). Sensitization occurred in response to contact
with powdered silver cyanide, radiographic processing solutions, and
apparently to silver in dental amalgam. The duration of exposure ranged from
6 months in a worker exposed to silver cyanide, 10 years for a woman employed
as a radiograph processor, to 20 years for a woman whose allergy had
apparently been caused by dental fillings. The concentration of silver that
caused these allergic responses is not known. No studies were located1
regarding immunological effects in animals after dermal exposure to silver or
silver compounds.
No studies were located regarding the following health effects in humans
and animals after dermal exposure to silver or silver compounds.
2.2.3.4	Neurological Effects
2.2.3.5	Developmental Effects
2.2.3.6	Reproductive Effects
2.2.3.7	Genotoxic Effects
2.2.3.8	Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
Studies in humans regarding the absorption of silver following inhalation
exposure are limited to occupational studies and a case study. It is assumed

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•2A
2. HEALTH EFFECTS
to Kilvet" in the workplace are
that the predominant routes of exposure	^
W dermal, with the dermal route being mor<' impot t cint wht:n
act with silver in solution occurs (as in phot aph i c
processing). Given this assumption, existing studies suggest that silver and
prolonged contact with s
processing). Given this	b^d w^,en inhaled, although t he degree of
silver compounds can be abso	the d fc, o( dennal absorption, is
absorption, both absolute and leiau
not known.
A case study involving an accidental exposure of one worker to
, , .-i	„+-~i Hnrine a nuclear reactor mishap suppo' ts the
radiolabe e si ver m	silver metal dust can occur following inhalation
assumption that ^sorption of si Radioactive sl]ver was measured using
exposure (Newton and	'beginning two days after a one-tirae
whole-body gamma ray P	Co 2Q0 g_ Localisation of silver
^tif n^rr/LSction ^feces indicated that passage through the lungS
iad occurred! Unfortunately this study did not measure exposure, and
therefore absorption could not be quantitated.
Twelve out of 30 workers in a chemical manufacturing facility which
• ^ v	and silver oxide were found to have blood, silver
produced silver nitrate ^sil^ ^ of q g ^ ailver/l00 mL bloQd
levels greater	Exposure levels were estimated to range from 0.039 to
(Rosenman et a iy r*zq et al. (1985) examined the silver content of
0.378 mg silver/m ¦ ^Vl^rkera exposed to TWA levels of 0.001 to 0.1 mgV
^l0°?uble1iilver in a photographic materials manufacturing facility. The
lns0 .	. e s cific silver compounds to which the workers were exposed
identity o ^_ted	exposed workers, silver was detected in 80% of the blood
was not repo	.	fecal samples (mean concentrations of 0.011 ^g/ml
samples an e Vively) . Silver was detected in 2 of 35 (67.) urine samples
^nd Jt t'd workers with a mean concentration of 0.009 ng/g. Silver was also
from e pos	fPf,es of controls (not exposed occupationally) at a mean
detecte in	ug/g- Although these studies suggests that silver
concentratio ai, 'he(i from the lungs, unknown exposure levels and lack of
Prevent estimation of extent or rate.
a «t-„dv i-n does indicates that absorption of inhaled metallic silver
. , ,rith a mpdian aerodynamic diameter of approximately 0.5 (ira is
particles wi	me	ndent upon particle size (Phalen and Korrow 1973).
extensive,	d in one dog that remained anesthetized during the
Absorption be S exposure and sacrifice. jn thls do&, 3.1% (0.8 Mg) of
entire per mat iai was dissolved, transported out of the lungs, and was
the depositedbiood 6 hours aftec exposure; & l ug/c^/day
found mostly iv aUtc sllver was estimated by the authors. Up to 90X
absorp ion	d . iver was estimated to be absorbed into the systemic
°f rulation t>ased a11 experimental data Clearance from the lung to the
Mood»ith	°£ 1 7' 8-". — « -y.

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25
2. HEALTH EFFECTS
2.3.1.2	Oral Exposure
Based on medical case studies and experimental evidence in humans, many
silver compounds, including silver salts and silver-protein colloids, are
known to be absorbed by humans across mucous membranes in the mouth and nasal
passages, and following ingestion. Absorption of silver acetate occurred
following ingestion of a 0.08 mg/kg/day dose of silver acetate containing
radiolabeled silver (110mAg). Approximately 21% of the dose was retained in
the body at 1 week (East et al. 1980; Maclntyre et al. 1978). Furthermore,
the occurrence of generalized argyria in a woman who repeatedly applied silver
nitrate solution to her gums (Marshall and Schneider 1977) suggests that
absorption across the oral mucosa can occur. Information concerning the rate
of oral absorption in humans was not located.
The extent of absorption of an administered dose has been found to be
associated with transit time through the gastrointestinal tract; the authors
report that this may explain some of the interspecies differences in silver
retention observed 1 week after exposure (see Table 2-3). The faster the
transit time, the less silver is absorbed (Furchner et al. 1968). Transit
times vary from about 8 hours in the mouse and rat to approximately 24 hours
in the monkey, dog, and human (Furchner et al. 1968).
2.3.1.3	Dermal Exposure
Several silver compounds appear to be absorbed through the intact skin of
humans, although the degree of absorption is thought to be low. For example,
silver thiosulfate penetrated the intact skin of a photochemical worker via
the eccrine sweat glands and deposited in the dermis, leading to the
development of localized argyria within 6 months of exposure (Buckley 1963).
Silver compounds also are absorbed through the damaged skin of humans. Silver
was detected in the urine, blood, and body tissues of humans with seriously
burned skin following treatment with topical preparations containing 0.5%
silver nitrate to prevent bacterial infection (Bader 1966). The levels of
silver found in one of the individuals studied by Bader (1966) were 0.038 and
0.12 ppm for urine and blood, respectively, and ranged from below detection in
lung and brain to 1,250 ppm in skin. Snyder et al. (1975) estimated that less
than 1% of dermally-applied silver compounds are absorbed through the intact
skin of humans.
Absorption of silver nitrate across intact skin has been demonstrated in
guinea pigs and is similar to that of intact human skin (Wahlberg 1965). The
amount absorbed was estimated to be approximately 1% of the applied dose
within 5 hours of exposure. Silver administered in the form of silver
sulphadiazine cream was minimally absorbed through both the intact and burned
skin of rats and distributed throughout the body (Sano et al. 1982). The
absorption of silver increased through burned skin after blister removal. The
authors did not determine the percentage of the applied dose that was absorbed
(Sano et al. 1982) .

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2 6


2. HEALTH EFFECT
S

TABLE 2-3.
Interspecies
Differences in the
Oral Absorption
of Silver
Species
Silver
Compound
Body Weight
<6)
Adminiseered
Do.se
(mg/lcg)
Dose Retention

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27
2. HEALTH EFFECTS
2.3.2 Distribution
2.3.2.1	Inhalation Exposure
Limited information was located concerning the distribution of silver in
humans following inhalation of elemental silver or silver compounds. Using
whole-body spectrometer measurements obtained from a person accidently exposed
to radiolabeled silver, Newton and Holmes (1966) estimated that 25% of the
detectable 110raAg was distributed to the liver between 2 and 6 days after
exposure.
Phalen and Morrow (1973) reported that 96.9%, 2.4%, and 0.35% of the dose
initially deposited in the lungs of a dog following intratracheal
administration was detected in the lungs, liver, and blood, respectively, 6
hours after exposure. The remaining silver was detected in the gall bladder
and bile (0.14%), intestines (0.10%), kidneys (0.06%), and stomach (0.02%).
The distribution of metallic silver (expressed as a percentage of the initial
amount deposited) 225 days after exposure differed from that at 6 hours, with
the majority of the metal detected in the liver (0.49%), brain (0.035%), gall
bladder and bile (0.034%), intestines (0.028%), lungs and trachea (0.019%),
bone (0.014%), stomach and contents (0.012%), heart (0.009%), and muscle
(0.007%). The distribution to tissues other than the lungs is similar at 6
hours and 225 days if silver in the lungs is not considered. At both time
points the majority of the silver is found in the liver (approximately 77% of
the total body silver excluding lung content).
2.3.2.2	Oral Exposure
The distribution of silver to various body tissues depends upon the route
and quantity of silver administered and its chemical form. An oral dose of
silver, following absorption, undergoes a first pass effect through the liver
resulting in excretion into the bile, thereby reducing systemic distribution
to body tissues (Furchner et al. 1968). The subsequent distribution of the
remaining silver is similar to the distribution of silver absorbed following
exposure by the inhalation and dermal routes and following intramuscular or
intravenous injection.
Silver distributes widely in the rat following ingestion of silver
chloride (in the presence of sodium thiosulfate) and silver nitrate in
drinking water (at 88.9 mg silver/kg/day for silver nitrate) (Olcott 1948)
The amount of silver in the various tissues was not measured, although
qualitative descriptions of the degree of pigmentation were made. High
concentrations were observed in the tissues of the reticuloendothelial system
in the liver, spleen, bone marrow, lymph nodes, skin, and kidney. Silver was
also distributed to other tissues including the tongue, teeth, salivary
glands, thyroid, parathyroid, heart, pancreas, gastrointestinal tract, adrenal
glands, and brain. Within these tissues advanced accumulation of silver

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28
2. HEALTH EFFECTS
particles was found in the basement membrane of the glomeruli, the walls of
blood vessels between the kidney tubules, the portal vein and other parts of
the liver, the choroid plexus of the brain, the choroid layer of the eye and
in the thyroid gland (Olcott 1948; Moffat and Creasey 19/2; Walker 19 71)
Approximately 18-19% of a single oral dose of silver acetate was retained
in the body of a human 8-30 weeks after exposure (East et al. 1980; Macintyre
et al. 1978). This amount is 10% greater than that retained in dog tissues 20
weeks after a single oral dose (Furchner et al. 1968).
2.3.2.3	Dermal Exposure
Following the topical application of silver nitrate for the treatment of
burns in two humans, silver was distributed to the muscles (0.03-2.3 ppm)
liver (0.44 ppm), spleen (0.23 ppm), kidney (0.14 ppm), heart (0.032-
0.04 ppm), and bones (0.025 ppm) (Bader 1966). No studies were located that
quantitated the distribution of silver in animals following dermal exposure to
silver or its compounds. However, Sano et al. (1982) detected silver in the
same tissues of rats following topical application of silver sulphadiazine
cream.
2.3.2.4	Other Routes of Exposure
In rats, silver was unevenly distributed in organs and tissues following
intravenous or intramuscular injection of radiolabeled metallic silver and/or
silver nitrate, respectively. The highest concentrations were found, in
decreasing order, in the gastrointestinal tract, liver, blood, kidney, muscle
bone, and skin following intramuscular injection (Scott and Hamilton 1950)
Following intravenous injection the highest concentrations were found, in
decreasing order, in the liver, pancreas, spleen, and plasma (Klaassen 1979a).
As is shown in Table 2-4, the proportion of the dose distributed to the
tissues is positively correlated with the dose administered (Scott and
Hamilton 1950).
Silver is cleared from the system via the liver (Furchner et al. 1968"
Scott and Hamilton 1950). Deposition of uncleared silver can occur along the
renal glomerular basement membrane (Creasey and Moffat 1973; Danscher 1981-
Ham and Tange 1972; Moffat and Creasey 1972) and mesangium (Day et al. 1976)
and in the Kupffer cells and the sinusoid endothelium cells of the liver
(Danscher 1981). Silver has also been detected intra- and extracellularly in
the skin and mucosa of the tongue, in the chromaffin cells, cells of the zona
glomerulosa, and zona fasciculata of the adrenal glands, and in the exocrine
and endocrine sections of the pancreas (Danscher 1981).
In rodents, silver has been shown to cross the placenta and to enter the
fetuses following an intraperitoneal injection of silver lactate to the
mothers (Rungby and Danscher 1983a). Silver was detected in the liver and
brain tissues of rat fetuses (Danscher 1981; Rungby and Danscher 1983a).

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29
2. HEALTH EFFECTS
TABLE 2-4. Distribution in Rats at Six Days of Intramuscularly Administered
Radioactive Silver Tracer Dose when Administered Alone and when
Coadministered with Additional Silver as Silver Nitrate
Percent of Tracer Dose Recovered
Tracer Dose	Silver Nitrate Silver Nitrate
Tissue	Alone	0,4 mg/kg/day	4.0 mg/kg/day
Heart and lungs
0.06
0.13
0.59
Spleen
0.01
0.13
2.69
Blood
0.5
0.95
3.03
Liver
0.36
2.24
33.73
Kidney
0.07
0.92
0.63
Gastrointestinal tract
1.12
4.22
8.21
Muscle
0.27
0.56
2.39
Bone
0.18
0.35
2.20
Skin
0.24
0.67
7.39
Urine
0.64
0.88
1.82
Feces
96.56
88.95
37.33
note: A small (unspecified) dose of radioactively labeled silver was used as
a tracer. The distribution of silver is reported as percentage of tracer dose
radioactivity recovered per organ.
Source: Scott and Hamilton 1950

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30
2. HEALTH EFFECTS
2.3.3 Metabolism
The deposition of silver in tissues is the result of tho precipitation of
insoluble silver salts, such as silver chloride and silver phosphat _ These
insoluble silver salts appear to be transformed into .soluble .silver sulfide
albuminates, to bind to or form complexes with amino or carboxyl groups in
RNA, DNA, and proteins, or to be reduced to metallic silver by ascorbic acid
or catecholamines (Danscher 1981). The blue or gray discoloration of skin
exposed to ultraviolet light in humans with argyria may be caused by the
photoreduction of silver chloride to metallic silver. The metallic silver is
then oxidized by tissue and bound as black silver sulfide (Dan.scher 1981).
Buckley et al. (1965) identified silver particles deposited in the dermis of a
woman with localized argyria as being composed of silver sulfide.
In rats, silver deposits in internal organs such as the kidney, have also
been identified as the sulfide (Berry and Galle 1982). Under conditions of
exposure to high doses of selenium, the sulfur can be replaced by selenium
(Berry and Galle 1982). The deposition of silver in the kidney was increased
under conditions of high selenium exposure. This may be important in the
development of argyria in people exposed to silver who ingest foods that
contain large amounts of selenium (See Section 2.7).
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
The clearance of radioactive silver metal dust in a man who was
accidentally exposed illustrated the rapid removal of silver from the lungs
primarily by ciliary action, with subsequent ingestion and ultimate
elimination in the feces (Newton and Holmes 1966). Lung clearance fit a
biexponential profile, with biological half-lives of 1 and 52 days.
Radioactive silver was detected in the feces up to 300 days after exposure,
but was not detected in urine samples (collected up to 54 days after
exposure).
Chronic exposure of workers to unidentified silver compounds resulted in
the detection of silver in 100% of the fecal samples and 6% of the urine
samples (DiVincenzo et al • 1985). This occupational exposure is assumed to
have occurred primarily by the inhalation route.
In dogs, lung clearance of metallic silver particles (average aerodynamic
diameter of 0.5fi) following intra-tracheal intubation was accompanied by an
increase in silver concentration in the area of the stomach and liver. The
increase in silver concentration in the stomach suggests that some proportion
of the silver particles are cleared by the mucociliary escalator and
swallowed. However, the predominant route of clearance from the lung appeared
to be through dissolution of the silver and transport through the blood. The

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31
2. HEALTH EFFECTS
silver was apparently carried by the blood to the liver, with little cleared
via the mucociliary passages (Phalen arid Morrow 1973). Approximately 90% of
the inhaled dose was excreted in the feces within 30 days of exposure.
Clearance of deposited silver particles from the lung fit a triexponential
profile, with biological half-lives of 1.7, 8.4, and 40 days, accounting for
59, 39, and 2% of the radioactivity excreted, respectively. Clearance of
absorbed silver from the liver fit a biexponential profile with biological
half-lives of 9.0 and 40 days accounting for 97% and 3% of the radioactivity
excreted, respectively (Phalen and Morrow 1973).
2.3.4.2	Oral Exposure
Following oral exposure to silver acetate in humans, silver is eliminated
primarily in the feces, with only minor amounts eliminated in the urine (East
et al. 1980). The rate of excretion is most rapid within the first week after
a single oral exposure (East et al. 1980). Whole-body retention studies in
mice and monkeys following oral dosing with radiolabeled silver nitrate
indicate that silver excretion in these species follows a biexponential
profile with biological half-lives of 0.1 and 1.6 days in mice and 0.3 and 3
days in monkeys. In similarly exposed rats and dogs, silver excretion
followed a triexponential profile with biological half-lives of 0.1, 0.7, and
5.9 days in rats and 0.1, 7.6, and 33.8 days in dogs (Furchner et al. 1968).
Data for whole body clearance of silver at two days after exposure for these
four species are presented in Table 2-5 (Furchner et al. 1968). Transit time
through the gut may explain some of these interspecies differences in silver
excretion. Transit time is approximately 8 hours in mice and rats, and
approximately 24 hours in dogs and monkeys (Furchner et al. 1968). Animals
excrete from 90% to 99% of an administered oral dose of silver in the feces
within 2 to 4 days of dosing (Furchner et al. 1968; Jones and Bailey 1974;
Scott and Hamilton 1950). Excretion in the feces is decreased and deposition
in tissues, such as the pancreas, gastrointestinal tract, and thyroid, is
increased when saturation of the elimination pathway in the liver occurs as a
result of chronic or high level acute exposure to silver (see Table 2-4)
(Constable et al. 1967; Olcott 1948; Scott and Hamilton 1950).
2.3.4.3	Dermal Exposure
No studies were located concerning the excretion of silver by humans or
animals following dermal exposure to elemental silver or silver compounds.
Once absorption through the skin and distribution to bodily tissues occurs, it
can be expected that elimination would be similar to that of silver absorbed
via oral or inhalation exposure, that is, primarily via the feces, with
minimal amounts excreted in the urine.
2.3.4.4	Other Routes of Exposure
Whole body retention studies in mice, rats, monkeys, and dogs following
intravenous injection of radiolabeled silver nitrate indicate that silver

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32
2. HEALTH FFFF.CTS
excretion in these species follows a triexponential profile (Furchner et al.
1968) For mice and monkeys, this differs from the biexponential profile seen
following oral exposure. Whole body clearance following intravenous exposure
was slower than clearance following oral exposure in each of the four species
observed. In addition, the difference in clearance rate between species was
more dramatic. Clearance at 2 days post-exposure ranged from 15% in the dog
to 82% in the mouse (see Table 2-5) (Furchner et al . 1968).
Silver removal from the liver by biliary excretion was demonstrated by
Scott and Hamilton (1950). Control rats and rats with ligated bile ducts were
administered radioactive metallic silver by intramuscular injection. In rats
with ligated bile ducts, excretion of silver in the feces was 19%, compared to
97% in controls Deposition in the liver of rats with ligated bile ducts was
48%° and 2.5% in the gastrointestinal tract compared to 0.36% and 1.12%,
respectively in the controls (Scott and Hamilton 1950). Klaassen (1979b)
ript-prmined that biliary excretion accounted for between 24% and 45% of the
silver administered to rats. The concentration of silver in the bile was
estimated to be between 16 and 20 times greater than that in plasma. An
increase in the bile/liver tissue ratio (/ig/ml per Mg/g) from 4.2 to 6.4
indicates that more silver is concentrated in the bile as the dose of silver
increases It is believed that active transport is involved in the transfer
of silver from the plasma to the bile (Klaassen 1979b). There are apparently
interspecies differences in this transport process. The variability in the
extent of biliary silver excretion appears to be related to the ability of the
liver to excrete silver into the bile. not to the ability of the silver to
pass between the plasma and the liver. Rats excreted silver in the bile at 10
times the rate of rabbits. Dogs excreted silver in the bile at a rate lower
than that of rabbits (Klaassen 1979b). Dogs had the highest amount of silver
retained in the liver (2-9 silver/g), as compared to the rabbit (2.13 Mg
silver/g) and rat (1.24 MS silver/g),
2.4 RELEVANCE TO PUBLIC HEALTH
The one clinical condition that is known in humans to be attributable to
long-term exposure to SUver and silver compounds is a gray or blue-gray
discoloring of the skin (argyrra). Argyria may occur in an area of repeated
or abrasive dermal cont^ct wlth silver or silver compounds, or more
extensively over widesp^eacl	of skin and the conjunctiva of the eyes
following long-term oral ?r ^halation exposure. Argyria was common around
the turn of the century wlien many pharmaceutical preparations contained silver
CH'll et al 1939). Ic ®Uch less common today, probably because most
current medications con^al""|f sJ;Jver are for dermal application only. Case
reports in humans have *ep ®d that repeated dermal contact with silver
compounds may in some	to c°ntact dermatitis, and a generalized
allergic reaction to si-lv
Evidence from both	rV^ animaI studl-es indicates that inhalation of
silver compounds can	6 respiratory pathway. Occupational studies

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33
2. HEALTH EFFECTS
TABLE 2~5. Interspecies Differences in the Clearance of Silver Compounds"
Spec i es
Silver
Compound
Route
Dose	X of Dose Cleared
(mg/kg/day)	at 2 Days
Mouse
Rat
Monkey
AgNO,
AgNO,
Dog
110m
AgNO,
Oral
Intravenous
Oral
Intravenous
Oral
Intravenous
Oral
0.0011
0.0010
0.0002
0.0002
0.00001
0.00001
0.000005
99 .61
82.08
98.35
70.73
94.35
44.08
90.38
Intravenous
0.000003
15.00
•Furchner et al. 1968.
Dose conversion: Specific Activity was 8.7 Ci/g Silver nitrate
8.7 Ci/g - 8.7 x 10s *iCi/l x 10"
/iCi/^Ci/mg^ng; mgAg/day-dose
mg - 8700 /iCi/mg
Dose Calculation:
Mouse: oral:
iv:
Rat: oral:
iv:
Monkey:oral:
iv:
Dog: oral:
iv:
0.25 *iCi/wt-26,5g:
0.25 
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34
2. HEALTH EFFKCTS
and reports of cases where individuals have accidentally swallowed Solutions
of silver nitrate show that both inhalation and ingestion may cause ga s trie
discomfort as well.
Studies in humans and animals indicate that silver compounds are absorbed
readily by the inhalation and oral routes and poorly by the dermal route, and
are distributed widely throughout the body. Observations made during surgery
on silver exposed individuals and histopathologic studies of animals exposed
to silver compounds demonstrate that within certain tissues of the body (most
notably liver, kidney, pancreas, skin, conjunctiva of the eyes, and. to a
lesser degree, certain brain areas) silver is deposited in the form of
granules visible with the light microscope. However, with the exception of
one report of decreased activity in mice exposed to silver nitrate, and one
report of enlarged hearts in rats exposed to silver nil r;il c or silver
chloride, there is no evidence that .suggest:;; that, the silver deposits might
interfere with the normal functioning of these organs in humans.
Death. There is no information concerning death in humans following
exposure to silver compounds by any route.
Data concerning death observed in animals following oral and dermal
exposure to silver compounds suggest that levels of exposure would have to be
quite high to cause death in humans. High levels of colloidal silver were
observed to cause death in rats when administered in drinking water for acute
and intermediate exposure durations. The cause of death was unknown. The
corresponding daily oral dose for a 70-kg man based on the dose levels tested
would be approximately 12 grams. Death caused by silver has not been observed
to occur in humans or animals following dermal exposure to silver compounds,
nor is it expected to occur.
Systemic Effects. Silver nitrate and/or silver oxide have been reported
to cause upper and lower respira^ory tract irritation in humans when inhaled.
In one case, inhalation of an unknown amount and chemical form of silver
during work with molten silver	produced respiratory failure the day
after exposure (Forycki et al •	)• Without treatment the worker may have
died. However, exposures such as this are not expected to be common and
should be examined on a case t>y case basis.
Upper respiratory irritati°n has been observed in humans at estimated
exposure levels of between 0.°	0.378 mg silver/m3 for less than 1 to
greater than 10 years. Evidence hat silver colloid can act as an irritant
provided by the fact that ulC^as^ ctural damage was seen in the tracheal
epithelium of rabbits following alation exposure to an unknown
concentration of silver coll°i'ieS °Wever, these effects are likely to be
related to the caustic ProPerCxpect ,the compounds, not to the presence of
silver. The effects are not e sto to Pers^-st when exposure to air
containing silver compounds	PPed.
is

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35
2. HEALTH EFFECTS
The same exposure conditions can also cause gastric discomfort in humans.
Again, this effect is likely to be caused by the caustic effects of the silver
compounds, and not the presence of silver. There is no evidence that suggests
that dermal exposure to silver can cause gastric effects.
Occupational exposure to silver compounds has not been observed to affect
blood counts. Although no supportive studies were located regarding
hematological effects in other species or by other routes, the occupational
exposure findings suggest that hematological effects are not a sensitive
indicator of silver toxicity.
Silver is deposited in the glomerular basement membrane of the kidney of
animals, and therefore might be expected to affect renal function. However,
no studies of renal function in animals were located, and occupational studies
in humans are not adequate for establishing a clear relationship between
exposure to silver and renal impairment.
No human studies were located that indicate that exposure to silver or
silver compounds will affect the cardiovascular system. However, an animal
study did show an increase in the relative size of the left ventricle of rats
that had been chronically exposed to silver nitrate or silver chloride in
drinking water. Despite the suggestion by the authors that the increase in
left ventricle size may be caused by vascular hypertension, this effect has
not been observed in animals-or in humans. These endpoints have not been
specifically addressed in reliable studies to date.
The predominant effect of exposure to silver in humans is the development
of a characteristic, irreversible pigmentation of the skin. This condition is
called argyria. Clinicians describe the pigmentation as slate-gray, blue-
gray, or gray in color and report it as most noticeable in areas of skin
exposed to light. The pigmentation is not a toxic effect per se, nor is it
known to be diagnostic of any other toxic effect. However, the change in skin
color can be severe enough to be considered a cosmetic disfigurement in some
cases.
The discoloring is likely to be caused by the photoreduction of silver
chloride and/or silver phosphate in the skin. X-ray dispersive analysis of
skin and other tissues reveals that the granules consist of silver complexed
with sulfur and/or selenium. The photoreduced deposits are not removed by the
body, and there are no clinical means of removing them.
Levels of silver exposure that have led to argyria in humans in the past
are poorly documented, and it is not possible to establish minimum risk levels
for this effect based on these data. Hill and Pillsbury (1939) in their
review of cases of argyria report that total doses of silver that have
resulted in argyria can be as low as a total of 1.4 grams of silver (as silver
nitrate) ingested in small unspecified doses over several months.

