EPA-540/1-86-025
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
&EPA
HEALTH EFFECTS ASSESSMENT
FOR COPPER
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EPA/540/1-86-025
September 1984
HEALTH EFFECTS ASSESSMENT
FOR COPPER
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with copper.
All estimates of acceptable Intakes and carcinogenic potency presented 1n
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon In the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) source has
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Copper. Environmental Criteria and Assessment Office, Cincinnati,
OH. EPA 440/5-80-036. NTIS PB 81-117475. (Cited In U.S. EPA,
1985)
U.S. EPA. 1983a. Technical Support Document on the Ranking of
Hazardous Chemicals Based on Cardnogenldty. Prepared by the
Carcinogen Assessment Group, OHEA, Washington, DC for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Drinking Water Criteria Document on Copper.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH OHEA for the Office of Drinking Water, Washington,
DC. Final Draft.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants In ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
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The AIC, acceptable Intake chronic, is similar 1n concept to the ADI
(acceptable daily intake). It is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the lifespan [see U.S. EPA (1980b) for a discussion
of this concept]. The AIC is route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes is insignificant.
Composite scores (CSs) for noncarcinogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development is explained in U.S. EPA (1983b).
For compounds for which there is sufficient evidence of carcinogenicity,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer is a
process that is not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader 1s referred to the preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the
appropriate Interpretation and use of the quantitative estimates.
Copper Is an essential trace element. In Individuals with normal copper
metabolism and normal levels of G6PD, there seems to be a wide separation
between required levels and toxic levels. The present document reflects the
estimate of 2.6 mg/day for both the AIS and AIC. This Is the dally exposure
level suggested by U.S. EPA (1985) and 1s based on human GI symptoms follow-
ing acute exposure. This value is also 1n good agreement with the limited
animal data. A CS of 19 was estimated for elevated serum AST activity and
jaundice In pigs fed high levels of copper sulfate.
No good quantitative animal data exist for Inhalation exposure and
effects of copper. For this reason the TLV values, 0.2 mg/m3 for fumes
and 1.0 mg/m3 for dusts and mists, were used to estimate Inhalation AICs.
The ACGIH (1983) based these levels on extensive Industrial experience with
copper In Great Britain. The estimated AICs are: 0.14 mg copper vapor/day;
0.71 mg copper mist or dust/day. These suggestions should be reviewed as
more complete data become available.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under- Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was >,the Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
,PPE
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral
6.1.2. Inhalation
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
6.3. CARCINOGENIC POTENCY (q-|*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
NDIX: Summary Table for Copper
Page
1
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4
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5
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12
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25
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LIST OF TABLES
No. Title Page
3-1 Effects of Copper Sulfate*5H20 Administered
1n Corn-Soy Diet 7
4-1 Tumorlgenlclty of Some Copper Compounds 16
5-1 Current Regulatory Standards and Criteria 19
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
AST Aspartate transamlnase
BCF Bloconcentration factor
bw Body weight
CAS Chemical Abstracts Service
CS Composite score
CNS Central nervous system
DNA Deoxyr1bonucle1c acid
GI Gastrointestinal
GRAS Generally regarded as safe
G6PD Glucose-6-phosphate dehydrogenase
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RVj Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Copper 1s a metal belonging to the First Transitional Series of the
periodic table. Elemental copper has a CAS number of 7440-50-8. Copper
occurs 1n nature as the elemental metal (zero valence), and In the +1 and +2
valence states. In addition to a variety of Inorganic compounds, copper
forms a number of compounds with organic Ugands. Both organic and
Inorganic copper compounds have a variety of uses (Kust, 1979). Most- Cu
compounds are not stable 1n the environment, particularly In the presence of
water or moisture and air, and tend to change to the stable Cu+ state
(Kust, 1979).
In the atmosphere, copper 1s present as dusts and fumes from copper
smelting Industries, Iron and steel Industries, coal burning power plants
and other miscellaneous fabricating operations Involving copper (NAS,
1977). The atmospheric fate of copper has not been studied comprehen-
sively. Any chemical Interaction of copper compounds 1n the atmosphere 1s
likely to result 1n spedatlon (I.e., conversion of copper compounds Into a
stable species such as CuO), not 1n Us direct removal through decomposi-
tion as frequently occurs with organic compounds. The principal removal
mechanisms for atmospheric copper are probably wet and dry deposition. The
atmospheric half-life for the physical removal mechanism 1s expected to
depend on the particle size and particle density of atmospheric copper. No
estimate for the atmospheric half-life of copper Is available.
The aquatic fate of copper has been studied more extensively than Us
atmospheric fate (Callahan et al., 1979). The two processes that are likely
to dominate the fate of copper 1n aquatic media are chemical spedatlon and
sorptlon (Callahan et al., 1979). The nature of chemical spedatlon of
copper in aquatic media 1s determined by the oxidation-reduction potential
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of the particular copper compound and the pH of the aquatic media. In
aquatic media of pH <7, copper may exist 1n Cu* form, whereas at pH >7,
copper may exist as the carbonate complex. In polluted water bodies, copper
may form complexes with organic material 1n the water. Various sorptlon
processes reduce the level of 1on1c state carbonate complex or organic
complex of copper from aquatic media. Sorptlon onto clay materials, hydrous
Iron, manganese oxides and organic material 1s the primary controlling
factor (Callahan et al., 1979). In organically rich sediments, the sorbed
and precipitated copper may become redlssolved through complexatlon and may
persist 1n the water for a long time. No estimate of the aquatic half-life
of copper 1s available 1n the literature.
