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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics
Type of information:
other: review
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This document is a peer-reviewed expert review.

Data source

Reference Type:
Copper Metabolism and Copper Requirements in the Pregnant Mother, Her Fetus, and Children. A Critical Review.
Ralph, A. and McArdle, H.
Bibliographic source:
International Copper Association, Ltd., New York.

Materials and methods

Test material

Constituent 1
Reference substance name:
Cu 2+ from several forms of copper compounds
Cu 2+ from several forms of copper compounds

Results and discussion

Applicant's summary and conclusion

Executive summary:

In Chapter 1 we introduce the importance of copper as an essential element to all aerobic life, including humans. The relevance to human health is explained by the involvement of copper in many enzymes, which are crucial to a wide range of physiological functions. Copper is also involved in gene transcription and in the immune system. In addition, copper deficiency is implicated in heart disease.


In Chapter 2 we examine the sources of dietary copper from food and water. We include data on the copper content of foods and explain why it varies. We consider the validity of dietary assessments and include tables of dietary copper intake from many regions of the world. The average adult dietary intake of copper is 1.5 mg/d in omnivores, and 2.5 mg/d in vegetarians. We report on copper in the water supply, and the possibility of copper leaching from copper pipes and the risk of adverse effects of drinking too much copper in solution.


Chapter 3 is an overview of copper metabolism that begins with whole body physiology of copper and develops to look at some of the latest research on intracellular transport and regulation. We note a remarkable homeostasis at whole body, organ, and cellular level with mechanisms to conserve copper when supply is limited and to reduce uptake, sequester, or excrete it when supply is high.


Chapter 4 examines genetic disorders and other conditions that affect copper metabolism. Menkes syndrome and Wilson's disease are characterized by a defect in genes that control copper distribution to the tissues. In Menkes patients we see the serious consequences of copper deficiency with failure of the copper-containing enzymes to function normally, resulting in early death. The Wilson's disease defect causes accumulation of copper in the liver. The effects are those of chronic copper toxicity, but treatments are available. Both conditions have serious neurological consequences. These conditions help our understanding of the normal control of copper transport and metabolism and its relevance to health.


In Chapter 5 we consider pregnancy and fetal development. We describe the remarkable adaptation of maternal metabolism with a rise of plasma copper and ceruloplasmin concentrations that do not seem to require an increase in maternal intake of copper. Copper deficiency in pregnancy is rarely due to insufficient dietary intake, but may occur for a variety of other reasons. There are considerable animal data, but limited human data, to indicate that copper deficiency in pregnancy is associated with birth defects and low birth weight. While overt deficiency is rare, the possible widespread, mild, sub-clinical copper deficiency is more likely. We found no data on toxic effects of copper in human pregnancy. There is evidence that the placenta can regulate the transfer of copper from the mother to the fetus, but the mechanisms are not yet understood. Most of the copper in the fetus is accumulated in the latter half of pregnancy and stored in the liver.

In Chapter 6 we discuss the needs of the newborn infant, the growing child and adolescent. Premature and very-Iow-birth-weight infants are particularly at risk of copper deficiency because of the small liver and incomplete liver stores of copper. Copper absorption is higher from breast milk than from infant formula, despite the low copper concentration. Copper deficiency is rare in breast-fed pre-term infants. Copper concentrations in human milk seem to be unrelated to maternal dietary intakes of copper and unaffected by a range of other variables. Maternal milk is a sufficient source of copper for about 4 months, but after that it is inadequate and weaning to a mixed diet provides adequate copper. Cow's milk contains very little copper and early weaning onto a diet of cow's milk or unsupplemented formula can result in copper deficiency. Malnourished children, those with infections, and those in a catch­up growth spurt are at risk of severe copper deficiency. Data suggest that most well-nourished children have adequate copper intakes but there is some evidence that recommended intakes are too low for rapid growth. Some adolescents may be at risk of marginal copper deficiency as reports indicate an average consumption below recommended intakes.


Chapter 7 examines some of the interactions that copper has with other dietary factors, especially minerals and other nutrients. Some of these factors, certain proteins, for example, enhance copper uptake, but minerals, particularly iron and zinc, hinder uptake. Many infant formulas, breakfast cereals, and prenatal vitamin and mineral supplements are fortified with iron and zinc but do not have any nutritionally Significant amount of copper. An inappropriate ratio of iron or zinc to copper can interfere with copper availability. Pregnant women and young children are particularly vulnerable. Those who take over-the-counter zinc supplements may be at risk of copper deficiency.


In Chapter 8 we compare the techniques for measuring copper status. Severe deficiency can be detected by laboratory-based clinical indicators, such as serum or plasma copper and ceruloplasmin concentrations. Other techniques are based on the activity of the copper-containing enzymes and the response of components of the immune system. A different approach to measuring marginal copper status has been suggested involving various functional tests, such as blood pressure, cardiac function, and sleep patterns. There is a need for specific and sensitive indicators of marginal copper intakes that are clearly related to health effects. Only when these are available can the extent and significance of marginal copper deficiency be quantified. Research, using a variety of markers of status, indicates that adults with intakes below 1 mg/d may be at some minor health risk.


Chapter 9 examines some of the existing recommendations and guidelines concerning copper intake in humans, and explains the rationale behind them. We compare various national and international dietary guidelines for optimum intake, upper limits set to avoid toxicity from high intakes, and regulations applying to the water supply. This chapter summarizes the findings of earlier chapters on intakes and requirements of our target groups in a format that allows comparison with the guidelines and identifies those most at risk.

We did not consider any evidence strong enough to warrant changes to present recommendations but we do suggest possible anomalies. We are able to only partly answer the questions set out in the preface.


1. The amount of copper in the daily diet sufficient for health is at least the lowest set out in the table of dietary reference values. This is in the range of 20-60 j.Jg Cu/kg/day for most children and adults. The needs of newborn infants are 40-150 j.Jg Cu/kg/day; premature babies may need 150-400 j.Jg Cu/kg/day and malnourished children may need over 500 j.Jg Cu/kg/day for recovery.


2. The question of how much copper is too much is more difficult to answer.

The upper safe limit of around 200 j.Jg Cu/kg/day is safe for most adults and children but formula-fed children may exceed this and the needs of preterm and marasmic infants are much higher. Copper intakes of 800-900 j.Jg/kg/day are toxic to some adults and children. There is uncertainty as to the risk of intakes in the range of 300-600 j.Jg Cu/kg/day for healthy adults and children.


3. The margin between safe and adequate intakes and intakes that are harmful is variable and not clear. For deficiency, it may be only a factor of 2 or less. For toxicity it may be a factor between 5 and 10.


Research questions. In the final section of this book we list questions and possible areas for research identified from gaps in our knowledge. It is to be hoped that the findings of any future research will aid our understanding of copper requirements of the pregnant mother, her developing fetus, and her children, so that in future we may be able to answer the questions with more certainty and precision.