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Copper is an essential mineral for human health and at the same time can be toxic, depending upon the amounts ingested. Copper is associated with bone health, immune function and increased frequency of infections, cardiovascular risk and alterations in cholesterol metabolism. Its metabolism is tightly intertwined with other microminerals and its deficiency is known to impair iron mobilisation, resulting in secondary iron deficiency. A pressing challenge in modern nutrition is to define both the copper dose and regimen of administration for safe human consumption; this is a difficult task because our knowledge about the limits of safe copper exposure (homeostasis), the consequences of moderate excess copper exposure and the indicators to detect early adverse effects are not well established. The article updates the knowledge of the early adverse effects derived from acute copper exposure, those associated with chronic copper exposure and discusses recent studies that explore potential indicators of early copper effects.
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608 Int. J. Environment and Health, Vol. 1, No. 4, 2007
Copyright © 2007 Inderscience Enterprises Ltd.
Copper in human health
Magdalena Araya*
Institute of Nutrition and Food Technology (INTA),
Universidad de Chile,
El Líbano 5524, Santiago, Chile
Fax: +56 2 221 4030
E-mail: maraya@inta.cl
*Corresponding author
Manuel Olivares and Fernando Pizarro
Institute of Nutrition and Food Technology (INTA),
University of Chile,
Macul 5540,
Casilla, Santiago 138-11, Chile
E-mail: molivare@inta.cl
E-mail: fpizarro@inta.cl
Abstract: Copper is an essential mineral for human health and at the same time
can be toxic, depending upon the amounts ingested. Copper is associated with
bone health, immune function and increased frequency of infections,
cardiovascular risk and alterations in cholesterol metabolism. Its metabolism is
tightly intertwined with other microminerals and its deficiency is known to
impair iron mobilisation, resulting in secondary iron deficiency. A pressing
challenge in modern nutrition is to define both the copper dose and regimen of
administration for safe human consumption; this is a difficult task because our
knowledge about the limits of safe copper exposure (homeostasis), the
consequences of moderate excess copper exposure and the indicators to detect
early adverse effects are not well established. The article updates the
knowledge of the early adverse effects derived from acute copper exposure,
those associated with chronic copper exposure and discusses recent studies that
explore potential indicators of early copper effects.
Keywords: copper; copper indicators; exposure; humans.
Reference to this paper should be made as follows: Araya, M., Olivares, M.
and Pizarro, F. (2007) ‘Copper in human health’, Int. J. Environment and
Health, Vol. 1, No. 4, pp.608–620.
Biographical notes: Magdalena Araya holds an MD obtained from the
University of Chile (1970) and a PhD from the University of Sydney, NSW,
Australia (1976). She is a Paediatric Gastroenterologist (1996). She joined the
Institute of Nutrition and Food Technology (INTA) of the University of Chile
in 1978, and in 1985, she was appointed Full Professor of the University of
Chile. She has been the Head of the Human Nutrition Department, Director of
the Teaching Department, and a Member of the Committee for Academic
Evaluation in the University of Chile. She has been a Consultant for
the Pan-American Health Organisation, the World Health Organisation and the
Chilean Commission for Copper (COCHILCO).
Copper in human health 609
Manuel Olivares studied medicine at the University of Chile (MD, 1968). He
pursued a Residency in Paediatrics at the University of Chile and Manuel
Arriarán Children’s Hospital, Santiago, Chile (1968–1971). He held a
haematology–oncology Fellowship at the Arriarán Children’s Hospital
(1969–1971), he was Attending Paediatrician and Head of the Blood Bank
Service at the Puerto Montt’s Regional Hospital, Chile (1971–1973) and
Attending Haematologist–Oncologist at the San Borja-Arriarán’s Hospital,
Santiago, Chile (1973–1986). He joined the Institute of Nutrition and Food
Technology (INTA) of the University of Chile in 1973 and since 1998, he has
been the Head of the Laboratory and Programme of Micronutrients at INTA. In
2001, he became a Full Professor of the University of Chile. He has been a
Consultant for the Pan-American Health Organisation, the World
Health Organisation, UNICEF, the International Atomic Energy Agency, the
Micronutrient Initiative and the Chilean Commission for Copper
(COCHILCO).