The fate of copper 1n soil has been studied Inadequately; however, the
fate may depend upon the pH of the soil, Us moisture content and Its clay
and organic matter content (NAS, 1977). In acidic soils, copper may be more
soluble, which would enhance Us mobility (NAS, 1977); the reverse may be
true 1n basic soils. Soils rich 1n organic matter may enhance the mobility
of copper through complexatlon. Both clay and organic matter may facilitate
the sorptlon of copper in soil, however, and may retard Its Teachability.
Soils with suitable moisture content may enhance the microorganism activity
and the partial removal of copper through uptake by microorganisms. No
estimate of the half-life of copper in soils is available; however, copper
is expected to be leached more readily from acidic and sandy soils than from
basic soils containing a higher percentage of clay and/or organic matter.
The BCFs for copper 1n aquatic organisms have been determined by several
investigators and have been found to vary from 12 for an alga, Scenedesmus
quadricarda. to 30,000 for molluscs (Callahan et al., 1979).
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
According to Schroeder et al. (1966), humans Ingest an average of 2.5-5
mg of copper/day from dietary sources. These authors estimated that 61
absorption of -3.2 and 0.2 mg of copper occurs from food and fluid Intake,
respectively. The actual quantities of copper absorbed depend on geography,
climate, soil chemistry, diet, water softness and pH.
Weber et al. (1969) administered 64Cu as copper acetate to seven
fasted human subjects without liver damage. Because of the short half-life
of 64Cu (12.8 hours), labeled (9SZr) zirconium oxalate was given as a
non-absorbable stool marker to enable location of the copper acetate bolus.
The radlonucHdes were counted dally for 4 days 1n a whole body scintilla-
tion counter, and GI movement of the administered bolus was monitored with a
scintillation camera. Radioactive copper 1n blood was determined hourly for
6 hours and 1n urine and stoo.ls dally.
Absorption of 64Cu appeared to be diphasic. Maximum absorption from
the stomach and duodenum occurred within 1 hour of administration. A second
and slower absorption phase was observed >3.5 hours post-administration. At
2 hours post-administration the 64Cu acetate bolus had left the stomach of
the subjects and was located 1n the small Intestine; 3 hours later H was
located in the terminal Heocecal region and proximal large Intestine.
Average net absorption of 64Cu was -60%, with a range of 15-97% (Weber et
al., 1969). Evans (1973) stated that, 1n mammals, alimentary absorption of
copper occurs only from the upper GI tract and that the extent of absorption
may be Influenced by competition of other metals for metallothloneln binding
sites (necessary for active transport of copper), levels of dietary protein,
kinds and amounts of anlons present and the level of dietary ascorbic add.
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2.2. INHALATION
Quantitative data regarding absorption of copper from Inhalation
exposure could not be located 1n the available literature; however, presump-
tive evidence has been located. Vlllar (1974) observed copper-containing
granulomas 1n the lung, liver and kidney upon necropsy of an Individual
occupatlonally exposed to Bordeaux mixture (an aqueous solution of lime and
1-2% copper sulfate) used 1n spraying vineyards. Plmental and Menezes
(1975) noted copper-containing liver granulomas 1n three patients who had
used Bordeaux mixture while spraying vineyards to prevent mildew. Gleason
(1968) reported symptoms of "metal fume fever" (general discomfort, fever,
chills, stuffiness of the head) In three workers exposed to fine copper dust
at concentrations of 0.03-0.12 mg/m3. Installation of an exhaust fan that
reduced air levels to <0.008 mg/m3 promptly alleviated these symptoms.
Batsura (1969) exposed rats (strain, sex and number not specified) for
15, 30, 45, 60 or 180 minutes to 50-80 mg copper ox1de/m3. Electron
microscopy showed that copper absorption had occurred 1n rats exposed for
180 minutes. Copper oxide particles had penetrated the epithelial cells of
the pulmonary alveoli and were found 1n plasma 6 hours after exposure began.
Particles were also found 1n the proximal convoluted tubules of the kidney.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral Exposure. There are a number of acute/subchronlc case
reports of accidental human exposure. Only those which provided data suffi-
cient to estimate exposure levels are summarized here.
Chattanl et al. (1965) evaluated clinical data from 53 patients who
Ingested copper sulfate 1n suicide attempts. The amounts of copper Ingested
ranged from 0.25-7.6 g of copper. Five patients died and the survivors
exhibited a variety of symptoms most prevalent of which were nausea,
vomiting and epigastric pain.
Semple et al. (1960) reported an outbreak of gastroenteritis affecting
18/50 workmen following 1ngest1on of copper sulfate contaminated water.
Symptoms Included dizziness, headache, diarrhea, vomiting and abdominal
pain. Later analysis of the water source showed copper levels of >44 ppm.
Assuming each man drank 1 cup (0.23 8.) the estimated dose was 0.143 mg/kg
copper (U.S. EPA, 1985).
Nicholas and Brlst (1968) reported a similar Incidence. In this case
9/20 had diarrhea, 6/20 vomiting and 9/20 nausea. A sample of tea showed 30
ppm copper. U.S. EPA (1985) estimated the dose was >0.1 mg/kg.
Wyllle (1957) reported an outbreak of copper poisoning due to copper
leaching from a cocktail shaker. Amounts of copper Ingested were estimated
to be 5.3-32 mg copper. Of the women exposed 10/15 reported symptoms
Including weakness, abdominal cramps, headaches, nausea, dizziness and
vomiting.
