Copper toxicity
Other namesCopperiedus
A Kayser-Fleischer ring, copper deposits found in the cornea, is an indication the body is not metabolizing copper properly.
SpecialtyToxicology

Copper toxicity (or Copperiedus) is a type of metal poisoning caused by an excess of copper in the body. Copperiedus could occur from consuming excess copper salts, but most commonly it is the result of the genetic condition Wilson's disease and Menke's disease, which are associated with mismanaged transport and storage of copper ions. Copper is essential to human health as it is a component of many proteins. But hypercupremia (high copper level in the blood) can lead to copper toxicity if it persists and rises high enough.

Chronic toxicity by copper is rare.[1] The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 1.3 mg/L.[2] So low is the toxicity of copper that copper(II) sulfate is a routine reagent in undergraduate chemistry laboratories.[3]

Signs and symptoms

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.[4] Individuals with glucose-6-phosphate dehydrogenase deficiency may be at increased risk of hematologic effects of copper.[4] Hemolytic anemia resulting from the treatment of burns with copper compounds is infrequent.[4]

Chronic (long-term) copper exposure can damage the liver and kidneys.[5] Mammals have efficient mechanisms to regulate copper stores such that they are generally protected from excess dietary copper levels.[5][6]

Those same protection mechanisms can cause milder symptoms, which are often misdiagnosed as psychiatric disorders. There is a lot of research on the function of the Cu/Zn ratio in neurological, endocrinological, and psychological conditions.[7][8][9] Many of the substances that protect us from excess copper perform important functions in our neurological and endocrine systems, leading to diagnostic difficulties. 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, and feeling out of control. 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.[4][10] 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.[11] 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.[12][13][14] 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.[15] Toxicity to other species of plants and animals is noted to varying levels.[11]

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.[16]

Pathophysiology

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 that recent studies suggest that a genetic defect is associated with this particular cirrhosis.[17]

Wilson 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.

Menke's disease

An X-linked recessive trait that is inherited named Menke's disease causes disruption of connective tissue due to mutations in genes. If severely affected the approximate span of life is three years. One treatment used to correct the mutation is copper-histidine treatment.[18]

Alzheimer's disease

Elevated free copper levels exist in Alzheimer's disease,[19] which has been hypothesized to be linked to inorganic copper consumption.[20] Copper and zinc are known to bind to amyloid beta proteins in Alzheimer's disease.[21] This bound form is thought to mediate the production of reactive oxygen species in the brain.[22]

Diagnosis

ICD-9-CM

ICD-9-CM code 985.8 Toxic effect of other specified metals includes acute and 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

CodeTerm
T56.4X1DToxic effect of copper and its compounds, accidental (unintentional), subsequent encounter
T56.4X1SToxic effect of copper and its compounds, accidental (unintentional), sequela
T56.4X2DToxic effect of copper and its compounds, intentional self-harm, subsequent encounter
T56.4X2SToxic effect of copper and its compounds, intentional self-harm, sequela
T56.4X3DToxic effect of copper and its compounds, assault, subsequent encounter
T56.4X3SToxic effect of copper and its compounds, assault, sequela
T56.4X4DToxic effect of copper and its compounds, undetermined, subsequent encounter
T56.4X4SToxic effect of copper and its compounds, undetermined, sequela

SNOMED

Concept IDTerm
46655005Copper
43098002Copper fever
49443005Phytogenous chronic copper poisoning
50288007Chronic copper poisoning
73475009Hepatogenous chronic copper poisoning
875001Chalcosis of eye
90632001Acute copper poisoning

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.[23] Treatment can also look like ozone oxidation for environmental toxicity problems, as well as removing sediment in water areas because sediment can be a home for toxicants to reside. [24]

There is some evidence that alpha-lipoic acid (ALA) may work as a milder chelator of tissue-bound copper.[25] Alpha lipoic acid is also being researched for chelating other heavy metals, such as mercury.[26]

Aquatic life

Too much copper in water may damage marine and freshwater organisms such as fish and molluscs.[27] 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) [28] 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.[29]

Copper-based paint is a common marine antifouling agent.[30] 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.[31] California has also pursued initiatives to reduce the effect of copper leaching, with the U.S. EPA pursuing research.[32]

Copper is an essential elemental for metabolic processes in marine algae. It is required for electron transport in photosynthesis and by various enzyme systems. Too much copper can also affect phytoplankton or marine algae in both marine and freshwater ecosystems. It has been shown to inhibit photosynthesis, disrupt electron transport in photosystem 2, reduce pigment concentrations, restrict growth, reduce reproduction, etc.[33] The toxicity of copper is widely recognized and is used to help prevent algal blooms. The effect of copper is solely dependent on the free copper the water is receiving. It's determined by the relative solubility and the concentration of the copper binding ligands.

