Invited review
Risks and benefits of copper in light of new insights of copper homeostasis

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Abstract

Copper is an essential micronutrient involved in a variety of biological processes indispensable to sustain life. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Potent, efficient regulatory mechanisms control copper absorption in the digestive tract and copper biliary excretion; absorption ranges between 12 and 60% in humans, depending on Cu intake, presence of other factors in the diet that may promote or inhibit its absorption and on the copper status of the individual. Current evidence suggests that copper deficiency may be more prevalent than previously thought, while copper toxicity is uncommon under customary daily life conditions. Menkes syndrome and Wilson disease are genetic conditions associated with severe copper deficiency and severe copper toxicity, respectively. Effects of milder degrees of copper deficiency and excess copper exposure are not well described, mainly due to lack of sensitive and specific indicators; serum copper concentration and ceruloplasmin are the most frequently used indicators, but they only detect rather intense changes of copper status. Of the many proteins assessed as potential markers of copper status the chaperone of Zn–Cu superoxide dismutase (CCS1) has yielded promising results; data on its performance under different conditions are needed to confirm its use as an indicator of early copper deficiency. Defining copper requirements and upper safe limits of consumption (UL) is a complex process since there are adverse health consequences from both copper deficiency and copper excess (U shape curve). The regulatory framework for risk assessment of essential trace elements introduced by the International Programme on Chemical Safety (IPCS) has proposed a homeostatic model to determine the Adequate Range of Oral Intake (AROI) of essential trace elements; the nadir of the resulting U shape curve serves to define the AROI. At this range of intake physiological mechanisms allow for normal homeostasis and basically, there are no detectable adverse effects. At present, Recommended Dietary Intakes (DRIs) and Adequate Intakes (AIs) are used to recommend copper intakes at different ages and life situations. Evidence obtained in humans and non-human primates presented here suggest that current copper UL should be re evaluated. Developing the scientific basis for a copper UL and evaluating the relevance of copper deficiency globally are future key challenges for copper researchers.

Introduction

Copper is an essential micronutrient that forms part of several proteins involved in a variety of biological processes indispensable to sustain life [1], [2], [3], [4], [5], [6]. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Nutritional recommendations for specific subgroups at risk of suffering adverse effects from moderate copper deficiency or excess is a challenge that requires better knowledge of relevant early changes associated with high and low copper intakes. Essentiality and toxicity of copper are well characterized by two rare genetic conditions: Menkes disease and Wilson disease. The former results in severe deficiency [7], [8], [9], with the primary outcome usually being death, while the latter results in severe liver damage (cirrhosis) due to copper induced oxidative damage in liver and other tissues [10], [11], [12]. However, when the degree of deficiency or copper excess is not so intense the effects are unclear; a major reason for this is that available copper indicators are not sensitive and specific to detect early changes [13], [14], [15].

During the last two decades there has been concern among investigators and health regulators for the possibility that the exposure to the customary amounts of copper encountered in daily life (mainly from drinking water and food) may represent health risk for special groups in the population, especially for children [16] and individuals that are heterozygotes for the mutated ATPase, copper transporting, beta polypeptide (ATP7B), also known as Wilsons disease protein (estimated at 1:90) [17]. Though the effects that copper deficiency has on the population can be important, up to date this situation is not well characterized. In this paper we will review relevant aspects of whole body copper metabolism, cell and molecular basis for copper homeostasis. We will also discuss the evidence available on adverse effects derived from copper deficiency and copper excess, the need for biomarkers that help defining the early adverse effects of high and low copper on human health. Finally, we will review the evidence supporting current dietary recommendations including upper safe limits of copper intake.

Section snippets

Copper homeostasis and metabolism

Copper is absorbed mainly in the duodenum, although it is thought that some absorption takes place in the stomach and in the distal part of the small intestine [18]. It is estimated that the efficiency of copper absorption in humans ranges between 12 and 60% [19] depending on copper intake, presence of dietary factors that may promote or inhibit its absorption and the copper status of the individual. As shown by studies using stable isotope techniques, the fractional absorption of copper

Copper intake from food

In humans, access to copper from the environment is limited. Food and drinking water and copper-containing supplements are the main sources of copper; acquisition of the metal through inhalation or dermal routes is negligible. Copper content in the diet varies widely because foodstuffs differ greatly in their natural copper content [52]. Factors such as season (copper concentration is higher in greener portions), soil quality, geography, water source and use of fertilizers influence the final

Copper deficiency

The idea of supplementing groups at risk for copper deficiency has been discussed for some time now during international venues. Potential beneficial effects of copper on bone health and cardiovascular disease are currently being investigated [65], [66], [67]. If these effects are confirmed, supplementing copper to vulnerable groups is an attractive strategy that deserves further evaluation. Nevertheless, studies will be required to assess how efficiently the biliary system will adapt to higher

Copper toxicity and adverse effects due to copper excess

Toxic effects associated with copper in individuals not suffering Wilson disease are rare. Acute toxicity has been widely described in individuals that by accident or with suicidal intention ingest large doses of copper. Depending on the copper dose, a lack of adequate and timely treatment may be fatal [83], [84], [85], [86], [87], [88]. At lower doses, early adverse responses after acute exposure to copper originate in the stomach and cause vagal stimulation, eliciting a reflex response of

Need for new biomarkers

The data discussed indicate that despite the wealth of knowledge gained in recent decades there is a clear need to improve our knowledge about early effects of both deficient copper intake and excess copper exposure. Copper status is tightly regulated, with potent mechanisms that downregulate intestinal copper absorption and upregulate biliary excretion within a rather wide range of exposure levels [31], [108]. As copper exposure or intake does not represent the body's ‘copper load’ at a given

Nutrient intake, requirements and recommendations

The concept of nutritional requirement has evolved over time. A nutritional requirement was defined by the World Health Organization, the Food and Agriculture Organization of the United Nations and the International Atomic Energy Agency (WHO/FAO/IAEA) Expert Consultation on Trace Elements in Human Nutrition and Health, as “the lowest continuing level of nutrient intake that, at a specified efficiency of utilisation, will maintain the defined level of nutriture in the individual” [124]. The

Risk assessment and safety considerations about copper intake

The basic premise of traditional trace element risk assessment is that it applies to toxic elements, which are not essential for life and have no function, such as lead. In these cases, reducing the recommended ingestion to zero represents the best option [136]. It is clear that this cannot be applied to essential minerals because both their deficiency and excess induce adverse health effects. To set an MRL for copper of 0.7 mg/d as done by SCF is an example of the dilemma posed by using the

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