Copper (Cu) occurs in nature in its metallic form and in ores and minerals, and was one of the first metals used by humans. The use of Cu has been traced back to approximately 5000 BC in the Aegean regions, where it was employed for creating valuable art objects. Cyprus, which draws its name from the Latin word cuprum, was a major source of Cu, as were regions in Anatolia and Spain. Copper mixed with tin in a 9:1 ratio comprises bronze, and the ability to form this alloy marked the end of the Stone Age and the beginning of the Bronze Age. Copper and its alloys are now used extensively in domestic and other plumbing systems and to make cooking utensils. Copper is also used in the production of electrical wire and microelectronic applications, in electroplating and photography, as a roofing material, and as a catalyst in the chemical industry.
Copper is an essential transition element that plays a fundamental role in the biochemistry of all aerobic organisms. Proteins exploit the unique redox nature of Cu to undertake a series of facile electron transfer reactions required for cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biogenesis, connective tissue biosynthesis and antioxidant defense. Conversely, exposure to high levels of copper can result in a number of adverse health effects. The reactivity of copper in biological systems also accounts for the potential toxicity of this metal when cellular Cu homeostasis is disturbed. For this reason, specific pathways have evolved for the trafficking and compartmentalization of Cu within cells.
As the body cannot synthesize copper, the human diet must supply regular amounts for absorption. The National Academy of Sciences (USA) recommends 2 to 3 mg of copper per day as a safe and adequate intake for adults. It is possible to become copper-toxic or copper-deficient, and there is a condition called bio-unavailable Cu (Cu is present, but cannot be utilized).
Exposure of humans to copper occurs primarily from the consumption of food and drinking water. The relative copper intake from food versus water depends on geographical location; generally, about 20–25% of copper intake comes from drinking water. Drinking water sources become contaminated with copper primarily because of its use in many different types of plumbing supplies. Hence, the principal route of excess exposure is through ingestion, but inhalation of Cu dust and fumes also occurs in industrial settings.
Cu occurs naturally in elemental form and as a component of many different compounds. The most toxic form of Cu is thought to be that in the divalent state, cupric (Cu2+). Because of its high electrical conductivity, copper is used extensively in the manufacturing of electrical equipment and different metallic alloys. Cu is released into the environment primarily through mining, sewage treatment plants, solid waste disposal, welding and electroplating processes, electrical wiring materials, plumbing supplies (pipes, faucets, braces, and various forms of tubing), and agricultural processes.
Copper is present in the air and water due to natural discharges like volcanic eruptions and windblown dust. It is a common component of fungicides and algaecides, and agricultural use of Cu for these purposes can result in its presence in soil, groundwater, farm animals (grazing animals like cows, horses, etc.). Cu is also present in ceramics, jewelry, monies (coins) and pyrotechnics.
Other sources of potential Cu excess include foods, particularly vegetarian proteins such as certain nuts, soybeans, seeds and grains. Meats contain Cu but are usually balanced by zinc that competes for its absorption and chocolate is high in copper. Cu cookware, hemodialysis units using copper-containing equipment, dental materials, topical Cu compounds used in burn treatment, Cu containing food supplements, and copper intra-uterine devices are minor sources. In prolonged contact with Cu cooking utensils, an acidic food or beverage can dissolve milligram quantities of Cu, sufficient to cause acute toxicity symptoms such as self-limited nausea, vomiting and diarrhea. Elevated levels of estrogens predispose individuals to copper toxicity.
Insufficient intake of competitively absorbed elements such as zinc and molybdenum can lead to or worsen Cu excess. Since Cu and zinc compete for absorption in the gut and enzymatically, zinc deficiency may result in copper excess.
Copper is an essential trace element for all biological organisms, from bacterial cells to humans. Depending on the source of the biological material, copper content ranges from parts per billion to parts per million. Copper’s essentiality was first discovered in 1928 when Hart et al. demonstrated that rats fed a copper-deficient milk diet were unable to produce sufficient red blood cells.
Cu is critical for energy production in the cells. It is also involved in nerve conduction, connective tissue, the cardiovascular system and the immune system. Cu is closely related to estrogen metabolism and is required for women’s fertility and to maintain a pregnancy. Cu stimulates production of the neurotransmitters epinephrine, norepinephrine and dopamine. It is also required for monoamine oxidase, an enzyme related to serotonin production.
The daily Cu requirement has been estimated at 30 micrograms/kg of body weight for an adult. After ingestion, maximum absorption of copper occurs in the stomach and jejunum.
The adult body contains between 1.4 and 2.1mg of copper per kilogram of body weight. In other words, a healthy human weighing 60 kilograms contains approximately 0.1 gram of Cu. However, this small amount is essential to the human’s overall wellbeing.
