Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) Allbri Natural Copper
2) ANAC 110
3) Arwood Copper
4) Bronze Powder
5) CDA 101
6) CDA 102
7) CDA 110
8) CDA 122
9) CE 1110
10) Copper-Airborne
11) Copper Bronze
12) Copper Fume
13) Copper M 1
14) Copper Compounds
15) Copper and Compounds
16) Copper Metal Dusts
17) Copper Metal Fumes
18) Copper, Metallic Powder
19) Copper-Milled
20) Copper Powder
21) Copper Slag-Airborne
22) Copper Slag-Milled
23) CU M3
24) Cuprum (Latin)
25) E 115 (Metal)
26) 1721 Gold
27) Gold Bronze
28) Kafar Copper
29) M 1
30) M 3
31) M 4
32) M1 (Copper)
33) M2 (Copper)
34) M3 (Copper)
35) M4 (Copper)
36) M3R
37) M3S
38) OFHC Cu
39) Raney Copper
40) CAS 7440-50-8
41) References: RTECS, 2001; HSDB, 2001; NIOSH, 2001

1) Copper acetate
2) Cupric acetate or cupric acetate, basic
3) Cuprous acetate (acetic acid copper (1+) salt)
4) Copper bromide
5) Cupric bromide (CuBr2)
6) Cuprous bromide (CuBr)
7) Copper carbonate
8) Cupric carbonate, basic (copper carbonate hydroxide)
9) Copper chloride
10) Cupric chloride (CuCl2)
11) Cuprous chloride (CuCl)
12) Copper cyanide
13) Cuprous cyanide (CCuN)
14) Copper fluoride
15) Cupric fluoride (CuF2)
16) Copper glycinate
17) Copper iodide
18) Cuprous iodide (CuI)
19) Copper nitrate
20) Cupric nitrate (CuN2O6)
21) Copper oxide
22) Copper oxychloride
23) Cupric oxide (Black copper oxide) (CuO)
24) Cuprous oxide (Red copper oxide) (Cu2O)
25) Copper sulfate
26) Cupric sulfate, basic (copper hydroxide sulfate)
27) Cupric sulfide (CuS)

1.2.1) MOLECULAR FORMULA
1) Cu

Available Forms Sources

A)

1) INDUSTRIAL

a) Industrially, copper is available as ingots, sheets, rods, wire, tubing, shot or powder, or in high purity (less than 10 ppm impurities) as single crystals or whiskers (HSDB , 2002; Lewis, 1997).
b) Commercial copper is available in the following purities (HSDB , 2002):

Electrolytic tough-pitch	99.90% Cu
Deoxidized	99.90% Cu
Oxygen-free	99.92% Cu
Silver-bearing	99.90% Cu
Arsenical	99.68% Cu
Free-cutting	99.40 to 99.50% Cu

B)

1) ISOTOPES: Copper occurs naturally in its elemental state. There are two naturally occurring stable isotopes, atomic weights 63 (69.09 percent) and 65 (30.91 percent), and nine artificial isotopes (atomic weights 58-62, 64, 66-68). It has valences 1 and 2. It is present in the earth's crust at 70 ppm and in seawater at 0.001 to 0.02 ppm (Budavari, 2000). It is the 26th-most-abundant element in the earth's crust (Harbison, 1998).
2) ORE: Copper is also found in various ores including chalcopyrite, chalcocite, bornite, tetrahedrite, enargite, antlerite, azurite, azurmalachite, covellite, cuprite and malachite (Lewis, 1993; Budavari, 2000). The main ore is chalcopyrite (approximately 85 percent). Most copper mined today (about 85 percent) comes from ores containing 2 percent or less copper (Bingham et al, 2001). Copper is a noble metal, like silver and gold (Barceloux, 1999).
3) BIOLOGICAL: Copper is an essential trace element in the human and animal diets, with many metabolic functions not fully understood, and is involved in plant metabolism. It occurs in biological complexes such as pheophytin (an analog of chlorophyll), hemocyanin, tyrosinase and ceruloplasmin (Baselt, 2000; Budavari, 2000). Copper is the third-most-abundant trace element in the human body (Barceloux, 1999).

a) In humans, copper is found in many proteins (Bingham et al, 2001). It is essential for the function of many enzymes such as catalase and peroxidase, and is an important catalyst for heme synthesis and iron absorption (Barceloux, 1999; Goldfrank, 1998).
b) Copper influences gene expression and is a cofactor for oxidative enzymes such as superoxide dismutase, cytochrome C oxidase and lysyl oxidase, as well as for aminolevulonic acid (Baxter et al, 2000a).

C)

1) Copper has excellent electrical conductivity, corrosion resistance, malleability and ductility, which make it very useful as an industrial metal (Baxter et al, 2000).
2) As much as 75 percent of the copper used in the USA is for electrical conductors such as wire and switches (Bingham et al, 2001a; ILO, 1998). Copper is widely used in applications for which high electrical and thermal conductivity are needed. Copper whiskers are used in thermal and electrical composites (ACGIH, 1996a; Lewis, 1997a).
3) Copper is used in important alloys such as bronze (copper alloyed with as much as 10 percent tin) and brasses (copper alloyed mainly with zinc). Monel metal, another copper alloys, is copper alloyed with nickel (Baxter et al, 2000; Lewis, 1997a).

a) Copper alloyed with cadmium is used in electrical conductors; with magnesium and aluminum, in resistance wire and heating wire; with nickel, for chemical equipment; and with beryllium, in electrical contacts, springs, dies, bellows and welding links (Ashford, 1994).
b) Brasses containing less than 58 percent copper have little application (Bingham et al, 2001a).

4) Copper is useful in electroplated coatings and undercoatings for products made from nickel, chromium, and zinc, and in cooking utensils. Copper is also made into corrosion-resistant plumbing pipes, used in heating and roofing materials for building construction, and has applications in industrial machinery and in automobiles (HSDB, 2002; ILO, 1998; Lewis, 1997a).
5) In agricultural applications, copper compounds (particularly copper sulfate) are used in insecticides, fungicides, herbicides, and algicides (Bingham et al, 2001a).
6) Copper's contraceptive effects (as a spermatocide) are exploited for intrauterine devices. Its contraceptive effects permit the use of a smaller device, resulting in fewer side effects such as pain and bleeding (Bingham et al, 2001a; Goldfrank, 1998; HSDB, 2002).
7) Copper and its compounds have many other miscellaneous uses:

a) They are used for chemical and pharmaceutical applications; in pollution control catalysts; in pigments, dyes and anti-fouling paints; in works of art; in coinage; in fabrics and textiles, glass and ceramics; in cement, nylon and paper products; for printing and photocopying; in pyrotechnics; as analytical reagents; and in wood preservatives.
b) They are also used in ammunition, flameproofing and fuel additives, and the flakes are used as insulation for liquid fuels (ACGIH, 1996a; Budavari, 2000; HSDB, 2002; ILO, 1998; Lewis, 1997a).
c) Copper naphthenate has been used as a coating material for hardwood floors, causing toxicity to residents (Kim & Chomchai, 1999).

8) COPPER COMPOUNDS (Copper I and Copper II compounds):

a) COPPER OXIDE: Cupric oxide (black copper oxide) (CuO) or Cuprous oxide (red copper oxide) (Cu2O). Copper oxide is used as a catalyst and a pigment for ceramic, glass, enamel, porcelain and artificial; it is used in copper metallurgy, pyrotechnics and welding and in the manufacture of rayon; it serves as a solvent for chromic iron ores; it is used as an optical glass polishing agent; and it is found in batteries, electrodes, desulfurizing oils, paints fungicides and insecticides (Bingham et al, 2001; Budavari, 2000; ILO, 1998).
b) COPPER ACETATE: Cupric acetate or cupric acetate, basic or Cuprous acetate (acetic acid copper (1+) salt). Copper acetate is used as a paint pigment, insecticide, fungicide, mordant and mildew preventive (Budavari, 2000).
c) COPPER CARBONATE: Cupric carbonate, basic (copper carbonate hydroxide). Copper carbonate is used in pigments, pyrotechnics, insecticides, fungicides and brass coloring (Clayton & Clayton, 1994).
d) COPPER CHLORIDE: Cupric chloride (CuCl2) or Cuprous chloride (CuCl). Copper chloride is used as a disinfectant, in metallurgy, for the preservation of wood pulp, for deodorizing and desulfurizing petroleum distillates, in photography, in water purification, and as a feed additive (Clayton & Clayton, 1994).
e) COPPER NITRATE: Cupric nitrate (CuN2O6). The nitrate shares many uses with copper chloride and, in addition, is used preferentially in pharmaceutical preparations and in paints, varnishes and enamels (Clayton & Clayton, 1994).
f) COPPER CYANIDE: Cuprous cyanide (CuCN). Its chief use is in the electroplating of copper on iron (Clayton & Clayton, 1994).
g) COPPER GLYCINATE - Copper glycinate is used in cattle to increase dairy yields (Oon et al, 2006).
h) COPPER SULFATE/SULFIDE: Cupric sulfate, basic (copper hydroxide sulfate) or Cupric sulfide(CuS) or Cuprous sulfide (Cu2S). It is used as a fungicide, molluscicide and wood preservative, for water treatment as a bactericide and algaecide, as a mordant, in electroplating, as a froth flotation agent, in leather tanning and hide preservation, in works of art, for animal nutrition, and in some fertilizers. It is also used medicinally as an emetic, and in several intrauterine contraceptive devices (Bingham et al, 2001; ILO, 1998; Kirk-Othmer, 1992).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) WITH POISONING/EXPOSURE

