《食品加工营养手册》参考资料（英文版）5 Measuring intake of nutrients and

5.1 Introduction In this chapter, copper is considered as a case study for the measurement of the effect of nutrient intake. The importance of the role of copper in biological systems is first explored in a brief review of selected human cuproenzymes.

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118 The nutrition handbook for food processo 5.2 The nutritional role of copper Copper was identified as an essential trace element, first for animals and sub sequently for humans- when anaemia was successfully treated by supplementin the diet with a source of copper. Since then the full significance of its role in bio- logical systems has continued to unfold as it has been identified in a large number of vital metalloproteins, as an allosteric component and as a cofactor for catalytic activity. These proteins perform numerous important roles in the body, relating to the maintenance of immune function neural function bone health. arterial compliance, haemostasis, and protection against oxidative and inflammatory damage. However, the accurate assessment of copper status is problematic. Func tional copper status is the product of many interacting dietary and lifestyle factors, and an adequate marker of body copper status has yet to be identified. Accurate measurement of dietary copper intake is difficult because while a number of dietary factors are known to limit copper bioavailability, the precise molecular mechanisms of copper absorption and metabolism are not completely understood Shown in Table 5.1 is a selection of the copper-containing enzymes and pro- teins known to be important in human systems. A number of these enzymes exhibit oxidative/reductive activity and use molecular oxygen as a co-substrate In these redox reactions, the ability of copper to cycle between cupric and cuprous states is crucial to its role as electron transfer intermediate. Cytochrome Table 5.1 Human copper-containing proteins, and their functions Protein Function Cytochrome-c oxidase Cellular energy production Ferroxidase I(Caeruloplasmin ron oxidation and transport; free radical avenging; amine and phenol oxidation acute-phase immune res Ferroxidase ll ron oxidatio Hephaestin Iron metabolism Copper/zinc superoxide dismutase Antioxidant defence Extracellular superoxide dismutase Antioxidant defence Monoamine oxidase Brain chemistr Dopamine B-hydroxylase Brain chemistry Diamine oxidase Limitation of cell growth, histamine deactivation Lysyl oxidase Connective tissue formation Peptidylglycine a-amid Peptide hormone activation Prion protein PrP Antioxidant defence and/or copper sequestration and transport Tyrosine Melanin synthesis Albumin Metal binding in plasma and interstitial fluids Chaperone proteins intracellular c tar proteins Chromatin scaffold protein Structural integrity of nuclear material Clotting factors v and vIll Thrombogenesis Metallothionein Metal sequestration Copper binding in plas

5.2 The nutritional role of copper Copper was identified as an essential trace element, first for animals1 and subsequently for humans2 when anaemia was successfully treated by supplementing the diet with a source of copper. Since then the full significance of its role in biological systems has continued to unfold as it has been identified in a large number of vital metalloproteins, as an allosteric component and as a cofactor for catalytic activity. These proteins perform numerous important roles in the body, relating to the maintenance of immune function, neural function, bone health, arterial compliance, haemostasis, and protection against oxidative and inflammatory damage. However, the accurate assessment of copper status is problematic. Functional copper status is the product of many interacting dietary and lifestyle factors, and an adequate marker of body copper status has yet to be identified. Accurate measurement of dietary copper intake is difficult because while a number of dietary factors are known to limit copper bioavailability, the precise molecular mechanisms of copper absorption and metabolism are not completely understood. Shown in Table 5.1 is a selection of the copper-containing enzymes and proteins known to be important in human systems. A number of these enzymes exhibit oxidative/reductive activity and use molecular oxygen as a co-substrate. In these redox reactions, the ability of copper to cycle between cupric and cuprous states is crucial to its role as electron transfer intermediate. Cytochrome-c 118 The nutrition handbook for food processors Table 5.1 Human copper-containing proteins, and their functions Protein Function Cytochrome-c oxidase Cellular energy production Ferroxidase I (Caeruloplasmin) Iron oxidation and transport; free radical scavenging; amine and phenol oxidation; acute-phase immune response Ferroxidase II Iron oxidation Hephaestin Iron metabolism Copper/zinc superoxide dismutase Antioxidant defence Extracellular superoxide dismutase Antioxidant defence Monoamine oxidase Brain chemistry Dopamine -hydroxylase Brain chemistry Diamine oxidase Limitation of cell growth, histamine deactivation Lysyl oxidase Connective tissue formation Peptidylglycine a-amidating Peptide hormone activation monooxygenase Prion protein PrP Antioxidant defence and/or copper sequestration and transport Tyrosinase Melanin synthesis Albumin Metal binding in plasma and interstitial fluids Chaperone proteins Intracellular copper delivery to specific target proteins Chromatin scaffold proteins Structural integrity of nuclear material Clotting factors V and VIII Thrombogenesis Metallothionein Metal sequestration Transcuprein Copper binding in plasma