Absorbed Cu is initially bound to albumin and is transported from the gastrointestinal tract to the liver – where it is transferred to ceruloplasmin, which binds more than 75% of circulating Cu. Ceruloplasmin is the major plasma antioxidant and Cu transport protein. It is synthesized in several tissues, including the brain. Absorption is increased in Cu deficiency and is impaired in small-bowel disease. Other factors that influence dietary copper absorption include competition by zinc, iron, molybdenum, lead, and/or cadmium. Zinc and cadmium appear to be the most potent inhibitors of copper absorption, possibly by competing with copper for transport and/or by increasing intestinal metallothionein concentrations. Metallothioneins are a group of small, heavy-metal binding proteins that serve in detoxification and metal buffering. Cu is distributed throughout the body, but is stored primarily in the liver, muscle, and bone. The normal concentration of Cu in blood plasma is 1 mg/liter.
Copper is an integral part of many important enzymes involved in a number of vital biological processes. Although normally bound to proteins, Cu may be released and become free to catalyze the formation of highly reactive hydroxyl radicals. Data obtained from in vitro and cell culture studies are largely supportive of Cu’s capacity to initiate oxidative damage and interfere with important cellular events. Oxidative damage has been linked to chronic Cu-overload and/or exposure to excess Cu caused by accidents, occupational hazards, and environmental contamination. Additionally, Cu-induced oxidative damage has been implicated in disorders associated with abnormal Cu metabolism and neurodegenerative changes. Interestingly, a deficiency in dietary Cu also increases cellular susceptibility to oxidative damage.
In all mammals, Cu is an essential trace element involved in:
* fundamental cellular respiration
* free radical defense
* connective tissue synthesis
* iron metabolism
Copper is present in three different forms in proteins:
1.) blue proteins without oxidase activity (e.g., plastocyanin), which function in one-electron transfer
2.) non-blue proteins, which produce peroxidases and oxidize monophenols to diphenols
3.) multicopper proteins containing at least four copper atoms per molecule, which act as oxidases (e.g., ascorbate oxidase and laccase) and catalyze the reaction:
2AH2 + O2 –> 2A + 2H2O
Cytochrome oxidase is a mixed copper-iron protein catalyzing the terminal oxidation in mitochondria.
Dioxygenases are enzymes that catalyze the incorporation of both atoms of molecular oxygen into organic substrates. They take part in the metabolism of biomolecules as different as amino acids, lipids, nucleic acids, and even carbohydrates. Their biological importance relates to their ability to catalyze the degradation of aromatic compounds. Quercetin 2,3-dioxygenase (2,3QD)1 is the only dioxygenase unambiguously known to contain copper. It cleaves the O-heterocycle of polyphenolic flavonols that represent a major class of flavonoids. These compounds are important dietary components and have attracted considerable attention in the past decade owing to their antioxidizing properties.
Deficiencies of manganese, iron, molybdenum, B-vitamins and vitamin C can cause Cu to accumulate. Adrenal hormones cause the liver to produce ceruloplasmin, the main copper-binding protein in the body. A functional impairment in the liver or adrenal glands may cause copper to build up in the tissues.
Physiological stress from any cause may lead to copper imbalance. Stress depletes the adrenal glands and lowers the zinc level in the body. Whenever zinc becomes deficient, Cu tends to accumulate. In addition, most US soil is deficient in zinc. Refined sugar, white rice and white flour have been stripped of their zinc. The trend toward vegetarianism reduces zinc in the diet, since red meat is a high dietary source of zinc. High Cu levels, especially when associated with low zinc levels, have been linked to a variety of symptoms and conditions.
Elimination of Cu is principally through the feces after excretion into the bile. Urinary excretion of copper is low in humans. Healthy adults have urinary concentrations of less than 100µg per 24 hours.
Absorption of Cu occurs through the lungs, gastrointestinal tract and skin. The degree to which Cu is absorbed in the gastrointestinal tract largely depends upon its chemical state and the presence of other compounds, like zinc. Once absorbed, Cu is distributed primarily to the liver, kidneys, spleen, heart, lungs, stomach, intestines, nails, and hair. Individuals with Cu toxicity show an abnormally high level of Cu in the liver, kidneys, brain, eyes and bones.
Copper toxicity in the general population was not a public health concern until recently, mainly because of a lack of reported toxicity, despite centuries of Cu use in a wide variety of applications. The identification of genetic disorders of Cu metabolism leading to severe copper toxicity (Wilson’s disease) or Cu deficiency (Menkes disease) has not only spurred research into the molecular genetics and biology of Cu homeostasis, but also focused attention on the potential consequences of Cu toxicity in normal and potentially susceptible populations.
