dizziness, vomiting and diarrhea, tachycardia, respiratory difficulty, hemolytic anemia, hematuria, massive gastrointestinal bleeding, liver and kidney failure, and death. episodes of acute gastrointestinal upset following single or repeated ingestion of drinking water containing elevated levels of copper (generally above 3–6 mg/l) are characterized by nausea, vomiting, and stomach irritation. these symptoms resolve when copper in the drinking water source is reduced. three experimental studies were conducted that demonstrate a threshold for acute gastrointestinal upset of approximately 4–5 mg/l in healthy adults, although it is not clear from these findings whether symptoms are due to acutely irritant effects of copper and/or to metallic, bitter, salty taste. in an experimental study with healthy adults, the average taste threshold for copper sulfate and chloride in tap water, deionized water, or mineral water was 2.5–3.5 mg/l. this is just below the experimental threshold for acute gastrointestinal upset. chronic exposures the long-term toxicity of copper has not been well studied in humans, but it is infrequent in normal populations that do not have a hereditary defect in copper homeostasis. there is little evidence to indicate that chronic human exposure to copper results in systemic effects other than liver injury. chronic copper poisoning leading to liver failure was reported in a young adult male with no known genetic susceptibility who consumed 30–60 mg/d of copper as a mineral supplement for 3 years. individuals residing in u.s. households supplied with tap water containing >3 mg/l of copper exhibited no adverse health effects. no effects of copper supplementation on serum liver enzymes, biomarkers of oxidative stress, and other biochemical endpoints have been observed in healthy young human volunteers given daily doses of 6 to 10 mg/d of copper for up to 12 weeks. infants aged 3–12 months who consumed water containing 2 mg cu/l for 9 months did not differ from a concurrent control group in gastrointestinal tract (git) symptoms, growth rate, morbidity, serum liver enzyme and bilirubin levels, and other biochemical endpoints.) serum ceruloplasmin was transiently elevated in the exposed infant group at 9 months and similar to controls at 12 months, suggesting homeostatic adaptation and/or maturation of the homeostatic response. dermal exposure has not been associated with systemic toxicity but anecdotal reports of allergic responses may be a sensitization to nickel and cross-reaction with copper or a skin irritation from copper. workers exposed to high air levels of copper (resulting in an estimated intake of 200 mg cu/d) developed signs suggesting copper toxicity (e.g., elevated serum copper levels, hepatomegaly). however, other co-occurring exposures to pesticidal agents or in mining and smelting may contribute to these effects. effects of copper inhalation are being thoroughly investigated by an industry-sponsored program on workplace air and worker safety. this multi-year research effort is expected to be finalized in 2011. measurements of elevated copper status although a number of indicators are useful in diagnosing copper deficiency, there are no reliable biomarkers of copper excess resulting from dietary intake. the most reliable indicator of excess copper status is liver copper concentration. however, measurement of this endpoint in humans is intrusive and not generally conducted except in cases of suspected copper poisoning. increased serum copper or ceruolplasmin levels are not reliably associated with copper toxicity as elevations in concentrations can be 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 therefore are inconsistent markers of excess copper status. a new candidate biomarker for copper excess as well as deficiency has emerged in recent years. this potential marker is a chaperone protein, which delivers copper to the antioxidant protein sod1 (copper, zinc superoxide dismutase). it is called "copper chaperone for sod1" (ccs), and excellent animal data supports its use as a marker in accessible cells (e.g., erythrocytes) for copper deficiency as well as excess. ccs is currently being tested as a biomarker in humans. hereditary copper metabolic diseases several rare genetic diseases (wilson disease, menkes disease, idiopathic copper toxicosis, indian childhood cirrhosis) are associated with the improper use of copper in the body. all of these diseases involve mutations of genes containing the genetic codes for the production of specific proteins involved in the absorption and distribution of copper. when these proteins are dysfunctional, copper either builds up in the liver or the body fails to absorb copper. these diseases are inherited and cannot be acquired. adjusting copper levels in the diet or drinking water will not cure these conditions (although therapies are available to manage symptoms of genetic copper excess disease). the study of genetic copper metabolism diseases and their associated proteins are enabling scientists to understand how human bodies use copper and why it is important as an essential micronutrient. the diseases arise from defects in two similar copper pumps, the menkes and the wilson cu-atpases. the menkes atpase is expressed in tissues like skin-building fibroblasts, kidneys, placenta, brain, gut and vascular system, while the wilson atpase is expressed mainly in the liver, but also in mammary glands and possibly in other specialized tissues. this knowledge is leading scientists towards possible cures for genetic copper diseases. menkes disease menkes disease, a genetic condition of copper deficiency, was first described by john menkes in 1962. it is a rare x-linked disorder that affects approximately 1/200,000 live births, primarily boys. livers of menkes disease patients cannot absorb essential copper needed for patients to survive. death usually occurs in early childhood: most affected individuals die before the age of 10 years, although several patients have survived into their teens and early 20s. the protein produced by the menkes gene is responsible for transporting copper across the gastrointestinal tract (git) mucosa and the blood–brain barrier. mutational defects in the gene encoding the copper atpase cause copper to remain trapped in the lining of the small intestine. hence, copper cannot be pumped out of the intestinal cells and into the blood for transport to the liver and consequently to rest of the body. the disease therefore resembles a severe nutritional copper deficiency despite adequate ingestion of copper. symptoms of the disease include coarse, brittle, depigmented hair and other neonatal problems, including the inability to control body