Scientific Opinion on Dietary Reference Values for copper

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Article
Panel on Dietetic Products, Nutrition and Allergies
EFSA Journal
EFSA Journal 2015;13(10):4253 [51 pp.].
doi
10.2903/j.efsa.2015.4253
Panel members at the time of adoption
Jean Louis Bresson, Barbara Burlingame, Tara Dean, Susan Fairweather-Tait, Marina Heinonen, Karen Ildico Hirsch-Ernst, Inge Mangelsdorf, Harry McArdle, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Dominique Turck, Hendrik Van Loveren, Marco Vinceti and Peter Willatts.
Acknowledgements

The Panel wishes to thank the members of the Working Group on Dietary Reference Values for Minerals: Peter Aggett, Carlo Agostoni, Susan Fairweather-Tait, Marianne Geleijnse, Ambroise Martin, Harry McArdle, Androniki Naska, Hildegard Przyrembel and Alfonso Siani for the preparatory work on this scientific opinion and EFSA staff: Anja Brönstrup, José Ángel Gómez Ruiz and Fanny Héraud for the support provided to this scientific opinion.

Contact
Type
Opinion of the Scientific Committee/Scientific Panel
On request from
European Commission
Question Number
EFSA-Q-2011-01210
Adopted
23 September 2015
Published
21 October 2015
Affiliation
European Food Safety Authority (EFSA), Parma, Italy
Note
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Abstract

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for copper. Owing to the absence of appropriate biomarkers of copper status and the limitations of available balance studies, the Panel was unable to derive Average Requirements (ARs) and Population Reference Intakes (PRIs). Hence, Adequate Intakes (AIs) were defined based on mean observed intakes in several European Union (EU) countries, given that there is no evidence of overt copper deficiency in the European population. Data from balance studies were used as supportive evidence. For adults, AIs of 1.6 mg/day for men and 1.3 mg/day for women are proposed. For children, AIs are 0.7 mg/day for children aged 1 to < 3 years, 1 mg/day for children aged 3 to < 10 years, and 1.3 and 1.1 mg/day for boys and girls aged 10 to < 18 years, respectively. For infants aged 7–11 months, based on mean observed intakes in four EU countries, an AI of 0.4 mg/day is proposed, which is supported by upwards extrapolation of estimated copper intake in exclusively breast-fed infants. For pregnant women, an increment of 0.2 mg/day is estimated to cover the amount of copper deposited in the fetus and the placenta over the course of pregnancy and in anticipation of the needs for lactation, and for lactating women the same increment is estimated to cover the amount of copper secreted with breast milk. Thus, for pregnant and lactating women, the Panel derived an AI of 1.5 mg/day.

Summary

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on Dietary Reference Values (DRVs) for the European population, including copper.

Copper is an essential micronutrient required for electron transfer processes. It is a central component of many enzymes, including those involved in neurotransmitter synthesis, in energy metabolism and in collagen and elastin cross-linking.

The main food group contributing to the copper intake of all population groups except infants is grains and grain-based products. Another important contributor to copper intake is the food group meat and meat products.

Based on balance studies and other studies, the Panel considered that copper absorption from the diet is around 50 % for all age and life-stage groups.

The primary site of copper absorption is the upper small intestine. Uptake is through a carrier protein, Ctr1, and once in the cell, the copper is directed towards its target via one of a series of chaperone proteins that ensure the metal is present in a non-toxic form. In the gut, the major pathway of transport into the portal circulation is via a Cu-ATPase, ATP7A. In the portal circulation, copper is bound to histidine, albumin or possibly transcuprein and transported to the liver, where it is incorporated into ceruloplasmin, which is then secreted into the systemic circulation. It is taken up into the liver through Ctr1 and, if it is not incorporated into ceruloplasmin, it is stored as metallothionein. Excess copper is excreted in bile after transport across the apical membrane of the hepatocytes via another ATPase, ATP7B. This copper is not reabsorbed. In humans, between 80 and 95 % of the copper in plasma is ceruloplasmin, with the remainder being a low-molecular weight form. It is not certain which of these two pools, ceruloplasmin or low-molecular weight copper complexes, makes the major contribution to uptake by organs other than the liver, although it is more likely to be low-molecular weight copper complexes than ceruloplasmin, with the latter playing a major role in the release of iron from the liver.