1) ROUTES OF EXPOSURE: Copper compounds may be toxic by inhalation, ingestion, injection, and skin or eye exposure. Copper salts are particularly irritating.
2) INHALATION: Exposure to fumes or dust may cause irritation of the nose and upper respiratory tract, as well as sneezing and coughing. Perforation of the nasal septum can also occur. 'Metal fume fever,' with respiratory and flu-like symptoms such as chills and muscle aches, may result from exposure to fumes or fine dust. The incidence of copper-induced metal fume fever is low due to the high temperatures required to volatilize copper.
3) INGESTION: Acute ingestion of copper salts can cause irritation, severe nausea and vomiting, salivation, abdominal pain, epigastric burning, hemolysis, gastrointestinal bleeding with hemorrhagic gastritis, hematemesis and melena, anemia, hypotension, jaundice, seizures, coma, shock and death. Hepatic and renal failure may develop several days after acute ingestion. Methemoglobinemia may rarely occur. Copper may produce a metallic or sweet taste.
4) INJECTION: Subcutaneous injection of copper glycinate resulted in nausea and vomiting, acute renal failure, hemolytic anemia, acute hepatic failure, disseminated intravascular coagulation, and dermal necrosis at the injection site.
5) DERMAL: Skin exposure may cause irritation, itching, eczema, allergic contact dermatitis, hypersensitivity, and a greenish discoloration of the hair, teeth and skin.
6) EYE: Exposure of the eyes to copper fumes or dust can cause irritation, conjunctivitis, palpebral edema, ulceration and corneal turbidity. Eye irritation, uveitis, abscess and loss of the eye may also occur from the mechanical action of lodged copper particles. Penetration of the eye by fine fragments can result in severe ocular damage. Corneal discoloration (Kayser-Fleischer ring) is a hallmark of Wilson disease.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Increased temperature may be noted in some cases.
2) Hypotension may occur.
3) Tachycardia and tachypnea have been reported following oral exposure to copper oxychloride.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Eye exposure may produce irritation, conjunctivitis, palpebral edema, ulceration and corneal turbidity. Eye irritation, uveitis, abscess and loss of the eye may result from severe mechanical irritation.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Hypotension, dysrhythmia and coronary artery disease have been linked with exposure to copper.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Metal fume fever, wheezing and rales have been reported in workers exposed to fine copper dust. Dyspnea and tachypnea have developed after oral copper exposure. Pulmonary edema and alveolar inflammation have been noted in animals.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Central nervous system depression, seizures and headaches have been associated with copper exposure.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Gastroenteritis with vomiting may occur after ingestion of some copper salts. Mucosal erosions, a metallic taste, burning epigastric sensation and diarrhea may also occur.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Hepatomegaly, liver tenderness, increased levels of transaminase and jaundice may occur on the second or third day after ingestion of copper salts. Childhood cirrhosis has been linked with ingestion of milk from copper or brass drinking vessels. Granulomas have also been associated with copper exposure.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Acute renal failure with oliguria followed by anuria may occur 24 to 48 hours after ingestion. Hemoglobinuria and hematuria may also occur.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Hemolysis and anemia have occurred and, rarely, methemoglobinemia.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Skin exposure can produce in severe irritation, itching, erythema, dermatitis and eczema; systemic toxicity may result.

0.2.21)

A) Increased deaths from cancers have been linked to exposure to copper, mixed with other exposures. However, copper is considered not classifiable as to human carcinogenicity.

Laboratory Monitoring

A)

B)

Treatment Overview

0.4.2)

A) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
B) Vomiting is rapid and spontaneous in most patients following ingestion of copper salts.
C) Copper salts may be caustic agents, capable of extensive mucosal damage, including perforation of the gastrointestinal tract. Gastric lavage and administration of charcoal may cause further complications. However, some clinicians have successfully utilized these techniques. Once charcoal is given, it is difficult to observe endoscopy findings. These are controversial techniques, and are left to the final judgement of the treating physician.

1) Gastric lavage may be indicated after ingestion of non-corrosive forms of copper. Following ingestion of a corrosive copper compound, such as copper sulfate (cupric sulfate), gastric lavage is not indicated because the risk of causing perforation may outweigh the potential benefit of removing caustic material.
2) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.

a) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.

D) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
E) Keep patients who have ingested corrosive copper salts NPO following mucosal decontamination until after endoscopy consultation.
F) Consider endoscopy in patients who have ingested corrosive copper salts.

1) ENDOSCOPY: Early endoscopy allows patients without gastrointestinal injury to be medically cleared, and provides important prognostic information in patients who do have varying degrees of gastrointestinal burns. In addition, it facilitates the safe placement of enteral feeding tubes thereby shortening the period of time that patients with burns are without enteral nutritional support. Endoscopy should be performed within the first 24 hours post-ingestion, and should be avoided from 2 days to 2 weeks post-ingestion since wound tensile strength is lowest and the risk of perforation highest during this time. Endoscopy is indicated for all adults with deliberate ingestion or any signs or symptoms attributable to ingestion, and for children with stridor, vomiting, or drooling. Consider endoscopy in children with dysphagia, refusal to swallow, significant oral burns, or abdominal pain. If second or third degree burns are found, follow 10 to 20 days later with barium swallow or esophagram.

G) The role of corticosteroids is controversial. Consider use in second-degree burns no more than 48 hours postingestion in patients without active upper gastrointestinal bleeding or evidence of gastroesophageal rupture. Antibiotics are indicated for definite infection or patients with gastroesophageal perforation.
H) SURGICAL OPTIONS: Initially, if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed; if unsuccessful, either colonic intraposition or gastric tube placement may be performed. Consider early laparotomy in patients with severe esophageal and/or gastric burns.
I) There is little clinical experience in the use of chelators in the setting of acute copper intoxication. Data on efficacy is derived from patients with chronic copper intoxication (Wilson disease, Indian childhood cirrhosis) and animal studies. BAL, penicillamine, DMPS and EDTA have been used. D-penicillamine is considered the drug of choice for Wilson disease, a condition of chronic copper overload.

1) D-PENICILLAMINE: Use only if less toxic agents not available or not tolerated. USUAL DOSE: ADULT: 1 to 1.5 g/day given orally in 4 divided doses. CHILD: 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3). Avoid if penicillin allergic. Monitor for proteinuria, hematuria, rash, leukopenia, thrombocytopenia.
2) Administer BAL (Dimercaprol) 3 to 5 mg/kg/dose IM every 4 hours for 2 days; then every 4 to 6 hours for an additional 2 days; then every 4 to 12 hours for up to 7 additional days.

J) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
K) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
L) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

1) ROUTES OF EXPOSURE: Copper compounds may be toxic by inhalation, ingestion, injection, and skin or eye exposure. Copper salts are particularly irritating.
2) INHALATION: Exposure to fumes or dust may cause irritation of the nose and upper respiratory tract, as well as sneezing and coughing. Perforation of the nasal septum can also occur. 'Metal fume fever,' with respiratory and flu-like symptoms such as chills and muscle aches, may result from exposure to fumes or fine dust. The incidence of copper-induced metal fume fever is low due to the high temperatures required to volatilize copper.
3) INGESTION: Acute ingestion of copper salts can cause irritation, severe nausea and vomiting, salivation, abdominal pain, epigastric burning, hemolysis, gastrointestinal bleeding with hemorrhagic gastritis, hematemesis and melena, anemia, hypotension, jaundice, seizures, coma, shock and death. Hepatic and renal failure may develop several days after acute ingestion. Methemoglobinemia may rarely occur. Copper may produce a metallic or sweet taste.
4) INJECTION: Subcutaneous injection of copper glycinate resulted in nausea and vomiting, acute renal failure, hemolytic anemia, acute hepatic failure, disseminated intravascular coagulation, and dermal necrosis at the injection site.
5) DERMAL: Skin exposure may cause irritation, itching, eczema, allergic contact dermatitis, hypersensitivity, and a greenish discoloration of the hair, teeth and skin.
6) EYE: Exposure of the eyes to copper fumes or dust can cause irritation, conjunctivitis, palpebral edema, ulceration and corneal turbidity. Eye irritation, uveitis, abscess and loss of the eye may also occur from the mechanical action of lodged copper particles. Penetration of the eye by fine fragments can result in severe ocular damage. Corneal discoloration (Kayser-Fleischer ring) is a hallmark of Wilson disease.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Increased temperature may be noted in some cases.
2) Hypotension may occur.
3) Tachycardia and tachypnea have been reported following oral exposure to copper oxychloride.

3.3.2)

A) WITH POISONING/EXPOSURE

1) TACHYPNEA has been reported following acute and chronic oral exposure to copper oxychloride (Gunay et al, 2006).

3.3.3)

A) WITH POISONING/EXPOSURE

1) FEVER has been reported with copper sulfate intoxication and might develop after ingestion of other copper salts (Akintonwa et al, 1989).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION has been reported with severe copper sulfate poisoning and might develop after ingestion of other copper salts (Chuttani et al, 1965; Agarwal et al, 1993).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA has been reported following acute and chronic oral exposure to copper oxychloride (Gunay et al, 2006).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Eye exposure may produce irritation, conjunctivitis, palpebral edema, ulceration and corneal turbidity. Eye irritation, uveitis, abscess and loss of the eye may result from severe mechanical irritation.

3.4.3)

A) WITH POISONING/EXPOSURE

1) CONJUNCTIVITIS: Exposure to copper can result in conjunctivitis and corneal ulceration or turbidity as well as palpebral edema (ACGIH, 1996; Goldfrank, 1998; Sittig, 1991).
2) IRRITATION: Transient irritation of the eyes occurred after exposure to a fine dust of oxidation products of copper produced in an electric arc (Hathaway et al, 1996). Copper chloride produced severe eye irritation and permanent corneal opacifications in rabbits (Grant & Schuman, 1993).
3) BURN: The strong alkalinity of copper cyanide solutions used in plating baths can result in severe eye burns with corneal damage (Grant & Schuman, 1993).
4) CHALCOSIS LENTIS: Copper or copper alloy foreign bodies lodged in the eye (chalcosis lentis) can result in uveitis, abscess, serious injury or loss of the eye; over time, the copper may dissolve and disseminate to the lens, cornea and iris, where it may produce a greenish-brown discoloration of the anterior capsule visible by slit-lamp microscope (Goldfrank, 1998; Grant & Schuman, 1993).
5) Retinal injury has been reported as a result of the intra-ocular retention of a copper foreign body. Electro-retinographic changes improved, but did not fully reverse, following removal of the object (Dayan et al, 1999).
6) Several outbreaks of severe corneal injury were reported after the introduction of plasma gas sterilization techniques. The injury is believed to be due to copper and/or zinc residues on the surface of the instruments (Duffy et al, 2000; Smith et al, 2000).
7) WILSON DISEASE: Discoloration of the peripheral parts of the corneas (Kayser-Fleischer rings) is a non-injurious hallmark feature of Wilson disease, a hereditary metabolic disorder characterized by deposition of copper in parenchymal tissue. A 'sunflower-like' discoloration of the most anterior layers of the lens has also been reported in patients with Wilson disease (Baselt, 2000; Grant & Schuman, 1993).

3.4.5)

A) WITH POISONING/EXPOSURE

1) IRRITATION: Nasal mucous membranes may become irritated after inhalation exposure to the dusts and mists of copper salts; ulceration and perforation of the nasal septum may result in some cases, with atrophic changes of the nasal mucous membranes (ACGIH, 1996; Sittig, 1991).