temperature, intellectual disability, skeletal defects, and abnormal connective tissue growth. menkes patients exhibit severe neurological abnormalities, apparently due to the lack of several copper-dependent enzymes required for brain development, including reduced cytochrome c oxidase activity. the brittle, kinky hypopigmented hair of steely appearance is due to a deficiency in an unidentified cuproenzyme. reduced lysyl oxidase activity results in defective collagen and elastin polymerization and corresponding connective-tissue abnormalities including aortic aneurisms, loose skin, and fragile bones. with early diagnosis and treatment consisting of daily injections of copper histidine intraperitoneally and intrathecally to the central nervous system, some of the severe neurological problems may be avoided and survival prolonged. however, menkes disease patients retain abnormal bone and connective-tissue disorders and show mild to severe intellectual disability. even with early diagnosis and treatment, menkes disease is usually fatal. ongoing research into menkes disease is leading to a greater understanding of copper homeostasis, the biochemical mechanisms involved in the disease, and possible ways to treat it. investigations into the transport of copper across the blood/brain barrier, which are based on studies of genetically altered mice, are designed to help researchers understand the root cause of copper deficiency in menkes disease. the genetic makeup of transgenic mice is altered in ways that help researchers garner new perspectives about copper deficiency. the research to date has been valuable: genes can be turned off gradually to explore varying degrees of deficiency. researchers have also demonstrated in test tubes that damaged dna in the cells of a menkes patient can be repaired. in time, the procedures needed to repair damaged genes in the human body may be found. wilson's disease wilson's disease is a rare autosomal (chromosome 13) recessive genetic disorder of copper transport that causes an excess of copper to build up in the liver. this results in liver toxicity, among other symptoms. the disease is now treatable. wilson's disease is produced by mutational defects of a protein that transports copper from the liver to the bile for excretion. the disease involves poor incorporation of copper into ceruloplasmin and impaired biliary copper excretion and is usually induced by mutations impairing the function of the wilson copper atpase. these genetic mutations produce copper toxicosis due to excess copper accumulation, predominantly in the liver and brain and, to a lesser extent, in kidneys, eyes, and other organs. the disease, which affects about 1/30,000 infants of both genders, may become clinically evident at any time from infancy through early adulthood. the age of onset of wilson's disease ranges from 3 to 50 years of age. initial symptoms include hepatic, neurologic, or psychiatric disorders and, rarely, kidney, skeletal, or endocrine symptomatology. the disease progresses with deepening jaundice and the development of encephalopathy, severe clotting abnormalities, occasionally associated with intravascular coagulation, and advanced chronic kidney disease. a peculiar type of tremor in the upper extremities, slowness of movement, and changes in temperament become apparent. kayser-fleischer rings, a rusty brown discoloration at the outer rims of the iris due to copper deposition noted in 90% of patients, become evident as copper begins to accumulate and affect the nervous system. almost always, death occurs if the disease is untreated. fortunately, identification of the mutations in the wilson atpase gene underlying most cases of wilson's disease has made dna testing for diagnosis possible. if diagnosed and treated early enough, patients with wilson's disease may live long and productive lives. wilson's disease is managed by copper chelation therapy with d-penicillamine (which picks up and binds copper and enables patients to excrete excess copper accumulated in the liver), therapy with zinc sulfate or zinc acetate, and restrictive dietary metal intake, such as the elimination of chocolate, oysters, and mushrooms. zinc therapy is now the treatment of choice. zinc produces a mucosal block by inducing metallothionein, which binds copper in mucosal cells until they slough off and are eliminated in the feces. and it competes with copper for absorption in the intestine by dmt1 (divalent metal transporter 1). more recently, experimental treatments with tetrathiomolybdate showed promising results. tetrathiomolybdate appears to be an excellent form of initial treatment in patients who have neurologic symptoms. in contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration. over 100 different genetic defects leading to wilson's disease have been described and are available on the internet at . some of the mutations have geographic clustering. many wilson's patients carry different mutations on each chromosome 13 (i.e., they are compound heterozygotes). even in individuals who are homozygous for a mutation, onset and severity of the disease may vary. individuals homozygous for severe mutations (e.g., those truncating the protein) have earlier disease onset. disease severity may also be a function of environmental factors, including the amount of copper in the diet or variability in the function of other proteins that influence copper homeostasis. it has been suggested that heterozygote carriers of the wilson's disease gene mutation may be potentially more susceptible to elevated copper intake than the general population. a heterozygotic frequency of 1/90 people has been estimated in the overall population. however, there is no evidence to support this speculation. further, a review of the data on single-allelic autosomal recessive diseases in humans does not suggest that heterozygote carriers are likely to be adversely affected by their altered genetic status. other copper-related hereditary syndromes other diseases in which abnormalities in copper metabolism appear to be involved include indian childhood cirrhosis (icc), endemic tyrolean copper toxicosis (etic), and idiopathic copper toxicosis (ict), also known as non-indian childhood cirrhosis. ict is a genetic disease recognized in the early twentieth century primarily in the tyrolean region of austria and in the pune region of india. icc, ict, and etic are infancy syndromes that are similar in their apparent etiology and presentation. both appear to have a genetic component and a contribution from elevated copper intake. in cases of icc, the elevated copper intake is due to heating and/or storing milk in copper or brass vessels. ict cases, on the other hand, are