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if)
2 . HEALTH F,FFKCTS
An animal model for studying the pigmentation changes seen in humans does
not exist Therefore existing experimental animal data arc of limited use in
predicting the exposure levels that would result in argyria in humans.
Granular deposits that contain silver have been observed in both pigmented and
unpigmented skin of silver-exposed humans. Similar granules have been
observed in various tissues in animals following stiver exposure see Section
2 2 and below) However, a direct correlation has not been established
between the granular deposits seen in animals following exposure to silver and
the deposition leading to skin discoloration in humans.
toxic
Immunological Effects. No studies were located that investigated
effects on the immune system in humans or animals exposed to silver, or that
indicate that immune-related disease can be affected by silver exposure.
Silver has been observed to elicit a mild allergic response (contact
dermatitis) in humans following dermal exposure to various silver compounds.
Neurological Effects. Neurological effects attributable to silver have
not been reported in humans nor have existing case or occupational studies
focused on this endpoint. Exposure to silver has been obsei'ved to result in
the deposit of silver in neurons of the central nervous system of a woman who
had used nasal drops containing silver nitrate and in animals exposed by
intraperitoneal injection and through drinking water. However, this effect is
not known to be toxic. As measured using a controlled, blind assay, the
activity of mice with silver deposits in their brain was less than that of
controls. The decrease in activity could be attributable to other factors
unrelated to central nervous system function (such as loss of appetite due to
gastric effects, or general malaise) and the relevance to humans is not known.
Exposure to silver has been observed to affect the volume of hippocampal
cell groups within the brain of animals. Several cell groups within the
hippocampus (a well defined structure of the brain involved in some aspects of
memory) are reduced in overall volume in rats exposed during their first 4
weeks of life to subcutaneously injected silver lactate (0.137 mg
silver/kg/day) (Rungby et al. 1987). Unfortunately, the study is limited in
that only one small region of the brain was examined. It is prudent to assume
that similar effects would be observed in humans; however, the implications of
the altered volume of these cell groups are not known.
Developmental Effects. Based on the existing information, it is not
known whether silver causes developmental toxicity in humans. No studies
were found concerning developmental effects in humans after exposure to
silver. However, a human study by Robkin et al. (1973) did investigate the
possibility of a relationship between the concentration of this heavy metal in
the tissue of fetuses and the occurrence of developmental abnormalities.
These authors reported that the concentration of silver in the fetal liver of
12 anencephalic human fetuses was higher (0.75±0.15 mg/kg) than the values
from 12 fetuses obtained either through therapeutic abortions

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37
2. HEALTH EFFECTS
(0.23±0.05 mg/kg), or in 14 spontaneously aborted fetuses (0.21±0.05 mg/kg).
The concentration in 9 premature infants was 0.68±0.22 mg/kg. The authors
could not determine if the higher concentrations of silver in anencephalic
fetuses were associated with the malformation, or with fetal age.
Silver has been demonstrated in the brains of neonatal rats whose mothers
received injections of silver lactate on days 18 and 19 of gestation (Rungby
and Danscher 1984). As mentioned above, treatment of neonatal rats has also
been found to reduce the volumes of certain cell groups within the hippocampus
(Rungby et al. 1987). However, functional tests were not performed on these
rats, and therefore, neither the significance of the silver accumulation, nor
the decrease in regional hippocampal volume can be determined.
Reproductive Effects. The existing evidence does not point to a strong
effect of silver on reproduction. However, no multigeneration reproductive
studies were located, and therefore a firm conclusion regarding reproductive
toxicity can not be made.
There is no historical evidence in humans to suggest that silver affects
reproduction, although studies specifically designed to address this endpoint
in humans were not located. One study in five male rats found that single
subcutaneous injections of 0 .-04 millimole/kg silver nitrate caused temporary
histopathological damage to testicular tissue (Hoey 1966). Eighteen hours
after a single injection, silver caused shrinkage, edema, and deformation of
the epididymal tubules. All affected tissues showed gradual recovery from
damage following the initial injection, in spite of continued daily
injections. Although treatment over a 30-day period had no effect on
spermatogenesis, spermatozoa were observed with separated and pyknotic heads.
A separate drinking water study in male rats did not observe changes in
spermatozoa or diminution in fertility.
Finally, direct intrauterine injection of silver nitrate terminated
pregnancies in monkeys (Dubin et al. 1981). Single dose intrauterine
injections of 1% silver nitrate solution (0.78 mg/kg) resulted in vaginal
bleeding for 1 or 2 days following treatment. The bleeding lasted for an
average of 5.3 days. Pregnancy was terminated in all these cases. In
subsequent pregnancies, these monkeys produced normal offspring. The
relevance of direct uterine injection to human exposure conditions from NPL
site contamination must be evaluated on a case by case basis since this effect
has not been studied by the more common exposure pathways.
Genotoxic Effects. No studies were located that examined the
mutagenicity or genotoxicity of silver in human cells in vivo or in vitro.
Existing data on mutagenicity are inconsistent, but data on genotoxicity
suggest that the silver ion is genotoxic. Table 2-6 presents the results of
in vitro genotoxicity studies using bacteria and nonhuman mammalian cell
cultures. From these studies and others it is evident that the silver ion

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38
2. HEALTH EFFECTS
does bind with DNA in solution in vitro, and that it can interact, with DNA in
ways that cause DNA strand breaks and affect the fidelity of DNA replication
(Goff and Powers 1975; Loeb et al. 1977; Luk et al . 19/5; Mauss et el. 1980;
Robison et al 1982; Scicchitano and Pegg 1987). However, silver has not been
found to be mutagenic in bacteria (Demerec et al. 1951; Kanematsu et al. 1980;
McCoy and Rosenkranz 1978; Nishioka 1975; Rossman and Molina 1986).
Cancer No studies were located regarding cancer in humans following
inhalation, oral, or dermal exposure to silver or silver compounds.
Fibrosarcomas have been induced in rats following subcutaneous imbedding of
silver foil (Oppenheimer et al. 1956). In this study, imbedded silver metal
foils appeared to produce fibrosarcomas earlier (latent period as short as 275
days compared to 364-714 days) and more frequently (32% of implantation sites
compared to 0-5%) than other metal foils (steel, tantalum, tin, and vitallium)
tested. However, experiments on several metals (steel, tantalum, and
vitallium) were not complete at the time of publication so adequate
comparisons could not be made. In addition, it should be noted that several
material are known to regularly produce such tumors when implanted
,	-i _ and the relevance to carcinogenesis m humans is
subcutaneously in animals, aTU\^OI_. „ *_ . _. /c ° , , , __ . , ...
- tr	paiPkar 1985). Both positive (Schmahl and Stemhoff
uncertain (Coffin and PaieKe"-	n „ r-	.	,
,	,-e	and Schlauder 1977) results for tumorlgenesis have
1960) and negative (Furst an"	_	&
j ^ in - ciVicutaneous and intramuscular miection,
been reported following sud<-	j
. t r	,-Joi silver In rats. However, the relevance of these
respectively, of colloidal	,.
r-	_ „vnn<;ure conditions at hazardous waste sites has not
routes of exposure to expo^
n ^	Animal toxicity and human occupational studies
been clearly established. "	-j j • j. -	^
¦i . p ovnosure nave not provided indications of
using normal routes or expu	f	...
°	, ,-iiTtit- is not expected to be carcinogenic m humans,
carcinogenicity, and silver	*¦	&
2.5 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly def	indicators signaling events in biologic
i	T)lpV have Dtseu classified as markers of exposure, markers
systems or samples^ They	ptiblUty (NAS/NRC 1989).
of effect, and markers or &	J	J>-
... i „ ovnnsure s a xen°biotic substance or its metabolite(s) or
A biomarker of expose . tw	K '
)nf0Mcti°n ,	a xenobiotic agent and some target
the produc o	measured within a compartment of an organism (NAS/NRC
^	biomarkers of exposure are generally the substance
1989)^ e pre e	meta olites in readily obtainable body fluid or
itse or su s a	rai factors can confound the use and interpretation of
excre a. owev ¦	The body urden of a substance may be the result of
biomarkers of exposure^	soUrce. The substance bel ;easured	be a
exposures from more than	r4C (e.B ,. v , .	. 6_ _ , .y
_ t • 4_ t: v^riol?1- urinary levels of phenol can
metabolite of another xerw , diffev.„ ^ ,	. . J	. . ^
, j-	/ rent aromatic compounds) . Depending on
result from exposure to se ^ce <	^	half.jP	^ ^onmental
the properties of the subs ^ ^ ^ e)[poiiure) ^ sub
stance and all of
conditions e.g., duration ^	^ ^
its metabolites may have ^	J	&	r

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TABLE 2-6. Genotoxicity of Silver In Vitro
Results
With	Without
End Point	Species (Test System)	Activation Activation	Reference
Prokaryotic organisms:
Gene mutation
Escherichia coli
Salmonella typhimurium (strains TA1535, 1537, 1538,
and 100)
E. coli (enhancement of UV-light induced
mutagenesis)
E. coll
E. coli
Photobacterium fischeri
ND
ND
ND
ND
ND
( + )
Demerec et al. 1951
McCoy and Rosenkranz 1973
Rossman and Molina 1986
Kanematsu et al. 1980
Nishioka 1975
Ulitzur and Barak 1988
Eukaryotic organisms:
DNA damage
Viral transformation
DNA effects:
Replication fidelity
Chinese hamster ovary cells (DNA strand breaks)
Syrian hamster embryo
Synthetic DNA
ND
ND
ND
Robinson et al. 1982
Casto et al. 1979
Loeb et al. 1977
X.
m
>
r
"X
m
m
n
H
oo
ND * no data; - = negative; (+) = weakly positive; + - positive.

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40
2. HEALTH EFFECTS
taken. It may be difficult to identify individuals exposed to hazardous
substances that are commonly found in body tissues and fluids (e.g., essential
mineral nutrients such as copper, zinc and selenium). Biomarkers of exposure
to silver are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical,
physiologic, or other alteration within an organism that, depending on
magnitude, can be recognized as an established or potential health impairment
or disease (NAS/NRC 1989) . This definition encompasses biochemical or
cellular signals of tissue dysfunction (e.g., increased liver enzyme activity
or pathologic changes in female genital epithelial cells), as well as
physiologic signs of dysfunction such as increased blood pressure or decreased
lung capacity. Note that these markers are often not substance specific.
They also may not be directly adverse, but can indicate potential health
impairment (e.g., DNA adducts). Biomarkers of effects caused by silver are
discussed in Section 2.5.2.
A biomarker of susceptibility is an indicator of an inherent or acquired
limitation of an organism's ability to respond to the challenge of exposure to
a specific xenobiotic. It can be an intrinsic genetic or other characteristic
or a preexisting disease that results in an increase in absorbed dose,
biologically effective dose, or target tissue response. If biomarkers of
susceptibility exist, they are discussed in Section	" POPlJLAl IONS THAT ARE
UNUSUALLY SUSCEPTIBLE."
2.5.1 Biomarkers Used to Identify or Quantify Exposure to Silver
Silver can be detected in blood, urine, feces, hair, and biopsy specimens
using standard analytic techniques, as well as whole body analysis using in
vivo neutron activation. The presence of silver in these samples can be used,
with varying degrees of accuracy depending on the sample, as a biomarker of
exposure to silver compounds. Analysis of hair has been used to monitor for
silver exposure (DiVincenzo et al. 1985). However, silver can be adsorbed
onto hair surfaces as well as deposited during hair formation, and since
current testing procedures cannot differentiate between the two modes, hair
monitoring is an unreliable biomarker of exposure (DiVincenzo et al. 1985),
Levels of silver in feces, blood, and urine have been associated with recent
exposure via inhalation, oral, and dermal routes. Levels in these biological
media may serve as more reliable, primary biomarkers of exposure to silver
than levels in hair (DiVincenzo et al. 1985; Rosenman et al. 1979, 1987).
These biomarkers appear to be independent of the route of exposure, but have
not been quantitatively correlated with level and duration of exposure. The
prevalence and estimated magnitude of silver deposition in the skin, however,
were associated with duration of occupational exposure.
Because silver is eliminated primarily through the feces, recent exposure
is most easily monitored through fecal analysis. Measurements of silver in
the blood are also significant and indicate exposure to the metal. However,

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41
2. HEALTH EFFECTS
silver is not always detected in the urine samples of workers with known
exposure to the chemical, and is not as reliable a biomarker as feces and
blood. DiVincenzo et al. (1985), for example, detected silver in 100% of
feces samples and only 6% of urine samples from workers chronically exposed to
silver compounds in air. Increased blood silver levels, above the detection
limit for silver (0.6 /ig/100 mL blood), have been associated with inhalation
exposure to the metal in a study by Rosenman et al. (19 79).
Levels in biopsy specimens (e.g., of skin) provide information concerning
repeated exposure (Blumberg and Carey 1934; East et al. 1980), After a burn
victim had been dermally exposed to silver nitrate (as a bactericidal agent),
Bader (1966) found silver primarily in the patient's skin as well as in the
blood and urine. Further information can be found in Section 2.3.
2.5.2 Biomarkers Used to Characterize Effects Caused by Silver
Several effects associated with silver exposure have been reported in
humans which may be useful as biomarkers of effects. The significance of
these biomarkers, however, is in doubt, because they do not appear
consistently in exposed individuals and do not seem to correlate well with
levels and duration of exposure.
One easily observed effect of silver exposure is argyria which is a
slate-gray or blue-gray discoloration of the conjunctivae, cornea, skin, and
other epithelial surfaces. Oral, inhalation, or dermal absorption of silver
may cause argyria in humans. A potential biomarker of silver deposition that
could lead to this effect would be the presence of insoluble silver salts
(e.g., silver chloride, sulfide, or phosphate) in skin biopsy, especially that
associated with basement membrane (Danscher 1981). The granular deposition of
silver in the cornea of workers has been loosely associated with complaints of
decreased night vision (Moss et al. 1979; Rosenman et al. 1979). However,
Pifer et al. (1989) studied various ophthalmological end points in workers
exposed to silver and silver compounds and could find no significant ocular
impairments associated with the metal.
Low oxygen content in capillary blood, scattered thickening of lungs (as
observed in chest radiograms), and upper respiratory irritation have been
observed in studies of workers exposed intensely or chronically to molten
silver or silver dusts (Forycki et al. 1983; Rosenman et al. 1979, 1987).
Inhalation exposure also led to decreased red blood cell count and an
increased mean corpuscular volume (Pifer et al. 1989). However, these
potential hematologic biomarkers are not specific for silver exposure, and do
not indicate or predict significant clinical sequelae.
Rosenman et al. (1987) found that inhalation exposure to silver caused
changes in two renal end points which could be biomarkers of mild
nephrotoxicity. In this study exposed workers exhibited lower creatinine
clearance and higher excretion of the urinary enzyme N-acetyl-/J-D

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4 2
2. HEALTH EFFECTS
glucoseaminidase. However, workers in the study were also exposed to cadmium
a known nephrotoxic agent, which may have been responsible for the observed
changes. Therefore, these biochemical effects cannot be considered reliable
biomarkers of silver exposure. Occupational exposure to silver nitrate and
silver oxide, leading to blood silver levels above 0.6 /xg/100 mL, correlated
strongly with increased complaints of abdominal pain (Roseiunan el al 1979)
Moreover, dermal exposure to silver and silver compounds has been associated
with a mild allergic reaction in humans which may be a biomarker of
immunological effects (Catsakis and Sulica 1978; Heyl 1979; Marks 1966).
Please refer to Section 2.2 of Chapter 2 for a more detailed discussion of the
effects caused by silver and its compounds.
2.6 INTERACTIONS WITH OTHER CHEMICALS
As with other metals, relationships exist through which silver can
influence the absorption, distribution, and excretion of one or more other
metals. These influences are not known to increase the toxicity of other
metals, nor are other metals known to add to any toxic effects of silver
However, high intake of selenium (e.g., as sodium selenite or selenium
oxide) may lead to increased deposition of insoluble silver salts in body
tissues through the formation of silver .selenide (Alexander and Aaseth 1981-
Berry and Galle 1982; Nuttall 1987). Exposure to silver nitrate in drinking
water concurrent with intraperitoneal injections of selenium dioxide results
in a higher rate of deposition of granular deposits in the kidneys of rats
than that seen with exposure to silver nitrate alone (Berry and Galle 1982)
Higher deposition rates are likely to accelerate the development of argyria
although no data were located to confirm this.
No other studies were located regarding additive or synergistic toxic
interactions of silver with any other substance. However, exposure to
moderate - to-high silver levels (130-1000 ppm) in rats with dietary
deficiencies such as vitamin E alone (Bunyan et al. 1968; Grasso et al 1969)
or vitamin E and selenium (Van Vleet 1976; Van Vleet et al. 1981) can cause
moderate - to - severe liver necrosis.
It should be noted that selenium plays a dual role in the toxicity of
silver. On the one hand, it increases the silver deposition rate in body
tissues, which suggests that humans exposed to both high selenium and high
silver may be more likely to develop argyria. On the other hand, a selenium-
deficient diet combined with high silver intake can cause liver necrosis.
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Populations that are unusually susceptible to toxic effects of silver
exposure are those that have a dietary deficiency of vitamin E or selenium or
that may have a genetically based deficiency in the metabolism of these
essential nutrients. Individuals with damaged livers may also be more

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43
2. HEALTH EFFECTS
susceptible to the effects of silver exposure. In addition, populations with
high exposures to selenium may be more likely to develop argyria.
Furthermore, some individuals may exhibit an allergic response to silver.
2.8 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of silver is available. Where adequate information is not available,
ATSDR, in conjunction with the National Toxicology Program (NTP), is required
to assure the initiation of a program of research designed to determine the
health effects (and techniques for developing methods to determine such health
effects) of silver.
The following categories of possible data needs have been identified by a
joint team of scientists from ATSDR, NTP, and EPA. They are defined as
substance - specific informational needs that, if met would reduce or eliminate
the uncertainties of human health assessment. In the future, the identified
data needs will be evaluated and prioritized, and a substance-specific
research agenda will be proposed.
2.8.1 Existing Information on Health Effects of Silver
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to silver are summarized in Figure 2-2. The
purpose of this figure is to illustrate the existing information concerning
the health effects of silver. Each dot in the figure indicates that one or
more studies provide information associated with that particular effect. The
dot does not imply anything about the quality of the study or studies. Gaps
in this figure should not be interpreted as "data needs" information.
The majority of literature reviewed concerning the health effects of
silver in humans described case reports of individuals who developed argyria
following oral exposure to silver. Occupational studies describing two
separate worker populations were also located. The predominant route of
exposure in the occupational studies is believed to have been inhalation, but
the possibility of some degree of oral or dermal exposure cannot be ruled out.
Information on human exposure is limited in that the possibility of concurrent
exposure to other toxic substances cannot be excluded, and the duration and
level of exposure to silver generally cannot be quantitated from the
information presented in these reports.
As can be seen in Figure 2-2, very little information exists on the
effects of dermal or inhalation exposure to silver in animals. Despite the
need to evaluate NPL site exposure on a case by case basis, these routes are
not expected to be significant sources of silver exposure. Furthermore, the
oral exposure route has been examined primarily in regards to silver

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kU
2. HEALTH EFFECTS
SYSTEMIC


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2
HEALTH EFFECTS
deposition in various tissues. The studies were not designed to examine other
end points.
2.8.2 Identification of Data Needs
Acute-Duration Exposure. Information exists on the effects of acute-
duration inhalation exposures to silver in humans and experimental animals.
The information located is limited to one case report and an animal study that
examined a single end point. Information concerning acute-duration exposure
by the oral and dermal routes was not located. Insufficient data exist to
establish a target organ or an MRL. Pharmacokinetic data that would support
the identification of target organs across routes for acute - duration exposures
were also not located. A more general data need is a comparative analysis of
the toxicity of various silver compounds. Comparative toxicity data of silver
compounds would allow a more accurate analysis of variations in toxicity
caused by site - specific conditions, as may occur at NPL sites, or oxidizing
and reducing conditions associated with specific exposure routes. Acute-
duration exposure information would be useful because there may be populations
adjacent to hazardous waste sites that might be exposed to silver for brief
periods.
Intermediate-Duration Exposure. Information exists on the effects of
intermediate dose exposures in both humans (inhalation and oral) and
experimental animals (oral only). However, sufficient data do not exist to
identify a target organ or establish an MRL for intermediate exposure
durations. The exact duration and level of exposure in the human studies
generally cannot be quantitated because the information is derived from
anecdotal case reports rather than controlled epidemiological studies.
Moreover, the animal studies predominantly describe deposition in the nervous
system, eyes, and skin. One animal study has implicated the heart as a target
organ. Controlled epidemiological studies in which exposure duration and
level are quantified could be useful in identifying target organs in humans
and for estimating the risk associated with intermediate-duration exposures.
Additional animal studies investigating possible functional changes in organs
in which silver deposition has been observed could also be used to identify
possible health effects in humans. Animal studies that report deposition of
silver in the skin employ intermediate or chronic exposure levels that are
well above those estimated to cause argvria in humans. A reliable animal
model of silver deposition rates and the occurrence of argyria may not be
possible because of the photoreduction role that light plays and the
difficulty in providing similar conditions for laboratory animals. However, a
dose-response study in which the deposition of silver in the skin is examined
would be helpful in deriving MRLs for the development of argyria.
Pharmacokinetic data that would support the identification of target organs
across routes for intermediate - duration exposures were also not located.
Little or no reliable information exists for other end points. Intermediate-
duration exposure information would be useful because there may be mobile or

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46
2. HEALTH EFFECTS
migratory populations adjacent to hazardous waste .sites that might he exposed
to silver for similar durations.
Chronic-Duration Exposure and Cancer. No controlled epidemiological
studies have been conducted in humans. Although argyria lias been known to
occur following chronic silver exposure, the general lack ol quantitative
information concerning this effect in humans or animals precludes the
derivation of an MRL for this duration. Occupational studies weakly suggest
that impairment of vision, gastrointestinal distress, or renal hi^topathology
nnv result from chronic exposure to silver m humans. Additional infoimatron
would be useful in confirming or denying these possibilities, and in
establishing an MRL for chronic exposure. Pharmacokinetic data that would be
useful in the identification of target organs or carcinogenic potential across
routes for chronic duration exposures were also not located. Predominantly
negative genotoxicity studies and the lack of reports of cancer associated
with silver in humans, despite long-standing and varied usage, suggest that
silver does not cause cancer. However, no chronic toxicity/carcinogenicity
bioassays have been conducted in animals, and one study has reported an
increase in tumors in rats following subcutaneous injections (the tumors
occurred predominantly at the site of injection). A combined chronic
toxicity/carcinogenicity study would be useful to address uncertainties m the
database Chronic - duration exposure information would be useful because there
may'be populations adjacent to hazardous waste sites that might be exposed to
silver for long periods of time.
Genotoxicity. No studies were located that address the genotoxic effects
of silver in humans. All information on silver genotoxicity comes from in
vitro studies (predominantly microbial assays). These studies indicate that,
while silver ions do interact with DNA in vitro, silver is not mutagenic.
However, there is evidence that silver can cause DNA strand breaks and
influence the fidelity of DNA replication. Better characterization of this
evidence of genotoxicity, especially in in vivo test systems, would assist in
the evaluation of silver genotoxicity.
Reproductive Toxicity. No information on the reproductive effects of
silver in humans was located. Limited information in one study in laboratory
animals suggests that chronic oral exposure to levels of silver high enough to
cause widespread granular deposition has a low potential to induce adverse
reproductive effects in either sex. However, this study did not examine all
relevant reproductive end points. Furthermore, no studies were located that
examined reproductive effects following silver exposure by inhalation or
dermal routes. One subcutaneous injection study in animals demonstrated an
effect on testicular tissue and sperm morphology (Hoey 1966). Examination of
reproductive pathology in a 90-day study would be useful to determine whether
or not a nvultigeneration reproductive study is warranted to clarify the issue
of reproductive effects of silver.

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U 1
2. HEALTH EFFECTS
Developmental Toxicity. No information concerning developmental effects
of silver in humans resulting from ingestion, inhalation, or dermal contact
with silver was found. One study did investigate the relationship between
silver levels in fetal tissue and the occurrence of deformities. However, a
causal relationship was not established between exposure to silver and the
deformities. Limited data in neonatal rats indicate that silver in drinking
water can reduce the volume of certain well-defined brain regions. However,
the functional significance of changes in volume of these small brain areas is
not known. Data from pharmacokinetic studies that would support cross-route
extrapolation were not located. Studies that further investigate the above
end points for all routes of exposure would be useful to characterize the
developmental effects of silver.
Immunotoxicity. Information on immunological effects of silver in humans
is limited to clinical observations of allergic reactions to silver compounds
after repeated dermal exposure in humans. No animal studies were located that
examine immunologic end points, or that provide additional information
regarding the allergic response to the silver ion. Information concerning the
allergic potential of silver by the dermal, oral, and inhalation routes would
be useful in identifying potential sensitive populations. A battery of immune
function tests (e.g., ratio of T cells to B lymphocytes, levels of antibody
classes, macrophage function, etc.) would be useful to determine whether
silver compounds adversely affect the immune system.
Neurotoxicity. Existing studies show that silver can be deposited in
anatomically defined regions of the brain in both humans and animals following
repeated oral exposure to silver. Other studies indicate that neuroanatomical
changes can occur in young rats, and that the general activity level of
exposed mice is less than that of unexposed mice. The significance of the
neuroanatomical changes is not clear, and the study investigated only one
small area that was not reported as an area of high silver deposition.
Studies of the neuroanatomical areas that concentrate silver, and more
specific neurobehavioral tests, would assist in defining the neurotoxic
potential of silver for all routes of exposure.
Epidemiological and Human Dosimetry Studies. Most of the existing
information on the effects of silver in humans comes from cases of individuals
diagnosed with argyria following the intentional ingestion of medicinal silver
compounds (silver nitrate and silver acetate) and from exposure of small
numbers of worker populations in chemical manufacturing industries. Inherent
study limitations include unquantified exposure concentrations and durations,
as well as possible concomitant exposure to other toxic substances. Well-
controlled epidemiological studies of communities living in close proximity to
areas where higher than background levels of silver have been detected in soil
and surface and/or groundwater, such as might occur near hazardous waste
sites, and occupationally exposed groups would help supply information needed
to clarify speculation regarding human health effects caused by silver.

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<4 8
2. HEALTH EFFECTS
Biomarkers of Exposure and Effect. Silver can be detected in blood,
urine, feces, hair, and skin biopsy specimens. The best indictor of recent
exposure to silver or silver compounds is detection of silver levels in feces
and blood. Intermediate as well as long-term exposures are best monitored by
measuring silver in blood or skin biopsy specimens. Argyria, the change in
skin color associated with silver exposure, is also an indicator of chronic
exposure. No other biomarkers for silver have been developed. Development of
alternative biomarkers capable of detecting early exposure to low levels of
silver would be useful in determining the possible toxic effects of this
metal.
The only biomarkers of effect that have been reliably associated with
silver exposure are argyria and granular deposits in the dermis and eyes.
These are normally observed only in cases of intermediate and long-term
exposure. Some clinical symptoms (e.g., gastrointestinal distress and
respiratory discomfort) have been loosely associated with exposure, but are
not definitive for exposure. No good quantitative correlations have been
drawn between body levels of silver and these observed effects. Development
of additional biomarkers of effect, especially for short-term and low-level
silver exposure would be useful in determining the potential of silver to
cause health impairment or disease. More information on the body burden of
individuals with argyria, including skin biopsies, would help clinicians
determine the risk of argyria for individuals with a history of silver
exposure. If exposure levels of silver can be shown to correlate with
specific adverse health effects, it may be possible to determine quantitative
relationships between changes in tissue and/or body levels of silver.
Absorption, Distribution, Metabolism, and Excretion. The database for
inhalation and dermal absorption of silver compounds in humans consists
primarily of qualitative evidence from occupational case studies. Limited
quantitative information exists on the oral absorption of silver compounds in
humans. Research into the quantitative absorption of various silver compounds
following relevant exposure routes would be useful to better predict the
potential for toxic responses to particular silver compounds in humans.
Additional research into the comparative absorption, distribution,
metabolism, and excretion of different silver compounds would allow a more
accurate determination of the effects of silver exposure under specific
environmental conditions. The current database primarily provides information
concerning silver nitrate. Certain compounds that may exist at hazardous
waste sites, such as silver oxide, silver thiosulfate, silver chloride, silver
phosphate, and silver sulfide, have not been studied.
Studies were located for oral and dermal absorption in animals, but are
lacking for absorption from inhalation exposure. Additional animal data would
be useful in predicting the rate and extent of the inhalation absorption of
various silver compounds in humans.

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h 9
2. HEALTH EFFECTS
The only information that exists regarding distribution of silver in
humans comes from an accidental exposure to an unknown quantity of
radiolabeled silver metal dust. The distribution of various silver compounds
is known in animals following inhalation and intravenous exposure; only
qualitative information exists for oral or dermal exposure. Quantitative data
on the distribution of various silver compounds following oral and dermal
exposure would be useful when predicting the distribution of silver following
exposure to specific silver compounds in humans.
There are data to assess the metabolic fate of silver compounds in humans
and animals. Additional studies may shed light 011 possible variation in
susceptibility to silver-related toxic effects. Elucidating the mechanism by
which sil\rer exerts toxicity in mammalian cells "would assist in evaluating how
this affects the health of the whole organism.
The kinetics of the excretion of various silver compounds are well
characterized in animals and limited human data exist for inhalation and oral
exposure. Further study into (1) the underlying basis for observed species
differences; (2) quantitation of the elimination of dermally absorbed silver
compounds; and (3) the basis for observed interpersonal differences in
tolerance would aid in identification of human subpopulations with varying
susceptibilities to the toxic effects of silver.
Comparative Toxicokinetics. A limited number of studies exist regarding
the comparative toxicokinetics of orally administered silver compounds in
rats, dogs, monkeys, and humans. A more complete comparison of the absorption
and elimination of silver in humans and rats may be warranted given that much
of the toxicokinetic data comes from rats. It would also be useful to acquire
data on the comparative toxicokinetics of various silver compounds in several
species of experimental animals and in humans following inhalation and dermal
exposure in order to model the kinetics of silver deposition across different
exposure scenarios and within sensitive populations.
2.8.3 On-going Studies
No on-going studies were identified that explore the health effects or
toxicokinetics of silver or that attempt to associate silver levels in human
tissues with effects.

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3. CHEMICAL AND PHYSICAL INFORMATION
3.1	CHEMICAL IDENTITY
The synonyms and identification numbers for silver and selected silver
compounds are listed in Tables 3-1 through 3-6.
3.2	PHYSICAL AND CHEMICAL PROPERTIES
Important physical and chemical properties of silver and selected silver
compounds are given in Tables 3-7 through 3-12.

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3. CHEMICAL AiND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Silver
Value
Reference
Chemical name
Synonyms
Trade names
Jh=-nr.caL formula
Chemical structure
Wiswesser
Identification nurnb-ers.:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
NCI
STCC
Si lver
Silver; argentum; argentum
crede; CI 77820; shell silver;
silver atom; silver colloidal;
sjIflaJfe; silpowder; silver
No data
Ag
Ag
AS
7A40-22.-4
W 3503000
DG11
7216881
No data
503t
No data
No data
CHEMLJNE 1983;
HSD3 1908
Srayscn 1SB3; Hindhalz
19 53
HSDB 1988
HSDB 1980
HSDB	1988
HSDB	1988
HSDB	1988
HSDB	1988
HSDB 1983
HSDB = Hazardous Substance Data Bank; CAS - Chemical Aistracts Services, NIOSH - National Institute for
Occupational Safety and Health; RTECS ¦ Registry of Toxic Effects of Chemical Substances; EPA
- Environmental Protection Agency; OHM/TADS ™ Oil and Hazardous Materials/Technical Assistance Data System-
DOT/UH/NA/IMCO - Department of Transportation/United Nations/North America/International Maritime Dangerous
Goods Code; NCI ¦ National Cancer Institute; and STCC = Standard Transport Commodity Code.

