EPA/600/8-87/001
February 1987
Summary Review of the Health Effects
Associated With Copper
Health Issue Assessment
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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Disclaimer
This document has been reviewed in accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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Preface
This Health Assessment Summary Document is a brief review of the
scientific knowledge on copper. The emphasis of this summary document
is on inhalation exposure from atmospheric copper and the environmental,
ecological and health effects from the species of copper expected to be present
in the atmosphere. Environmental media other than air and occupational
exposure is discussed only if a process in that medium has a direct or indirect
impact on the atmosphere or if a process in the atmosphere has an impact
on other media. The information provided in this summary document indicates
areas where adequate data are available and areas where the data are limited
or lacking. Information on copper summarized in this document has been
obtained from examination of primary scientific literature identified through
a computerized literature search, a subsequent peer-review workshop and
major literature published since that workshop in 1985. This selective
presentation of the data is designed to illustrate the major environmental
and health effects of copper arising from the atmospheric medium.
HI
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Table of Contents
Page
1. Summary 1
2. Physical and Chemical Properties. 5
3. Sampling and Analytical Methods 9
4. Sources and Uses in the Environment 13
5. Environmental Fate and Transport 16
6. Environmental and Exposure Levels 19
6.1. Atmospheric Levels , 19
6.1.1. Remote Areas 19
6.1.2. Rural Areas 19
6.1.3, Urban and Suburban Areas 19
6.1.4, Hot Spots ,. 20
6.1.5. Occupational Levels 20
6.2. Water Levels 22
6.3. Food and Dietary Levels 22
6.4. Exposure 22
6.4.1. Inhalation 22
6.4.2. Ingestion 23
6.5. Contribution of Inhalation to Total Exposure to Copper 23
7. Terrestrial and Aquatic Effects 25
7.1. Terrestrial Ecosystems 25
7.2. Aquatic Ecosystems 26
7.3. Conclusions , , .27
8, Pharmacokinetics and Mammalian Toxicology 28
8.1. Pharmacokinetics ...28
8.1.1. Absorption 28
8.1.2. Distribution 29
8.1.3. Metabolism/Homeostatic Control Processes .31
8.1.4. Excretion 31
8.2. Mammalian Toxicology 32
8.3. Other Effects 37
8.3.1. Carcinogenicity 37
8.3.2, Mutagenicity 38
8.3.3. Teratogenicity and Reproductive Toxicity. 38
8.4. Summary 49
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9. Human Health Effects and Populations at Risk 51
9.1. Human Health Effects 51
9.2, Populations at Risk 55
9.2,1. Wilson's Disease 56
9.2.2. G6PD Deficient Individuals 56
9.2.3. Hemolysis Patients 56
9.2.4. Infants and Children 57
9.2.5. Combined Exposure Populations 57
10. Assessment , 59
10.1. Overview 59
10.2. Principal Effects and Target Organs 60
10.3. Factors Influencing Health Hazard Assessment from
Inhalation of Copper. .60
11. References 62
V!
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List of Tables
No. Page
1 Selected Physical Properties of Copper and Some Copper
Compounds 6
2 The Detection Limits, Advantages and Disadvantages of
Selected Methods for the Determination of Copper 12
3 Sources of Worldwide Copper Emission to the Atmosphere in
1975 13
4 Atmospheric Copper Emission Sources in the United States in
1984 14
5 Representative MMD of Copper Particles in Aerosols from
Some United States Cities 16
6 Summary of Atmospheric Copper Concentrations in United States
Urban and Suburban Locations During the Period 1970-1974 21
7 Inhalation Exposure to Copper for Populations at Different
Locations 23
8 Tissue and Body Copper Levels in Representative Adult Man ,30
9 The Toxicity of Copper in Experimental Studies in Mammals 34
10 Tumorigenicity of Some Copper Compounds 39
11 Mutagenfcity Data for Copper Compounds. 40
12 Teratogenicity Data for Copper Compounds 45
13 Effects of Oral Exposure of Copper and Copper Compounds in
Humans 53
VII
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List of Abbreviations
AA Atomic absorption
AE Atomic emission
BCF Bioconcentration factor
bw Body weight
Gl Gastrointestinal
G6PD Glucose-6-phosphate dehydrogenase
GSH Glutathione
ICP-AES Inductively coupled plasma-atomic emission spectroscopy
INAA Instrumental neutron activation analysis
LDso Dose lethal to 50% of recipients
MMD Mass median diameter
NOAEL No-observed-adverse-effect level
ppb Parts per billion
PVC Polyvinyl chloride
SCOT Serum glutamic oxaloacetic transaminase
SRM Standard reference material
XRF X-ray fluorescence
VIII
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Document Development
David J. Reisman, Document Manager
W, Bruce Peirano, Document Manager
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Jerry F. Stara, Director
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Authors and Major Contributors:
David J. Reisman
W. Bruce Peirano
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Jonathan B, Lewis
Dipak K. Basu
David Hohrseiter
Michael Neal
Syracuse Research Corporation
Syracuse, New York
Scientific Reviewers and Contributors:
Harlal Choudhury
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Beth Hassett, OAQPS Project Manager
John J, Vandenberg
Office of Air Quality Planning and Standards
Research Triangle Park, NC
Richard Walentowicz
Exposure Assessment Group
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington, DC
Robert Beliles
Carcinogen Assessment Group
Office and Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington, DC
ix
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Lawrence Valcovic
Reproductive Effects Assessment Group
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington, DC
External Consultants:
Thomas Clarkson
Division of Toxicology
University of Rochester School of Medicine
Rochester, NY
Joan Cranmer
Department of Pediatrics #5128
University of Arkansas for Medical Sciences
Little Rock, AR
Vincent N. FinelH
Toxicology Consultant
497 N.W. 15th Street
Boca Raton, FL
Rolf Hartung
Professor of Environmental Technology
University of Michigan
Ann Arbor, Ml
Paul Mushak
Department of Pathology
University of North Carolina
Chapel Hill, NC
Herbert E. Stokinger
Toxicology Consultant
3 Twin Hills Ridge Drive
Cincinnati, OH
Editorial Reviewer.
Judith Olsen
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Document Preparation".
Patricia A. Daunt
Bette L Zwayer
Environmental Criteria and Assessment Office, Cincinnati
Office of Health and Environmetal Assessment
U.S. Environmental Protection Agency
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Contractual Preparation and Review:
An initial draft and subsequent work on this document was completed
under Contract No. 68-03-3229 with Syracuse Research Corporation. Several
peer reviews and a peer review workshop were held under Contract No.
68-03-3234 with Eastern Research Group. David J, Reisman served as Project
Officer on both contracts. Albert Ahlquist served as the USEPA Contract
Officer.
XI
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Summary
Copper is a metallic element belonging to group IB of the periodic table.
The United States production of copper in 1981 was 1.54 million metric
tons, compared to a demand of 2.35 million metric tons. Most copper
compounds occur in +1 and +2 valence states. The Cu(l) ion is unstable
in aqueous solution; however, Cu(l) can be stabilized in aqueous solution
by some ligands. The Cu(ll) species, on the other hand, is stable in aqueous
solution. Although copper is present as numerous chemical species, the
biological availability and toxicity of copper is probably related to free Cu2+
ion activity.
A large number of methods are available for the analysis of copper in
different matrices. In ambient air, copper is commonly sampled with high
volume samplers. Isokinetic sampling has been used for the collection of
copper from industrial plumes. The most widely used methods for the
determination of copper are atomic absorption, atomic emission. X-ray
fluorescence and neutron activation analysis. The precision and accuracy
of a method for the quantification of copper depends both on the method
used and the sample matrix under analysis. The detection limits of copper
in water solution with the four most widely used methods are in the ppb
or sub-ppb range. The precision of copper analysis is usually lower as the
complexity of the sample matrix increases (e.g., the precision of copper
analysis is higher for particulate copper collected from an industrial area
than in the case of copper in biological samples).
On a global basis, the atmospheric copper flux from anthropogenic sources
are ~3 times higher than its flux from natural sources. Non-ferrous metal
production is the largest contributor of atomspheric copper flux in the United
States. It has been estimated that the atmospheric emission rate of copper
from anthropogenic sources in the United States in the 1980's ranges from
940x103 kg/year to 8200x103 kg/year. Atmospheric deposition plays a major
role in the overall copper loading to both surface water and soil. The majority
of copper produced in the United States is used as the metal and its alloys
and <5% is used for the production of chemical compounds. By far, the
highest utilized copper compound in the United States is copper suifate.
A few studies on the fate and transport of copper in the atmosphere are
available, but some data gaps still exist. The average MMD for copper aerosols
in the United States is 1.3 //m. Since particulate matter in the size range
of 0.5 and 5.0/um is commonly assumed to be respirable, the copper particles
in United States aerosols predominantly occur in the respirable range. The
chemical form of copper in aerosol is not well studied. It has been speculated
that copper sulfides, oxides and suifate and possibly silicate may originate
from mining and ore crushing and beneficiation processes. Smelting
operations may produce oxides, suifate and elemental copper. Although no
direct experimental evidence exists, it is likely that municipal incineration
will produce copper and copper oxide in its emission.
It has also been speculated that copper suifate may also be formed in
the atmosphere through the reaction of copper oxide with sulfur dioxide
in the presence of oxygen. There is some experimental evidence that
elemental copper, copper oxide and CuFeSa are present in the atmosphere
near smelting areas. The primary modes of copper removal from the
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atmosphere are dry deposition (dustfall) and wet deposition (rainfall and
snowfall}. The copper content of dustfall varies from 20 to >50,000 #g/
g near smelters. Although the ratio of wet to dry deposition is dependent
on several factors, the typical ratio is close to unity. There is some evidence
of long range transport of copper from polluted areas. It has been speculated
that the atmospheric residence time of copper in the unpolluted troposphere
is 2-10 days. In urban and polluted areas, the residence time may be even
shorter. It is unlikely for copper to reach the stratosphere at levels that could
cause a significant reaction or any depletion of the ozone layer.
The average atmospheric level of copper in the 1970's was 0.4 ng/m3
in remote areas, 25 ng/m3 in rural areas, 160 ng/m3 in urban areas and
190 ng/m3 in suburban areas. Although the introduction of clean air
regulations in the United States have resulted in —20% reduction in airborne
particulates from 1970-1974, the atmospheric copper levels in the United
States have not changed and may have remained constant between 1965
and 1974. Limited data presented in this document,however, indicate that
a decrease in atmospheric copper concentration may be taking place during
this decade.
Based on the average atmospheric copper concentration in the United
States in the 1970's, the inhalation exposure of copper has been estimated
at 0.5 //g/day in rural areas, 3.2 /t/g/day in urban areas and 3.8 jug/day
In suburban areas. The average daily intake of copper through drinking water
in the United States is 260 jug/day and <2000-4QOO /ug/day through foods.
Several reviews of copper toxicity have indicated that the contribution of
atmospheric copper to the total daily intake and body burden is very minor.
Therefore, the daily intake of copper through inhalation is negligible compared
to its intake through ingestion. The mechanisms surrounding any toxicity
of copper are different depending on the route of exposure.
Copper is an element, essential for proper nutrition and is distributed
throughout the body. Absorption of copper and copper compounds can occur
by oral and inhalation routes of exposure, with highest uptake rates occurring
in the Gl tract followed by respiratory absorption. Very little percutaneous
absorption occurs. Copper can also cross the placenta! barrier and is taken
up by the fetus. Only 20% of inhaled copper mists, fumes or dusts is estimated
to be absorbed by the lungs, with the remainder removed by the bronchial
mucosa or deposited unabsorbed in the lung tissue. Studies using radioactive
copper have demonstrated that 32-70% of ingested copper is absorbed
through the Gl tract. As discussed in this document, inhaled copper may
actually be ingested and absorbed through the Gl tract. This occurs when
the human homeostatic mechanisms create a "coughing and swallowing"
action, leading to ingestion of copper. In the blood, absorbed copper is bound
to ceruloplasmin as well as amino acids and albumin, which function as
the main distributors of copper in the body. The copper body burden in adults
ranges from 70-120 mg with the liver acting as the main storage organ.
Other organs containing high copper concentrations include the brain, heart
and kidneys. Fetal copper content and distribution differs from that observed
in adults in that total body content and liver concentration of copper are
much higher in the fetus.
Fecal excretion is the primary route of copper elimination and consists
mostly of unabsorbed dietary copper as well as body copper eliminated
through biliary clearance and intestinal mucosal secretion. Relatively lesser
amounts of copper are also found in urine, sweat, saliva, hair, nails and
menstrual fluid.
The pharmacokinetic properties of copper in animals and humans
demonstrate that sophisticated homeostatic mechanisms have evolved to
cope with copper intake deficiencies and excesses. Despite fluctuations in
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copper intake, proper copper balance in the body can be maintained by varying
the amount of copper absorbed and excreted and by altering copper's
distribution to various tissues. In this way, the nutritional status of the
organism is normally matched with daily intake to maintain a physiologically
optimal level of copper in the body. It should be noted that since the
pharmacokinetic properties of copper were elucidated using predominantly
oral exposure, the question of whether these same mechanisms are effective
for other routes of exposure (inhalation, dermal, transplacental) still remains.
As a required element, copper is incorporated into >12 specific copper
proteins, such as cytochrome oxidase, tyrosinase and erythrocyte
superoxidedismutase. Copper is essential for hemoglobin formation,
carbohydrate metabolism, catecholamine biosynthesis, and cross-linking of
collagen, elastin and hair keratin. Other metals such as zinc, iron and
molybdenum interact with copper to affect copper's absorption, distribution,
metabolism and utilization.
Because of well-developed homeostatic mechanisms, episodes of toxicosis
from excess copper exposure in man and animals are relatively rare. There
is a notable lack of information concerning the pharmacokinetics and toxic
effects of inhaled copper in experimental animals. Limited inhalation studies
with copper compounds generally resulted in minor, transient effects in
experimental animals; however, guinea pigs exposed to Bordeaux,mixture,
a fungicide containing copper sulfate, exhibited various lung lesions. The
available data from copper inhalation studies are limited in their usefulness
for predicting and assessing human risk, since the issue of systemic toxicity
resulting from copper in the atmosphere was not addressed. Most of these
studies have mixed exposures or have been done using a copper-related
compound or salt.
Acute and subchronic oral toxicity studies have shown that copper can
elicit a wide range of toxic effects in the liver, kidneys, blood, GI tract, brain
and fetus. The doses used in these studies, however, generally were much
higher than those levels likely to be encountered by human consumption.
Oral ingestion of large quantities of copper compounds in swine and rats
resulted in heavy copper deposition and necrosis in the liver and kidneys,
as well as hemolytic anemia and GI irritation. Limited evidence of
teratogenicity in mice and hamsters was reported, though the administered
doses were very high and the routes of exposure were primarily not relevant
to human exposure situation. Equivocal results have been obtained from
studies designed to test the mutagenicity and carcinoflenicity of copper
compounds. Using USEPA Guidelines for Carcinogen Risk Assessment, the
overall weight of evidence suggests that there is insufficient data to determine
the carcinogenic potential of copper to humans, and therefore, copper is
in Group D: Not classifiable.
Occupational exposure to copper mists, fumes and dusts has reportedly
caused a transient condition known as "metal fume fever," a disorder
characterized by influenza-like symptoms. Vineyard workers exposed to
Bordeaux mixture reportedly had various histological lesions in the lungs
and liver.
Reports of copper intoxication most often arise from accidental poisonings
or suicide attempts using copper sulfate or from the consumption of water
containing high copper concentrations. A number of symptoms have been
reported from these incidents including gastrointestinal irritation, headache,
dizziness, hemolytic anemia, hematuria and reduced glucose-6-phosphate
dehydrogenase activity. More serious cases have involved ulceration of the
gastric mucosa, hepatic and renal necrosis, coma and death, Indian Childhood
Cirrhosis, a condition affecting certain segments of the Indian population,
is characterized by widespread hepatic necrosis and extremely high hepatic
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copper levels. This disease is through! to arise, in part, from the leaching
of copper into milk and water stores, leading to excess copper intake in
children. Epidemiology studies have reported marginal evidence linking
copper smelters and excess dietary copper to increased incidences of cancer,
mortality and central nervous system congenital malformations. These data,
however, are confounded by the presence of other metals such as arsenic
leading to uncertainty in the interpretation of the results.
The population most sensitive to elevated environmental copper levels is
that afflicted with Wilson's disease (~1 in 200,000 individuals). These
individuals represent a documented case of endogenous chronic copper
toxicosis in man. Hepatic ceruloplasmin synthesis is severely impaired and
copper levels in all tissues, especially in liver, are markedly increased, thus
causing these people to be extremely vulnerable to minor variations in copper
intake. Reports of Indian Childhood Cirrhosis and copper intoxication in
children exposed to food and water contaminated with higher copper levels
represent external exposure situations, and indicate that newborns and young
children are more sensitive to excess copper than a re normal adults. Increased
copper concentrations in the body and underdeveloped homeostatic
mechanisms probably contribute to this susceptibility. One study indicates
that 13% of the Black American male population has red cell G6PD deficiency
which could be at an increased risk to environmental oxidants. Another study
disagrees with this issue and is reviewed in this document.
In summary, human homeostatic mechanisms act to control copper balance
by regulating the absorption, storage, distribution, utilization and excretion
of the metal. Deficiencies or excesses in copper intake rarely result in episodes
of copper toxicosis. In cases where homeostatic mechanisms are genetically
disrupted as in Wilson's disease or underdeveloped as in the fetus and young
children, excess copper intake is not regulated resulting in the symptoms
of copper toxicosis. Very few cases of intoxication from airborne copper in
the workplace have been reported, indicating that acute occupational
exposure to copper dusts or fumes has not been a significant toxic health
hazard. The role which homeostatic mechanisms play in controlling the
pharmacokinetics of inhaled copper has yet to be investigated.
Atmospheric inputs of copper and other compounds and metals have been
found to cause adverse effects in terrestrial and aquatic ecosystems. These
effects range from complete destruction of terrestrial vegetation in areas
immediately down wind from copper smelters to more subtle ecological effects
such as disruption of nutrient cycling or elimination of sensitive species
and potential disruption of food chains. Accumulation of copper in terrestrial
plants can also lead to toxic effects in herbivore populations such as sheep,
which are sensitive to copper poisoning. The available information indicates,
however, that atmospheric copper inputs in most areas of the United States
are generally not large enough to cause significant ecological effects in
terrestrial and aquatic ecosystems. Effects may occur, however, in certain
"hot spots" receiving unusually high copper inputs.
