The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for COPPER

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

DECEMBER 1992

Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Copper occurs naturally in elemental form and as a component of many minerals. Because of its high electrical and thermal conductivity, it is widely used in the manufacture of electrical equipment. Common copper salts, such as the sulfate, carbonate, cyanide, oxide, and sulfide are used as fungicides, as components of ceramics and pyrotechnics, for electroplating, and for numerous other industrial applications (ACGIH, 1986). Copper can be absorbed by the oral, inhalation, and dermal routes of exposure. It is an essential nutrient that is normally present in a wide variety of tissues (ATSDR, 1990; U.S. EPA, 1987).

In humans, ingestion of gram quantities of copper salts may cause gastrointestinal, hepatic, and renal effects with symptoms such as severe abdominal pain, vomiting, diarrhea, hemolysis, hepatic necrosis, hematuria, proteinuria, hypotension, tachycardia, convulsions, coma, and death (U.S. AF, 1990). Gastrointestinal disturbances and liver toxicity have also resulted from long-term exposure to drinking water containing 2.2-7.8 mg Cu/L (Mueller-Hoecker et al., 1988; Spitalny et al., 1984). The chronic toxicity of copper has been characterized in patients with Wilson's disease, a genetic disorder causing copper accumulation in tissues. The clinical manifestations of Wilson's disease include cirrhosis of the liver, hemolytic anemia, neurologic abnormalities, and corneal opacities (Goyer, 1991; ATSDR, 1990; U.S. EPA, 1987). In animal studies, oral exposure to copper caused hepatic and renal accumulation of copper, liver and kidney necrosis at doses of >=100 mg/kg/day; and hematological effects at doses of 40 mg/kg/day (U.S. EPA, 1986; Haywood, 1985; 1980; Rana and Kumar, 1978; Gopinath et al., 1974; Kline et al., 1971).

Acute inhalation exposure to copper dust or fumes at concentrations of 0.075-0.12 mg Cu/m³ may cause metal fume fever with symptoms such as cough, chills and muscle ache (U.S. AF, 1990). Among the reported effects in workers exposed to copper dust are gastrointestinal disturbances, headache, vertigo, drowsiness, and hepatomegaly (Suciu et al., 1981). Vineyard workers chronically exposed to Bordeaux mixture (copper sulfate and lime) exhibit degenerative changes of the lungs and liver. Dermal exposure to copper may cause contact dermatitis in some individuals (ATSDR, 1990).

Oral or intravenous administration of copper sulfate increased fetal mortality and developmental abnormalities in experimental animals (Lecyk, 1980; Ferm and Hanlon, 1974). Evidence also indicates that copper compounds are spermicidal (ATSDR, 1990; Battersby et al., 1982).

A Reference Dose (RfD) for elemental copper is not available (U.S. EPA, 1992). However, EPA established an action level of 1300 ug/L for drinking water (56 FR 26460, June 7, 1991). Data were insufficient to derive a Reference concentration (RfC) for copper.

No suitable bioassays or epidemiological studies are available to assess the carcinogenicity of copper. Therefore, U.S. EPA (1991a) has placed copper in weight-of-evidence group D, not classifiable as to human carcinogenicity.

1. INTRODUCTION

Copper (Cu, CAS Reg. No. 7440-50-8) is classified as a noble metal and occurs naturally in elemental form and as a component of many minerals. It has a molecular weight of 63.55, a density of 8.94, a melting point of 1083C, and a boiling point of 2595C (Budavari et al., 1989). Copper is soluble in nitric acid and hot sulfuric acid, very slightly soluble in hydrochloric acid and ammonia, and insoluble in water (Stokinger, 1981). Because of its high electrical and thermal conductivity and other properties such as malleability, metallic copper is widely used in the manufacture of electrical equipment. Copper forms many important alloys that modify its properties for special applications (ATSDR, 1990; Stokinger, 1981). Copper sulfate is the most common copper salt; however, other important copper salts include carbonate, cyanide, oxide, and sulfide. These are used as fungicides, as components of ceramics and pyrotechnics, for electroplating, and for numerous other industrial applications (ACGIH, 1986).