Measuring intake of nutrients and their effects: the case of copper 119 oxidase. embedded in the inner mitochondrial membrane is the terminal link in the electron transport chain. It catalyses the reduction of oxygen to water. One molecule of cytochrome-c oxidase contains three copper atoms and possesses two active sites. At one site two copper atoms receive, from the electron-carrier cytochrome-C, electrons which are then transferred to the second active site. where the third copper atom functions as a reducing agent. Because this is the rate-limiting step in electron transport, cytochrome-c oxidase is considered the single most important enzyme of the mammalian cell Ferroxidases I and Il are plasma glycoproteins Ferroxidase I, also known as caeruloplasmin, oxidises Fe (m) to Fe (im) without formation of hydrogen per- oxide(H2O2)or oxygen radicals. It is primarily this role which gives rise to caeru- loplasmin's well-known antioxidant function. It also scavenges H2O2, superoxide and hydroxyl radicals, and inhibits lipid peroxidation and DNA degradation stimulated by free iron and copper ions. Caeruloplasmin is also an acute-phase protein: in acute response to inflammatory cues caeruloplasmin concentration rises, binding free circulating iron and limiting the amount available to partici pate in oxidative reactions. One molecule of caeruloplasmin contains six copper ions, of which three provide active sites for electron transfer processes, while the remaining three together form an oxygen-activating site for the enzymes catalytic action. Superoxide dismutase (SOD)is another important and well studied enzyme. In human systems, it exists in several forms, of which two contain copper: the cytosolic copper/zinc variety sometimes termed SoDI present in most cells; and the extracellular SOD2, found in the plasma and also in certain cell types in the lung, thyroid and uterus. SOD catalyses the dismuta tion of superoxide radicals to hydrogen peroxide and oxygen In several amine oxidases, copper acts as an allosteric component, conferring the structure required for catalytic activity. Monoamine oxidase(MAO) inacti vates, by deamination, substrates such as serotonin and catecholamines includ- ing adrenalin, noradrenalin and dopamine. Tricyclic antidepressants are MOA inhibitors. Diamine oxidase (DAO)deaminates histamine and polyamines involved in cell proliferation. It is present at low levels in the plasma, but at higher concentrations in the small intestine where histamine stimulates acid secretion. in the kidney where it likely inactivates diamines filtered from the blood, and in the placenta, where it is thought to inactivate foetal amines in maternal blood. Lysyl oxidase deaminates lysine and hydroxylysine, which are present as sidechains of immature collagen and elastin molecules. It thereby enables the formation of crosslinks which lend strength and flexibility to mature connective tissue Peptidyl-glycine a-amidating mono-oxygenase(PAM) is found in the plasma nd in a number of tissues, including the brain. It produces mature, a-amidated, peptide hormones from their glycine-extended precursors. The enzyme contains two copper atoms per molecule. Dopamine B-hydroxylase(DBM) is a mono- oxygenase similar to PAM in structure and activity. Found in the adrenal gland and the brain, it catalyses the synthesis of the catecholamines adrenalin and noradrenalin from dopamine. Tyrosinase, or catechol oxidase, is the only enzyme involved in the synthesis of melanin from tyrosine. Tyrosinase first hydroxylates the amino acid to dopa, then oxidises it to dopaquinone. Subsequent reactions

oxidase, embedded in the inner mitochondrial membrane, is the terminal link in the electron transport chain. It catalyses the reduction of oxygen to water. One molecule of cytochrome-c oxidase contains three copper atoms and possesses two active sites. At one site two copper atoms receive, from the electron-carrier cytochrome-c, electrons which are then transferred to the second active site, where the third copper atom functions as a reducing agent.3 Because this is the rate-limiting step in electron transport, cytochrome-c oxidase is considered the single most important enzyme of the mammalian cell. Ferroxidases I and II are plasma glycoproteins. Ferroxidase I, also known as caeruloplasmin, oxidises Fe (II) to Fe (III) without formation of hydrogen peroxide (H2O2) or oxygen radicals. It is primarily this role which gives rise to caeruloplasmin’s well-known antioxidant function. It also scavenges H2O2, superoxide and hydroxyl radicals, and inhibits lipid peroxidation and DNA degradation stimulated by free iron and copper ions.4 Caeruloplasmin is also an acute-phase protein: in acute response to inflammatory cues caeruloplasmin concentration rises, binding free circulating iron and limiting the amount available to participate in oxidative reactions. One molecule of caeruloplasmin contains six copper ions, of which three provide active sites for electron transfer processes, while the remaining three together form an oxygen-activating site for the enzyme’s catalytic action.5 Superoxide dismutase (SOD) is another important and wellstudied enzyme. In human systems, it exists in several forms, of which two contain copper: the cytosolic copper/zinc variety sometimes termed SOD1, present in most cells; and the extracellular SOD2, found in the plasma and also in certain cell types in the lung, thyroid and uterus.6 SOD catalyses the dismutation of superoxide radicals to hydrogen peroxide and oxygen. In several amine oxidases, copper acts as an allosteric component, conferring the structure required for catalytic activity. Monoamine oxidase (MAO) inactivates, by deamination, substrates such as serotonin and catecholamines including adrenalin, noradrenalin and dopamine. Tricyclic antidepressants are MOA inhibitors. Diamine oxidase (DAO) deaminates histamine and polyamines involved in cell proliferation. It is present at low levels in the plasma, but at higher concentrations in the small intestine where histamine stimulates acid secretion, in the kidney where it likely inactivates diamines filtered from the blood, and in the placenta, where it is thought to inactivate foetal amines in maternal blood. Lysyl oxidase deaminates lysine and hydroxylysine, which are present as sidechains of immature collagen and elastin molecules. It thereby enables the formation of crosslinks which lend strength and flexibility to mature connective tissue. Peptidyl-glycine a-amidating mono-oxygenase (PAM) is found in the plasma and in a number of tissues, including the brain. It produces mature, a-amidated, peptide hormones from their glycine-extended precursors. The enzyme contains two copper atoms per molecule.7 Dopamine b-hydroxylase (DbM) is a monooxygenase similar to PAM in structure and activity. Found in the adrenal gland and the brain, it catalyses the synthesis of the catecholamines adrenalin and noradrenalin from dopamine. Tyrosinase, or catechol oxidase, is the only enzyme involved in the synthesis of melanin from tyrosine. Tyrosinase first hydroxylates the amino acid to dopa, then oxidises it to dopaquinone. Subsequent reactions Measuring intake of nutrients and their effects: the case of copper 119