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53
CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Chemical Identity of Silver Nitrate
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Wiswesser
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
NCI
STCC
Silver nitrate
Lunar caustic; fused silver
nitrate; molded silver nitrate;
argenti; nitras; nitric acid
silver (I) salt; nitric acid
silver (1+) salt; Silver (1+)
nitrate
No data
AgN03
Ag+ N03-
AG N-03
7761-88-8
VW 4725000
Ho data
7216883
DOT 1493
UN 1493
IMCO 5.1
685
No data
49 187 42
HSDB 1988; Weiss
1986; Windholz
Grayson 1983;
Weiss 1986
HSDB 1988
HSDB 1988
Grayson 1983;
Weiss 1986
HSDB 1988
HSDB 1988
Weiss 1986
HSDB 1988
HSDB 1938
HSDB 1988
HSDB = Hazardous Substance Data Bank; CAS » Chemical Abstracts Services; NIOSH ¦ National Institute for
Occupational Safety and Health; RTECS » Registry of Toxic Effects of Chemical Substances; EPA
= Environmental Protection Agency; OHM/TADS - Oil and Hazardous Materials/Technical Assistance Data System;
DOT/\WRA/IMCO ™ Department, of Transportation/United Hations/Sorth America/International Maritime Dangerous
Goods Code; NCI - National Cancer Institute; and STCC ¦ Standard Transport Commodity Code.

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54
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-3. Chemical Identity of Silver (I) Oxide
Value
Refe rence
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Wiswesser
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
MCI
STCC
Silver (I) oxide
Argentous oxide; silver (1+)
oxide; disilver oxide; silver
oxide
No data
Ag20
Ag+ 02* Ag +
AG 2-0
20667-12-3
VW 4900000
Ho data
No data
IMO/UN-not listed
Ho data
Ho data
No data
Windholz 1983
Grayson 1983;
Weiss 1986
RTECS 1989
RTECS 1989
Grayson 1983
RTECS 1989
Weiss 1986
RTECS « Registry of Toxic Effects of Chemical Substances; CAS - Chemical Abstracts Services; NIOSH -
national Institute for Occupational Safety and Health; EPA - Environmental Protection Agency; OHM/TADS
and Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO - Department of
Transportation/United Nations/North America/International Maritime Dangerous Goods Cede; HSDB - Hazardous
Substance Data Bank; NCI - National Cancer Institute; and STCC - Standard Transport Commodity Code.
Oil

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55
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-*. Chemical Identity of Silver (II) Oxide
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Wiswesser
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Haste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
NCI
STCC
Silver (II) oxide
Argentic oxide; silver
peroxide; silver suboxide;
divas i1
No data
AgO
Ag2* 02'
No data
1301-96-8, 35366-11-1
No data
No data
No data
No data
No data
No data
No data
Windholz 1983
Grayson 1983
Grayson 1983
Grayson 1983
CAS * Chemical Abstracts Services; NIOSH m National Institute for Occupational Safety and Health; RTECS "
Registry of Toxic Effects and Chemical Registry; EPA - Environmental Protection Agency; OHM/TADS " Oil and
Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; HSDB ~ Hazardous Substance Data Bank; NCI
» National Cancer Institute; and STCC « Standard Transport Comnodity Code.

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56
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-5. Chemical Identity of Silver Sulfide
Chemical name
Synonyms
Value
Silver sulfide
Acanthite; argentous
sulfide
Reference
Weast 1988
Windholz 1983
Trade names
Chemical formula
Chemical structure
Wiswesser
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DCT/W/NA/IMCO shipping
HSDB
NCI
STCC
No data
AggS
Ag* S2" Ag*
No data
21548-73-2
No data
No data
No data
So data
No data
No data
No data
Grayson 1983
Windholz 1983
Grayson 1983
CAS ¦ Chemical Abstracts Services; NIOSH ¦ National Institute for Occupational Safety and Health; RTECS »
Registry of Toxic Effects of Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS = Oil and
Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO - Department of Transportation/United
Nations/North America/International Maritime Dangerous Goods Code; HSDB - Hazardous Substances Data Bank-
NCI » National Cancer Institute; and STCC - Standard Transport Commodity Code.

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57
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-6. Chemical Identity of Silver Chloride
Value
Reference
Chemical name
Synonyms
Trade names
Chemical formula
Chemical structure
Wi swesser
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO shipping
HSDB
NCI
STCC
Silver chloride
Silver (I) chloride;
Silver monochloride
No data
AgCl
Ag* Cl-
No data
7783-90-6
VW 3563000
No data
No data
No data
No data
No data
No data
RTECS 198 8
Grayson 1983
RTECS 1988
Grayson 1983
RTECS 1988
RTECS = Registry of Toxic Effects of Chemical Substances; CAS - Chemical Abstracts Services; NIOSH =
National Institute for Occupational Safety and Health; EFA » Environmental Protection Agency; OHM/TADS = Oil
and Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO " Department of
Transportation/United Nations/North America/International Maritime Dangerous Goods Code; HSDB =• Hazardous
Substance Data Bank; NCI ¦ National Cancer Institute; and STCC » Standard Transport Commodity Code.

-------
Molecular weight
Color
Physical state
Valence state
Melting point
Boiling point
Density at 20°C
20 "C
20 °C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20°C
Organic solvents
Partition coefficients
Vapor pressure:
Liquid silver at 1,865°C
Henry's law constant
Autoignition temperature
FLashpoint
Flaramability limits
Conversion factors
58
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-7. Physical and Chemical Properties of Silver
Value
Reference
107.868
Lustrous, white
Solid metal
+ 1 r +2
961.93'C
2,212°C at 760 ranHg
10.50 g/cm3
10.A3 g/cm3 (hard drawn)
10.49 g/cm3 (annealed
No data
Weast 1988
Weast 1968
Grayson 1983
Windholz 1983
Weast 1988
Weast 1988
Weast 1988
Grayson 1983
Grayson 1983
No data
No data
Insoluble; soluble in nitric acid, not in
sulfuric acid and aLkali cyanide
solutions
No data
No data
Windhol2 1983; ITII
1982
100 mniHg	Weast 1988
No data
No data
No data
Dust is moderately flammable	ITII 1982
Troy ounces x 31.1034768	Weast 1988
¦ grams

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59
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-8. Physical and Chemical Properties of Silver Nitrate
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 19°C
at 19°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 0*C
Organic solvents
Partition coefficients
Vapor pressure
Henry's law constant
Autoignition temperature
Flashpoint
Flanmability limits
169.89
Colorless or white
Solid crystalline
212*C
Decomposes at 
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60
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-9. Physical and Chemical Properties of Silver (I) Oxide
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 20°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 25"C
Organic solvents
Partition coefficients
Vapor pressure
Henry's law constant
Autoignitiort temperature
Flashpoint
Flammability limits
231.8
Dark brown-to-black
Solid crystalline
Decomposes at 230°C
Decompcses between 200"-300"
Decomposition complete at
300 °C
7.14 g/cm3
Odorless
No data
No data
Z.ZxlO'2 g/L
Practically insoluble in
alcohol
No data
No data
No data
Wo data
Not flammable
Not flammable
Weiss 1986
Windholz 1983
Weast 1988; Wei
1986;
Windholz 1983
Weast 19B8
Windholz 1983
Grayson 1983
Weiss 1986
Weiss 1986
Grayson 1983
Windholz 1983
Weiss 1986
Weiss 1986

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61
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-10. Physical and Chemical Properties of Silver (II) Oxide
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20"C
Organic solvents
Partition coefficients:
Vapor pressure
Henry's law constant
Autoignition temperature
Flashpoint
Flamnability limits
123.88
CharcoaL gray powder, black
crystal
Solid
No data
Decomposes above 100°C
No data
No data
No data
No data
Decomposes
No data
No data
data
data
No data
No data
No data
in aqueous solution
No
No
Windholz 1983
Grayson 1983;
Windholz 1983
Windholz 1983
Windholz 1983
Windholz 1983

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62
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-11. Physical and Chemical Properties of Silver Sulfide
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 2Q*C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20°C
Organic solvents
Partition coefficients
Vapor pressure
Henry's law constant
Autoignition temperature
Flashpoint
Flammability limits
267.80
Gray-black
Solid
No data
Decomposes at 810°C
7.326 g/cm3
No data
No data
No data
1.4xlCT4 g/L
No data
No data
No data
No data
No data
No data
No data
Weast 1988
Weast 19S8
Grayson 1983
Grayson 1983
Weast 1988
Grayson 1983

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63
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-12. Physical and Chemical Properties of Silver Chloride
Value
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 2C°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 25°C
Organic solvents
Partition coefficients
Vapor pressure
Henry's law constant
Autoignition temperature
Flashpoint
Flanmability limits
U3.34
White
Solid
455°C
1,550°C
5.56 g/cm-3
No data
No data
No data
1.93 mg/L
No data
No data
No data
No data
No data
No data
Windholz	1983
Windholz	1983
Windholz	1983
Windholz	1983
Windholz	1983
Windholz	1983
Windholz 1983

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6 5
4. PRODUCTION, IMPORT, USE AND DISPOSAL
4. 1 PRODUCTION
Silver is a rare, but naturally occurring, element. It is often found
deposited as a mineral ore in association with other elements. It is acquired
primarily as a by-product during the retrieval of copper, lead, zinc, and gold
ores (Grayson 1983). The primary silver mines of the United States are
located in the Coeur d'Alene mining district in the northern Idaho panhandle
(Smith and Carson 1977). This area accounts for approximately 71% of domestic
mine production (Drake 1980). It is mined using either open pit or
underground methods, and the ore is then upgraded through a series of
processes including flotation and smelting. The silver is finally extracted
electrolytically by the Moebius process, the Balbach-Thum process, or the
Parkers process (Grayson 1983; Smith and Carson 1977),
World mine production in 1986 was 419.8 million troy ounces (for
conversion: troy ounces x 31.1034768 = grams) (Reese 1986), Mine production
in the United States declined from 1978 to 1986, reaching a low of 34.2
million troy ounces in 1986, due to a combination of falling silver prices and
rising production costs (Ree$e 1986) . This trend appeared to continue
according to a survey conducted by The Silver Institute in 1988 and 1989. The
United States production of silver from ores and concentrates was 3.4 and 4.2
million troy ounces in 1988 and 1989, respectively. However, when recovered
silver is included in the production figures, total production was 8.8 and 9.3
million troy ounces for 1988 and 1989, respectively (The Silver Institute
1990). United States consumption in 1986 reached a high of 126.4 million troy
ounces, largely due to increased industrial consumption and use in special
issue coinage (Reese 1986). In 1987, the estimated consumption was 63.7
million troy ounces for the United States and 172 million troy ounces
worldwide (The Silver Institute 1988)
Since 1951, silver consumption has exceeded its extraction from ore.
Secondary silver production involves the recovery of silver from new and old
scrap, resulting from silver-containing wastes generated by industry and the
consumer. Recycled silver accounted for 40% of U.S. refinery production in
1971 and had increased to 67% by 1974 (Smith and Carson 1977). It was
estimated to be 61% and 56% in 1988 and 1989, respectively (The Silver
Institute 1990) . The estimated world-wide recovery of silver from the
photographic industry is about 67% of the total used (The Silver Institute
1988). It has been estimated that 80%, 68%, and 75% of today's annual
consumption by the electrical, industrial-alloy, and art industries,
respectively, is recycled silver, but these estimates may be high.

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66
4. PRODUCTION, IMPORT, USE AND DISPOSAL
4.2	IMPORT
The United States 1986 net import reliance approximated 60% of apparent
domestic consumption. Despite this, the 1986 U.S. dependence on foreign
imports decreased. Import levels fell from 152.6 million troy ounces m 1985
to 144.9 million troy ounces in 1986 (Reese 1986).
The largest decrease in imported sliver was from the United Kingdom and
Switzerland. For these two countries import levels fell by 18,1 million^
ounces primarily in the form of refined bullion. A total of 125.4 million
troy ounces of refined silver were imported in 1986 with only 9.5 million troy
ounces accounted for in other forms.
U.S. exports of silver decreased slightly from 28.8 million troy ounces
in 1985 to 25.1 million troy ounces in 1986 (Reese 1986).
4.3	USE
Silver metal and silver compounds have been and still are used in a wide
variety of ways. In the past, silver was used for surgical prostheses and/or
.	fnnpicides (both of which are now obsolete), and coinage
(discontinued from general circulation within the United States in 1970).
Although silver still serves some of the above functions the current uses .r,
even more varied. Photographic materials accounted for 454 of the U.S
e	. .	F1metrical and electronic products, such as electrical
r„rt"t "siivei paintS! and batteries, consumed approximately 25.. Silver
has been'an important component in the manufacture of bearings in the past,
although today its use in this area is limited by cost and availability.
Silver is also an important component in brazing alloys and solders, which
represent approximately 5% of the 1986 silver consumption. More aesthetic
uses of silver include electroplated ware, sterling ware, and jewelry; m
1986, they accounted for 11% of recorded uses.
Other uses account for the remaining 14%; these include use in mirrors,
dental amalgam, and medical supplies for treatment of burns, use as a catalyst
in the manufacture of formaldehyde and ethylene oxide, as an active agent for
purification and disinfection of drinking water and water m swimming pools,
In certain chemical analyses involving titration, and in cloud seeding
in certai	^ ig?7_ Smi(;h amJ Carson 1977). Silver 10ns are
also^used medically as aA antibacterial agent (Becker 1987; Becker et al.
1978; Fox et al. 1969; Webster et al. 1981).
4.4 DISPOSAL
Treatment of air emissions containing silver is not a concern as
atmospheric emissions rarely approach ^he federal threshold limit value for
occupational exposure of 0.01 mgV (Smith and Carson 1977).

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67
4. PRODUCTION, IMPORT, USE AND DISPOSAL
Moreover, as consumption of silver-containing products outweighs supply,
these products tend to be recycled whenever feasible. The largest source of
nonrecycled silver in the waste stream is attributable to photographic
material use by small-scale consumers (Smith and Carson 1977). This tends to
be released in the form of silver thiosulfate, which is converted into
insoluble silver forms by micro-organisms during wastewater treatment (Grayson
1983). Several methods have been suggested for recovering silver from various
waste media, including waste water, solid waste, and gas effluents. These
include electrolytic recovery, agglomeration, and metal concentration (CHMR
1989). At present the criteria for land disposal practices are undergoing
significant revision, and consultation with environmental regulatory agencies
is advised (HSDB 1988).

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69
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Silver is a rare element, which occurs naturally in its pure form as a
white, ductile metal, and in ores. It has an average abundance of about 0.1
ppm in the earth's crust and about 0.3 ppm in soils. There are four oxidation
states (0, 1+, 2+, and 3+); the 0 and 1+ forms are much more common than the
2+ and 3+ forms. Silver occurs primarily as sulfides, in association with
iron (pyrite), lead (galena), and tellurides, and with gold. Silver is found
in surface waters in various forms: (1) as the monovalent ion (e.g.,
sulphide, bicarbonate, or sulfate salts); (2) as part of more complex ions
with chlorides and sulfates; and (3) adsorbed onto particulate matter.
Silver is released to air and water through natural processes such as the
weathering of rocks and the erosion of soils. Important sources of
atmospheric silver from human activities include the processing of ores, steel
refining, cement manufacture, fossil fuel combustion, municipal waste
incineration, and cloud seeding. The total U.S. annual release of silver to
the environment as a result of human activities in 1978 was estimated to be
approximately 2 million kg. ,0f this amount, 77% was from land disposal of
solid waste, 17% was discharged to surface waters, and 6% emitted to the
atmosphere. Ore smelting and fossil fuel combustion emit fine particles of
silver that may be transported long distances and deposited with
precipitation. The major source of release to surface waters is effluent from
photographic processing. Releases from the photographic industry and from
disposal of sewage sludge and refuse are the major sources of soil
contamination with silver. Sorption is the dominant process controlling
partitioning in water and movement in soil. Silver may leach from soil into
groundwater; acidic conditions and good drainage increase the leaching rate.
Silver is bioconcentrated to a moderate extent in fish and invertebrates.
The general population is exposed to silver primarily through the
ingestion of drinking water and food. The most recent estimate by NIOSH
indicates that about 70,000 people are potentially exposed to silver in
workplace environments in the United States. Inhalation is probably the most
important route of occupational exposure. Populations with exposure to higher
than background levels of silver include workers in industries processing or
using the compound and members of the general public who consume drinking
water or food containing elevated levels of silver. Sources of elevated
dietary silver include seafood from areas near sewage outfalls or industrial
sources and crops grown in areas with high ambient levels of silver in the air
or soil.
According to the VIEW Database (1989) , silver has been found at 27 sites
on the National Priority List of 1,177 sites. The frequency of these sites

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70
5, POTENTIAL FOR HUMAN EXPOSURE
within the United States can be seen in Figure 5-1. EPA's Contract Laboratory
Program (CLP) statistical database indicates that silver has been detected at
100% of the 2,783 Superfund hazardous waste sites that: have had samples of all
media analyzed by the CLP (CLP 1988).
5.2 RELEASES TO THE ENVIRONMENT
5.2.1	Air
The total U.S. annual anthropogenic release of silver to the atmosphere
from production processes and consumptive uses in 1978 was estimated at 77,700
kg (Scow et al. 1981). Of this amount, an estimated 30,000 kg were released
from metals production, 22,000 kg from use in electrical contacts and
conductors, 9,000 kg from coal and petroleum combustion, 7,000 kg from iron
and steel production, 2,000 kg from cement manufacture, and the remainder from
miscellaneous uses. Urban refuse was the source of an additional 10,000 kg.
Smith and Carson (1977) estimated that cloud seeding with silver iodide
contributed 3,100 kg annually (based on data from the early 1970s).
5.2.2	Water
The total U.S. annual release of silver to surface waters in 1978 from
production processes and consumptive uses was estimated to be 125,000 kg (Scow
et al. 1981). Of this amount, an estimated 65,000 kg were released from
photographic developing, 54,000 kg from photographic manufacture, 5,000 kg
from metals production, and the remainder from miscellaneous uses. An
additional 70,000 kg were estimated to be released from sewage treatment
plants, 72,000 kg from urban runoff, and 438,000 kg from natural sources
(e.g., soil erosion). Silver released in precipitation as a result of cloud
seeding has decreased and is not expected to contribute significant amounts to
water (Scow et al. 1981). Leachates containing silver may enter ground waters
when tailing ponds or piles are situated in areas with high water tables or
when abandoned mines or sections of mines are saturated (Letkiewicz et al.
1984).
Other sources of silver release to surface waters include textile plant
wastewater effluent (Rawlings and Samfield 1979) ; petroleum refinery effluents
(Snider and Manning 1982); and quench water and fly ash scrubber water
effluents from municipal incinerators (Law and Gordon 1979). Silver was
detected in 7 of 58 (12%) samples from the National Urban Runoff Program
survey (Cole et al. 1984).
5.2.3	Soil
The total U.S. annual release of silver to land from production processes
and consumptive uses in 1978 was estimated at 1.01 million kg (Scow et al.
1981). Of this amount, an estimated 630,000 kg were released from the
photographic industry (in manufacture and developing), 165,000 kg from metals

-------
FREQUENCY
1 SITE
3 TO A SITES
2 SITES
5 TO 6 SITES
FIGURE 5-1. FREQUENCY OF SITES WITH SILVER CONTAMINATION

-------
72
5. POTENTIAL FOR HUMAN EXPOSURE
production, 150,000 kg from uses in electrical contacts and conductors, 60,000
kg from uses in brazing alloys and solders, and the remainder from
miscellaneous uses. An additional 370,000 to 520,000 kg were estimated to be
released from urban refuse and 220,000 kg from sewage treatment. Smith and
Carson (1977) estimated that the use of silver containing photographic
materials contributed an annual 370,000 kg in sewage sludge; of this amount an
estimated 52.5% was placed in landfills, 26.7% was lagooned, and 20.8% was
spread on land.
The major source of elevated silver levels in cultivated soils is from
the application of sewage sludge and sludge effluents as agricultural
amendments. Additional anthropogenic sources of silver in soil include
atmospheric deposition (especially from ore processing); landfilling of
household refuse, sewage sludge, or industrial wastes; and leaching of metal
tailings (Smith and Carson 1977).
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
The global biogeochemical movements of silver are characterized by
releases to the atmosphere, water, and land by natural and man-made sources,
possible long-range transport of fine particles in the atmosphere, wet and dry
deposition, and sorption to soil and sediments. The major forms of silver in
the atmosphere are probably metallic silver, silver sulfide, silver sulfate,
silver carbonate, and silver halides (Smith and Carson 1977). Silver is
released to the atmosphere as an aerosol (suspension of solid or liquid
particles in a gas such as air). Mining operations such as grinding emit
large particles (more than 20 ji diameter) that settle near the source while
particles emitted from smelting, fossil-fuel fired power plants, and solid
waste incinerators are smaller and are likely to be transported away from the
source of release (Scow et al. 1981) . Fine particles (less than 20
diameter) in the aerosol tend to be transported long distances in the
atmosphere and are deposited with precipitation. Long-range atmospheric
transport of silver is indicated by several studies in which atmospheric
particulate concentrations were elevated above background levels in areas
removed from cloud seeding or mining activities (Davidson et al. 1985;
Struempler 1975). Scow et al. (1981) estimated that about 50% of the silver
released into the atmosphere from industrial operations will be transported
more than 100 km and will eventually be deposited by precipitation.
The transport and partitioning of silver in surface waters and soils is
influenced by the particular form of the compound. Lindsay and Sadiq (1979)
stated that under oxidizing conditions the primary silver compounds would be
bromides, chlorides, and iodides, while under reducing conditions the free
metal and silver sulfide would predominate. In water, the major forms of
silver are as the monovalent ion in the form of sulfate, bicarbonate, or
sulfate salts; as part of more complex ions with chlorides and sulfates; and

-------
73
5. POTENTIAL FOR HUMAN EXPOSURE
as an integral part of, or adsorbed onto, particulate matter (Boyle 1968). In
one study, silver in river water was primarily found in the following forms:
silver ion (Ag+) -- 53-71%, silver chloride (Ag Cl°) -- 28-45%, silver
chloride ion (AgCl2~) -- 0.6-2.0% (Whitlow and Rice 1985), Callahan et al.
(1979) stated that sorption is the dominant process leading to the
partitioning of silver in sediments. Significant quantities of silver in
water are sorbed by manganese dioxide; pH and oxidation-reduction conditions
affect sorption (Anderson et al. 1973). Kharkar et al. (1968) reported that
approximate^' 90of the silver in rivers was in a dissolved form and 10% was
a suspended solid. Concentrations in lake sediments were reported to be 1000
times that of the overlying waters; the highest content was associated with
fine-grained sediments (Freeman 1977).
The mobility of silver in soils is affected by drainage (silver tends to
be removed from well-drained soils); oxidation-reduction potential and pH
conditions (which determine the reactivity of iron and manganese complexes
which tend to immobilize silver); and the presence of organic matter (which
complexes with silver and reduces its mobility) (Boyle 1968). The
distribution coefficient (Kd: ratio of the concentration in soil to the
concentration in water) for silver in a number of soils ranged from 10 to
1,000 (Baes and Sharp 1983). Factors that affect the Kd include soil pH, clay
content and particle size distribution, organic matter content, and free iron
and manganese oxide content. The enhanced ability of organic matter to
immobilize silver is demonstrated by the increased levels of silver found in
peat and bog soils and in marshes (Boyle 1968). In pasture plants growing in
the vicinity of an airborne source of silver such as a smelter, silver in the
leaves is apparently derived from deposition of airborne silver, while
concentrations in the roots are from soil uptake (Ward et al. 1979). Silver
levels in the leaves were slightly greater than levels in the roots.
Silver accumulation in marine algae appears to result from adsorption
rather than uptake; bioconcentration factors of 13,000-66,000 have been
reported (Fisher et al. 1984).
Data on the potential for accumulation of silver has been studied in
several aquatic species. Several of these studies do not conform to current
bioconcentration test procedures in terms of numbers of fish, duration of
exposure, and measurement of concentrations in aquaria. EPA (1980a) reported
a bioconcentration factor of less than 1 in bluegills (Lepomis macrochirus)
exposed to silver nitrate for 28 days. Approximate bioaccumulation factors of
4-6 for bluegill were calculated based on a 6-month study and 2-10 for large
mouth bass (Micropterus salmoides) exposed to silver nitrate for 4 months
(both dry weight) (Coleman and Cearley 1974).
Terhaar et al. (1977) studied bioconcentration (uptake from water) and
bioaccumulation (uptake from food and water) of silver thiosulfate complexes
in algae (Scenedesmus sp.), water flea (Daphnia magna). mussels (Ligumia sp.
and MarEaritifera sp.), and fathead minnow (Pimephales promelas) in 10-week

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74
5. POTENTIAL FOR HUMAN EXPOSURE
exposures. Bioconcentration indices were 96-150 tor algae, 12.2-26 for
Daphnia. 5,9-8.5 for mussels, and 1.8-28 for fish. Bioaccumulation indices
were 9-26 for Daphnia. 6.6-9.8 for mussels, and 4.0-6.2 for fish. These
indices, which are based on measured wet weight concentrations in biota and
nominal concentrations in water, indicate little potential for silver
biomagnification (systematic increase in residue concentrations moving up a
food chain) in the tested aquatic food chain.
Bioconcentration factors of 1,055-7,650 (wet weight) were estimated in a
21-month study with the mussel (Mvtilus edulis) in salt water (Calabrese et
al. 1984). The clam, Macoma balthica, contained silver at 32-133 ^g/g (dry
weight tissue) in an area of San Francisco Bay near a sewage outfall;
background concentrations in this species in the bay were less than 1 fjg/g
(Thomson et al. 1984). These data indicate that inputs of silver to an
estuary are available to sediment-dwelling animals. Silver from sewage sludge
at an ocean disposal site was bioaccumulated by the sea scallop (Placopecten
magellanicus). Maximum concentrations in scallops located near the disposal
site were 9.08 ppm (dry weight tissue) while scallops located away from the
site had levels less than 1 ppm (Pesch et al. 1977). The estimated biological
half-lives for the elimination of silver were 26.4 days for the Pacific oyster
(Crassostrea eigas) and 149.1 days for the American oyster (C. vireinicat
(Okazaki and Panietz 1981).
5.3.2 Transformation and Degradation
5.3.2.1	Air
Particulates of metallic silver emitted from the burning of fossil fuels
and municipal refuse are likely to become coated with silver oxide, silver
sulfide, and silver carbonate as the particles cool and undergo deposition
(Smith and Carson 1977).
5.3.2.2	Water
In fresh water, silver may form complex ions with chlorides, ammonium (in
areas of maximum biological activity), and sulfates; form soluble organic
compounds such as the acetate and the tartrate; become adsorbed onto humic
complexes and suspended particulates; and become incorporated into, or
adsorbed onto, aquatic biota (Boyle 1968). Where decaying animal and plant
material are abundant, silver strongly precipitates as the sulfide or combines
with humic materials (Smith and Carson 1977).
5.3.2.3	Soil
Silver tends to form complexes with inorganic chemicals and humic
substances in soils (Boyle 1968). Since silver is toxic to soil
microorganisms and inhibits bacterial enzymes (Domsch 1984), biotransformation
is not expected to be a significant process.

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75
5. POTENTIAL FOR HUMAN EXPOSURE
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1	Air
Silver was measured in particulate samples from rural and urban areas
both adjacent to and removed from activities such as metal smelting, refining,
and silver iodide cloud seeding. Background levels appear to be less than
1 ng/m3 as evidenced by the measurement of average silver concentrations of
0.018 ng/m3 at Great Smoky Mountains National Park; 0.012 ng/m3 at Olympic
National Park; and less than 0.19 ng/m3 at Glacier National Park (Davidson et
al. 1975). The highest particulate levels (mean -- 10.5 ng/m3; range --
0.936-36.5 ng/m3) were measured in Kellogg, Idaho (in the Coeur d'Alene River
Basin) near a large smelter complex (Ragaini et al. 1977). In an
industrialized area of northwest Indiana, silver was measured at less than 1-5
ng/mJ (Harrison et al. 1971). A level of 1 ng/m3 was reported by Douglas
(1968) In a rural cloud-seeding target area. In a rural area of Nebraska
where no cloud seeding was known to have occurred, Struempler (1975) found
particulate silver concentrations averaged 0.04-0.15 ng/m3 during three
sampling periods. This researcher theorized that anthropogenic sources, such
as long-range transport from cloud seeding, were responsible for the
enrichment of silver by factors of 326-355 over its average concentration in
the earth's crust. Silver concentrations in precipitation resulting from
seeding clouds with silver iodide were 10-4500 ng/L compared with
concentrations of 0-20 ng/L without cloud seeding (Cooper and Jolly 1970).
5.4.2	Water
Boyle (1968) reported average (background) ambient concentrations of
silver in fresh waters of 0.2 ^g/L and in sea water of 0.25 (*g/L. Waters that
leach silver-bearing deposits (e.g., in raining areas) may carry up to 100
times more silver than other fresh waters (Scow et al. 1981). Leaching is
enhanced by low pH (Smith and Carson 1977) . In samples of 170 lakes in
California, silver concentrations averaged 0.1 jj,g/L with a maximum of 6.0 /ig/L
(Bradford et al. 1968). Kharkar et al. (1968) reported that the average
silver concentration of 10 U.S. rivers was 0.30 jj,g/L (range: 0.092-0.55 /ig/L).
In another survey, Kopp (1969) found silver in 6.6% of 1,577 surface waters
sampled with a mean detected concentration of 2.6 fig/L (range: 0.1-38 /ig/L) .
For 1970-1979, according to U.S. surface water sampling data from EPA's STORET
database, the annual mean levels ranged from 1 Mg/L to 9 pg/L and annual
maximum concentrations were 94 /ig/L to 790 /ig/L (Scow et al. 1981). In 10 out
of 13 major U.S. river basins, silver concentrations decreased from 1975-1979
as compared with 1970-1974. Concentrations increased in the North Atlantic,
Southeast, and Lower Mississippi basins. In the U.S. Geological Survey, Water
Resources Division portion of the database (from the early 1960s to mid-1988),
silver was detected in 2,195 of over 10,000 surface water samples; the mean
and median concentrations in these samples were 1.9 ^g/L and 2.0 /ig/L,
respectively (Eckel and Jacob 1988).