Copper is an essential trace element that is widely distributed in animal and plant tissues. It is a component of a number of metalloenzymes such as catalase, peroxidases, and cytochrome oxidase, and is essential for the utilization of iron (Goyer, 1991; Stokinger, 1981). Although most copper salts occur in two valence states, as cuprous (Cu⁺) or cupric (Cu²⁺) ions, the biological availability and toxicity of copper is most likely associated with the divalent state (ATSDR, 1990). The general population may be exposed to increased levels of copper in drinking water largely as a result of the corrosion of plumbing materials (U.S. EPA, 1987). Contact with copper may also result from use of copper fungicides and algicides. Workers may be exposed to copper in agriculture, and in various industries such as copper production and metal plating. The largest anthropogenic releases of copper to the environment result from mining operations, agriculture, solid waste, and sludge from sewage treatment plants. Natural discharges to air and water, such as windblown dust and volcanic eruptions, may be significant (ATSDR, 1990).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Copper can be absorbed into the systemic circulation from the gastrointestinal tract, the lungs, and skin (U.S. EPA, 1987). Gastrointestinal absorption of copper is normally regulated by homeostatic mechanisms, providing a balance between copper intake and elimination (Goyer, 1991; U.S. EPA, 1987). Humans absorb approximately 50% of the dietary copper (U.S. Air Force, 1990), with values ranging from 15 to 97% (Strickland et al., 1972; Weber et al., 1969). Absorption of ingested copper occurs primarily in the upper portion of the gastrointestinal tract, with rapid appearance of copper bound to albumin and amino acids in the blood 1-2 hours after administration (U.S. EPA, 1987). The gastrointestinal absorption of copper is influenced by a number of factors, including it's chemical form: soluble copper compounds (oxides, hydroxides, citrates) are readily absorbed but water-insoluble compounds (sulfides) are poorly absorbed (Venugopal and Luckey, 1978). The biological availability of copper is also affected by the presence of other chemicals. For example, zinc, molybdenum and other metals decrease dietary copper absorption (U.S. AF, 1990); whereas, certain amino acids appear to enhance its absorption (Venugopal and Luckey, 1978). The amount of stored copper does not appear to influence copper absorption in humans (Strickland et al., 1972).

Data regarding the absorption of inhaled copper in humans are limited. Deposition of copper in the lungs and liver was observed in workers exposed to Bordeaux mixture (an aqueous solution of lime and 1-2% copper sulfate) during the spraying of vineyards (U.S. AF, 1990). Copper oxide was found in alveolar capillaries 3 hours after rats were exposed to welding dusts generated from pure copper wires (Batsura, 1969). Dermal absorption of copper has been demonstrated through intact and burned human skin. In animals, copper was absorbed from copper-containing intrauterine devices (IUDs) (U.S. EPA, 1987).

2.2. DISTRIBUTION

Copper is an essential trace element that is normally present in a wide variety of tissues such as liver, kidney, spleen, heart, lung, muscle, stomach, intestine, nails, and hair. The recommended safe and adequate dietary intake for copper is 1.5-3.0 mg/day for adults, 0.7-2.5 mg/day for children and adolescents, and 0.4-0.7 mg/day for infants (U.S. AF, 1990). Absorbed copper binds to plasma albumin and amino acids in the portal blood and is transported to the liver where it is incorporated into ceruloplasmin and later released into the plasma (ATSDR, 1990). Ceruloplasmin contains about 95% of the copper found in adult human plasma (Venugopal and Luckey, 1978). Hepatic copper is distributed in several subcellular fractions associated with copper-dependent enzymes and copper-dependent proteins. Copper is also found in erythrocytes in the form of erythrocuprein and other proteins (U.S. EPA, 1987) and in bone marrow bound to metallothionine (Goyer, 1991). Age, sex, amount of dietary copper, and overall health determine the amount of copper distributed to the various tissues. Newborns have 6-10 times higher copper concentrations in the liver than adults (U.S. EPA, 1987).

