Copper toxicity

Copperiedus
A Kayser-Fleischer ring, copper deposits found in the cornea, is an indication the body is not metabolizing copper properly.
Classification and external resources
Specialty	emergency medicine
ICD-10	T56.4
ICD-9-CM	985.8
MedlinePlus	002496

Copper toxicity, also called copperiedus, refers to the consequences of an excess of copper in the body. Copperiedus can occur from eating acid foods cooked in uncoated copper cookware, or from exposure to excess copper in drinking water or other environmental sources.

Representation in ICD-9-CM, ICD-10-CM and SNOMED-CT

ICD-9-CM 985.8 Toxic effect of other specified metals

ICD-9-CM code 985.8 Toxic effect of other specified metals includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc.

• In addition, it includes poisoning and toxic effects of other metals including tin, selenium nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc.
• Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium.

ICD-10-CM

SNOMED-CT 46655005 Copper poisoning (disorder)

Toxicity

Copper in the blood and blood stream exists in two forms: bound to ceruloplasmin (85–95%), and the rest "free", loosely bound to albumin and small molecules. Free copper normally reduces oxidative stress, as it is involved in the metabolic elimination of reactive oxygen species, such as with the superoxide radical through Cu-Zn dependent superoxide dismutase.^[1] Excessive free copper impairs zinc homeostasis, and vice versa, which in turn impairs antioxidant enzyme function, increasing oxidative stress.^[1] Chronically elevated levels of copper intake produces zinc deficiency.^[1]

Nutritionally, there is a distinct difference between organic and inorganic copper, according to whether the copper ion is bound to an organic ligand.^[2][3] Organic copper, like that found in food, is a beneficial micronutrient needed for good health.^[4] Inorganic metallic copper, like that found in electrical wire, plumbing pipes, brass fittings, redox water filters, sheet metal, cooking utensils, jewelry and pennies, is a neurotoxic heavy metal linked to physical and psychiatric symptoms on par with mercury and lead.^[5][6][7][8]

Symptoms and presentation

Acute symptoms of copper poisoning by ingestion include vomiting, hematemesis (vomiting of blood), hypotension (low blood pressure), melena (black "tarry" feces), coma, jaundice (yellowish pigmentation of the skin), and gastrointestinal distress.^[9] Individuals with glucose-6-phosphate deficiency may be at increased risk of hematologic effects of copper.^[9] Hemolytic anemia resulting from the treatment of burns with copper compounds is infrequent.^[9]

Chronic (long-term) effects of copper exposure can damage the liver and kidneys.^[10] Mammals have efficient mechanisms to regulate copper stores such that they are generally protected from excess dietary copper levels.^[10][11]

Those same protection mechanisms can cause milder symptoms, which are often misdiagnosed as psychiatric disorders. There is a lot of research going on regarding the function of the Cu/Zn ratio in many conditions, neurological, endocrinological and psychological.^[12][13][14] The diagnostic difficulties arise from the fact that many of the substances that protect us from excess copper perform important functions in our neurological and endocrine systems. When they are used to bind copper in the plasma, to prevent it from being absorbed in the tissues, their own function may go unfulfilled. Such symptoms often include mood swings, irritability, depression, fatigue, excitation, difficulty focusing, feeling out of control, etc. To further complicate diagnosis, some symptoms of excess copper are similar to those of a copper deficit.

The U.S. Environmental Protection Agency's Maximum Contaminant Level (MCL) in drinking water is 1.3 milligrams per liter.^[9][15] The MCL for copper is based on the expectation that a lifetime of consuming copper in water at this level is without adverse effect (gastrointestinal). The US EPA lists copper as a micronutrient and a toxin.^[16] Toxicity in mammals includes a wide range of animals and effects such as liver cirrhosis, necrosis in kidneys and the brain, gastrointestinal distress, lesions, low blood pressure, and fetal mortality.^[17][18][19] The Occupational Safety and Health Administration (OSHA) has set a limit of 0.1 mg/m³ for copper fumes (vapor generated from heating copper) and 1 mg/m³ for copper dusts (fine metallic copper particles) and mists (aerosol of soluble copper) in workroom air during an eight-hour work shift, 40-hour work week.^[20] Toxicity to other species of plants and animals is noted to varying levels.^[16]

EPA cancer data

The EPA lists no evidence for human cancer incidence connected with copper, and lists animal evidence linking copper to cancer as "inadequate". Two studies in mice have shown no increased incidence of cancer. One of these used regular injections of copper compounds, including cupric oxide. One study of two strains of mice fed copper compounds found a varying increased incidence of reticulum cell sarcoma in males of one strain, but not the other (there was a slightly increased incidence in females of both strains). These results have not been repeated.^[21]

Treatment

In cases of suspected copper poisoning, penicillamine is the drug of choice, and dimercaprol, a heavy metal chelating agent, is often administered. Vinegar is not recommended to be given, as it assists in solubilizing insoluble copper salts. The inflammatory symptoms are to be treated on general principles, as are the nervous ones.

There is some evidence that alpha-lipoic acid (ALA) may work as a milder chelator of tissue-bound copper.^[22] Alpha lipoic acid is also being researched for chelating other heavy metals, such as mercury.^[23]

Cookware

Cookware in which copper is the main structural element (as opposed to copper clad, copper sandwiched or copper colored) is sometimes manufactured without a lining when intended to be used for any of a number of specific culinary tasks, such as preparing preserves or meringues. Otherwise, copper cookware is lined with a non-reactive metal to prevent contact between acidic foods and the structural copper element of the cookware.