Mild forms of acute Cu toxicity produce nausea, vomiting, diarrhea, and malaise. Severe Cu poisoning, as through Cu sulfate ingestion, produces a severe inflammation of the gastrointestinal tract. Any amount in excess of 10 g of Cu sulfate is sufficient to cause abdominal pain, nausea, vomiting, diarrhea, malaise, and hematemesis. However, in severe acute ingestion, the following is also encountered: convulsions, dehydration, shock, cellular hemolysis, and liver and kidney necrosis.
Patients who developed intense jaundice from liver centrolobular necrosis after massive acute Cu sulfate poisoning had a more fulminant course than did patients with milder jaundice from intravascular hemolysis. Kidney abnormalities have been observed after acute Cu sulfate ingestion. Hematuria, rising blood urea nitrogen, and oliguria were frequently observed in a large series of poisonings. A picture of acute tubular necrosis was observed on urinalysis and renal biopsy in these cases.
The long-term toxicity of copper has not been well studied in humans. Medical conditions that may be associated with chronic Cu excess include: liver disease (hepatitis or cirrhosis), biliary obstruction (reduced ability to excrete copper and other toxic elements) and renal impairment.
Wilson’s disease, an inherited, autosomal recessive error in copper metabolism, epitomizes chronic disease from excessive Cu storage. Unless treated in time, Wilson’s disease is fatal. This disease is characterized by excess copper deposition in most organs, especially the liver, kidneys, brain, and eyes. Manifestations of Wilson’s disease include brain damage and progressive demylination, psychiatric disturbances, such as depression, suicidal tendencies and aggressive behavior, hemolytic anemia, cirrhosis of the liver, motor dysfunction and corneal opacities. Some patients may also experience poor coordination, tremors, disturbed gait, muscle rigidity, and myocardial infarction.
Menkes syndrome is an X-linked disorder of Cu transport characterized by progressive neurological degeneration and arterial changes. The disorder results in death in infancy.
Eczematous dermatitis and urticaria have been associated with the use of copper intrauterine devices. Except for adenocarcinoma of the lung and angiosarcoma of the liver seen in patients with vineyard sprayer’s lung, no evidence corroborates carcinogenesis from copper exposure.
Symptoms associated with excess Cu accumulation are joint and muscle pain, irritability, tremor, hemolytic anemia, learning disabilities and behavioral disorders.
Today, many children are born with excessive tissue Cu. It is passed from high-copper mothers to their children through the placenta. The major syndrome with which copper excess is associated in younger children is with Attention Deficit Disorder (ADD). Increasing evidence indicates that Cu excess may be related to ADD with and without hyperactivity.
Careful history taking is essential to diagnose acute and chronic Cu toxicity. Attention should be given to ingestion of food and drink, especially acidic beverages or alcohol prepared in copper-containing vessels. Investigation for abnormal liver and renal function and hemolytic anemia should be conducted. Dermatitis is often a suspicious sign of copper toxicity. Inquiry as to exposure to copper salts at work, use of copper-containing jewelry, or use of a copper intrauterine device should be conducted. Patch testing may be necessary to confirm the diagnosis.
The best means of testing for Cu toxicity are 24-hour urine copper or serum ceruloplasmin level tests. Also, serial hair mineral analysis every 120 days is valuable in following treatment. The normal concentration of copper in blood plasma is 1 mg/liter. 95% of the copper in plasma is in ceruloplasmin, but it is one of the acute-phase reactant proteins and it increases in acute and chronic inflammatory conditions. It is also elevated in patients taking estrogen and birth control pills and in those who are pregnant or have cirrhosis, cancer, or thyrotoxicosis. Erythrocytes also contain a significant portion of the Cu found in the blood in the form of an enzyme, superoxide dismutase. Hence, RBC mineral analysis will often reflect toxic levels.
The mineral antagonists such as zinc, manganese and iron compete with Cu for absorption and utilization. Vitamin B6 phosphate, gram quantities of vitamin C, folic acid, molybdenum and selenium are all helpful in displacing copper. Cu may be conjugated with glutathione and other sulfur-containing amino acids such as methionine and N-acetyl-cysteine. More powerful chelators such as D-penicillamine and DMPS also give excellent therapeutic results, but may involve side effects.
As with other toxic metals, Cu can be measured in the urine, blood and hair.
Although several indicators are useful in diagnosing copper deficiency, there are no reliable biomarkers of copper excess resulting from dietary intake. Copper levels can be measured in a 24-hour urine collection as well as hair analysis. Probably the most reliable indicator of excess copper status is liver copper concentration.
Blood Testing: Increased serum copper or ceruloplasmin levels are not reliably associated with copper toxicity. Ceruloplasmin is an acute-phase reactant, and elevations in serum copper and ceruloplasmin concentrations are induced by inflammation, infection, disease, malignancies, pregnancy, and other biological stressors. Levels of copper-containing enzymes, such as cytochrome-c-oxidase, superoxide dismutase, and diaminase oxidase vary not only in response to copper state, but also in response to a variety of other physiological and biochemical factors and thus are inconsistent markers of excess copper status.