3.4.6)

A) WITH POISONING/EXPOSURE

1) METALLIC TASTE: Acute systemic intoxication may produce a metallic or sweet taste in the mouth (ACGIH, 1996; Burnett, 1989).
2) ORAL FIBROSIS: Oral submucous fibrosis has been reported rarely (0.05% incidence) in areca-nut chewers. It has been suggested that copper may be involved in the pathogenesis of this disorder, although this has not been adequately substantiated (Meghji et al, 1997).
3) CASE REPORT: Pharyngeal erythema with mild dysphagia was reported in an 89-year-old woman following a suspected ingestion of an algaecide containing copper ethanolamine complex (Graham et al, 2015).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Hypotension, dysrhythmia and coronary artery disease have been linked with exposure to copper.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension has been noted after acute ingestion of copper sulfate and might develop after ingestion of other copper salts (Stein et al, 1976; Chugh et al, 1977; Schwartz & Schmidt, 1986).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) In a nested case-control study within a prospective population study, cardiovascular mortality was found to be significantly increased in a population of patients with high serum copper and low serum zinc levels (Reunanen et al, 1996).
b) Tachycardia has been reported following acute and chronic oral exposure to copper oxychloride (Gunay et al, 2006).

C) DISORDER OF CORONARY ARTERY

1) WITH POISONING/EXPOSURE

a) Limited epidemiologic data indicate that coronary heart disease is associated with modest (5%) increases in serum copper. It is not apparent whether copper is a cause of heart disease or simply serves as a marker of some other phenomenon (Ford, 2000).
b) Additional epidemiologic studies of copper and heart disease have been reviewed and do not provide convincing evidence of a causal relationship (Anon, 1998).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Metal fume fever, wheezing and rales have been reported in workers exposed to fine copper dust. Dyspnea and tachypnea have developed after oral copper exposure. Pulmonary edema and alveolar inflammation have been noted in animals.

3.6.2)

A) METAL FEVER

1) WITH POISONING/EXPOSURE

a) Metal fume fever has been reported in workers exposed to an extremely fine copper dust at concentrations of 0.075 to 0.12 mg/m(3) (Proctor & Hughes, 1978). Symptoms include upper respiratory irritation, chills and muscle aches (Baselt, 2000).
b) Some authors have questioned this association (Borak et al, 2000).

B) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) Wheezing and rales on auscultation were reported in eight patients exposed to fumes while cutting brass pipes. Increased urine copper levels were noted (Armstrong et al, 1983).

C) DISORDER OF RESPIRATORY SYSTEM

1) WITH POISONING/EXPOSURE

a) DYSPNEA: 40-year-old man developed methemoglobinemia, cyanosis and dyspnea approximately 5 hours after ingestion of a fungicide containing copper 8-hydroxyquinolate (Yang et al, 1997).
b) TACHYPNEA has been reported following acute and chronic oral exposure to copper oxychloride (Gunay et al, 2006).
c) LACK OF INFORMATION

1) Lung damage after chronic exposure to fumes in industry has not been described. The higher incidence of respiratory cancer reported in copper smelters has been attributed to the presence of arsenic in the ore (Hathaway et al, 1996).

3.6.3)

A) ANIMAL STUDIES

1) PULMONARY EDEMA

a) Pulmonary edema has been reported in dogs following exposures to copper acetate dusts (Brodskii, 1933).

2) RESPIRATORY DISORDER

a) INFLAMMATION: Chronic inhalation of copper-containing aerosols has caused pulmonary alveolar proteinosis in rats (Likhaechev et al, 1975).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Central nervous system depression, seizures and headaches have been associated with copper exposure.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy and coma have been reported in patients with severe copper sulfate intoxication and might develop after ingestion of other copper salts (Schwartz & Schmidt, 1986; Agarwal et al, 1993).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Copper is reportedly linked with toxin-induced seizures (Goldfrank, 1998).

C) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache, vomiting and abdominal pain immediately developed in an adult after ingestion of two mouthfuls of a fungicide containing copper 8-hydroxyquinolate; methemoglobinemia with hemolysis developed later (Yang et al, 1997).

D) PARKINSON'S DISEASE

1) WITH POISONING/EXPOSURE

a) Limited epidemiologic evidence associates the development of Parkinson disease with occupational exposure to copper in excess of 20 years. Possible interactions with lead, iron and manganese have been suggested (Gorell et al, 1999).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Gastroenteritis with vomiting may occur after ingestion of some copper salts. Mucosal erosions, a metallic taste, burning epigastric sensation and diarrhea may also occur.

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) The irritant effects of ingestion of sufficient concentrations of copper salts may include a metallic taste, salivation, nausea, vomiting, burning in the epigastrium, abdominal/gastric pain and bloody diarrhea. Copper sulfate has been reported to cause gastrointestinal bleeding (hemorrhagic gastritis), which may potentially occur with other irritating copper salts (ACGIH, 1996; Agarwal et al, 1975; ILO , 1998) Jantsch et al, 1984; (Sittig, 1991; Yang et al, 1997).
b) Copper salts may induce a rapid onset of repeated vomiting (98% within 15 minutes of ingestion), with a range of two to ten episodes of vomiting following a single oral dose. The vomitus is characteristically greenish-blue (Gulliver, 1991; Gunay et al, 2006). The emetic effect seems to be secondary to the irritant effects of copper.
c) Reported cases of acute gastrointestinal 'upset' due to copper have been reviewed, and diagnostic criteria proposed (Eife et al, 1999a; Eife et al, 1999b). Acute gastrointestinal symptoms have occurred as a result of several incidents in which new copper piping was installed to supply domestic water (Knobeloch et al, 1998).
d) An outbreak of gastroenteritis occurred after the leaching of copper into drinking water as a result of carbon dioxide gas, which lowered the pH of the water. The water had a strong metallic taste (Witherell et al, 1980). Another outbreak was reported in several children who drank an acidic lime cordial from a copper urn; the beverage was found to have a copper concentration of 300 mg/L (Gill & Bhagat, 1999).
e) CASE SERIES: In a cluster of cases, an outbreak of abdominal pain, vomiting and complaint of metallic taste occurred on a small industrial estate in the United Kingdom in which copper was present in the water supply system (water was obtained from two boreholes and chlorinated by salt electrolysis before distribution). Of note, the only workers who became ill typically consumed only bottled water; those that did ingest the tap water regularly did not become ill. Prior to this outbreak, many individuals had stopped consuming the tap water because of a "bad taste". The authors suggested that people who were regularly exposed to high concentrations of copper may have become tolerant. Copper levels dropped after water was received from a public water supply (Hoveyda et al, 2003).
f) CASE REPORT (PEDIATRIC): A 2-year-old-boy experienced abdominal pain and vomiting within a few hours, and bright-green-colored stools within 48 hours of ingestion of a blue ballpoint pen refill containing copper phthalocyanines (Forrester, 1975).
g) CASE REPORT (PEDIATRIC): Three cases of children with protracted diarrhea after exposure to copper in domestic water were reported. The symptoms resolved on withdrawal and reappeared on re-institution of domestic water use (Stenhammer, 1999).
h) CASE REPORT (ADULT): A 40-year-old man immediately developed vomiting, abdominal pain and headache after ingestion of a fungicide containing copper 8-hydroxyquinolate. Diarrhea developed within five hours of the exposure (Yang et al, 1997).
i) CASE REPORT: Nausea and vomiting were reported in a 41-year-old woman following intentional subcutaneous administration of copper glycinate (equivalent to 2.5 grams of copper) into 3 sites on her left forearm (Oon et al, 2006).
j) CASE REPORT: An 89-year-old woman presented with vomiting, that was green in color, and diarrhea after a suspected ingestion of an algaecide containing copper ethanolamine complex. She also developed pharyngeal erythema with mild dysphagia, mixed hyperbilirubinemia, and pancreatitis. Laboratory data revealed elevated copper levels at 2002 mcg/dL (reference 70 to 175 mcg/dL). There was no evidence of hemolysis, significant hepatotoxicity, renal dysfunction, or methemoglobinemia. With supportive care, the patient's symptoms improved and she was discharged (Graham et al, 2015).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Hepatomegaly, liver tenderness, increased levels of transaminase and jaundice may occur on the second or third day after ingestion of copper salts. Childhood cirrhosis has been linked with ingestion of milk from copper or brass drinking vessels. Granulomas have also been associated with copper exposure.

3.9.2)

A) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) Jaundice appears in about 25% of patients on the second or third day after acute ingestion of copper salts and may be accompanied by hepatomegaly, increased levels of transaminase and liver tenderness, with biopsy showing centrilobular necrosis and biliary stasis (Gunay et al, 2006; Baxter et al, 2000a; Zimmerman, 1978). Hepatic accumulation of copper is an essential feature of the development of copper toxicosis (Bremner, 1998).
b) Hepatic necrosis was reported in a 46-year-old man after chronic ingestion of copper coins. Electron micrograph showed dense deposits of copper in the hepatocytes at autopsy (Hasan et al, 1995).

B) CIRRHOSIS OF LIVER

1) WITH POISONING/EXPOSURE

a) CHILDHOOD CIRRHOSIS: Indian childhood cirrhosis has been associated with increased hepatic copper concentrations, partly attributable to the use of copper or brass drinking vessels used to prepare animal milk or water. Milk apparently takes up copper more readily than water does, and thus milk copper contamination may be the cause (Bhave et al, 1987; Horslen et al, 1994; O'Neill & Tanner, 1989; Tanner et al, 1983; Tanner, 1998).

1) Multiple cases of childhood cirrhosis have been reported from various locations, but the involvement of copper in these cases is not entirely apparent (Rodec et al, 1999; (Walker, 1999; Walker-Smith, 1999) Trollman et al, 1999). The histological pattern of liver damage in a series of 12 German infants was noted to be variable (Muller-Hocker et al, 1998).
2) Various authors have suggested that at least some of these cases may be due to an inherited disorder, an inherited predisposition in conjunction with increased copper intake, or the result of copper in conjunction with some other environmental factor(s) (Horslen et al, 1994; Scheinberg & Sternlieb, 1994; Tanner, 1998; Tanner, 1998; Muller et al, 1998; Anon, 1998).

b) IDIOPATHIC COPPER TOXICOSIS is related to abnormal hepatic copper accumulation with cirrhosis and cholestasis, not always due to an exogenous copper source, and is characterized by distinct clinical and pathologic features.

1) This disorder is generally found in such pediatric liver diseases as Wilson disease, Indian childhood cirrhosis, the non-Indian disease called idiopathic copper toxicosis, and disorders associated with chronic cholestasis (Muller et al, 1998). These diseases usually result from a genetic predisposition to the hepatic accumulation of copper (Barceloux, 1999; Anon, 1998).
2) CASE REPORT: An adult consuming copper supplements for 3 years at doses of 30 to 60 mg per day developed cirrhosis necessitating liver transplantation (O'Donohue et al, 1999).

C) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute hepatic failure was reported in a 41-year-old woman approximately 4 days following intentional subcutaneous administration of copper glycinate (equivalent to 2.5 grams copper). Her ALT and AST levels peaked at 2903 Units/L and 6654 Units/L, respectively, 3 days after admission (Oon et al, 2006).
b) CASE REPORT (CHILD): A 6-year-old boy presented with fatigue and abdominal distention that progressed over a period of several weeks. An abdominal ultrasound indicated hepatosplenomegaly and laboratory data revealed elevated liver enzymes (ALT 275 units/L, AST 707 units/L, GGT 155 units/L) and a total bilirubin of 1.2 mg/dL. Urine copper was slightly elevated at 212 mcg/L; however a penicillamine challenge test indicated a 24-hour urine copper of 1600 mcg/day. A liver biopsy showed extensive fibrosis and microscopic staining was positive for copper. The dry copper weight was 1400 mcg/g of liver tissue and, because there was no indication of copper exposure in his history, Wilson disease was suspected; however, genetic testing showed no mutations known to code for Wilson disease. Despite chelation therapy with trientene and zinc, acute liver failure occurred, with a bilirubin concentration of 50 mg/dL and an INR of 6. The patient received a liver transplant and recovered uneventfully. Further questioning of the patient's mother revealed that he had been receiving an energy drink mixed with chocolate milk on a daily basis for the previous 8 months, as well as 2 multivitamins daily. Total amount of copper consumed was 9088 mcg/day, approximately 21 times the recommended daily allowance for his age (Bartlett & Erickson, 2012).

1) His fraternal twin brother, who also consumed the same amount of copper (9088 mcg/day for 8 months), developed mildly elevated ALT and AST concentrations; however, a liver biopsy was negative for fibrosis or inflammation. Microscopic staining was positive for copper and he had a dry copper weight of 3020 mcg/g of liver tissue. He remained stable following chelation therapy with penicillamine. It is suspected that the first patient may have had either underlying liver disease or a possible unidentified defect of copper metabolism, resulting in liver failure despite a dry copper weight of less than half that of his brother (Bartlett & Erickson, 2012).

D) INJURY OF LIVER

1) WITH POISONING/EXPOSURE

a) Vineyard workers exposed to an antifungal spray containing copper sulfate developed liver granulomas with accompanying increased serum alkaline phosphate levels and hepatomegaly. Other effects of chronic exposure in these workers included Kupffer cell proliferation, fibrosis, cirrhosis and portal hypertension (Baxter et al, 2000a).

E) HYPERBILIRUBINEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Mixed hyperbilirubinemia (total 3.2 mg/dL, direct 1.1, indirect 2.2) occurred in an 89-year-old woman following a suspected ingestion of an algaecide containing copper ethanolamine complex. The patient also developed vomiting that was green in color, diarrhea, pancreatitis, and pharyngeal erythema with mild dysphagia. Laboratory data revealed elevated copper levels at 2002 mcg/dL (reference 70 to 175 mcg/dL). There was no evidence of hemolysis, significant hepatotoxicity, renal dysfunction, or methemoglobinemia. With supportive care, the patient's symptoms improved and she was discharged (Graham et al, 2015).

3.9.3)

A) ANIMAL STUDIES

1) HEPATIC CIRRHOSIS

a) Animal studies suggested that pyrolizidine alkaloids secreted into milk by grazing animals may contribute to the development of Indian childhood cirrhosis (Morris et al, 1994). In rats, chronic ingestion of copper and retroserine increased hepatic injury and copper accumulation and decreased survival compared with chronic ingestion of copper or retroserine alone (Morris et al, 1994).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Acute renal failure with oliguria followed by anuria may occur 24 to 48 hours after ingestion. Hemoglobinuria and hematuria may also occur.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure develops in 20% to 40% of patients with acute copper sulfate intoxication and is believed to be mainly due to intravascular hemolysis. This might also occur after ingestion of other copper salts. Anuria or oliguria may develop 24 to 48 hours after ingestion, accompanied by an increase in BUN (Wahl et al, 1963; Chugh et al, 1977; Chugh et al, 1977a).
b) Acute tubular necrosis follows by several hours the acute gastrointestinal symptoms of copper salt ingestion (Baxter et al, 2000a).
c) Biopsies showing swelling or necrosis of the tubular cells, glomerular congestion and occasional hemoglobin cast have been noted. Necrosis seems to be due to a direct toxicity to renal tubular cells, as many of these patients do not have severe hemolysis or hypotension (Dash, 1989).
d) CASE REPORT: Acute renal failure with hemoglobinuria occurred in a 41-year-old woman following intentional subcutaneous administration of copper glycinate (equivalent to 2.5 grams of copper). At admission, her serum creatinine level was 0.249 mmol/L and her BUN was 13.9 mmol/L. Despite supportive care with fluids, chelation with d-penicillamine, and sodium thiosulfate administration, her renal failure progressed to anuria, requiring continuous veno-venous hemodiafiltration (CVVHDF) that continued intermittently over a 16-day period (a total of 394 hours). Three weeks after initial presentation, following discharge from the ICU, the patient continued to have severe renal insufficiency with a serum creatinine level of 0.590 mmol/L (Oon et al, 2006).
e) CASE REPORT: Acute renal failure was reported in a 19-year-old man who intentionally ingested a glassful of liquid pesticide containing copper oxychloride. His urinary output was decreased and laboratory data revealed a serum creatinine of 13.2 mg/dL and an elevated urea concentration of 318 mg/dL. Urinalysis showed evidence of proteinuria (+4 protein) and hematuria (+3 red blood cells). Despite treatment with 5 hemodialysis sessions, the renal failure persisted and the patient was subsequently enrolled in a dialysis program (Gunay et al, 2006).

B) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hemoglobinuria and hematuria have been reported after copper sulfate ingestion and might occur with intoxication from other copper salts (Walsh et al, 1977).

C) ABNORMAL URINE

1) WITH POISONING/EXPOSURE

a) Dark urine developed in a 40-year-old man within 5 hours of ingesting two mouthfuls of a fungicide containing copper 8-hydroxyquinolate (Yang et al, 1997).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been described in patients with hemodialysis-induced copper toxicity (Klein et al, 1972; Eastwood et al, 1983).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Hemolysis and anemia have occurred and, rarely, methemoglobinemia.

3.13.2)

A) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Intravascular red cell hemolysis has been reported after acute ingestion (Chugh et al, 1977; ILO , 1998; Walsh et al, 1977; Yang et al, 1997; Yang et al, 2004; Gunay et al, 2006). Hemolytic anemia may follow several hours after the acute gastrointestinal symptoms of copper salt ingestion (Baxter et al, 2000a).
b) Severe hemolysis (lowest hemoglobin reported, 7.3 g/dL) requiring repeated blood transfusions occurred in a 40-year-old man after ingestion of two mouthfuls of a fungicide containing copper 8-hydroxyquinolate. The patient was also treated for persistent methemoglobinemia (Yang et al, 1997; Yang et al, 2004).
c) CASE REPORT: A 41-year-old woman developed acute hemolytic anemia (lowest hemoglobin reported, 58 g/L) requiring several blood transfusions over a two-week period, totalling 11 units of packed cells, after intentionally injecting herself subcutaneously with copper glycinate (equivalent to 2.5 grams of copper). The patient also developed a coagulopathy requiring treatment with fresh-frozen plasma and cryoprecipitate (Oon et al, 2006).

B) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Rarely, methemoglobinemia has been reported (Chugh et al, 1975; Eastwood et al, 1983; Kim & Chomchai, 1999; Matter et al, 1969; Todd & Thompson, 1961; Yang et al, 1997; Yang et al, 2004).
b) CASE REPORT (INFANT): A case was reported of a 6-week-old infant with methemoglobinemia due to well water with a high copper and nitrate content. Nitrates in well water are well-established inducers of methemoglobin, especially in susceptible populations such as infants. It is likely that nitrates contributed more than copper to the methemoglobinemia in this case (MMWR, 1993).
c) CASE REPORT: Methemoglobinemia (24%) and hemolysis were reported in a 40-year-old man after ingestion of two mouthfuls of a fungicide containing copper 8-hydroxyquinolate. It was suggested that methylene blue was only partially effective in decreasing the methemoglobinemia level (20.7%) due to the fungicide's ability to inhibit G6PD activity.

1) BAL and plasma exchange therapy were also initiated and the methemoglobin level dropped to 1.1%. The patient recovered without sequelae (Yang et al, 1997; Yang et al, 2004).

d) CASE REPORT: Increased methemoglobin levels and serum copper levels were reported in a 40-year-old woman after residential exposure to copper naphthenate after a heavy spraying onto a hardwood floor with spillage of the container into a crawl space. Three months after continuous exposure, her methemoglobin level was 16%, which decreased to 0.9% 12 days after removal from the copper source. Naphthenic acid may have contributed to the methemoglobinemia (Kim & Chomchai, 1999).

C) ANEMIA

1) WITH POISONING/EXPOSURE

a) CHRONIC: Chronic exposure to copper may produce anemia (ACGIH, 1996). Normocytic normochromic anemia (hemoglobin level ranging from 8.7 to 10.4 g/dL) was reported in 4 patients following chronic exposure to a pesticide containing copper oxychloride (Gunay et al, 2006).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Skin exposure can produce in severe irritation, itching, erythema, dermatitis and eczema; systemic toxicity may result.

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Skin contact with some copper salts may result in severe irritation, with itching, erythema and dermatitis, and may produce systemic toxicity (Holzman et al, 1966).

B) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Six cases of allergic contact dermatitis have been reported in the world literature up to 1972: three involved contact with industrial exposure to brass (2 Cu; 1 Zn); one case was a worker who transported sacks of CuSO4; another, a telephone wire man exposed to copper; and the sixth worker exposed to various pieces of copper-containing jewelry (Clayton & Clayton, 1981).
b) Peri-menstrual recurrence of contact dermatitis has been reported in a patient using a copper-containing intrauterine device (Pujol et al, 1998).

C) ECZEMA

1) WITH POISONING/EXPOSURE

a) The irritating effects of copper salts on the skin result in itching eczema (ACGIH, 1996).

D) PUNCTURE WOUND - INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 27-year-old agricultural worker inadvertently injected his left lower leg with 120 mg (2 mL) of a copper glycinate cattle veterinary solution. At the injection site a 3 x 3 cm central dark necrotic area developed along with a 10 cm area of erythema and edema. Skin debridement showed evidence of extensive blackish-grey discoloration of the skin, subcutaneous fat and deep fascia, which were all necrotic. Serum copper level drawn the next day after the injury was not elevated. Treatment included split skin grafting that needed to be partially redone due to a staph aureus infection and poor adherence of the graft. Healing was noted at approximately 11 weeks. However, the patient remained symptomatic with persistent neurogenic pain (Atkinson et al, 2004).
b) CASE REPORT: Dermal necrosis at the injection site occurred in a 41-year-old woman following intentional subcutaneous administration of copper glycinate (equivalent to 2.5 grams of copper) at 3 different sites on her left forearm. The patient required extensive debridement and split-skin grafting (Oon et al, 2006).