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2. Physical and Chemical Properties
Copper is a metallic element that is listed as the first element of subgroup
IB of the periodic table. Although copper occurs naturally as the free metal,
80% of the copper production is refined from low grade minerals containing
<2% of the metal. A few of the common copper-containing ores used to
derive the metal are: chalcocite, CusS; covellite, CuS; chaleopyrite, CuFeSi;
cuprite, CuaO; tenorite, CuO; and malachite Cu2COa(OH)2 (Stokinger, 1981;
Demayo et al., 1982).
Although copper and its compounds occur in four oxidation states, the
0, +1 and +2 valency states are the most common. The consumption of a
few selected copper compounds in the United States in 1975 was as follows
(Kust, 1979):
copper (II) sulfate: 35,600 tons
copper (II) naphthenate: 450 tons
copper (I) oxide; 200 tons
copper (II) oleate: 100 tons
copper (II) carbonate: 50 tons
The United States production of Cu(l) oxide in 1981 was 4661 tons (U.S.
Dept. of Commerce, 1983) and 4616 tons in 1i76 (U.S. Dept. of Commerce,
1982), Considering the United States consumption and production data, it
can be concluded that Cu(l) oxide is largely exported, The relevant physical
properties of these copper compounds and a few other commonly used copper
compounds [Cu(ll) acetate, Cu(l) chloride, Cu(ll) chloride, Cu(ll) nitrate, Cu(ll)
oxide] are given in Table 1. Cu(ll) arsenate, Cu(l) cyanide and Cu(ll)
phthalocyanides are also produced in high volume in the United States {SRC,
1980), These compounds have been excluded from the table, however,
because their observed health effects may be attributed to the anionic portion
of the compounds and should be included in a discussion of cyanide and
arsenic compounds, not copper.
The relative stabilities of Cu(l) and Cu(ll) states are indicated by the following
reduction potential data (Kust, 1979);
Cu* + e-Cu E° = 0.521V
Cu2+ + e-Cu+ E° = 0.153V
Cu^ + 26-Cu E° = 0.337V
Therefore, any system with the oxidation potential of XX153V will oxidize
Cu+ ions to Cu+2 ions. The Cu(l) ion is unstable in aqueous solution;
consequently, only small concentrations of Cu+1 can exist in aqueous solution,
In the presence of some ligands, however, Cu(l) can be stabilized in aqueous
solution (Kust, 1979). The Cu(ll) species is stable in aqueous solution. In
most natural waters containing carbonates, Cu4"2 ions exist up to pH 6 and
CuCOa exists in the pH range 6-9.3 (Stumm and Morgan, 1970). Although
copper is present as numerous chemical species in aquatic media, the in
situ biological availability and toxicity of copper is probably related to free
Cu*2 ion activity (Sanders et al., 1983).
Copper forms complexes with several inorganic and organic compounds
and the stability of such complexes is dependent upon the pH, temperature
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Table 1. Selected Physical Properties of Copper and Some Copper Compounds'
Chemical
Copper
Copper (II)
acetate,
monohydrate
Copper(ll)
carbonate,
basic
Copper (1)
chloride
Copper(ll)
chloride
Copper (II)
naphthenate
Copper (II)
nitrate,
trihydrate
CAS
Formula Registry No.
Cu 7440-50-8
/*** i/f* LJ /""I 1 LJ I *f A O "7 ^ O
LUf C- 2rf3U:3/2"**2/ * **£'* ' *~
CuCOaCufOHk 12069-69-1
CuCI (or CuzCtd 7758-89-6
CuCk 7447-39-4
Cu-salt of naph- 1 338-02-9
thenic acid also
called cuprinol
CuNOfSHzO 10031-43-3
Atomic or
Molecular
Weight
63.55
199.65
221.11
98.99
134.44
variable
241.60
Appearance
reddish metal
dark green
powder
dark green
crystal
white crystal
brown or
yellow hygro-
scopic powder
green-blue
solid
blue
deliquescent
crystal
Density or Melting
Specific Point
Gravity (°C)
8.92 1083.4
1.882 115
4.0 decomposes
at 200°
4.14 430
3*3tK* £+5 Q^U*
NA NA
2.32e5 114.5
Soiling
Point
PC)
2567
decomposes
at 240
NR
1490
decomposes
at 993
NA
decomposes
at 170
Vapor
Pressure
1 mmHg
at 1628°C
NA
NA
1 mm Hg
at 546°C
NA
NA
NA
Aqueous
Solubility
insoluble
72 g/l in cold
wafer1*
insoluble in
cold water
but
decomposes
in hot water
0.062 g/l in
cold water
706g/latO°C
NA
1378 g/l at
0°C
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Table 1, (continued)
Atomic or Density or Melting Boiling
CAS Molecular Specific Point Point
Chemical Formula Registry No. Weight Appearance Gravity (°C) (°C)
Vapor Aqueous
Pressure Solubility
Copper(li) CufCieHasOda.
oleate
Copperfl} CuvQ
oxide
Copperfll) CuO
oxide
Copper(ll) CuSOi'SHzQ
sulfate,
pentahydrate
1120-44-1 626.47 brown powder
or green-blue
solid
1317-39-1 143.08 reddish,
crystal
1317-38-0 79.54 black crystal
7758-99-8- 249.68 blue crystal
NA NA
6.0 1235
6.3-6.49 1323
2.284 decomposes
at 10°C
NA
decomposes
at 18QQ°C
NA
NR
NA insoluble
NA insoluble
NA insoluble
NA 316g/latO°C
"Source; Weast, 1980; SRC, 1980.
bThe temperature of cold water was not specified.
NA = Not available,' NR - Not relevant.
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and concentration of the ligands (Cotton and Wilkinson, 1980; USEPA, 1980b).
In the atmosphere, the following chemical reactions of copper oxides have
been speculated to occur (Nriagu, 1979):
CuO + SOa + Oz ~ CuSO« —
2 Cu2O + 2SO2 + 2O2 + 2H2O (vapors) — Cu3(OH)SO4 + CuSO4
The details of other chemical reactions of copper are reported in Cotton
and Wilkinson (1980). Very little is known about the possible heterogenous
reactions of copper (reactions of paniculate copper with gaseous compounds
in the atmosphere) and its compounds in the atmosphere. Metallic copper
may oxidize in air with the formation of hydroxo carbonate Cua(OH)aC03
(Cotton and Wilkinson, 1980). Whether the oxides of copper can form copper
nitrate as a result of reactions with oxygen and oxides of nitrogen under
atmospheric conditions is not known.
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3. Sampling and Analytical Methods
A large number of publications are available that deal with the sampling
and analysis of copper in different matrices. References to a few publications
in the subsequent discussion does not necessarily mean that these are the
only key publications on the subject. These publications have been used
to illustrate the different methods available for the sampling and analysis
of copper.
The sampling of copper in ambient and occupational air is usually performed
by collecting airborne particulate copper on glass fiber, PVC or cellulose
acetate filters (Wilson et al., 1981; Moyers et al., 1977; Hammerle et al.,
1973; NIOSH, 1978). High volume samplers and a longer sampling time
are used for the collection of samples where the copper concentration is
low, as in the case of ambient air. The selection of a filtering medium is
important since the impurities in the filters may contribute to a high
background reading. For the separation of airborne particulate matter into
different size fractions, cascade impactors are used (Paciga and Jervis, 1976;
Chan et al., 1983; Lee et al., 1972). The isokinetic sampling of copper from
industrial plumes has also been described (Small et al., 1981; Serth and
Hughes, 1980; Que Hee et al., 1982), and is usually done with a modified
USEPA method 5 sampling train (Que Hee et al., 1982; Serth and Hughes,
1980).
The sampling of copper from aquatic, biological, soil and sediment media
is normally performed by the grab method, although proportional samplings
with mechanical samplers can be used for composite sampling of industrial
wastewater samples (Sandhu et al., 1977; Hogan and Wotton, 1984; Strain
et al., 1975; Young and Blevins, 1981; Wood and Nash, 1976; Lytle and
Lytle, 1982). For collection of sediment samples from different depths, gravity
cores have been used (Stoffers et al., 1977).
Several methods are available for the analysis of copper. One of these
methods is direct aspiration atomic absorption with and without complexation
of copper (Lytle and Lytle, 1982; NIOSH, 1978; Chambers and McClellan,
1976). The complexation method increases the sensitivity by orders of
magnitude over direct aspiration (Chambers and McClellan, 1976) as a result
of concentration of the Cu-complex from the aquatic to organic phase and
the enhancement of the atomic absorption signal due to the solvent. The
atomic absorption technique with a graphite furnace has higher sensitivity
than the direct aspiration atomic absorption method (Strain et al., 1975;
Koizumi et al., 1977; Geladi and Adams, 1978; Young and Blevens, 1981).
In the graphite furnace method, the sample can be introduced directly into
the graphite tube without further treatment. To minimize matrix interference
a deuterium arc or xenon arc background corrector is normally used with
graphite furnace atomic absorption. A graphite furnace atomic absorption
background corrector based on the polarization characteristics of the Zeeman
effect was developed by Koizumi et al. (1977). This method was claimed
to reduce matrix interference to such an extent that no sample ashing was
required for the quantification of low level copper in serum and urine samples.
The probability of copper loss through volatilization during the ashing process
(a process used to reduce matrix interference), however, is minimal as long
as the ashing temperature does not exceed 800°C (Geladi and Adams, 1978).
Additional information on this subject is reported by Van Ormer (1975).
-------
inductively coupled plasma-atomic emission spectroscopy has also been
used for the analysis of copper (Que Hee et al., 1982; Aziz et al., 1982;
Boom and Browner, 1982). With a concentric nebulizer, the sensitivity of
copper determination increased in many organic solvents (e.g., xylenes,
butanol), but no increase was observed with a crossflow nebulizer (Boorn
and Browner, 1982). The X-ray fluorescence method has been used by several
investigators (Giaque et al., 1977; Van Grieken, 1977; Ragaini et al., 1977);
however, errors may occur due to the matrix effect with such samples as
soil. This problem has been overcome by fusion of the samples with lithium
metaborate or sulfur powder (Giaque et al., 1977; Ragaini et al., 1977), The
neutron activation analysis has also been used for the quantification of copper
(Dams et al., 1970; Ragaini et al., 1977; Small et al., 1981). While direct
gamma counting with a Ge(Li) detector following neutron irradiation by
instrumental neutron activation analysis was successful for the quantification
of copper in air pollution participates, this method was not suitable for
biological samples. Guzzi et al, (1976) demonstrated that an extensive
radiochemical group separation procedure was necessary before counting
gamma activity for biological samples containing tow levels of copper.
Copper has been analyzed by the following methods that are not commonly
used: kinetics of a catalytic reaction (Igov et al., 1980); X-ray photoelectron
spectroscopy (Holm and Storp, 1976); anode stripping voltametry (Lund and
Onshus, 1976; Woolston et al., 1982); gas chromatography with flame
ionization detection (Uden and Waldman, 1975); ring oven technique (West
and Sachdev, 1969); thin-layer chromatography (Bark et al., 1971);
spBctropolarimetric (Mirti, 1974); colorimetric (NAS, 1977); spectrof Iuorimet-
ric {Lazaro Boza et al., 1984); chemiluminescence {Wehry and Varnes, 1973);
ion scattering spectrometry; and secondary ion mass spectrometry (Karasek
etal., 1978).
The most widely used methods for the determination of copper are atomic
absorption, atomic emission. X-ray fluorescence and neutron activation
analysis. The analysis of copper in air particulates by atomic absorption and
atomic emission is commonly done by wet digestion of the filter paper with
nitric acid/hydrochloric acid, or a nitric acid/perchloric acid mixture in open
beakers. An additional hydrofluoric acid digestion step is used for airborne
particulate samples that may contain copper associated with silica either
as silicate or sorbed on silica, as in the case of fly ash from power plants
(Que Hee et al., 1982; Movers et al., 1977). Since the hydrofluoric acid
digestion step may cause loss of some elements due to volatilization (e.g.,
B and Si), digestion in Parr acid digestion bombs has also been used (Movers
et al., 1977). Digestion in Parr bombs, however, is not necessary for copper
determination. The acid digested aqueous solution at a proper pH is then
quantified for copper by atomic absorption in the flame orflameless (graphite
furnace) mode, or by inductively coupled plasma-atomic emission
spectroscopy. The analysis of copper in air particulate by instrumental neutron
activation analysis is done by placing the whole or a part of the filter in
a polyethylene bag and irradiating it with a neutron source. The quantification
is done by counting the y-radiation with Ge(Li) detectors (Dams et al., 1970;
Small et al., 1981; Ragaini et al., 1977). In X-ray fluorescence analysis of
copper in air particulate matter, discs cut from filter paper are mounted on
the instrument and the Kcr X-rays are used for the quantification (Hammerle
etal., 1973; Ragaini etal., 1977).
The analysis of copper in blood and urine or tissue is usually performed
by wet ashing with a sulfuric/perchloric acid mixture (NAS, 1977) and by
quantifying with the atomic absorption method. A graphite furnace atomic
absorption with a background corrector based on the Zeeman effect, however,
has been used for the direct quantification of copper in serum and urine
10
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samples without the prior ashing step (Koizumi et al., 1977). The analysis
of biological samples containing low levels of copper by neutron activation
analysis will require an extensive radiochemical group separation procedure
to eliminate interference during the gamma-counting step of the
quantification procedure (Guzzi et al., 1976). A procedure where the
lyophilized dry muscle of aquatic organisms are pulverized and pressed into
pellets for the determination of copper by X-ray fluorescence has been
described by Popham and D'Auria (1983).
The precision and accuracy of a certain method for the quantification of
copper depends not only on the method used, but also on the sample matrix,
Ideally, this precision and accuracy can be best evaluated by analyzing
standard reference materials containing copper in the same matrix as the
sample that is being analyzed. A few such standard reference materials for
copper are available from the National Bureau of Standards which provides
standard bovine livers (Lytle and Lytle, 1982); coal standards, SRM 1632a
and 163i (Small et al., 1981); orchard leaves, SRM 1571 (WooJston et al.,
1982); fly ash standard, SRM 1633 (Ragaini et al., 1977) containing known
amount of copper. The International Atomic Energy Agency provides several
biological samples with certified copper values (Lytle and Lytle, 1982). The
USEPA and U.S. Geological Survey may be a source of water standards
(Strain et al., 1975). The detection limits and the advantages and
disadvantages of copper quantification by the widely used methods are given
in Table 2.
-------
Table 2, The Detection Limits, Advantages and Disadvantages of Selected Methods for the Determination of Copper
Detection*
Method Limit Advantages and Disadvantages
Reference
ro
A A—direct aspiration 2 ppb
AA—ftameless 0,1 ppb
ICP—AES 2-3 ppb
AA—complexation 0.01 ppb
INAA 0.05 fjg
XRF 0.4 ppb
The method is simple and instrumentation is available in most labs.
Method is destructive and will not allow simultaneous
determination of other metals.
Same asAA method, but the method is faster and has lower
detention limit, but has less precision than flame AA.
The method Is rapid and versatile, but is destructive. It will not
allow simultaneous determination of other metals.
The method is the same as AA orAES, but provides lower detection
limit. It is more time-consuming.
Method is nan-destructive and will allow simultaneous
determination of many metals. Instrumental facility available to
limited laboratories.
Same as INAA, but the precision and accuracy could be less,
Fernandez and Manning,
1971
Fernandez and Manning,
1971
Que Hee et al., 1982;
Boom and Browner, 1982
Chambers and McClellan,
1976; Boom and Browner,
1982
Damsetal., 1970
Van Grieken et at., 1977
^Detection limits are for simple aqueous solutions. Complex matrices with high background may have considerable higher detection limits;
ppb for solution = fjg/l; ppb for solid matrix = ug/kg.
-------
4. Sources and Uses in the Environment
The United States production of copper was 1.45 million metric tons in
1974, 1.46 million metric tons in 1976 and 1.54 million metric tons in 1981.
An additional 0.60 million metric tons were produced in 1981 from old scrap.
The United States demand for copper in 1981 was 2.35 million metric tons.
An estimated 0,76 million metric tons of copper were imported in the United
States in 1981. Industry stocks account for the rest of the U.S. copper supply
in 1981 (Stokinger, 1981; Tuddenham and Dougall, 1979; Weant, 1985).
The principal copper-processing states in the United States in 1984 and
their percentages of the total were: Arizona, 73.3%; Montana, 8.4%; New
Mexico, 7.7%; Utah, 4.8%; and Michigan, 4.3% (Weant, 1985). The primary
copper smelting states in the United States in 1984 with percentages of
the total were: Arizona, 63,9%; Utah, 12,5%; Michigan, 10.5%; Nevada, 6.2%;
and New Mexico, 3.7% {Weant, 1985).
The sources of copper in the environment are reasonably well-studied.
Both anthropogenic and natural sources contribute to the emission of copper
to the atmosphere. Table 3 lists the worldwide copper emission sources
in the atmosphere in 1975, showing that windblown dust accounts for —65%
of the overall nonanthropogenic sources of copper emission to the
atmosphere. Nonferrous metal production, wood combustion, and iron and
steel production constitute ~69% of the overall emission from anthropogenic
sources. It can be concluded from Table 3 that the atmospheric copper flux
from anthropogenic sources are ~3 times higher than its flux from natural
Table 3. Sources of Worldwide Capper Emission to the Atmosphere in 1975*
Emission Rate
Source (10s MT/yearj
Natural:
windblown dust 12
volcanoes 3.6
vegetation 2.5
forest fires 0,3
sea spray 0.08
Total 18.5
Anthropogenic:
nonferrous metal production 21.2
wood comb ust/on 11.5
iron and steel production 6.3
coal comb ustion 5.6
waste incineration 5.3
industrial applications 4.9
nonferrous metal mining O.8
oil and gasoline combustion O.7
Total 56.3
*Source: Nriagu, 1979
MT = Metric ton
13
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sources. Global anthropogenic emissions of copper have been increased from
23,000 metric tons during the period 1951-1960, to 43,500 metric tons
during the period 1961-1970, to 58,500 metric tons during 1971-1980
(Davies and Bennett, 1983). The anthropogenic atmospheric emission sources
of copper in the United States in 1984 are shown in Table 4. It can be
concluded from Table 4 that ore processing and smelting are the primary
sources of anthropogenic copper in the United States atmosphere constituting
77.8% of the overall anthropogenic input Other sources of copper emission
are: iron and steel production, 7.4%; coal and oil combustion, 4.6%; zinc
smelting, 3.3%; copper sulfate production, 2.7%; municipal incineration, 1.9%;
others, 2.3% (Weant, 1985). A comparison of Tables 3 and 4 indicates that
a maximum of 14.6% of the worldwide copper emission to the atmosphere
originates from the United States. Considering that the U.S. copper production
In 1975 constituted ~18.4% of the world production (Tuddenham and Dougall,
1979), the overall atmospheric emission estimate given in Table 4 is likely
to be a conservative estimate.