Urine element analysis is an invaluable tool for the identification or confirmation of copper deficiency and toxicity, as well as for the monitoring of detoxification therapy.
It is very important to note the total time and volume of urine collections. Otherwise, one cannot calculate the actual mass or rate of excretion of elements (i.e., ug/24 hours). This can be especially problematic during detoxification therapy that is associated with markedly increased urine volume. For increased convenience, urine elements can also be analyzed in specimens that are collected for less than 24 hours. For shorter collection periods, elements will be reported per mg creatinine.
Hair copper levels are usually indicative of body status, except that exogenous contamination may occur giving a false normal (or false high). If hair Cu is in the normal range, this usually means tissue levels are in the normal range. However, under circumstances of contamination, a real Cu deficit could appear as a (false) normal. If symptoms of Cu deficiency are present, a whole blood or red blood cell elements analysis can be performed for confirmation of Cu status.
As with all detoxification protocols, the type, dose and duration of detoxification agents should always be individually assessed, and administered by a licensed medical practitioner.
The following may serve as a basic guideline for detoxification of excess Cu caused by chronic exposure. Before initiating a detoxification program, a CBC with chemistry, including a thyroid panel with lipids, should be performed. In addition, whole blood elements to assess the mineral status and a urine creatinine clearance should be performed every 60 days when using synthetic detoxifying agents. Administration of glycine and synthetic agents may cause a depletion of essential elements such as copper, zinc, iron, calcium, magnesium, and other trace minerals. Of greatest concern is potential kidney toxicity – which can occur when the body releases its Cu stores for excretion through the kidneys. Those with underlying kidney disease may not be able to undergo aggressive copper detoxification therapy.
1. First, identify the source(s) of copper in the individual’s environment and remove them or remove the individual from the source(s). Check food supplementation for copper excess.
2. Assess whole blood cell element analysis to determine mineral nutrient deficiency and supplement appropriately (often low zinc-high copper values exist).
3. Supplement with vitamin C (corn free source) to reduce oxidative stress caused by excess copper. May administer gram quantities to bowel tolerance.
4. Supplement with magnesium glycinate 100 to 300 mg daily (watch for diarrhea and, if present, reduce dose of magnesium).
5. Supplement natural vitamin E (D-alpha tocopherol) at 400 IU daily.
6. Supplement 200 mcg of selenium daily.
7. Administer alpha lipoic acid 200 to 500 mg daily.
8. Administer Vit B6 Phosphate 100 mg daily.
9. Administer molybdenum at 200-mcg daily.
10. Supplement zinc at 100 mg for 30 days, followed by 50 mg for 50 days.
11. Algal cells have a remarkable ability to take up and accumulate heavy metals from their external environment. The primary ones used for toxic metal excess are Chlorella vulgaris, a green microalga, and Laminaria japonica, a brown alga. Chlorella and Laminaria japonica are both chelators, moving toxic metals out of the body, and transporters, moving metals from deeper stores to more readily removable areas. Both work in unison with each other and can remove toxic metals from the body through urinary excretion. Administer 1000 to 2000 mg of Laminaria japonica concentrate (Modifilan) daily and 1000 to 2000 mg of chlorella. Adjust dosage to bowel tolerance; may be taken for long periods of time.
12. Instruct patient to drink adequate amounts of pure water (Adult’s urine volume should be about 2 liters per day).
13. IV Chelators: For most cases of copper toxicity, the above oral supplements will be adequate if taken over time. However, some individuals have a combination of mercury and copper toxicity that may require IV chelators. Sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) is an effective means for reduction of both mercury and copper.
Be advised that ideally intravenous DMPS should not be used in patients who still have mercury/silver amalgam fillings. DMPS seems to appear in the saliva and dissolves the surfaces of the existing amalgam fillings. This process occurs over a series of several days. However, the blood concentration of DMPS lessens very quickly. Therefore, the patient with amalgam fillings can become acutely toxic from heavy metal injury to the mucosa of the gut following a DMPS injection.
In China there is substantial experience with the use of DMSA in the treatment of Wilson’s disease. Comparing the long-term therapeutic effects between DMSA and d-penicillamine, it has been asserted that DMSA is superior to penicillamine because the former caused clinical symptoms to exacerbate less frequently than the latter did. It might be relevant that the DMSA molecule, which has a dithiol structure, can embrace and shield the deleterious and “soft” Cu(I)-species, whereas penicillamine presumably prefers Cu(II). Furthermore, side effect incidence of DMSA is lower than that of penicillamine.