Little Information exists concerning subchronlc toxldty of copper In
the usual laboratory species. Howell (1959) maintained rats on diets con-
taining 5000 ppm copper acetate for 16 months. Assuming that rats consume
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food equivalent to 5% of their bw/day, these rats consumed -250 mg copper
acetate or -80 mg Cu/kg bw/day. No criteria of toxldty were mentioned.
Liver and kidney were found to accumulate copper heavily, but no accumula-
tion was found 1n the cornea or brain.
Dietary levels of -200 ppm copper have long been used as growth pro-
moters In the production of market hogs. Kline et al. (1971) exposed groups
of 12 Hampshire and Yorkshire pigs weighing an average of 22.2 kg to dietary
levels of 0, 150, 200 or 250 ppm copper sulfate for 88 days (Table 3-1).
Accelerated rate of weight gain and elevated levels of liver copper were
demonstrated at all treatment levels. Hepatic copper levels linearly
(p<0.05) correlated with dose. Depressed growth rate and blood hemoglobin
concentration were observed 1n pigs fed a diet containing 500 ppm copper
sulfate for 61 days.
Suttle and Mills (1966a) added 750 ppm of basic copper carbonate
(CuCO/,'Cu(OH)9'H_0) to the cornmeal diets of weanling female Large
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TABLE 3-1
Effects of Copper Sulfate«5H20 Administered 1n Corn-Soy Diet*
Species/Strain
Pig/Hampshire
and Yorkshire
Pig/Hampshire
Sex/No.
NR/8
NR/8
Average
Body Weight
(kg)
23.6
23.6
Dose
250 ppm diet
3.2 mg Cu+2/kg/day
500 ppm diet
Duration
(days)
61
61
Effects
accelerated growth with
less feed
reduced growth and
and Yorkshire
Pig/Hampshire NR/12
and Yorkshire
Pig/Hampshire NR/12
and Yorkshire
Pig/Hampshire NR/12
and Yorkshire
Pig/Hampshire NR/12
and Yorkshire
22.2
22.2
22.2
22.2
5.5 mg Cut2/kg/day
0 supplemental
Cu
150 ppm diet supplement;
1.8 mg Cu*2/kg/day
200 ppm diet supplement;
2.5 mg Cu*2/kg/day
250 ppm diet supplement;
2.9 mg Cu*2/kg/day
hemoglobin levels.
Increased liver copper
concentrations
88 normal hemoglobin,
hematocrlt and liver
copper levels
88 accelerated weight gain
88 accelerated weight gain
88 accelerated weight gain
'Source: Kline et al., 1971
NR = Not reported
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appears that the Increases 1n AST levels, jaundice and anemia principally
reflected liver damage, since the postmortem examinations revealed gross
hepatic degenerative changes, hlstologlc centrllobular necrosis and bile
canallcull disruption, and there was no evidence of Increased erythrocyte
fragility. The addition of zinc or Iron eliminated the jaundice and pro-
duced serum copper and AST concentrations similar to control levels after 4
weeks, but only supplemental Iron afforded protection against the anemia.
In a second study (Suttle and Mills, 1966b), weanling female Large White
pigs (6/group) were maintained on cornmeal diets that contained either soya-
bean meal, dried skim milk or whlteHsh meal as protein supplements with 600
ppm basic copper carbonate for 48 days (6.4, 11.0 and 15.4 mg Cu "Vkg/day,
respectively). The soya-bean meal diet was similar to that used previously
1n the 750 ppm study (Suttle and Mills, 1966a). Results for control experi-
ments (no supplemental copper) were not reported, but 1t was concluded that
600 ppm copper carbonate was only marginally toxic (causing slight growth
depression and a temporary Increase 1n serum copper, negligible effect on
AST levels and gross evidence of toxicosis and jaundice 1n only 1 of the 6
pigs). The effect of the dried skim milk diet with 600 ppm copper carbonate
on the pigs was also unremarkable, but the Introduction of whlteflsh meal to
the diet reportedly caused a moderately severe toxicosis (marked growth
retardation, elevated serum Cu and AST levels, visible loss of condition and
jaundice 1n 4 of the 6 pigs). The greater toxlclty of the whlteflsh meal
diet was attributed to a higher calcium level, which presumably adversely
Influenced zinc availability. Anemia developed gradually throughout
exposure 1n pigs maintained on all the diets.
In a related experiment, 250 or 425 ppm of copper sulfate pentahydrate
(CuSO.-5H?0) was added to the high calcium cornmeal whlteflsh diet and
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fed to weanling female Large White pigs (6/group), creating optimal condi-
tions for the development of copper toxicity (Suttle and Mills, 1966b).
Administration of 425 ppm copper sulfate 1n the diet caused severe growth
depression after 14 days, when "severe toxicosis" became evident; three pigs
were slaughtered on the 47th day and another one on the 60th day to prevent
unnecessary suffering. Autopsy revealed generalized jaundice, hypertrophy
and cirrhosis of the liver, and GI hemorrhages. Food consumption and food
conversion efficiency data were not provided for these animals; therefore,
the daily intake of Cu * could not be estimated. When pigs were fed 250
ppm in the whHeflsh meal diet for 79 days (2.6 mg Cu /kg/day), slight
weight gain was noted over the first 30 days of treatment, but both serum
AST and copper concentrations were significantly greater than control values
at the 46th day, when three of the six pigs showed signs of jaundice.