Table 4. Atmospheric Copper Emission Sources in the United States In 1984*
Emission Rate
Source (MT/year)
Ore processing 480-660
Ore smelting 203-6160
Iron and steel production 112-240
Coal and oil combustion 45-360
Copper sulfate production 45
Zinc smelting 24-340
Carbon black production 13
Iron foundries 7.9
Lead smelting 5.5-65
Municipal incineration 3.3-270
Ferro alloy production 1.9-3.2
Brass and bronze production 1.8-36
Total 942,4-8200.1
'Source: Weant, 1985
MT- Metric ton
Although the overall amount of atmospheric emissions of copper in the
United States are from the sources given in Table 4, the contribution of
different sources in any given area is strongly dependent upon the localized
conditions. For example, it was estimated that 81 and 12% of the copper
aerosol in New York City was from incineration and automobile emission,
respectively, and 37, 31, 22% and 10% of the copper aerosol in Cleveland,
OH, was from incineration, coal combustion, gasoline combustion and
distillate fuel combustion, respectively (Nriagu, 1979).
The sources of copper in surface water in the United Kingdom was estimated
by Critchley (1983). Atmospheric deposition, river discharge, direct discharges
to coastal waters and estuaries, industrial waste and sewage sludge dumping
contributed 57, 33, 5, 3 and 2%, respectively, of the total copper input to
the North Sea. A similar loading pattern was also estimated for Lake Michigan,
where atmospheric deposition, stream discharge and shoreline erosions
constituted 56.7-79.4%, 25.1r37.6% and 5.5-5.7%, respectively of the total
copper loading (Schmidt and Andren, 1984). Critchley (1983) studied the
sources of copper in agricultural land in the United Kingdom and estimated
14
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that atmospheric deposition, sewage sludge, inorganic phosphatic fertilizers
and miscellaneous other sources contributed to 77, 6, 1 and 16% of the
overall loading of copper. It can be concluded from the above discussions
that atmospheric deposition plays an important role in the overall copper
loading to both large bodies of surface water and soil. In small water bodies,
however, localized sources may overshadow input from atmospheric
deposition, especially in rivers in industrialized areas. Examples of the
localized sources include effluents from industrial operations, storm water
runoff from city streets or agricultural lands, and water from mine drainage
(Demayo et a!., 1982).
The majority of copper produced in the United States in 1976 was used
as the metal and its alloys, and only 5% was devoted to other uses including
the manufacture of copper chemicals. In 1976, the following categories
accounted for the overall usage of copper in the United States; electrical
equipment and supplies, 53.8%; construction materials, 15.4%; transportation
industry and machinery, 10.7%; ordinance materials, 1,6%; and other uses
(including chemical production and coin making), 5% (Tuddenham and
Dougall, 1979, Weant, 1985).
Some of the uses of copper compounds are in agricultural products
(insecticides, fungicides, herbicides), anti-fouling paints, catalysts, corrosion
inhibitors, electrolysis and electroplating processes, electronics, fabric and
textiles, flameproofing, fuel additives, glass and ceramics. Copper is also
used in cement, food and drugs, metallurgy, nylon, paper products, pigment
and dyes, pollution control catalyst, printing and photocopying, pyrotechnics
and wood preservatives (Kust, 1979).
15
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5. Environmental Fate and Transport
There are a few studies available regarding the fate and transport of copper
in the atmosphere. The particle size distribution of copper aerosols is
important both in terms of the persistence of the particles in the atmosphere
and respirability of the particles. Representative particle-size measurements
expressed as mass median diameter (MMD) for copper aerosols in a few
United States cities are given in Table 5.
Milford and Davidson (1985) calculated the average MMD for copper to
be 1,29 fjm. The average MMD of copper aerosol calculated from Table 5
is 1,3 fjrn. Since particulate matter in the size range of 0.5 pm and 5.0
//m is commonly assumed to be respirable (Nriagu, 1979), the copper particles
in United States aerosols predominantly occur in the respirable range. For
copper particles of —1 /im MMD, —50-60% of the inhaled amount would
be expected to be deposited in the pulmonary compartment, ~20-30% in
the nasopharyngeal compartment and <10% in the tracheobronchial
compartment. About 50-80% of the particles of <1 pm MMD retained in
the respiratory system are absorbed into the bloodstream (Nriagu, 1979).
It should be recognized, however, that the sizes of copper particles emitted
into the atmosphere are source dependent and the MMD data may range
from <0.4-10 fan (Nriagu, 1979). It is probable that high temperature
processes that volatilize copper also cause the eventual condensation of
copper to provide particles of fine particle sizes (Sugimae, 1984). In contrast,
copper particles entering the atmosphere through ore crushing and
windblown dusts are likely to have a larger particle size. Thus, at least 40%
of the total copper particles emitted from non-emission controlled open-hearth
furnaces, smelting operations, municipal incineration, and coal combustion
produce particles of <2 /urn diameter. (Nriagu, 1979). Although direct
investigation demonstrating the particle size of copper in windblown dust
is not available, the study by Dorn et al. (1976) can be interpreted to conclude
that these particles will have larger sizes than particles from high temperature
Table 5. Representative MMD of Copper Particles in Aerosols from Some
United States Cities
City. State or Region
Denver, CO
Chicago, IL
Cincinnati, OH
Washington, DC
Philadelphia, PA
$L Louis, MO
San Francisco Bay. CA
Mies, Ml
Northwest Indiana
Boston, MA
Buffalo, NY
Average (11 locations)
MMD
(urn)
1.54
1.53
1.34
1.24
1.21
1.07
3.0
1.0
0.9
0,8
0.4
1.8
Reference
Lee at at., 1972
Lee et al., 1972
Lee era/., 1972
Lee et al., 1972
Lee et al.r 1972
Lee et al., 1972
fiahn, 1976
Rahn, 1976
fiahn, 1976
Rahn, 1976
Rahn, 1976
MMD - Mass median diameter
16
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processes, Dorn et al. (1976) measured the particle size of copper near a
lead smelter and in a remote area (control area) and found that the smelter
area contained —54% of the copper aerosol with a particle size of <4.7 #m
diameter and the control area, presumably with a higher proportion of
windblown dust, contained —47% of the copper aerosol of diameter <4.7
The chemical form of copper in aerosols has not been well studied. It
has been speculated by Nriagu (1979) that copper sulfides, copper oxides,
copper sulfates and possibly copper silicate particles may originate from
mining, ore crushing and ore beneficiation processes. Smelting operations
may produce particles of copper oxides, elemental copper and copper sulfates.
Copper brazing from various residential and commercial objects are subjected
to municipal incineration and are, therefore, likely to produce emissions
containing copper and copper oxide (Jacko and Neuendorf, 1 977). Copper
sulfate (CuSO4) may also be formed in the atmosphere (Oa) through the
following atmospheric reaction, since sulfur dioxide (SQa) is released during
many processes including smelting operations:
2 CuO + 2 SO2 + O2 — 2 CuSO4
Although no direct evidence of the presence of CuSO^ in aerosol was
reported, indirect evidence such as the presence of a water soluble fraction
in the dust fallout and the presence of an average of 49% soluble fraction
in bulk precipitation from Ontario (Nriagu, 1979) suggests that CuSO4 is
present in the aerosol.
From measurements of particle density of a collected aerosol in
metropolitan Osaka, Japan, Sugimae (1 984) presented some indirect evidence
that the primary chemical composition of the copper particles consists of
copper oxide and elemental copper. The chemical composition of dust particles
collected near a copper smelter in Poland was studied using an X-ray
diffractometer. The authors presented evidence of the presence of CuFeSa
and CuAI2 in the dust fallout near the smelter (Glowiak et al., 1 979).
The removal of copper aerosol from the atmosphere through dry deposition
(dust fall) and wet deposition (rainfall and snowfall) has been studied by
several investigators because of the possible effects of copper loading on
a given ecosystem. The copper content of dustfalls varies from background
soil levels of 1 9-30 vg/g to >50,000 jug/g near smelters. The rate of copper
deposition through dustfall may range from <0.02 //g/emz-year in remote
locations to >20 ^rg/cm2-year in urban areas (lower Manhattan, NY). The
average dry deposition rate for 46 sampling sites in the United States was
3.3 yug/cmz-year. The dry deposition velocity of copper aerosol may vary from
0.4 cm/sec in rural areas to 9.5 cm/sec in heavily urbanized areas (Nriagu,
1979). The concentrations of copper in snowfall and rainfall from different
locations have also been measured. For example, the copper concentration
in rainfall and snowfall at Chedron, NB, was measured to be 4.5 and 4.0
fjg/l, respectively, (Struempler, 1976). The ratio of wet to dry deposition
of atmospheric copper from several locations has been estimated. Depending
on the location, the dry deposition may vary from 2-60% of the total (dry
and wet) deposition of atmospheric copper. Although the ratio of wet to
dry deposition is dependent upon the particle size distribution, topography
of the area and meteorological conditions, the typical ratio is close to unity
(Nriagu, 1 979). For aerosols with lower particulate sizes, however, the wet
deposition rate usually exceeds the dry deposition rate (Davidson et al., 1 981 ;
Lannefors et al., 1 983).
The possibility of long range transport of copper aerosols was studied by
Ouellet and Jones (1983). These authors could not find evidence of any
17
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significant long-range transport of copper into a remote Canadian region
from suspected industrial sources. However, the enhancement of copper
deposition from the atmosphere into sediments of a remote Adirondack lake
in New York, in lake sediments of a remote area in New Hampshire (Galloway
and Likens, 1979), and the increase of copper concentration in snowfall
and ice-sheets in Greenland with the increase of industrialization (Weiss
et al., 1975) show that long-range atmospheric transport of copper is possible.
No direct study estimating the atmospheric residence time of copper
aerosols is available; however, it has been estimated that the residence time
of copper aerosols in an unpolluted troposphere is 2-10 days, in urban and
polluted areas is 0.1 to >4 days, and near an industrial point source (<100
km from source) is <2.0 hours (Nriagu, 1979). Assuming a tropospheric
residence time of 10 days and 30 years as the tropospheric to stratospheric
turnover time (time for all but 37% of tropospheric air to diffuse into the
stratosphere) (Callahan et al., 1979), <0.1% of tropospheric copper aerosol
will be transported to the stratosphere.
The aquatic fate and transport of copper depends on the pH of water,
its redox potential and the availability of other ions, ligands or sorbents present
in water. Gibbs (1973) reported that most of the copper present in river
water was present in the crystalline sediments (74-87%). The author defined
the crystalline portion of the sediment to be that portion that did not release
copper after extraction with MgCIa solution, reduction with sodium dithionite,
and oxidation with sodium hypochlorite. The remaining copper was present
in solution, as organic complexes, in the adsorbed state, in the precipitated
and coprecipitated states and in inorganic solids. The maximum mobile part
was present in the precipitated and coprecipitated states. The speciated
inorganic copper in lake water of pH 7-9 was the following;
Cu(OH)2» CuCO3> [Cu(CO3)a]2"
>CuCI2>[Cu(OH)f >CuSO4 - [Cu2(OH)d2+ >[CuCI]+
>[Cu(QH)<]z~ (Sanchez and Lee, 1978).
At pH >7 and in oxidizing environmental conditions, the controlling
speciated form of copper may be CugCOa (OH}2 rather than Cu(OH)2 and
CuCOa (Lu and Chen, 1977), In a reducing medium, the primary chemical
form may be CuS (Lu and Chen, 1977). The major soluble complexes (both
organic and inorganic) of copper under both oxidizing and reducing conditions
were also determined by these authors (Lu and Chen, 1977). In acidic water
{pH 4.6-5.7), the major copper species may be aquated Cu (II) ion. Other
species, such as CuCO3 and Cu-organic complexes were also present (Sposito,
1981). Therefore, acidification of aquatic media will increase the mobility
of copper in such environments.
The fate of copper with respect to its leachability in purely organic spruce
forest soils was studied by Tyler (1978). Appreciable mobilization of copper
occurred only with prolonged leaching at pH 2.8. Therefore, it does not appear
likely that acidic rainfall will result in significant mobilization of copper from
organic soils unless the pH of rainfall decreases to <3. These authors
estimated that —50% of copper in the top few centimeters of these soils
was organically bound, —18% was in the hydroxy-carbonate form, —7% was
in the adsorbed state, -~11% was bound by other anions and 6% was
irreversibly adsorbed. Only 3% of the copper was extractable with water
at pH 4.S; hence only 3% was mobile at this pH. These authors speculated
that fn urbanized areas the effects of land clearing, profile disruption and
increased acid rainfall may increase copper mobilization in these soils.
18
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6. Environmental and Exposure Levels
6.1. ATMOSPHERIC LEVELS
The atmospheric concentrations of copper are dependent upon the
contribution of the emission sources in a particular area. As noted previously,
these levels are highly dependent upon localized conditions and vary from
one locale to another. Based on the varying concentrations, it is logical to
divide the atmospheric levels into four categories: remote, rural, urban and
suburban, and hot spots (defined as the areas within the heavy dust fall-
out ranges of smelter or ore processing sites). Besides these ambient
atmospheric levels, the level of copper in occupational settings will also be
discussed briefly as it pertains to the scope of this document.
6.1.1. Remote Areas
The atmospheric concentrations of copper in remote locations are important
in that such data can serve as comparison background concentrations. These
are useful to view to gain an idea of anthropogenic contributions of copper
to the total atmospheric burden. The concentrations of copper in several
remote locations (middle of ocean, mountain tops, etc.) were measured and
found to vary from a low value of O.01 ng/m3 at Chacaltraya Mountain,
Bolivia to a high value of 12 ng/ma at the North Indian Ocean {Nriagu, 1979).
The median concentration of copper in these remote locations sampled during
the late 1960's and early 1970's was O.4 ng/m3. Since local soils or crustal
rocks should contribute to the atmospheric copper levels in remote locations,
the enrichment factor for these aerosols is expected to be close to unity;
however, the measured enrichment factors exceeded unity in almost all cases
and were several hundred times higher in a few instances, indicating the
substantial contribution from external sources other than background (e.g.,
aerial transportation) to the total atmospheric burden of copper, even at these
remote locations.
6.1.2. Rural A reas
The atmospheric concentrations of copper in rural locations ranges from
5-50 ng/m3 (Nriagu, 1979). Dorn et al. (1976) measured the atmospheric
copper concentration at ~10 ng/m3 at a rural farm in Southeast Missouri.
The concentration of copper in aerosols from rural locations in Norway and
Sweden was reported to range from 2.3-4.6 ng/m3 (Lannefors et al., 1983).
Stevens et al. (1980) reported the mean concentration of copper in aerosols
from the Great Smoky Mountains, TN, to be <8 ng/m3 and Lioy and Daisey
(1983) reported a mean copper concentration of 10 ng/m3 at Ringwood State
Park, NJ (lightly populated and free of major local sources).
6.1.3. Urban and Suburban Areas
Pertinent data regarding the atmospheric levels of copper in urban and
suburban areas in the United States are available from a number of sources
(McMullen et al., 1970; Lee et aJ., 1972; Hammerle et al., 1973; Moyers
et al., 1977). From these references, the United States atmospheric copper
IS
-------
level ranges from 30-200 ng/m3, with the level of copper in urban air being
2-10 times higher than in rural air (Nriagu, 1979), A summary of the
atmospheric levels of copper in United States urban and suburban locations,
as measured by the National Air Surveillance Networks (U.S. EPA, 1976b)
Is given in Table 6, The mean copper concentrations at urban and suburban
locations in the United States between 1970 and 1974 are 160 and 190
ng/m3, respectively. The atmospheric copper levels in the United States have
not changed and may have remained constant between 1965 and 1974
(Nriagu, 1979). The introduction of various clean air regulations in the United
States since the late 1960's has resulted in an —20% reduction in airborne
participates from 1970-1974; particulate emissions for several elements
including arsenic, cadmium and zinc were reduced by this amount (Nriagu,
1979). During the early 1970's, however, copper followed a different trend.
Data regarding the United States atmospheric concentrations of copper
in the early 1980's are limited. The measurement of atmospheric copper
levels in three urban areas in NJ (Camden, Newark and Elizabeth) from 1981-
1982 showed a range between 17 and 33 ng/m3 with a mean value of
25 ng/m3 (Lioy and Daisey, 1983). Similarly, the atmospheric copper level
In Houston, TXr in 1980 was —30 ng/m3 (Dzubay et al., 1982).
Reports on the seasonal variations in atmospheric copper concentrations
are conflicting. While some authors have reported high concentrations in
summer and low concentrations in winter at certain locations, other authors
have observed the opposite trend in other locations (Nriagu, 1979). This
illustrates that the atmospheric level is more dependent on source than on
seasonal variation. The burning of fossil fuels for heating during the winter
may cause an increase in copper concentration in certain locations. The
increased dispersion of street dusts in the atmosphere during the summer
months may enhance copper concentration in certain locations (urban);
however, the U.S. EPA (1976) study on copper levels during the summer
and winter months for many urban and rural locations showed no consistent
seasonal trend between 1970 and 1974.
6.1,4. Hot Spots
This term is being used to describe specialized areas located near processing
plants. These areas have higher atmospheric levels of copper. For example,
the median copper concentration in Sudbury, Ontario, was 371 ng/m3 prior
to the installation of a tall stack. After this installation, the median copper
concentration decreased to 120 ng/m3 (Nriagu, 1979). The typical copper
concentration in the plumes from several copper smelters in Southeastern
Arizona varied from 2000-9500 ng/m3 compared to an average background
level of 170 ng/m3 (Small et al., 1981). The mean concentration of copper
near a lead smelter In Kellogg, ID, was reported to be 186 ng/m3. The smelting
operation increased the concentration of copper in grass from a background
level of 21-26 ppm to 38-110 ppm (Small et al., 1981). The mean copper
levels near two secondary lead refineries in Toronto were reported to be
340 and 820 ng/m3 (Paciga and Jervis, 1976). Therefore, the highest air
concentration of copper in the United States will be localized and dependent
upon industrial operations in that area.