Studies have shown that copper concentrations are toxic when marine phytoplankton are confined to areas that are heavily impacted by anthropogenic emissions.[34] Some of the studies have used a marine amphipod to show how Copper affects it. This particular study said that the juveniles were 4.5 more times sensitive to the toxins than the adults.[35] Another study used 7 different algal species. They found that one species was more sensitive than the others, which was Synechococcus, and that another species was more sensitive in seawater, which wasThalassiosira weissflogii.[36]

One study used cyanobacteria, diatoms, coccolithophores, and dinoflagellates. This study showed that cyanobacteria was the most sensitive, diatoms were the least sensitive, and the coccolithophores and dinoflagellates were intermediate. They used copper ion in a buffer system and controlled it at different levels. They found that cyanobacteria reproduction rates were reduced while other algae had maximum reproduction rates. They found that Copper may influence seasonal successions of species.[37]

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.[38]

References

  1. ↑ Barceloux, Donald G.; Barceloux, Donald (1999). "Copper". Journal of Toxicology: Clinical Toxicology. 37 (2): 217–230. doi:10.1081/CLT-100102421. PMID 10382557.
  2. ↑ "The Water Supply (Water Quality) Regulations 2000".
  3. ↑ Rodríguez, Emilio; Vicente, Miguel Angel (2002). "A Copper-Sulfate-Based Inorganic Chemistry Laboratory for First-Year University Students That Teaches Basic Operations and Concepts". Journal of Chemical Education. 79 (4): 486. Bibcode:2002JChEd..79..486R. doi:10.1021/ed079p486.
  4. 1 2 3 4 Casarett, L.; Casarett, L.J.; Amdur, M.O.; Doull, J. (1996). Casarett & Doull's Toxicology, The Basic Science of Poisons (5th ed.). McGraw-Hill. p. 715. ISBN 0071054766.
  5. 1 2 "Copper: Health Information Summary" (PDF). Environmental Fact Sheet. New Hampshire Department of Environmental Services. 2005. ARD-EHP-9. Archived from the original (PDF) on 20 January 2017.
  6. ↑ Lutsenko, Svetlana; Barnes, Natalie L.; Bartee, Mee Y.; Dmitriev, Oleg Y. (2007). "Function and Regulation of Human Copper-Transporting ATPases". Physiological Reviews. 87 (3): 1011–46. doi:10.1152/physrev.00004.2006. PMID 17615395.
  7. ↑ Desai, Vishal; Kaler, Stephen G. (2008). "Role of copper in human neurological disorders". The American Journal of Clinical Nutrition. 88 (3): 855S–8S. doi:10.1093/ajcn/88.3.855S. PMID 18779308. Retrieved 20 December 2015.
  8. ↑ Kaplan, Bonnie J.; Crawford, Susan G.; Gardner, Beryl; Farrelly, Geraldine (2002). "Treatment of Mood Lability and Explosive Rage with Minerals and Vitamins: Two Case Studies in Children". Journal of Child and Adolescent Psychopharmacology. 12 (3): 205–219. doi:10.1089/104454602760386897. PMID 12427294.
  9. ↑ Faber, Scott; Zinn, Gregory M.; Kern Ii, John C.; Skip Kingston, H. M. (2009). "The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders". Biomarkers. 14 (3): 171–180. doi:10.1080/13547500902783747. PMID 19280374. S2CID 205770002.
  10. ↑ Federal Register / Vol. 65, No. 8 / Wednesday, January 12, 2000 / Rules and Regulations. pp. 1976.
  11. 1 2 US EPA Region 5 (2011-12-28). "Ecological Toxicity Information". US EPA. Retrieved 17 June 2015.{{cite web}}: CS1 maint: numeric names: authors list (link)
  12. ↑ "Toxicological Profile for Copper". Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Retrieved 17 June 2015.
  13. ↑ Kabata-Pendias, Alina (2010). Trace Elements in Soils and Plants, Fourth Edition (4th ed.). Taylor & Francis. ISBN 9781420093681. Archived from the original on 16 July 2015. Retrieved 17 June 2015.
  14. ↑ Ware, George W. (1983). Pesticides: Theory and application. New York: W.H. Freeman. OCLC 669712126.
  15. ↑ Occupational Safety and Health Administration, U.S. Department of Labor, Copper, Available Online at: https://www.osha.gov/SLTC/metalsheavy/copper.html
  16. ↑ EPA results for copper and cancer. Accessed March 11, 2011
  17. ↑ "Copper". Merck Manuals — Online Medical Library. Merck. November 2005. Retrieved 2008-07-19.
  18. ↑ Tümer, Zeynep; Møller, Lisbeth B. (May 2010). "Menkes disease". European Journal of Human Genetics. 18 (5): 511–518. doi:10.1038/ejhg.2009.187. ISSN 1476-5438. PMC 2987322. PMID 19888294.
  19. ↑ Brewer GJ (Apr 2010). "Copper toxicity in the general population". Clin Neurophysiol. 121 (4): 459–60. doi:10.1016/j.clinph.2009.12.015. PMID 20071223. S2CID 43106197.