Fernando Pizarro received his degree in Medical Technology in 1974 from the
University of Chile where he has worked since graduation. In 1980, he received
a post-graduate Fellowship from the Instituto Venezolano de Investigaciones
Cientifica (IVIC – Venezuelan Institute for Scientific Investigations) on the use
of radioactive isotopes in research. In 1990, he was named a Visiting Fellow to
the Centres for Disease Control and Prevention in Atlanta, Georgia where he
worked on epidemiological techniques to study nutritional anaemias. Currently,
as an Associate Professor at the Institute of Nutrition and Food Technology
(INTA) of the University of Chile, he studies the role of microminerals in
human health. He has been a Consultant for the International Atomic Energy
Agency on several occasions.
1 Introduction
Currently, that a large segment of the world population consume adequate amounts of
macronutrients has not led to an improvement of the global nutritional situation; instead,
it has made evident the relevance of micronutrients, including minerals like copper. This
is an interesting metal because is an essential and at the same time can be toxic,
depending upon the amounts ingested. Copper is essential because it is a component in
several proteins indispensable for life. Copper deficiency has been associated with bone
malformation during development (Allen, Manoli and LaMont, 1982), and as a
contributory factor to osteoporosis in adults (Conlan, Korula and Tallentire, 1990). It has
also been associated with altered immune responses and increased frequency of
infections (Bonham et al., 2002). Marginal copper deficiency may participate in increased
cardiovascular risk (Uriu-Adams and Keen, 2005) and alterations in cholesterol
metabolism (Rayssiguier et al., 1993). Copper metabolism is tightly intertwined with
other microminerals and its deficiency is known to impair iron mobilisation resulting in
secondary iron deficiency.
610 M. Araya, M. Olivares and F. Pizarro
Should these evidences be confirmed it is likely that copper supplementation becomes
a part of the health programs aimed at protecting high risk groups. In addition,
self-administering mineral supplements is a growing practice in the population and
creates the need to protect the population against copper excess. All this makes necessary
that both the copper dose and regimen of administration are defined for safe human
consumption, but this is difficult to accomplish because our knowledge about copper
metabolism and the consequences of moderate excess copper exposure are restricted: the
limits of copper homeostasis (or range of safe exposure) is not clear, the early adverse
effects due to excess copper have not been defined, and the indicators to detect early
adverse effects are not available. In the following sections, we will briefly review our
knowledge about copper homeostasis, the acute and chronic effects of copper and the
state of the art about potential indicators of early copper effects.
2 Copper handling in homeostasis
Classic studies of copper homeostasis in adult men showed that when copper intake was
between 0.8 and 7.5 mg day-1, no significant changes were measured in plasma copper,
ceruloplasmin, Cu–Zn–Superoxide Dismutase (SOD) activity in erythrocytes and urinary
copper. But when intake was 0.38 mg day1, these indicators diminished to increase again
after a repletion period (Turnlund et al., 1989). The adaptive response seems to be more
efficient when copper content in the diet is poor (Turnlund, Keen and Smith, 1990).
In children, the evidence is scarce; Olivares, Pizarro and Speisky (1998) randomly
assigned healthy infants (n = 128) to receive drinking water with either <0.01 mg l1
(|50 Pg kg1 per day) (n = 48) or 2 mg l1 of copper (|150 Pg kg1 per day) (n = 80) from
3 to 12 months of age. Serum copper, ceruloplasmin, SOD, erythrocyte metallothionein,
bilirubin, transaminases and gamma glutamyl transferase were measured at ages 6, 9 and
12 months. Children grew normally and all biochemical parameters remained normal
along the period of study (Olivares, Pizarro and Speisky, 1998). In another study, the
same authors (Olivares et al., 2002) assessed copper absorption using 65Cu in 39 infants
(1–3 months of age) that received in a controlled way 80 Pg kg1 per day of copper
supplementation (as CuSO4) for 14 days. The range of intakes studied was two- to
threefold higher than the most recent adequate intake defined by the Food and Nutrition
Board/National Academy of Sciences for one month and 1.2- to 2-fold above the
adequate intake for 3-month-old infants (Institute of Medicine, Food and Nutrition
Board, 2001).