6.1.5. Occupational Levels
The primary sources of occupational exposure to copper are ore smelting
and related metallurgical operations, welding, handling of copper in
rnetalwork and polishing operations (Stokinger, 1981). The health effects
of industrial exposure to copper in a Norwegian copper plant, a Swedish
20
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Table 6. Summary of Atmospheric Copper Concentrations in United States Urban and Suburban Locations During the Period 1970-
1974*
Year
Number of
Observations
Copper Concentration (ng/m3)
Range
Mean
Median
Urban Locations
1970
1971
1972
1973
1974
790
715
706
555
590
<1-1560
<1-157Q
<1-1440
<1-1330
150
180
160
150
170
100
110
100
100
120
Suburban Locations
1970
1971
1972
1973
1974
124
96
137
99
78
1-1195
14- 880
1- 812
11- 983
23-1147
158
205
178
196
208
81
150
116
138
147
•Source.- U.S. EPA, 1976b
-------
plant handling copper sheeting and in other instances have been described
by Stokinger (1981); however, the breathing zone copper levels were not
reported for these occupational situations.
The occupational concentration of copper in a western copper smelter was
reported by Cant and Legendre (1982). The time-weighted average
concentration in the worker breathing zone varied between 22,000 ng/m3
{22 j/g/m3) at the nickel recovery plant and 487,100 ng/m3 (487 pg/m3)
at a converter furnace area. The level of copper fumes for stainless steel
welders at a petrochemical plant was reported by Wilson et al. (1981). The
mean concentration of copper around a maintenance shop area was reported
to be 3000 ng/m3 (3 /ug/m3); however, personal monitoring data based on
time-weighted average concentrations from welding operations performed
in confined spaces (distillation towers, reactors, etc.) showed a much higher
mean copper concentration of 512,000 ng/m3 (512 //g/m3).
6.2. Water Levels
Data regarding the concentrations of copper in United States drinking water
have been reported in several sources (U.S. EPA, 1980b, 1985; Sandhu et
al., 1975,1977; Page, 1981; Sharrett et al., 1982). Depending on the plumbing
system, pH and hardness of water, copper concentration in drinking water
may vary from a few jjg/l to >1 mg/l (Piscator, 1979). A combination of
low pH, and soft water passing through copper pipes and fittings may produce
the high copper levels in drinking water; however, only a little over 1% of
United States drinking water exceeds the drinking water standard of 1 mg/
I, with the average copper concentration in drinking water reported as —0.13
mg/l {U.S. EPA. 1980b).
Copper concentrations in surface water vary worldwide from 0.5-1000
//g/l with a median of 10 jug/I (Davies and Bennett 1983). The background
concentration of copper in the U.S. surface waters is <20 j/g/l. Higher
concentrations of copper are usually from anthropogenic sources (U.S. EPA,
1980b). The levels of copper in sea water range from 1-5 /ig/l (Davies and
Bennett, 1983). Further details regarding the levels of copper in drinking
and surface water are reported in U.S. EPA (1980b, 1985).
6.3. Food and Dietary Levels
Pertinent data regarding the levels of copper in different foods are available
from several sources (U.S. EPA, 1980b; NAS, 1977; Underwood, 1973,1977).
A general range of copper concentration in foodstuff is 0.1-44.0 ptg/g (wet
weight). Crustaceans, shellfish, organ meats, dried fruits, legumes and nuts
are particularly rich in copper, with copper contents ranging from 20-400
pg/g (dry weight) (Underwood, 1977; NAS, 1977).
Studies conducted between 1930 and 1970 on the dietary intake of copper
generally concluded that the typical U.S. diet provided an intake of at least
2 mg/day of copper, the level that is considered to be adequate for normal
copper metabolism (Andelstein et al,, 1956). Tompsett (1934) reported that
the typical daily intake of copper from food appeared to be 2-2.5 mg/day.
The reported average intake of copper by young children was 1.48 mg/day
(Daniels and Wright, 1934).
6.4. Exposure
6.4.1. Inhalation
For comparison purposes, the inhalation exposure to copper has been
derived based on the average copper concentrations in rural (see Section
22
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6.1.2.) and urban and suburban (see Section 6.1.3.) atmospheres and using
an adult inhalation rate of 20 m3 air/day (Table 7). The mean copper
concentration in hot spots has been derived from its concentration values
measured in three such spots (see Section 6.1.4.). These values are used
to show the relative difference in copper exposures in the four areas, and
should not be considered as any type of average copper exposure. Additionally,
these estimates are for copper and do not consider mixed exposures to
additional compounds.
An increased intake of copper may occur as a result of other environmental
media. Children who eat paint, dirt or clay, smokers and individuals who
spend more time outdoors near high fallout areas are likely to experience
increased exposures to copper (Hartwell et al., 1983). As in the case of a
few other heavy metals (Hartwell et al., 1983), hair may be an easily accessible
indicator of increased body burden. The relationship between increased body
burden and enhanced levels of copper in hair has limitations, but has been
demonstrated for occupational situations where copper-exposed workers had
706 ftg/g of copper in hair compared to a 9 #g/g level for a control group
(Finelli et al., 1984).
Table 7. Inhalation Exposure to Copper for Populations at Different Locations
Daily Inhalation
Mean Concentration Exposure*
Location
Rural
Urban
Suburban
Hot spots
(ng/m3}
25"
160
190
449°
(Mff)
0.5
3.2
3.8
9.0
mBased on an inhalation rate of 20 ms air/day.
bThe mean concentration Is assumed to be an intermediate value for the concentration
range of 5-50 ng/m3.
cThe mean concentration for hot spots has been derived from the concentration values
measured in three spots (186 ng/m3 for Idaho, 340 and 820 ng/m3 for Toronto)
given in Section 6.1.4.
6.4.2. Ingestion
Assuming a daily consumption of 2 I of water with a mean copper
concentration of 0,13 mg/P (see Section 6.2.), the daily intake of copper
through drinking water is ~260 fig,
The average daily dietary intake of copper by an individual in the United
States may range from <2 to ~-4 mg (U.S. EPA, 1980b; Davies and Bennett,
1983). For ingestion, the dietary intake is, in general, an order of magnitude
higher than intake from drinking water, except in rare cases of consumption
of soft water which has been supplied by copper pipes. In the latter case,
intake from drinking water may be as high as >2 mg/day based on the
data of Piscator {1979).
6.5. Contribution of Inhalation to Total Exposure to Copper
In order to achieve a perspective of the levels of copper exposure from
the inhalation route, this section utilizes the estimates from the previous
sections of this chapter. As illustrated in Table 7, the daily inhalation exposure
of the general population to copper would be in the range of 0.5-3.8 fjg/
day. For those individuals living in the immediate vicinity of a major copper
23
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emitting source, the exposure would increase to —9.0 pg/day. This values
does not include those individuals with a combined exposure from living
in the area and working in the processing facility. That exposure could vary
greatly depending upon the plant area which the worker is employed, as
well as the personal protective equipment used. In comparison, the average
daily intake of copper through drinking water is —0.26 mg/day, and may
in ~1% of the cases exceed 2 mg/day (see Section 6.4.2.), The intake of
copper in the diet is 2-4 mg/day (see Section 6.4.2.), and represents the
major source of copper intake for the majority of individuals in the United
States, In —19% of the exposure cases, the intake of copper from drinking
water will be comparable to its dietary intake.
The International Commission on Radiological Protection {ICRPr 1975)
estimated that the daily intake of airborne copper based on the average copper
concentration in air is —0.02 mg/day for a 70 kg reference human. This
indicates that inhalation of air containing background levels of copper would
contribute negligible amounts (<1%) to the average daily intake of copper
and would have little, if any, impact on the overall copper body burden.
Davies and Bennett (1983) estimated that the inhalation pathway will
contribute no more than 0.15 jug/kg to a total copper body burden of —800
A^/kg. Using a high value of a range of median concentrations for copper
in ambient air, the U.S. EPA (1985) estimated that atmospheric copper
contributes no more than 1% to the total daily copper intake. Given that
the above data are estimates, it is still very apparent that exposure from
ambient atmospheric copper concentrations represents a very minor fraction
of total individual copper exposure.
24
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7. Terrestrial and Aquatic Effects
Significant quantities of copper can be deposited in areas downwind from
smelters or other copper-emitting industries. Copper can accumulate to very
high levels in soils and plants in these areas (Hutchinson, 1979), causing
direct effects on terrestrial ecosystems. Runoff from affected terrestrial areas
and direct atmospheric deposition may also contribute significant copper
loadings to aquatic ecosystems {Hutchinson, 1979; Demayo et al., 1982).
Possible consequences of these copper inputs will be discussed in this
chapter.
7.1. Terrestrial Ecosystems
Adverse effects in terrestrial ecosystems occur as a result of atmospheric
deposition from copper and other smelters; however, since smelter emissions
contain a variety of toxic substances beside copper, it is difficult to attribute
these effects to atmospheric copper deposition alone (Hutchinson, 1979).
In soils exposed to atmospheric deposition, high levels of copper and other
metals may occur that can be directly toxic to certain soil microorganisms
and can disrupt important microbial processes in soil, such as nutrient cycling.
Hutchinson (1979) summarized several studies concerning heavy metal
effects on microbial and fungal activity in soils, and found that copper and
other metals inhibited mineralization of nitrogen and phosphorus in
contaminated forest soils. Regression analysis indicated that copper was
more important than other metals in controlling these processes. Hutchinson
(1979) also cited studies that reported lower fungal species diversity in soils
contaminated with heavy metals; copper was found to be more toxic to these
species than other metals. This evidence suggests that while other metals
in contaminated soils contribute to the observed effects, copper may be the
most important in terms of toxicity.
Certain plant species (e.g., lichens and mosses) are especially sensitive
to copper. High levels may cause elimination of sensitive species and selection
for resistant ones, thereby changing community composition and species
diversity. These effects have been observed in areas near smelters in Arizona,
Pennsylvania, Ontario and Sweden (Hutchinson, 1979). In general, vegetation
is completely devastated near the smelter, with a gradient of increasing
species abundance and diversity radiating outward with the more tolerant
plant species appearing closest to the smelter.
Some plants accumulate copper at high levels, with low-growing grasses
generally having the highest concentrations and tree foliage the lowest. The
major route of uptake appears to be from soil rather than direct atmospheric
deposition (Hutchinson, 1979), since copper is unlikely to be transported
across leaf cuticles. Radishes grown in controlled environments in soils taken
from areas of atmospheric deposition exhibited elevated copper levels. Plants
grown on soils from areas closest to smelters exhibited decreased growth,
but growth was improved by addition of lime, presumably because higher
soil pH decreased metal solubility and uptake (Hutchinson, 1979). Davis and
Beckett (1978) reported decreased yields of lettuce, rape, wheat and ryegrass
grown in sand culture with nutrient solutions containing 1.1-1.4, 0.3-2.8,
1.3 and 2.0 mg Cu/l, respectively. Decreased plant yields and/or elimination
of important species in the food chain due to copper toxicity would result
25
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in a decreased food supply for herbivore populations and man in the case
of crop species.
Aside from the potential decrease in food supply, there has been little
documentation of effects of atmospheric copper on wildlife. Some effects
on domestic animals have been reported, however. Ruminants, especially
sheep, are sensitive to copper poisoning (Gooneratne et al., 1980; Underwood,
1977). Describing chronic copper toxicity in sheep, Ishmael and Gopinath
(1972) reported that copper accumulated in the liver for several weeks or
months, followed by the sudden onset of severe hemolytic effects. Liver
lesions developed progressively in the prehemolytic phase. Gracey et al.
(1976) reported high SGOT enzyme levels, indicative of hepatic damage,
and slightly elevated renal and hepatic copper levels in sheep grazed on
copper rich grassland. No deaths from chronic copper exposure (during grazing
season) occurred over a 3-year period during which a total of 47 kg Cu/
ha was applied to the area. Theil and Calvert (1978) reported the development
of massive hernolysis with high levels of copper in the liver, kidney and
plasma in sheep treated orally with 20 mg CuSOvSHzO/kg bw/day (copper
sulfate) within 7 weeks. The excess copper caused an increase in the
concentration of iron in the plasma and spleen, possibly by interfering with
iron metabolism and binding. Hepatic damage was observed in three
histopathological studies of sheep chronically exposed to copper. King and
Bremner (1979) fed sheep diets containing 29 ppm copper for 24 weeks;
Wilhelmsen (1979) gave sheep daily doses of 4600 mg/day in food; and
Gooneratne et al. (1980) administered oral doses of 20 mg/kg/day, 5 days/
week for 48 days. Hepatic changes in these studies consisted of necrosis,
hepatocyte swelling and significant increases in lysozyme content. Gopinath
et al. (1974) also reported kidney effects (copper accumulation, proximal
tubule degeneration and necrosis) in sheep developing copper-hemolysis after
receiving copper sulfate at doses of 20 mg/kg/day for up to 10 weeks.
Incidents of chronic copper poisoning in sheep generally have occurred
in areas of high copper levels in soils where sheep graze on plants that
tend to concentrate copper (Underwood, 1977). In ruminants, relatively low
copper levels in the diet (<16 mg/kg) may cause toxic effects if the
molybdenum content of the food is low, while a high level of molybdenum
fn the diet may cause copper deficiency (Friberg et al., 1979). Although no
such incidents have been reported in wildlife, it is reasonable to assume
that chronic copper poisoning can affect those species as well. To the extent
that atmospheric inputs increase copper levels in soil and vegetation, and
may disrupt the food chain, they have the potential to affect wildlife
populations.
7.2. Aquatic Ecosystems
It Is likely that atmospheric sources contribute significant amounts of copper
to certain bodies of water, especially those that lie downwind from industrial
regions (Critchley, 1983; Demayo et al., 1982; Nriagu, 1979). The possible
ecological and toxicological effects of copper in aquatic ecosystems must
therefore be addressed; however, a detailed review of the literature is beyond
the scope of this document. For ambient water, the reader is directed to
U.S. EPA (1980b); for drinking water, an excellent review can be found in
U.S. EPA (1985).
U.S. EPA(1980b) thoroughly summarized the information that was available
at that time and drew several conclusions. The acute toxicity of copper to
aquatic organisms is greatly affected by water chemistry, the toxicity
decreases with increasing hardness and alkalinity. Apparently, chronic
toxicity is not strongly affected fay these parameters, however. Some of the
26
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more sensitive aquatic species comprise daphnidS, SCUdS, midges
(chironomids) and snails, which are important food organisms for fishes (U.S.
EPA, 1980b). Elimination of these organisms could result in decreased fish
production if alternative food sources were not available. Elevated copper
concentrations could also be directly toxic to fish, resulting in elimination
of desirable sensitive species (e.g., salmonids) and possible replacement by
less desirable resistant species. A large volume of laboratory data concerning
the toxicity of copper to a variety of aquatic species was tabulated and
summarized by U.S. EPA (1980b). These data are highly variable because
of differences in test conditions (water chemistry, temperature, form of copper
and life stage of organism that was used) that greatly influence copper toxicity.
Because of the variability in toxicity due to environmental conditions, it is
difficult to relate laboratory results to field situations. It would therefore not
be useful to present these data in this report. In general, however, lab studies
indicate that 0.005-0.015 mg Cu/l is a NOAEL for several aquatic animal
species (U.S. EPA, 1976). Although copper sulfate has been used to control
nuisance aquatic plants in ponds, no adverse effects on aquatic plant species
were reported at concentrations lower than this. Additional data in the more
recent literature did not contradict this level. U.S. EPA (1980b) concluded
that the ambient water quality criteria to protect aquatic life is 0.0056 mg/
I for freshwater species and 0.0040 mg/l for saltwater species, expressed
as a 24-hour average of total recoverable copper.
Some of the field studies concerning effects of copper on aquatic
ecosystems were summarized by Demayo et al. (1982). Shifts in fish and
invertebrate community structure occurred in streams that were experimen-
tally polluted with copper. Sensitive insect species such asPsephenus(beetle),
Baetis sp. and Stenonema interpunctatum (mayflies) disappeared, and the
community was dominated by chironomids (midges) when copper
concentrations exceeded O.O52 rng/l. Fish community structure changed,
probably as a result of impaired reproduction or movements of sensitive
species.
7.3. Conclusions
Elevated copper concentrations can affect both terrestrial and aquatic
ecosystems, causing changes in community structure and nutrient cycling.
In most cases, however, atmospheric copper inputs alone are not large enough
to cause substantial ecological effects. The worst case examples of the
influence of copper on terrestrial and aquatic ecosystems are those near
processing plants in the areas termed hot spots. In these areas, species
diversity has been drastically changed. A full study on the food chain effects
has not been documented.
27
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8. Pharmacokinetics and Mammalian Toxicology
8.1. Pharmacokinetics
8.1.1. Absorption
Limited data are available regarding the absorption of inhaled copper or
copper compounds. Copper-containing granules in the lung, liver and kidney
have been observed in vineyard workers exposed during spraying of Bordeaux
Mixture (an aqueous solution of lime and 1 -2% copper sulfate used to control
mildew on grapes) (Viltar, 1974; Pimental and Menezes, 1975), Workers
exposed to copper dusts and/or fumes have exhibited signs of metal fume
fever (MFF) or "brass-founders' ague," an occupational disease characterized
by malarialike symptoms (Gleason, 1968; Armstrong et al., 1983; Finelli et
al., 1984). This is indirect evidence that copper can be absorbed through
the lungs. Pulmonary absorption of copper has been reported in rats exposed
to 50-80 mg/m3 of a copper oxide aerosol (Batsura, 1969). Copper oxide
crystals were observed to migrate across the air-blood barrier in the lung
and were found in the plasma 6 hours after exposure. Oavies and Bennett
(1983) estimated that in humans only 20% {based on 50% absorption of
the fractional amount retained in the lungs) of inhaled copper is eventually
absorbed through the lung. Another 20% is retained in the lung tissue, while
the remainder is probably removed by the bronchial mucosa (Davies and
Bennett, 1983). The mechanism of copper absorption in the lung is unknown
at this time.
Copper absorption in mammals after oral administration occurs primarily
in the upper gastrointestinal tract (Evans, 1973) and is apparently regulated
by the intestinal mucosa (Mason, 1979). At least two mechanisms serve
to control Gl absorption of copper (Gitlan et al., 1960; Crampton et al., 1965),
an energy-dependent process involving the absorption of eopper-amino acid
complexes {Kirchgessner et al., 1967) and an inducible carrier protein
mechanism that presumably involves binding to metailothionein (Mason,
1979; Evans, 1973; Sternlieb, 1980; Evans and Johnson, 1977). Absorbed
copper is predominantly bound to albumin and is transported in the plasma
where peak concentration levels are reached 1 -3 hours following ingestion,
Absorption of dietary copper can be affected by a number of factors, including
competition with other metals (e.g., cadmium and zinc)for binding sites (Ogisu
et al,, 1974, 1979; El-Shobaki and Hummel, 1979; Fischer et al., 1981),
nutritional status (Kirchgessner et al., 1973; Krishnamachari, 1974;
Sandstead et al., 1979; Harmoth-Hoene and Schelenz, 1980; Miller and
Landes, 1976), and treatment with other substances such as oral
contraceptives (Onderka and Kirksey, 1975), carbon tetrachloride (Tichy and
Cikrt, 1976), chelating agents (Forth et al., 1973) and a variety of other
chemicals (Pleho, 1979; Moffitt et al., 1972).