-------
76
5. POTENTIAL FOR HUMAN EXPOSURE
Hem (1970) reported a median silver concentration of 0.23 /ig/L in U S
drinking water. Letkiewicz et al. (1984) analyzed the results of three
surveys of U.S. groundwater and surface water used as drinking water supplies
These surveys were the 1969 U.S. Public Health Service Community Water Supply
Survey (CWSS 1969) , the 1978 EPA Community Water Supply Survey (CWSS 1978)
and the 1978 through 1980 EPA Rural Water Survey (RWS). In CWSS 1969, silver
was detected (minimum positive value was 0.1 //g/L) in 309 of 677 groundwater
supplies, (mean 1.7 fig/L, median 1.3 //g/L, and range 0.1 to 9 //g/L). Silver
was detected in 59 of 109 surface water supplies with a mean and median of
//g/L and a range of 0.1 to 4 //g/L. In CWSS 1978, silver was detected
(minimum positive value was 30 // g/L) in 8 of 81 groundwater supplies (range
30-40 //g/L, mean 31.9 //g/L, and median 30 /ig/L). Silver was found in 4 of 25
surface water supplies (range 30-40 Hg/L, mean 36.2 /ig/L, and median
37.5 /ig/L). In the RWS conducted between 1978 and 1980, silver was detected
(minimum quantifiable concentration apparently -was 20 jug/L) in 10 of 71
groundwater supplies (mean and median 40 //g/L and range 20-80 //g/L). Silver
was detected in 8 of 21 surface water supplies. The range, mean, and median
of these 8 supplies were 20-60 pg/L, 36.2 //g/L, and 35 //g/L, respectively.
Letkiewicz et al. (1984) also summarized information from EPA's Federal
Reporting Data System as of 1984, which indicated that 14 public water
supplies (13 from groundwater) in the United States reported silver levels
above 50 //g/L. Letkiewicz et al. (1984) stated that it is not; possible to
determine which of these surveys is representative of current levels of silver
in the U.S. water supply. The large range in apparent detection limits
further limits the usefulness of these data in estimating silver levels in
U.S. water supplies.
Silver has been detected with a geometric mean concentration of 6.0 fig/L
in groundwater samples from 613 of the 2,783 (22%) hazardous waste sites
included in EPA's Contract Laboratory Program (CLP) statistical database (CLP
1988). It has also been detected in surface water samples from 552 of the
2,783 (20%) sites in the CLP statistical database with a geometric mean
concentration of 9.0 /ig/L (CLP 1988).
5.4.3 Soil
From a series of measurements in Canada, Boyle (1968) estimated that the
average silver content of soils (except for mineralized zones such as mining
areas) was 0.30 ppm and the average abundance in the earth's crust was 0.10
ppm. The major source of elevated silver levels in cultivated soils is from
the application of sewage sludge and sludge effluents (Smith and Carson 1977)
The average silver concentration in soils near a lead smelting complex in
Kellogg, Idaho (in the Coeur d'Alene River Basin) was 20 ppm (range: 3.2-31
ppm) (Ragaini et al. 1977). Klein (1972) measured soil metal concentrations
in the. Grand Rapids, Michigan area in order to examine possible relationships
between concentrations and land use. Silver concentrations in soils that were
classified by land use were 0.13 ppm Residential), 0.19 ppm (agricultural)
and 0.37 ppm (industrial) (Klein 1972).

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11
POTENT I Al. FOR HUMAN EXPOSURE
The Contract. Laboratory Program (CLP) statistical database indicates that
silver lias been de tee ted with a geomet r i c mean concentration of 4.5 ppm in
soil, samples 1 roin 1.80/ of 2, / 83 (65%) hazardous waste sites that have had
samples analyzed by the CLP (CLP 1988).
5.A.A Other Media
Coal has been report.ed to contain silver at concentrations ot up to 10
ppm (Boyle 1968). Klusek ct al. (1983) measured the following silver
concentrations at. a hi t ominous coal- f ire.d el eel ric generating station: coal -
0.29 rag/kg; flv ash -- 1 . (> ing/kg; and bottora ash -- <0.1 mg/kg. In the
combustible port ions ot municipal .solid waste, mean silver concentrations were
3 ppm (range: <3-7 ppm) (Law and Gordon .19/9). A municipal incinerator was
found to emit particle.1, containing 390 ppm silver (Law and Gordon 1.979). The
mean and max i mum silver concentrations in U.S. sewage sludge were 225 mg/kg
and 960 mg/kg (dry weight), respectively (Bunch 1982). Sludge silver
concentrations (jng/kg dry weight) were reported as follows: from sewage
treatment, plants with industrial or municipal wastes -- 15-120 mg/kg; from
plants w i tli phot oprocess tug elflaents as a source -- 450-2 / ,000 mg/kg (Lytle
1934).
Scow et a!. ("1981) reported that the median silver concentrations in
sewage treatment plant influent, and effluent were 0.008 rag/L and 0.002 mg/L,
respectively. Treated effluents from a large photographic processing plant
contained an average ot 0.0/ mg/L silver (range: <0.02-0.30 mg/L) in the form
of silver thiosulfate complexes, silver bromide, and silver sulfide (Bard et
al . 1976) .
Cunningham and Stroube (1.98/) collected samples of various foods in 20
U.S. cities between 19/9 and 1980. Silver concentrations (mg/kg wet weight)
in composite samples of the following food groups were: dairy products
<0.061; meat, fish, and poultry -- mean 0.015, range 0-87; cereal and grain
products -- mean 0.008, range 0-0.140; leafy vegetables -- mean 0.007, range
0-0.039; fruits -- <0.050; oils and fats -- <0.030. The average silver
concentration of a mixture of 201 foods prepared to represent the typical U.S.
diet was 0.0091 mg/kg dry weight (Iyengar et al. 1987). The average
concentration in cow's milk in the United States has been reported to be 0.047
ppm (range : 0 .037 -0 . 059 ppm) (Murtzhy and Rhea 1968). EPA (1980a) summarized
data on silver content in food as follows: beef -- 0,004-0.024 mg/kg; pork
-- 0.007-0.012 mg/kg; mutton and lamb -- 0.006-0.011 mg/kg; tea -- 0.20-2.00
mg/kg (dry weight); mollusks -- 0.1-10.0 mg/kg.
Mean silver concentrations in one brand of nonfilter and filter
cigarettes were reported to be 0.18 mg/kg and 0.27 mg/kg, respectively
(Nadkarni et al. 1970).
In a summary of 1975-1979 data on fish tissue from EPA's STORET database,
the mean concentration of silver in 221 samples was 0.225 mg/kg (wet weight

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78
5. POTENTIAL FOR HUMAN EXPOSURE
total fish), with a range of 0.004-1.900 mg/kg (Scow et al. 1981). in Lake
Pontchartrain, Louisiana (which is likely to receive substantial, inputs of
metals from municipal and agricultural activities) silver concentrations in
clams and American oyster tissues were 0.4-2.4 mg/kg and 5.5 mg/kg (all dry
weight), respectively (Byrne and DeLeon 1986).
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Food and water are the most likely major sources of exposure to natural
and anthropogenic silver for the general U.S. population (Letkiewicz et al.
1984). The general population is also exposed through the inhalation of
airborne silver and the dental and medical uses of silver. Letkiewicz et al.
(1984) estimated that about 50% of the 214 million people in the United States
who use public drinking water supplies had silver present in their water at
0.01-10 /ig/L; 10-30% may receive water with levels greater than 30 /ig/L. They
estimated that 46,000 people in the U.S. receive drinking water with silver
concentrations exceeding the current U.S. Safe Drinking Water Act maximum
contaminant limit of 50 /ig/L. Swimming pool water purified with silver-
containing systems is another possible source of exposure to silver.
The averaged daily dietary intake (including fluids) of silver has been
estimated to be 70 ng/day (Snyder et al. 1975) and 88 Mg/day (Kehoe et al.
1940). The average daily dietary intake of two subjects over 30 days was
determined to be 35-44 Mg/day (Tipton et al. 1966). The silver content of
food was estimated at 4.5 /Jg/day based on the content of a mixture of 201
foods prepared to represent the typical U.S. diet (Iyengar et al. 1987). Most
of the U.S. population breathes air containing a maximum of 1.0 ng/m3 silver,
which contributes a maximum of 0.023 ^g/day. Drinking water supplies
containing 10 /xg/L would provide an estimated 20 /ig/day of the 70-88 Mg/day
estimated daily intake. At levels of 30-50 p.g/L, drinking water contributes
60-100 pg/day (based on an estimated daily water intake of 2 L) and
constitutes the major source of silver intake (Letkiewicz et al. 1984).
Although silver has been detected in cigarettes, the average daily intake from
smoking has not been determined. A vefY limited use of silver salts is in
purification systems in isolated locations (such as mountain cabins and in
space missions) (Silver Institute I9 )¦
The 1972-1974 National Occupational Hazard Survey (NOHS), conducted by
NIOSH estimated that 19,343 workers in 2,163 plants were potentially exposed
to silver in 1970 (NIOSH 1976). The *argest number of exposed workers were in
special trade contracting, primary al industries, and industries using
electrical machinery and electrical equipment and supplies. The occupational
groups with the largest number of exposed workers were air conditioning,
heating and refrigeration mechanics and repairmen; plumbers and pipefitters;
miscellaneous assemblers; welders an amecutters; and miscellaneous machine
operators.

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79
5. POTENTIAL FOR HUMAN EXPOSURE
Preliminary data from a second workplace survey, the 1980-1983 National
Occupational Exposure Survey (NOES) conducted by NIOSH, indicated that 67,054
workers, including 15,763 women, in 3,123 plants were potentially exposed to
silver in the workplace in 1980 (NIOSH 1984a). These estimates were derived
from observations of the actual use of silver (67% of total estimate) and the
use of trade name products known to contain the compound (33%). The largest
number of workers were exposed in the primary metal industries, business
services, health services, instruments and related products industries, and
fabricated metal products industries.
Neither the NOHS nor the NOES databases contain information on the
frequency, concentration, or duration of exposure of workers to any of the
chemicals listed therein. These surveys provide only estimates of the number
of workers potentially exposed to chemicals in the workplace.
Additional industrial processes which act as potential sources of
occupational exposure to silver include the processing of silver chemicals
such as silver nitrate and silver oxide for uses such as photography, and
smelting and refining of silver-containing ores (DiVincenzo et al. 1985).
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
The most likely sources of higher than background levels of silver for
the general population are ingestion of contaminated food and drinking water.
The estimated 46,000 persons in the United States whose drinking water
contains more than 50 fig/L silver (attributable to natural and/or
anthropogenic sources) would have an estimated daily intake of at least 100
Hg/day from water alone (Letkiewicz et al. 1984). Higher levels of silver
have been detected in shellfish near industrial or sewage inputs (Byrne and
DeLeon 1986; Pesch et al. 1977; Thomson et al. 1984) and are likely to occur
in crops grown on sludge-amended soils, in the vicinity of smelters or mining
operations, or in areas with naturally high background silver levels.
Elevated atmospheric silver concentrations have been attributed to
smelting and refining of silver and other metals, and the use of silver iodide
in cloud seeding (Scow et al. 1981). Populations living close to mines may
have higher exposures. Approximately 71% of domestic mine production occurs
in Idaho, Arizona, and Colorado; the Coeur d'Alene River Basin in Idaho
supplies the greatest amount of silver (Drake 1980). Crops grown on soils
with elevated silver concentrations (either from anthropogenic sources or from
naturally high background levels) or exposed to high ambient atmospheric
concentrations are likely to become enriched with silver (Ragaini et al. 1977;
Ward et al. 1979) .
Silver has been used in lozenges and chewing gums designed to aid the
cessation of smoking. Silver acetate In chewing gum has been classified as an
over-the-counter smoking deterrent by the Food and Drug Administration
(Malcolm et al. 1986). Several cases of high body levels of silver have been

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80
5. POTENTIAL FOR HUMAN EXPOSURE
reported (Malcolm et al. 1986) . A skin silver concentration thousands of
times higher than would be expected as a normal value was found in a patient
after an estimated 6 month exposure to silver acetate lozenges (East et al.
1980; Maclntyre et al. 1978).
Scow et al. (1981) estimated that a person developing six rolls of film
could be exposed to up to 16 grams of silver through dermal contact with
photographic solutions. However, many people use implements or wear gloves
during film developing and therefore this is not expected to result in
widespread, high level exposures. Inhalation was not expected to be a
significant route of uptake during film processing because of the low
volatility of silver in solution.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of silver is available. Where adequate information is not available,
ATSDR, in conjunction with the National Toxicology Program (NTP), is required
to assure the initiation of a program' of research designed to determine the
health effects (and techniques for developing methods to determine such health
effects) of silver.
The following categories of possible data needs have been identified by a
joint team of scientists from ATSDR, NTP, and EPA. They are defined as
substance-specific informational needs that, if met would reduce or eliminate
the uncertainties of human health assessment. In the future, the identified
data needs will be evaluated and prioritized, and a substance-specific,
research agenda will be proposed.
5.7.1 Identification of Data Needs
Physical and Chemical Properties. No data exist on the partition
coefficients and Henry's law constant for silver and its compounds. A vapor
pressure has been determined for silver at very high temperatures (greater
than 900°C), but not for any of its compounds. Generally, the fate of silver
in the environment is fairly well understood; however, a determination of
these environmentally relevant values for silver compounds might provide a
more complete estimation of the fate of silver in the environment. Tables 3-7
to 3-12 contain information on the known physical and chemical properties of
silver and several important silver compounds.
Production, Use, Release, and Disposal. The production, use, release,
and disposal of silver is well characterized and indicates that risk of
exposure for the general population is potentially high. Silver and silver
compounds are produced and used for a wide variety of common products and

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81
5. POTENTIAL FOR HUMAN EXPOSURE
applications, including photographic materials, jewelry, tooth amalgams,
medical supplies, and water purification. The extensive production and use of
silver leads to a high risk of release to the environment, particularly to
soil and water. Silver has been detected in various food products, with the
highest levels detected in fish. Silver is both rare and valuable, and
consumption exceeds production. Therefore, manufacturers attempt to conserve
the metal by limiting releases and recycling instead of disposing of the
metal. Methods exist for recovering silver from several waste media.
Improvements in capturing released silver before it reaches the environment
would be beneficial for both economic and health reasons.
According to the Emergency Planning and Community Right-to-Know Act of
1986, 42 U.S.C. Section 11023, industries are required to submit chemical
release and off-site transfer information to EPA. The Toxics Release
Inventory (TRI), which contains this information for 1987, became available in
May of 1989. This database will be updated yearly and should provide a list
of industrial production facilities and emissions.
Environmental Fate. The factors governing the environmental fate of
silver are not well characterized. While silver and its compounds are
transported in the air, water, and soil, and are partitioned between these
media, the mechanisms of transport and partitioning are not well-defined. No
partition coefficients or constants have been determined for silver or its
compounds. Little information was found in the available literature on
transformation of silver in water or soil. Some microorganisms present in
these media may be able to transform silver and silver compounds; however,
silver is not expected to be significantly transformed in the environment
because it is toxic to microorganisms. Further information on the size and
flux of environmental compartments and the transport and transformations of
silver and silver compounds in the environment would be useful in defining
pathways for potential human exposure.
Bioavailability from. Environmental Media. Silver is known to be absorbed
from the lungs following inhalation exposure to silver dust or air
contaminated with silver compounds, but data on the extent and rate of
absorption are limited. Silver is also absorbed following oral or dermal
exposure to drinking water, solutions and medical products containing silver
compounds. No data were located on bioavailability of silver from soil, plant
material, or foods. However, silver is found in all these environmental media
and it is likely that some silver might be absorbed from these sources.
Further information on the bioavailability of silver from contaminated air,
water, soil, plants, and other foods would help in assessing the health risk
associated with increased exposures that might occur in populations in the
vicinity of hazardous waste sites.
Food Chain Bioaccumulation. The data available indicate that silver can
bioconcentrate to a limited extent in algae, mussels, clams, and other aquatic

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8 2
5. POTENTIAL FOR HUMAN EXPOSURE
Food Chain Bioaccumulation. The data available indicate that silver can
bioconcentrate to a limited extent in algae, mussels, clams, and other aquatic
organisms. However, many of the studies that were performed do not conform to
the current state of the art in terms of sample size, duration, and analysis
of contaminant levels in aquaria. Reliable data would be useful m
determining the possibility of biomagnification and m defining pathways for
general population exposure, as well as in estimating exposures from NPL site
contamination.
Exposure Levels in Environmental Media. Silver has been detected in all
environmental media, but most of the data are not current. Current data from
EPA's CLP indicate silver is found at levels above background m ground water,
surface water and soil near hazardous waste sites. Elevated levels of silver
have been detected in shellfish located near sources of silver pollution.
Estimates of average daily human intake from air, drinking water, food, and
total diet have been calculated. More current information, that better
defines maior sources and forms of silver, would increase the accuracy of
estimates of daily exposure to silver. This information could be used to
develop a more thorough representation of the contribution of silver exposure
from contamination at hazardous waste sites. Data that better characterize
levels in fish and shellfish would aid in identifying populations with
potentially high exposures to silver from these sources.
Exposure Levels in Humans. Silver has been detected in the blood,
tissues urine, and feces of humans. The only biological monitoring studies
located consisted of small numbers of worker populations in chemical
manufacturing industries. Studies that better characterize important sources
of general population exposure and define populations with potentially high
exposure such as those located near hazardous waste sites, would be helpful.
More specific information concerning the chemical form of silver present at
hazardous waste sites would also be useful. These data would assist in
developing a more accurate estimate of the potential for silver exposure from
hazardous waste sites contaminated with the metal.
Exposure Registries. No exposure registries for silver were located.
This compound is not currently one of the compounds for which a subregistry
has been established in the National Exposure Registry. The compound will be
considered in the future when chemical selection is made for subregistries to
be established. The information that is amassed in the National Exposure
Reeistry facilitates the epidemiological research needed to assess adverse
health outcomes that may be related to the exposure to this compound.
5.7.2 On-going Studies
No long-term research studies on the environmental fate of silver were
identified However, environmental monitoring being conducted m conjunction
with remedial investigation/feasibility studies at NPL sites where silver has

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83
5. POTENTIAL FOR HUMAN EXPOSURE
been found should add useful information regarding environmental
concentrations, chemical species, fate, and transport of the compounds.
No on-going studies or long-term research concerning occupational or
general population exposures to silver were identified.

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85
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods that
are available for detecting and/or measuring and monitoring silver in
environmental media and in biological samples. The intent is not to provide
an exhaustive list of analytical methods that could be used to detect and
quantify silver. Rather, the intention is to identify well-established
methods that are used as the standard methods of analysis. Many of the
analytical methods used to detect silver in environmental samples are the
methods approved by federal agencies such as EPA and the National Institute
for Occupational Safety and Health (NIOSH). Other methods presented in this
chapter are those that are approved by a trade association such as the
Association of Official Analytical Chemists (AOAC) and the American Public
Health Association (APHA). Additionally, analytical methods are included that
refine previously used methods to obtain lower detection limits, and/or to
improve accuracy and precision.
The analytical methods used to quantify silver in biological and
environmental samples are summarized in two tables. Applicable analytical
methods for determining silver in biological fluids and tissues are listed in
Table 6-1, and those used for determining silver in various environmental
samples are listed in Table 6-2.
6.1 BIOLOGICAL MATERIALS
Trace levels (10~6 to 10~9 g/g of sample) of silver can be accurately
determined in biological samples by several different analytical techniques,
provided that the analyst is well acquainted with the specific problems
associated with the chosen method. These methods include high frequency
plasma torch-atomic emission spectroscopy (HFP-AES), neutron activation
analysis (NAA)., graphite furnace (flameless) atomic absorption spectroscopy
(GFAAS), flame atomic absorption spectroscopy (FAAS), and micro-cup atomic
absorption spectroscopy (MCAAS).
Atomic absorption spectroscopy equipped with various atomizers is the
best and most prevalent analytical method used to analyze trace amounts of
silver in biological tissues and fluids. GFAAS offers high detectability
(subnanogram/gram of sample) and requires relatively small samples for
analysis of biological tissues (DiVincenzo et al. 1985; Segar and Gilio 1973).
Background absorption from sample matrix components can be a problem, but
correction using a deuterium continuum light source is adequate if cautiously
applied (Segar and Gilio 1973). The detection limit of silver in biological
tissues was 2xl0~5 p.g/g of sample.

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TABLE 6-1. Analytical Methods for Determining Silver in Biological Materials
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Biological
tissues
Whole blood
Digest sample with HH03; evaporate to
GFAAS
0.0012
No data
Se&ar and Gilio 1974
dryness; add glacial acetic acid and

^g/g


adjust to pH 3; add ammonium pyrrolidine

(ketone


dithiocarbamate and extract with methyl"

extract)


isobutyl ketone; heat organic phase to




dryness; dissolve residue with HN03

0.00002




Mg/g




(extract




after re-




version




to aque-




ous solu-




tion)


Dilute sample with water; agitate in
GFAAS
0.5
100-120%
DiVincnzo et al.
ultrasonic bath and analyze

Mg/lOO roL
recovery
1985
Pipette sample into nickel micro-cup and
MCAAS
0.27
98%-llOX
Howlett and Taylor
dry at 150»C

^g/100 mL
recovery
1978
Add EDTA solution to sample; dilute
GFAAS
0.015
95*-104.53;
Starkey et al. 1987
sample with triton and ainnonium hydrogen

Mg/100 mL
recovery

phosphate; introduce sample solution into
a graphite furnace tube; ash sample at
900»C and atomize at 2,000*0
Digest sample with 70Z perchloric acid
and concentrated HHO^; evaporate to
dryness; add 0.4 M Nal and bismuth
solution; heat and analyze
Add EDTA solution to sample; add
concentrated HNO^ and shake vigorously;
centrifuge at 5,000 g, separate
supernatant and analyze
HFP-AES or DCP-AES
GFAAS
0.025
#ig/100 mL
0.24 MS/
100 mL
9GX-110X
recovery
98Z recovery
Nakashima et al.
1975
Vinc6 and Williams
1987
>
r
H
~—<	CO
O ON
>
r*
Efi
tn
H
ac
o
o
Hair
Wash sampl® with benzene; filter solution
on paper disk and dry disk; insert sample
into quartz tube open from both ends;
wash sample with water at 50*C and
irradiate
NAA
0.69 ppm
No data
Dutkiewicz et al.
1978

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TABLE 6-1 (Continued)
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Hair (Cont.) Hash hair with water and air-dry; digest
sample with concentrated HN03 by heating;
cool sample and dilute to required volume
with water
GFAAS
0.02 pg/g
901-955:
recovery
DiVincenro et al
1985
Feces
Liver
Homogenize sample with water and	GFAAS
lyophilize; dissolve ash residue with
concentrated H^S04 and HNO^ and evaporate FAAS
excess acid to dryness; add HNO^ and di-
lute to required volume with water
Dry sample at 100»C overnight; digest	FAAS
with a mixture of 16 M HNOj and 12 M HC1
at 100'C; centrifuge and decant super-
natant; extract remaining lipid with hot
water; cool and recentrifuge; evaporate
supernatant to a small volume and dilute
with water
0.2 fig/g
3.0 »ig/g
0 . 34 g/g
80Z-100Z
recovery
99X-101X
recovery
DiVincenzo et al.
1985
Johnson 1976
Pulmonary
tissues
Urine
Ash sample overnight at 450*C with HN03;	AAS
dissolve ash with 50X aqueous HC1; filter
sample and analyze at 328.1 nm
Fix tissue sample in 10X buffered	XES and SEM
formalin for 24 hours; dehydrate in
alcohol and embed in paraffin; section
sample at 7 microns; stain in hematoxylin
and eosin solutions
Evaporate sample to dryness; wet ash	GFAAS
residue by heating with concentrated
H2S04 and HHO^ and evaporate excess acid
to dryness; add HNO^ and dilute to re-
quired volume with water
0.0001-
0.0005
ng/g
Seven-
micron-
thick
sections
0.005
Mg/L
88-92*
recovery
No data
1101-1305;
recovery
Pickston et al. 1983
Brody et ai. 19?8
DiVincenzo et al.
1985
>
r
k
H
t—t
O
>
r1
3
m
H
x
o
CT
c/i
CO
-J
Adjust sample to pH 2 with HHO^ and
analyze
GFAAS
1.4 V&/L
995!
Vince and Williams
1987
GFAAS = graphite furnace (flameless) atomic absorption spectroscopy; MCAAS = micro-cup atomic absorption spectroscopy; DCPAES = direct
current plasma-atomic emission spectroscopy; HFP-AES = high frequency plasma-torch-atoroic emission spectroscopy; NAA = neutron activation
analysis; FAAS = flame atomic absorption spectroscopy; AAS ~ atomic absorption spectrophotometer; XES = X-ray energy spectrometry; and
SEM = scanning electron microscopy.

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TABLE 6-2. Analytical Methods for Deteminins Silver in Environmental Samples
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Simulated
solid-waste
leaches
Digest sample with a mixture of HN03 and
HF at 100*C overnight; cool solution and
add HCIO^; heat until sample is evapo-
rated to dryness; dissolve residue in HC1
and water
FAAS
0. 568
jig/mL
(level 1)
0.473
Mg/mL
(level 2)
No data
Rains et al. 1984
DCP-AES
Rain and
stream water
Fresh water
Conmercial
condensed
milk
Extract sample with organic solvent;
concentrate and analyze atom
Add 21 citric acid solution to sample
and evaporate solution; add buffer
(pH 7.2) and react with succinate
dehydrogenase — chromogenic complex
solution
Digest sample with 702 perchloric acid
and concentrated HNO^ solution, evaporate
solution to almost dryness; dissolve
residue in water and add 0.4 M Nal and
bismuth solution; heat and analyze
GFAAS
Paper chromatography or
micro TLC
HFP-AES or DCP-AES
0.53
#ig/mL
(level 1)
0.38
**g/mL
(level 3)
ng/mL
range
1 jig/sam-
ple
No data
No data
No data
89X-94X
recovery
Rattonetti 1974
Devi and Kumar 1981
Nakashima et al.
1975
5
>
H
i—i
n
>
r1
35
(71
H
rc
o
a
CO
00
00
Collect sample through a Delbag
Hikrosorban filter or General Electric
filter; store sample in sealed poly-
ethylene bag; irradiate sample and
analyze
NAA
0.13 j*g/
10 cm2
(Delbag
Mikro-
sorban
filter);
0.008 ^g/
10 cm2
(General
Electric
filter)
No data
Bogen 1973
Calibrate sampling pump; collect sample
at known flow rate; add concentrated HNO^
and HC104; heat sample solution to dry-
ness; dissolve residue ash in 4X HN03 and
IX HC104 solution; analyze at 328.3 nm
ICP-AES
26 ng/mL
91Z-111Z
recovery
NIOSH 1984b (method
7300)

-------
TABLE 6~2 (Continued)
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit
Accuracy
Reference
Collect sample at rate of 20 liter/min
using acetyl~cellulose filter and analyze
at 328 nm
AAS
3x10-"
mg/mL
No data
Soldatenkova and
Smirnov 1963
Filter particulate matter from air; ir-
radiate and count sample
NAA (nondestructive)
0.1 ^g/	No data
sample
Dams et al. 1970
Raw beef	Prepare ash of sample by heating to
500*C; hydrolyze ash sample with 6 N
H2S04and adjust pH to 1.8-2.0; add 2 N
anrooniuro acetate solution and stir
overnight; centrifuge and analyze
GSE
0.013 ppm No data
Mitteldorf and
Landon 1952
Waste water
Metallic
silver
Eye lotion
Digest sample and add 52 potassium	UV
citrate, phenolphthalein indicator, and
4 M NaOH until solution turns red; add
HNOj to decolorize solution; finally add
buffer (pH 5), 0.1 M EDTA, IX sodium
lauryl sulfate and 0.5 m/g (3,5-diBr-
PADAP) in ethanol; measure absorbance at
570 nm
Add 0.3 N HNO^ to sample and adjust to pH FAAS
2.3; extract sample with an automated
extraction system
Add silver nitrate sample to 952 HN03	PD
solution and heat to 80~90*C while
agitating; cool and filter solution;
react filtrate by shaking with a solution
of 0.22 dithizone in chloroform; analyze
silver in silver nitrate solution at
400 nm
0.39 ppcn
>902 recovery Hung et al. 1982
0.4 ms/l
50 ppm
No data
42 error
Pierce et al. 1975
Massa 1969
>
n
t—<	CO
o
>
r
2
m
H
3C
O
o
LO
FAAS = flame atomic absorption spectroscopy; DCP-AES » direct current plasma-atomic emission spectroscopy; GFAAS = graphite furnace
(flameless) atomic absorption spectroscopy; TLC = thin layer chromatography; HFP-AES = high frequency plasma-atomic emission spectroscopy;
NAA = neutron atomic analysis; ICP-AES * inductively coupled plasma-atomic emission spectroscopy; AAS = atomic absorption spectrometry;
GSE * graphite spectroscopic electrode; UV ¦ ultraviolet spectrophotometry; PD * photodensitometer; and (3,5-diBr-PADAP) = 2(-3,5-dibromo-
2-pyridylazo)-5-diethyl-aminophenol,

-------
90
6. ANALYTICAL METHODS
Recently, Starkey et al. (1987) modified the GFAAS technique for
de temining trace levels of silver in the blood of exposed and unexposed
individuals. Ethylene diamine tetraacetic ac.id (anticoagulant) and ammonium
hydrogen phosphate buffer (matrix modifier) were added to blood samples prior
to analysis. Starkey and co-workers indicated that the GFAAS technique is
highly selective and sensitive and does not require a complex sample
pretreatment (ashing and digestion with strong acids). A detection limit of
15xl(T3 fj.g/100 mL of sample was reported.
Howiett and Taylor (1978) used an atomic absorptioii spectroscopy fitted
with a micro-cup assembly (MCAAS) for determining silver levels in human whole
blood. The MCAAS technique affords a rapid, precise, and relatively simple
method for the measurement of silver in blood. Furthermore, this technique
requires no sample preparation prior to analysis except pipetting and drying
A detection limit level of 0.27 ng/100 mL of blood sample was measured
Hewlett and Taylor (1978) noted that repeated measurement of silver in blood
using a single nickel cup showed a gradual decrease in sensitivity
FAAS technique has been successfully used to detect levels of silver in
post-mortem human liver; the detection limit for this method was 0 34 llp/p
(Johnson 1976).	'	6
HFP-AES can determine ng amounts of silver in a small sample of human
blood. Prepared human blood sample was introduced into the atomizer chamber
as an aerosol, formed by nebulization of the sample solution (Nakashima et al
19/5). The authors noted that the sensitivity of the HFP-AES technique was
improved by eliminating moisture in the aerosol with a second condenser at -3
to - 5 °C. The use of bismuth as a coprecipitate showed an enhancing effect on
the silver emission at 328.06 nm. A detection limit of 0.25 /^g/100 mL of
sample was attainable. Advantages of the HFP-AES methodology include freedom
from most types of chemical interference, high sensitivity, and multi-
elemental capability. However, this technology might have to be adapted to
currently available instrumentation in order to be useful. The presence of
spectral interferences is a disadvantage of plasma emission spectroscopy
These interferences are caused when a sample contains elements that have
analytical emission lines that overlap the line chosen for the analyte. Blood
is particularly troublesome because of high concentration of iron. Iron has a
very complex emission spectrum. Also, the analytical line for silver used in
the Nakashima et al. paper has interference from manganese. For this reason
the blood is subjected to dangerous perchloric acid/nitric acid digestion and
preconcentration of silver ion prior to analysis. Other inherent
disadvantages of HFP-AES include the employment of time-consuming procedure
the need for standard additions for accurate quantification, and its high
costs when compared to GFAAS. Unless a laboratory is already furnished with
the instrumentation, purchase of HFP-AES is not recommended for the analysis
of silver alone. GFAAS or even DCP-AES could be employed for the
determination of silver in biological samples.