120 The nutrition handbook for food processors Table 5.2 Dietary Reference Values for copper Dietary Reference value Copper(mg/d) Source US EAR 0.7 Food and Nutrition Board, 2001 Food and Nutrition Board, 2001 WHO AROI 1.2 to 2 or 3 WHO International Programme of Chemical Safety, 1998 leading to melanins occur spontaneously in vitro. Regulation of pigment forma- tion is also provided by tyrosinase, as it can remove substrates from this pathway by catalysing alternative reactions for them. Congenital deficiency of tyrosinase results in albinism In the nucleus, copper has a structural role as an essential component of chromatin scaffold proteins, which contribute to nuclear stability, It does not however, appear to be required for DNA synthesis in mammalian cells. Although in yeast cells, copper has been identified as a component of gene regulatory mech anisms, if equivalent proteins exist in human cells they remain to be identified 5.3 Dietary copper requirements Despite the known essentiality of copper in humans, dietary requirements are still uncertain. World-wide, a number of Dietary Reference Values are recommended for copper intake(see Table 5. 2) but the variability between them is indicative of the lack of consensus between advisory bodies. Making dietary recommenda- tions, even of Estimated Average Requirements(EAR), is difficult owing to a lack of adequate data. In the UK, the Department of Health considers the avail- able data on human copper requirements to be insufficient to determine an EAR, 12 In the US, an EAR of adults for copper was derived from a combination of bio- chemical indicators of copper requirement, as no single indicator was judged ufficiently sensitive, specific and consistent to be used alone. A Recommended Daily Allowance(RDA)can be calculated by extrapolatin the EAr to account for inter-individual variation in requirements. The US RDA, te the UK Reference Nutrient Intake (RND) is intended to provide enough copper for about 97% of adults. The World Health Organization has loosely defined an Acceptable Range of Oral Intake(AROD). Its upper limit could not be specifically confirmed because of the limited information available on the level of intake that would provoke adverse heath effects. It is apparent that more data are needed if sound and defensible guidelines are to be derived. 5.4 Sources of copper In most diets. sources of ecause copper is widespread in foods. Rich sources include organ meats, nuts, shellfish, seeds, legumes and the germ portion of grains. Other foods including cereals, meats, mushrooms, pota-

leading to melanins occur spontaneously in vitro. Regulation of pigment formation is also provided by tyrosinase, as it can remove substrates from this pathway by catalysing alternative reactions for them.8 Congenital deficiency of tyrosinase results in albinism. In the nucleus, copper has a structural role as an essential component of chromatin scaffold proteins, which contribute to nuclear stability.9,10 It does not, however, appear to be required for DNA synthesis in mammalian cells. Although in yeast cells, copper has been identified as a component of gene regulatory mechanisms, if equivalent proteins exist in human cells they remain to be identified.11 5.3 Dietary copper requirements Despite the known essentiality of copper in humans, dietary requirements are still uncertain. World-wide, a number of Dietary Reference Values are recommended for copper intake (see Table 5.2) but the variability between them is indicative of the lack of consensus between advisory bodies. Making dietary recommendations, even of Estimated Average Requirements (EAR), is difficult owing to a lack of adequate data. In the UK, the Department of Health considers the available data on human copper requirements to be insufficient to determine an EAR.12 In the US, an EAR of adults for copper was derived from a combination of biochemical indicators of copper requirement, as no single indicator was judged as sufficiently sensitive, specific and consistent to be used alone. A Recommended Daily Allowance (RDA) can be calculated by extrapolating the EAR to account for inter-individual variation in requirements. The US RDA, like the UK Reference Nutrient Intake (RNI) is intended to provide enough copper for about 97% of adults. The World Health Organization has loosely defined an Acceptable Range of Oral Intake (AROI). Its upper limit could not be specifically confirmed because of the limited information available on the level of intake that would provoke adverse heath effects. It is apparent that more data are needed if sound and defensible guidelines are to be derived. 5.4 Sources of copper In most diets, sources of copper are numerous because copper is widespread in foods. Rich sources include organ meats, nuts, shellfish, seeds, legumes and the germ portion of grains. Other foods including cereals, meats, mushrooms, pota- 120 The nutrition handbook for food processors Table 5.2 Dietary Reference Values for copper Dietary Reference Value Copper (mg/d) Source US EAR 0.7 Food and Nutrition Board, 2001 US RDA 0.9 Food and Nutrition Board, 2001 UK RNI 1.2 Department of Health, 1991 WHO AROI 1.2 to 2 or 3 WHO International Programme on Chemical Safety, 1998

Measuring intake of nutrients and their effects: the case of copper 121 toes, tomatoes, bananas and other dried fruits provide sufficient copper in a normal diet to ensure that overt copper deficiency is rare in human populations. Nonethe- less, many Western diets are estimated to supply a level of copper only barely dequate to meet the body's requirements Published estimates of copper intake vary around 1-2mg/d, with few diets containing more than 2 mg/d. 3.1415, 16 17 5.5 Copper deficiency Clinical copper deficiency is seen mainly in malnourished and recovering chil- dren, in premature babies, in patients receiving total parenteral nutrition (TPN) and as a consequence of malabsorption. Copper deficiency also occurs as the result of Menkes syndrome, a rare inherited defect of copper transport. Mal- nourished children are reported to be at particular risk of copper deficiency. A diet consisting exclusively or predominantly of cow's milk, with its poor bioavail- ability of copper, increases the likelihood of copper malabsorption. During nutri tional recovery, growth rate can be 5-10 times the normal rate, increasing copper requirements beyond the dietary intake. Copper deficiency during this period has been shown to impair growth rate and to be associated with increased incidence of respiratory infection. 9 Preterm babies are also at particular risk of copper deficiency, for several reasons. Copper stores are acquired late in foetal development, as metallothionein bound copper accumulates in the foetal hepatocyte nuclei over the last trimester Although neonates appear not to absorb copper well, particularly from highly refined carbohydrate-based diets or cows milk, full-term infants have well leveloped copper stores which can be mobilised during the first six months rapid growth, to supplement dietary intake. Full-term infants are therefore independent of dietary intake for the first weeks of life. Premature babies, especially those with very low birth-weight, do not have such a resource. They also have higher growth rate than full-term babies, with accordingly higher copper requirements. 23 Clinical copper deficiency in adults was unknown until the introduction of TPN, which is now well known to result in elevated urinary copper output and a net depletion of copper status. Although copper is now usually added to TPN infusates, it is often withheld from cholestatic patients since their impaired biliary excretion is expected to result in reduced intestinal losses. The complex interac tions between disease states and copper metabolism, however, make individuals requirements difficult to anticipate, and TPN-related copper deficiency continues to occur intestinal copper losses leading to deficiency. Such conditions include coeliac disease26, cystic fibrosis, shortened intestine following surgery, and chronic or recurrent diarrhoea 29.30 Menkes disease is an X-linked recessive disorder of copper metabolism in which mutations in the mnK gene impair copper transport from cells. The disease is manifest as copper deficiency, because although copper is absorbed by gut cells, very little is transported to the tissues where it is required