Concentrations of copper in the liver were significantly Increased relative
to unexposed controls after 79 days of treatment, but hemoglobin levels
remained normal.
It is well recognized that sheep are especially sensitive to toxicity
due to copper. Underwood (1977) described chronic copper toxicity 1n sheep
grazing pastures in Australia in which the content of copper In soil and
forages was abnormally high and/or forage levels of molybdenum were
unusually low. Liver damage from grazing Heliotropium europaeum exacerbated
the toxicity of high levels of copper. In ruminants, dietary levels of
other trace elements, such as zinc, affect the toxicity of copper (MAS,
1977). Ruminants, however, are particularly unsuitable for use as a basis
for human risk assessment, and further discussion of copper toxicity in
these species will not be included in this document.
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3.1.2. Inhalation. Pertinent data regarding the subchronlc Inhalation
toxlclty of copper 1n laboratory species could not be located In the
available literature.
3.2. CHRONIC
Pertinent data regarding chronic exposure of laboratory animals to
copper could not be located In the available literature. The most studied
form of chronic copper toxlclty 1n humans Is Wilson's disease, or hepatolen-
tlcular degeneration (Williams, 1982). An Inherited autosomal recessive
disorder of copper metabolism, this disease 1s characterized by abnormally
low plasma levels of ceruloplasmln, Increased plasma copper levels and In-
creased copper deposition In liver, brain, kidneys and cornea (Schroeder et
al., 1966; Evans, 1973). Copper may accumulate In the liver of affected
persons to a level -20-fold that of unaffected Individuals. This high level
of hepatic copper destroys the hepatocytes, resulting In a release of copper
Into the general circulation. This released copper has many adverse effects
Including damage to erythrocytes, kidneys, corneas and the CNS (Schelnberg
and Sternlleb, 1969). Symptoms Include tremors to drooling, Incoordlnatlon,
seizures, behavioral abnormalities, anemia, jaundice and eventually death.
Another manifestation of chronic copper toxlclty 1n man Is the occur-
rence of "vineyard sprayer's lung" resulting from exposure to copper sulfate
1n Bordeaux mixture, used to control mildew 1n grapes (Plmental and Marques,
1969). Vlllar (1974) further described the symptoms of vineyard sprayer's
disease 1n 14 male patients and 1 female patient with a prolonged history of
Intermittent (~3 months/year) exposure to Bordeaux mixture. Dyspnea, weak-
ness, anorexia, weight loss, radlographlc opacities and the presence of
copper In the lungs were noted. Eventually the pulmonary opacities showed
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regression followed by calcification. Later, Plmental and Menezes (1975)
demonstrated copper-containing granulomas In vineyards sprayer's lung
patients exposed for 3-15 years to Bordeaux mixture.
The occurrence of metal fume fever In workmen Involved 1n polishing
copper plates has been discussed 1n Section 3.1 (Gleason, 1968). General-
ly, air samples 1n the workplace contained 0.30-0.75 mg Cu/m3. A breath-
Ing zone air sample of the polishing wheel operator contained 0.120 mg
Cu/m3. Installation of a ventilation system reduced copper levels 1n air
to <0.008 mg/m3 and resulted 1n total abatement of symptoms.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Copper deficiency has been associated with neural degenera-
tion, reduced growth, skeletal malformations and cardiovascular lesions 1n
lambs, goats, rats, guinea pigs, dogs and chickens (Hurley and Keen, -1979).
Ferm and Hanlon (1974) and DICarlo (1980) showed conclusively that paren-
teral administration of solutions of copper sulfate or copper citrate
produced terata 1n golden hamsters. Ferm and Hanlon (1974) demonstrated
that the chelated (citrate) form was a far more potent teratogen than the
Inorganic (sulfate) form.
The teratogenldty of copper sulfate administered In the diets to two
strains of mice was studied by Lecyk (1980). Groups of 7-22 DBA or C57B1
mice were given diets containing 0, 500, 1000, 1500, 2000, 3000 or 4000 ppm
copper sulfate equivalent to added concentrations of 0, 199, 398, 597, 796,
1195 or 1593 ppm copper, respectively. Assuming that mice consume food
equivalent to 13% of their body weight/day, these doses correspond to
Intakes of 0 (Intrinsic copper content not specified for control group),
25.9, 51.7, 77.6, 103.5, 155.3 and 207.1 mg Cu/kg bw/day, respectively.
Mice were treated from 30 days before mating until day 19 of gestation.
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Low doses (500 and 1000 ppm) of copper sulfate stimulated embryonic de-
velopment; Increased Utter size and fetal weight resulted. Higher doses
Increased fetal mortality, resulting In decreased Utter size. Dietary
levels of 3000 and 4000 ppm copper sulfate caused a low level of embryonic
malformation, which was not observed 1n control mice or mice on lower die-
tary concentrations. In 55 living fetuses from C57B1 mice given 3000 ppm
copper sulfate, 1 malformed fetus was noted with a defect In the -lumbar
vertebrae. Among 35 living fetuses from C5781 mice given 4000 ppm copper
sulfate, 3 abnormal fetuses were found: 1 with a hernia of the thoracic
wall, 1 with hydrocephalus and 1 with Mb and vertebral fusions. In 56 sur-
viving fetuses from DBA mice given 3000 ppm copper sulfate, 2 abnormal
fetuses were found, both with fusions of adjacent ribs. From DBA mice given
3000 ppm copper sulfate, 45 fetuses were found alive; 2 had encephaloceles
and 2 had defects 1n their lumbar vertebrae. The Incidence of terata ap-
peared to be similar for both strains of mice tested. The levels of copper
that resulted 1n formation of terata were considerably higher than those
that resulted 1n toxic effects 1n pigs (Kline et al., 1971); hence, this
study 1s not suitable for quantitative risk assessment.