High levels of copper are found in liver, kidneys, brain, bones, and cornea of patients with Wilson's disease (a genetic disorder characterized by impaired copper metabolism) and in the liver of patients with primary biliary cirrhosis, cholestasis, and Indian childhood cirrhosis (Stokinger, 1981; Scheinberg, 1983). Low tissue levels of copper resulting from abnormally low copper absorption are seen in patients with Menke's syndrome (kinky hair disease), a neurodegenerative disorder (Aaseth and Norseth, 1986).

Localized copper deposits in liver and kidneys were observed in monkeys with copper IUDs and in rats with uterine copper wire implants (U.S. EPA, 1987). Copper (as the citrate) has been shown to pass through the placenta of hamsters (Ferm and Hanlon, 1974).

2.3. METABOLISM

The metabolism of copper involves mainly its transfer to and from various organic ligands, most notably sulfhydryl and imidazole groups on amino acids and proteins (ATSDR, 1990). The liver, the most important organ involved in copper disposition, receives its copper from serum -globulin. It serves as a storage depot of copper; as a site for ceruloplasmin synthesis, which is then released into the blood; and as a site for the formation of various copper complexes for subsequent biliary excretion (U.S. EPA, 1987). Biliary copper is returned to the intestine and excreted in the feces (Stokinger, 1981). The half-life of injected copper was approximately 4 weeks in normal human subjects (Aaseth and Norseth, 1986).

2.4. EXCRETION

The major pathway of copper excretion in humans and animals is the biliary system. About 80% of the absorbed copper is excreted in the bile, while about 15% of unabsorbed copper passes directly into the bowel. Only 2-4% of the absorbed copper is excreted in the urine, with small amounts appearing in sweat (Venugopal and Luckey, 1978). Other potential routes of excretion are nails and hair. Following intravenous injection of radioactive copper, normal human subjects excreted only about 10% of the administered dose in urine and feces after 72 hours. Although patients with Wilson's disease have an increased urinary excretion of copper, they excrete copper at about half the rate of healthy individuals (Aaseth and Norseth, 1986).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

A number of reports describe accidental as well as intentional poisoning in humans following copper ingestion. Symptoms occurring immediately after ingestion are metallic taste in the mouth, abdominal pain, diarrhea, and vomiting (ATSDR, 1990). Ingestion of gram quantities of copper may cause systemic toxicity including hemolysis, hepatic necrosis, gastrointestinal bleeding, oliguria, azotemia, hemoglobinuria, hematuria, proteinuria, hypotension, tachycardia, convulsions, coma, and death (U.S. AF, 1990). Acute hemolytic anemia and kidney effects, indicative of renal tubular damage, were observed in a child 2 days after drinking a solution containing approximately 3 g copper sulfate (Walsh et al., 1977). Gastrointestinal irritation can result following ingestion of carbonated water or citrus fruit juices that have been in contact with copper containers or pipes (Scheinberg, 1983).

3.1.1.2. Animal

Rat oral LD₅₀ values for various copper compounds are 140 mg/kg for copper chloride (CuCl₂); 470 mg/kg for copper oxide (Cu₂O); 940 mg/kg for copper nitrate [Cu(NO₃)₂3H₂O]; and 960 mg/kg for copper sulfate (CuSO₄5 H₂O) (Stokinger, 1981). Deaths in animals given lethal doses of copper have been attributed to extensive hepatic centrilobular necrosis (U.S. AF, 1990).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Recurrent nausea, vomiting, and abdominal pain was observed in a family over a period of about 1.5 years after drinking water or beverages made with water containing 7.8 mg Cu/L. The effects disappeared when the family stopped drinking the water (Spitalny et al., 1984). Two children who were exposed to drinking water containing 2.2-3.4 mg Cu/L for <=9 months exhibited hepatosplenomegaly, and increased serum transaminase and bilirubin levels. A liver biopsy revealed micronodular cirrhosis (Mueller-Hoecker et al., 1988).