toes, tomatoes, bananas and other dried fruits provide sufficient copper in a normal diet to ensure that overt copper deficiency is rare in human populations. Nonetheless, many Western diets are estimated to supply a level of copper only barely adequate to meet the body’s requirements. Published estimates of copper intake vary around 1–2 mg/d, with few diets containing more than 2 mg/d.13,14,15,16,17 5.5 Copper deficiency Clinical copper deficiency is seen mainly in malnourished and recovering children, in premature babies, in patients receiving total parenteral nutrition (TPN) and as a consequence of malabsorption. Copper deficiency also occurs as the result of Menkes syndrome, a rare inherited defect of copper transport. Malnourished children are reported to be at particular risk of copper deficiency. A diet consisting exclusively or predominantly of cow’s milk, with its poor bioavailability of copper, increases the likelihood of copper malabsorption. During nutritional recovery, growth rate can be 5–10 times the normal rate, increasing copper requirements beyond the dietary intake.3 Copper deficiency during this period has been shown to impair growth rate18 and to be associated with increased incidence of respiratory infection.19 Preterm babies are also at particular risk of copper deficiency, for several reasons. Copper stores are acquired late in foetal development, as metallothioneinbound copper accumulates in the foetal hepatocyte nuclei over the last trimester.11 Although neonates appear not to absorb copper well, particularly from highlyrefined carbohydrate-based diets or cow’s milk20, full-term infants have welldeveloped copper stores which can be mobilised during the first six months’ rapid growth, to supplement dietary intake.21 Full-term infants are therefore independent of dietary intake for the first weeks of life.22 Premature babies, especially those with very low birth-weight, do not have such a resource. They also have higher growth rate than full-term babies, with accordingly higher copper requirements.23 Clinical copper deficiency in adults was unknown until the introduction of TPN, which is now well known to result in elevated urinary copper output and a net depletion of copper status.20 Although copper is now usually added to TPN infusates, it is often withheld from cholestatic patients since their impaired biliary excretion is expected to result in reduced intestinal losses. The complex interactions between disease states and copper metabolism, however, make individuals’ requirements difficult to anticipate, and TPN-related copper deficiency continues to occur.24,25 Anumber of malabsorption syndromes have been reported to result in increased intestinal copper losses leading to deficiency. Such conditions include coeliac disease26, cystic fibrosis27, shortened intestine following surgery28, and chronic or recurrent diarrhoea.29,30 Menkes disease is an X-linked recessive disorder of copper metabolism in which mutations in the MNK gene impair copper transport from cells. The disease is manifest as copper deficiency, because although copper is absorbed by gut cells, very little is transported to the tissues where it is required Measuring intake of nutrients and their effects: the case of copper 121

122 The nutrition handbook for food processors for enzyme function. Symptoms usually appear within the first months of life, and can result in death in early childhood. In clinical copper deficiency, the most common defects are: cardiovascular and haematological disorders including iron-resistant anaemia, neutropenia and thrombocytopenia; bone abnormalities including osteoporosis and fractures; and alterations to skin and hair texture and pigmentation.Immunological changes have also been indicated. 9.32These changes may be accompanied by depressed serum copper and blood cupro- enzymes, with caeruloplasmin concentrations observed at 30% of normal.6 It has been clearly demonstrated that very many of the changes induced by severe copper deficiency are also risk factors for ischaemic heart disease in humans. Human copper depletion studies have produced impaired glucose clearance, blood pressure changes, electrocardiographic irregularities and significantly increased LDL cholesterol with decreased HDL cholesterol. In copper-deficient animals, cardiovascular disorders observed include lesion and rupture of blood vessels, cardiac enlargement, myocardial degeneration and infarction(MI). It has been argued that copper deficiency is the only nutritional deficit known to affect adversely so many risk factors for ischaemic heart disease. The proposed link between copper deficiency and cardiovascular disease is supported by data gathered from studies of cardiovascular patients Post-mortem measurement of tissue copper has revealed lower-than-normal opper concentrations in ischaemic hearts, in the liver and heart of individuals with severe atherosclerosis, and in leucocytes of patients with highly occluded coronary arteries A variety of mechanisms may contribute to the cardiovascular effects of copper deficiency. There is evidence for alterations in the activity of copper- dependent enzymes, increased oxidative stress and damage to biomolecules, and interference with the maintenance of blood pressure. An interaction of these three mechanisms of damage has been proposed to have even further potential for harm.36 which need not be limited to cardiovascular defects. The adverse effects elicited by copper deficiency are numerous and as varied as the roles of copper in health. In the light of this, it has been proposed that long-term sub-clinical opper deficiency may contribute to the pathogenesis of a number of degenera- tive and inflammatory conditions. 37 5.6 Copper toxicity Copper toxicity is rare because levels in food and water are generally low and because increased dietary intake results in decreased absorption and increased excretion. Cases of both acute and chronic poisoning have, however, been reported. Acute toxicity has been known to result from accidental or deliberate consumption of copper salts and, more commonly, from contamination of drinks by copper containers. A 1957 report of contamination of cocktails stored for just two hours in a metal cocktail shaker was used in 1988 by US Environmental Pro- tection Agency(EPA)Office of Drinking Water to derive drinking water regula