No reports of terata 1n humans associated with oral exposure to copper
have been located In the available literature.
3.3.2. Inhalation. No reports of terata 1n humans or animals resulting
from Inhalation exposure to copper or Us compounds have been located 1n the
available literature.
3.4. TOXICANT INTERACTIONS
Suttle and Mills (1966a,b) demonstrated an Interaction of copper with
both zinc and Iron. Groups of six Large White female pigs were maintained
-12-
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on diets containing 750 ppm of basic copper carbonate
H_0] alone or with 500 ppm zinc carbonate or 750 ppm Iron sulfate
(FeSO.'7H»0). Severe toxic effects (elevated serum copper and AST,
jaundice, reduced hemoglobin, centrllobular liver necrosis and bile canall-
cu!1 disruption) were noted 1n control (copper carbonate fed) pigs, but the
addition of either zinc carbonate or Iron sulfate appeared to afford
protection.
In ruminants, an antagonism between copper and molybdenum has long been
recognized (Underwood, 1977). High levels of molybdenum In feedstuff may
protect sheep exposed to high levels of copper or may precipitate copper
deficiency 1n animals exposed to marginal levels of dietary copper.
Excessive dietary levels of copper, particularly when combined with high
levels of inorganic sulfate, have been shown to elevate the dietary require-
ment of selenium (Underwood, 1977).
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the cardnogenldty of copper compounds 1n
humans were not located 1n the available literature.
4.2. BIOASSAYS
B1onet1cs Research Labs (BRL, 1968) studied the cardnogenldty of
copper hydroxyqulnonne In B6C3F.J and B6AKF, mice. Groups of 18 male
and 18 female 7-day-old mice of both strains were given 1000 mg copper
hydroxyqulnonne In 0.5% gelatin by gavage until 28 days of age, at which
time the compound was added to the basal diet (containing 5.7 ppm copper) at
the rate of 2800 ppm (505.6 ppm copper). Animals were fed the treatment
diet until 78 weeks of age, at which time they were killed. All mice killed
or found dead were subjected to necropsy and hlstologic examination. Data
were compared to those from positive, negative and vehicle control groups.
No statistically significant Increases in the Incidence of lymphatic
leukemias, retlculum cell sarcomas, pulmonary adenomas or carcinomas,
hepatomas, hepatic carcinomas, mammary carcinomas, skin carcinomas or
cancerous anglomas were observed in orally treated mice.
In the same study, groups of 18 male and 18 female 28-day-old B6C3F,
and B6AKF, mice were maintained on the basal diet described above and
given a single subcutaneous injection of 0.5% gelatin or 1000 mg copper
hydroxyquinoline/kg bw in 0.5% gelatin (BRL, 1968). The animals, were
observed for 78 weeks, after which they were killed and subjected to exami-
nation as described previously for Incidence of tumors. Treated male
B6C3F.J mice had a significantly (p<0.001) Increased Incidence of reticulum
cell sarcomas (6/17), compared with controls (8/141). Male B6AKF, mice
evidenced no tumor formation. Female treated and control B6C3F, mice had
-14-
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Incidences of 1/18 and 1/154 re.tlculum cell sarcomas, respectively. Female
B6AKF, treated and control females had Incidences of 3/18 and 5/157
retlculum cell sarcomas, respectively. Presumably, these Incidences of
retlculum cell sarcomas 1n female rats were not statistically significant.
In an earlier study, Gllman (1962) studied the carclnogenldty of cuprlc
oxide, cuprlc sulflde and cuprous sulflde 1n 2-3-month-old Wlstar rats.
Groups of 30-32 rats were given single-dose bilateral Injections of 20 mg
cuprlc oxide (16 mg copper), cuprlc sulflde (13.3 mg copper) or cuprous
sulflde (16 mg copper) Into the thighs. Control groups were not mentioned.
All groups were observed for up to 20 months, and survivors were subjected
to histopathologlcal examination. Surviving to termination were 10/32,
19/30 and 18/30 of the rats treated with cuprlc oxide, cuprlc sulfate and
cuprous sulfate, respectively. No Injection-site tumors were observed.
Rats 1n the cuprlc oxide, cuprlc sulfate and cuprous sulfate groups had 0, 2
and 1 tumors, respectively. No further explanation of tumor types was
available.
Haddow and Horning (1960) published bloassay results on various copper
compounds (Table 4-1); no other experimental details were provided.
4.3. OTHER RELEVANT DATA
The available data from in vitro mutagenldty bloassays In micro-
organisms are not sufficient to allow a conclusion regarding the mutagenl-
dty of copper. Demerec et al. (1951) reported positive results In an
Escher1ch1a coll reverse mutation assay with 2-10 ppm copper sulfate.
