February 15, 2010; Vol. 23; No. 2; pp. 319 – 326 George J. Brewer Departments of Human Genetics and Internal Medicine, University of Michigan Medical School (this article has 89 references) KEY POINTS FROM THIS ARTICLE: 1) Copper and iron are essential but also toxic metals. 2) Copper and iron toxicity are important in public health significance, yet arevirtually unknown to the general medical community and there is completeunawareness of the public. 3) The subtle toxicity of copper and iron affects almost all of us as we age. 4) Copper and iron contribute to the production of excess damaging freeradicals. 5) Diseases of aging such as Alzheimers disease, other neurodegenerativediseases, arteriosclerosis, diabetes mellitus, and others may all be contributed to byexcess copper and iron. 6) In the general population, those in the highest fifth of copper intake, losecognition at over three times the normal rate. [Very Important] 7) Inorganic copper in drinking water and in supplements is handled differentlythan food copper and is therefore more toxic. 8) Trace amounts of copper in drinking water, less than one-tenth of thatallowed in human drinking water by the Environmental Protection Agency, greatlyenhanced an Alzheimers-like disease in an animal model. 9) Humans use oxygen in the mitochondria to generate energy in the form ofadenosine triphosphate (ATP). Toxic byproducts of this metabolism are generated,called reactive oxygen species (ROS). 10) ROS can cause damage to most biological molecules, including DNA, protein,and lipids, resulting in damage to membranes and various cellular organelles. 11) Copper and iron are essential for life, and especially for their roles in energyproduction. But both copper and iron have their toxic side that allows them tocatalyze the generation of damaging reactive oxygen species (ROS). 12) Copper and iron are particularly damaging when they exist in theirfreestate. 13) 85-95% of the copper in human blood is safely bound to a molecule calledceruloplasmin (Cp). The other 5-15% is loosely bound to albumin and this 5-15% iscalled free copper. It is this free copper that causes generation of the toxic ROS. 14) Those living on the high side of the 5-15 µg/dL range may be suffering fromsubtle copper toxicity. 15) Organic food copper is bound to proteins and is processed by the liver, whichdoes not allow excess release into the free copper pool in the blood. 16) Inorganic copper consumed in drinking water or mineral supplementsbypasses the liver and contributes immediately to the free copper pool in the blood. 17) The higher the free iron, the greater the risks of developing the diseases ofaging. 18) Evolution favors reproduction. In youth, high levels of copper and ironincrease energy production, wound repair, compensate for blood loss, and thereforeincrease reproductive fitness. After about age 50 when reproduction is no longer afactor, high levels of copper and iron are toxic because they increase free radicalproduction, enhancing the degenerative diseases of aging. There is no natural selection against diseases of aging. 19) The levels of copper and iron considered normal for humans are acceptableduring the reproductive years but are too high after age 50 and contribute todiseases of aging. 20) Rabbits fed diets to develop Alzheimers disease would only do so if they alsodrank tap water; they did not develop Alzheimers disease on the same diet if theydrank only distilled water. The researchers determined that it was trace amounts ofcopper in the tap water that made the difference. 21) 0.12 ppm (parts per million) of copper added to distilled water triggerAlzheimers plaques. The Environmental Protection Agency (EPA) allows over 10times (1.3 ppm) that much copper in human drinking water. [Very Important] 22) The inorganic copper in drinking water contributes directly to the free copperpool in the blood. 23) Free copper levels are elevated in the blood of AD patients compared to age-matchedcontrols; the higher the free copper, the lower the cognitive ability. 24) The amino acid cysteine binds to copper and removes it from the brain.The ApoE protein has three alleles:ApoE2, has 2 copper binding cysteines and is protective against Alzheimers.ApoE3, has 1 copper binding cysteine.ApoE4, has no copper binding cysteines and increases the risk of Alzheimers. 25) Homocysteine interacts with copper to produce increased oxidant stress,oxidizing low-density lipoprotein (LDL) that contributes to the development of AD. 26) Parkinsons disease, Huntingtons disease, amyotrophic lateral sclerosis (LouGehrigs disease), and prion diseases such as Creutzfeldt-Jakob disease, are alldiseases of neurodegeneration, all have misfolded proteins that form inclusionbodies that are a copper dependent mechanism. 27) People in the highest quintile of copper intake with a high fat diet, lostcognition at a rate of 19 years in a six year period. In other words, they lostcognition at over three times the rate expected! These people were in the highestquintile of copper intake primarily because they took copper in their vitamin/mineral supplement pill. These data are frightening! Almost allvitamin/mineral supplementscontain copper. Copper deficiency is extremely rare; therefore, almost no one needscopper supplements, yet tens of millions of people are taking copper supplementsand in my view are running the risk of poisoning themselves with copper. 28) The interaction of copper and homocysteine generates oxidant stress andoxidize LDL, which is a component of the atherosclerotic plaque. 29) Abnormal copper metabolism increases diabetes and is involved in theetiology of diabetic neuropathy. 30) Increased copper has also been linked to Parkinsons disease, autism,Tourettes syndrome, age related macular degeneration and cancer. 