lysyl oxidase and superoxide dismutase activities reduced; impaired substrate metabolism 2 μg/kg body weightperipheral pools disrupted; gross dysfunction and disturbance of metabolism of other nutrients; death dietary recommendations various national and international organizations concerned with nutrition and health have standards for copper intake at levels judged to be adequate for maintaining good health. these standards are periodically changed and updated as new scientific data become available. the standards sometimes differ among countries and organizations. adults the world health organization recommends a minimal acceptable intake of approximately 1.3 mg/day. these values are considered to be adequate and safe for most of the general population. in north america, the u.s. institute of medicine (iom) set the recommended dietary allowance (rda) for copper for healthy adult men and women at 0.9 mg/day. as for safety, the iom also sets tolerable upper intake levels (uls) for vitamins and minerals when evidence is sufficient. in the case of copper the ul is set at 10 mg/day. the european food safety authority reviewed the same safety question and set its ul at 5 mg/day. adolescents, children, and infants full-term and premature infants are more sensitive to copper deficiency than adults. since the fetus accumulates copper during the last 3 months of pregnancy, infants that are born prematurely have not had sufficient time to store adequate reserves of copper in their livers and therefore require more copper at birth than full-term infants. for full-term infants, the north american recommended safe and adequate intake is approximately 0.2 mg/day. for premature babies, it is considerably higher: 1 mg/day. the world health organization has recommended similar minimum adequate intakes and advises that premature infants be given formula supplemented with extra copper to prevent the development of copper deficiency. pregnant and lactating women in north america, the iom has set the rda for pregnancy at 1.0 mg/day and for lactation at 1.3 mg/day. the european food safety authority (efsa) refers to the collective set of information as dietary reference values, with population reference intake (pri) instead of rda. pri for pregnancy is 1.6 mg/day, for lactation 1.6 mg/day – higher than the u.s. rdas. food sources foods rich in copper foods contribute virtually all of the copper consumed by humans. in both developed and developing countries, adults, young children, and adolescents who consume diets of grain, millet, tuber, or rice along with legumes (beans) or small amounts of fish or meat, some fruits and vegetables, and some vegetable oil are likely to obtain adequate copper if their total food consumption is adequate in calories. in developed countries where consumption of red meat is high, copper intake is also likely to be adequate. as a natural element in the earth's crust, copper exists in most of the world's surface water and groundwater, although the actual concentration of copper in natural waters varies geographically. drinking water can comprise 20–25% of dietary copper. in many regions of the world, copper tubing that conveys drinking water can be a source of dietary copper. copper tube can leach a small amount of copper, particularly in its first year or two of service. afterwards, a protective surface usually forms on the inside of copper tubes that slows leaching. in france and some other countries, copper bowls are traditionally used for whipping egg white, as the copper helps stabilise bonds in the white as it is beaten and whipped. small amounts of copper may leach from the bowl during the process and enter the egg white. supplementation copper supplements can prevent copper deficiency. copper supplements are not prescription medicines, and are available at vitamin and herb stores and grocery stores and online retailers. different forms of copper supplementation have different absorption rates. for example, the absorption of copper from cupric oxide supplements is lower than that from copper gluconate, copper sulfate, or carbonate. supplementation is generally not recommended for healthy adults who consume a well-balanced diet which includes a wide range of foods. however, supplementation under the care of a physician may be necessary for premature infants or those with low birth weights, infants fed unfortified formula or cow's milk during the first year of life, and malnourished young children. physicians may consider copper supplementation for 1) illnesses that reduce digestion (e.g., children with frequent diarrhea or infections; alcoholics), 2) insufficient food consumption (e.g., the elderly, the infirm, those with eating disorders or on diets), 3) patients taking medications that block the body's use of copper, 4) anemia patients who are treated with iron supplements, 5) anyone taking zinc supplements, and 6) those with osteoporosis. many popular vitamin supplements include copper as small inorganic molecules such as cupric oxide. these supplements can result in excess free copper in the brain as the copper can cross the blood-brain barrier directly. normally, organic copper in food is first processed by the liver which keeps free copper levels under control. copper deficiency and excess health conditions (non-genetic) main article: copper deficiency if insufficient quantities of copper are ingested, copper reserves in the liver will become depleted and a copper deficiency leading to disease or tissue injury (and in extreme cases, death). toxicity from copper deficiency can be treated with a balanced diet or supplementation under the supervision of a doctor. on the contrary, like all substances, excess copper intake at levels far above world health organization limits can become toxic. acute copper toxicity is generally associated with accidental ingestion. these symptoms abate when the high copper food source is no longer ingested. in 1996, the international program on chemical safety, a world health organization-associated agency, stated "there is greater risk of health effects from deficiency of copper intake than from excess copper intake." this conclusion was confirmed in recent multi-route exposure surveys. the health conditions of non-genetic copper deficiency and copper excess are described below. copper deficiency there are conflicting reports on the extent of deficiency in the u.s. one review indicates approximately 25% of adolescents, adults, and people over 65, do not meet the recommended dietary allowance for copper. another source states less common: a federal survey of food consumption determined that for women and men over the age of 19, average consumption from foods and beverages was 1.11 and 1.54 mg/day, respectively. for women, 10% consumed less than the estimated average requirement, for men fewer than 3%. acquired copper deficiency