Morlya et al. (1983) reported a lack of mutagenldty 1n E_. coll and In Sal-
monella typhlmurlum strains TA98, TA1535, TA1537 and TA1538 with up to 5 mg
copper qulnollnolate/plate. This compound was mutagenlc to S. typhlmurlum
strain TA100, but only 1n the presence of a mammalian metabolic activation
-15-
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TABLE 4-1
Tumor 1 genIdty of Some Copper Compounds*
Agent Under Test
Copper -dextran
L 8-Hydroxyqu1nol1ne
T copper complex
Cross-conjugated
macrocycle copper
porphyrln
Copper phthalocyanlne
Copper phthalocyanlne
tetra-3-sulfonlc acid
Copper phthalocyanlne
tetra-4-sulfonlc 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 cc of 1 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)
8(11)
Tumors
Recorded
none
1 pleomorphlc
sarcoma
none
none
none
none
'Source: Haddow and Horning, 1960
-------
system. Up to 5 mg of copper sulfate/plate failed to Induce reverse muta-
tions In S. typh1mur1um strains TA98 or TA100 either with or without meta-
bolic activation (Moriya et al., 1983). Negative results with copper sul-
fate and copper chloride In Saccharomyces cerevlslae D-7 (Singh, 1983) and
Bacillus subt111s (N1sh1oka, 1975; Matsul, 1980; Kanematsu et al., 1980)
have also been reported.
Results from several Isolated cell mutagenldty bloassays indicate
mutagenlc potential for some copper compounds. Errors In ONA synthesis have
been Induced 1n viruses (Slrover and Loeb, 1976), and chromosomal aber-
rations in rat hepatocytes have been Induced by 15-20 mM cupric chloride or
cuprlc acetate and 1.0 mM copper sulfate, respectively. Simian adenovirus
cell transformation in Syrian hamster embryo cells was induced by 0.38 mM
cuprlc sulflde and, to a lesser extent, with 0.08 mM copper sulfate (Casto
et al., 1979). A positive recessive lethal response 1n D. melanogaster was
observed to result from exposure of larvae or eggs to copper sulfate (Law,
1983).
4.4. WEIGHT OF EVIDENCE
Data regarding the carcinogenicity of copper were not sufficient to
enable an IARC rating on the carcinogenicity of this element (UrfS. EPA,
1983a). Cuprlc acetoarsenlte was classified 1n 2A, but this was based on
the weight of evidence for the arsenical moiety to react as arsenic trlox-
ide, and was not related to the carcinogenicity of copper. Applying the
criteria for evaluating the overall weight of evidence for carcinogenicity
to humans proposed by the Carcinogen Assessment Group of the U.S. EPA
(Federal Register, 1984), copper 1s most appropriately designated a Group
D-Not Classified substance.
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5. REGULATORY STANDARDS AND CRITERIA
Current regulatory standards and criteria for copper are shown 1n Table
5-1.
The AC6IH (1983) has set the TWA-TLV for copper fumes at 0.2 mg Cu/m3
and the TLV for copper dusts and mists at 1 mg Cu/m3 of air. Although
Gleason (1968) reported symptoms of metal fume fever 1n workers exposed to
0.1 mg copper dust/m3 air, the ACGIH felt that extensive Industrial
experiences with copper welding and refining experience 1n Great Britain
supported the view that no 111 effects result from exposure to fumes at
concentrations up to 0.4 mg Cu/m3.
The NAS (1977) has given 15 ppm copper In pig feed a GRAS categoriza-
tion. Levels up to 200 ppm are often used 1n market hogs as a growth
promoter.
The U.S. EPA (1980a), based on the organoleptlc threshold of copper, .has
set the ambient water quality criterion for human effects at 1.0 mg/a.
U.S. EPA (1985) recommended this same level as the criterion for drinking
water based on organoleptlc criteria.
-18-
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TABLE 5-1
Current Regulatory Standards and Criteria
Criteria
Value
References
TLV:fumes
TLVrdust
GRAS
Ambient water quality
criterion
Dally recommended
allowance for man
0.2 mg/m3
1.0 mg/m3
15 ppm 1n pig feed
1.0 mg/9.
2-5 mg
AC6IH, 1980
ACGIH, 1980
NAS, 1977
U.S. EPA, 1980a
NAS, 1980
-19-
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6. RISK ASSESSHENT
Pertinent risk assessment data are summarized In the Appendix of this
report.
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral. Very few pertinent data were located In the available
literature concerning the subchronlc toxlclty of orally administered cop-
per. Howell (1959) studied the tissue distribution of copper In stock
laboratory rats maintained for 16 months on diets containing 5000 ppm copper
acetate (250 mg copper acetate or 80 mg Cu/kg bw/day). Both the liver and
kidneys heavily accumulated copper. Since only one treatment level was
used, and presumably no other criteria of toxlclty were evaluated, this
study was judged Inadequate for use In deriving an MOT. Suttle and Mills
(1966b) observed elevated serum AST activity and jaundice 1n pigs fed a diet
containing 250 ppm copper sulfate (2.6 mg Cu Vkg/day). Although this
level of copper 1s slightly less than that in the Kline et al. (1971) study
(3.2 mg Cu/kg/day) In which no adverse effects were observed. It Is Inappro-
priate to use the dosage from the Suttle and Mills (1966b) study for deriva-
tion of an AIS because the diet was artificially altered to maximize the
probability of copper toxlcity. Kline et al. (1971) exposed groups of 12
pigs to dietary levels of 0, 150, 200 or 250 ppm copper sulfate for 88
days. In an earlier study, Kline et al. (1971) determined that 500 ppm
dietary copper sulfate depressed the rate of weight gain. In these studies,
therefore, 250 ppm dietary copper sulfate appeared to be a NOAEL. Assuming
that a pig eats food equivalent to 5% of Its body weight/day, this dietary
level corresponds to a dally Intake of 12.5 mg copper sulfate/kg bw, which,
assuming 5 molecules of water of hydratlon, corresponds to 3.2 mg Cu/kg bw.