-------
91
6. ANALYTICAL METHODS
Owing to its high sensitivity, the NAA technique has been widely employed
for determination of trace elements (including silver) in biological and envi-
ronmental samples. The NAA technique is based on interaction of the nuclei of
individual silver atoms of the sample with neutron irradiation, resulting in
the emission of 7-rays (photons). The radioactivity of the irradiated sample
is measured with a high-resolution lithium-drifted germanium detector. The
long-lived, metastable UOmAg isotope of silver was formed following
irradiation of human hair samples. A half-life of 250.4 days for 110mAg gives
ample time to initiate counting after an irradiation and cooling period
(Dutkiewicz et al. 1978). The authors noted a detection limit for silver of
0.69 ppm in human hair. (See Section 2.5 for a discussion of the
disadvantages of using hair samples for monitoring exposure to silver.) A
disadvantage of NAA is that it is a very expensive technique and may not be
readily available in most laboratories.
DiVincenzo et al. (1985) employed the GFAAS technique to evaluate human
samples for biological monitoring of silver exposure levels in the workplace.
The authors determined the total silver concentration in urine, blood, feces,
and hair with detection limits of 0.005 ng/L, 0.5 /zg/100 mL, 0.2 /ig/g, and
0.02 ^g/g, respectively.
Scanning electron microscopy (SEM) in concert with x-ray energy
spectrometry (XES) has been used to detect silver in pulmonary, lacrimal sac,
and skin tissues of individuals with diffuse interstitial lung disease,
chronic dacryocystitis, and skin disorders, respectively (Brody et al. 1978;
Loeffler and Lee 1987; Tanita et al. 1985). Brody et al. (1978) observed
particles of preselected lesions of human pulmonary tissue magnified to 300x
by SEM, and the silver content was analyzed by XES. The authors noted that
SEM and XES techniques permit a rapid and conclusive determination of silver,
silver compounds, and complexes in tissue lesions.
6.2 ENVIRONMENTAL SAMPLES
Atomic absorption and plasma emission spectroscopy are perhaps the most
widely used analytical techniques for the determination of silver levels in
air, soil, and water.
Rains et al. (1984) employed atomic absorption spectroscopy with flame
atomization (FAAS) and direct current plasma-atomic emission spectroscopy
(DCP-AES) to determine silver levels in solid-waste leachate. In the FAAS
technique, a diluted solution of the sample following ashing and digestion is
sprayed into a flame by means of a nebulizer. The high temperature causes
formation of atoms, which can be observed (at 328.1 run resonance line) by
absorption spectroscopy. The authors noted that interference encountered by
the FAAS technique was largely alleviated by the use of 1% solution of
ammonium dibasic phosphate buffer as a matrix modifier. In the DCP-AES
technique, Rains and co-workers observed silver as a broad band emission at
328.068 nm resonance line. Addition of lithium carbonate to sample solution

-------
92
6. ANALYTICAL METHODS
reduces the inter - element interferences observed in unbuffered direct-current
plasmas, but does not significantly degrade. DCP-AES detection limits.
Detection limits of silver in solid-waste leachate sample by FAAS and DCP-AES
techniques were 0.473xl0~6 g/mL sample and 0.38xlCT6 g/L sample, respectively
(Rains et al. 1984).
GFAAS technique is more sensitive than FAAS methodology for determination
of silver in water samples. Rain and stream water have been analyzed by GFAAS
technique to detect silver at ng/mL levels (Rattonetti 1974).
Inductively coupled argon plasma with atomic emission spectroscopy
(ICP-AESj has been recommended by NIOSH (method 7300) for determining silver
in air. ICP-AES offers multi-element capabilities and high sensitivity but
spectral (background) interference can be a problem (NIOSH 1984b). The EPA-
established analytical test procedure (method 200.7) to analyze dissolved,
suspended or total silver in drinking water, surface water, and domestic and
industrial wastewaters employs the ICP-AES technique (EPA 1987a) . An
estimated detection limit of 7.0xl0~6 g silver/L sample was measured.
Neutron activation analysis (NAA) methodology has been used to determine
silver levels in environmental samples. Bogen (1973) reported a detection
limit of 8xl0~9 g silver/10 cm2 filter. The author indicated that the use of
high-resolution lithium-drifted-germanium detection allows multi-elemental
analysis to be performed in a single measurement without any chemical
pretreatment of the air sample. A highly precise, sensitive, and
nondestructive computer-assisted NAA technique for the determination in air of
multi-element particulate matter has been designed by Dams et al. (1970). The
authors reported a detection limit of lxlO"7 g silver/sample. The NAA
technique by Bogen (1973) and Dams et al. (1970), utilizes the long-lived
isotope of silver (UOraAg) for quantifying silver levels in air. The faster
nondestructive NAA technique developed by Dams et al. (1970) utilizes the
short-lived isotope 110Ag (half-life = 24.6 seconds) to detect silver in air
following an 18-second neutron irradiation of air sample. Hence, counting can
be initiated after an irradiation and cooling period of a few minutes.
Hung et al. (1982) developed a sensitive and selective method for silver
analysis by reacting silver (I) with 2(-3,5-dibromo-2-pyridylazo)- 5 - diethyl
amino phenol in the presence of an anionic surfactant, sodium lauryl sulfate.
The ternary complex formed is red and exhibits an absorption peak at 570 nm.
Hung and his co-workers employed EDTA as a chelating agent, thereby reducing
the interference of common ions. Recoveries were good, and a detection limit
of 0.39 ppm of silver was achieved.
Paper chromatographic, micro thin-layer chromatographic (TLC) and
photodensitometric (PD) methods have also been successfully used to determine
levels of silver compounds in freshwater and eye lotion samples (Devi and
Kumar 1981; Massa 1969). Simple paper and micro thin layer chromatographic
(TLC) techniques were employed by Devi and Kumar (1981) to detect and quantify

-------
93
6. ANALYTICAL METHODS
trace (40 ppm) levels of silver nitrate in fresh water. Devi and Kumar
reacted a prepared silver nitrate sample with succinate dehydrogenase enzyme-
chromogenic reagent complex solution prior to paper chromatographic or micro
TLC analysis. The metals are recognized by their ability to inhibit the
enzymatic formation of a pink reaction product.
Soil samples have been analyzed for silver by AAS (Klein 1972) , NAA, and
x-ray fluorescence analysis (Ragaini et al. 1977). No statements on the
sensitivity, accuracy, or precision of these methods for soil analysis were
presented in the brief description of these methods.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of silver is available. Where adequate information is not available,
ATSDR, in conjunction with the National Toxicology Program (NTP), is required
to assure the initiation of a program of research designed to determine the
health effects (and techniques for developing methods to determine such health
effects) of silver.
The following categories of possible data needs have been identified by a
joint team of scientists from ATSDR, NTP, and EPA. They are defined as
substance-specific informational needs that, if met would reduce or eliminate
the uncertainties of human health assessment. In the future, the identified
data needs will be evaluated and prioritized, and a substance-specific
research agenda will be proposed.
6.3.1 Identification of Data Needs
Methods for Determining Biomarkers of Exposure and Effect. Existing
methods of measuring levels of silver in blood, urine, feces, hair, and
tissues are extremely sensitive and can measure levels in the low ppm to ppt.
These methods are accurate and reliable and can be used to measure both
background levels of exposure and levels at which biological effects occur.
No additional analytical methods for determining trace levels of silver in
biological materials are needed.
Highly sensitive methods exist to measure silver concentrations in blood,
urine, hair, and skin samples of individuals showing the few health effects
that have been associated with silver exposure. These methods are also able
to accurately measure background levels in the population. No additional
analytical methods appear to be needed for the known biomarkers of effect.
Methods for Determining Parent Compounds and Degradation Products in
Environmental Media. Sophisticated and highly refined methods are available

-------
94
6. ANALYTICAL METHODS
to detect trace levels of silver arid its compounds in air, solid waste
leachate, water (the medium of most concern for human exposure), food, and
other environmental media. These methods can accurately measure background
levels in environmental samples, as well as levels at which health effects
occur. There are no known deficiencies in the analytical methods for
determining silver in environmental media, and no additional analytical
methods appear to be necessary.
6.3.2 On-Going Studies
No on-going studies concerning techniques for measuring and determining
silver in biological and environmental samples were located.

-------
95
7. REGULATIONS AND ADVISORIES
Silver is on the list of chemicals appearing in "Toxic Chemicals Subject
to Section 313 of the Emergency Planning and Community Right-to-Know Act of
1986" (EPA 1987b).
No international regulations pertaining to silver were found. The
national and state regulations and guidelines regarding silver in air, water,
and other media are summarized in Table 7-1.

-------
96
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Silver
Agency
Description
Va lue
Refer
ence
Regulations:
a Air:
OSHA
b Water:
EPA ODW
FDA
Other:
EPA OSW
EPA OERK
EPA OTS
OSHA
Guidelines :
a . Air:
ACGIH
NIOSH
NIOSH
National
PEL TWA (metal and soluble compound!
Drinking water MCL*
Proposed drinking water SMCL
Permissible levels in bottled water
Silver nitrate designated as hazardous
waste substance
Reportable Quantity (RQ)
(silver and compounds)
(silver nitrate)
Toxic chemical release reporting;
community right-to-known (proposed)
(silver and compounds)
Meets proposed medical records rule
TLV TWA:
Silver metal dust
Airborne soluble silver compounds
Recommended exposure limit
IDLH (silver and soluble silver
compounds)
0.01 trig/m3
0.C5 mg/L
0 . 09 mg/L
0.05 mg/L
No data
1000 lb
1 lb
No data
No data
0 .1 mg/m3
0.01 mg/m3
0.01 mg/m3
0.01 mg/m3
OSHA 19 88b (29
CFR 19 10.1000)
EPA 1987d ( 4c
CFR Hi)
EPA 1989b
FDA 1988a (21
CFR 103.35)
EPA 1987a (40
CFR 116.4 )
EPA 1988b (40
CFR 302.4)
EPA 1987b (52 FR
21152)
OSHA 1988a (29
CFR 1910.20)
ACGIH 1986
NIOSH 1985
NIOSH 1985
b. Water:
EPA ODW
EPA OMRS
Recommended drinking water limits
Ambient water quality criteria to protect
human health ingesting water and
organisms
0.05 mg/L
0.05 mg/L
EPA 1985a
EPA 19BOb (45 FR
79318)
c. Other:
EPA
EPA ODW
Water:
Alabama
Alaska
Arkansas
Arizona
California
Colorado
Connecticut
Delaware
District of
Columbia
Florid*
Hawaii
RfD (oral)
Carcinogen classification
State
Regulations:
Maximum concentration Levels in
drinking water:
3xl0"3 mg/kg/day IRIS 1989
Group Db	EPA 1988a
0.05 mg/L
CELDS 1988

-------
97
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency	Description	Value	Reference
Idaho
Illinois
Ind l ana
Kansas
Kentucky
Louisiana
Maine
Maryland
Massachu-
setts
Michigan
Mississippi
Minnesota
Missouri
Montana
Nebraska
Nevada
New Hamp-
shire
New Mexico
New York
North
Carolina
North
Dakota
Ohio
Oklahoma
Oregon
Pennsyl-
vania
Rhode
Island
South
Carolina
South
Dakota
Tennessee
Texas
Utah
Vermont
Virginia
Washington
West
Virginia
Wisconsin
Wyoming
Groundwater concentration limits0:	0.05 mg/L	CELDS 1988
Colorado
Indiana
Kentucky
Massachu-
setts
Nevada
New Mexico
New York
Wisconsin	0.05 mg/L	WDHSS 1989

-------
98
7. REGULATIONS AND ADVISORIES
TABLE 7~1 (Continued)
Description Value Reference
Agency	^				
Water quality criteria"	c-°5 mg/L	CELDS 1968
Arizona
Mississippi
New Jersey
New York
South
Dakota
Virginia
aThe EPA has proposed to delete the MCL for silver (EPA 1989b).
bGroup D. Not classifiable as to carcinogenicity in humans.
cThe classification of groundwater by future use may vary between states.
dThe criteria upon which this value is based may vary between states, e.g., recreation aquatic life, etc
ACGIH » American Conference of Government Industrial Hygienists; EPA = Environmental Protection Agency; FDA
= Food and Drug Administration; IDLH * Immediately Dangerous to Life or Health; MCL * Maximum Contaminant
Level; NIOSH » National Institute for Occupational Safety and Health; ODW =• Office of Drinking Water; QERR
= Office of Emergency and Remedial Response; CSKA « Occupational Safety and Health Administration; OSW
¦ Office of Solid Wastes; OTS = Office of Toxic Substances; OWRS » Office of Water Regulations and
Standards; PEL - Permissible Exposure Limit; RfD - Reference Dose; RQ » Reportable Quantity; SMCL *
Secondary Maximum Contaminant Level; TLV = Threshold Limit Value; TWA * Time-Weighted Average

-------
99
8. REFERENCES
*Aaseth J, Olsen A, Halse J, et al. 1981. Argyria-tissue deposition of
silver as selenide. Scand J Clin Lab Invest 41:247-251.
Abdel Rahim AG. 1985. The effects of dietary L-ascorbic acid on the
absorption and utilization of Na75Se03 of silver-treated rats. Comp Biochem
Physiol 810:131-132.
*ACGIH. 1986. Documentation of the threshold limit values and biological
exposure indices. 5th ed. American Conference of Governmental Industrial
Hygienists, Inc., Cincinnati, OH, 529.
^Alexander J, Aaseth J. 1981. Hepatobiliary transport and organ distribution
of silver in the rat as influenced by selenite. Toxicology 21:179-186.
Alexander J, Aaseth J, Refsvik T. 1980. Biliary excretion of glutathione in
the rat-significance for the biliary excretion of heavy metals [Abstract].
Naunyn-Schmiedeberg Arch Pharmacol 313:R66.
Andelman JB. 1973. Incidence, variability and controlling factors for trace
elements in natural, fresh waters. In: Singer PC, ed. Trace metals and
metal-organic interactions in natural waters. Ann Arbor, MI: Ann Arbor
Science Publishers Inc., 57-88.
*Anderson JB, Jenne EA, Chao TT. 1973. The sorption of silver by poorly
crystallized manganese oxides. Geochimica et Cosmochimica Acta 37:611-622.
Anghileri LJ . 1968. In vivo and in vitro deiodination of silver iodide.
Experientia 24:895.
Anghileri LJ. 1969. Studies on the in vivo breakdown of insoluble halides.
Acta Isotope 9:347-356.
Aoki K, Hori J, Kawashima K. 1967. Effect of metallic cations on human
serum: Study by starch-gel electrophoresis. II Effect of Hg++, Cr+++, Ag+,
Ni++, Cd++, Zn++, Ba++, Mg++, A1+++ and Fe+++. Arch Biochem Biophys
120:255-267.
*Cited in text.

-------
100
8. REFERENCES
Aronstam RS, Eldefrawi ME. 1979. Transition and heavy metal inhibition of
ligand binding to muscarinic acetylcholine receptors from rat brain. Toxicol
Appl Pharmacol 48:489-496.
Baba S, Shinohara Y, Sano H, et al. 1984. Application of high-performance
liquid chromatography with synchronized accumulating radioisotope detector to
analysis of glyceryl trinitrate and its metabolites in rat plasma. J
Chromatog 305:119-126.
*Bader KF. 1966. Organ deposition of silver following silver nitrate therapy
of burns. Plast Reconstr Surg 37:550-551.
*Baes CP 111, Sharp RD. 1983. A proposal for estimation of soil leaching and
leaching constants for use in assessment models. J Environ Qual 12:17-28.
Bailey JA, Jones AM, Roy DR. 1973. Effects of silver from cloud seeding on
microflora of animal digestive systems. Report to US Bureau of
Reclamation, Division of Atmospheric Water Resources Management, Denver, CO,
by Department of Fishery and Wildlife Biology, Colorado State University, Fort
Collins, CO. NTIS PB226-062.
Ballinger PM, Brown BS, Griffin MM, et al. 1982. Evidence for carriage of
silver by sulphadimidine: Hemolysis of human erythrocytes. Br J Pharmacol
77:141-145.
*Bard CC, Murphy JJ, Stone DL, et al. 1976. Silver in photoprocessing
effluents. Water Pollut Cont Fed 48:389-394.
*Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
Description and use in health risk assessments. Appendix A: Integrated risk
information system supportive documentation. Washington, DC: US
Environmental Protection Agency, Office of Health and Environmental
Assessment. EPA/600/8-86-032a.
Barrie HJ, Harding HE. 1947. Argyro-siderosis of the lungs in silver
finishers. Brit J Industr Med 4:225-232.
*Becker RO. 1987. The effect of electrically generated silver ions on human
cells. In: Proceedings of the First International Conference on Gold and
Silver in Medicine, Bethesda, Maryland, May 13-14, 1987. Washington, DC: The
Gold and Silver Institutes, 227-243.
*Becker RO, Spadaro JA. 1978. Treatment of orthopedic infections with
electrically generated silver ions. The Journal of Bone and Joint Surgery 60-
A:871 - 881 .

-------
101
8. REFERENCES
Bergmann M, Engel C. 1968. [Silver deposits in the gastric mucosa and liver
o? u"->-ve"al argyrosis due to treatment with tragesine], Dtsch Gesundheitsw
23:629-31. (German).
*Berry JP, Galle P. 1982. Selenium and kidney deposits in experimental
argyria. Electron microscopy and microanalysis. Pathol Biol (PariO
30:136-140.	^	;
Bertine KK, Goldberg ED. 1971. Fossil fuel combustion and the maior
sedimentary cycle. Science 173:233-235.
Bertine KK, Goldberg ED. 1972. Trace elements in clams, mussels, and shrimp
Limnology Oceanography 17:877-884.
Bessing C, Kallus T. 1987. Evaluation of tissue response to dental allovs bv
subcutaneous implantation. Acta Odontol Scand 45:247-255.
Biddinger GR, Gloss SP. 1984. The importance of trophic transfer in the
bioaccumulation of chemical contaminants in aquatic ecosystems. Resi
Rev 91:103-145.
Blaha K Jr,_Havrdova J, Rosina J, et al. 1987. The effect of HOmAg on
3ir39°43aSmin °XidaSe activity in rats• J Hyg Epidemiol Microbiol Immunol
*Bleehen SS, Gould DJ, Harrington CI, et al. 1981. Occupational argyria;
e"'"ect:ron microscopic studies and x-ray microanalysis. Br J Dermatol
*Blumberg H, Carey TN. 1934. Argyremia: Detection of unsuspected and
obscure argyria by the spectrographic demonstration of high blood silver t
Am Med Assoc 103:1521-1524.	6	silver. J
*Bogen J. 1973. Trace elements in atmospheric aerosol in the Heidelberg
area, measured by instrumental neutron activation analysis. Atmos Environ
7:1117-1125.
Boissevain CH, Drea WF. 1936. Relation between the occurrence of endemic
goiter and the presence of traces of silver and barium in drinking water
Endocrinology 26:686-687.	6
Bourdon-Ranisteano S, Bourdon R, Prouillet F. 1977. [Determination of silver
in biological materials], Ann Biol Clin 35:397-400. (French).
*Boyle RW. 1968. Geochemistry of silver and its deposit notes on geochemical
prospecting for the element. Geological Survey of Canada. Ottawa, Ont:
Canada, Department of Energy, Mines and Resources. 160., 1-96.

-------
102
8. REFERENCES
Bradford GR, Bair FL, Hunsaker V. 1968. Trace and major element content of
170 High Sierra Lakes in California. Limnology and Oceanography 13:526-530.
Braidech MM, Emery FH. 1935. The spectrographs determination of minor
chemical constituents in various water supplies in the United States. J Amer
Water Works Assoc 27:557-580.
Brar SS, Nelson DM, Kline JR, et al. 1970. Instrument analysis for trace
elements present in Chicago area surface air. Journal of Geophysics Research
7 5 : 2939-2945.
Braunstein HM, Pack DJ, Oakes TW. 1982. Intercomparison of stable element
content of foods by statistical methods. Proc Univ MO Annu Conf Trace Subst
Environ Health. 16:377-390.
Breton J, Foncin JF, Caroff J, et al. 1971. [Argyria and argyrism: Two
unusual cases. Value of electron microscopy and derived methods], Med Leg
Doinmage Corp 4:245-248. (French).
-"Brody AR, Vallyathan NV, Craighead JE. 1978. Use of scanning electron
microscopy and x-ray energy spectrometry to determine the elemental content of
inclusions in human tissue lesions. Scanning Microsc 2:615-622.
Brooks SM. 1981. Lung disorders resulting from the inhalation of metals.
Clin Chest Med 2:235-254.
Brooks SM. 1986. Pulmonary reactions to miscellaneous mineral dusts,
man-made mineral fibers, and miscellaneous pneumoconioses. In: Merchant JA
ed. Occupational respiratory diseases. Morgantown, WV: US Department of
Health and Human Services, Division of Respiratory Disease Studies, 401-458,
Brozman M, Chorvath D, Jakubovsky J. 1976. [Localization of silver in
glomerular basement membranes in experimental argyrosis], Bratisl Lek Listy
66:253-263. (Polish).
Bruevich TS, Bogomolets NN, Berezovskii AD. 1980. [Sensitizing action of
precious metal compounds: Gold, platinum, ruthenium, rhodium and silver].
Gig Tr Prof Zabol:42-44. (Russian).
Brulaud KW, Bertine K, Koide M, et al. 1974. History of metal pollution in
the Southern California coastal zone. Environ Sci Technol 8:425-432.
Brune D, Beltesbrekke H. 1979. Levels of mercury and silver in dust from the
trimming of amalgam dies. Scand J Dent Res 87:462-465.

-------
103
8. REFERENCES
Brune D, Nordberg G, Wester PO. 1980. Distribution of 23 elements in the
kidney, liver and lungs of workers from a smeltery and refinery in north
Sweden exposed to a number of elements and of a control group. The Science of
the Total Environment 16:13-35.
^Buckley WR. 1963. Localized argyria. Arch Dermatol 88:531-539.
Buckley WR, Terhaar CJ. 197 3. The skin as an excretory organ in argyria
Trans St John's Hosp Dermatol Soc 59:39-44.
*Buckley WR, Oster CF, Fassett DW. 1965. Localized argyria: II. Chemical
nature of the silver containing particles. Arch Dermatol 92:697-705.
*Bunch RL. 1982. Sewage sludge dilemma of the eighties. In: Pawlowski L
ed. Physiochemical methods for water and wastewater treatment. Amsterdam'
Elsevier, 69-81.
*Bunyan J, Diplock AT, Cawthorne MA, et al. 1968. Vitamin E and stress. 8.
Nutritional effects of dietary stress with silver. Br J Nutr 22*165-182
Butt EM, Nusbaum RE. Gilmour TC, et al. 1964. Trace metal levels in human
serum and blood. Arch Environ Health 8:60-65.
*Byrae CJ, DeLeon JR. 1986. Trace metal residues in biota and sediments from
Lake Pontchartrain, Louisiana. Bull Environ Contain Toxicol 37:151-158
Cabe PA, Carmichael NG, Tilson HA. 1979. Effects of selenium, alone and in
combination with silver or arsenic, in rats. Neurobeh Toxicol'1:275-278
Caffee HH, Bingham HG. 1982. Leukopenia and silver sulfadiazine J Trauma
22:586-587.
*Calabrese A, Madnnes JR, Nelson DA, et al. 1984. Effects of long-term
exposure to silver or copper on growth, bioaccumulation and histopathology in
the blue mussel Mytilus edulis. Marine Environmental Research 11:253-274
*Callahan MA, Slimak MW, Gabel NW, et al. R; 1979. Water-related
environmental fate of 129 priority pollutants. EPA-440/4-79-Q29a,b.
Camner P,	Lundborg M, Hellstrom P. 1974. Alveolar macrophages and 5 pm
particles coated with different metals. Arch Environ Health 29:211-213.
Camner P,	Hellstrom PA, Lundborg M, et al. 1977. Lung clearance of U-fim
particles	coated with silver, carbon, or beryllium. Arch Environ Health
32:58-62 .

-------
104
8. REFERENCES
Carson BL, Ellis HV III, McCann JL. 1986. Toxicology and biological
monitoring of metals in humans. Chelsea, MI: Lewis Publishers, Inc
219-225.
*Casto BC, Meyers J, DiPaolo JA. 1979. Enhancement of viral transformation
for evaluation of the carcinogenic or mutagenic potential of inorganic metal
salts. Cancer Res 39:193-198.
*Catsakis LH, Sulica VI. 1978. Allergy to silver amalgams. Oral Surg
46:371-375 .
CELDS. 1989. Computer-Environment Legislative Data Systems. The
Environmental Technical Information System (ETIS). Department of Urban and
Regional Planning, Planning Information Program, University of Illinois
Urbana-Champaign, IL. January 6, 1989.
Cerrai E, Ghersini G. 1966. Reversed-phase paper chromatography of some
cations with two nitrophenylthiophosphate derivatives as stationary phases J
Chromatogr 22:425-430.
Charley RC, Bull AT. 1979. Bioaccumulation of silver by a multispecies
community of bacteria. Arch Microbiol 123:239-244.
*CHEMLINE. 1988. National Library of Medicine, National Toxicology
Information Program, Bethesda, MD. December 5, 1988.
Cherian MG, Goyer RA. 1978. Role of metallothioneins in disease. Ann Clin
Lab Sci 8:91-94.
Chien PT. 1979. Metallic copper and silver dust hazards... [editorial]. Am
Ind Hyg Assoc J 40:747-748.
¦*CHMR. 1989. Hazardous waste minimalization manual for small quantity
generators. Center for Hazardous Materials Research, University of Pittsburgh
Applied Research Center, Pittsburgh, PA.
Chorvath D, Brozman M, Jakubosky J. 1976. [Morphology of experimental
argyrosis in kidneys], Cesk Patol 4:161-165. (Czech).
CCRIS. 1988. Chemical Carcinogenesis Research Information System. Chemical
Information System (CIS). December 5, 1988.
Clemente GF, Cigna Rossi L, Santaroni GP. 1977. Trace element intake and
excretion in the Italian population. J of Radioanal Chem 37:549-558.