Results showed that 80% copper was retained at both ages, with no relation to copper
supplementation. This was interpreted as suggesting that either at these concentrations
regulatory mechanisms were not triggered or that at these ages regulatory mechanisms
are not efficient (Olivares et al., 2002). More recent studies in Maccacus rhesus assessed
the absorptive response to bottle-feeding containing 900 Pg kg1per day (estimated
copper load in children that developed cirrhosis in India) administered from birth to six
months of age. By using 67Cu, retention was demonstrated to diminish from 75
(in controls) to 25% at one month and to 12% at six months (Araya et al., 2005), showing
that down regulation of copper absorption is present since early after birth.
Copper in human health 611
3 Effects of acute copper exposure
Acute effects due to single, short-term copper exposure result in gastrointestinal
manifestations. When copper reaches the stomach bound to dietary components
(proteins, lipids and others) it is less available to interact with the mucosa than ionic
copper, which explains why copper toxicity from food intake is rare and that the highest
likelihood of appearance of gastrointestinal responses derives from ionic copper present
in fluids (mainly water). Most reports of acute copper toxicity represent suicidal attempts
(with ingestion of up to 100 or more grams of copper salts, mainly sulphate) or
consumption of accidentally contaminated drinks (tea and coffee made from water from
copper lined boilers or kettles or soft drinks dispensed through copper containing spouts).
In most cases, copper induces acute nausea, vomiting and diarrhoea, but multiple organ
failure, shock and death have been described in individuals that ingest very high doses.
Early acute responses originate in the stomach; copper ions stimulate receptors, which
in turn stimulate the vagus nerve eliciting a reflex response of nausea. When the copper
dose is somewhat larger, in addition to the vagal response there is direct stimulation of
the hypothalamic vomit centre triggering retching and vomiting (Wang and Borison,
1951). The mechanism to explain diarrhoea associated to larger copper doses is not well
understood. In recent years, the possibility that low copper concentrations (such as those
contained in drinking water) may induce acute adverse effects in humans was raised and
quickly became a concern of health authorities and regulators (Araya, Koletzko and
Uauy, 2003). Most natural drinking water has copper concentrations not exceeding a few
milligrams per litre, but variations of water pH, oxygen and oxidative agents able to bind
copper will modify the copper availability in water such that soft, acidic water, especially
when going through new copper pipes, may deliver higher amounts of copper.
During the last ten years, a series of studies characterising the effects of acute copper
exposure were conducted at the Institute of Nutrition and Food Technology, University of
Chile. They were experimental clinical trials in healthy adults (women and men), who
provided informed consent prior to the protocols. The Institutional Review Board
approved these. A ‘worst scenario’ design was used in order to maximise the chance to
obtain responses in a controlled design. Different types of water (tap water, mineral, still
waters), copper salts (copper sulphate, copper gluconate and copper oxide), copper doses
(1–12 mg Cu l1) and populations (from Chile, USA, Ireland, China) were tested
(Araya et al., 2001; Gotteland et al., 2001; Olivares et al., 2001; Pizarro et al., 2001;
Zacarías et al., 2001; Araya et al., 2003a,b).