E) HAIR DISCOLORATION

1) WITH POISONING/EXPOSURE

a) Very high levels of exposure to copper dust or fume may result in symptomless greenish discoloration of the hair, tongue and teeth (ACGIH, 1996; Baxter et al, 2000a; Hathaway et al, 1991).
b) GREEN HAIR: Green pigmentation of blonde hair has been reported after exposure to copper-contaminated tap water, swimming pools containing copper-based algicides and application of copper contaminated henna (Mascaro et al, 1995; Person, 1985; Tosti et al, 1991).

Reproductive

3.20.2)

A) FETAL DISTRESS

1) Fetuses of women with Wilson disease, a disorder of copper metabolism involving high serum copper levels, are at risk for intrauterine growth retardation (Chin, 1991; DuPont et al, 1991).

B) ANIMAL STUDIES

1) Copper salts were not found to be teratogenic to laboratory animals in some studies (Schardein, 2000). Copper was not teratogenic in hamsters (HSDB). The results of teratogenicity studies in rats, however, have been conflicting (RTECS , 2002; Giavini, 1980).
2) In rats, copper was found to affect female fertility index and pre- and post-implantation mortality; it also produced fetotoxicity and developmental abnormalities of the central nervous system and musculoskeletal system (RTECS , 2002).
3) Metallic copper was lethal to mouse and rat embryos (Brinser & Cross, 1972; Webb, 1973). Copper sulfate and citrate were teratogenic when injected in hamsters (Ferm & Hanlon, 1974). Copper may have been toxic to the embryos of rats when inhaled and to mice when given orally (Baghramian, 1975).
4) Although excess copper may be harmful to reproduction, so also is copper DEFICIENCY. Copper deficiency produced positive results for teratogenicity in rats, pigs, sheep, guinea pigs and horses; mainly limb abnormalities or polymorphic defects resulted (Bennetts & Chapman, 1937; Everson & Wang, 1967; O'Dell, 1961; Schardein, 2000). A copper-deficient diet did not produce skeletal abnormalities in rats, however (Jankowski et al, 1993).

3.20.3)

A) ABORTION

1) A possible link between occupational exposure to copper and miscarriages in women working in the metallurgy industry in Finland with mixed exposures has been reported (Hemminki, 1980; Hemminki, 1983).
2) One woman with Wilson disease had eight spontaneous abortions before having a normal gestation and delivery after receiving zinc sulfate treatment (Schagen van Leeuwen & Christiaens, 1991).

B) PLACENTAL BARRIER

1) Copper levels correlated with levels of cadmium and zinc in the placentas of 292 low-risk (multiparous) women (Kuhnert et al, 1993). Iron-folate supplementation beginning in the second trimester resulted in lower serum copper levels late in pregnancy (Burns & Patterson, 1993).
2) Copper from intrauterine devices is available to the fetus, but fetal blood levels were lower than maternal levels, although fetal liver levels were higher (Creason, 1976; Friberg, 1986). Fetal cord blood copper levels averaged 35 percent of those in maternal blood; the latter averaged 135.3 (+/- 26.26) mcg/dL and were higher than levels found in nonpregnant women (Veena et al, 1991).

C) LACK OF EFFECT

1) Serum copper levels in pre-eclamptic pregnant women were not significantly different from those in women with normal pregnancies (Kisters et al, 1993).
2) No differences in levels of serum copper and ceruloplasmin were found in pregnant women with gestational diabetes. Copper-zinc (CuZn) superoxide dismutase activity was significantly increased, but this response to oxidative stress was evidently not due to a deficiency of copper (Loven et al, 1992).

D) ANIMAL STUDIES

1) Copper was a possible cause of abortions in sheep (James, 1966).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7440-50-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Increased deaths from cancers have been linked to exposure to copper, mixed with other exposures. However, copper is considered not classifiable as to human carcinogenicity.

3.21.3)

A) LACK OF INFORMATION

1) Copper is classified by IRIS as D (not classifiable as to human carcinogenicity), based on a lack of human human data, inadequate animal data from assays of copper compounds, and equivocal mutagenicity data (HSDB , 2002).

B) CARCINOMA

1) Several epidemiological studies have reported increased deaths from various cancers in copper miners (Enterline & Marsh, 1982), in persons living near a copper smelter (Cordier, 1983), and in copper and zinc refiners (Logue, 1982), but these have all involved mixed exposures with other metals.
2) Chinese copper miners (7088) exposed from 1969 to 1988 had an increased risk of mortality from lung cancer, related to duration of exposure and time since first exposure (Chen et al, 1993).
3) Plasma copper concentrations were slightly but significantly higher in women diagnosed with breast cancer than in controls. Levels were 1.31 mg/L in breast cancer cases and 1.26 mg/L in controls who had been in a prospective breast cancer study for an average of 11 years (Overvad et al, 1993).

3.21.4)

A) NEOPLASM

1) According to the WHO review (Anon, 1998), "The available studies of the carcinogenicity studies of copper compounds in rats and mice have given no indication that copper salts are carcinogenic." However, the studies are noted to be inadequate in many cases.
2) When implanted intrapleurally in rats, copper was found to be an equivocal tumorigenic agent in the respiratory system (RTECS , 2002).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain whole blood copper levels if symptomatic.
B) Obtain baseline liver function tests, renal function tests and CBC.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Acute whole blood copper levels should be obtained.

a) Serum copper concentrations normally range from 10.5 to 23 micromoles/Liter (Bentur et al, 1988). Average levels are 1.09 mg/L for men, 1.20 mg/L for non-pregnant women and 2.39 mg/L for pregnant women (Baselt, 2000).
b) Serum copper levels rise with age in men. Mean levels by age 80 were 1.3 mcg/mL, compared with 1.05 mcg/mL in 20-year-old men (Madaric et al, 1994).
c) In packed red blood cells, erythrocyte copper levels are around 0.89 mg/L (Baselt, 2000).

2) Baseline liver function tests and renal function tests should be obtained and followed daily until symptoms abate.

B) HEMATOLOGIC

1) Obtain hematologic evaluation and monitor methemoglobin levels in cyanotic patients.

4.1.3)

A) URINARY LEVELS

1) Normal daily excretion of copper in the urine is less than 0.6 micromole/day (Bentur et al, 1988).

4.1.4)

A) OTHER

1) Electroretinograms are useful in detecting and following damage to the retina by intraocular copper. Abnormal ERG results indicate serious injury may be imminent and the copper should be removed. Analysis of aqueous humor by chemical assay and atomic absorption spectrophotometry has also been used as an early warning measure (Grant & Schuman, 1993).

Radiographic Studies

A)

1) Metallic copper is radiopaque (Bentur et al, 1988). X-rays may be useful to establish diagnosis. Copper salts are not considered radiopaque.

Methods

A)

1) Copper determinations can be done by atomic absorption spectrophometry (Bentur et al, 1988). Flame and flameless atomic absorption procedures are used for serum and urine samples (Baselt, 2000).

B)

1) A colorimetric procedure using bathocuproine sulfonate is used to measure copper levels in protein-free filtrates of biological samples (Baselt, 2000).

Treatment

Life Support

A)

Monitoring

A)

B)

Oral Exposure

6.5.1)

A) SUMMARY

1) Vomiting is rapid and spontaneous in most patients following ingestion of copper salts.

B) ACTIVATED CHARCOAL

1) There are no studies demonstrating adsorption of copper to activated charcoal. Most highly charged metal ions are not well adsorbed to activated charcoal. Activated charcoal may obscure endoscopy findings after ingestion of corrosive copper salts as well as creating a risk of corrosive GI perforation with copper. Activated charcoal is NOT recommended in the pre-hospital setting.

6.5.2)

A) SUMMARY

1) Vomiting is rapid and spontaneous in most patients following ingestion of copper salts.

B) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

C) NASOGASTRIC SUCTION

1) Copper salts may be caustic agents, capable of extensive mucosal damage, including perforation of the gastrointestinal tract. Gastric lavage and administration of charcoal may cause further complications. However, some clinicians have successfully used these techniques. These are controversial techniques, and are left to the final judgement of the treating physician.
2) Some clinicians may choose to insert a small, flexible nasogastric tube through the mouth, if the patient is alert and cooperative, in an attempt to remove the corrosive substance following a recent ingestion.

a) The decision should be based on the amount of the ingestion, the concentration of the copper sulfate, and the risk and potential benefit to the patient.
b) In the typical pediatric ingestion involving small volumes of corrosive materials, nasogastric suction is unlikely to be of benefit. In suicidal ingestions involving large quantities of material and an increased likelihood of severe mucosal burns, the risk of causing perforation may outweigh the potential benefit of removing caustic material.

3) Gastric lavage may be indicated after ingestion of non corrosive forms of copper.

D) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

1) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

E) PRECAUTIONS:

1) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
2) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

F) LAVAGE FLUID:

1) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
2) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
3) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

G) COMPLICATIONS:

1) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
2) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

H) CONTRAINDICATIONS:

1) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

I) ACTIVATED CHARCOAL

1) There are no studies demonstrating adsorption of copper to activated charcoal. Activated charcoal may obscure endoscopy findings after ingestion of corrosive copper salts and is NOT recommended.

6.5.3)

A) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

B) CHELATION THERAPY

1) SUMMARY: There is little clinical experience in the use of chelators in the setting of acute copper intoxication. Data on efficacy is derived from patients with chronic copper intoxication (Wilson disease, Indian childhood cirrhosis) and animal studies. BAL, penicillamine, DMPS and EDTA have been used. D-penicillamine is considered the drug of choice for Wilson disease, a condition of chronic copper overload.
2) Chelation therapy is generally recommended in symptomatic patients. If the patient is asymptomatic, confirmation from the laboratory may be received before instituting chelation therapy.

C) PENICILLAMINE

1) Penicillamine increases urinary copper excretion in animal models (Owen et al, 1975), complexes copper in vitro (Borchard & Schneider, 1974) and slows or reverses the progression of hepatic disease in patients with chronic copper intoxication (Wilson disease and Indian childhood cirrhosis) (Bhusnurmath et al, 1991; Schilsky et al, 1991).

a) Penicillamine has been used to treat acute copper intoxication but data regarding efficacy are lacking (Hantson et al, 1996; Jantsch et al, 1985; Holtzman et al, 1966) Rodec et al, 1999).