Although estimates of the percentage of orally absorbed copper in humans
vary widely, more recent studies have reported a figure of ~50% for general
assessment with a range of 32-70% for adults (Strickland et al,, 1972; King
et al., 1978; Oavies and Bennett, 1983) and 42-85% for children 3-6 years
of age (ICRP, 1975). Since absorption (as well as other kinetic processes)
of copper is governed by homeostatic mechanisms, the percentage of
absorbed copper would be expected to be greater when the body stores are
28
-------
depleted and ambient concentrations are low, and would be expected to
be significantly less whenthe body stores are adequate and the dietary copper
concentration is high. Data on rates of copper absorption in human tissue
could not be located in the available literature.
Copper is also reportedly absorbed through burned skin when applied as
copper sulfate during debridement procedures (Holtzman et al., 1966) and
through intact skin as bis(glycinato)-copper (II) (Walker et al., 1977). In rats,
absorption occurred from copper wire (Oreke et al., 1972) or a copper
intrauterine device (Oster and Salgo, 1977) implanted in the uterus as a
spermicidal contraceptive agent. In addition, elevated fetal copper levels
indicate that copper can cross the placenta! barrier to be absorbed by the
fetus.
8.1.2. Distribution
Following absorption, copper is loosely bound to albumin and amino acids
and is transported to the liver, the main storage organ for copper. Once
in the liver, copper is either retained, excreted into the bile or incorporated
into ceruloplasmin, an cr-globulin, which represents ~90% of the serum
copper (Sternlieb et al., 1961; Underwood, 1977; Stokinger, 1981). Copper
can also be released for incorporation into several copper-dependent enzymes
or for the synthesis of erythrocuprein, a superoxide dismutase, which
accounts for 60% of the copper present in red blood cells (Shields et al.,
1961). Because copper is tightly bound to ceruloplasmin, the albumin and
amino acid-associated copper complexes are responsible for copper
distribution to and uptake from various tissues. Ceruloplasmin functions as
a major regulator of copper retention and storage and represents an important
homeostatie mechanism for controlling copper levels in the body (Underwood,
1977; Stokinger, 1981).
The total body copper content in a representative 70 kg man is estimated
to range from 70-120 mg (USEPA, 1980b; ICRP, 1975; Stokinger, 1981;
Underwood, 1977) of which —33% is present in the liver and brain and
—33% is found in muscle tissue (Williams, 1982). Smaller quantities are
found in the kidneys and heart. Table 8 outlines the tissue levels measured
in human adults in both normal subjects and in patients with Wilson's disease
(see Section 9.2.). Levels of copper in whole blood, red blood cells, white
blood cells, and serum in a normal individual reportedly are 89, 93, 20 and
108 ug copper/100 ml, respectively (Stokinger, 1981).
Copper distribution in the fetus is very different from distribution in the
adult. Fetal copper concentrations have been found to increase 3- to 4-fold
in the last trimester due in part to rapid tissue growth and the formation
of liver stores (Shaw, 1973; Dauncey et al., 1977). Approximately 50% of
the cooper found in a newborn is present in the liver as neonatal hepatic
mitochondracuprein (Porter, 1966). At birth, the copper body burden in an
infant is ~-4 mg/kg compared with —1.4 mg/kg in adults (Underwood, 1977).
Furthermore, the liver in a newborn has a 6- to 10-fold higher concentration
of copper than the adult liver (USEPA, 1980b). The liver of the newborn
has concentrations of copper of ~30 mg/kg wet weight, but during the first
year of life its level decreases to between 5 and 10 mg/kg wet weight (Friberg
et al., 1979). Plasma copper and serum ceruloplasmin levels are low at birth
(—33% of that found in adults), but increase rapidly as the liver begins
synthesizing ceruloplasmin, so that by 3-5 months of age circulating copper
concentrations are similar to those observed in older children and adults
(Henkin et al,, 1973; Schorr et al., 1958), This limited research suggests
that infants could be especially susceptible to higher levels of copper intake
before their copper homeostatie mechanisms are fully developed,
29
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CO
o
Table 8. Tissue and Body Copper Levels in Representative Adult Man*
Copper /jtfg/g Fresh Tissue)
Tissue/ Body Part
Liver
Kidney
Heart
Spleen
Lung
Muscle
Stomach
Intestine (large)
Rib
Long bone
Brain
Nail
Skin
Adrenal
Pancreas
Testis
Ovary
Cornea
Cartilage
Hair
CS fluid
Bile
Normal"
7,8
2.8
3.8
1,5
1,5
1,2
2,3
2.1
NR
2,9
5,4
15.6
0.80
1.8
2.4
1,1
1.7
3.8
0,55
23.4
0.13
2.6
Normal6
7.1
1.66
1.90
0.85
1.10
1.2S
1,07
1.1
0,4
1.19
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Wilson's Disease
99.2
36.2
3.2
NR
NR
1.2
4.9
1.6
NR
31.0
54,9
16.4
1.1
2,4
3.1
NR
1.3
35.1
1.8
15,8
0.15
0.7
"Source: Stokinger, 1981
^Levels were determined several decades apart, which may account for the different values.
NR = Not reported
-------
8.1.3. Metabolism/Homeastat/c Control Processes
Upon entering the liver, the primary organ of copper metabolism (Evans,
1979), copper is initially bound to a 10,000 dalton protein (Terao and Owen,
1973), presumed to be a thionein (Evans, 1973). Other hepatic copper binding
proteins have also been reported (Winge et al., 1975; Riordan and Gower,
1975; Evans et al., 1975) and the transcription of the genes for some of
these (i.e., metallothionein) has been observed to be induced by the presence
of copper (Winge et al., 1975; Premakumar et al., 1975; Durnam and Palmiter,
1981).
Copper bound to proteins in the liver will eventually reappear in the blood,
in copper-dependent enzymes and in bile components (Terao and Owen,
1973). Ceruloplasmin is a major regulator of plasma copper (Broman, 1964;
Owen, 1965). Through its synthesis and release, ceruloplasmin is able to
help maintain copper balance in the body (USEPA, 1980b), as evidenced
by plasma copper levels in pregnant women which are 2- to 3-fold higher
than normal. This has been related to increased synthesis of ceruloplasmin
and increased stores of copper in the maternal liver which may be associated
with increased estrogen levels (Henkin et al., 1971; Markowitz et al., 1955;
Scheinberg et al., 1954). Ceruloplasmin is presumed to release copper at,
or within, the target cell membrane (Marceau and Aspin, 1973a,b; Owen,
1971 ),from which it is incorporated into eytochrorne oxidase and other copper
proteins (Hsieh and Frieden, 1975). Copper is required in hemoglobin
formation, pigment formation, carbohydrate metabolism, tissue respiration
(Van Ravensteyn, 1944), catecnolamine biosynthesis (Ahmed et al., 1981),
crosslinking of collagen and elastin (Rucker and Tinker, 1977; O'Dell et al.,
1978) and cross-linking of hair keratin (Danks et al., 1972),
Copper metabolism is highly dependent on the presence of other metals,
most notably zinc, cadmium, molybdenum and iron. Underwood (1979)
reviewed the literature pertaining to the interactions between copper and
several of these trace elements. Molybdenum, along with sulfate, can alter
the copper status of animals by increasing urinary and biliary copper excretion
(Underwood, 1979; NAS, 1977). Zinc and iron both antagonize the absorption
of dietary copper in experimental animals probably by competing for binding
sites in the stomach and duodenum. This results iri lower hepatic and plasma
copper concentrations (Demayo et al., 1982). High levels of cadmium in the
diet also can inhibit copper uptake, plasma ceruloplasmin content, and hepatic
copper levels while enhancing copper retention in the blood, heart and spleen.
Mercury and silver also apparently interfere with copper distribution
(Underwood, 1979; Demayo et al., 1982) without affecting uptake, while
lead reportedly disturbs copper absorption leading to depressed plasma copper
and ceruloplasmin levels (Underwood, 1979).
8.1.4. Excretion
Copper is removed from the body by being incorporated into the feces,
urine, perspiration, saliva, hair, nails and menstrual fluid (Sorel et al., 1984).
Fecal copper represents unabsorbed dietary copper in addition to copper
excreted in the bile, the saliva and from the gastric and intestinal mucosa
(Goflan and Delier, 1973). Approximately 50% of the daily ingested copper
will pass directly to the feces, while "~25% will appear in the bile (ICRP.
1975; Stokinger, 1981; Williams, 1982). Daily fecal excretion amounts to
~2.4-3.5 mg in a reference man and represents >95% of total copper
excretion (ICRP, 1975). Urinary excretion of copper in humans is estimated
to account for only —0.5-4,0% of the daily turnover (Mason, 1979; Dowdy,
1969). The ICRP (1975) estimated that in a reference man —50 /ig/day is
31
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excreted in urine, 40 fig/day in sweat and 3 //g/day in the hair and nails.
Copper is also lost in the female menses with estimated losses of 0.11-
0.74 rng per menstrual period (Greger and Buckley, 1977; Leverton and
Binkley, 1944; Ohlson and Daum, 1935). The ICRP (1975) reported menstrual
copper loss to be —Q.55 mg per 28 days or 20 /tig/day.
Underwood (1977) estimated that of the 2-5 mg copper ingested daily
by adults, 0.6-1.6 mg (32%) is absorbed, while the remainder is lost from
the body with the feces. The majority of the absorbed copper (0.5-1.3 mg)
is excreted in the bile while only 0.01-0.06 mg appears in the urine. The
ICRP (1975) reported that copper balance in a reference man is maintained
by an average daily copper intake of 3,5 mg from food and fluids and 0.02
mg from airborne sources and average daily losses of 0.05 mg in the urine,
3.4 mg in the feces (unabsorbed copper and biliary excretions) and 0.07
mg by other routes (sweat, hair, and menstrual fluid). These reports indicate
that humans have sophisticated homeostatic mechanisms involving
absorption, distribution and excretion that are able to maintain a physiological
level of copper in the body.
The mean retention time for copper, based on the body burden, intake
rate and absorption fraction, was calculated to be -40 days, which
corresponds to a half-life of ~4 weeks (Davies and Bennett, 1983). A short
biological half-life for copper, coupled with well-established homeostatic
mechanisms (rate of absorption, ceruloplasmin synthesis and release), makes
it apparent that in normal individuals, there is significant protection against
excess copper accumulation as when daily intakes exceed daily requirements
(USEPA, 1980b); however, there are special susceptible groups at risk to
high levels of copper (see Chapter 9).
8.2, Mammalian Toxicology
Table 9 summarizes the various noncancer health effects of copper
observed in experimental animals. Two recent inhalation studies reported
the effects of 0.6 mg/ma copper chloride (CuCIa) administered to rabbits
6 hours/day, 5 days/week for 4-6 weeks. Examination of lung tissue revealed
no significant differences in phospholipid content or in the number of
histological lesions between treated and control animals; the lungs from
copper-treated animals appeared essentially normal. A statistically significant
increase in the number of alveolar type II cells was observed (Johansson
et al.. 1984). Lundborg and Camner (1984) reported that the number of
alveolar macrophages and the lysozyme concentration in lavage fluid from
the lungs of rabbits treated as indicated above were similar to control animals.
Averaging the dose to 24 hours/day, 7 days/week and assuming that 1.9
kg rabbits have an inhalation rate of 1.06 mVday, the daily dose is calculated
to be 60/JB/kg/day (0.6 mg/m3x6/24x5/7x1.06 mgVday -5-1.9 kg). Because
these studies only involved examination of tissues directly exposed to copper,
they are difficult to interpret when systemic toxicity resulting from inhalation
exposure is of concern.
Pimental and Marques (1969) exposed a group of 12 guinea pigs to an
atmosphere saturated with Bordeaux Mixture (aqueous solution of lime and
1.5% CuSO4) 3 times/day for 6,5 months (duration of each exposure was
not reported). Examination of the lungs of the exposed guinea pigs revealed
micronodular lesions and small histiocytic granulomas. A daily copper expo-
sure level cannot be derived from this study, nor can the effects of copper
sulfate be separated from those due to the lime. Whether the exposure
situation was analogous to that of vineyard workers also cannot be determined
from the given information. In a German paper (Eckert and Jerochin, 1982),
the researchers showed that inhalation of Bordeaux mixture (copper sulfate
32
-------
aerosol) was responsible for the development of lung changes. Copper suifate
was the responsible agent. Transitory pulmonary effects have also been
observed in dogs following short exposures to dusts of copper stearate and
copper acetate (Stokinger, 1981).
The toxicity of copper in experimental animals has also been investigated
using oral and intraperitoneal routes of exposure. Acute toxicity studies have
demonstrated intraperitoneal LDso values in mice ranging from 3.5 mg/kg
for copper metal dust (Stokinger, 1981) to 8.7 mg/kg for CuSO^BHaO (Jones
et al., 1980). Rat oral LDso values reportedly fall between 140 mg/kg for
CuCI2 and 960 mg/kg for CuSQ4-5H2O (Stokinger, 1981).
Short-term (90 days) oral studies in swine and rats exposed to the equivalent
of ~2-40 mg copper/kg/day have consistently demonstrated the accum-
ulation of copper in several tissues as well as toxic effects mainly in the
liver, kidneys, blood and gastrointestinal tract (see Table 9). Dose- dependent
copper accumulation in the blood, spleen and liver was observed in rats
fed 0-4000 ppm copper (as copper suifate) in the diet for 4 weeks and was
accompanied by dose-related decreases in food intake and weight gain
(Boyden et al., 1938), Heavy copper deposition in the livers and kidneys and
copper-induced histopathology in these organs were reported in rats given
TOO mg/kg/day copper suifate for 20 days (Rana and Kumar, 1978).
Parenchymal degeneration and perilobular sclerosis were seen in the livers
and tubular engorgement and necrosis were observed in the kidneys of these
rats. Rats treated similarly exhibited significant decreases in skeletal growth
and weight gain, as well as an altered hematological profile (Rana and Kumar,
1980).
Statistically significant increases in brain dopamine, norepinephrine and
copper levels were observed in male albino rats treated daily for 21 days
by intraperitoneal injection of 2 mg Cu/kg as cupric chloride (Malhotra et
al.. 1982).
Pigs maintained on diets supplemented with copper carbonate (600-750
ppm) or copper suifate (250-425 ppm) for 48-79 days exhibited a variety
of toxic effects including the gradual development of anemia, jaundice, hepatic
necrosis, gastrointestinal hemorrhage and decreased weight gain (Suttle and
Mills, 1966a,b)- Kline et al. (1971) reported that pigs exposed to 100-500
ppm copper suifate in the diet for 54-88 days had alterations in weight gain,
reductions in hemoglobin and hematocrit and greater than normal hepatic
copper levels compared with control animals.
In a subchronic study, Haywood (1980) noted that the liver and kidneys
of rats treated with 2000 ppm copper (as copper suifate) in the diet for 15
weeks experienced a triphasic response during the exposure period. The
first stage was characterized by the accumulation of copper with some signs
of cellular disruption followed by a second stage of severe hepatic and renal
necrosis. The final phase was marked by decreasing copper content and
regeneration of damaged tissue as the animals appeared to develop tolerance
against the effects of copper.
Another subchronic study (Narasaki, 1980) reported significant copper
accumulations in the liver, serum, brain and kidneys as well as depressed
weight gain and hepatic necrosis in rats receiving daily intraperitoneal
injections of 1.5 mg copper/kg as copper lactate. These effects are similar
to those seen in animals exposed acutely to copper.
There are limited data concerning the chronic toxicity of copper in
experimental animals. Heavy accumulation of copper was observed in the
liver and kidneys of rats maintained for 16 months on a diet supplemented
with 5000 ppm copper acetate (Howell, 1959). Similar depositions were seen
in the liver and kidney as well as the brain and the large and small bowel
in rats exposed to 1250 ppm cupric acetate monohydrate in the drinking
33
-------
Table 9, The Toxiclty of Copper In Experimental Studios In Mammals
Species/
Strain
Rats/NR
Rats/albino
Rats/NR
Rats/white
Sex/No,
M.F/10
M/10
M/12
F/2-4
M/1-B
Duration
of
Exposure
(days)
20
20
21
28
Route
of
Adminis-
tration
gavage
gavage
Intra-
peritoneal
oral
Vehicle
NR
NR
saline
diet
Dose/
Exposure
asCu
{mg/kg/
day}
40
40
2
21.3*
34,9*
46.0s
32.3s
Compound
CuSOt
CuSO*
CuC/z
CuSO*
CuSO*
CuSO*
CuSOt
Effect
Necrosis of the kidneys
and liver
Decreased weight gain
and blood components
Increased brain dopamine
and norepinephrine
Dose-dependent decrease
in food intake and
growth; increased blood,
liver and spleen copper
concentration
Rapid weight loss and
Reference
Rana and
Kumar, 1978
Rana and
Kumar, 1980
Malhotra
etal.,1982
Boyden
et al,, 1938
Rabbits/NR
Rabbits/NR
Pigs/large
white
Pigs/large
white
M/8
M/8
F/6
28-42 Inhalation
28-42 Inhalation
47-60 oral
air
air
diet
F/6
48
oral
diet
0,06"
0.06"
108
ppm*
6,4-
15.4*
CuClz
CuSOn-
SHZO
CuCOa-
Cu
death within 1 week
50% increase in volume
density of alveolar
type II cells
No change in lung
lysozyme levels
Growth depression after
14 days; gastrointestinal
hemorrhages, jaundice,
hypertrophy and cirrhosis
of liver
Three groups of animals
on different basal diets
all developed anemia
Johansson
etal,, 1984
Lundborg and
Camner,1984
Suttle and
Mills, 1966b
Suttfeand
Mills, 196Gb
-------
Table 9. (continued)
01
Dose/
Duration Route Exposure
of of as Cu
Species/ Exposure Adminis- (mg/kg/
Strain Sex/No, (days) tration Vehicle day)
Pigs/ large F/12
white
Pigs/Hampshire, NR/8
Yorkshire
NR/8
Pigs/large F/6
white
Pigs/Hampshire, NR/ 1 2
Yorkshire
Rats/NR M/4
Rats/Wfstar M/36
49 oral diet 22'
54 oral diet 3.2*
ft/1
61 oral diet 3.21
5.5'
79 oral diet 2.6"
88 oral diet 1.8'
2,5'
2.9'
105 oral diet 40°
>160 Intra- water 1.5
peritoneal
Compound Effect
CuCOa' Liver necrosis and hypo-
Cu chromic microcytic anemia
(OHh-
CuSOA' None
SHzO
Decreased weight gain.
decreased hemoglobin.
hematocrit
CuSO*- No effect compared with
SHzO control
Reduced growth and
hemoglobin levels
CuSOA' Slight weight increase;
SHzO jaundice
CuSOA' Slight increase in aver-
SHsO age weight gain
None
Slight increase in aver-
age daily weight gain
CuS04 Liver necrosis through
week 6 followed by
regeneration
CufCsHs Decreased growth rate;
Oa)z increased serum liver
enzymes; altered kidney
Reference
Suttle and
Mills, 1966a
Kline etal..