  20. ↑ Brewer GJ (June 2009). "The risk of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease". J. Am. Coll. Nutr. 28 (3): 238–42. doi:10.1080/07315724.2009.10719777. PMID 20150596. S2CID 21630019.
  21. ↑ Faller P (2009-12-14). "Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer". ChemBioChem. 10 (18): 2837–45. doi:10.1002/cbic.200900321. PMID 19877000. S2CID 35130040.
  22. ↑ Hureau C, Faller P (October 2009). "Abeta-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer's disease". Biochimie. 91 (10): 1212–7. doi:10.1016/j.biochi.2009.03.013. PMID 19332103.
  23. ↑ Royer, Amor; Sharman, Tariq (2022), "Copper Toxicity", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32491388, retrieved 2022-09-27
  24. ↑ "Treatment of high toxicity and high concentration organic wastewater includes adding copper sulfate and sodium sulfate to high toxicity and high concentration organic wastewater and treating organic wastewater by biological denitrification". Web of Science.
  25. ↑ Marangon, Karine; Devaraj, Sridevi; Tirosh, Oren; Packer, Lester; Jialal, Ishwarlal (November 1999). "Comparison of the effect of α-lipoic acid and α-tocopherol supplementation on measures of oxidative stress". Free Radical Biology and Medicine. 27 (9–10): 1114–1121. doi:10.1016/S0891-5849(99)00155-0. PMID 10569644.
  26. ↑ "Mercury toxicity and antioxidants: part I: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. (Mercury Toxicity)". Thorne Research Inc. 2002. Archived from the original on 22 December 2015. Retrieved 20 December 2015.
  27. ↑ Van Genderen EJ, Ryan AC, Tomasso JR, Klaine SJ (February 2005). "Evaluation of acute copper toxicity to larval fathead minnows (Pimephales promelas) in soft surface waters". Environ. Toxicol. Chem. 24 (2): 408–14. doi:10.1897/03-494.1. PMID 15720002. S2CID 6612606.
  28. ↑ Ezeonyejiaku, CD, Obiakor, MO and Ezenwelu, CO (2011). "Toxicity of copper sulphate and behavioural locomotor response of tilapia (Oreochromis niloticus) and catfish (Clarias gariepinus) species". Online J. Anim. Feed Res. 1 (4): 130–134.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ↑ C. A. Flemming; J. T. Trevors (1989). "Copper toxicity and chemistry in the environment: a review". Water, Air, & Soil Pollution. 44 (1–2): 143–158. Bibcode:1989WASP...44..143F. doi:10.1007/BF00228784. S2CID 98175996.
  30. ↑ Earley, Patrick J.; Swope, Brandon L.; Barbeau, Katherine; Bundy, Randelle; McDonald, Janessa A.; Rivera-Duarte, Ignacio (2014-01-01). "Life cycle contributions of copper from vessel painting and maintenance activities". Biofouling. 30 (1): 51–68. doi:10.1080/08927014.2013.841891. ISSN 0892-7014. PMC 3919178. PMID 24199998.
  31. ↑ "Is Copper Bottom Paint Sinking? - BoatUS Magazine". Retrieved 2016-09-22.
  32. ↑ "Marine Coatings: Making Sense of U.S., State, and Local Mandates of Copper-Based Antifouling Regulations". American Coatings Association. Retrieved 2016-09-22.
  33. ↑ Gledhill, Martha; Nimmo, Malcolm; Hill, Stephen J.; Brown, Murray T. (1997). "The Toxicity of Copper (II) Species to Marine Algae, with Particular Reference to Macroalgae". Journal of Phycology. 33: 2–11. doi:10.1111/j.0022-3646.1997.00002.x. S2CID 84128896.
  34. ↑ Lopez, Johann S.; Lee, Lillian; Mackey, Katherine R. M. (2019-01-24). "The Toxicity of Copper to Crocosphaera watsonii and Other Marine Phytoplankton: A Systematic Review". Frontiers in Marine Science. 5: 511. doi:10.3389/fmars.2018.00511. ISSN 2296-7745.
  35. ↑ Ahsanullah, M.; Florence, T. M. (1984-12-01). "Toxicity of copper to the marine amphipod Allorchestes compressa in the presence of water-and lipid-soluble ligands". Marine Biology. 84 (1): 41–45. doi:10.1007/BF00394525. ISSN 1432-1793. S2CID 84484414.
  36. ↑ Quigg, Antonietta; Reinfelder, John R.; Fisher, Nicholas S. (2006). "Copper uptake kinetics in diverse marine phytoplankton". Limnology and Oceanography. 51 (2): 893–899. Bibcode:2006LimOc..51..893Q. doi:10.4319/lo.2006.51.2.0893. ISSN 1939-5590.
  37. ↑ Brand, Larry E.; Sunda, William G.; Guillard, Robert R. L. (1986-05-01). "Reduction of marine phytoplankton reproduction rates by copper and cadmium". Journal of Experimental Marine Biology and Ecology. 96 (3): 225–250. doi:10.1016/0022-0981(86)90205-4. ISSN 0022-0981.
  38. ↑ Prociv P (September 2004). "Algal toxins or copper poisoning—revisiting the Palm Island 'epidemic'". Med. J. Aust. 181 (6): 344. doi:10.5694/j.1326-5377.2004.tb06316.x. PMID 15377259. S2CID 22054004.
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