Results of this series of clinical assays led to build a family of curves that describe the
effects observed (Figure 1). Nausea was the first and most frequent finding after copper
exposure; the concentration at which nausea increased significantly in the experimental
individuals was 4 mg l1. The mean capacity to test copper in the solution ranged from
2.6 to 3.4 mg Cu l1, depending upon the water quality and the salt ingested; early effects
were detected first in the stomach and not in the intestine. Since these results came from
experimental assays, they were subsequently re-assessed in a ‘daily life’ situation, i.e. a
community study. For two months, healthy adults used ‘experimental’ waters to drink
(water proper and to prepare tea, coffee, soups and meals that require water for their
preparation; Araya et al., 2004). This study confirmed results previously obtained and led
to calculate a No observed Effect or NOEL for water (Figure 2). It was also interesting to
find that the risk of developing acute symptoms was greater in women than in men and
that in both sexes the responses diminished along time, strongly suggesting an adaptive
612 M. Araya, M. Olivares and F. Pizarro
phenomenon (Figure 3). Further, to assess differences derived from cultural factors, these
studies were complemented with two international protocols that included participants
from three and four different countries. The first one was reported in 2001 and
administered copper dosing (as copper sulphate) to healthy adults in a single 200 ml
bolus of distilled-deionised water once per week in a double-blind controlled study. In the
second international study the copper salt was maintained and the vehicle to administer
copper was a laboratory generated water source that could be consistently duplicated all
three sites of study (Grand Forks, ND, USA; Santiago, Chile; and Coleraine, Northern
Ireland, Shanghai, China; Araya et al., 2003a). Using a 3 u 3 factorial (volume u dose)
design, a total of 269 volunteers were given 100, 150 or 200 ml of bottled drinking water
with 0.4, 0.8 or 1.2 mg of copper (Cu) as the sulphate salt once each week. Two
additional doses (0 and 1.6 mg Cu) were added at the 200 ml volume to determine a dose-
response relationship and corroborate previously reported results. Nausea was confirmed
to be the earliest and most prevalent symptom reported (water volume p< 0.032, copper
dose p < 0.0001 and water volume u copper interaction is p < 0.97). As Cu dose
increased, the incidence of nausea increased and as volume increased, the effect of Cu-
induced nausea decreased. At 200 ml, the reported incidence of nausea significantly
increased at 1.2 mg Cu (6 mg Cu l1), indicating a NOAEL of 0.8 mg Cu (4 mg Cu l1)
for adult females.
All together, these investigations determined the human acute NOAEL for Cu in
water, and provided evidence in humans that help establishing the safe concentrations of
Cu in drinking water. WHO guideline for drinking water was set at 2 mg l1, as a figure
considered safe for chronic population exposure (WHO, 2003). Yet, it is worth
mentioning that a USA NAS expert group asked to examine whether the USA limit of
1.3 mg l1 of copper in water could be raised to 2 mg l1, following the WHO safe level,
maintained the existing level because the experts could not reach agreement
(National Research Council, 2000; Food and Nutrition Board – National Academy of
Medicine, 2002). The reason for this was that although the data about the acute effects
of copper exposure is robust, the knowledge of chronic exposure to excess copper is still
insufficient.
Copper in human health 613
Figure 1 Gastrointestinal response curves to acute copper exposure
Figure 2 Subjects that reported one or more adverse gastrointestinal outcomes
(•) or nausea alone (o) as a function of copper concentration
614 M. Araya, M. Olivares and F. Pizarro
Figure 3 Risk of developing symptoms in women and men after 1, 5 and 9 weeks of
copper exposure
Dotted lines represent CI, and curves were built by counting process analysis.
Copper in human health 615
4 Effects of chronic copper exposure
As for copper deficiency, effects associated with excess copper are best described in a
severe disease state, in this case Wilson disease, an autosomic, recessive genetic
condition (Wilson, 1912) due a the mutation of the Wilson protein (enzyme ATPase 7B;
Bull et al., 1993). The gene is expressed mainly in the liver; its defect results in the
accumulation of copper in the liver because it cannot be incorporated to ceruloplasmin
and exported into the bile system. The effects of chronic exposure to excess copper are
badly understood in individuals that do not suffer the genetic disease. Neither the copper
dose nor the time of exposure necessary to induce adverse effects is known. The Food
cue Study showed that copper intakes of up to 6–7 mg Cu day1 are not associated with
adverse effects (Turley et al., 2000; O’Connor et al., 2003). There is only one case
reported in the literature of a man that was apparently healthy that self-administered
30 mg Cu day1 for two years and increased the dose to 60 mg Cu day1 during the third
year, dose that is equivalent to 400–900 Pg kg1 per day (the recommended WHO intake
for adults is 50 Pg kg1 per day). He developed severe liver disease, required liver
transplant and survived. Although anecdotal, this is the only case of chronic toxic effects
reported in a non-Wilson case (O'Donohue et al., 1993). A few clinical conditions are
thought to be related to chronic excess copper, but it is not clear whether individuals that
suffer them have some specific genetic polymorphism that render them more susceptible
to copper. These conditions are Indian Childhood Cirrhosis (ICC), Idiopathic Cirrhosis
and Idiopathic Toxicosis. ICC was described in India, in small children who died of liver
cirrhosis before five years of age; copper and bronze utensils to cook and keep food were
common in the area. Since dwellers were advised to avoid using these utensils, the
disease disappeared.