For a 70 kg man, this exposure would be equivalent to 3.2 mg Cu/kg bw x
-20-
-------
70 kg * 100 = 2.2 mg Cu/man/day. Division by 100 represents an uncer-
tainty factor of 10, Introduced for Interspedes extrapolation, and another
uncertainty factor of 10 to afford greater protection for unusually sensi-
tive populations. This estimate 1s essentially the same as the ADI of 2.6
mg/day estimated by the U.S. EPA (1985). It 1s suggested that the ADI of
2.6 mg/day be adopted here as the AIS (see Section 6.2.1. for the derivation
of this number).
Patients suffering from G6PD deficiency may be at greater risk from
excess levels of copper than the general population. Excessive copper has
been shown to reduce the activity of the hexose monophosphate shunt, 1n
which G6PD Is apparently Involved (D1ess et a!., 1970; Boulard et al., 1975;
Calabrese et al., 1980). It has been reported that -13% of the American
Black male population has G6PD deficiency, and consequently may be at exces-
sive risk from the toxic effects of copper. Individuals occupatlonally
exposed to fine aerosols of copper or sprays containing copper sulfate
(Plmental and Menezes, 1975) may be at additional risk, although 1t 1s not
known what effect elevated oral Intake of copper may have on this population.
The derived AIS 1n this report of 2.2 mg for humans Is consistent with
the recommendations of the NAS (1980) that an "adequate and safe" Intake of
2-3 mg copper In a 70 kg man will satisfy the nutritional requirements and
be protective of health. The Food and Drug Administration suggested that a
40-fold Increase 1n the dietary requirement may represent a threshold for
mild to severe chronic toxldty (U.S. EPA, 1985). It 1s also consistent
with the drinking water standard of 1 mg/a when water consumption 1s
estimated at 2 l/day (U.S. EPA, 1980a).
U.S. EPA (1983c) calculated a CS for copper, based on the elevated serum
AST activity and jaundice observed by Suttle and Mills (1966b) 1n pigs fed a
-21-
-------
diet containing copper sulfate that contributed 2.6 mg Cu +/kg bw/day for
79 days. Since this was a subchronlc study, the animal MED was divided by
10 to convert to chronic exposure. The result was multiplied by the cube
root of the ratio of the body weight of the pigs (33 kg) to that of an aver-
age man to derive a human MED of 0.20 mg/kg/day of Cu + or 14 mg/day for a
70 kg human. This MED corresponds to an RVd of 3.8. The elevated serum
AST activity and jaundice were assigned an RVg of 5, since anemia was not
observed. A CS of 19, the product of RVd and RVg, was calculated.
6.1.2. Inhalation. No satisfactory reports of subchronlc Inhalation
exposure of laboratory animals to copper have been located 1n the available
literature. Consequently, no subchronlc maximum dally dose for Inhalation
exposure 1n man can be derived.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral. Howell (1959) exposed rats to 5000 ppm dietary copper
acetate for 16 months. By histochemlcal techniques, both the liver and
kidneys were shown to "heavily accumulate" (U.S. EPA, 1985) copper. U.S.
EPA (1985) calculated a dally Intake 1n treated rats of 250 mg copper
acetate/kg bw/day, corresponding to -80 mg Cu/kg bw/day. This figure Is -25
times the level of copper (3.2 mg Cu/kg bw/day) to which pigs (Kline et al.,
1971) were exposed In the study from which a reasonable subchronlc oral
acceptable Intake was calculated. Since only one treatment level 1n rats
was studied (Howell, 1959), and since copper was observed to "heavily
accumulate" In the Hver and kidneys, this study was judged unsatisfactory
for determining an oral acceptable Intake 1n man. Furthermore, a dally
Intake of -6.4 mg Cu/kg bw/day for 61 days has been shown to reduce the rate
of body weight gain 1n pigs (Kline et al., 1971), assuming that market pigs
eat the equivalent of 5% of their body weight/day.
-22-
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Frequently, when no suitable chronic studies are available from which to
derive a maximum tolerable oral dose, the maximum tolerated subchronlc oral
dose 1s divided by an uncertainty factor of 10 to derive a maximum tolerated
chronic oral dose. That rationale was considered and rejected for copper,
because copper 1s an essential trace element 1n human nutrition, and the
body ordinarily has homeostatlc mechanisms to deal with reasonably moderate
deficiencies or excesses. Furthermore, the animal based subchronlc
acceptable Intake for oral exposure, 2.2 mg/man/day, 1s consistent with the
recommended dally allowance proposed by the National Research Council (NAS,
1980). A recommended dally allowance (U.S. EPA, 1985) of 2-5 mg/day has
been proposed by the National Research Council (NAS, 1980). This estimate
1s also 1n good agreement with U.S. EPA (1985). In that document an ADI of
2.6 mg/day was estimated based on a human LOAEL for acute GI symptoms of 5.3
mg/day (Chattanl et al., 1965; Semple et a!., 1960; WylUe, 1957). An
uncertainty factor of 2 was applied to this LOAEL due to a number of con-
siderations Including the transient nature of the effects and the essential-
ity of copper 1n human nutrition. It 1s proposed that the U.S. EPA (1985)
ADI of 2.6 mg/day be adopted here as the oral AIC.