1971
Suttle and
Mills, 1966b
Kline et al,
1971
Hay wood, 1980
Marasaki,
1980
-------
Table 9. (continued)
w
en
Species/
Strain
Guinea pigs/NR
Rats/NR
Rats/Sprague-
Dawley
Sex/No.
NR/12
M.F/NR
M/22
Duration
of
Exposure
(days)
198
486
902
Route
of
Adminis-
tration
Inhalation
oral
oral
Vehicle
air
(hydrated
lime)
diet
drinking
water
Dose/
Exposure
as Cu
(mg/kg/
day)
saturated
«>*
80°
20.7'
Compound
CuSO*
(Bordeaux
Mixture)
Cu(CzHa
OdfHzO
Cu(C2Hs
Oa/2-WzO
Effect
Micronodular lesions and
small histiocytic granu-
lamas in the lung
Deposition of copper in
the liver and kidneys
functions
Deposition of copper
in the liver and kidneys
Reference
Pimental and
Marques, 1969
Howell, 1959
Owen, 1974
11 These doses were calculated from reported daily food intakes for each exposure group using an average rat weight of 235 g which was
derived from the daily food intake for control animals using the assumption that the rats consume food equivalent to 5% of their body weight,
The high dose group had a severely restricted food intake that was partially responsible for the deaths observed in this group,
b Dose was calculated by multiplying copper concentration of 0.6 mg/m3 by 5/7 and 6/24 to expand dosage to a 7-day week and 24-hour
day, respectively, and by assuming that a 1.9 kg rabbit has an inhalation rate of 1.06 m3/day. An absorption factor was not included,
" Daily dose cannot be calculated from reported data. The only information given was a starting pig weight of 17 kg.
d Dose calculated from weight and food intake data. The dose range was due to food intake levels of pigs on different basal diets fU.S, EPA,
1985).
8 Dose calculated from weight and food intake data (U.S. EPA, 198SJ.
' Daily doses were calculated using the reported feed/weight gain ratio and the average of the reported weights before and after the exposure
period for each treatment group.
fl Assumes a rat consumes food equivalent to 5% of its body weight/day.
h Equivalent daily dose cannot be calculated from the available information.
' The daily intake of copper in a 300 g rat was reported to be 0.2 mg from 22 g food and 6 mg from 15 ml Hs.0.
NR = Not reported
-------
water for up to 9O2 days (Owen, 1974). Neither of these studies reported
any other signs of copper toxicity, which limits their usefulness in assessing
the hazard of chronic copper exposure,
8.3. Other Effects
8.3,1. Carc/nogenicity
Bionetics Research Laboratory (BRL, 1968} studied the carcinogenicity of
a copper-containing compound, copper hydroxyquinoline, in two strains of
mice (B6C3F1 and B6AKF1) fed a diet that provided sufficient copper (i.e.,
5.7 mg Cu/kg feed). The copper complex was administered orally and by
subcutaneous injection. Using subcutaneous administration, groups of 18
male and 18 female 28-day-oId mice of both strains were given a single
injection of gelatin or 1000 mg copper hydroxyquinoline/kg bw (180,6 mg
Cu/kg) suspended in 0.5% gelatin. The animals were observed until they
were 78 weeks old, and then killed. Oral exposure consisted of similar groups
of 7-day-old mice treated daily by gavage with 1000 mg copper hydroxy-
quinoline/kg bw (i.e., 180.6 mg Cu/kg) suspended in 0.5% gelatin until age
28 days, whereupon the compound was administered in the feed at a
concentration of 2800 ppm (505.6 ppm Cu). Animals were fed the treated
diet until they were 78 weeks old, at which time they were killed. Positive,
negative, vehicle and untreated control animals were also maintained and
compared with treated animals. All animals killed or found dead were
subjected to routine macro-and microscopic histological analysis to identify
tumor-bearing tissues. No statistically significant increases (with respect to
controls) in the incidence of lymphatic leukemias, reticulum cell sarcomas,
pulmonary adenomas or carcinomas, hepatomas, hepatic carcinomas,
mammary carcinomas, skin carcinomas or cavernous angiomas were
observed in orally-treated mice,
In the portion of the study using subcutaneous exposure, male B6C3F1
mice had an increased incidence of reticulum cell sarcomas compared with
controls (e.g., 6/17 treated; 8/141 control; p<0.001). No tumors were
observed in treated male B6AKF1 mice. Female mice of either strain had
low incidences of reticulum cell sarcomas. Treated and control B6C3F1
females had incidences of reticulum cell sarcoma of 1/18 and 1/154,
respectively. Treated and control B6AKF1 females had incidences of reticulum
cell sarcoma of 3/18 and 5/157, respectively (BRL, 1968).
Oilman (1962) studied the carcinogenicity of cupric oxide, cupric sulfide
and cuprous sulfide in 2-to 3-month-old Wistar rats. Groups of 30-32 rats
were given single intramuscular injections containing 20 mg of cupric oxide
(16 mg Cu), cupric sulfide (13.3 mg Cu) and cuprous sulfide (16 mg Cu)
into the left and right thigh of each rat. All animals were observed for up
to 20 months, after which histopathological evaluation was conducted.
Controls were not reported. Of the animals receiving cupric oxide, cupric
sulfate and cuprous sulfate, the ratios of animals surviving the experiment/
animals dosed were 10/32, 19/30 and 18/30, respectively. No injection-
site tumors were observed, and the groups of animals receiving cupric oxide,
cupric sulfide and cuprous sulfide had 0, 2 (mammary fibroadenomas and
reticulocytoma), and 1 (mammary fibroadenoma), respectively.
Crystalline CuS has been shown to induce DNA strand breaks in Chinese
hamster ovary cells (Robison et al., 1982). In the study, the researchers
found that water insoluble crystalline sulfide of copper induced considerable
reductions in the molecular weight of DNA, Accordingly, these compounds
are all actively phagocytosed by the ovary cells and thereby can have
pronounced intracellular effects. The fact that some metal sulfides cause
DNA strand breaks and reduce its molecular weight may account for the
37
-------
ability of these compounds to cause cellular transformation (Robison et al.,
1982). The effects of insoluble metal compounds have not been investigated.
Haddow and Horning (1980) published a table of bioassay results on various
copper compounds from which Table 10 was prepared; however, no
experimental detail was provided. Data for determining the carcinogenicity
of inhaled copper or copper compounds are not available. Some short-term
tests have indicated that certain of the copper salts may have characteristics
suggestive of carcinogens. However, the overall weight-of-evidence suggests
that there is insufficient data to determine the carcinogenic potential at this
time. Using the USEPA Guidelines for Carcinogenic Risk Assessment (USEPA,
1986), copper is in Group D; Not classifiable as to human carcinogenicity.
8,3.2. Mutagenicity
The available data obtained from in vitro mutagenicity assays do not provide
sufficient evidence to form a conclusion regarding the mutagenicity of copper
(Table 11).
A reverse mutation assay reported dose-related mutation in £. coli with
2-10 ppm copper sulfate (Demerec et al,, 1951). More recently, Moriya et
al. (1983) reported the absence of mutation in E. coli incubated with up
to i mg copper quinolinolate/plate and in Salmonella typhimuriurn strains
TA98, TA1535, TA1537 and TA1538. Copper 8-quinolinolate was mutagenic
to S. typhimurium strain TA100, but only when a source of mammalian
metabolic activation was included (Moriya et al., 1983). Up to 5 mg of copper
sulfate/plata did not induce reverse mutations in S, typhfmurium TA98 and
TA100 either with or without metabolic activation.
Other Investigators have obtained negative mutagenic results with copper
sulfate or copper chloride in other microbial assays. These include
Saccharomyces cerevisiae D-7 (Singh, 1983) and Bacillus subtillis (Nishioka,
1975; Matsui, 1980; Kanematsu et al., 1980).
Several isolated cell mutagenicity assays have produced positive results
with copper compounds. Errors in DNA synthesis from poly(c)templates have
been induced in viruses (Sirover and Loeb, 1976) when incubated in 20-
150 mM CuClzor CutCaHaOJa. Casto et al. (1979) induced enhanced simian
adenovirus cell transformation in Syrian hamster embryonic cells with the
addition of 0.38 mM Cu2S and to a lesser extent with 0.08 mM of CuSO4.
Single strand breaks in DNA in isolated rat hepatocytes were detected after
exposure to 1.0 mM, but not 0.03 or 0.3 mM cupric sulfate (Sina et al.,
1983). The authors suggest that this is false-positive because cytotoxicity
was >30% and cell lysis would result in DNA fragmentation.
High concentrations of copper compounds have been reported to induce
abnormalities at mitosis in rat ascites cells and recessive lethals in Drosophila
mefanogaster. Law (1938) reported increases in the percent lethals observed
in Drosophila larvae and eggs when exposed to copper by rnicroinjection
(0.1% CuSO4) or immersion (concentrated aqueous CuSC^), respectively.
8.3.3. Teratogenicity and Reproductive Toxicity
Copper deficiency has been observed to produce teratogenic response in
lambs, goats, rats, guinea pigs, dogs and chicks. Terata include neural
degeneration, reduced growth, skeletal malformations and cardiovascular
lesions (Hurley and Keen, 1979).
The spermicrdal properties of copper are well known and were first
demonstrated in the 19th century (Holland and White, 1982). Prevention
of mammalian embryogenesis because of the small amounts of copper
38
-------
Table 10. Tumorigenicity of Some Copper Compounds*
u
CD
Agent Under Test
Copper-dextran
8-hydroxyquinoline
copper complex
Cross-conjugated
macrocode copper
porphyrin
Copper
phthalocyanine
Copper
phthalocyanine
tetra-3-
sulfonic acid
Copper
phthalocyanine
tetra-4-
sulfonic acid
Number and
Strain of Mice
20 stock
20 stock
20 stock
20 stock
20 stock
20 stock
Number of Weekly
Subcutaneous Injections/
Dose
6/0.1 ccofl
in 4 dilution
39/0.1 mg
4/0.5 mg
34/0.5 mg
36/0,5 mg
25/0,5 mg
Months of
Experiment to
Date and Survivors
10 (13}
10 (14)
10 (14)
8(17)
8 (20)
S (11)
Tumors
Recorded
None
1 pleomorphic
sarcoma
None
None
None
None
*Source; Haddow and Horning, 1960
-------
Table 11. Muiagenfcity Data for Copper Compounds
Assay
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Indicator/
Organism
Salmonella
typhimurium
TA98, TA100
S. typhimurium
TA100
S, typhimurium
TA100
S. typhimurium
TA98, TA1S3S,
TA1537, TA1538
S. typhimurium
TA100,LT2
Saccharomyces
cerevisiae D-7
Escherichia
coli WP2 her
E, coli Sd-4
Application
plate
incorporation
plate
incorporation
plate
incorporation
plate
incorporation
spot test
(paper disc)
spot test
(center wall]
plate
incorporation
plate
incorporation
Concentration
or Dose
< 5000 pg
copper
sulfate/plate
0.6-10 ug copper
8-quinotinolate/
plate
0,8-10 ug copper
8-quinolinolate/
plate
< 5000 fig
copper
8-quinolinolate/
plate
Wfjlof10~9to
W~3M
aqueous
solution of
0.1 M copper
sulfate
< 5000 ug
copper
8-quinolinolate/
plate
2-10 ppm copper
sulfate
Activating
System
± rat liver
S-9
+ rat liver
S-9
- rat liver
S-9
±rat liver
S-9
NA
NA
NA
NA
Response Comment
NC
+ NC
NC
NC
NC
NC
NC
•*• Dose
related
Reference
Moriya et al.,
1983
Moriya et al.,
1983
Moriya et al,,
1983
Moriya et al.,
1983
Tso and Fung,
1981
Singh, 1983
Moriya et al.,
1983
Demerec
et al., 1951
at >2
ppm
-------
Table 11. (continued}
Assay
Growth
inhibition
free)
Growth
inhibition
(rec)
Growth
inhibition
(rec)
Errors in
DNA
synthesis
DNA
single-
strand
breaks
DNA
single-
strand
breaks
Indicator/
Organism
Bacillus
subtilis
H17.M4S
B. subtilis
N1617,N1645
B. subtifis
H17,M45
Avian myelo-
blastosis
virus, DNA
polymemse
rat
hepatocytes
rat
hepatocytes
Application
spot test
(paper disc)
liquid
cultivation
spot test
(paper disk)
liquid
holding
plate
incorporation.
then alkaline
elution
plate
incorporation.
then alkaline
elution
Concentration
or Dose
0.05 ml of
0.05 M
Cud or Cuds
solution
16.5-18 mg
copper
sulfate/l
0,05 ml of 0.001-
10MCuCI
or CuClz
solution
20-1 50 mM
CuC/2 or
CujCzHzOdz
0.03-0.3 mM
cupric
sulfate
1.0 mM
cupric
sulfate
Activating
System
NA
NA
NA
,
NA
NA
NA
Response Comment
NC
NC
NC
+• NC
Elution
rate > 3
times
the
control
rates
+ Elution
rate > 3
times
controls
rates.
toxicity
>30%
Reference
Nishioka, 1975
MatsuL 1980
Kanematsu
era/., 1980
Sirover and
Loeh, 1976
Sina etal..
1983
Sina et al. ,
1983
-------
Table 11. (continued)
Assay
Cell
transforma-
tion
Cell
transforma-
tion
Recessive
lethals
Recessive
lethals
Indicator/
Organism
Syrian hamster
embryo cells
by simian
adenovirus
SA7
Syrian hamster
embryo cells
by simian
adenovirus
SA7
Drosophila
melanogaster
Oregon-R
D, melanogaster
Oregon-R
Application
plate
incorporation
plate
incorporation
microinjection
into larvae
Immersion of
eggs for 10
minutes
Concentration
or Dose
>0,38mM
CtlyjS
0,08-0,64 mM
CuSO*
0.1%CuS04
concentrated
aqueous
solution of
Ct/S0<
Activating
System Response Comment
NA + Enhancement
ratio:
Transformation
frequency
treated
Transformation
frequency
control
= 16,2
NA + Enhancement
ratio =
2,2
NA + 1.06%
lethals
(0% in
controls)
NA + 1,25%
lethals
(0%in
controls)
Reference
Casto et at.
1973
Casto et at,,
1979
Law, 1938
Law, 1938
-------
Table 11, (continued)
u
Assay
Mitotic
abnormal-
ities
Mitotic
abnormal-
ities
Indicator/
Organism Application
MTK-sarcoma in vivo
III
rat ascites
MTK-sarcoma in vivo
///
rat ascites
Concentration
or Dose
ISOmg
copper
sulfide/kg
l,p.
300 mg
copper
sulfate/kg
i.p.
Activating
System Response Comment
NA + Chromatic
aggregation
stickiness
contraction.
scattering.
fagging
and
clumping
of
chromosomes
NA + Reversible
events;
lobated
nuclei,
karyorrhexis
and
multipolar
spindle
formation
Reference
Kumura and
Makino, 1963
Kimura and
Makino, 1963
NA = Not applicable; NC = No comment
-------
absorbed from intrauterine loops or wires fashioned from copper has been
demonstrated (Oster and Salgo, 1977; Hurley and Keen, 1979).
The embryotoxicity and teratogenicity of i.v. injection of copper salts was
first demonstrated in hamsters by Ferhn and Hanlon (1974). Copper sulfate
and copper citrate dissolved in demineralized water were both observed to
reduce embryonic viability and produce abnormal offspring when injected
into the lingual vein of pregnant dams on the 8th day of gestation. Day
1 of gestation was considered the day after which mating occurred.
Administration of demineralized water alone produced no abnormal embryos
(Table 12). Administration of copper sulfate (2.13 mg Cu/kg) to 16 dams
caused the formation of 12 abnormal of 155 live embryos (five thoracic wall
hernias, four encephalocoeles, two spina bifida and one microphthalmia).
Similar administration of copper sulfate (at 4.25 mg Cu/kg) to three dams
caused the development of four abnormal of seven live embryos (one
exencephaly. one hydrocephalus, one abdominal hernia and one abnormal
spinal curvature). Administration of higher doses of copper sulfate (7.5 and
10 mg/kg) resulted in 100% mortality of embryos and dams, respectively.
Copper administered in a chelated form (copper citrate) was observed to
be a more potent teratogen than the uncomplexed form (copper sulfate).
Administration of 0.25-1.5 mg Cu/kg (as citrate) to 13 dams resulted in
the development of four abnormal of 172 live embryos (two tail defects,
one microphthalmia and one cranioarchischisis). Similar administration of
1.8 mg Cu/kg to six dams produced 14 abnormal of 81 live embryos (13
tail defects and 1 meningocele). Administration of 2.2 mg Cu/kg to eight
dams produced 35 abnormal embryos (25 tail defects, 6 thoracic wall defects,
2 microphthalmias, 1 abdominal wall defect and 1 facial cleft). Administration
of 4.0 mg Cu/kg to two dams resulted in the death of both.
Experiments with 64Cu nitrate injected into pregnant dams showed that
with 0.55,12.8, 0.53, 1.47 and 0.81 jug S4Cu/g tissue in the maternal blood,
maternal liver, uterus, placenta and embryo, respectively, copper permeates
the hamster placenta (Perm and Hanlon, 1974).
DiCarlo (1980) produced terata in hamsters by i.p. injection of copper citrate.
Pregnant female Golden hamsters were given an i.p. injection of
demineralized water either alone or containing 2.7 mg copper citrate/kg
on the 8th day of gestation. The day after mating was considered day 1
of gestation. The control and dosed groups consisted of 37 and 89 animals,
respectively. All dams were killed on the 12th or 13th day of gestation,
whereupon all viable embryos were removed for histopathological analysis.