Studies of the effects of chronic exposure to excess copper are scarce, especially in
humans due to ethical constraints. In the last few years, studies conducted at INTA using
human models have assessed the limits of copper homeostasis, shedding light about
several factors that influence responses to variations in copper exposure (Araya et al.,
2003c, 2005, 2006; Méndez et al., 2004; 2005; Muñoz et al., 2005). In healthy adults, a
transactional study assessed healthy individuals after nine weeks exposure to 0 to 6 mg
Cu l1 of drinking water; actual daily copper ingestion through water was 0–12 mg Cu in
some individuals. None of the variables measured changed significantly, including
indicators of copper, iron, zinc status, and liver function
(Araya et al., 2003b). In a subsequent study, healthy participants received controlled
exposure to 10 mg of copper (CuSO4) for two months, administered as an enteric-coated
capsule ingested at mid morning; this did not induce health complaints on the part of the
participants (Araya et al., 2005). During the first days of study, some participants
reported nausea shortly after copper administration; however, after suspending copper
dosing for 48 hour, these individuals remained in the trial because they did not reported
nausea again. This finding coincided with the results obtained during the ‘acute’ studies,
where responses dramatically and progressively decreased after the second week of
study. In both cases, the reduction in reporting nausea was interpreted as due to an
adaptation phenomenon. Since ceruloplasmin is a relevant protein in diagnosing
disturbances of copper metabolism such as Wilson disease (low concentrations of
serum/plasma ceruloplasmin strongly suggest this condition), in this protocol participants
were selected among those representing the highest and lowest values of ceruloplasmin
616 M. Araya, M. Olivares and F. Pizarro
(protein) concentrations in a distribution curve of 800 individuals tested. The rationale
was that those whose ceruloplasmin serum concentration was in the low ‘tail’ in the curve
could behave differently because, as a group, they would include heterozygote
individuals for Wilson disease. The two extreme groups proved to be significantly
different and serum ceruloplasmin concentration and sex were the two main variables
associated with the results (principal component analysis and linear discriminant analysis;
Araya et al., 2005). All three aminotransferases increased significantly after two-month
loading in women and in men (ANOVA repeated measures p = 0.0013), but the increases
were well below the figures used to diagnose liver dysfunction, in all affected individuals
there was only one enzyme showing the increased value and in all cases the enzyme
activity returned to basal figures after 12 months. In addition, glutathione measured in
Mononuclear Cell (MNC) increased significantly after the two-month copper dosing
(ANOVA repeated measures p = 0.0013). Erythrocyte Zn–Cu–SOD activity, serum
homocysteine, serum Cu, Fe and Zn concentrations and ceruloplasmin (protein) did not
change. Abundance of Cu–Zn–Superoxide Dismutase (CCS) mRNA transcripts in MNC
significantly decreased, suggesting that this protein could be a marker of early changes in
copper status and that deserves further assessment (Suazo et al., 2007).
5 Biomarkers for copper status
The data analysed in previous paragraphs indicate a clear need for more investigation to
further improve our knowledge about early effects of excess copper exposure. Copper
status within the body is tightly regulated, with potent mechanisms that downregulate
copper uptake in the duodenum and upregulate biliary excretion depending upon the
exposure (copper in diet) (Turnlund et al., 1989, 1998; Turnlund, Keen and Smith, 1990;
Harvey et al., 2003; Araya et al., 2005). Thus, copper exposure or intake does not
represent body ‘copper load’, copper status cannot be estimated by the exposure or intake
and thus, the only indicator of copper load is the copper content in the liver (Hambidge,
2003; Araya et al., 2003a). The recent article by Danzeisen et al. (2007) reviews in detail
the problems encountered in trying to identify copper biomarkers.