for enzyme function. Symptoms usually appear within the first months of life, and can result in death in early childhood.31 In clinical copper deficiency, the most common defects are: cardiovascular and haematological disorders including iron-resistant anaemia, neutropenia and thrombocytopenia; bone abnormalities including osteoporosis and fractures; and alterations to skin and hair texture and pigmentation.23 Immunological changes have also been indicated.19,32 These changes may be accompanied by depressed serum copper and blood cuproenzymes, with caeruloplasmin concentrations observed at 30% of normal.6 It has been clearly demonstrated that very many of the changes induced by severe copper deficiency are also risk factors for ischaemic heart disease in humans. Human copper depletion studies have produced impaired glucose clearance,33 blood pressure changes,34 electrocardiographic irregularities and significantly increased LDL cholesterol with decreased HDL cholesterol.21 In copper-deficient animals, cardiovascular disorders observed include lesion and rupture of blood vessels, cardiac enlargement, myocardial degeneration and infarction (MI).33 It has been argued that copper deficiency is the only nutritional deficit known to affect adversely so many risk factors for ischaemic heart disease.35 The proposed link between copper deficiency and cardiovascular disease is supported by data gathered from studies of cardiovascular patients. Post-mortem measurement of tissue copper has revealed lower-than-normal copper concentrations in ischaemic hearts, in the liver and heart of individuals with severe atherosclerosis, and in leucocytes of patients with highly occluded coronary arteries.33 A variety of mechanisms may contribute to the cardiovascular effects of copper deficiency. There is evidence for alterations in the activity of copperdependent enzymes, increased oxidative stress and damage to biomolecules, and interference with the maintenance of blood pressure. An interaction of these three mechanisms of damage has been proposed to have even further potential for harm,36 which need not be limited to cardiovascular defects. The adverse effects elicited by copper deficiency are numerous and as varied as the roles of copper in health. In the light of this, it has been proposed that long-term sub-clinical copper deficiency may contribute to the pathogenesis of a number of degenerative and inflammatory conditions.37 5.6 Copper toxicity Copper toxicity is rare because levels in food and water are generally low and because increased dietary intake results in decreased absorption and increased excretion.38 Cases of both acute and chronic poisoning have, however, been reported. Acute toxicity has been known to result from accidental or deliberate consumption of copper salts and, more commonly, from contamination of drinks by copper containers.6 A 1957 report of contamination of cocktails stored for just two hours in a metal cocktail shaker was used in 1988 by US Environmental Protection Agency (EPA) Office of Drinking Water to derive drinking water regula- 122 The nutrition handbook for food processors

measuring intake of nutrients and their effects: the case of copper 123 tions which are still in place. Acute toxicity results, initially, in symptoms such as abdominal pain, nausea, vomiting and diarrhoea. These gastrointestinal effects are often sufficiently severe and prompt to prevent systemic toxicity which, like chronic copper poisoning, is associated with liver damage. Chronic toxicity has most often been caused by contaminated water supplies, and occasionally by contamination of haemodialysis equipment by copper parts The highest intake which has been shown experimentally to produce no adverse effects is defined as the No-Observed-Adverse-Effects-Level (NOAEL) While a NOael of 4 mg/ in drinking water has been observed for acute effects, a higher NOAEL of 10mg supplemental copper per day has been demonstrated to provoke no ill effect upon liver function after 12 weeks. 4 The IS Food and nutrition board have used the latter value to calculate a theoreti cal Tolerable Upper Intake Level (UL), defined as the highest level of daily intake considered likely to pose no threat to the health of almost all individuals. The UL is in agreement with the World Health Organizations provisional maximum tolerable daily intake(PTDD), an estimate of the amount that can be ingested daily over a lifetime without appreciable risk to health In drinking water, copper levels vary considerably depending on factors including the ph and hardness of the water supply and the length of piping. In some systems, copper salts are added to control the growth of algae. Suggested pper limits for copper in drinking water differ world-wide, and while some are based on health issues, others consider only aesthetic values. The issue is currently under review by several international groups. Table 5.3 shows current permissible levels of copper in drinking water, and recommended limits of total copper intake A number of disorders of copper homeostasis can result in toxicity leading to liver cirrhosis at dietary copper levels which are tolerated by the general popu lation. Copper-induced cirrhosis is mainly restricted to children, possibly because Table 5.3 Recommended limits of copper intake Reference Value Copper limit Source In drinking water( UK standard Water Quality)Regulation WHO standard 2.0 ines for Drinking Water Quality, EU standard 98/83L30,32-54 LXlImun EPA Drinking Water Regulations, 1988 contaminant Total intake(mg/d) Food and Nutrition Board. 2001 WHO PTDI 10.0(women) World Health Organization, 1996 12.0(men)