An increased dietary intake of copper may be partially responsible for a disease known as Indian childhood cirrhosis, which usually occurs in children, ages 6 months to 5 years. The disease is characterized by high levels of copper in the liver, Mallory's hyaline inclusions in hepatocytes, intralobular fibrosis, and widespread hepatic necrosis with poor hepatic regeneration (U.S. AF, 1990).

3.1.2.2. Animal

Rats treated by gavage with copper sulfate at a dose of 100 mg/kg/day for 20 days exhibited significantly decreased skeletal growth and weight gain, heavy deposition of copper in the livers and kidneys, parenchymal degeneration and perilobular sclerosis of the liver, and tubular engorgement and necrosis of the kidneys (Rana and Kumar, 1978). Increased serum alanine aminotransferase (ALT) activity in the absence of histopathological liver changes was seen in rats fed a diet containing 100 mg Cu/kg/day as copper sulfate for 1 week (Haywood and Comerford, 1980). Rats exposed to dietary levels of 150-250 mg Cu/kg/day for 4-5 weeks exhibited extensive liver necrosis and associated inflammatory responses (Haywood, 1985). Exposure of rats to 300 mg Cu/kg/day for 6 weeks induced chronic hepatitis. Regeneration of parenchymal tissue was observed in rats killed between week 6 and 15 and regeneration was complete after 15 weeks (Haywood, 1980; 1985). Decreased hemoglobin and hematocrit values were observed in rats receiving 40 mg Cu/kg/day by gavage for 20 days (Rana and Kumar, 1980). Increased blood pressure was reported in rats exposed to 20 mg Cu/kg/day (as copper carbonate) for 20 weeks (Liu and Medeiros, 1986).

In a 90-day subchronic study with copper cyanide (CuCN), male and female Sprague-Dawley rats were administered by gavage 0, 0.5, 5, or 50 mg CuCN/kg/day (U.S. EPA, 1986). Mean body weights, body weight gains, and food consumption for CuCN-treated rats were significantly decreased. CuCN affected both absolute organ weights and relative organ weight ratios of the kidneys, spleen and brain in rats receiving 50 mg/kg/day. In the high-dose group, there were also significantly decreased serum globulin concentrations, increased ALT and aspartate aminotransferase (AST) activities, decreased red blood cell counts (RBC), and increased mean cell volume (MCV) and platelet counts. High mortality, attributed to hemolytic anemia, was seen in both male and female rats receiving 50 mg/kg/day. Microscopic findings included the presence of hemoglobin in the cytoplasm of the renal tubular epithelium, pigmentation of the spleen and liver, and hyperplasia of hematopoietic tissue. In general, male rats appeared to be more sensitive to the effects of CuCN than female rats.

Pigs exposed to dietary copper levels equivalent to 6.1 mg Cu/kg/day (as copper sulfate) for 54 days exhibited decreased weight gain, reduced hemoglobin and hematocrit values, and increased levels of copper in the liver (Kline et al., 1971). Pigs that accidentally received feed containing 700 mg Cu/kg for a period of several months developed iron-deficiency anemia and gastric ulcers (Hatch et al., 1979). Hemolysis associated with acute tubular renal damage was observed in sheep receiving daily oral doses of copper sulfate (20 mg/kg) for 9 weeks (Gopinath et al., 1974). Access by sheep to salt licks containing 5-9% copper sulfate caused a sudden onset of anorexia, hemolytic anemia, icterus, and hemoglobinuria, followed by death within two days. The estimated ingested dose was 40-49 g over a 25 to 86-day period. At necropsy, the liver, kidneys, and spleen showed degenerative changes (Stokinger, 1981).