31) Zinc is an anti-inflammatory and antioxidant agent. Supplemental zinc of 15mg or more significantly protects against advanced prostate cancer. 32) Increased iron levels play a major role in producing atherosclerosis. 33) Menstruating women have reduced iron load as a result of blood loss andhave strong protection against atherosclerosis compared to men. Post-menopausalwomen lose this protective effect. Blood donors have less atherosclerotic disease. 34) The interaction of iron and cholesterol promote oxidative damage, causingboth atherosclerosis and neurodegeneration. 35) The constant production of toxic free radicals, particularly reactive oxygenspecies, slowly produces mitochondrial damage. The slow loss of mitochondria andtheir energy production is associated with aging and may be the major cause ofaging; greater levels of free iron and free copper accelerate the production of toxicradicals. 36) The toxicity of free copper and free iron extends to the very basic processof aging itself. 37) To Minimize Copper and Iron Toxicity: * Avoid taking supplements containing copper and iron. Most multivitamin/multimineral pills have copper, and this copper is potentiallydangerous. Scan the label on your supplement bottle, and stop taking it if itcontains copper. Copper deficiency is extremely rare, and almost no one needscopper. Those with the highest quintile of copper intake lose cognition at over 3times the normal rate, and got there for the most part by taking copper supplements. * Men rarely need iron supplements unless they have chronic blood loss. Butsome menstruating girls and women, particularly if menstrual flow is heavy, maybecome iron deficient. * Both copper and iron are much more bioavailable from meat than fromvegetable foods. That means that these metals are much more easily absorbedfrom meat sources. Liver and shellfish are particularly high in copper content. Redmeat is particularly high in bioavailable iron. But copper and iron are readilybioavailable from all meat foods. * Those who averaged 2/3 of an ounce of red meat/day had 30% lessmortality than those who averaged 5 ounces of red meat/day. Processed meats alsoincreased mortality. Mortality was 20% higher in those who averaged 2 ounces ofprocessed meat per day (an average of one hot dog/day), compared to those whoate almost 15% that much. It is possible that the reduction in mortality seen in thestudy is at least partially due to the reduction of copper and iron intake. * Avoid drinking water with elevated copper content, one has to measure thecopper in their drinking water. 38) 80% of homes in the U.S. have copper water pipes. Whether toxic amountsof copper leaches from the copper pipes depends mostly on the acidity of the water.The more acidic the water, the more copper leaches from the pipes. If the plumbingsystem is used as the electrical ground for the house (which is legal in many places, but should not be), more copper can leach from the pipes. 39) There are various laboratories where copper in the water can be measured. Itis best to measure both the first draw water in the morning and water after allowingthe tap to run for five minutes. Because stagnant water may contain more copper,it is good to know if this is the case so that it can be avoided if necessary. 40) We recommend the drinking water contain no more than about 0.01 ppm.(The EPA allows 1.3 ppm!) 41) If the drinking water contains too much copper, a reverse osmosis devicecan be installed on the tap used for drinking and cooking water. Alternatively,distilled water, which contains no copper, can be purchased for drinking andcooking. 42) Bottled waters, which many people now drink, are an unknown for coppercontent, and at this point cannot be used to avoid copper in drinking water. 43) The intervention step required to further lower free copper is to take oral zincsupplements; zinc will lower free copper levels. It does so by strongly limitingcopper absorption. The minimal dose of zinc to do this is about 40 mg twice aday. The zinc dose must be separated from food and beverages other than waterby at least 1 h before and 2 h after. The best is zinc acetate and zinc gluconate. 44) Lowering free copper levels is beneficial in fibrotic, inflammatory, andautoimmune disease processes. 45) The intervention for lowering free iron is blood donation or removal of asignificant amount of blood on a regular basis. Men and menopausal women coulddonate 500 mL of blood every 2 months (or have that much removed if they arenot suitable blood donors), until their percent transferrin saturation is in the15-25 range. 46) If one is going to intervene by taking zinc to lower free copper and or donateblood to lower free iron, it is important to monitor free copper and/or free ironlevels. 47) It appears very likely that copper and iron toxicity are occurring in a largeproportion of our population. 48) Both copper and iron toxicity are likely contributing to Alzheimers disease. 49) There is a major epidemic of AD in the industrialized world, and this diseasedid not exist until 100 years ago. It still is rare in India and Africa. 50) The process of loss of cognition during aging may be greatly speeded up byincreased free copper exposure, and the very process of aging itself, if due to alifetime of oxidant stress, is likely increased by higher levels of free copper and freeiron since the toxicities of these two metals is through the production of oxidantstress. 51) Lower the risks of free copper and iron by throwing away supplementscontaining these metals, by lowering meat intake, and by avoiding drinking waterwith elevated levels of copper. 52) Rigorous methods of lowering free copper and free iron exposure includetaking zinc to lower copper and using blood donation to lower iron.