2) USUAL ADULT DOSE

a) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).

3) USUAL PEDIATRIC DOSE

a) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004a; Prod Info DEPEN(R) titratable oral tablets, 2009).

4) PRECAUTIONS

a) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
b) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
c) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).

5) ADVERSE EFFECTS

a) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).

1) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).

6) PREGNANCY

a) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
b) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.

D) DIMERCAPROL

1) BAL increases urinary copper excretion in patients with Wilson disease (Schilsky et al, 1991) and complexes copper in vitro (Borchard & Schneider, 1974). It has been used in patients with acute copper sulfate intoxication but data regarding efficacy are lacking (Hantson et al, 1996; Jantsch et al, 1985; Walsh et al, 1977; Fairbanks, 1967).
2) DOSE: BAL (DIMERCAPROL) 3 to 5 milligrams/kilogram/dose deep intramuscularly every 4 hours for 2 days, every 4 to 6 hours for an additional 2 days, then every 4 to 12 hours for up to 7 additional days.
3) ADVERSE EFFECTS: Adverse reactions such as urticaria may respond to diphenhydramine. Persistent hyperpyrexia is not uncommon.

E) UNITHIOL

1) Administration of sodium 2,3-dimercaptopropanesulfonate (DMPS) to mice shortly after copper sulfate intoxication prevented the formation of renal tubular degeneration and renal necrosis as well as hepatic lesions, which are normally seen in mice following copper poisoning (Mitchell et al, 1982).
2) DMPS is not FDA-approved in the US.
3) DOSE: 5% solution IM or subcutaneously 5 mg/kg three or four times during the first 24 hours, 2 to 3 times on day two, and 1 to 2 times daily thereafter.

F) EDETATE CALCIUM DISODIUM

1) EDTA has been used to treat patients with acute copper sulfate intoxication but data regarding efficacy are lacking (Walsh et al, 1977).
2) DOSE: 75 milligrams/kilogram/24 hours deep intramuscularly or slow intravenous infusion given in 3 to 6 divided doses up to 5 days; may be repeated for a second course after a minimum of 2 days; each course should not exceed a total of 500 milligrams/kilogram body weight. Complications include renal tubular necrosis, so fluids must be at least maintained and should be intravenous at first.

G) GENERAL TREATMENT

1) AMMONIUM THIOMOLYBDATE has been successfully administered to sheep for the prevention and treatment of chronic copper sulfate poisoning (Gooneratne et al, 1981). Use of thiomolybdate for copper toxicity in humans has not been reported, and the material is not readily available.

H) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

I) BURN

1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) SUPPORT

1) Copper fumes may cause a metal fume fever syndrome or respiratory signs such as wheezing or rales on auscultation. Be prepared to administer respiratory support to symptomatic patients. Copper may be absorbed by this route and should then be chelated.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) IRRITATION SYMPTOM

1) Eye contact may result in severe irritation.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) IRRITATION SYMPTOM

1) Skin exposure may result in severe irritation.

B) SKIN ABSORPTION

1) Metallic copper embedded in the skin has produced increased serum copper concentrations (Bentur et al, 1988). Monitor serum and urine copper concentrations in patients with significant dermal exposure. Chelation therapy should be considered if copper concentrations are excessive.
2) CONTACT DERMATITIS - A skin cream containing 10 percent DTPA as a chelator decreased the occurrence of positive patch tests to copper in sensitized individuals (Wohrl et al, 2001).

C) DISORDER OF HAIR COLOR

1) GREEN HAIR - Use of shampoos containing penicillamine (250 milligrams in 5 milliliters of water and 5 milliliters of shampoo) (Person, 1985; Mascaro et al, 1995) or EDTA (Goldschmidt, 1979) have been effective in removing green color from hair due to copper exposure.

D) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Hemodialysis was ineffective in a 41-year-old patient who ingested copper sulfate (Agarwal et al, 1975), but may be indicated in patients with renal failure secondary to copper poisoning (Csata et al, 1971).

B)

1) Continuous peritoneal dialysis with salt-poor albumin over 60 hours resulted in removal of 9.1 milligrams of copper in a child who had ingested approximately 10 to 60 grams of copper sulfate. Concentration of copper in the albumin containing dialysate was 38 micrograms/deciliter, compared with copper concentrations of 3.88 to 4.02 when dialysate without albumin was used. Exchange transfusion was also done during this time and may have contributed to removal of copper (Cole & Lirenman, 1978).

Abstracts

Case Reports

A)

1) ORAL: Chronic ingestion of copper-containing coins in a mentally disturbed patient resulted in severe copper toxicity and death. Copper-containing coins were corroded by prolonged contact with gastric fluids, with subsequent absorption. Deposition of copper was found at autopsy in the liver and kidneys. Death was due to the acute toxic phase of chronic copper poisoning. At autopsy, 275 US coins were found in the stomach (Yelin et al, 1987).

B)

1) ORAL: Acute ingestion of a refill for a blue ballpoint pen, containing copper phthalocyanines, resulted in nausea and vomiting within a few hours, followed by passage of bright green colored stools within 48 hours in a 2-year-old boy (Forrester, 1975).

Range Of Toxicity

Summary

A)

Therapeutic Dose

7.2.1)

A) GENERAL

1) Copper, empirical formula Cu and atomic weight 63.5, is an essential mineral. The average daily diet supplies an adequate 2 to 5 milligrams of copper per day (Baselt, 2000).
2) The daily requirement has been estimated as 30 mcg/kg for adults (Zenz, 1994).

7.2.2)

A) GENERAL

1) The daily requirement has been estimated as 40 mcg/kg for children or 80 mcg/kg for infants (Zenz, 1994).

Minimum Lethal Exposure

A)

B)

C)

D)

1) Chronic ingestion of copper-containing coins by a mentally disturbed patient resulted in severe copper toxicity and death. At autopsy, 275 US coins were found in the stomach (Yelin et al, 1987).
2) Hasan et al (1995) reported the death of a mentally handicapped 46-year-old man due to chronic ingestion of British coins. At autopsy, over 700 coins were removed, mostly 1-pence and 2-pence, which were composed of 97 percent copper (Hasan et al, 1995).

Maximum Tolerated Exposure

A)

1) ORAL

a) The lowest published toxic dose for humans via the oral route is 120 mcg/kg, with nausea and vomiting reported (RTECS , 2002). The ingestion of as little as one gram of copper may cause toxic serum concentrations (Barceloux, 1999). Ingestion of greater than 25 mg/L copper in beverages or foods has been associated with acute gastroenteritis (Barceloux, 1999).
b) Tap water copper concentrations of 1 to 2 mg/L have been tolerated by adults with no adverse effects, but are not as well tolerated by children (Nordberg et al, 1985).
c) Children developed severe liver disorders after ingestion of 10 mg of copper in contaminated milk (Bingham et al, 2001).
d) In studies of 61 healthy volunteers drinking single 200-mL volumes of copper sulfate, nausea developed at 4 mg/L (33 subjects, concentration as elemental copper) and vomiting developed at 6 mg/L (7 subjects). In this study, 2 mg/L seemed to be generally tolerated (Olivares et al, 2001).
e) In a study involving 1-week-long exposures to drinking water with varying copper concentrations in a Latin-squares design, no association of gastrointestinal symptoms with cumulative copper intake was noted at concentrations of 0 to 5 mg/L. However, exposure to concentrations of 3 mg/L or more was associated with nausea, abdominal pain and vomiting (Pizarro et al, 1999a; Pizarro et al, 1999b).
f) The taste threshold for copper in water in the Olivares (2001) study was separately reported to be 2.6 mg/L (Zacarias et al, 2001). Various authors have reported taste thresholds of 0.8 to 5 mg/L copper (Anon, 1998).
g) CASE REPORT: Two 6-year-old boys (fraternal twins) developed hepatotoxicity following consumption of an energy drink mixed with chocolate milk on a daily basis for the previous 8 months, as well as 2 multivitamins daily. Total amount of copper consumed was 9088 mcg/day, approximately 21 times the recommended daily allowance for their age. Both patients had elevated liver enzyme concentrations; however, a liver biopsy of one of the patients revealed extensive fibrosis with positive staining for copper and a dry copper weight of 1400 mcg/g of liver tissue. Despite chelation therapy with trientine and zinc, the patient developed liver failure within a week of presentation. He received a liver transplant within 72 hours and recovered uneventfully. The second patient's liver biopsy was negative despite a dry copper weight of 3020 mcg/g of liver tissue. He remained stable following chelation therapy with penicillamine. It is suspected that the first patient may have had either underlying liver disease or a possible unidentified defect of copper metabolism, resulting in liver failure despite a dry copper weight of less than half that of his brother (Bartlett & Erickson, 2012).

2) INHALATION

a) Inhalation of 60 to 100 mg/kg of copper dust caused gastrointestinal symptoms including vomiting and inflammation (ITI, 1995).

B)

1) Workers exposed to concentrations of one to three mg/m(3) for short periods experienced altered taste response but no nausea. Airborne levels from 0.02 to 0.4 mg/m(3) produced no complaints (Hathaway et al, 1996).
2) Studies on exposures from industrial copper welding and refining operations in Great Britain indicate that concentrations up to 0.4 mg/m(3) cause no ill effects (ACGIH, 1996).

a) However, another study reported symptoms similar to metal fume fever in workers exposed to metallic copper dust at an airborne concentration of 0.1 mg/m(3) (ACGIH, 1996).

C)

1) COPPER VESSELS: Preparation of food (particularly acidic foods) in copper vessels with loss of the tinned surface has produced gastroenteritis (Gill & Bhagat, 1999).

a) Indian childhood cirrhosis has been associated with increased hepatic copper concentrations, partly attributable to the use of copper or brass drinking vessels used to prepare animal milk (Bhave et al, 1987).
b) Beverages (especially those that are acidic) prepared or stored in brass containers may become contaminated by copper ions and cause poisoning when consumed. Symptoms are nausea and vomiting, which may occur within 10 minutes of consumption.