3.1.3. Chronic Toxicity

3.1.3.1. Human

Although the chronic toxicity from long-term exposure to copper has not been investigated extensively, studies of patients with Wilson's disease, a genetic defect that results in accumulation of copper in tissues, provide information on the chronic toxicity of copper. Wilson's disease may affect many organs and systems and is characterized by hepatic cirrhosis, brain damage and demyelination, kidney damage, and hemolytic anemia. Patients may also suffer from poor coordination, psychological impairment, tremors, disturbed gait, rigidity, and eye opacities (Goyer, 1991; ATSDR, 1990; U.S. EPA, 1987).

A recent prospective population study of men residing in eastern Finland, an area with high levels of copper in drinking water, established a positive correlation between serum copper levels and risk of acute myocardial infarction (Salonen et al., 1991).

3.1.3.2. Animal

Lifetime exposure to 42.5 mg Cu/kg/day (as copper gluconate) in drinking water caused a 13% decrease of the maximal lifespan in mice (Massie and Aiello, 1984).

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental and reproductive toxicity of copper in humans following oral exposure was unavailable.

3.1.4.2. Animal

Lecyk (1980) observed reduced litter size, decreased fetal weights, and skeletal abnormalities in the offspring of mice fed diets supplemented with 3000 or 4000 ppm copper sulfate (155 or 207 mg Cu/kg/day, respectively) for one month prior to gestation and on days 0-19 of gestation. Aulerich et al. (1982) reported an increased mortality rate in the offspring of minks fed a diet supplemented with >3 mg Cu/kg/day as copper sulfate for 50 weeks. The reproductive performance was not affected.

Copper deficiency has been associated with teratogenic effects such as neural degeneration, reduced growth, skeletal malformations, and cardiovascular lesions in several animal species (U.S. EPA, 1987).

3.1.5. Reference Dose

A Reference Dose (RfD) for elemental copper is not available at this time (U.S. EPA, 1992). However, EPA established an action level of 1300 ug/L for drinking water (56 FR 26460, June 7, 1991). The RfD calculated for copper cyanide (CuCN) is presented below.

3.2.5.1. Subchronic

Oral RfD: 0.05 mg/kg/day (CuCN) (U.S. EPA, 1992)
UNCERTAINTY FACTOR: 100
PRINCIPAL STUDY: U.S. EPA (1986)
COMMENTS: The same study applies to the subchronic and chronic RfD. The study is described in Section 3.1.2.2. An uncertainty factor (UF) of 100 was used to account for species extrapolation (10) and interspecies variability (10).

3.1.5.2. Chronic

Oral RfD: 0.005 mg/kg/day (CuCN) (U.S. EPA, 1991b)
UNCERTAINTY FACTOR: 1000
PRINCIPAL STUDY: U.S. EPA (1986)
CONFIDENCE: Study: Medium Data Base: Medium RfD: Medium
COMMENTS: The chronic RfD was based on a no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day derived from a 90-day gavage study with rats. Decreased organ and body weights and morphological changes of liver and kidneys were seen at 15 mg/kg/day which was considered the lowest-observed-adverse-effect level (LOAEL). An uncertainty factor (UF) of 1000 was used to account for species extrapolation (10), interspecies variability (10), and extrapolation from subchronic to chronic exposure (10).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Short-term occupational exposure to copper dust or fumes can cause eye and respiratory tract irritation, headaches, vertigo, drowsiness, and a condition known as "metal fume fever". This 24-48 hour illness is characterized by an influenza-like syndrome with chills, fever, aching muscles, and dryness in the mouth and throat (U.S. AF, 1990). In one study in which workers reported such symptoms, airborne copper levels ranged from 0.075 to 0.12 mg/m³. Recovery takes place within days, usually without any sequelae. Other effects resulting from exposure to coppers fume include metallic or sweet taste and, in some instances, discoloration of the skin and hair (ATSDR, 1990).