Copper was not observed to affect maternal survival, but did reduce maternal
body weight gain, possibly by inducing a high resorption rate. Control embryos
were observed to be free of gross teratological effects, but on histopathological
examination, 2 of 68 randomly-chosen embryos were observed to have cardiac
muscular ventricular septal defects. Of the treated embryos, 45 of 855
embryos examined had gross malformations (e.g., limb and tail defects and
edema}. On histopathological examination, 58 cardiac defects (various
ventricular septal malformations) were observed in 49 embryos with gross
malformations. The author stated that copper's role as a prosthetic group
in oxidative enzymes could lead to teratogenesis when present in excessive
amounts by interfering with these metabolic reactions during organogenesis.
However, the relevance of these studies is questionable because i.p. injection
of a high level of copper does not duplicate any of the means whereby toxic
levels might enter the body under normal environmental conditions.
Lecyk (1980) observed teratogenic effects in two strains of mice fed diets
supplemented with copper sulfate before mating. Various numbers (see Table
12) of C57BL and DBA mice were maintained for 1 month on diets
supplemented with 0, 500, 1000, 1500, 2000, 3000 and 4000 ppm copper
44
-------
Table 12, Teratogenicity Data for Copper Compounds
Daily Dose Observa-
Compound, Species/ No. Dams or Treatment tion Maternal
Route Strain at Start Vehicle Exposure Days* Day Response
in
Fetal Response
Reference
CuSQ* mouse/ 21 diet 0 30toO 19
oral C57BL
10 25.9 mg
Cu/kg/
daf
18 51.7mg
Cu/kg/
daf
7 77.6 mg
Cu/kg/
day10
10 103.5mg
Cu/kg/
daf
22 155.3 mg
Cu/kg/
day*
18 207,1 mg
Cu/kg/
daf
Avg.
Litter
Size
NR 3,1
4.6
4.5
4.4
4.2
2.5
1.9
Avg,
Weight
fgf
1,1
1.3
1.2
1.1
1.2
1.0
1.0
Malforma-
tions
0 Lecyk,
1980
0
0
0
0
1 skeletal
3 hernia,
hydro -
cephalus,
skeletal
-------
Table 12, (continued)
Daily Dose Qbserva-
Compound, Species/ No, Dams or Treatment tion Maternal
Route Strain at Start /• Vehicle Exposure Days" Day Response
Fetal Response
Reference
O)
CuSO*, mouse/ 17 diet 0 30toO 19
oral DBA
10 25,9 mg
Cu/kg/
day*
10 51.7 mg
Cu/kg/
day*
14 77,6 mg
Cu/kg/
day*
10 103.5mg
Cu/kg/
day*
18 155.3 mg
Cu/kg/
day"
20 207,1 mg
Cu/kg/
day*
Avg.
Litter
Size
NR 4,5
5,4
5.1
4,1
4.1
3.1
2,7
Avg.
Weight
(91
1.0
1,2
1.2
1,2
1.1
1.1
1.1
Malforma-
tions
0 Lecyk,
1980
0
0
0
0
2 skeletal
4 encepha-
loceles,
skeletal
-------
Table 12. (continued)
Compound,
Route
Copper
citrate,
i.p.
Species/
Strain
hamsters/
Golden
No. Dams
at Start
37
Vehicle
D.I,
H20
Daily Dose
or
Exposure
0
Treatment
Days"
8
Observa-
tion
Day
12-13
Maternal
Response
NR
Fetal Response
Avg. Avg.
Litter Weight Malforma-
Size fgj tions
Free of gross teratogenic effects
(0/455), 2/37 had abnormalities,
2/68 heart defects
Reference
DiCarlo,
1980
CuS04,
i.v.
hamsters/
Golden
89
10
D.I. 27mg/kg
D.I.
HZ0
12-13
No effect 45/855 fetuses with gross defects
on survival, (limb, tail, edema) 19/89 litters
but a 10% had abnormalities, 58 ventricular
reduction septal defects in 49 fetuses
in body
weight
gain.
NR 92% viable embryos,
8% resorption,
0% abnormal
Perm and
Hanlon,
1974
16
2,13 mg
Cu/kg
NR 74% viable embryos, 26% resorp-
tion, 6% abnormal
4,25 mg
Cu/kg
NR 14% viable embryos, 86% resorp-
tion, 8% abnormal
7.50 mg
Cu/kg
NR 0% viable embryos, 74% resorp-
tion, 8% abnormal
10,0 mg
Cu/kg
Death
-------
Table 12. (continued)
00
Compound,
Route
Copper
citrate
Species/ No, Dams
Strain at Start
hamsters/ 13
Golden
6
8
2
Daily Dose Observe- *
or Treatment tion
Vehicle Exposure Days* Day
D.I. 0.25-1.5 8 12-13
HzO mg
Cu/kg
1.8 mg
Cu/kg
2.2 mg
Cu/kg
4.0 mg
Cu/kg
/
Maternal
Response
NR
NR
NR
Death
Fetal Response
Avg. Avg.
Litter Weight Malforma-
Size fgj lions
83% viable embryos, 16% resorp-
tions, 2% abnormal
59% viable embryos, 41% resorp-
tions, 17% abnormal
66% viable embryos, 34% resorp-
tions, 35% abnormal
Reference
Ferm and
Hanlon,
1974
* Relative to day of conception (day 0)
b Assume mice consume 13%ofbw/day
NR = Not reported
-------
sulfate. These concentrations are equivalent to 0, 199, 398, 597, 796, 1195
and 1593 ppm Cu, respectively. Assuming that mice consume food at a
rate of 13% of their body weight per day, doses at 199 and 398 ppm copper
are equivalent to 25.9 and 51.7 mg Cu/kg/day, respectively. After 30 days
of treatment, the females were mated with males of respective strains and
the day on which a vaginal plug was observed was determined as day 0
of gestation. Pregnant mice were allowed to gestate until the 19th day, at
which time they were killed and the fetuses were examined for morphological
defects. Low doses (500-1000 ppm) of copper were observed to stimulate
embryonic development; increased litter size and increased fetal weight
resulted. Higher copper doses (>1000 ppm) increased fetal mortality and
decreased Utter size. When supplemented in the diet at 3000 and 4000
ppm, copper sulfate caused a level (2-8% of living fetuses) of various skeletal
and other malformations that were absent at lower doses and controls. No
abnormal fetuses were observed in control groups. However, the observations
by Boyden et al. (1938) imply that food intake decreases at high concentrations
of copper. Therefore, the actual food intake may have been seriously reduced,
therefore adversely affecting fetal development.
8.4. Summary
Efficient homeostatic mechanisms generally protect mammals from the
adverse effects of dietary copper deficiency or excess. With the exception
of ruminant animals, the chronic toxicity of orally-administered copper has
not been well investigated. An inborn error in copper metabolism in humans
(Wilson's disease) may be the only form of chronic copper toxicosis in man
(see Chapter 9).
Ingestion of 100 mg Cu/kg/day by rats for 1 week resulted in no observable
adverse effects (e.g., no liver accumulation and no adverse renal or hepatic
morphology). Administration of this dose for up to 6 weeks caused severe
renal and hepatic effects in rats. Further administration of copper at this
dose to rats for up to 15 weeks resulted in no further damage; rather,
regeneration of hepatic and renal tissues was observed (Haywood, 1980).
Support for these observations was reported by Rana and Kumar (1980)
who observed liver and kidney necrosis in rats fed 25.4 mg Cu/kg/day for
20 daysl
Increased liver copper concentrations were observed in rats fed 16.7 mg
Cu/kg/day for 27 days (Boyden et al., 1938) and 11.0 mg Cu/kg/day for
21 days (Miranda et al., 1981). Administration of higher levels of dietary
copper resulted in elevated liver and splenic copper levels, growth reduction
and reduced dietary intake resulting in death (Boyden et al., 1938).
Ma I hotra et al. (1982) observed that rats given daily i.p. injections of 2
mg Cu/day had significantly (p<0.05) elevated levels of brain dopamine and
norepinephrine when compared with controls.
Pigs appear to be more sensitive than rats to the acute toxicity of copper.
Suttle and Mills (1966a,b) reported adverse effects in pigs given copper
supplements in doses as low as 6.4 mg Cu*Vkg/day for 48 days and 2.6
mg Cu+a/kg/day for 79 days. Kline et al. (1971) reported beneficial effects
of copper (as copper sulfate) supplementation in Hampshire and Yorkshire
pigs (—24 kg) at doses of 1.8-3.2 mg Cu+2/kg/day for 61-88 days.
Administration of 5.5 mg Cu*2/kg/day for 61 days caused adverse effects
(e.g., growth reduction, reduced hemoglobin and increased hepatic copper)
(Kline et al., 1971).
Liver damage, hemolytic anemia, renal damage and gastrointestinal
irritation are effects of acute copper poisoning that have been observed to
occur in laboratory animals and man (Bremner, 1979; Owen, 1981).
49
-------
Equivocal results have been obtained from experiments designed to
evaluate the carcinogenicity and mutagenicity of copper compounds.
Administration of copper compounds to mice by subcutaneous injection has
been reported to induce tumor formation (BRL, 1968; Haddow and Horning,
1960}. The only tumorigenicity studies for orally-administered copper were
negative (BRL, 1968).
Microbial mutation assays using copper compounds have generally
provided negative results. Some mutagenic activity by copper compounds
at high concentrations has been observed in cell culture assays. Copper
sulfate was observed to increase the frequency of recessive lethal mutations
in D. melanogaster at high concentrations (Law, 1938).
Copper compounds have been observed to elicit a teratogenic response
at ~2 mg Cu/kg when injected into female hamsters on the 8th day of
pregnancy (DiCarlo, 1980; Perm and Hanlon, 1974). Lecyk (1980) reported
a teratogenic response of orally-administered copper sulfate in mice for the
30-day dietary exposures at 103.5 mg Cu/kg/day. Copper deficiency has
also been shown to produce teratogenic responses.
Pertinent data regarding the carcinogenicity, mutagenicity or teratogenicity
of copper or copper compounds following inhalation exposure could not be
located in the available literature. Data pertaining to the selective effects
elicited by copper species of different valences also could not be located
in the available literature. The studies reviewed in this chapter are concerned
primarily with copper-related compounds, since data on elemental copper
and health effects have not been located.
50
-------
9. Human Health Effects and Populations at Risk
9.1. Human Health Effects
The noncaneer health effects of airborne copper fumes, dusts or mists
in humans result primarily from industrial exposures and are manifested
predominantly by dermatologic and respiratory symptoms. Despite the fact
that occupational exposure to copper and copper products is common, cases
of copper intoxication are rare (Cohen, 1974; Williams, 1982). A condition
known as "metal fume fever" characterized by influenza-like symptoms
(stuffiness of the head, sensations of chills or warmth, general aches and
pains) has been reported in workers exposed to fine copper dusts (—0.1 mg
Cu/m3) (Gleason, 1968), copper fumes (Armstrong et al., 1983) and copper
oxide and copper acetate dusts (Stokinger, 1981; Cohen, 1974), In the Gleason
(1968) study, the author noted that the data do not permit broad
generalizations about the toxicological aspects of fine airborne copper dust;
the purpose of the study was to Justify exhaust control. The study design
was very limited and high levels of aluminum from the polishing abrasive
were found. Once exhaust fans were installed, the final air samples showed
negligible amounts «8 /jg/m3) of copper dust in the air. In general, the
acute effects of copper intoxication are readily reversible since removal of
the offending agent is usually the most effective treatment (Cohen, 1974).
Chronic effects observed from industrial exposures to copper include contact
dermatitis (Stokinger, 1981; Cohen, 1974; Williams, 1982), mild anemia (0.6-
1 mg Cu/m3) (Finelli et al., 1984) and leukocytosis (Armstrong et al., 1983).
A study of 14,562 white male workers from the copper and zinc smelting
industries did not show any overall mortality excesses as compared with
the mortality of the total U.S. population (Enterline et al., 1986). In this study,
there were only two disease associations of importance. Neither association
involved copper per se; however, an association between arsenic exposure
and lung cancer was found to be strong, even at low levels. The other finding
was between sulfur dioxide exposure and emphysema mortality.
Reports of local and systemic effects in vineyard workers exposed to
Bordeaux mixture (see Chapter 8) have revealed a potentially more serious
consequence of inhaled copper. Two male vineyard sprayers reportedly had
histological lesions in the lungs characterized by desquamation, intra-alveolar
acrophages and inter-alveolar septal histiocytic granulomas (Pimental and
Marques, 1969). These lesions were similar to those observed in guinea
pigs exposed to Bordeaux mixture (see Chapter 8). Villar (1974) analyzed
15 cases of "vineyard sprayer's lung" and reported that dyspnea, weakness,
decreased appetite, weight loss, radiographic opacities and copper deposits
in the lungs were common symptoms. Copper-containing liver granulomas
and nodular fibrohyaline scars were observed in three other cases of the
disorder (Pimental and Menezes, 1975). Estimates of the level of exposure
were not reported in any of these studies. It should be noted, however, that
the adverse conditions found in vineyard workers may be complicated by
concomitant exposures to many other agents in addition to Bordeaux mixture.
For instance, vintners have been reported to experience elevated exposures
to arsenic compounds used in vineyards (USEPA, 1980a) and arsenic
inhalation exposures have been implicated as possible causative agents for
lung cancers.
51
-------
In another study examining cytologic changes of the respiratory tract in
vineyard sprayer workers, professional inhalation of copper sulfate was
shown to affect the respiratory epithelium and the pulmonary parenchyma!
(Plamenac et al., 1985). Sputum specimens from 52 rural workers engaged
in vine-spraying Bordeaux mixtures (1.5% copper sulfate solution} were
compared with 51 rural workers from the same region who did not work
In the vineyards and did not come in contact with the copper sulfate solution.
Subjects were 25-55 years of age with normal chest roentgenograms and
were subdivided into smokers and nonsmokers. The vineyard workers
averaged 9 years of exposure. Results showed enhanced expectoration of
sputum in a high percentage of vineyard sprayers and considerably more
frequent than those of the control group. Atypical squamous metaplasia was
noted in 29% of smoking vineyard sprayers. The authors (Plamenac et al.,
1985} suggest that occupational exposure to the copper (i.e., the copper sulfate
solution) may be a significant etiological factor in the occurrence of
bronchogenic carcinoma in these individuals. The presence of large numbers
of eosinophils in the sputa of vineyard sprayers suggests the possibility of
an allergic reaction to the Bordeaux mixture (i.e., to one of its constituents).
However, the investigators concluded that it is uncertain which mechanism
(toxic, allergic or inflammatory) was responsible for the occurrence of changes
in the respiratory epithelium (Plamenac et al., 1985).
Most reports of copper intoxication have resulted from ingestion of copper
compounds usually by accidental poisonings, suicide attempts or drinking
copper-contaminated water. Typical symptoms include Gl irritation,
headache, dizziness and a metallic taste in the mouth. Table 13 summarizes
the health effects of ingested copper in humans.
Chuttani et al. (1965) reported the clinical data from 53 cases of acute
copper sulfate poisonings, fngestion of up to 12g copper resulted in immediate
metallic taste, nausea, vomiting, epigastric pain, diarrhea, jaundice,
hemoglobinuria and/or hematuria, anuria, oliguria, hypotension and coma.
Autopsy of five patients revealed ulceration of the gastric mucosa, hepatic
centrilobular necroses, biliary stasis and renal tubular cell necrosis.
Daily intakes of copper ranging from 2-32 mg due to contaminated drinking
water has reportedly caused general gastric irritation characterized by nausea,
vomiting, abdominal cramps and diarrhea (see Table 13) (Spitalny et al., 1984;
Nicholas and Brist, 1968; Semple et al., 1960; Wyllie, 1957).
Copper sulfate has been involved in a number of poisoning episodes that
involved doses of copper ranging from <1-20 g. An 18-month-old boy who
drank a solution containing 3 g cupric sulfate (—1.2 g Cu) developed acute
hemolytic anemia, reduced glucose-6-phosphate dehydrogenase activity,
hematuria, glycosuria and proteinuria. High copper levels in serum and urine
were also observed (Walsh et al., 1977). The child gradually recovered and
after 1 year clinical signs were normal with serum copper levels within the
normal range. A 24-year-old man ingested ~600g of copper sulfate over
a 4-month period (~2 g Cu/day) and developed symptoms that included
gastrointestinal pain and hemolytic anemia (Roberts, 1956). The patient was
discharged after 2 weeks with only mild signs of anemia. No follow-up
examination was conducted.
A 27-year-old man who ingested at least 50 g of copper sulfate (20 g
Cu) was reported by Chugh et al. (1975) to be cyanotic, oliguric and anemic.
The patient also showed signs of severe intravascular hemolysis and
methemoglobinemia and died 16 hours after the poisoning. Another episode
of copper sulfate poisoning (the amounts were unknown) resulted in
sulfhemoglobinemia, acute tubular necrosis, renal failure and death (Sanghvi
et al., 1957). In this case, however, anoxia caused by sulfhemoglobinemia
may have caused the renal necrosis (USEPA, 1985) implying that sulfate
52
-------
Table 13. Effects of Oral Exposure of Copper and Copper Compounds in Humans
en
CO
Sex/Age/
Number
Male/ 32/1
Female/5,7/2
Male, female/
14-60/53
Male/NR/20
Male/ NR/ 150
Female/NR/15
Male/ 2/1
Compound
copper
copper
copper
sulfate
copper
copper
sulfate
copper
copper
sulfate
Vehicle
drinking water
drinking water
oral fngestion
contaminated
tea
contaminated
tea
contaminated
cocktails
oral ingestion
Dose
(mg Cu/kg/
Exposure day}
2-8 mg/l for 1.5 years 0,06-0. 23"'b
2-8 mg/l for 1.5 years 0, 1 -0,4°
1-30gCuSO< 6-171*
7-210"
8 oz, tea containing >Q, 1 b
>30 ppm Cu
8 oz, tea containing >0, 1 4b
>44 ppm Cu
5-32 mg estimated 0,09-0,55*
exposure from cocktail
shaker
3g(1dose) 120*
Effect
Episodic emesis and
abdominal pain
Episodic emesis and
abdominal pain
Diarrhea,
hemoglobinuria,
and/or
hematuria.
anuria, jaundice,
ofiguria, death, coma.
hypotension8
Diarrhea, nausea.
vomiting'1
Gastroenteritis,
dizziness,
headache in
18/150
Weakness, abdominal
cramps, headaches.
nausea, dizziness
and vomiting in
10/15
Hemolytic anemia.
hematuria,
glycosuna.
poteinuria
Reference
Spitalny
etal., 1984
Spitalny
etal., 1984
Chuttani
et al., 1965
Nicholas and
Brist, 1968
Semple
etal., 1960
Wyllie, 1957
Walsh
etal., 1977
-------
Table 13. (continued)'
01
Sex/Age/
Number
Male/27/1
Male/24/1
Compound
copper
sulfate
copper
sulfate
Dose
(mg Cu/kg/
Vehicle Exposure day) Effect
oral ingestion S0g(1dose) 286" Cyanosis, oliguria.
severe intra-
vascular hemolysis.
methemoglobinemia;
death within
16 hours
water 600 g over a 4-month 29" Gastrointestinal
period pain, hemolytic
anemia
Reference
Chugh
etal,, 1975
Roberts,
1956
"Assumes an adult daily water intake of 21
^Assumes adult 70 kg man
^Assumes a weight of 20 kg and a daily water intake of 11 for a child
^Assumes adult 58 kg women
"Listed in order of frequency
'Assumes 10 kg child
NR = Not reported
-------
may have contributed to the effects of the poisoning. Stein et al. (1976)
reported the death of a 44-year-old female after being given an emetic dose
of copper sulfate (796 mg Cu) administered after the patient had ingested
alcohol and diazepam. The woman suffered from respiratory collapse, massive
gastrointestinal hemorrhage, hemolytie anemia and renal and hepatic failure.