-------
105
8. REFERENCES
*Coffin DL, Palekar LD. 1985. Bioassays for asbestos and other solid
materials. In: Milman HA and Weisburger EK, ed. Handbook of Carcinogen
Testing. Park Ridge, NJ: Noyes Publications, 384-419.
Coglianese MP, Martin M. 1981. Individual and interactive effects of
environmental stress on the embryonic development of the pacific oyster,
Crassostrea gigas. I. The toxicity of copper and silver. Mar Environ Res
5:13-27.
«Cole RJ, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the
priority pollutant monitoring project of the nationwide urban runoff program.
Water Pollut Cont Fed 56:898-908.
*Coleman RL, Cearley JE. 1974. Silver toxicity and accumulation in
largeraouth bass and bluegill. Bull Environ Contain Toxicol 12:53-61.
Connors RC, Daniels F Jr. 1973. Generalized argyria. Cutis 11:796-801.
^Constable J, Morris P, Burke J. 1967, Absorption pattern of silver nitrate
from open wounds. Plast Reconst Surg 39:342-348.
^Contract Laboratory Program Statistical Database. 1988. US Environmental
Protection Agency, Contract Laboratory Program, Washington, DC.
*Cooper CF, Jolly WC. 1970. Ecological effects of silver iodide and other
weather modification agents. Water Resource Research 6:88-98.
Costello J. 1983. Mortality of metal miners a retrospective cohort and case
control study. In: Wagner WL, Rom WN, Merchant JA, eds. Health issues
related to metal and nonmetallic mining. Boston, MA: Butterworth Publishers,
227-240.
*Creasey M, Moffat DB. 1973. The deposition of ingested silver in the rat
kidney at different ages. Experientia 29:326-327.
Creason JP, Hinners TA, Bumgarner JE, et al. 1975. Trace elements in hair,
as related to exposure in metropolitan New York. Clin Chem 21:603-612.
*Creason JP, Svendsgaard D, Bumgarner J, et al. 1976. Maternal-fetal tissue
levels of 16 trace elements in 8 selected continental United States
communities. Proc Univ MO Annu Conf Trace Subst Environ Health. 10:53-62.
*Cunningham WC, Stroube WB Jr. 1987. Application of an instrumental neutron
activation analysis procedure to analysis of food. Sci Total Environ
63:29-43.

-------
106
8. REFERENCES
Curtin GC, King HD, Mosier EL. 1974. Movement of elements into the
atmosphere from coniferous trees in subalpine forests of Colorado and Idaho.
Journal of Geochemical Exploration 3:245-263.
*Dams R, Robbins JA, Rahn KA, et al. 1970. Non destructive neutron
activation analysis of air pollution particulates. Anal Chem 42:861-867.
'¦Dams R, Billet J, Hoste J. 1975. Neutron activation analysis of F, Sc Se
Ag, and Hf, in aerosols using short-lived isotopes. Int J Environ Anal Chem
4: 141-153.
*Dam;cher G. 1981. Light and electron microscopic localization of silver in
biological tissue. Histochemistry 71:177-186.
^Davidson CI, Goold WD, Mathison TP, et al. 1985. Airborne trace elements in
Great Smoky Mountains, Olympic, and Glacier National Parks. Environ Sci
Techno1 19:27-35.
Davies PH, Goettl JP Jr, Sinley JR. 1978. Toxicity of silver to rainbow
t rout. (Salmo gairdneri) . Water Research 12:113-117.
*Day WA, Hunt JS, McGiven AP. 1976. Silver deposition in mouse glomeruli.
Pathology 8:201-204.
Deby C, Bacq ZM, Simon D. 1973. In vitro inhibition of the biosynthesis of a
prostaglandin by gold and silver. Biochem Pharmacol 22:3141-3143.
*Demerec M, Bertani G, Flint J. 1951. A survey of chemicals for mutagenic
action on E. coli. The American Naturalist 85:119-136.
*Dequidt J, Vasseur P, Gromez-Potentier J. 1974. [Experimental toxicological
study of some silver derivatives]. Bulletin de la Societe de Pharmacie de
Lille 1:23-35. (French).
*Devi YP, Kumar NV. 1981. Simple paper and micro thin layer chromatographic
method for separation and detection of mercuric chloride, copper sulfate,
cadmium sulfate, and silver nitrate in fresh water. J Assoc Off Anal Chem
64:1301-1304.
Dick WA, Bonta JV, Haghiri F, et al. 1983. Stream water quality of two small
watersheds as affected by surface coal mining. J Environ Qual 12:351-358.
Di1 lard CJ, Tappel AL. 1986. Mercury, silver, and gold inhibition of
selenium-accelerated cysteine oxidation. J Inorg Biochem 28:13-20.

-------
107
8. REFERENCES
Diplock AT, Green J, Bunyan J, et al. 1967. Vitamin E and stress. 3. The
metabolism of D-alpha-tocopherol in the rat under dietary stress with silver.
Br J Nutr 21:115-125.
Diplock AT, Baum H, Lucy JA. 1971. The effect of vitamin E on the oxidation
state of selenium in rat liver. Biochem J 123:721-729.
Dissanayake CB, Tobschall HJ, Palme H, et al. 1983. The abundance of some
major and trace elements in highly polluted sediments from the Rhine river
near Mainz, West Germany. Sci Total Environ 29:243-260.
*DiVincenzo GD, Giordano CJ, Schriever LS. 1985. Biologic monitoring of
workers exposed to silver. Int Arch Occup Environ Health 56:207-215.
*Domsch KH. 1984. Effects of pesticides and heavy metals on biological
processes in soil. Plant Soil 76:367-378.
*Douglas WJ. 1968. Toxic properties of materials used in weather
modification. Proceedings of the first national conference on weather
modification. Boston, MA: American Meteorological Society, 351-360.
~Drake HJ. 1980. Silver. Mineral facts and problems. Washington, DC: U.S.
Department of the Interior, Bureau of Mines. Preprint from Bulletin 671.
Dreisback RH, Robertson WO, ed. 1977. Handbook of poisoning: Prevention,
diagnosis and treatment. 12th ed. Los Altos, CA: Lang Medical Publications,
373-376.
*Dubin NH, Parmley TH, Cox RT, et al. 1981. Effect of silver nitrate on
pregnancy termination in cynomolgus monkeys. Fertil Steril 36:106-109.
Dunn JA, Holland KB, Jezorek JR. 1987. Argentation liquid chromatography of
polynuclear aromatic hydrocarbons on a silver(I)- loaded mercaptopropyl silica
gel stationary phase. J Chromatog 394:375-381.
Dupont T, Gomez J, Cuvillier P, et al. 1984. [Drug-induced generalized
argyria. Value of blood and urine analysis. Apropos of 2 cases], IARC
Medical 4:103-105. (French).
*Dutkiewicz T, Paprotny W, Sokolowska D, et al. 1978. Trace element content
of human hair determined using neutron activation analysis as monitor of
exposure effects to environmental metals. Chemia Analityczna 23:261-272.
Dyck W. 1967. Adsorption and coprecipitation of silver on hydrous ferric
oxides. Can J Chem 46:1441-1444.

-------
108
8. REFERENCES
Dymond AM, Kaechele LE, Jurist JM, et al . 1970. Brain tissue reactions to
some chronically implanted metals. J Neurosurg 33:574-580.
*East BW, Boddy K, Williams ED, et al. 1980. Silver retention, total bodv
silver and tissue silver concentrations in argyria associated with exposure to
an anti-smoking remedy containing silver acetate. Clin Exp Dermatol
5:305-311.
Eaton DL. 1985. Effects of various trace metals on the binding of cadmium
rat hepatic metallothionein determined by the cd/hemoglobin affinity assav °
Toxicol Appl Pharmacol 78:158-162.
Eaton DL, Stacey NH, Wong K-L, et al. 1980. Dose-response effects of
various metal ions on rat liver metallothionein, glutathione, heme oxygenase
and cytochrome P-450. Toxicol Appl Pharmacol 55:393-402.
*Eckel WP, Jacob TA. 1988, Ambient levels of 24 dissolved metals in US
surface and ground waters. American Chemical Society, Annual Meeting Los
Angeles, CA, September 25-30, 1988. Preprint Extended Abstract.
Eley BM, Garrett JR. 1983. Tissue reactions to the separate implantation of
individual constituent phases of dental amalgam, including assessment by
energy dispersive x-ray microanalysis. Biomaterials 4:73-80.
El-Yazigi A, Al-Saleh I, Al-Mefty 0. 1984. Concentrations of Ag, Al, Au R"
Cd, Cu, Pb, Sb, and Se in cerebrospinal fluid of patients with cerebral ' X'
neoplasms. Clin Chem 30:1358-1360.
EPA. 1977. Heavy metals in gardens near the ASARCO Smelter Tacoma
Washington. US EPA/OTS Public Files. 40-7748027.
EPA. 1979. US Environmental Protection Agency. Federal Register
44:15926-15981.
*EPA. 1980a. Ambient water quality criteria for silver. Cincinnati OH-
Environmental Protection Agency, Environmental Criteria and Assessment Off-
PB81 -117822 .	Hce.
*EPA. 1980b. U.S. Environmental Protection Agency. Federal Register
45:79318-79319.
EPA. 1982. Mortality in employees of the ASARCO Lead Refinery, Omaha
Nebraska with cover letter. US EPA/OTS Public Files.	'
*EPA. 1985a. Drinking water criteria document for silver. Cincinnati OH
US Environmental Protection Agency, Environmental Criteria and Assessmeni-
Office. PB86-118288.

-------
109
8. REFERENCES
*EPA. 1985b. Silver. Chemical, physical and biological properties of
compounds present at hazardous waste sites. Washington, DC: US
Environmental Protection Agency, Office of Waste Programs and Enforcement.
PB89-132203.
*EPA 1986. Reference values for risk assessment. Final draft. Cincinnati,
OH: US Environmental Protection Agency, Office of Solid Waste. ECAO-CIN-477
*EPA. 1987a. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 136.1.
*EPA. 1987b. US Environmental Protection Agency. Federal Register 52:21152.
*EPA. 1987c. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 116.4.
*EPA. 1987d. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 141.
EPA. 1987. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 117.3.
*EPA. 1988a. Health Advisory Draft for Silver. US Environmental Protection
Agency, Office of Drinking Water, Washington, DC. (Prepublication draft).
*EPA. 1938b. US Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 302.4.
EPA. 1988. Drinking water criteria document for silver (final draft),
Cincinnati, OH: US Environmental Protection Agency, Environmental Criteria
and Assessment Office. ECAO-CIN-026.
*EPA. 1989a. Interim Methods for Development of Inhalation Reference Doses.
US Environmental Protection Agency, Office of Health and Environmental
Assessment. Washington, DC. EPA 600/8-88/066F.
*EPA. 1989b. US Environmental Protection Agency. Federal Register 54:22062.
Eturska M, Obreshkova E. 1979. [Argyria in the prolonged use of adsorgan].
Vutr Boles 18:121-3.
Evans WH, Read JI, Caughlin D. 1985. Quantifications of results for
estimating elemental dietary intakes of lithium, rubidium, strontium,
molybdenum, vanadium and silver. Analyst 110:873-877.

-------
110
8. REFERENCES
Fallon ME, Horvath FJ. 1985. Preliminary assessment of contaminants in soft
sediments of the Detroit River. J Great Lakes Res 11:373-378.
Farhan FM, Hibibi N, Mofidi J, et al. 1979. Direct determination of traces
of heavy metals in canned vegetables by arc spectrography. J Agric Food Chem
27:637-638.
*FDA. 1988a. US Food and Drug Administration. Code of Federal Regulations.
21 CFR 103.35.
*Fisher NS, Bohe M, Teyssie J-L. 1984. Accumulation and toxicity of Cd, Zn,
Ag, and Hg in four marine phytoplankters. Mar Ecol Prog Ser 18:201-213.
Flessel CP, Furst A, Radding SB. 1980. A comparison of carcinogenic metals.
In: Sigel H, ed. Metal ions in biological systems. Vol. 10, New York, NY:
M. Dekker, 23-54.
*Forycki Z, Zegarski W, Bardzik J, et al. 1983. Acute silver poisoning
through inhalation. Bulletin of the Institute of Maritime and Tropical
Medicine in Gdynia 34:199-203.
Fowler BA, Nordberg PF. 1986. Specific metals. In: Friberg L, Nordberg GF,
Vouk VB, eds. Handbook on the toxicology of metals. Vol. 2, 2nd ed. New
York, NY: Elsevier Science Publishing Co., Inc., 521-531.
*Fox CL, Rappole BW, Stanford W. 1969. Control of Pseudomonas infection in
rats. Surg Gynecol and Obstet 128:1021-1026.
Frank R, Stonefield KI, Luyken H, et al. 1986. Survey of elemental contents
in two organs of slaughtered bovine, porcine and avian specimens, Ontario,
Canada 1980-83. Environmental Monitoring and Assessment 6:259-265.
Franz H. 1968. [Demonstration of small amounts of tissue-bound silver].
Histochemie 12:227-229.
*Freeman RA. 1979. Ecological kinetics of silver in an alpine lake
ecosystem. In: Marking LL, Kimerle RA, eds. Aquatic toxicology.
Philadelphia, PA: American Society for Testing and Materials, 342-358.
Frei JV, Stephens P. 1968. The correlation of promotion of tumor growth and
of induction of hyperplasia in epidermal two-stage carcinogenesis. Br J
Cancer 22:83-92.
Fujita S. 1971. Silver-palladium-gold alloys carcinogenicity and acid
mucopolysacharides in the induced tumors. Chem Abstracts 77:136075a.

-------
Ill
8. REFERENCES
*Furchner JE, Richmond CR, Drake GA. 1968. Comparative metabolism of
radionuclides in mammals-IV. Retention of silver-HOm in the mouse, rat,
monkey, and dog. Health Physics 15:505-514.
Furst A. 1981. Bioassay of metals for carcinogenesis: Whole animals.
Environ Health Perspect 40:83-91.
Furst A, Schlauder MC. 1977. Inactivity of two noble metals as carcinogens.
J Environ Pathol Toxicol 1:51-57.
Galloway JN, Likens GE. 1979. Atmospheric enhancement of metal deposition in
Adirondack lake sediments. Limnology Oceanography 24:427-433
Gallyas F. 1979. Factors affecting the formation of metallic silver and the
binding of silver ions by tissue components. Histochemistry 64:97-109.
Gammill JC, Wheeler B, Carothers EL, et al. 1950. Distribution of
radioactive silver colloids in tissues of rodents following injection by
various routes. Proc Soc Exp Biol Med 74:691-695.
Ganther HE. 1980. Interactions of vitamin E and selenium with mercury and
silver. Ann NY Acad Sci 355:212-226.
Ganther HE, Wagner PA, Sunde ML, et al. 1973. Protective effects of selenium
against heavy metal toxicities. Proc Univ MO Annu Conf Trace Subst Environ
Health. 7:247-252.
*Gaul LE, Staud AH. 1935. Clinical spectroscopy. Seventy cases of
generalized argyrosis following organic and colloidal silver medication,
including a biospectrometric analysis. J Am Med Assoc 104:1387-1390.
George SG, Pirie BJS, Calabrese A, et al. 1986. Biochemical and
ultrastruetural observations of long-term silver accumulation in the mussel,
Mytilus edulis. Marine Environmental Research 18:255-265.
Gerritse RG, Vriesema R, Dalenberg JW, et al. 1982. Effect of sewage sludge
on trace element mobility in soils. J Environ Qual 11:359-364.
Gjerdet NR, Kallus T, Hensten-Pettersen A. 1987. Tissue reactions to
implanted orthodontic wires in rabbits. Acta Odontol Scand 45:163-169.
Goebel HH, Muller J. 1973. Ultrastructural observations on silver deposition
in the choroid plexus of a patient with argyria. Acta Neuropathol {Berl")
26:247-251.
Goff H, Powers EL. 1975. Effects of X-rays on Ag-DNA complexes. Int J
Radiat Biol 27:503-507.

-------
112
8. REFERENCES
Goldberg ED. 1986. The mussel watch concept. Environmental Monitoring and
Assessment 7:91-103.
Goldberg RL, Kaplan SR, Fuller GC. 1983. Effect of heavy metals on human
rheumatoid synovial cell proliferation and collagen synthesis. Biochecn
Pharmacol 32:2763-2766.
Goldschmidt PR, Cogen RB, Taubman SB. 1976. Effects of amalgam corrosion
products on human cells. J Periodontal Res 11:108-115.
Goodman Gilman A, Goodman LS, Rail TW, et al., ed. 1985. Goodman and
Gilman's the pharmacological basis of therapeutics. New York, NY: Macmillan
Publishing Company, 951; 966-967; 1107.
Gould GW, Colyer J, East JM, et al. 1987. Silver ions trigger Ca2+ release
by interaction with the (Ca2+-Mg2+)-ATPase. J Biol Chem 262:7676-7679.
Grabowski BF, Haney WG Jr. 1972. Characterization of silver deposits in
tissue resulting from dermal application of a silver-containing
pharmaceutical. J Pharm Sci 61:1488-1490.
Granati A, Lenzi R, Poggini G, et al. 1982. [Evaluation of the impact of
silver on human health], Difesa Sociale 61:90-112. (Italian).
*Grasso P, Abraham R, Hendy R, et al. 1969. The role of dietary silver in
the production of liver necrosis in vitamin E-deficient rats. Exp Mol Pathol
11:186-199.
Grasso P, Abraham R, Hendy R, et al. 197 3. Hepatocellular necrosis from
dietary silver in vitamin E-deficient rats [Abstract], J Pathol 100:ix.
*Grayson M, ed. 1978. Silver and silver alloys; Silver and compounds.
Kirk-Othmer encyclopedia of chemical technology. Vol. 21, 3rd ed. 1-32.
Green B. 1967. Effects of silver ions on deoxyribonucleic acid-polycyclic
hydrocarbon complexes. Biochem J 104:63-64.
Greenberg RR, Zoller WH, Gordon GE. 1978. Composition and size distributions
of particles released in refuse incineration. Environ Sci Technol 12:566-573
Greene RM, Su WPD. 1987. Argyria. American Family Physician 36:151-154.
Gregus Z, Klaassen CD. 1986. Disposition of metals in rats: A comparative
study of fecal, urinary, and biliary excretion and tissue distribution of
eighteen metals. Toxicol Appl Pharmacol 85:24-38,

-------
113
8. REFERENCES
Greig RA, Wenzloff DR, Adams A, et al. 1977. Trace metals in organisms from
ocean disposal sites of the middle eastern United States. Arch Environ Contam
Toxicol 6:395-409.
Greig RA, Schurman S, Pereira J, et al. 1983. Metals and PCB concentrations
in Windowpane Flounder from Long Island Sound. Bull Environ Contam Toxicol
31:257-262.
Habu T. 1968. Histopathological effects of silver-palladium-gold alloy
implantation on the oral submucous membranes and other organs [Abstract],
Shika Igaku 31:17-48.
*Ham KN, Tange JD. 1972. Silver deposition in rat glomerular basement
membrane. Aust J Exp Bio Med Sci 50:423-434.
Hamilton A, Hardy HL. 1974. Silver. Industrial toxicology. 3rd ed. Acton,
MA: Publishing Sciences Group, Inc., 171-172.
Hamilton EI, Minski MJ. 1972/1973. Abundance of the chemical elements in
man's diet and possible relations with environmental factors. Sci Total
Environ 1:375-394.
Hamilton EI, Minski MJ, Cleary JJ. 1972/1973. The concentrations and
distribution of some stable elements in healthy tissues from the United
Kingdom. An environmental study. Sci Total Environ 1:341-374.
Hanna C, Fraunfelder FT, Sanchez J. 1974. Ultrastructural study of the
cornea and conjunctiva. Arch Ophthalmol 92:18-22.
Hanzlik PJ, Presho E. 1923. Comparative toxicity of metallic lead and other
heavy metals for pigeons. J Pharmacol Exp Ther 21:145-150.
Harding HE. 1951. Fibrosis in the lungs of a silver finisher. Br J Ind Med
8:256-263.
Harker JM, Hunter D. 1935. Occupational argyria. Br J Dermatol Syph
47:441-455.
^Harrison PR, Rahn KA, Dams R, et al. 1971. Areawide trace metal
concentrations measured by multielement neutron activation analysis. Journal
of the Air Pollution Control Association 21:563-570.
Harvey RW, Luoma SN. 1985. Effect of adherent bacteria and bacterial
extracellular polymers upon assimilation by Macoma balthica of sediment-bound
cadmium, zinc and silver. Mar Ecol Prog Ser 22:281-289.

-------
114
8. REFERENCES
Hauser TR, Bromberg SM. 1982. EPA's monitoring program at Love Canal 1980,
Environmental Monitoring and Assessment 2:249-272.
Heit M. 1979. Variability of the concentrations of seventeen trace elements
in the muscle and liver of a single striped bass, Marone saxatilis. Bull
Environ Contain Toxicol 23:1-5.
Heit M, Tan Y, Klusek C, et al. 1981. Anthropogenic trace elements and
polycyclic aromatic hydrocarbon levels in sediment cores from two lakes in the
Adirondack acid lake region. Water Air Soil Pollut 15:441-464.
*Hem JD. 1970. Study and interpretation of the chemical characteristics of
natural waters. US Geological Survey Paper 1473. Washington, DC: US
Geological Service., 202-203.
Henry SA. 1950. Cutaneous cancer in relation to occupation. Annals of the
Royal College of Surgeons of England 7:425-454.
Henry WM, Knapp KT. 1980. Compound forms of fossil fuel fly ash emissions
Environmental Science and Technology 14:450-456.
Hershelman GP, Schafer HA, Jan T-K, et al. 1981. Metals in marine sediments
near a large California municipal outfall. Marine Pollution Bulletin
12:131-134.
*Heyl T. 1979. Contact dermatitis from silver coat. Contact Dermatitis
5:197.
Hildebrand SG, Cushman RM, Carter JA. 1976. The potential toxicity and
bioaccumulation in aquatic systems of trace elements present in aqueous coal
conversion effluents. Proc Univ MO Annu Conf Trace Subst Environ Health.
10:305-313.
*Hill WR, Pillsbury DM. 1939. Argyria, the pharmacology of silver.
Baltimore, MD: The Williams and Wilkins Co.
Hill CH, Matrone G. 1970. Chemical parameters in the study of in vivo and in
vitro interactions of transition elements. Fed Proc 29:1474-1481.
Hirakawa K. 1983. Determination of silver and cerium in the liver and the
kidney from a severely burned infant treated with silver sulfadiazine and
cerium nitrate. Radioisotopes 32:59-65. (Japanese).
Hodge VF, Folson TR. 1972. Estimate of the world budget of fallout silver
nuclides. Nature 237:98-99.

-------
115
8. REFERENCES
Hoekstra WG. 1975. Biochemical function of selenium and its relation to
vitamin E. Fed Proc 34:2083-2089.
*Hoey MJ. 1966. The effects of metallic salts on the histology and
functioning of the rat testis. J Reprod Fertil 12:461-471.
^Holland MK, White IG. 1980. Heavy metals and spermatozoa. 1. Inhibition
of the motility and metabolism of spermatozoa by metals related to copper.
Fertil Steril 34:483-489.
Holland MK, Suter DAI, White IG. 1976. Possible mechanisms involved in the
reduction in motility of human spermatozoa by copper zinc and silver. J
Reprod Fertil 46:507-508.
Housley M, Heckingbottom R, Todd CJ. 1977. The interaction of Ag with
Si(III). Surface Science 68:179-188.
*Howlett C, Taylor A. 1978. Measurement of silver in blood by
atomic-absorption spectrophotometry using the micro-cup technique. Analyst
103:916-920.
*HSDB. 1988. Hazardous Substances Databank. National Library of Medicine,
National Toxicology Information Program, Bethesda, MD. December 5, 1988.
Hudson E. 1970. A survey of silver recovery. Part I. The mechanics of
silver recovery. Radiography 36:263-269.
Huff B, ed. 1988. Physicians desk reference. 42nd ed. Oradell, NJ:
Medical Economics Co., 122, 409, 416, 961.
Huggins HA. 1983. Mercury--a factor in mental disease? Part 1. Can
mercury-silver amalgams cause psychiatric symptoms. Oral Health 73:42-45.
*Hung S-C, Qu C-L, Wu S-S. 1982. Spectrophotometry determination of silver
with 2-(3,5-dibromo-2-pyridylazo)-5-diethylaminophenol in the presence of
anionic surfactant. Talanta 29:85-88.
Hunt JS, McGiven AR, Day WA. 1976. Immune complex glomerular disease in
argyric mice. Pathology 8:205-210.
Hunter D. 1983. Silver and compounds. In: Parmeggiani L, ed.
Encyclopaedia of occupational health and safety. Vol. 2, 3rd ed. Geneva:
International Labour Office, 2047-2048.
Iridraprasit S, Alexander GV, Gonick HC. 1974. Tissue composition of major
and trace elements in uremia and hypertension. J Chronic Dis 27:135-161.

-------
116
8. REFERENCES
Ireland MP. 1988. A comparative study of the uptake and distribution of
silver in a slug, Arion water and a snail, Achatina fulica. Comp Biochem
Physiol 90C:189-194.
*1RIS. 1989. Integrated Risk Information System. US Environmental
Protection Agency, Cincinnati, OH.
^Iyengar GV, Tanner JT, Wolf WR, et al. 198 /. Preparation of a mixed human
diet material for the determination of nutrient elements, selected toxic
elements and organic nutrients: A preliminary report. Sci Total Environ
235-252.
Jensen LS. 1975. Modification of a selenium toxicity in chicks by dietary
silver and copper. J Nutr 105:769-775.
Jensen LS, Peterson RP, Falen L. 1974. Inducement of enlarged hearts and
muscular dystrophy in turkey poults with dietary silver. Poultry Science
53:57-64.
John W, Kaifer R, Rahn K, et al. 1973. Trace element concentrations in
aerosols from the San Francisco Bay area. Atmospheric Environment 7-107-118
*Johnson CA. 1976. The determination of some toxic metals in human liver
a guide to normal levels in New Zealand. Part I. Determination of Bi Cd
Cr, Co, Cu, Pb, Mn, Ni, Ag, Ti and Zn. Analytica Chemica Acta 81:69-74.
Johnson JS, Kilburn KH. 1983. Cadmium induced metal fume fever: Results of
inhalation challenge. Am J Ind Med 4:533-540.
*Jones AM, Bailey JA. 1974. Effect of silver from cloud seeding on cecal
flora of rabbits. Water Air Soil Pollut 3:353-363.
Jones CJ, McGugan PJ, Lawrence PF. 1978. An investigation of the degradatio
of some dry cell batteries under domestic waste landfill conditions. Journ 1**
of Hazardous Material 2:259-290.	a
Just J, Szniolis A. 1938. Germicidal properties of silver in water. Jour
American Water Works Association 28:492-506.	n
*Kaczmar SW, D'ltri FM, Zabik MJ. 1984. Volatilization rates of selected
haloforms from aqueous environments. Environmental Toxicology and Chemist
3:31-35.	ry
Kalistratova VS, Kogan AG, Kozlova MD. 1966. [Behavior of lllAg in animal 1
In: Moskalev I, ed. Raspredel Biol Deistria Radioacktiv Izotop, Sb Statei
Moscow, Russia: Atomizdat, 146-151. (Russian).

-------
117
8. REFERENCES
Kallus T, Hensten-Pettersen A, Mjor 1 A. 1983. Tissue response to allergenic
leachables from dental material. J Biomed Mater Res 17:741-755
*Kanematsu N, Hara M, Kada T. 1.980. Rec assay and mutagenicity studies on
metal compounds. Mutation Research 77:109-116.
Kargov SI, Korolev NI, Stanislavskii OB, et al. 1986. [Interaction of
immobilized DNA with silver ions], Mol Biol (Mosk) 20:1499-1505. (Russian).
Kehoe JC. 1984. Intracanal corrosion of a silver cone producing a localized
argyria. Scanning electron microscope and energy dispersive x-ray analyzer
analyses. Journal of Endodontics 10:199-201.
*Kehoe RA, Cholak J, Story RV. 1940. A spectrochemical study of the normal
ranges of concentrations of certain trace metals in biological materials J
Nutr 19:579-592.	6 materials. j
Kempton S, Sterritt RM, Lester JN. 1987. Heavy metal removal in primary
sedimentation. I. The influence of metal solubility. Sci Total Environ
63:231-247.
Kempton S, Sterritt RM, Lester JN. 198 7. Heavy metal removal in primary
sedimentation II. The influence of metal speciation and particle size
distribution. Sci Total Environ 63:247-258.
Kent NL, McCance RA. 1941. The absorption and excretion of 'minor' elements
by man. I. Silver, gold, lithium, boron and vanadium. Biochemical Journal
35:837-844.
Kesseru E, Leon F. 1974. Effect of different solid metals and metallic pairs
on human sperm motility. Int J Fertil 19:81-84.
Kesseru E, Hurtado H, Muhe B. 1974. Copper IUD: Enhancement of its efficacy
by the addition of silver and nickel. Contraception 9:141-151.
Kettner VW, Vogel K, Kruger G. 1970. Contribution to the clinical picture of
argyrosis. Deut Gesundheitsw 25:1746-1747.
Kharchenko PD, Stepanenko PZ. 1972. [Peculiarities of disturbances of albino
rat higher nervous activity during the action of silver electrolytic
solutions], Fiziol Zh (Kiev) 18:596-600. (Ukranian).
Kharchenko PD, Berdyshev GD, Stepanenko PZ, et al. 1973. [Change in the
nucleic acid level in rat brain and liver during long-term introduction of
silver ions in drinking water]. Fiziol Zh (Kiev) 19:362-368. (Ukranian).