Excepting for acute or chronic conditions, exposure to copper in cooking is generally considered harmless.^[24] Following Paracelsus, dosage makes the poison; as this pertains to copper "a defense mechanism has apparently evolved as a consequence of which toxicity in man is very unusual."^[25]

Acute exposure and attendant copper toxicity is possible when cooking or storing highly acidic foods in unlined copper vessels for extended periods, or by exposing foodstuffs to reactive copper salts (copper corrosion, or verdigris). Continuous, small ("chronic") exposures of acidic foods to copper may also result in toxicity in cases where either surface area interaction potentials are significant, pH is exceptionally low and concentrated (in the case of cooking with, for example, vinegar or wine), or both, and insufficient time elapses between exposures for normal homeostatic elimination of excess copper.

Exceptions to the above may be observed in the case of jam, jelly and preserve -making, wherein unlined copper vessels are used to cook (not to store) acidic preparations, in this case of fruit. Methods of jamming and preserving specify sugar as chemically necessary to the preserving (antibacterial) action, which has the additional effect of mediating (buffering) the interaction of fruit acid with copper,^[26] permitting the use of the metal for its efficient thermal transfer properties.^[27]

Non-sparking tools

OSHA has set safety standards for grinding and sharpening copper and copper alloy tools, which are often used in nonsparking applications. These standards are recorded in the Code of Federal Regulations 29 CFR 1910.134 and 1910.1000.^[28]

Note: The most important nonsparking copper alloy is beryllium copper, and can lead to beryllium poisoning.

Drinking water

With an LD₅₀ of 30 mg/kg in rats, "gram quantities" of copper sulfate are potentially lethal in humans.^[29] The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 2.0 mg/l.^[30]

Birth control

Estrogen birth control pills may increase the amount of copper in humans, but was not shown to increase absorption.^[31] Copper Intrauterine devices (IUDs) have been questioned anecdotally, with people claiming copper toxicity, but there is currently no scientific evidence to substantiate this claim. Estrogen increases the absorption of copper, making women more likely to carry excess copper even when no birth control is used.

The amount of estrogen (or copper) contained in these modern forms of contraception are generally considered safe, and the former restrictions for estrogen use (not to be used by women older than 40, 35 for smokers) were lifted in 1989.

There are conditions in which an individual's copper metabolism is compromised to such an extent that birth control may cause an issue with copper accumulation. They include toxicity or just increased copper from other sources, as well as the increased copper level of the individual's mother via the placenta before birth.^[32] The two hormones commonly used in birth control, estrogen and progestin, protect from each other's complications, so a combination method may work best. At least when existing imbalances have been treated.

Pathophysiology

A significant portion of the toxicity of copper comes from its ability to accept and donate single electrons as it changes oxidation state. This catalyzes the production of very reactive radical ions, such as hydroxyl radical in a manner similar to Fenton chemistry.^[33] This catalytic activity of copper is used by the enzymes with which it is associated, thus is only toxic when unsequestered and unmediated. This increase in unmediated reactive radicals is generally termed oxidative stress, and is an active area of research in a variety of diseases where copper may play an important but more subtle role than in acute toxicity.

Some of the effects of aging may be associated with excess copper.^[34]

Indian childhood cirrhosis

One manifestation of copper toxicity, cirrhosis of the liver in children (Indian childhood cirrhosis), has been linked to boiling milk in copper cookware. The Merck Manual states recent studies suggest that a genetic defect is associated with this particular cirrhosis.^[35]

Wilson's disease

An inherited condition called Wilson's disease causes the body to retain copper, since it is not excreted by the liver into the bile. This disease, if untreated, can lead to brain and liver damage, and bis-choline tetrathiomolybdate is under investigation as a therapy against Wilson's disease.

Alzheimer's disease

Elevated free copper levels exist in Alzheimer's disease,^[36] which has been hypothesized to be linked to inorganic copper consumption.^[37] Copper and zinc are known to bind to amyloid beta proteins in Alzheimer's disease.^[38] This bound form is thought to mediate the production of reactive oxygen species in the brain.^[39]

Aquatic life

Too much copper in water may damage marine and freshwater organisms such as fish and molluscs.^[40] Fish species vary in their sensitivity to copper, with the LD50 for 96-h exposure to copper sulphate reported to be in the order of 58 mg per litre for Tilapia (Oreochromis niloticus) and 70 mg per litre for catfish (Clarias gariepinus) ^[41] The chronic effect of sublethal concentrations of copper on fish and other creatures is damage to gills, liver, kidneys and the nervous system. It also interferes with the sense of smell in fish, thus preventing them from choosing good mates or finding their way to mating areas.^[42]

Copper-based paint is a common marine antifouling agent.^[43] In the United States, copper-based paint replaced tributyltin, which was banned due to its toxicity, as a way for boats to control organic growth on their hulls. In 2011, Washington state became the first U.S. state to ban the use of copper-based paint for boating, although it only applied to recreational boats.^[44] California has also pursued initiatives to reduce the effect of copper leaching, with the U.S. EPA pursuing research.^[45]

Bacteria

Copper and copper alloys such as brass have been found to be toxic to bacteria via the oligodynamic effect. The exact mechanism of action is unknown, but common to other heavy metals. Viruses are less susceptible to this effect than bacteria. Associated applications include the use of brass doorknobs in hospitals, which have been found to self-disinfect after eight hours, and mineral sanitizers, in which copper can act as an algicide. Overuse of copper sulfate as an algicide has been speculated to have caused a copper poisoning epidemic on Great Palm Island in 1979.^[46]

References