The most frequently used blood markers of copper metabolism are serum
concentration of copper and ceruloplasmin, which are useful tools to diagnose Menke’s
and Wilson’s disease. However, these markers are not sensitive enough when changes are
of lesser magnitude. SOD, diaminoxidase and lysil oxidase activities have been proposed
as potential markers of early deficiency (Kehoe et al., 2000a,b), but their sensitivity
remains to be demonstrated. On the excess side, no markers have been proposed.
In the last several years, others and we have tested a series of potential indicators of
early effects in different controlled conditions. Many proteins and enzymes present in
blood have been measured in different conditions, but all these studies have failed to
identify a potential indicator of early effects of copper (Araya et al., 2005). This made the
search for indicators moved to the area of cell biology, searching for specific cell
responses detectable in cells that may be easily accessible. This line of work is proving
fruitful; recent studies in rats and mice show that the chaperone protein of CCS
significantly and specifically increases in copper deficient rats (Prohaska and Brokate,
2001; Bertinato, Iskandar and L'Abbe, 2003; Prohaska, Broderius and Brokate, 2003;
Prohaska et al., 2003a; West and Prohaska, 2004; Iskandar et al., 2005), while our studies
in humans show that CCS significantly and specifically decreases in healthy adults that
Copper in human health 617
received 8 mg Cu day1 for 6 months or 10 mg Cu day1 for 2 months (unpublished).
Although these are the first positive results obtained there is still a long way before
demonstrating whether this protein is a useful indicator of early effects of copper
in humans.
6 Conclusions
There are relevant aspects of copper metabolism and the effects of this metal on human
health that are not clear. However, the state of the art permits drawing some conclusions:
xA pressing challenge in modern nutrition is to define both the copper dose and
regimen of administration for safe human consumption. A first concern arises from
the potential need of supplementing with copper certain subgroups of population.
Copper is associated with bone health, immune function and increased frequency of
infections, cardiovascular risk and alterations in cholesterol metabolism. In addition,
its metabolism is tightly intertwined with other microminerals and its deficiency is
known to impair iron mobilisation, resulting in secondary iron deficiency. If these
effects are demonstrated it is likely that copper supplementation at levels close or
above the upper limit may be proposed as a strategy for subgroups with
polymorphisms that render them more vulnerable to copper deficiency. A second
concern about the limits of copper homeostasis originates from self-administration of
micromineral and vitamin supplements, which has become a common practice in
western countries.
xTo set the limit of safe copper consumption is difficult because there are potent,
redundant mechanisms that tightly regulate (intestinal) absorption and (biliary)
excretion.
xAcute effects due to single, short-term copper exposure take place in the digestive
tract, mainly the stomach and small intestine. After extensive studies WHO set 2 mg
Cu l1 of drinking water as a figure considered safe for chronic population exposure.
xEffects derived from chronic exposure to copper are best described in Wilson
disease, a severe, autosomic, recessive genetic disease. However, chronic effects
resulting from excess copper are not clear in individuals that do not carry the
mutated gene of the Wilson protein.
xThe main problem to improve our knowledge on these issues comes from the lack of
specific and sensitive indicators able to detect early copper effects and predict risk of
damage, mainly in liver. Copper exposure or intake does not represent body ‘copper
load’, copper status cannot be estimated by the exposure or intake and thus, the only
indicator of copper load is the copper content in the liver.
xRecent studies revealed that CCS, the chaperone of SOD, responds in a sensitive and
specific manner to changes in copper uptake/intake. This promising finding is
currently being investigated to decide whether this may be a marker of early changes
in copper status.
618 M. Araya, M. Olivares and F. Pizarro
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... Therefore, controlling the Cu content in crops is of high importance to protecting human health. Copper is an important factor to affect the synthesis of chlorophyll molecules as well as some enzymes involved in physiological and biochemical processes of various plants (Epstein 1972;Yruela 2005;Araya et al. 2007;Dey et al. 2014), such as respiration, electron transport chain in photosynthesis, and signal transduction, etc. (Yruela 2009;Kabata-Pendias 2010;Feigl et al. 2015). In recent years, Cu accumulation in crops has increased due to industrial pollution and the overuse of Cu-containing sterilizers and pesticides (Mackie et al. 2012;Ballabio et al. 2018). ...
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