Inhalation of dusts and mists of copper salts can result in irritation of nasal mucous membranes, sometimes of the pharynx, and occasionally in ulceration with perforation of the nasal septum. If copper salts reach the gastrointestinal tract, they act as irritants and may produce increased salivation, nausea, vomiting, gastric pain, hemorrhagic gastritis, and diarrhea (ACGIH, 1986).

3.2.1.2. Animal

Mild respiratory effects were reported in mice and hamsters exposed to 3.3 mg Cu/m³ (as copper sulfate) for 3 hours (Drummond et al., 1986).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Pulmonary copper deposition, fibrosis, and granulomas of the lung have been reported in workers after years of exposure to Bordeaux mixture while spraying vineyards (U.S. AF, 1990). In addition, some workers developed liver disease (morphological changes in Kupffer cells, fibrosis, and cirrhosis) (Stokinger, 1981). Anorexia, nausea, occasional vomiting, headache, vertigo, drowsiness, and hepatomegaly were recorded in factory workers sieving copper dust (Suciu et al., 1981). Although inhalation was considered an important exposure route for these workers, a portion of the airborne copper dust was probably swallowed (ATSDR, 1990).

3.2.2.2. Animal

Daily inhalation exposure of mice to an aerosol prepared from a 5% aqueous solution of copper sulfate for 4 months resulted in focal accumulation of macrophages in alveoli and interstitial infiltration of cells (Eckert and Jerochim, 1982). Guinea pigs exposed 3 times daily for 6.5 months to an atmosphere saturated with Bordeaux mixture exhibited copper-containing micronodular lesions and small histiocytic granulomas of the lungs. The lesions were described as similar to those seen in the lungs of vineyard workers exposed to Bordeaux mixture (Pimental and Marques, 1969). A significant increase in the number of alveolar type II cells in the absence of gross signs of pulmonary toxicity was observed in rabbits exposed to 0.6 mg/m³ cupric chloride, 6 hours/day, 5 days/week for 4-6 weeks (Johansson et al., 1984).

3.2.3. Chronic Toxicity

3.2.3.1. Human

ACGIH (1986) reports that chronic inhalation exposure to copper salts may result in anemia. Swedish workers exposed for 17-40 years to dusts of mixed copper salts (copper nitrate, sulfate, silicate, and oxide) while handling copper sheeting resulted in atrophic rhinitis with complaints of metallic taste, runny nose, and mucosal irritation of the mouth and eyes (Askergren and Mellgren, 1975). An epidemiologic study of 14,562 white male workers in the copper and zinc smelting industries revealed no overall increase in the mortality rates as compared with the mortality rates for the total U.S. population (Enterline et al., 1986).

3.2.3.2. Animal

Information on the chronic inhalation toxicity of copper in animals was unavailable.

3.2.4. Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity following inhalation exposure in humans or animals was unavailable.

3.2.5. Reference Concentration/Dose

Data are insufficient to calculate a Reference Concentration (RfC) for copper.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Exposure to metallic copper in jewelry may produce pruritic dermatitis. Patch tests using a copper penny and/or a copper sulfate solution have been shown to induce allergic contact dermatitis in some individuals. Eye irritation has been reported by factory workers exposed to copper dust (ATSDR, 1990). Fragments of copper metal or copper alloys that lodge in the eye, a condition known as chalcosis, may lead to uveitis, abscess, and loss of the eye (Scheinberg, 1983).

3.3.1.2. Animals

Mouse intraperitoneal LD₅₀s are 3.5 mg/kg for copper metal dust, 7 mg/kg for copper sulfate and chloride, and 33 and 9.4 mg/kg for the hydrated forms of copper sulfate and chloride, respectively (Stokinger, 1981). Subcutaneous LD₅₀s for copper compounds in rodents range from 3 to 7 mg/kg (Aaseth and Norseth, 1986). Rats treated intraperitoneally with 2 mg Cu/kg (as cupric chloride) showed significantly increased brain dopamine and norepinephrine levels (Malhotra et al., 1982).