tions which are still in place.39 Acute toxicity results, initially, in symptoms such as abdominal pain, nausea, vomiting and diarrhoea. These gastrointestinal effects are often sufficiently severe and prompt to prevent systemic toxicity which, like chronic copper poisoning, is associated with liver damage. Chronic toxicity has most often been caused by contaminated water supplies, and occasionally by contamination of haemodialysis equipment by copper parts.40 The highest intake which has been shown experimentally to produce no adverse effects is defined as the No-Observed-Adverse-Effects-Level (NOAEL). While a NOAEL of 4 mg/l in drinking water has been observed for acute effects,41 a higher NOAEL of 10 mg supplemental copper per day has been demonstrated to provoke no ill effect upon liver function after 12 weeks.42 The US Food and Nutrition Board have used the latter value to calculate a theoretical Tolerable Upper Intake Level (UL), defined as the highest level of daily intake considered likely to pose no threat to the health of almost all individuals. The UL is in agreement with the World Health Organization’s provisional maximum tolerable daily intake (PTDI), an estimate of the amount that can be ingested daily over a lifetime without appreciable risk to health. In drinking water, copper levels vary considerably depending on factors including the pH and hardness of the water supply and the length of piping. In some systems, copper salts are added to control the growth of algae.16 Suggested upper limits for copper in drinking water differ world-wide, and while some are based on health issues, others consider only aesthetic values. The issue is currently under review by several international groups.39 Table 5.3 shows current permissible levels of copper in drinking water, and recommended limits of total copper intake. A number of disorders of copper homeostasis can result in toxicity leading to liver cirrhosis at dietary copper levels which are tolerated by the general population. Copper-induced cirrhosis is mainly restricted to children, possibly because Measuring intake of nutrients and their effects: the case of copper 123 Table 5.3 Recommended limits of copper intake Reference Value Copper limit Source In drinking water (mg/l) UK standard 3.0 Water Supply (Water Quality) Regulations, 1989 WHO standard 2.0 WHO Guidelines for Drinking Water Quality, 1993 EU standard 2.0 EU Directive 98/83 L330, 32–54 US maximum 1.3 EPA Drinking Water Regulations, 1988 contaminant level Total intake (mg/d) US UL 10.0 Food and Nutrition Board, 2001 WHO PTDI 10.0 (women) World Health Organization, 1996 12.0 (men)

124 The nutrition handbook for food processors of the lower capacity of their biliary excretory mechanisms. Indian Childhood Cirrhosis (ICC)is a fatal condition of copper metabolism which was, at one time, a major cause of infant mortality on the Indian subcontinent. ICC sufferers usually infants aged between 6 months and 5 years, are often found to have been exposed at an early age to milk contaminated with copper from untinned brass or copper vessels. High copper intake, however, is not thought to be the sole cause of the illness; both environmental and genetic components are thought to contribute. Cases of a similar infantile condition have been reported in Germany and in the Tyrol, Austria. Incidence of both ICC and Tyrolean Infantile Cirrhosis has dropped in recent years. One possible explanation is reduced use of brass vessels, while an alternative is the dilution of the responsible gene by increased population mobility and fewer consanguineous marriages. A rare inherited disorder of copper metabolism leads to Wilson's disease, in which copper cannot be properly transported out of the liver and so accumulates to toxic levels. When the hepatocytes die, copper is released into the plasma and deposited in other tissues including the central nervous system. Treatment of Wilsons disease is aimed at removing copper from the body and preventing its reaccumulation 5.7 General limitations in assessing nutrient intake As for any nutrient where deficiency and toxicity are issues, the reliable assess- ment of intake is paramount. The ultimate aim of defining optimal dietary intakes is hampered by difficulties in determining certain key facts, namely, individual copper intakes and status. Dietary intake can be assessed by a number of methods, involving either the recording of actual consumption(prospective) or the assess- ment by questionnaires of diet in the recent past (retrospective). At each stage in the application of any method, errors are introduced, producing as a result either a systematic bias or random deviations from the true values. Of the methods in ommon use, the weighed dietary record is widely accepted to be the most accu- rate, but it requires a considerable amount of co-operation from human subjects This disadvantage may give rise to substantial bias, most likely toward under reporting habitual dietary intakes. In clinical practice the most frequently used method of dietary assessment is the diet history, which is highly dependent on accurate recall by the individual. It is possible to verify these reports, to some extent, by independent methods. Under- and over-estimation of an individuals total food intake can be identified by measuring total energy expenditure, either directly, using the doubly-labelled water technique, or indirectly, by calculatin basal metabolic rate. Another check is a comparison of the individuals 24-hour urinary nitrogen output with the reported protein intake. The accuracy of these methods is limited either by the involvement of estimates, or by reliance on the assumption that body weight is constant One means of assessing nutrient requirements is the metabolic balance study The aim of a balance study is to compare the intake of a nutrient with the amount

of the lower capacity of their biliary excretory mechanisms.38 Indian Childhood Cirrhosis (ICC) is a fatal condition of copper metabolism which was, at one time, a major cause of infant mortality on the Indian subcontinent. ICC sufferers, usually infants aged between 6 months and 5 years, are often found to have been exposed at an early age to milk contaminated with copper from untinned brass or copper vessels.43 High copper intake, however, is not thought to be the sole cause of the illness; both environmental and genetic components are thought to contribute.44 Cases of a similar infantile condition have been reported in Germany and in the Tyrol, Austria.45,46 Incidence of both ICC and Tyrolean Infantile Cirrhosis has dropped in recent years. One possible explanation is reduced use of brass vessels, while an alternative is the dilution of the responsible gene by increased population mobility and fewer consanguineous marriages. A rare inherited disorder of copper metabolism leads to Wilson’s disease, in which copper cannot be properly transported out of the liver and so accumulates to toxic levels. When the hepatocytes die, copper is released into the plasma and deposited in other tissues including the central nervous system. 47 Treatment of Wilson’s disease is aimed at removing copper from the body and preventing its reaccumulation. 5.7 General limitations in assessing nutrient intake As for any nutrient where deficiency and toxicity are issues, the reliable assessment of intake is paramount. The ultimate aim of defining optimal dietary intakes is hampered by difficulties in determining certain key facts, namely, individual copper intakes and status. Dietary intake can be assessed by a number of methods, involving either the recording of actual consumption (prospective) or the assessment by questionnaires of diet in the recent past (retrospective). At each stage in the application of any method, errors are introduced, producing as a result either a systematic bias or random deviations from the true values. Of the methods in common use, the weighed dietary record is widely accepted to be the most accurate, but it requires a considerable amount of co-operation from human subjects. This disadvantage may give rise to substantial bias, most likely toward underreporting habitual dietary intakes.48 In clinical practice the most frequently used method of dietary assessment is the diet history, which is highly dependent on accurate recall by the individual. It is possible to verify these reports, to some extent, by independent methods. Under- and over-estimation of an individual’s total food intake can be identified by measuring total energy expenditure, either directly, using the doubly-labelled water technique, or indirectly, by calculating basal metabolic rate. Another check is a comparison of the individual’s 24-hour urinary nitrogen output with the reported protein intake. The accuracy of these methods is limited either by the involvement of estimates, or by reliance on the assumption that body weight is constant. One means of assessing nutrient requirements is the metabolic balance study. The aim of a balance study is to compare the intake of a nutrient with the amount 124 The nutrition handbook for food processors