6.2.2. Inhalation. Pertinent data regarding chronic Inhalation of copper
1n laboratory animals have not been located 1n the available literature. On
the basis of extensive Industrial experience with copper welding and metal
refining operations In Great Britain, the ACGIH (1983) adopted a TLV of 0.2
mg/m3 for fumes and 1.0 mg/m3 for dusts and mists. Since these TLVs
were based on extensive experience with Industrial exposure, and since no
animal toxldty studies were available, 1t was deemed prudent to use the
TLVs as a starting point to derive a maximum tolerated chronic Inhalation
-23-
-------
dose. Assuming a man Inhales 10 m3 of air 1n a workday and works 5 days/
week, the dose of copper vapor expected to be Inhaled can be estimated to be
0.2 mg Cu/m3 x 10 m3 Inhalation rate x 5/7 days/week = 1.4 mg copper
vapors/day. Similarly, starting with a TLV of 1.0 mg copper dust or
m1st/m3 of air, the dose 1s equivalent to 7.14 mg of copper dust or mist/
day. An uncertainty factor of 10 1s Introduced to provide an additional
safety factor for susceptible populations. Dividing the values for the dose
by the uncertainty factor of 10 results 1n an AIC for chronic Inhalation
exposure of 0.14 mg copper vapors or fumes/day and 0.71 mg copper mists or
dusts/day. The use of Inhalation exposure levels expressed 1n units of
mg/kg Implicitly assumes that the exposure will be spread uniformly across
the day.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Blonetlc Research Labs (BRL, 1968) studied the carcino-
genldty of copper hydroxyquinoline 1n B6C3F1 and B6AKF1 mice. Dietary
levels of 2800 ppm copper hydroxyqulnollne (505.6 ppm copper, 25.3 mg Cu/kg
bw) failed to produce tumors 1n mice after 77 weeks of exposure. In another
part of this study, a single subcutaneous Injection of 1000 mg copper
hydroxyqu1no!1ne/kg bw was associated with a significantly (p<0.001)
Increased incidence of reticulum cell sarcomas 1n male B6C3F, mice. Male
B6AKF, mice manifested no tumor formation, and treated female mice of both
strains had no statistically significant Incidence of tumor formation com-
pared to controls. Mutagenidty bioassays do not clearly delineate a car-
cinogenic role of copper in the systems tested. Lack of sufficient data
regarding carcinogenicity of copper in humans or 1n animal bioassays pre-
cluded derivations of health advisories on this basis.
-24-
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6.3.2. Inhalation. The only evidence of human cancer related to inhala-
tion exposure to copper was the suggestion by Plmental and Menezes (1975)
that persons exposed to copper sulfate mist In Bordeaux mixture (vineyard
sprayer's disease) may be at additional risk for the development of pul-
monary alveolar cell carcinoma. No cardnogenlcHy bloassays Involving
Inhalation exposure were found; hence, H was not possible to derive a q^*
for Inhalation exposure to copper.
-25-
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Documentation of the Threshold Limit Values, 4th ed. (Includes Supplemental
Documentation, 1981). ACGIH, Cincinnati, OH.
ACGIH (American Conference of Government Industrial Hygienists). 1983.
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Workroom Environment with Intended Changes for 1984. ACGIH, Cincinnati, OH.
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Boulard, M., K.G. Blume and E. Beutler. 1975. The effect of copper on red
cell enzyme activities. J. CUn. Invest. 51: 456-461. (Cited in U.S. EPA,
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BRL (Bionetlcs Research Labs). 1968. Evaluation of Carcinogenic, Terato-
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Calabrese, E.J., G.S. Moore and S.C. Ho. 1980. Low glucose-6-phosphate
dehydrogenase (G-6-PD) activity in red blood cells and susceptibility to
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-26-
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Callahan, M.A., H.W. SUmak, N.W. Gabel, et al. 1979. Water-Related
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transformation for evaluation of the carcinogenic or mutagenlc potential of
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sulphate poisoning. Am. J. Med. 39: 849.
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-28-
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NAS (National Academy of Sciences). 1980. Recommended Dally Allowances,
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occupational disease. Thora. 24: 678-688. (Cited 1n U.S. EPA, 1985)
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In vineyards sprayer's lung. A new etiology of hepatic granulomatosls. Am.
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development of copper toxicosis. Brit. J. Nutr. 20: 135-148.
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response to high and moderate intakes of copper. Br. J. Nutr. 20: 149.
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U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Copper.
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APPENDIX
Summary Table for Copper
CO
4k
I
Inhalation
AIS
AIC
Oral
AIS
AIC
Maximum
composite
score
Species Experimental Dose/
Exposure
NA NA
man NA
man 5.3 mg/day
man 5.3 mg/day
pig 250 ppm copper sulfate
1n diet for 79 days
(2.6 mg Cu?Vkg/day
(RVd = 3.8)
Effect
NA
NA
GI symptoms
GI symptoms
elevated serum
AST and jaundice
(RVe = 5)
Acceptable Intake Reference
(AIS or AIC)
ND NA
0.14 mg fumes/day ACGIH, 1980
0.71 mg dusts/day
2.6 mg/day U.S. EPA. 1985
2.6 mg/day U.S. EPA, 1985
19 Suttle and
Mills, 1966b
NA = Not applicable
ND = Not derived
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