3.3.2. Subchronic Toxicity

3.3.2.1. Human

Several episodes of copper-induced hemolysis after hemodialysis have been reported. The clinical symptoms included chills, nausea, abdominal pain, vomiting, and watery yellow stools. Copper was introduced into the dialysate from the copper tubing and copper-containing semipermeable membranes in the equipment. Hemolytic anemia has also been reported in a patient treated with applications of copper sulfate to large areas of burned skin (U.S. AF, 1990). Internal exposure to copper in the form of IUDs has caused contact dermatitis and eczematous dermatitis (Venugopal and Luckey, 1978).

3.3.2.2. Animal

Information on the subchronic toxicity of copper in animals by other routes of exposure is unavailable.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of copper in humans or animals by other routes of exposure is unavailable.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Incubation of human spermatozoa with metallic copper caused a significant decrease in sperm motility (Battersby et al., 1982).

3.3.4.2. Animal

Intravenous administration of 2.13 mg Cu/kg (as copper sulfate) to female hamsters on the 8th day of gestation resulted in 26% resorptions and 6% abnormalities (thoracic wall hernias, encephalocoeles, spina bifida, and microphthalmia). A dose of 4.25 mg Cu/kg caused 86% resorptions and 8% abnormalities (exencephaly, hydrocephalus, abdominal hernia, and abnormal spinal curvature), and a dose of 7.5 mg Cu/kg resulted in 100% embryo mortality, 74% resorptions, and 8% abnormalities. A dose of 10 mg/kg was lethal to dams. In the same study, intravenous administration of 0.25-1.5, 1.8, or 2.2 mg Cu/kg (as the citrate) produced resorptions in 16, 41, or 34% resorptions and 2, 17, or 35% abnormalities, respectively. A dose of 4 mg Cu/kg was lethal to both embryos and dams (Ferm and Hanlon, 1974).

Copper compounds have been shown to be spermicidal in animals and use of copper-containing IUDs has been shown to prevent mammalian embryogenesis (U.S. AF, 1990). The insertion of copper wire into the vas deferens or uterus prior to conception or at gestational day 3 resulted in decreased fertility or decreased number of implantation sites in monkeys, rats, hamsters, and rabbits (ATSDR, 1990).

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

Gastrointestinal system: In humans, exposure to high levels of copper in drinking water has resulted in gastrointestinal irritation characterized by recurrent nausea, vomiting, and abdominal pain. Gastric ulcers were observed in pigs exposed to high dietary levels of copper.
Liver: Hepatomegaly and cirrhosis of the liver were reported in children exposed to high levels of copper in drinking water. Cirrhosis of the liver may occur in patients with Wilson's disease. Hepatic effects observed in animals include increased copper deposition, necrosis, inflammation, and increased ALT and AST levels.
Kidneys: Renal effects observed in animals include deposition of copper in the kidneys, and degenerative kidney changes including necrosis and acute tubular damage. Patients with Wilson's disease may suffer kidney damage.
Hematopoietic system: Hemolytic anemia, hyperplasia of hematopoietic tissue, decreased hemoglobin and hematocrit values, and hemolytic anemia were reported in animals orally exposed to copper. Hemolytic anemia is also one of the effects seen in patients with Wilson's disease.
Reproduction and development: Increased fetal mortality and developmental abnormalities were seen in animals receiving oral doses of copper.

3.4.1.2. Other Target Organs

Spleen: Enlarged spleens were observed in children exposed to high levels of copper in drinking water. Sheep ingesting high levels of copper exhibited degenerative changes of the spleen.
Cardiovascular system: One epidemiologic study correlated high levels of copper in drinking water with an increased risk of myocardial infarction in Finnish men. Rats fed a diet supplemented with copper exhibited increased systolic blood pressure.
Nervous system: Although neurological effects have not been observed in healthy humans exposed to high copper levels, symptoms in patients with Wilson's disease include poor coordination, psychological impairment, tremors, disturbed gait, and rigidity.
Eyes: Eye opacities have been reported in patients with Wilson's disease.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