Autopsy revealed acute renal tubular necrosis and a liver copper concentration
of 75 ppm. Copper was responsible for most of these effects as they are
consistent with those seen in other copper sulfate poisoning incidents.
Children may be especially susceptible to copper overdoses, A 15-month-
oid boy developed symptoms that included prostration, vomiting, red
extremities, hypotonia, photophobia and peripheral edema (Salmon and
Wright, 1971), The serum copper level was very high (286 //g/100 ml) while
the plasma ceruloplasmin level was essentially normal (22.5 mg/100 ml),
thus eliminating the possible involvement of Wilson's disease. These effects
were presumably caused by the copper content (0.35-0.79 mg/l) in the
drinking water ingested over a 3-month period, suggesting that some infants
may be responsive to daily intakes of <1 mg copper/day.
A disease known as Indian Childhood Cirrhosis has frequently been
associated with high intakes of copper in children ranging in age from 6
months to 5 years (Bhandari and Sharda, 1982; Bhargava, 1982; Chaudhary,
1983; Pandit, 1982; Pandit and Bhave, 1983; Sharda, 1984; Tanner et al.,
1983). This disorder is characterized by widespread hepatic necrosis,
Mallory's hyaline inclusions in many hepatocytes, intralobular fibrosis, poor
regeneration and very high hepatic copper content (Pandit, 1982; Pandit and
Bhave, 1983). It is generally believed that milk and water stored in brass
and copper containers leads to increased dietary copper in children, which
is at least partly responsible for the pathogenesis of the disease (Bhandari
and Sharda, 1982; Bhargava, 1982; Sharda, 1984). In addition, many of
the epidemiological features of Indian Childhood Cirrhosis (sibling studies,
geographical and religious influences) can be explained by this hypothesis
(Chaudhary, 1983; Tanner et al., 1983).
Other epidemiology studies have failed to establish a definite link between
chronic exposure to copper and cancer or other diseases. Increased mortality
from hypertension or hypertensive heart disease and elevated rates of cancer
of the trachea, lung, bronchus, liver and biliary passages have been observed
in counties containing primary copper smelters (PEDCo, 1978); however,
copper ore concentrates also contained arsenic, lead, nickel, antimony and
selenium and the authors cautioned against overemphasizing the association
between copper and increased disease rates.
Schrauzer et al. (1977) reported that there is a direct proportionality
between blood copper concentrations and mortality due to cancer of the
intestine in males and females and cancer of the lung, breast and thyroid
in females. The authors contended that excess copper in the diet may be
the cause of the elevated blood copper levels. Morton.et al, (1976) observed
a significant negative association between copper concentrations in tap water
samples and central nervous system malformations (e.g., anencephalus,
neural tube malformations) in South Wales. These associations, however,
can only be critically evaluated when additional epidemiological information
becomes available.
9.2. Populations at Risk
Several populations may be considered especially susceptible to excess
environmental copper exposure. The following sections discuss these groups
briefly.
55
-------
9.2.1. Wilson's Disease—Hepatolenticular degeneration, also known
as Wilson's disease, is an autosomal recessive disorder (Scheinberg, 1979)
that occurs in perhaps 1 of 200,000 individuals (Schernberg and Sternlieb,
1969). This disease affects normal copper homeostasis and is characterized
by an excess retention of hepatic copper, decreased concentration of plasma
ceruloplasmin, impaired biliary capper excretion and hypercupuria (Evans,
1979; Schroeder et at., 1966). Increased copper deposition in the brain,
kidneys and cornea are also characteristic of Wilson's disease (see Table
6) (Evans, 1973). Limiting copper intake through air, water and food is
essential in treating the disease (Schroeder et al., 1966). It is apparent that
patients with this disease should have low intakes of copper. This has been
mainly achieved in the past by checking and limiting copper intake from
water and diet. When air concentrations are low, the contribution of copper
from air to the total absorbed amount of copper will still be negligible, since
this air amount will be far below the concentrations from food and water.
9.2.2. G6PD Deficient Individuals—An inherited deficiency of the
enzyme glucose-6-phosphate dehydrogenase (G6PD) was first discovered in
1956, and was found to be the basic defect in cases of hernolytic anemia
following exposure to certain drugs, mothballs and fava beans (Naiman and
Kosoy, 1964). This abnormal gene has been shown to be more prevalent
in newborns of Chinese, Greek and Italian origin (Naiman and Kosoy, 1964).
It has been estimated that 13% of the male American black population has
a hereditary deficiency of red blood cell G6PD, an enzyme whose activity
is also known to be reduced in Wilson's disease patients (Diess et al., 1970),
in acute copper sulfate poisoning cases (Chugh et al., 1975) and in human
erythrocytes incubated with 0.1 mM copper (Bouland et al., 1975). This
enzyme is essential to the formation of NADPH which is necessary to produce
reduced glutathione (GSH), the major intracellular thiol active in protecting
against free radicals and oxidizing agents. Individuals with this enzyme
deficiency may be at increased risk to the hematologic effects of copper
caused by a reduction in the amount of red blood cell GSH (Calabrese et
al,, 1979,1980; Calabrese and Moore, 1979). However, Goldstein et al. (1985)
reviewed the available exposure and hematological data pertinent to G6PD
deficient individuals and concluded that a significant reduction in GSH would
most probably not occur and even if it did, serious consequences such as
chronic anemia would be highly unlikely. The authors further stated that
even if a decrease in red cell GSH led to a fall in hematocrit (a "worst case"
scenario), functional deficits would be highly improbable. Finally, it was
concluded that "exclusion from the workplace on the basis of susceptibility
to oxidant hemolysis of the more than 1,000,000 black Americans with this
genetic variation is inappropriate." In humans with a preexisting condition
(e.g., G6PD-deficient individuals) the threshold for copper exposure may be
expected to be lower than those in the population without the condition.
There is considerable controversy as to whether these individuals represent
a population at risk to excess copper exposure in the workplace or general
environment.
9.2.3. Hemolysis Patients—Several kidney dialysis patients exposed to
excess copper in the dialysate have reportedly suffered from acute hemolytic
anemia and may also be considered a population at risk (Williams, 1982).
Hemolysis in copper poisoning is caused mainly by a large exposure to copper,
resulting in free copper ions in the blood (e.g., during dialysis). The
homeostatic mechanisms will prevent the accumulation of free copper ions,
even during high-industrial exposure. This problem, however, can be
controlled by closely monitoring the pH and conductivity of the dialysis fluid
56
-------
(Williams, 1982), and exposure to airborne copper would not be expected
to exacerbate this condition.
9.2.4. Infants and Children—Infants and children are also susceptible
to the effects of copper as evidenced by the incidence of Indian Childhood
Cirrhosis and the reports of copper intoxication in young children caused
by drinking water containing moderate levels of copper. Because the fetus
and newborn have elevated hepatic copper levels (Sternlieb, 1980) and since
homeostatic mechanisms are not fully developed at birth (Underwood, 1977),
the newborn represents a risk group that may not be able to cope with
excess copper exposure. The fetus does not have an "abnormal burden"
of copper; it needs a store of copper from which it will start using as a
newborn.
As a specific diet-linked syndrome, Indian Childhood Cirrhosis is apparently
not a health problem in the United States because of better cooking methods.
However, in small children, ingestion of ~1 mg Cu/kg bw or 10 mg Cu/
10 kg child/day from contaminated milk can cause severe liver disorders
{Tanner et al., 1983). These data are relevant in the United States mainly
in defining a dose-response relationship in very young children regardless
of the source of exposure. Given that 1 mg/kgbwisan upper limit of exposure,
it is conceivable that, for instance, 20% of this level (2 mg/child/day) could
result in less severe, though still significant, liver damage. This intake is
well within the normal adult recommended nutritional level, indicating that
children may be more susceptible systemically to copper than adults. The
main action may be the intestinal mucosa, especially in infants with pre-
existing Gl tract disturbances. Thus, preparation of the formula with tap
water with high copper concentrations may create some health problems.
There is very little possibility that the small amounts in ambient air can
play a role in this association.
Indian Childhood Cirrhosis data are also relevant to infants and toddlers
living around copper smelters where mouthing activities can put them at
high risk. Children living near these smelters where copper concentrations
in soil can exceed 50,000 ppm (Nriagu, 1879) may ingest >5 mg Cu/day
which is well above the level at which signs of copper toxicosis in children
appear. This figure is based on the observation that children ingest an average
of 100 mg soil/day (USEPA, 1980c). It is, therefore, important to recognize
that children and infants appear to be more sensitive to copper intake and
extra care should be taken to prevent excess exposure through food, water,
air and soil especially in hot spot areas.
The fetus (i.e., occupationally-exposed working mother) may also represent
a population at risk since fetal copper distribution is markedly different from
that in the adult (USEPA, 1980b). Also, there is no apparent trans-placenta I
barrier to fetal copper uptake and homeostatic mechanisms (ceruloplasmin
synthesis) are not completely expressed in utero. Thus, the fetus can act
as a copper depot, making it extremely sensitive to increases in maternal
exposure and indicating that there is a potentially large population at risk.
Again, pregnancy is a normal physiological state with its own set of values.
In pregnancy, it is recommended to increase the intake of essential elements.
The fetus has high levels, but these levels will drop as the newborn starts
using the copper after birth.
9.2.5. Combined Exposure Populations—These probable popula-
tions at risk (previous four groups) are diversely scattered throughout the
United States, The highest individuals at risk when exposed to copper would
be those persons who belong to more than one group.
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Marecek and Nevstmalova (1984) reported on a study of heterozygous
children and adults whose parents were diagnosed with Wilson's disease.
These investigators observed the serum copper and ceruloplasmin levels
and rates of urine copper excretion before and after exposure to penicillamine.
Wilson's heterozygotes are difficult to distinguish from asymptomatic
patients, particularly in siblings. The siblings showed decreased levels of
both serum copper and ceruloplasmin. Serum ceruloplasmin and copper levels
in the 16 children studied were significantly reduced as compared with those
of 20 healthy children of the same age. The differences were pronounced
if compared with a heterozygous adult population, where reduced
ceruloplasmin values were found in only 18% (Marecek and Nevstmalova,
1984). The authors found that it is quite conceivable that in children with
a partial defect of ceruloplasmin synthesis, the level of synthesis will lag
behind that found in the normal population, reaching the normal physiological
values later in life. These authors indicated that only a long-term follow-
up can show whether these are merely temporary phenomena or whether
they will persist until adulthood. This position is contrary to Sternleib's
viewpoint in which he stated that heterozygous carriers never become
clinically ill and need no treatment (Sternlieb et al., 1973). More definitive
research must be undertaken before this group can be identified as one
at risk to high copper levels.
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10. Assessment
10.1. Overview
Although there is substantial published literature on copper and copper-
related compounds, supporting information for determining the noncancer
health effects from exposure to copper by inhalation is very limited. Copper
is an essential element with —2-3 mg/day being required for proper nutrition.
However, excessive human exposure to copper has been shown to create
acute toxic effects. In the human body, there are demonstrated homeostatic
mechanisms which control copper levels and regulate tissue levels so as
not to bioaccumulate copper in large amounts and to distribute it to all human
tissues. However, in cases of excess copper absorption or abnormal
metabolism, such as Wilson's disease, the metal can accumulate and exert
detrimental and toxic effects.
Although its production volume has decreased in recent years, copper is
still produced in high volume, with its atmospheric anthropogenic flux being
3 times higher than that from natural sources. In the urban sector, major
sources of copper to the atmosphere are from incineration and automobile
exhaust, while in the highest (hot) spots of copper levels in air, the sources
are ore processing and smelting. Human exposure to copper in air in the
United States can vary widely depending on the locality and copper-related
industries in the area.
The average MMD of copper aerosol is ~1.3 fjM. Since particulate matter
in the size range of 0.5 and 5.0 fiM is commonly assumed to be respirable,
most available copper in the atmosphere is respirable. Again, this is dependent
upon locale since the particle size is source dependent. However, inhalation
of air containing background levels of copper would contribute negligible
amounts {<1%) to the average daily intake of copper. Direct inhalation of
copper by humans at the reported levels in this document have been shown
to add much less to body burden than exposure through ingestion and drinking
water. With these intake levels, one estimate has shown that the inhalation
pathway contributes no more than 0.1 i f/g/kg to a total copper body burden
of —800 /jg/kg.
Given this brief analysis, there still remains several identifiable populations
(subgroups) at risk to high levels of copper. These include infants and young
children and the developing fetus, as well as individuals with Wilson's disease.
These groups are susceptible to excess copper exposure either because of
an inborn error in copper metabolism or because of underdeveloped
homeostatic mechanisms combined with higher relative copper body burdens.
In addition, members of these groups that are located in hot spot areas
and occupational settings should be considered more susceptible because
of their inability to deal with the higher ambient levels of copper and combined
exposures. Multimedia exposures to copper, combined with deficiencies or
excesses of other compounds that interact with copper in the body, may
cause adverse human or animal health effects. Interactive relationships
between copper and elements such as" cadmium, zinc, iron and molybdenum
are germane to the assessment of copper's health effects, since the degree
of both exposure (i.e., the amount absorbed) and the expression of systemic
effects are modulated by these elements. These interactions have been
reviewed in the literature for copper, but the degree to which these
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Interactions are expressed during the inhalation process has not been well
documented.
10.2. Principal Effects and Target Organs
The effects of airborne copper fumes, dusts or mists result primarily from
industrial exposures and are manifested predominantly by dermatologic and
respiratory symptoms. As shown in Chapter 9, cases of copper intoxication
are rare, with the exception of metal fume fever seen in oecupationally-
expossd individuals. In general, acute effects of copper intoxication are readily
reversible after removal of the offending agent. In the vineyard workers,
the combined exposure to copper and other agents has been related to lung
cancer. Chronic inhalation data on copper is very limited because exposure
is found in the presence of the other offending agents. Mild anemia, contact
dermatitis and leukocytosis have been observed in long-term occupational
exposures to copper.
Copper is distributed to all body parts, with the liver being the main storage
depot for copper. The specific etiology of copper-induced liver damage has
not been completely determined. Kidney damage has been associated with
copper toxicosis. In laboratory rats, excess copper ingestion caused renal
tubular damage and renal failure. In suicide victims using copper sulfate,
hematuria, hemoglobinuria and oliguria were found. One hypothesis for the
observed renal effects was that copper thioneine leaked from the liver of
copper-poisoned animals and was responsible for the subsequent renal
damage. In the sheep studies, the investigators described sudden hemolytic
crises in copper-poisoned animals.
Wilson's disease individuals and patients undergoing kidney dialysis using
copper components have suffered hemolytic anemia. In the lungs, adverse
effects such as metal fume fever and vineyard sprayers' lung are associated
with copper inhalation. Other body parts have been shown to be affected
by excessive copper exposure.
10.3. Factors Influencing Health Hazard Assessment from
Inhalation of Copper
In reviewing the various factors determining the health effects from
inhalation of copper, it is apparent that increases from ambient air exposure
add little to the copper body burden for normal individuals. However, the
data base for determining these effects from copper, per se, is very weak.
In almost every case presented in this document, the exposure is to a copper-
related compound or combined with other compounds, making an individual
chemical assessment difficult. In the exposure area it has been shown that
the population at large Is exposed to copper through a variety of media and
that copper intake is essential to nutritional health. There is no available
evidence that human health effects have resulted from nonoccupationaf
inhalation of existing ambient air levels. Direct exposure through inhalation
of copper by humans at the reported levels in urban and rural areas of the
United States contributes significantly less to the body burden than ingestion
does, and does not appear to be a health issue to those individuals able
to handle excess levels. However, different biological or homeostatic
mechanisms may account for different pharmacokinetics and elicitations of
any toxic effect. This may not necessarily be true for those individuals in
the susceptible populations which are identifiable and shown in Chapter
9.
In the only chronic inhalation study reviewed in Chapter 8, Pimental and
Marques (1969) exposed a group of 12 guinea pigs to an atmosphere saturated
with Bordeaux mixture for over 6 months. However, this study cannot be
60
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used for determining any quantitative risk assessment because 1) the study
size and experimental techniques are limited; 2) the exposure was to Bordeaux
mixture, an aqueous solution of lime and copper sulfate and some effects
may be from lime not copper; and most importantly, 3} a daily copper exposure
level cannot be derived from this study.
There is no available evidence to show that copper exposure, per se, is
carcinogenic. Studies concerning the carcinogenicity, mutagenicity and
teratogenicity of inhaled copper or copper compounds could not be located
in the available literature. However, some short-term tests have indicated
that certain of the copper salts may have characteristics suggestive of
carcinogens. The overall weight-of-evidence suggests that there are
insufficient data to determine the carcinogenic potential of copper to humans.
Therefore, based on the USEPA's Guidelines for Carcinogenic Risk
Assessment (USEPA, T 986), copper is classified in Group D: Not classifiable.
Limited epidemiological data have failed to establish a link between copper
exposure and cancer or other disorders. Industrial copper inhalation
exposures have elicited mild, infrequent and transient effects, with airborne
copper being less bioavailable than copper from food and water.
The special subgroups are identifiable and in most cases personal protective
measures can be taken to prevent excess copper exposure, A controversy
still remains as to whether the American black population with the hereditary
G6PD red blood cell deficiency represents a population at risk. These
populations are scattered throughout the United States; however, those
individuals with the highest possibility of excess exposure would be found
in areas known as hot spots or ore processing and smelting areas.
61
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