2) TAP WATER: Excessive copper in tap water may occur as a result of leaching of copper from pipes; acidity increases the leaching (Spitalny et al, 1984; Prociv, 1997).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Mean normal serum blood levels of copper are reported as 109 micrograms percent (range 89 to 137 micrograms percent) in men, and 120 micrograms percent (range 87 to 153 micrograms percent) in women (Walsh et al, 1977). Severe intoxication or lethality has been associated with serum copper levels greater than 500 micrograms percent (Holtzman et al, 1966; Agarwal et al, 1975).
b) Normal copper concentration in blood is about 1 mg/L, although this may vary during pregnancy or with infection (Zenz, 1994). Whole blood copper concentrations near 3 mg/L are associated with gastrointestinal symptoms (Barceloux, 1999).
c) Chronic poisoning from continuous ingestion of smaller doses of copper may not elicit clinical effects until a threshold storage capacity of hepatocytes for copper is exceeded, at which point lysis of these cells results in acute cupremia with increased serum copper levels. Thus, excessive serum copper levels may not be detected until hepatocytolytic crisis occurs. Because of rapid renal clearance, these later increased levels return to normal within days (Prociv, 1997).
d) CASE REPORT - A serum copper concentration of 33 mcmol/L was reported in a 41-year-old woman 3 days after injecting herself subcutaneously with 2.5 grams of copper as copper glycinate (Oon et al, 2006).
e) CASE REPORT - A serum copper concentration of 320 micrograms percent (reference interval 180 to 250) was reported in a 19-year-old man who intentionally ingested a glassful of liquid pesticide containing an unknown amount of copper oxychloride (Gunay et al, 2006).
f) CASE SERIES - Serum copper concentrations ranged from 190 to 270 micrograms percent (reference interval 180 to 250) in 4 patients following chronic oral exposure to copper oxychloride (Gunay et al, 2006).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Copper, fume

a) TLV:

1) TLV-TWA: 0.2 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): Irritation; GI; metal fume fever
d) Molecular Weight: 63.55

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Adopted Value

1) Copper, dusts and mists, as Cu

a) TLV:

1) TLV-TWA: 1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): Irritation; GI; metal fume fever
d) Molecular Weight: 63.55

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS7440-50-8 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Copper (dusts and mists, as Cu)
2) REL:

a) TWA: 1 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): [*Note: The REL also applies to other copper compounds (as Cu) except Copper fume.]

3) IDLH:

a) IDLH: 100 mg Cu/m3 (as Cu)
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS7440-50-8 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Copper, fume
2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Copper, dusts and mists, as Cu
3) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Copper

a) D : Not classifiable as to human carcinogenicity.

4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Copper (dusts and mists, as Cu)
6) MAK (DFG, 2002): Not Listed
7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS7440-50-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Copper Fume (as Cu)
2) Table Z-1 for Copper Fume (as Cu):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 0.1

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

3) Listed as: Copper Dusts and mists (as Cu)
4) Table Z-1 for Copper Dusts and mists (as Cu):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 1

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: RTECS, 2002 ITI, 1995

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 3500 mcg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

A)

B)

1) Sokol et al (1994) found lipid peroxidation and copper content to be significantly increased in mitochondria from patients with Wilson disease, an idiopathic copper toxicosis, indicating hepatic mitochondrion to be an important target in hepatic copper toxicity, with an involvement of oxidant damage to the liver.
2) Copper influences gene expression and is a co-factor for oxidative enzymes such as superoxide dismutase, cytochrome C oxidase and lysyl oxidase, as well as for aminolevulonic acid (Baxter et al, 2000a).

C)

Physicochemical

Physical Characteristics

A)

1) In water, the color of copper is often blue or green (OHM/TADS , 2002).
2) When exposed to moist air, copper gradually develops a coating of green basic carbonate (Budavari, 2000).
3) Copper salts are usually blue or green in color (ACGIH, 1996).

B)

C)

Molecular Weight

A)

Other

A)

1) Odorless (HSDB , 2002)

Animal Toxicology

Clinical Effects

11.1.2)

A) Signs of copper toxicosis (hyperexcitability, hypermetria, hindlimb weakness, head pressing, depression, and opisthotonus) occurred 6 to 24 hours after subcutaneous injection of 120 mg of copper to calves over 150 kg and 60 mg to calves less than 150 kg, as copper disodium edetate. Necropsy showed massive liver necrosis (Bulgin et al, 1986).
B) CHRONIC COPPER TOXICOSIS results in a sudden onset of hemolytic crisis after gradual copper accumulation in the liver. Trembling, weakness, anorexia, icterus, and hemoglobinuria are frequently seen (Banton et al, 1987).

11.1.3)

A) Incidence of copper toxicosis is high in Bedlington terriers. As many as 66 percent may have copper-related liver disease (Stockman, 1988).
B) Dogs may experience a hemolytic crisis (Beasley et al, 1989), but this is not a consistent finding (Noaker et al, 1999).
C) Acute hepatic failure was reported in a 1.5-year-old Dalmatian dog with high serum copper concentrations (Noaker et al, 1999).

11.1.4)

A) Goats are 3 to 4 times more tolerant of large amounts of copper than sheep (Beasley et al, 1989).

11.1.5)

A) Horses are relatively resistant to copper poisoning. Experimental toxicosis by subcutaneous injection of 4 mg Cu/kg as copper D-penicillamine in a horse caused hypersensitivity within 5 minutes. Trembling, defecation, and collapse followed. Signs of abdominal pain, sweating, and purple urine were noticed until recovery at 36 hours after the treatment (Auer et al, 1989).

11.1.9)

A) Sheep are commonly affected animals; usually occurs when sheep are fed complete cattle, horse, or poultry diets. Sheep exhibit acute signs, including hemolytic crisis and death, after a long period of excessive copper uptake; morbidity is usually 5% or less but mortality is over 75% (Howard, 1986).
B) Sheep are highly susceptible to copper poisoning. Copper poisoning was diagnosed in two sheep. The animals had no known copper exposure except the commercial mineral mixture. Before death the animals showed pyrexia, dehydration, icterus, and pasty, golden feces. Serum was hemolyzed, with high nucleated erythrocyte count (13 and 26/100 WBC), neutrophilia and azotemia (150 mg/dL). Urine was cloudy brown, acidic and contained blood and protein. Necropsy indicated icteric connective tissue, and multifocal, irregular, pale areas in the subendocardial myocardium. Livers were smaller, firmer, and showed hepatocellular loss, vacuolization, and swelling in the centrilobular areas. Necrotic hepatocytes and pyknotic nuclei were scattered in liver parenchyma. Kidneys were enlarged and bulged. The poisoning was presumably due to incorrect copper/molybdenum ratio in the mineral supplement (Martin et al, 1988).
C) Chronic copper poisoning (source unknown) was associated with polioencephalomalacia in a 10-month-old ram lamb. The lamb presented with an acute onset of depression and blindness and poor body condition. Treatment with thiamine and dexamethasone for 3 days improved the lamb's condition. Three weeks later, however, he regressed with the same symptoms and became increasingly ataxic with CNS depression, progressing to stupor and eventually death (Sargison et al, 1994).

11.1.10)

A) Swine and sheep are the species most commonly affected by copper toxicosis (Beasley et al, 1989). Signs of toxicity in swine include anorexia, weight loss, weakness, melena, and death (Beasley et al, 1989).
B) Swine with chronic copper toxicity due to feed containing excessive copper concentrations (700 ppm) resulted in anorexia, weight loss, melena, weakness, and pallor. Necropsy results showed centrilobular liver necrosis and hypochromic anemia with iron deficiency (Hatch et al, 1979).

11.1.13)

A) OTHER

1) SIGNS - Excessive salivation, vomiting, abdominal pain, diarrhea (greenish tinged feces).
2) Copper poisoning was reported in four llamas in a zoologic herd and was attributed to excessive dietary intake of this metal. The symptoms were generally similar to those observed in other animals (recumbency, labored breathing, pale mucous membranes, hypothermia, sinus arrhythmia, leukocytosis and high levels of serum aspartate transaminase, lactate dehydrogenase and gamma-glutanyl transferase). Characteristic liver pathology was observed (Junge & Thornburg, 1989).
3) FERRETS -

a) Sibling ferrets diagnosed with copper toxicosis were found to have staining of copper deposits in the liver as well as prominent degeneration, necrosis, and hemorrhage involving central and middle hepatic zones (Fox et al, 1994).
b) Copper toxicosis in sibling ferrets resulted in hemoglobin casts with renal tubules, and hemoglobin within Bowman's space. Hemoglobinuric nephrosis was particularly prominent in the proximal convoluted tubules (Fox et al, 1994).
c) No source of copper intoxication was found in these animals and the disorder was suspected to be inherited.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) SMALL ANIMALS

a) SUMMARY -

1) Emesis, lavage, activated charcoal, and cathartic are recommended only in the unlikely event of an acute exposure to a large amount of copper. These administrations are NOT indicated in the treatment of animals with chronic exposure or copper storage diseases such as Bedlington terrier storage syndrome.

b) EMESIS AND LAVAGE -

1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

c) ACTIVATED CHARCOAL -

1) Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.

d) CATHARTIC -

1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate 20% (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium hydroxide (Milk of Magnesia) per os for dilution.

2) LARGE ANIMALS

a) SUMMARY -

1) Emesis, lavage, activated charcoal, and cathartic are recommended only in the unlikely event of an acute exposure to a large amount of copper. These administrations are NOT indicated in the treatment of animals with chronic exposure or acute signs of chronic exposure.

b) EMESIS -

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

c) ACTIVATED CHARCOAL -

1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
2) Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
3) Adult cattle: administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
4) Sheep may be given 0.5 kilogram charcoal in slurry.

d) CATHARTIC -

1) Administer an oral cathartic:

a) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
b) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
c) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses Mg(OH)2 per os).

2) Give these solutions via stomach tube and monitor for aspiration.

11.2.5)

A) DOG

1) ACUTE OVERDOSE

a) MAINTAIN VITAL FUNCTIONS - as necessary.
b) FLUIDS - If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema. Add dextrose and KCl to fluids as needed to prevent hypokalemia and hypoglycemia.
c) TRANSFUSION - If in hemolytic crisis, transfuse with whole blood or plasma, 25 milliliters/kilogram.
d) HEPATIC DAMAGE - Treat for acute hepatic failure including cleansing enemas, antibiotics, dietary restrictions, and controlling coagulopathies or gastrointestinal bleeding.
e) GLUCOCORTICOIDS - Courses of medium-dose glucocorticoids are sometimes beneficial.
f) ASCORBIC ACID - Ascorbic acid can be given at 500 to 1,000 milligrams/day to enhance urinary excretion of copper.
g) 2,2,2 TETRAMINE (TRIENTINE) - Experimental studies suggest trientine may be useful as a chelator during an acute episode. Dosage: 10 to 15 milligrams/kilogram orally twice daily (Kirk, 1989). 2,3,2 tetramine tetrahydrochloride 300 to 600 milligrams/day was considered effective in decreasing mean hepatic copper concentrations and enhancing urinary copper excretion (25-fold with the higher dose) on Bedlington terriers with hereditary copper hepatotoxicosis. Reversal of acute hepatic necrosis and hemolytic anemia was observed in one dog (Twedt et al, 1988).