If the dietary supply of copper is less than adequate, the body upregulates transfer systems to make more copper available. If these are not able to rectify the problem, the result is copper deficiency. Clinical symptoms are not common in humans, and generally are seen as a consequence of mutations in the genes involved in copper metabolism. Symptoms of copper deficiency include anaemia that is refractory to iron supplementation, neurological defects and cutis laxa (“floppy” skin). There are also changes in hair colour and texture, and an increased risk of aneurysm as a consequence of impaired collagen and elastin synthesis.

The Panel noted that there are no biomarkers of copper status that are sufficiently robust, sensitive and specific to be used for deriving requirements for copper. The Panel also considered whether health outcomes can be used to derive DRVs for copper. However, it was concluded that the limited evidence available on copper intake and cardiovascular disease-related outcomes and cancer cannot be used for setting DRVs for copper.

There have been several balance studies examining the relationship between copper intake and losses in men, but few in women and children. Studies differed with regard to experimental conditions, and many studies had limitations and their results varied. Nevertheless, the Panel considered that they may be used, for men at least, in conjunction with data on observed intakes in the European Union (EU) to inform the setting of DRVs for copper.

The Panel decided to derive Adequate Intakes (AIs) based on observed intakes in several EU countries. Mean copper intakes in eight EU countries range from 1.27 to 1.67 mg/day in men aged 18 years and older and from 1.15 to 1.44 mg/day in non-pregnant women aged 18 years and older. The Panel noted that midpoints of ranges for intake estimates in three age groups of adults and in both sexes are in good agreement with medians, for the corresponding sex and age groups, of the average intakes estimated per survey. The Panel noted that there is, at present, insufficient evidence to set different DRVs according to age in adults, but decided to set different AI values for women and men, as intakes are lower for women. For men, based on observed intakes and taking into account that zero copper balance was reported at a copper intake of approximately 1.6 mg/day in men, the Panel proposed an AI of 1.6 mg/day. For women, based on observed intakes, the Panel proposed an AI of 1.3 mg/day.

For infants aged 7–11 months, based on results from four surveys in infants, the Panel proposed an AI of 0.4 mg/day. The Panel noted that upwards extrapolation by allometric scaling of estimated copper intake in exclusively breast-fed infants aged 0–6 months results in an estimated intake at 7–11 months of 0.36 mg/day, which supports the AI of 0.4 mg/day.

For boys and girls aged 1 to < 3 years, considering the absence of a strong basis for a distinct value according to sex and the distribution of observed mean intakes of 0.60–0.86 mg/day in boys and 0.57–0.94 mg/day in girls, the Panel selected the midpoint of average intakes and set an AI of 0.7 mg/day. In children aged 3 to < 10 years, mean observed intakes range from 0.92 to 1.44 mg/day in boys and from 0.82 to 1.30 mg/day in girls. The Panel considered the distribution of the observed mean intakes and set an AI of 1.0 mg/day for boys and girls aged 3 to < 10 years. In children aged 10 to < 18 years, mean observed intakes range from 1.16 to 1.59 mg/day in boys and from 0.98 to 1.41 mg/day in girls. Considering the rather large differences in intakes of boys and girls, the Panel decided to set separate AI values. Taking into account the distribution of observed average intakes, the Panel proposed an AI of 1.3 mg/day for boys and of 1.1 mg/day for girls aged 10 to < 18 years.

In pregnancy, taking into account the requirement for the developing fetus and its placenta, the additional requirement for copper was calculated to be 0.06 mg/day. Considering that about 50 % of ingested copper is absorbed, and in anticipation of copper requirements for lactation, the Panel proposed that the AI of non-pregnant women be increased by 0.2 mg/day during pregnancy.

For lactation, taking into account that copper absorption is about 50 %, an increment of 0.56 mg/day would be required to compensate for copper losses in breast milk. The Panel assumed that this can be mitigated in part by the increased AI in pregnancy. Thus, the Panel proposed that the AI of non-pregnant women be increased by 0.2 mg/day during lactation.

Keywords
copper, balance, observed intake, Adequate Intake, Dietary Reference Value
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Number of Pages
51