Measuring intake of nutrients and their effects: the case of copper 125 leaving the body. A constant daily intake of the nutrient in question is provided throughout the study period, and collection of stools and urine are made. Crucial to the success of the investigation is the accuracy of measurement of intake and excretion. For this reason, balance studies demand careful planning and execu tion, good facilities for food preparation, sample collection and sample storage, and good laboratory services. A major limitation is that balance studies provide little information about nutrient transport or utilisation within the body Nutrient intake can also be assessed by the use of experimental diets with different mineral intakes. The use of experimental diets to determine nutrient requirements depends on the selection and measurement of a biochemical endpoint, to serve as a marker of nutrient sufficiency. However, experimental diets must be carefully constituted to minimise the possibility that other dietary components may modify absorption of the nutrient, or even influence directly e chosen marker. A limitation of this method is that it permits the estimation of the basal nutrient requirements, but not the amount needed to maintain bodily nutrient reserves Epidemiological studies such as the US Total Diet Study or the North/South Ireland Food Consumption Survey> are often carried out with the aim of esti mating the fraction of the population at risk from deficiency or excess intake Attempts are made to assess long-term average intake of populations from data gained using short-term measures of intake. Few studies have reported testing the validity of such an extrapolation, but a recent study which examined values cal culated from up to six samples, spaced over a year, found significant temporal variability for individual subjects. In addition, when the reliability of short-term (4-day) samples was estimated by comparing individual values to the aggregate value, results suggested that three short-term samples would be required to achieve a strong correlation(r=0.9)between short- and long-term values. Tra tional reliance on short-term measures for estimation of long-term copper status could produce erroneous result 5.8 Putative copper indicators Determination of copper status suffers from the lack of sensitive, reliable and easy measures for detecting marginal copper status. Copper levels in the hair, nails or saliva do not appear to reflect copper status. Urinary copper is normally extremely low, and although it can decline in extreme copper deficiency, this is usually seen only after changes are seen in other copper indices. In copper de- pletion and repletion studies, cuproenzyme activities have appeared relatively insensitive to change I The traditional and most commonly used putative indicator of copper status is serum or plasma copper. Under normal circumstances, strong homeostatic mechanisms maintain the range between 0. 64 and 1.56ug/ml. Although in severe copper depletion it has been known to fall to very low levels, and to recover upon copper repletion, it does not appear to reflect dietary levels when

leaving the body. A constant daily intake of the nutrient in question is provided throughout the study period, and collection of stools and urine are made. Crucial to the success of the investigation is the accuracy of measurement of intake and excretion. For this reason, balance studies demand careful planning and execution, good facilities for food preparation, sample collection and sample storage, and good laboratory services. A major limitation is that balance studies provide little information about nutrient transport or utilisation within the body.22 Nutrient intake can also be assessed by the use of experimental diets with different mineral intakes. The use of experimental diets to determine nutrient requirements depends on the selection and measurement of a biochemical endpoint, to serve as a marker of nutrient sufficiency. However, experimental diets must be carefully constituted to minimise the possibility that other dietary components may modify absorption of the nutrient, or even influence directly the chosen marker.23 A limitation of this method is that it permits the estimation of the basal nutrient requirements, but not the amount needed to maintain bodily nutrient reserves. Epidemiological studies such as the US Total Diet Study13 or the North/South Ireland Food Consumption Survey15 are often carried out with the aim of estimating the fraction of the population at risk from deficiency or excess intake. Attempts are made to assess long-term average intake of populations from data gained using short-term measures of intake. Few studies have reported testing the validity of such an extrapolation, but a recent study which examined values calculated from up to six samples, spaced over a year, found significant temporal variability for individual subjects.49 In addition, when the reliability of short-term (4-day) samples was estimated by comparing individual values to the aggregate value, results suggested that three short-term samples would be required to achieve a strong correlation (r = 0.9) between short- and long-term values. Traditional reliance on short-term measures for estimation of long-term copper status could produce erroneous results. 5.8 Putative copper indicators Determination of copper status suffers from the lack of sensitive, reliable and easy measures for detecting marginal copper status. Copper levels in the hair, nails or saliva do not appear to reflect copper status.50 Urinary copper is normally extremely low, and although it can decline in extreme copper deficiency, this is usually seen only after changes are seen in other copper indices.17 In copper depletion and repletion studies, cuproenzyme activities have appeared relatively insensitive to change.51 The traditional and most commonly used putative indicator of copper status is serum or plasma copper. Under normal circumstances, strong homeostatic mechanisms maintain the range between 0.64 and 1.56mg/ml.50 Although in severe copper depletion it has been known to fall to very low levels, and to recover upon copper repletion, it does not appear to reflect dietary levels when Measuring intake of nutrients and their effects: the case of copper 125