has recently been implicated in adult-onset progressive myeloneuropathy and in the development of severe blood disorders including myelodysplastic syndrome. fortunately, copper deficiency can be confirmed by very low serum metal and ceruloplasmin concentrations in the blood. other conditions linked to copper deficiency include osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disease, colon cancer, and chronic conditions involving bone, connective tissue, heart and blood vessels. nervous system and immune system. copper deficiency alters the role of other cellular constituents involved in antioxidant activities, such as iron, selenium, and glutathione, and therefore plays an important role in diseases in which oxidant stress is elevated. a marginal, i.e., 'mild' copper deficiency, believed to be more widespread than previously thought, can impair human health in subtle ways. populations susceptible to copper deficiency include those with genetic defects for menkes disease, low-birth-weight infants, infants fed cow's milk instead of breast milk or fortified formula, pregnant and lactating mothers, patients receiving total parenteral nutrition, individuals with "malabsorption syndrome" (impaired dietary absorption), diabetics, individuals with chronic diseases that result in low food intake, such as alcoholics, and persons with eating disorders. the elderly and athletes may also be at higher risk for copper deficiency due to special needs that increase the daily requirements. vegetarians may have decreased copper intake due to the consumption of plant foods in which copper bioavailability is low. on the other hand, bo lönnerdal commented that gibson's study showed that vegetarian diets provided larger quantities of copper. fetuses and infants of severely copper deficient women have increased risk of low birth weights, muscle weaknesses, and neurological problems. copper deficiencies in these populations may result in anemia, bone abnormalities, impaired growth, weight gain, frequent infections (colds, flu, pneumonia), poor motor coordination, and low energy. copper excess main article: copper toxicity copper excess is a subject of much current research. distinctions have emerged from studies that copper excess factors are different in normal populations versus those with increased susceptibility to adverse effects and those with rare genetic diseases. this has led to statements from health organizations that could be confusing to the uninformed. for example, according to a u.s. institute of medicine report, the intake levels of copper for a significant percentage of the population are lower than recommended levels. on the other hand, the u.s. national research council concluded in its report copper in drinking water that there is concern for copper toxicity in susceptible populations and recommended that additional research be conducted to identify and characterize copper-sensitive populations. excess copper intake causes stomach upset, nausea, and diarrhea and can lead to tissue injury and disease. the oxidation potential of copper may be responsible for some of its toxicity in excess ingestion cases. at high concentrations copper is known to produce oxidative damage to biological systems, including peroxidation of lipids or other macromolecules. while the cause and progression of alzheimer's disease are not well understood, research indicates that, among several other key observations, iron, aluminum, and copper accumulate in the brains of alzheimer's patients. however, it is not yet known whether this accumulation is a cause or a consequence of the disease. research has been ongoing over the past two decades to determine whether copper is a causative or a preventive agent of alzheimer's disease. for example, as a possible causative agent or an expression of a metal homeostasis disturbance, studies indicate that copper may play a role in increasing the growth of protein clumps in alzheimer's disease brains, possibly by damaging a molecule that removes the toxic buildup of amyloid beta (aβ) in the brain. there is an association between a diet rich in copper and iron together with saturated fat and alzheimer's disease. on the other hand, studies also demonstrate potential beneficial roles of copper in treating rather than causing alzheimer's disease. for example, copper has been shown to 1) promote the non-amyloidogenic processing of amyloid beta precursor protein (app), thereby lowering amyloid beta (aβ) production in cell culture systems 2) increase lifetime and decrease soluble amyloid production in app transgenic mice, and 3) lower aβ levels in cerebral spinal fluid in alzheimer's disease patients. furthermore, long-term copper treatment (oral intake of 8 mg copper (cu-(ii)-orotate-dihydrate)) was excluded as a risk factor for alzheimer's disease in a noted clinical trial on humans and a potentially beneficial role of copper in alzheimer's disease has been demonstrated on cerebral spinal fluid levels of aβ42, a toxic peptide and biomarker of the disease. more research is needed to understand metal homeostasis disturbances in alzheimer's disease patients and how to address these disturbances therapeutically. since this experiment used cu-(ii)-orotate-dihydrate, it does not relate to the effects of cupric oxide in supplements. copper toxicity from excess exposures in humans, the liver is the primary organ of copper-induced toxicity. other target organs include bone and the central nervous and immune systems. excess copper intake also induces toxicity indirectly by interacting with other nutrients. for example, excess copper intake produces anemia by interfering with iron transport and/or metabolism. the identification of genetic disorders of copper metabolism leading to severe copper toxicity (i.e., wilson disease) has spurred research into the molecular genetics and biology of copper homeostasis (for further information, refer to the following section on copper genetic diseases). much attention has focused on the potential consequences of copper toxicity in normal and potentially susceptible populations. potentially susceptible subpopulations include hemodialysis patients and individuals with chronic liver disease. recently, concern was expressed about the potential sensitivity to liver disease of individuals who are heterozygote carriers of wilson disease genetic defects (i.e., those having one normal and one mutated wilson copper atpase gene) but who do not have the disease (which requires defects in both relevant genes). however, to date, no data are available that either support or refute this hypothesis. acute exposures in case reports of humans intentionally or accidentally ingesting high concentrations of copper salts (doses usually not known but reported to be 20–70 grams of copper), a progression of symptoms was observed including abdominal pain, headache, nausea,