2) CHRONIC OVERDOSE

a) PENICILLAMINE - Penicillamine must be given for months to years to reduce the amount of copper stored in the liver. Dosed at 10 to 15 milligrams/kilogram per os twice daily. A common side effect is vomiting (Beasley et al, 1989).
b) DIETARY RESTRICTION - No commercial diet is substantially low in copper, so homemade diets may be considered for young dogs who have not yet built up large amounts of copper in their livers (Kirk, 1989).
c) ZINC - Zinc prevents copper reaccumulation in animals who have gone through chelation therapy. Zinc acetate or sulfate is dosed at 5 to 10 milligrams/kilogram per os twice daily. This treatment is currently experimental and may result in side effects such as hemolytic anemia (Kirk, 1989).

1) Zinc acetate was used to treat dogs with hepatic copper toxicosis, an autosomal recessive disorder in some dogs. Optimal dosage was 50 to 100 mg orally per day. As plasma zinc concentration increased above 200 mcg/dL, copper uptake was suppressed (Brewer et al, 1992).

B) RUMINANTS/SWINE

1) MAINTAIN VITAL FUNCTIONS - Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
2) FLUIDS - Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.
3) WHOLE BLOOD TRANSFUSIONS - In adult horses, 4 to 8 liters blood are normally transfused at one time. This amount of fresh blood may be collected from a single healthy adult donor that has not been bled in the last 30 days. Epinephrine should be available in case of transfusion reaction. Dose: 3 to 5 milliliters 1:1000 dilution intravenously.
4) PENICILLAMINE - Dosed orally at 11 milligrams/kilogram four times daily for 7 to 10 days.
5) MOLYBDATE - Ammonium or sodium molybdate is dosed at 50 to 500 milligrams/day orally (Howard, 1986).
6) THIOSULFATE - Dosed at 0.3 to 1 gram/day orally for up to 3 weeks (Howard, 1986). Dietary supplementation with sodium molybdate (0.5 gram/cow/day) and sodium thiosulfate (5 grams/cow/day) ameliorated signs of chronic copper toxicosis in cattle (Banton et al, 1987).
7) SHEEP

a) Intravenous injection of tetrathiomolybdate in copper-loaded sheep reduced the copper concentration in liver and reduced the number and size of electron-dense lysosomes in hepatocytes (Kumaratilake & Howell, 1989a).
b) Subcutaneous injections of ammonium tetrathiomolybdate (3.4 mg/kg, three doses on alternate days) were effective in substantial reduction of copper content in liver and liver damage in copper poisoned sheep (Humphries et al, 1988).
c) Ammonium molybdate in a dose of 300 mg orally per day was administered for 4 weeks to ewes exhibiting signs of copper intoxication (Kerr & McGavin, 1991).
d) Sodium thiosulfate in a dose of 500 mg orally per day was administered for 4 weeks to ewes exhibiting signs of copper intoxication (Kerr & McGavin, 1991).

Range Of Toxicity

11.3.1)

A) SHEEP

1) The required ratio of copper to molybdenum in sheep is 6 to 1. If copper rises beyond this level, clinical toxicosis is likely (Beasley et al, 1989).

11.3.2)

A) GENERAL

1) Toxic dose ranges from 20 to 150 mg/kg body weight depending upon species, age, feed type, and health status (Beasley et al, 1989). Copper chloride is 2 to 4 times more toxic than copper sulfate (Howard, 1986).

B) RUMINANT

1) 30 to 50 ppm copper in the feed may be toxic to ruminants (Beasley et al, 1989). 200 to 800 mg copper sulfate/kilogram may poison cattle. Sheep may be poisoned by single doses of 20 to 100 mg copper sulfate (Howard, 1986).
2) CASE REPORT - Copper poisoning was reported in a flock of sheep grazing on pastures fertilized with swine manure. Mean copper concentration in forage samples was 13.25 mg/kg and in soil 26.35 mg/kg (compared to 7.25 mg/kg in soil from an adjacent pasture with no manure application). Molybdenum concentrations in soil was similar to non-treated pastures (Kerr & McGavin, 1991).
3) A mixture containing 213 mg copper sulfate and 80 mg cobalt chloride given to 2- to 6-week-old lambs caused death, characterized by signs of copper poisoning (MacLeod et al, 1990).
4) Sheep died in an average of 77 days after feeding on pollutants from a copper work. The intake of copper averaged 467 mg/animal for whole period, the copper concentration in liver was 2138 mg/kg dry matter. Although various other metals were present in pollutant mixture, the symptoms were characteristic of copper poisoning (Vrzgula et al, 1989).
5) Sheep died of copper poisoning when fed a diet consisting of 80 to 90% palm kernel cake. The cake contained 32 ppm (dry matter) of copper; livers of these sheep had 927 to 3898 ppm copper as dry matter (Chooi et al, 1988).

C) SWINE

1) Toxicoses appear when copper concentrations in the feed exceed 100 ppm, especially in the presence of low zinc or iron concentrations in the diet (Howard, 1986).

D) RODENT

1) Rats can tolerate levels up to 250 ppm in the feed (Beasley et al, 1989).

E) POULTRY

1) Turkey poults can tolerate up to 767 ppm copper in feed for 21 days (Beasley et al, 1989).

11.3.5)

A) DOG

1) Hepatic tissue concentration in a dog fatality was reported to be 2,356 micrograms/gram wet weight (reference range, 30 to 100 micrograms/gram). Serum copper concentration was reported to be 163.0 micrograms/deciliter (reference range, 20 to 80 micrograms/deciliter) (Noaker et al, 1999).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) SMALL ANIMALS

a) SUMMARY -

1) Emesis, lavage, activated charcoal, and cathartic are recommended only in the unlikely event of an acute exposure to a large amount of copper. These administrations are NOT indicated in the treatment of animals with chronic exposure or copper storage diseases such as Bedlington terrier storage syndrome.

b) EMESIS AND LAVAGE -

1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

c) ACTIVATED CHARCOAL -

1) Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.

d) CATHARTIC -

1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate 20% (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium hydroxide (Milk of Magnesia) per os for dilution.

2) LARGE ANIMALS

a) SUMMARY -

1) Emesis, lavage, activated charcoal, and cathartic are recommended only in the unlikely event of an acute exposure to a large amount of copper. These administrations are NOT indicated in the treatment of animals with chronic exposure or acute signs of chronic exposure.

b) EMESIS -

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

c) ACTIVATED CHARCOAL -

1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
2) Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
3) Adult cattle: administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
4) Sheep may be given 0.5 kilogram charcoal in slurry.

d) CATHARTIC -

1) Administer an oral cathartic:

a) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
b) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
c) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses Mg(OH)2 per os).

2) Give these solutions via stomach tube and monitor for aspiration.

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) LABORATORY--ANTEMORTEM -

a) DOG

1) SGPT may increase late in the disease and indicates hepatocellular injury. There usually is no increase in serum copper levels (Beasley et al, 1989).

b) RUMINANTS AND SHEEP -

1) Copper concentrations in the blood of normal healthy animals usually fall between 0.7 and 2 ppm (Howard, 1986).

2) LABORATORY--POSTMORTEM -

a) SWINE

1) Pale liver with centrilobular necrosis, gastric ulcers, pale muscles, and watery blood (Beasley et al, 1989).

b) DOG

1) Liver of abnormal size, and microscopic lesions including prominent cytoplasmic granules in hepatocytes and cirrhosis (Beasley et al, 1989).

c) RUMINANTS AND SHEEP -

1) Classic postmortem findings include hemoglobinuria, gun-metal colored kidneys, pale or yellow liver, and liver copper concentrations of greater than 150 ppm (wet-weight basis)(Howard, 1986).

Kinetics

11.5.1)

A) SPECIFIC TOXIN

1) Absorption varies greatly depending on the formulation of the diet and acidity of the intestine (Beasley et al, 1989).
2) Livers of sheep had 22 to 40 ppm copper when fed a ration with 95 ppm copper and 2.5 ppm molybdenum (Stahr et al, 1989).
3) Plasma copper level in a horse increased from 0.4 g/mL to 7.7 g/mL at 8 hours after acute copper poisoning. It returned to baseline after 30 hours (Auer et al, 1989).

11.5.2)

A) SPECIFIC TOXIN

1) After absorption, copper is 90% protein bound (Beasley et al, 1989).
2) Sheep dosed with 0.2% solution of copper sulfate at the rate of 15 mL/kg body weight (30 mg copper sulfate/kg) daily contained 1061 ppm copper in kidney cortex and 2500 ppm copper in liver during the hemolytic stage (Gooneratne et al, 1989a). High levels of copper were localized in the nuclear and cytosolic fractions of kidney cortex (compared to mitochondrial and microsomal fractions). The distribution of copper in the cytosolic fraction was altered after treatment with thiomolybdate; the absolute copper level increased but percent of total copper in tissue decreased (Gooneratne et al, 1989b).
3) The increase in the copper concentration after copper dosing was primarily in lysosomes and cytosolic fraction in sheep liver (Kumaratilake & Howell, 1989b).

11.5.3)

A) SPECIFIC TOXIN

1) In the liver, copper is incorporated into the mitochondria, microsomes, nuclei, and cytosol of hepatocytes (Beasley et al, 1989).

11.5.4)

A) SPECIFIC TOXIN

1) Copper is eliminated into the bile, feces, and urine. The majority is excreted in the feces.

Pharmacology Toxicology

A)

1) Chronic copper poisoning of sheep caused a linear increase in hepatocytic lysosomes, except the lysosomes decreased during hemolysis. It was suggested that the necrosis of hepatocytes packed with electron-dense lysosomes resulted due to high accumulation of copper in these organelles (Kumaratilake & Howell, 1989c).
2) SHEEP - The acute signs follow a chronic overingestion of copper and buildup in the liver. The acute episode is usually brought on by some stress factor which correlates with massive copper release from the damaged liver. Hemolysis results, leading to anemia, icterus, hemoglobinemia, renal failure, and death within 24 to 48 hours after onset of signs (Beasley et al, 1989).

References

General Bibliography

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

314)

315)

316)

317)

318)

319)

320)

321)

322)

323)

324)

325)

326)

327)

328)

329)

330)

331)

332)

333)

334)

335)

336)

337)

338)

339)

340)

341)

342)

343)

344)

345)

346)

347)

348)

349)

350)

351)

352)

353)

354)

355)

356)

357)

358)

359)

360)

361)

362)

363)

364)

365)

366)

367)

368)

369)

370)

371)

372)

373)

374)

375)

376)

377)

378)

379)

380)

381)

382)

383)

384)

385)

386)

387)

388)

389)

390)

391)

392)

393)

394)

395)

396)

397)

398)

399)

400)

401)

402)

403)

FeedBack

COPPER

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Pharmacology Toxicology

General Bibliography