Respiratory system: Pulmonary copper deposition, fibrosis, and granulomas of the lung were seen in vineyard workers exposed to Bordeaux mixture. Similar lung lesions occurred in guinea pigs exposed to an atmosphere saturated with Bordeaux mixture. Workers exposed to various copper salts experienced irritation of the nose, mouth, and eyes.
Liver: Hepatic effects in vineyard workers exposed to Bordeaux mixture included morphological changes in Kupffer cells, fibrosis, and cirrhosis. Hepatomegaly was recorded in workers exposed to copper dust.
Gastrointestinal tract: Workers exposed to copper dust experienced anorexia, nausea, and occasional vomiting.
Nervous system: Headache, vertigo, and drowsiness have been reported in factory workers exposed to copper dust.

3.4.2.2. Other Target Organs

No other target organs following inhalation exposure to copper or copper compounds were identified.

3.4.3. Other Routes of Exposure

3.4.3.1. Primary Target Organs

Hematopoietic system: Copper-induced hemolysis has been reported in patients undergoing hemodialysis. Repeated applications of copper sulfate to large areas of burned skin may induce hemolytic anemia.
Reproduction and development: Increased fetal mortality and developmental abnormalities were seen in animals injected with copper. Intrauterine placement of a copper wire resulted in decreased fertility or decreased number of implantation sites in animals. Copper has been shown to have spermicidal effects in animals.
Skin: In humans, dermal exposure to metallic copper may cause pruritic dermatitis.
Immune system: In humans, dermal exposure to copper or exposure via IUDs may cause allergic contact dermatitis.

3.4.3.2. Other Target Organs

Additional target organs by other routes of exposure to copper or copper compounds have not been identified.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

In studies conducted at several U.S. locations, Schrauzer et al. (1977) reported a positive association between dietary copper intake, blood copper concentrations and cancer of the intestine in men and cancer of the intestine, lung, breast, and thyroid in women. However, the study was inconclusive because a positive correlation was also established for zinc, cadmium, and chromium.

4.1.2. Animal

Male and female B6C3F₁ and B6AKF₁ mice were treated daily by gavage with 1000 mg copper hydroxyquinoline/kg body weight (180.6 mg Cu/kg) until they were 28 days old, after which they were given 2800 ppm (505.6 ppm Cu) in their diet for an additional 50 weeks. The incidence of tumors was not significantly increased in treated mice compared with controls (BRL, 1968).

4.2. INHALATION EXPOSURES

Information on the carcinogenicity of copper in humans or animals following inhalation exposure was unavailable.

4.3. OTHER ROUTES OF EXPOSURE

4.3.1. Human

Information on the carcinogenicity of copper in humans by other routes of exposure was unavailable.

4.3.1. Animal

Gilman (1962) administered intramuscular injections containing 20 mg cupric oxide (CuO), cupric sulfide (CuS), or cuprous sulfide (Cu₂S) into the right and left thighs of 2- to 3-month-old Wistar rats. There were no injection-site tumors after 20 months of observation in any of the animals, but a very low incidence of other tumors occurred in the animals receiving cupric sulfide (2/30) and cuprous sulfide (1/30).

BRL (1968) administered a single subcutaneous injection of 1000 mg copper hydroxyquinoline/kg (180.6 mg Cu/kg) to male and female B6C3F₁ and B6AKF₁ mice. After 50 days of observation, the male B6C3F₁ mice had an increased incidence of reticulum cell sarcomas compared with controls. A low incidence of reticulum cell sarcomas was also observed in copper-treated female mice of both strains.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification D -- Not classifiable as to human carcinogenicity (U.S. EPA, 1991a).
Basis -- There are no human data, inadequate animal data from assays of copper compounds, and equivocal mutagenicity data.

4.5. CARCINOGENICITY SLOPE FACTORS

Data were insufficient to derive carcinogenicity slope factors.

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Last Updated 8/29/97