-------
118
8. REFERENCES
™ i • ~ vv nort-inp KK 1968. Stream supply of dissolved
*Kharkar DP, ure ia fcimony seienium, chromium, cobalt, rubidium and cesium
silver, molybdenum, ant y,	o«s OQH
to the oceans. Geochimica et Cosmochiraxca Acta 32.28,-298.
Kin, JS 1966. A comparative investigation of neuroglia in representative
vertebrates: A silver carbonate study. J Horphol 119.435-465.
Klaassen CD. 1978. Effect of metallothionein on hepatic disposition of
metals. Am J Physiol 234:E47-E53.
™ iQiQa Effect of spironolactone on the biliary excretion and
distribution'of metals. Toxicol Appl Pharmacol 50:41-48.
¦'"Klaassen CD. 1979b. Biliary excretion of silver in the rat, rabbit and dog.
Toxicol Appl Pharmacol 50:49-56.
*Klein DH. 1972. Mercury and other metals in urban soils. Environmental
Science and Technology 6:560-562.
hp 1973 Heavy metals: Fallout around a power plant.
Klein DH Ru.s scll-P* J- *	-?. q 7 ^ s 8
Environmental Science and Technology 7.357-356.
u ¦ t- M 1983 Trace element and radionuclide mass
a"o"-med"Uric generating station. Environ l„t 9:139-144.
KoberCM.	^ ^
SuShil?' "%.TaSto„.s Son and Co ., 580-585 .
1 1986 [Experimental studies of the effect of
Kojo T, Kaneko T, Ito A, e • einRival tissue. 2nd report. Extensive
metal cores (silver a loy)	j Jpt) Prosthoclort Soc
investigation of gin6
30:1278-1286. (Japanese).
m r-iil l A-ns SR 1988. Silver ion (Ag+) - induced increases in
Kone BC, Kaleta	sodium permeability in the renal proximal tubule:
^Bio1102;11-15-
r Tvovama T et al. 1982. Industrial hygienic approach to
Konga M, Nakamura , y ^ n[c sliver. Proceedings of the tenth Asian
inference5occupational health, 2:584-587. September 5-10, Singapore.
1Q6R The ultrastructure of the tracheal epithelium in rabbits
*Konradova	. f aerosols of colloidal solutions of heavy metals. II.
following lnhalatron^of^aeroSh^ ^ g h(mr inhalaUon of
colloidal solutions of iron and silver. Folia Horphol (Praha) 16:265-271.

-------
119
8. REFERENCES
Konradova V. 1968. The ultrastructure of the tracheal epithelium in rabbits
following the inhalation of aerosols of colloidal solutions of heavy metals.
1. Changes in the ultrastructure of the tracheal epithelium after 2-hour
inhalation of colloidal solutions of iron and silver. Folia Morphol (Praha)
16:258-264.
*Kopp JF. 1969. The occurrence of trace elements in water. Proc Univ MO
Annu Conf Trace Subst Environ Health. 3:59-73.
Kopp JF, Kroner RC. 1967. Tracing water pollution with an emission
spectrograph. J Water Pollut Cont Fed 39:1659-1668.
Kosarek LJ. 1981. Removal of various toxic heavy metals and cyanide from
water by membrane processes. In: Cooper WJ, ed. Chemistry in water reuse.
Vol. 1, Ann Arbor, MI: Ann Arbor Science Publishers, Inc., 261-280.
Krebs A. 1983. [Drug induced nail disorders], Deutsch Apotheker Zeitung
123:557-561. (German).
Kroner RC, Kopp JF. 1965. Trace elements in six water systems of the United
States. Journal American Water Works Association 57:150-156.
Kulskii LA, Kharchenko PD, Stepanenko PZ. 1972. [Dynamics of cortical
activity changes in albino rats after chronic silver intoxication]. Dopov
Akad Nauk Ukr RSR Ser B 34:660-662. (Ukranian).
*Landas S, Fischer J, Wilkin LD, et al. 1985. Demonstration of regional
blood-brain barrier permeability in human brain. Neurosci Lett 57:251-256.
Larsen PF, Zdanowicz V, Johnson AC. 1983. Trace metal distribution in the
surficial sediments of Penobscat Bay, Maine. Bull Environ Contam Toxicol
31:566-573.
La Torraca F. 1962. [Anatomic, histopathological, and histochemical aspects
of acute experimental intoxication with silver salts]. Folia Medica
45:1065-1069. (Italian).
*Law SL, Gordon GE. 1979. Sources of metals in municipal incinerator
emissions. Environmental Science and Technology 13:432-438.
Lee RE Jr, Von Lehmden DJ. 1973. Trace metal pollution in the environment.
Journal of the Air Pollution Control Association 23:853-857.
Leirskar J. 1974. On the mechanism of cytotoxicity of silver and copper
amalgams in a cell culture system. Scand J Dent Res 82:74-81.

-------
12.0
8. REFERENCES
Leirskar J, Heigeland K. 1972. A methodologic study of the effect of dental
materials on growth and adhesion of animal cells in-vitro. Scand J Dent Res
80:120-133.
Leirskar J, Heigeland K. 1981. Mechanism of toxicity of dental materials
International Endodontic Journal 14:42.-48.
Lemez L. 1980. Sites for experimental production of tracheal and/or
oesophageal malformations in 4-day-old chick embryos. Folia Morphol (Praha)
28:52-55.
Leroux-Robert C, Benevent J, Benevent D, et al. 1982. [Renal argyria
discovered in nephrotic syndrome], Nephrologie 3:101. (French).
Lester JN. 1983. Significance and behavior of heavy metals in waste water
treatment processes 1. Sewage treatment and effluent discharge. Sci Total
Environ 30:1-44.
^Lester JN, Sterritt RM, Kirk PWW. 1983. Significance and behavior of heavy
metals in waste water treatment processes II. Sludge treatment and disposal
Sci Total Environ 30:45-83.
*Letkiewicz F, Spooner C, Macaluso C, et al. 1984. Occurrence of silver in
drinking water, food, and air. Report to US Environmental Protection Agency,
Office of Drinking Water, Criteria and Standards Division, Washington, DC, by
JRB Associates, McLean, VA.
Lindh U, Brune D, Nordberg G, et al. 1980. Levels of antimony, arsenic,
cadmium, copper, lead, mercury, selenium, silver, tin and zinc in bone tissue
of industrially exposed workers. Sci Total Environ 16:109-116.
*Lindsay WL, Sadiq M. 1979. Theoretical solubility relationships of silver
in soils. In: Klein DA, ed. Environmental impacts of artificial ice
nucleating agents. Dowden, Hutchinson, and Ross, Inc.
Lockhart SP, Rushworth A, Azmy AAF, et al. 1983. Topical silver
sulphadiazine: Side effects and urinary excretion. Burns 10:9-12.
*Loeb LA, Sirover MA, Weymouth LA, et al. 1977. Infidelity of DNA synthesis
as related to mutagenesis and carcinogenesis. J Toxicol Environ Health
2:1297-1304.
*Loeffler KU, Lee WR. 1987. Argyrosis of the lacrimal sac. Graefe's Arch
Clin Exp Ophthalmol 225:146-150.

-------
121
8. REFERENCES
Luis AS, Duarte CS. 1960. Experimental study on the pathogenesis of acute
pulmonary edema. I. Pulmonary edema induced by silver nitrate [Abstract], Mai
Cardiovasc 56:39-49.
*Luk KFS, Maki AH, Hoover RJ. 1975. Studies of heavy metal binding with
polynucleotides using optical detection. J Am Chem Soc 97:1241-1242.
Lukanov J, Atmadjov P. 1979. Investigating the effect of silver ions on the
contractile function of smooth-muscle preparations from guinea pig stomach, in
vitro. Folia Med (Plovdiv) 21:11-19.
Luoma SN, Jenne EA. 1977. The availability of sediment-bound cobalt, silver
and zinc to a deposit - feeding clam. In: Drucker H, Wilding RE, eds.
Biological implications of metals in the environment. Springfield, VA:
National Technical Information Service.
Lyons WMB, Fitzgerald WMF. 1980. Trace metal fluxes to nearshore Long Island
Sound sediments. Mar Pollut Bull 11:157-161.
Lytle PE. 1984. Fate and speciation of silver in publicly owned treatment
works. Environmental Toxicology and Chemistry 3:21-30.
Maclntyre EH, McClatchy JK, Rudolph H, et al. 1973. Identification of silver
in a periapical lesion of a tooth. Am J Clin Pathol 60:613-615.
*MacIntyre D, McLay ALC, East BW, et al. 1978. Silver poisoning associated
with an antismoking lozenge. Br Med J 2:1749-1750.
Mackison FW, Stricoff RS, Partridge LJ Jr. 1980. Pocket guidelines to
chemical hazards. Washington, DC: US Government Printing Office, 1661.
Magos L, Webb M. 1978. Theoretical and practical considerations on the
problem of metal-metal interaction. Environ Health Perspect 25:151-154.
*Malcolm R, Currey HS, Mitchell MA, et al. 1986. Silver acetate gum as a
deterrent to smoking. Chest 90:107-111.
Malins DC, McCain BB, Brown DW, et al. Chemical pollutants in sediments and
diseases of bottom-dwelling fish in Puget Sound, Washington. Environmental
Science and Technology 18:705-713.
Mangal PC, Verma KB. 1979. Effect of induced skin cancer on the
concentration of some trace elements. Indian J Med Res 69:290-295.
Marie J, Leveque B, Watchi JM, et al. 1966. [Argyria in a child following
pharyngeal spracy of silver salts repeated for 6 years]. Ann Pediatr
13:2657-2659. (French).

-------
1'). 2
8. REFERENCES
Marino AA, Berger TJ , Becker RO, et. al. 1974. The effect of selected metals
on marrow cells In culture. Chem Biol Interact 9:21 7-223.
*Marks R. 1966. Contact dermatitis due to silver. Br J Dermatol 78:606-607.
^Marshall JP II, Schneider RP. 1977. Systemic argyria: Secondary to topical
silver nitrate. Arch Dermatol 113:1077-1079.
Martin M, Castle W. 1984. Petrowatch: Petroleum hydrocarbons, synthetic
organic compounds and heavy metals in mussels from the Monterey Bay area of
cenLral California. Marine Pollution Bulletin 15:259-266.
Masiak M, Owczarek H, Skowron S, et al. 1982. Serum levels of certain trace
elements (Ag, Co, Cr) in healthy subjects (part; II). Acta Physiol Pol
33:65-73.
Maslenko AA. 1976. [Effects of "silver water" and drinking water treated
with silver on the digestive organs]. Vrach Delo, Issue 5, 88-90. (Russian).
*Massa V. 1969. [Analysis of silver, in the presence of other metals, by
means of dithizonate chromatography and photodensitometry, Drug control
applications], Trav Soc Pharm Montpellier 29:221-224. (French),
Matuk Y. 1983. Distributi.on of radioactive, silver in the subcellular
fractions of various tissues of the rat and its binding to low molecular
weight proteins. Can J Physiol Pharmacol 61:1391-1395.
*Matuk Y, Ghosh M, McCulloch C. 1981. Distribution of silver in the eyes and
plasma proteins of the albino rat. Can J Ophthalmol 16:145-150.
*Mauss Y, Poulet P, Steibel J, et al. 1980. Interaction of proflavine-calf
thymus DNA complexes with Ag+ and Hg++ ions. Studia Biophysica 81:95-96.
McCabe LJ, Symons JM, Lee RD, et al. 1970. A survey of community water
supply systems. Journal of the American Water Works Association 62:670-687.
*McCoy EC, Rosenkranz HS. 1978. Silver sulfadiazine: Lack of mutagenic
activity. Chemotherapy (Basel) 24:87-91.
McDermot DJ, Alexander GV, Young DR, et al. 1976. Metal contamination of
flatfish around a large submarine outfall. Journal of the Water Pollution
Control Federation 48:1913-1918.
McDowell LR, Forseth JA, Piper RC. 1978. Influence of arsenic, sulfur,
cadmium, tellurium, silver and selenium on the selenium-vitamin E deficiency
in the pig. Nutrition Reports International 17:19-34.

-------
1 ? 3
8. REFERENCES
McGirmls JP Jr, Greer JL, Daniels DS. 1985. Amalgam tattoo: Report of an
unusual clinical, presentation and the use of energy dispersive x-ray analysis
as an aid to diagnosis. J Am Dent Assoc 110:52-54.
McLaughlin AIG, Grout JLA, Barrie HJ, et al. 1945. Iron oxide dust and the
lungs of silver finishers. Lancet, March 17, 337-341.
*McMahon JT, Bergfeld WF. 1983. Metallic cutaneous contaminant mimicking
malignant melanoma. Cleveland Clinic Quarterly 50:177-181.
Mehregan AH, Faghri B. 1974. Implantation dermatoses. Acta Dermatovener
(Stockholm) 54:61 -64.
"Mehta AC, Dawson-Butterworth K, Woodhouse MA. 1966. Argyria. Electron
microscopic study of a case. Br J Dermatol 78:175-179.
Mertz DP, Koschnic.k R, Wilk G, et al. 1968. [Studies on the metabolism of
trace elements in humans. I. Serum values for cobalt, nickel, silver, cadmium,
chromium, molybdenum, manganese], Z Klin Chem Klin Biochem 6:1/1-174.
(German).
Mertz DP, Wilk G, Koschnick R. 1975. [Conditions affecting renal excretion
of silver by humans. Studies on metabolism of trace elements. VIII]. Z Klin
Chem Klin Biochem 13:13-15. (German).
Minoia C, Oppezzo MC, Pozzoli L, et al. 1985. [Environmental and biological
monitoring of subjects occupationally exposed], G Ital Med Lav 7:65-73.
(Ital3 an).
*Mitteldorf AJ, Landon DO. 1952. Spectrochemical determination of the
mineral-element content of beef. Analytical Chemistry 24:469-472.
*Moffat DB, Creasey M. 1972. The distribution of ingested silver in the
kidney of the rat and of the rabbit. Acta Anat 83:346-355.
Mogilnicka EM, Piotrowski JK, Tomaszewski A. 1976. Effect of some metals
(Rb, Cs, Ag, Ti, Sb, U) on metallothionein level in the liver and kidney of
the rat. Bromat Chem Toksykol 9:357-359. (Polish)
Mogilnicka EM, Milaszewicz M, Piotrowsk JK. 1978. [Binding of silver in the
liver of the rat], Bromat Chem Toksykol 11:59-65. (Polish).
Moller B. 1979. Reactions of human dental pulp to silver amalgam
restorations. A study with emphasis on source material characteristics.
Swedish Dent [Suppl] 2:1-37.

-------
124
8. REFERENCES
Moore JW, Sutherland DJ. 1981. Distribution of heavy metals and
radionuclides in sediments, water, and fish in an area of Great Bear Lake
contaminated with mine wastes. Arch Environ Contam Toxicol 10:329-338.
Morgan WKC. 1984. Other pneumoconioses. In: Morgan WKC, Seaton A, eds.
Occupational lung disease. 2nd ed. Philadelphia, PA: W.B. Saunder Company,
449-497.
*Moss AP, Sugar A, Hargett NA, et al. 1979. The ocular manifestations and
functional effects of occupational argyrosis. Arch Ophthalmol 97:906-908.
Muroma A. 1961. Skin reactions produced by certain metallic salts. Annales
Medicine Experimentalis et Biologiae Fenniae 39:277-279.
*Murthy GK, Rhea U. 1968. Cadmium and silver content of market milk.
J Dairy Science 51:610-613.
*Nadkarni RA, Ehmann WD, Burdick D. 1970. Investigations on the relative
transference of trace elements from tobacco into smoke condensate. Tobacco
170:25-27.
Naganuma A, Tanaka T, Maeda K, et al. 1983. The interaction of selenium with
various metals in vitro and in vivo. Toxicology 29:77-86.
Nakamuro K, Sayato Y. 1986. Studies on the toxicity of silver ion in water
filtered through a household water purifier equipped with a silver-coated
charcoal filter. Eisei Kagaku 32:28-33.
*Nakashima R, Sasaki S, Shibata S. 1975. Determination of silver in
biological materials by high-frequency plasma-torch emission spectrometry.
Analytica Chimica Acta 77:65-70.
*NAS/NRC. 1989. Biological markers in reproductive toxicology. National
Research Council. Board of Environmental Studies and Toxicology. Committee
on Biological Markers. 15-35.
Nathanson JA, Bloom FE. 1976. Heavy metals and adenosine cyclic
3',5'-monophosphate metabolism: Possible relevance to heavy metal toxicity.
Mol Pharmacol 12:390-398.
Nechay BR, Saunders JP. 1984. Inhibition of adenosine triphosphates in vitro
by silver nitrate and silver sulfadiazine. Journal of the American College of
Toxicology 3:37-42.
Nehring RB. 1976. Aquatic insects as biological monitors of heavy metal
pollution. Bull Environ Contam Toxicol 15:147-154.

-------
125
8. REFERENCES
Neri LC, Hewitt D, Schreiber GB, et al. 1975. Health aspects of hard and
soft waters. Journal American Water Works Association 67:403-409.
*Newton D, Holmes A. 1966. A case of accidental inhalation of zinc-65 and
silver-llOm. Radiat Res 29:403-412.
Nilner K, Glantz P-0. 1982. The prevalence of copper-, silver-, tin-, and
zinc-ions in human saliva. Swed Dent J 6:71-77.
*NI0SH. 1976. National Occupational Hazard Survey (1970) Database. US
Department of Health and Human Services, National Institute for Occupational
Safety and Health, Cincinnati, OH
*NIOSH. 1984a. National Occupational Exposure Survey (1980-1983) Database.
US Department of Health and Human Services, National Institute for
Occupational Safety and Health, Cincinnati, OH.
*NI0SH. 1984b. NIOSH, manual of analytical methods. Washington, DC: US
Government Printing Office., 73001-73005.
*NIOSH. 1985. Pocket guide to chemical hazards. Washington, DC: US
Department of Health and Human Services. DHEW (NIOSH) Publication No 78-210.
Nishimura M. 1978. [A study on the cytotoxicity of Au-Pd-Ag alloys
containing Cd (in vitro)]. Shika Rikogaku Zasshi 19:1-7. (Japanese).
*Nishioka H. 1975. Mutagenic activities of metal compounds in bacteria.
Mutat Res 31:185-189.
Nordberg GF, Gerhardsson L. 1988. Silver. In: Seiler HG, Sigel H, eds.
Handbook on toxicity of inorganic compounds. New York, NY: Marcel Dekker,
Inc., 619-624.
Norden B, Matsuoka Y, Kurucsev T. 1986. Nucleic acid-metal interactions: V.
The effect of silver(I) on the structures of A- and B-DNA forms. Biopolymers
25:1531-1545.
Nriagu JR. 1979. Global inventory of natural and anthropogenic emissions of
trace metals to the atmosphere. Nature 279:409-411.
*NRC. 1977. Silver. In: Drinking water and health. Vol. 2. Washington,
DC: National Academy of Sciences, National Research Council, 102-106.
*Nuttall KL. 1987. A model for metal selenide formation under biological
conditions. Med Hypotheses 24:217-221.

-------
126
8. REFERENCES
Oh SH, Whanger PD, Deagen JT. 1981. Tissue metallothionein: Dietary
interaction of cadmium and zinc with copper, mercury, and silver. J Toxicol
Environ Health 7:547-560.
OHM, TADS. 1988. Oil and Hazardous Materials Technical Assistance Data
System. Chemical Information System (CIS). December 5, 1988.
*0kazaki RK, Panietz MH. 1981. Depuration of twelve trace metals in tissues
of the oysters Crassostrea gigas and Crassostrea virginica. Marine Bioloev
63:113-120.
*01cott CT. 1947. Experimental argyrosis. III. Pigmentation of the eyes of
rats following ingestion of silver during long periods of time. Am J Pathol
23:783-789.
*01cott CT. 1948. Experimental argyrosis. IV. Morphologic changes in the
experimental animal. Am J Path 24:813-833.
*01cott CT. 1950. Experimental argyrosis. V. Hypertrophy of the left
ventricle of the heart. Archives of Pathology 49:138-149.
Olson BH, Guinn VP. 1978. Accumulations of trace elements in soil and plants
from land disposal of secondary domestic wastewater. In: Land treatment of
wastewater international symposium, Hanover, NH. 2:289-299
Oppenheimer BS, Oppenheimer ET, Danishefsky I, et al. 1956. Carcinogenic
effect of metals in rodents. Cancer Res 16:439-441.
Orentreich N, Pearlstein HH. 1969. Traumatic tattoo due to silver salt
Arch Dermatol 100:107-108.
Orstavik D, Hongslo JK. 1985. Mutagenicity of endodontic sealers.
Biomaterials 6:129-132.
Osborn JF, Santhanam S, Davidson CI, et al. 1984. Characterization of
airborne trace metal and trace organic species from coal gasification.
Environmental Monitoring and Assessment 4:317-333.
*OSHA. 1988a. US Department of Labor, Occupational Safety and Health
Administration. Code of Federal Regulations. 29 CFR 1910.20
*0SHA. 1988b. US Department of Labor, Occupational Safety and Health
Administration. Code of Federal Regulations. 29 CFR 1910.1000
Owens CJ, Yarbrough DR III, Brackett NC. 1974. Nephrotic syndrome following
topically applied sulfadiazine silver therapy. Arch Intern Med 134:332-335

-------
127
8. REFERENCES
Page AL. 1974. Fate and effects of trace elements in sewage sludge when
applied to agricultural lands. A literature review study. Ultimate Disposal
Research Program. Cincinnati, OH: US Environmental Protection Agency, Office
of Research and Development. NTIS PB-231 171.
Palmer GR, Weine FS, Palmer MJ, et al. 1979. A study of the tissue reaction
to silver cones and Ti-6Al-4V in the rhesus monkey. Journal of Endodontics
5:116-120.
*Pariser RJ. 1978. Generalized argyria: Clinicopathologic features and
histochemical studies. Arch Dermatol 114:373-377.
Parkki MG. 1981. Inhibition of rat hepatic microsomal epoxide hydrase by
heavy- and organometals in vitro. Adv Exp Med Biol 136:729-738. Part A.
Perry KMA. 1947. Diseases of the lung resulting from occupational dusts
other than silica. Thorax 2:91-120.
*Pesch G, Reynolds B, Rogerson P. 1977. Trace metals in scallops from within
and around two ocean disposal sites. Marine Pollution Bulletin 8:224-228.
Petering HG. 1976. Pharmacology and toxicology of heavy metals: Silver.
Pharmacol Ther 1:127-130. Part A.
Peterson RP, Jensen LS, Harrison PC. 1973. Effect of silver-induced enlarged
hearts during the first four weeks of life on subsequent performance of
turkeys. Avian Diseases 17:802-806.
Pezzarossa E, Alinovi A, Ferrari C. 1983. Generalized argyria. J Cutan
Pathol 10:361-363.
Pfitzer EA. 1975. Toxicology. In: Cralley LV, Atkins PR, eds. Industrial
environmental health. The worker and the community. New York, NY: Academic
Press, 67-128.
*Phalen RF, Morrow PE. 1973. Experimental inhalation of metallic silver.
Health Phys 24:509-518.
*Pickston L, Lewin JF, Drysdale JM, et al. 1983. Determination of
potentially toxic metals in human livers in New Zealand. J Anal Toxicol
7:2-6.
*Pierce FD, Gortatowski MJ, Mecham HD, et al. 1975. Improved automated
extraction method for atomic adsorption spectrometry. Analytical Chemistry
47:1132-1135.

-------
128
8. REFERENCES
*Pifer JW, Friedlander BR, Kintz RT, et al. 1989. Absence of toxic effects
in silver reclamation workers. Scand J Work Environ Health 15:210-221.
Pokorny J. 1983. [A model of interaction of metal ions with the phosphate
group], Biologia (Bratisl) 38:289-292. (German).
Polachek AA, Cope CB, Williard RF, et al. 1960. Metabolism of radioactive
silver in a patient with carcinoid. J Lab Clin Med 56:499-505.
Pratt JR, McCormick PV, Pontasch KW, et al. 1988. Evaluating soluble
toxicants in contaminated soils. Water Air Soil Pollut 37:293-307.
Prose PH. 1963. An electron microscopic study of human generalized argyria.
Am J Pathol 42:293-299
Quijada S, Soza X, Croxatto HB. 1978. Fertility inhibition by intraoviductal
copper beads in rabbits. Contraception 17:553-562.
*Ragaini RC, Ralston HR, Roberts N. 1977. Environmental trace metal
contamination in Kellogg, Idaho, near a lead smelting complex. Environ Sci
Techno1 11:773-781.
*Rains TC, Watters RL Jr, Epstein MS. 1984. Application of atomic absorption
and plasma emission spectrometry for environmental analysis. Environment
International 10:163-168.
Ramelow GJ, Maples RS, Thompson RL, et al. 1987. Periphyton as monitors for
heavy metal pollution in the Calcasieu River estuary. Environ Poll
43:247-263.
Raskin RB. 1984. Toxicity of silver amalgam: Fact or fiction. NY State
Dent J 50:582, 585, 587.
*Rattonetti A. 1974. Determination of soluble cadmium, lead, silver, and
indium in rainwater and stream water with the use of flameless atomic
absorption. Anal Chem 46:739.
Rauber A, Bruner B. 1987. Ingestion of concentrated silver nitrate: A
report of two cases. Vet Hum Toxicol 29:321-322.
*Rawlings GD, Samfield M. 1979. Textile plant wastewater toxicity.
Environmental Science and Technology 13:160-164.
*Reese RG Jr. 1986. The minerals year book. Vol. 1, Washington, DC: US
Department of the Interior, Bureau of Mines, 837-856.

-------
129
8. REFERENCES
Reichenbach DD. 1985. Cardiovascular system. In: Mottet NK, ed.
Environmental pathology. New York, NY: Oxford University Press, 356-367.
Reuss M. 1983. Comparison of different methods for estimating the leaching
of heavy metals from coal combustion wastes. Nat Sci Tech 15:193-205.
Reymond J-L, Stoebner P, Amblard P. 1980. [Cutaneous argyria: An electron
microscopic study of four cases with microanalysis X study of one case]. Ann
Dermatol Venereol 107:251-255. (French).
Ribadeau Dumas JL, Larmande P, flourin M, et al. 1978. [Is there such a thing
as encephalopathy related to organic compounds of silver], Nouv Presse Med
7:1956. (French).
Ribarov SR, Benov LC. 1981. Relationship between the hemolytic action of
heavy metals and lipid peroxidation. Bioch Biophys Acta
640:721-726.
Ribarov S, Benov L. 1985. Glutathione reductase and glucose-6-phosphate
dehydrogenase in erythrocytes treated with heavy metals. Acta Physiol
Pharmacol Bulg 11:51-54.
Ribarov S, Benov L, Benchev I. 1986. The mechanism of AgN03 induced lipid
peroxidation in erythrocytes. Biomed Biochim Acta 45:321-330.
Ridlington JW, Whanger PD. 1981. Interactions of selenium and antioxidants
with mercury, cadmium and silver. Fundam Appl Toxicol 1:368-375.
Rimerman RA, Buhler DR, Whanger PD. 1977. Metabolic interactions of selenium
with heavy metals. In: Lee SD, ed. Biochemical effects of environmental
pollutants. Ann Arbor, MI: Ann Arbor Science Publishers, Inc., 377-396.
*Robison SH, Cantoni 0, Costa M. 1982. Strand breakage and decreased
molecular weight of DNA induced by specific metal compounds. Carcinogenesis
(Lond) 3:657-662.
*Robkin MA, Swanson DR, Shepard TH. 1973. Trace metal concentrations in
human fetal livers. Trans Am Nucl Soc 17:97.
Roe FJC, Lancaster MC. 1964. Natural, metallic and other substances, as
carcinogens. Brit Med Bull 20:127-133.
Roediger WEW. 1973. The nature of silver binding in the canine thyroid "C"
cell. S Afr J Med Sci 38:17-22.

-------
130
8. REFERENCES
Roesijadi G, Young JS, Drum AS, et al. 1984. Behavior of trace metals in
Mytilus edulis during a reciprocal transplant field experiment. Mar Ecol Prog
Ser 18:155-170.
*Rosenman KD, Moss A, Kon S. 1979. Argyria: Clinical implications of
exposure to silver nitrate and silver oxide. J Occup Med 21:430-435.
*Rosenman KD, Seixas N, Jacobs I. 1987. Potential nephrotoxic effects of
exposure to silver. Br J Ind Med 44:267-272.
Roshchin AV, Ordzhonikidze EK. 1986. [Metal toxicokinetics and its
significance for the prevention of occupational poisoning]. Gig Tr Prof
Zabol, Issue 3, 1-6. (Russian).
*Rossman TG, Molina M. 1986. The genetic toxicology of metal compounds: II.
Enhancement of ultraviolet light-induced mutagenesis in Escherichia coli WP2.
Environ Mutagen 8:263-271.
Roy DR, Bailey JA. 1974. Effect of silver from cloud seeding on rumen
microbial function. Water Air Soil Pollut 3:343-351.
*RTECS. 1988. Registry of Toxic Effects of Chemical Substances. National
Library of Medicine, National Toxicology Information Program, Bethesda, MD.
December 5, 1988.
*Rungby J. 1986. Experimental argyrosis: Ultrastructural localization of
silver in rat eye. Exp Mol Pathol 45:22-30.
Rungby J. 1986. Exogenous silver in dorsal root ganglia, peripheral nerve,
enteric ganglia, and adrenal medulla. Acta Neuropathol (Berl) 69:45-53.
Rungby J. 1986. The silver nitrate prophylaxis of crede causes silver
deposition in the cornea of experimental animals. Exp Eye Res 42:93-94.
*Rungby J. 1987. Silver-induced lipid peroxidation in mice: Interactions
with selenium and nickel. Toxicology 45:135-142.
*Rungby J, Danscher G. 1983a. Neuronal accumulation of silver in brains of
progeny from argyric rats. Acta Neuropathol (Berl) 61:258-262.
*Rungby J, Danscher G. 1983b. Localization of exogenous silver in brain and
spinal cord of silver exposed rats. Acta Neuropathol (Berl) 60:92-98.
*Rungby J, Danscher G. 1984. Hypoactivity in silver exposed mice. Acta
Pharmacol Toxicol 55:398-401.