126 The nutrition handbook for food processors intake is close to normal. It does not increase after a meal or decrease during short-term fasting and has been shown to correspond poorly with reported dietary intakes. In some studies of copper depletion, serum copper responses have been absent even in the presence of other biochemical or physiological changes. 3 Serum copper is known to be altered by a number of factors not directly related to copper status. Concentrations are low in infancy and rise to adult levels over the first 4-6 months, or longer following a low birth weight. In adult women. serum copper concentration is generally higher than in men, and is further raised during pregnancy and by oestrogen treatments. There is also a normal diurnal variation with a slight peak in the morning. Plasma copper fluctuates with age. and is raised in a number of other conditions including exercise, rheumatoid arthritis, dilated cardiomyopathy and anticonvulsant chemotherapy. Between 60 and 95%o of serum copper is associated with caeruloplasmin, so serum copper levels often mirror those of caeruloplasmin. Normal levels of serum or plasma caeruloplasmin protein are 180-400ug/mL Like serum copper, caeruloplasmin has shown variable responses to marginal depletion. Its concentration and activity fall with severe copper deficiency and return to normal with copper repletion; but because of its role as an acute phas protein, caeruloplasmin concentration in the plasma reflects oxidative status more reliably than copper status. Copper depletion may be masked by caeruloplasmin elevated in response to exercise, infection or inflammation, liver disease, malig- nancy and MI. Like serum copper, normal caeruloplasmin values also vary with age and gender, and during pregnancy Erythrocyte copper/zinc SOD concentration is normally 0.471 t 0.067 mg/g protein. SOD activity has appeared in some studies to be more sensitive than ceruloplasmin to changes in copper status, while in other studies its activity has fallen with depletion but failed to respond to repletion. Copper/zinc SOD activ- ity has been reported to rise in response to physical exercise. As an antioxidant enzyme, SOD is likely to respond to conditions of oxidative stress. A further com- plicating factor is that SOD measured in erythrocytes is unlikely to reflect short- term changes in dietary intake owing to the 100-day lifetime of erythrocytes Leucocyte copper has been found to decline along with other indices of copper status. Platelet copper has been shown to decline with copper depletion and to recover with copper repletion. However, there are not yet sufficient experi- mental data to confirm the validity of leucocyte or platelet copper as indicators of suboptimal copper status. DAO has been indicated in some studies of copper depletion as a possible marker of copper status. Its measurement is currently difficult cause of its extremely low levels in plasma. Furthermore, its use as an indicator may be limited because it is elevated during pregnancy, after heparin treatment and in some conditions of intestinal damage A valid functional index must respond sensitively, specifically and predictably to changes in the dietary supply or stores of copper, and must be measurable and accessible for measurement. Validation of a candidate marker would require status and also, ideally, between copper status and health measures. ss d copper demonstration of a cause and effect relationship between the marker an

intake is close to normal.17 It does not increase after a meal or decrease during short-term fasting and has been shown to correspond poorly with reported dietary intakes.52 In some studies of copper depletion, serum copper responses have been absent even in the presence of other biochemical or physiological changes.53 Serum copper is known to be altered by a number of factors not directly related to copper status. Concentrations are low in infancy and rise to adult levels over the first 4–6 months, or longer following a low birth weight. In adult women, serum copper concentration is generally higher than in men, and is further raised during pregnancy and by oestrogen treatments.54 There is also a normal diurnal variation with a slight peak in the morning. Plasma copper fluctuates with age, and is raised in a number of other conditions including exercise, rheumatoid arthritis, dilated cardiomyopathy and anticonvulsant chemotherapy. Between 60 and 95% of serum copper is associated with caeruloplasmin, so serum copper levels often mirror those of caeruloplasmin.11 Normal levels of serum or plasma caeruloplasmin protein are 180–400mg/ml.17 Like serum copper, caeruloplasmin has shown variable responses to marginal depletion. Its concentration and activity fall with severe copper deficiency and return to normal with copper repletion; but because of its role as an acute phase protein, caeruloplasmin concentration in the plasma reflects oxidative status more reliably than copper status. Copper depletion may be masked by caeruloplasmin elevated in response to exercise, infection or inflammation, liver disease, malignancy and MI.55 Like serum copper, normal caeruloplasmin values also vary with age and gender, and during pregnancy.23 Erythrocyte copper/zinc SOD concentration is normally 0.471 ± 0.067 mg/g protein.50 SOD activity has appeared in some studies to be more sensitive than caeruloplasmin to changes in copper status, while in other studies its activity has fallen with depletion but failed to respond to repletion.56 Copper/zinc SOD activity has been reported to rise in response to physical exercise.57 As an antioxidant enzyme, SOD is likely to respond to conditions of oxidative stress. A further complicating factor is that SOD measured in erythrocytes is unlikely to reflect shortterm changes in dietary intake owing to the 100-day lifetime of erythrocytes. Leucocyte copper has been found to decline along with other indices of copper status.51 Platelet copper has been shown to decline with copper depletion and to recover with copper repletion.56 However, there are not yet sufficient experimental data to confirm the validity of leucocyte or platelet copper as indicators of suboptimal copper status. DAO has been indicated in some studies of copper depletion as a possible marker of copper status.58 Its measurement is currently difficult because of its extremely low levels in plasma. Furthermore, its use as an indicator may be limited because it is elevated during pregnancy, after heparin treatment and in some conditions of intestinal damage. A valid functional index must respond sensitively, specifically and predictably to changes in the dietary supply or stores of copper, and must be measurable and accessible for measurement. Validation of a candidate marker would require demonstration of a cause and effect relationship between the marker and copper status and also, ideally, between copper status and health measures.59 126 The nutrition handbook for food processors

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