-------
131
8. REFERENCES
*Rungby J, Slomianka L, Danscher G, et al. 1987. A quantitative evaluation
of the neurotoxic effect of silver on the volumes of the components of the
developing rat hippocampus. Toxicology 43:261-268.
Rungby J, Ellermann-Eriksen S, Danscher G. 1987. Effects of selenium on
toxicity and ultrastructural localization of silver. Arch Toxicol 61:40-45.
Rungby J, Hultman P, Ellermann-Eriksen S. 1987. Silver affects viability and
structure of cultured mouse peritoneal macrophages and peroxidative capacity
of whole mouse liver. Arch Toxicol 59:408-412.
Ryan DE, Holzbecher J, Stuart DC. 1978. Trace elements in scalp-hair of
persons with multiple sclerosis and of normal individuals. Clin Chem
24:1996-2000.
Saffiotti U, Shubik P. 1963. Studies on promoting action in skin
carcinogenesis. National Cancer Institute Monograph 10:489-506.
Sakai K, Umeda T, Yamane Y. 1985. In vitro DNA methylation by
methylnitrosourea in isolated copper- or silver-preloaded rat liver nuclei.
Biochemical Pharmacology 34:4071-4073.
*Sano S, Fujimori R, Takashima M, et al. 1982. Absorption, excretion and
tissue distribution of silver sulphadiazine. Burns 8:278-285.
Saxena J, Howard PH. 1977. Environmental transformation of alkylated and
inorganic forms of certain metals. In: Perlman D, ed. Advances in applied
microbiology. Vol. 21, New York, NY: Academic Press, 185-226.
Schatz H. 1982. Unusual cases. Retina 2:189-90.
Schelenz R. 1977. Dietary intake of 25 elements by man estimated by neutron
activation analysis. J Radioan Chem 37:539-548.
Schmahl D, Steinhoff D. 1960. [Experimental carcinogenesis in rats with
colloidal silver and gold solutions], Z Krebsforsc 63:586-591. (German)
Schopf E, Schulz KH, Isensee I. 1969. [Investigations on lymphocyte
transformation in mercury sensitivity. Non specific transformation due to
mercury compounds]. Arch Klin Exp Derm 234:420-433. (German).
Schultka R, Schmidt R, Drosner H-P. 1971. [Histochemical localization of
heavy metal in the kidneys of white rats during embryonal and postnatal
development]. Acta Histochem (Jena) 40:123-130. (German).
Schulze A, Bingas B. 1968. {Meningioma development induced by a foreign
body], Beitr Neurochir 15:297-301. (German).

-------
132
8. REFERENCES
*Sc icchitano DA, Pegg AE. 1987. Inhibition of 06-alkylguanine-DNA-
alkyltransferase by metals. Mutat Res 192:207-210.
Scott WL Jr. 1967. Silver uptake in brains of chronically gamma-irradiated
rats: A study by neutron activation analysis. Radiat Res 31:522-528.
*Scott KG, Hamilton JG. 1950. The metabolism of silver in the rat with
radio-silver used as an indicator. University of California Publications in
Pharmacology 2:241-262.
Scott KG, Hamilton JG. 1948. The metabolism of silver [Abstract], J Clin
Invest: 2 7:555-556.
Scott R, Norman PM. 1980. Silver deposition in arteriolar basal laminae in
the cerebral cortex of argyric rats. Acta Neuropatnol (Berl) 52:243-246.
*Scow K, Goyer M, Nelken L, et al. 1981. Exposure and risk assessment for
silver. Report to US Environmental Protection Agency, Office of Water
Regulations and Standards, Washington, D.C., by Arthur D. Little, Inc.,
Cambridge, MA. PB85-211993.
*Segar DA, Gilio JL. 1973. The determination of trace transition elements in
biological tissues using flameless atom reservoir atomic absorption. Int J
Environ Anal Chem 2:291-301.
Sharma DC, Sharma M, Rathore AS, et al. 1980. Effect of silver, gold, and
mercury colloids on erythrocyte and iron metabolism. Indian J Exp Biol
18:1309-1311.
Shaver SL, Mason KE. 1951. Impaired tolerance to silver in vitamin E
deficient rats. Anat Rec 109:382.
Shaw EB. 1980. Questions the need for prophylaxis with silver nitrate.
Pediatrics 59:792.
*Shelton D, Goulding R. 1979. Silver poisoning associated with an
antismoking lozenge [letter]. Br Med J, January 27; 1(6158):267.
*Shimamoto Y, Shimamoto H. 1987. Systemic argyria secondary to breath
freshener "Jintan Silver Pills". Hiroshima J Med Sci 36:245-247.
*Shouse SS, Whipple GH. 1931. I. Effects of the intravenous injection of
colloidal silver upon the hematopoietic system in dogs. Jour Exp Med
53:413-420.

-------
133
8. REFERENCES
Sieuiiatycki J Gerin M, Hubert J. 1981. Exposure-based case control approach
to discovering occupational carcinogens: Preliminary findings. In: Peto R,
Schneiderman M, eds. Quantification of occupational cancer, Banbury Report
Ko. 9. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 471-481.
Silver Institute, 197 5. Silver guards good health. Silver Inst. Lett.
5(5):1.
Sirover MA, Loeb LA. 1976. Infidelity of DNA synthesis in vitro: Screening
for potential metal mutagens or carcinogens. Science 194:1434-1436.
Sittig M. 1985. Silver and Compounds. Handbook of toxic and hazardous
chemicals and carcinogens. 2nd ed. Park Ridge, NJ: Noyes Data Corporation,
789-790.
Skouby SO, Tabor A. 1978. [Experience with a copper-silver IUD, Cu-T 2200
U]. Ugeskr Laeg 140:1882-1885. (Danish).
Smirnov VG. 1983. [Experimental studies of toxicology of silver and
establishment of maximum permissible levels for its compounds in the air of
worksites]. Gig Tr Prof Zabol, Issue 12, 33-37. (Russian).
Smith DR, Stephenson MD, Flegal AR. 1986. Trace metals in mussels
transplanted to San Francisco Bay. Environmental Toxicology and Chemistry
5:129-138.
*Smith IC, Carson BL. 1977. Trace metals in the environment, Vol. 2. Silver.
Ann Arbor, MI: Ann Arbor Science Publishers, Inc.
Smith TJ, Blough S. 1982. Chromium, manganese, nickel,and other elements.
In: Rom WN, ed. Environmental and occupational medicine. Boston, MA:
Little, Brown and Co., 491-510.
*Snider EH, Manning FS. 1982. A survey of pollutant emission levels in waste
waters and residuals from the petroleum refining industry. Environment
International 7:237-258.
*Snyder WS, et al. 1975. Report of the task group on reference man. Oxford,
England: Pergamon Press, 407-708.
*Soldatenkova NA, Smirnov VG. 1983. [Atomic absorption method of determining
silver in the air]. Gig Tr Prof Zabol, Issue 6, 53-54. (Russian).
Spiegel L. 1931. A discoloration of the skin and mucous membranes resembling
argyria, folio-wing the use of bismuth and silver arsphenamine. Archives of
Dermatology and Syphilology 23:266-286.

-------
L34
8. REFERENCES
Spielman A, Gutman D, Laufer D. 1981. Anesthesia following endodontic
overfilling with AH26. Report of a case. Oral Surg Oral Med Oral Pathol
52:554-556 .
Splittgerber AG, Tappel AL. 1979. Inhibition of glutathione peroxidase by
cadmium and other metal ions. Arch Biochem Eiophys 197:534-542.
Stammberger H. 1982. [Argyrosis of the nasal mucosa], Laryng Rhinol Otol
(Stuttg) 61:234-237. (German).
Stanley JS. 1986. Broad scan analysis of the FY82 national human adipose
tissue survey specimens. Volume 1. Executive Summary. Washington, DC: US
Environmental Protection Agency, Office of Toxic Substances, Design and
Development Branch, National Human Monitoring Program. EPA 560/5-86-035.
*Starkey BJ, Taylor AP, Walker AW. 1987. Measurement of silver in blood by
electrothermal atomic absorption spectrometry (ET-AAS). Ann Clin Biochem
24 : SI91-SI93.
Starzynska T, Mandat A. 1987. [A case of argyria after peroral treatment of
peptic ulcer with silver albuminate]. Wiad Lek 40:691-693. (Polish).
Stephenson T, Lester JN. 1987. Heavy metal behavior during the activated
sludge process I. Extent of soluble and insoluble metal removal. Sci Total
Environ 63:199-214.
Stephenson T, Lester JN. 1987. Heavy metal behavior during the activated
sludge process II. Insoluble metal removal mechanisms. Sci Total Environ
63 : 215-230.
*Stokinger HE. 1981. The metals. In: Clayton GD, Clayton FE, eds. Patty's
industrial hygiene and toxicology. Vol. 2A, 3rd ed. New York, NY: John
Wiley and Sons, Inc., 1881-1894.
Strassburg M, Schubel F. 1967. [Generalized allergic reaction caused by
silver amalgam fillings], Deutsch Zahnarztuche Zeitschrift 22:3-9. (German).
Strauch B, Buch W, Grey W, et al. 1969. Methemoglobinemia: A complication of
silver nitrate therapy used in burns. AORN Journal 10:54-56.
Strauch B, Buch W, Grey W, et al. 1969. Successful treatment of
methemoglobinemia secondary to silver nitrate therapy. New England Journal of
Medicine 281:257-258.
Strong CR, Luoma SN. 1981. Variations in the correlation of body size with
concentrations of copper and silver in the bivalve Macoma balthica. Can J
Fish Aquat Sci 38:1059-1064.

-------
135
8. REFERENCES
*Struempler AW. 1975. Trace element composition in atmospheric particulates
during 1973 and the summer of 1974 at Chadron, Neb. Environ Sci Technol
9:1164-1168.
Sugawara N, Sugawara C. 1984. Effect of silver on ceruloplasmin synthesis in
relation to low-molecular-weight protein. Toxicology Letters 20:99-104.
Suissa M. 1983. Spectrophotometric quantitation of silver grains eluted from
autoradiograms. Anal Biochem 133:511-514.
Sujari ANA, Bowen HJM. 1986. Interactions of silver with humates and other
species in natural waters. J Radioanal Nucl Chem 106:213-222.
Sunderman FW Jr. 1987. Metal induction of heme oxygenase. In: Silbergeld
EK, Fowler RA, eds. Annals of the New York Academy of Sciences. Vol. 514,
New York, NY: New York Academy of Sciences, 65-80.
Swanson AB, Wagner PA, Ganther HE, et al. 1974. Antagonistic effects of
silver and tri-o-cresyl phosphate on selenium and glutathione peroxidase in
rat liver and erythrocytes [Abstract]. Fed Proc 33:693.
Tan E-L, Williams MW, Schenley RL, et al. 1984. The toxicity of sixteen
metallic compounds in Chinese hamster ovary cells. Toxicol Appl Pharmacol
74:330-336.
*Tanita Y, Kato T, Hanada K, et al. 1985. Blue macules of localized argyria
caused by implanted acupuncture needles. Electron microscopy and
roentgenographic microanalysis of deposited metal. Arch Dermatol
121:1550-1552.
Temple RM, Farooqi AA. 1985. An elderly, slate-grey woman. Practitioner
229:1053-1054.
Teraok H. 1981. Distribution of 24 elements in the internal organs of normal
males and the metallic workers in Japan. Archives of Environmental Health
36:155-165.
*Terhaar CJ, Ewell WS, Dziuba SP, et al. 1977. A laboratory model for
evaluating the behavior of heavy metals in an aquatic environment. Water
Research 11:101-110.
Terner K, Javor R. 1982. The effect of PGF2a on human oral mucous membrane.
Pharmacol Res Commun 14:511-522.
*The International Technical Information Institute (ITII). 1982. Toxic and
hazardous industrial chemicals safety manual. Tokyo, Japan: International
Technical Information Institute, 464-465.

-------
136
8. REFERENCES
Theodossiadis G, Kouris T, Papadopoulou C. 1982. Determination of trace
element Ag and Sc concentrations in human cataractous lenses. Ophthalmic Res
14:436-441.
*The Silver Institute. 1988. Silver consumption in the photographic
industry. The Silver Institute, Washington, DC. 20008.
*The Silver Institute. 1990. Latest Silver Institute refining statistics
The Silver Institute, Inc., Washington, DC. 20008.
Thompson JD, Nechay BR. 1981. Inhibition by metals of a canine renal
calcium, magnesium activated adenosine triphosphatase. J Toxicol Environ
Health 7:901-908,
^Thomson EA, Luoma SN, Johansson CE, et al. 1984, Comparison of sediments
and organisms in identifying sources of biologically available trace metal
contamination. Water Research 18:755-766.
Thorlacius-Ussing 0, Rungby J. 1984. Ultrastructural localization of
exogenous silver in the anterior pituitary gland of the rat. Exp Mol Pathol
41:58-66.
Thorlacius-Ussing 0, Graabaek PM. 1986. Simultaneous ultrastructural
demonstration of heavy metals (silver, mercury) and acid phosphatase.
Histochemical Journal 18:639-646.
Tichy P, Rosina J, Blaha K Jr, et al. 1986. Biliary excretion of HOmAg and
its kinetics in the isolated perfused liver. J Hyg Epidemiol Microbiol
Immunol 30:145-148.
Timperley MH. 1978. Collaborative tests of water analysis (the CHEMAQUA
program). New Zealand Journal of Science 21:557-564.
Tipton IH, Cook MJ. 1963. Trace elements in human tissue. Part II. Adult
subjects from the United States. Health Phys 9:103-145.
*Tipton IH, Stewart PL, Martin PG. 1966. Trace elements in diets and
excreta. Health Phys 12:1683-1689.
Tomokuni K. 1979. Interaction of zinc and other metals on the activity of
erythrocyte delta- aminolevulinic acid dehydratase in vitro. J Toxicol Sci
4:11-18.
Tomokuni K, Ogata M. 1980. Comparative study of effects of lead on the
activity of erythrocyte pyrimidine 51-nucleotidase and delta-aminolevulinate
dehydratase in vivo and in vitro. Arch Toxicol 45:197-201.

-------
137
8. REFERENCES
Tomokuni K, Ogata M. 1980. [In-vitro effect of heavy metals on the activity
of pyrimidine 5' nucleotidase and gamma amino levulinate dehydratase in the
human erythrocyte], Jap J Ind Health 22:282-283. (Japanese).
Tomza U, Janicki T, Kossman S. 1983. Instrumental neutron activation
analysis of trace elements in hair: A study of occupational exposure to a
non-ferrous smelter. Radiochem and Radioanal Letters 58:209-220.
*Ulitzur S, Barak M. 1988. Detection of genotoxicity of metallic compounds
by bacterial bioluminescence test. Journal of Bioluminescence and
Chemiluminescence 2:95-99.
Underwood EJ. 1979. Interactions of trace elements. In: Oehme FW, ed.
Hazardous and toxic substances. Vol. 2, New York, NY: Marcel Dekker, Inc.,
641-668.
Valente P, Axelrod JL. 1978. Acute leukopenia associated with silver
sulfadiazine therapy. J Trauma 18:146-147.
Van Campen DR. 1966. Effects of zinc, cadmium, silver and mercury on the
absorption and distribution of copper-64 in rats. J Nutr 88:125-130.
Van Vleet JF. 1976. Induction of lesions of selenium-vitamin E deficiency in
pigs fed silver. Am J Vet Res 37:1415-1420.
*Van Vleet JF. 1977. Protection by various nutritional supplements against
lesions of selenium- vitamin E deficiency induced in ducklings fed tellurium
or silver. Am J Vet Res 38:1393-1398.
Van Vleet JF. 1982. Amounts of twelve elements required to induce
selenium-vitamin E deficiency. Am J Vet Res 43:851-857.
*Van Vleet JF, Boon GD, Ferrans VJ. 1981. Induction of lesions of
selenium-vitamin E deficiency in ducklings fed silver, copper, cobalt,
tellurium, cadmium, or zinc: Protection by selenium. Am J Vet Res
42:1206-1217.
Venugopal B, Luckey TD. 1978. Introduction to heavy metal toxicity in
mammals. Metal toxicity in mammals. Vol. 2, New York, NY: Plenum Press,
36-37.
Veron C, Hildebrand HF, Martin P. 1986. [Dental amalgams and allergy]. J
Biol Buccale 14:83-100. (French).
*VIEW Database. 1989. Agency for Toxic Substances and Disease Registry
(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch,
Atlanta, GA. February 21, 1989.

-------
138
8. REFERENCES
Vik H, Andersen KJ, Julshawn K, et al. 1985. Neuropathy caused by silver
absorption from arthroplasty cement [letter]. Lancet, April 13; 1(8433)'872
*Vince DG, Williams DF. 1987. Determination of silver in blood and urine by
graphite furnace atomic absorption spectrometry. The Analyst 112:1627-1629
Von Mallinckrodt MG, Pooth M. 1969. [Simultaneous spectrographic testing for
25 metals and metaloids in biological material]. Arch Toxikol 25:5-18
(German).
Von Rosen G. 1954. Breaking of chromosomes by the action of elements of the
periodical system and by some other principles. Hereditas 40:258-263.
Von Rosen G. 1957. Mutations induced by the action of metal ions in pisum
Hereditas 43:644-664.
Wagner PA, Hoekstra WG, Ganther HE. 1975. Alleviation of silver toxicity by
selenite in the rat in relation to tissue glutathione peroxidase. Proc Soc
Exp Biol Med 148:1106-1110.
*Wahlberg JE. 1965. Percutaneous toxicity of metal compounds. A comparative
investigation in guinea pigs. Arch Environ Health 11:201-204.
Walberg JE. 1982. Metals and skin. In: Malbach HI, Gellin GA, eds
Occupational and industrial dermatology. Chicago, IL: Year Book Medical
Publishers, Inc., 346-350.
*Walker F. 1971. Experimental argyria: A model for basement membrane
studies. Br J Exp Pathol 52:589-593.
Wallace A, Alexander GV, Chaudhry FM. 1977. Phytotoxicity of cobalt
vanadium, titanium, silver, and chromium. Communication in Soil Science and
Plant Analysis 8:751-756.
*Ward NI, Roberts E, Brooks RR. 1979. Silver uptake by seedlings of Lolium
perenne L. and Trifolium repens L. New Zealand Journal of Science 22:129-132
*WDHSS. 19S9. Written communication regarding State of Wisconsin regulation
of silver levels in groundwater. Madison, WI: Wisconsin Department of Health
and Social Services. (June 8).
*Weast RC, Astle MJ, Beyer WH, ed. 1988-1989. Handbook of chemistry and
physics. 69th ed. Boca Raton, FL: CRC Press, Inc.
*Webster DA, Spadaro JA, Becker RO, et al. 1981. Silver anode treatment of
chronic osteomyelitis. Clinical Orthopedics and Related Research 161:105-114

-------
139
8. REFERENCES
Weir FW. 1979. Health hazard from occupational exposure to metallic copper
and silver dust. American Industrial Hygiene Association Journal 40:245-247.
*Weiss G, ed. 1986. Hazardous chemicals data book. 2nd ed. Park Ridge, NJ:
Noyes Data Corporation, 887-893.
Weitzenblum S, Peter J-D, Zawislak PR, et al. 1977. [Argyria: Apropos of a
case in a child], Pediatrie 32:371-375. (French).
Wenzloff DR. 1976. Distribution and abundance of heavy metals in finfish,
invertebrates, and sediments collected at a deepwater disposal site. Marine
Pollution Bulletin 7:185-187.
West HD, Goldie H. 1956. Topical localization in mouse of radioactive silver
oxide (Aglll)20 introduced by various routes. Proc Soc Exp Biol Med
92:116-120.
West HD, Elliott RR, Johnson AP, et al. 1950. In vivo localization of
radioactive silver at predetermined sites in tissues. American Journal
Roentgenology Radium Therapy 64:831-834.
Weston RF, Chairman PE, Morrell RA. 1977. Treatment of water and waste water
for removal of heavy metals. Viruses and trace contaminants in water and
wastewater. Ann Arbor, MI: Ann Arbor Science Publishers, Inc., 167-181.
Whanger PD. 1976. Selenium versus metal toxicity in mammals. Proceedings of
the Symposium on Selenium-Tellurium in the Environment:234-252.
Whanger PD. 1985. Metabolic interactions of selenium with cadmium, mercury,
and silver. Adv Nutr Res 7:221-250.
Whanger PD, Weswig PH, Schraitz JA, et al. 1976. Effects of selenium,
cadmium, mercury, tellurium, arsenic, silver and cobalt on white muscle
disease in lambs and effect of dietary forms of arsenic. Nutrition Reports
International 14:63-72.
White IR, Rycroft RJG. 1982. Contact dermatitis from silver
fulminate-fulminate itch. Contact Dermatitis 8:159-163.
*Whitlow SI, Rice DL. 1985. Silver complexation in river waters of central
New York. Water Res. 19:619-626.
Wilhelm FX, Daune M. 1969. [Interactions of metallic ions with DNA. III.
Stability and configuration of Ag-DNA complexes], Biopolymers 8:121-137.
(French).

-------
140
8. REFERENCES
*Wirtdholz M, ed. 1983. The Merck index. 10 ed. Rahway, NJ : Merck & Co.
Inc., 8338, 8343, 8352-8357.
Wise SA, Zeisler R. 1984. The pilot environmental specimen bank program.
Environ Sci Technol 18:302a-307a.
Wood M. 1965. Silver nitrate and burns--caution. Ariz Med 2:817.
Wright DC, Gallant RF, Spangberg L. 1982. Correlation of corrosion behavior
and cytotoxicity in Au-Cu-Ag ternary alloys. J Biomed Mater Res 16:509-517
Wysor MS. 1975. Orally administered silver sulfadiazine: Chemotherapy and
toxicology in CF-1 mice; Plasmodium berghei (malaria) and Pseudomonas
&erygubis. Chemotherapy 21:302- 310.
Yatomi H. 1986. Study on the Interaction of trace metals, silver and copper.
J Yonago Med Ass 37:405-414.
Yatomi H, Nose T, Sugiyama K, et al. 1983. [The interaction between silver
and copper in the rat], Igaku to Seibutsugaku 107:265-267. (Japanese).
Yoshida M, Tashiro H, Iwami K, et al. 1983. Bioavailability of selenite,
selenomethionine and selenocystine in rats with silver loading. Agric Biol
Chem 47:807-813.
Yoshikawa H. 1970. Preventive effect of pretreatment with low dose of metals
on the acute toxicity of metals in mice. Ind Health 8:184-191.
Zakour RA, Kunkel TA, Loeb LA. 1981. Metal-induced infidelity of DNA
synthesis. Environ Health Perspect 40:197-205.
Zech P, Colon S, Labeeuw R, et al. 1973. [Nephrotic syndrome with deposits
in the glomerular basement membranes during argyria]. Nouv Presse Med
2:161-164. (French).
Zegarelli EV, Kutscher AH. 1978. Toxicity reactions. In: Zegarelli EV,
Kutscher AH, Hyman GA, eds. Diagnosis of diseases of the mouth and jaws. 2nd
ed. Philadelphia, PA: Lea & Febiger, 327-331.
Zieker AW, Wisnicki J. 1979. Corneal burns from watch battery explosion. Am
J Ophthalmol 88:798-9.

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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as
specified in the toxicological profiles.
Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical adsorbed
per unit weight of organic carbon in the soil or sediment to the concentration
of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
soil (i.e., the solid phase) divided by the amount of chemical in the solution
phase, which is in equilibrium with the solid phase, at a fixed solid/solution
ratio. It is generally expressed in micrograms of chemical sorbed per gram of
soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete time
period of exposure divided by the concentration in the surrounding water at
the same time or during the same period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group
of studies, that produces significant increases in the incidence of cancer (or
tumors) between the exposed population and its appropriate control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling Value -- A concentration of a substance that should not be exceeded,
even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified
in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the developing
organism that may result from exposure to a chemical prior to conception
(either parent), during prenatal development, or postnatally to the time of
sexual maturation. Adverse developmental effects may be detected at any point
in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature between
the two terms is the stage of development during which the insult occurred.
The terms, as used here, include malformations and variations, altered growth,
and in utero death.

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9. GLOSSARY
EPA Health Advisory --An estimate of acceptable drinking water levels for a
chemical substance based on health effects information. A health advisory is
not a legally enforceable federal standard, but serves as technical guidance
to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
concentration of a contaminant from which one could escape within 30 min
without any escape-impairing symptoms or irreversible health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days
as specified in the Toxicological Profiles.
Immunologic Toxicity -- The occurrence of adverse effects on the immune system
that may result from exposure to environmental agents such as chemicals.
In Vitro -- Isolated from the living organism and artificially maintained, as
in a test tube.
In Vivo -- Occurring within the living organism.
Lethal Concentration(L0) (LCL0) -- The lowest concentration of a chemical in
air which has been reported to have caused death in humans or animals.
Lethal Concentration{50) (LC50) -- A calculated concentration of a chemical in
air to which exposure for a specific length of time is expected to cause death
in 50% of a defined experimental animal population.
Lethal Dose(LO) (LDlq) -- The lowest dose of a chemical introduced by a route
other than inhalation that is expected to have caused death in humans or
animals.
Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated to
cause death in 50% of a defined experimental animal population.
Lethal Time(50) (LT50) -- A calculated period of time within which a specific
concentration of a chemical is expected to cause death in 50% of a defined
experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in
a study, or group of studies, that produces statistically or biologically
significant increases in frequency or severity of adverse effects between the
exposed population and its appropriate control.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.

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9. GLOSSARY
Minimal Risk Level --An estimate of daily human exposure to a chemical that
is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in the
genetic material in a body cell. Mutations can lead to birth defects,
miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
there were no statistically or biologically significant increases in frequency
or severity of adverse effects seen between the exposed population and its
appropriate control. Effects may be produced at this dose, but they are not
considered to be adverse.
Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the
concentrations of a chemical in n-octanol and water, in dilute solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in workplace
air averaged over an 8-hour shift.
qx* -- The upper-bound estimate of the low-dose slope of the dose - response
curve as determined by the multistage procedure. The can be used to
calculate an estimate of carcinogenic potency, the incremental excess cancer
risk per unit of exposure (usually ng/L for water, mg/kg/day for food, and
/ig/m3 for air) .
Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious effects
during a lifetime. The RfD is operationally derived from the NOAEL (from
animal and human studies) by a consistent application of uncertainty factors
that reflect various types of data used to estimate RfDs and an additional
modifying factor, which is based on a professional judgment of the entire
database on the chemical. The RfDs are not applicable to nonthreshold effects
such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are (1) 1 lb or
greater or (2) for selected substances, an amount established by regulation
either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are
measured over a 24-hour period.

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9. GLOSSARY
Reproductive Toxicity -- The occurrence of adverse effects on the reproductive
system that may result from exposure to a chemical. The toxicity may be
directed to the reproductive organs and/or the related endocrine system. The
manifestation of such toxicity may be noted as alterations in sexual behavior,
fertility, pregnancy outcomes, or modifications in other functions that are
dependent on the integrity of this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers
can be exposed for up to 15 min continually. No more than four excursions are
allowed per day, and there must be at least 60 min between exposure periods.
The daily TLV-TWA may not be exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse effects on
target organs or physiological systems (e.g., renal, cardiovascular) extending
from those arising through a single limited exposure to those assumed over a
lifetime of exposure to a chemical.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) - - A concentration of a substance to which most
workers can be exposed without adverse effect. The TLV may be expressed as a
TWA, as a STEL, or as a CL.
Time-Weighted Average (TWA) --An allowable exposure concentration averaged
over a normal 8-hour workday or 40-hour workweek.
Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route
other than inhalation, which is expected to cause a specific toxic effect in
50% of a defined experimental animal population.
Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the variation in
sensitivity among the members of the human population, (2) the uncertainty in
extrapolating animal data to the case of human, (3) the uncertainty in
extrapolating from data obtained in a study that is of less than lifetime
exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data.
Usually each of these factors is set equal to 10.

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APPENDIX
PEER REVIEW
A peer review panel was assembled for sliver. The panel consisted of the
following members: Dr. Rajendar Abraham, Abraham Associates Limited, Albany,
NY; Dr. Thomas Hinesly, University of Illinois, IL; Dr. Arthur Furst,
University of San Francisco, CA; Dr. Ernest Foulkes, University of Cincinnati,
OH. These experts collectively have knowledge of silver's physical and
chemical properties, toxicokinetics, key health end points, mechanisms of
action, human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer review
specified in Section 104(i)(13) of the Comprehensive Environmental Response,
Compensation, and Liability Act, as amended.
A joint panel of scientists from ATSDR and EPA has reviewed the peer
reviewers' comments and determined which comments will be included in the
profile. A listing of the peer reviewers' comments not incorporated in the
profile, with a brief explanation of the rationale for their exclusion, exists
as part of the administrative record for this compound. A list of databases
reviewed and a list of unpublished documents cited are also included in the
administrative record.
The citation of the peer review panel should not be understood to imply
its approval of the profile's final content. The responsibility for the
content of this profile lies with the Agency for Toxic Substances and Disease
Registry.

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