1 FINAL REPORT INCA PROJECT NO. 223 THE BIOLOGICAL IMPORTANCE OF COPPER A Literature Review June, 1990 INCA PROJECT 223 Preface In 1973 the International Copper Research Association initiated a grant to review the literature dealing with the biological importance of copper in marine and estuarine environments. This was followed by a second review in 1978. It was then apparent that there was a very large number of publications concerning copper in the marine environment. As a result, an annual review was initiated. Reviews prior to 1984 considered copper only in marine and estuarine environments. However, events occurring on land and in freshwater were often mentioned because chemical and biological factors and processes pertinent to one environment could often be applied to the others. As a result, the review became larger, covering not only freshwater, saltwater and terrestrial environments but also agriculture and medicine. These broad reviews pointed out the broad application of concepts about the biological importance of copper. The present review includes literature for the period 1987-1988 although a number of earlier references are included and, where appropriate, a few appearing in 1989 have been used. Many of the earlier references are from Eastern Europe and Asia because this literature takes time to appear in the North American data review bases. References were obtained in major part through literature search programs available through the Woodward Biomedical Library at the University of British Columbia. Mr. Brian Moreton, the European INCA Director, kindly provided the metals section of the Marine Pollution Research Titles as a source of European as well as North American References. The 1989 review was written using 3,766 references selected from the literature searches. The appropriate sections of each reference have been catalogued with the references used in previous reviews. This collection now contains appropriate sections of 20,106 references which have been indexed for search purposes. Sharon DeWreede is responsible for this outstanding collection. It will be apparent to the reader that the background of the reviewer is in marine science. With the reviewer aware of this, special effort has been made to cover all aspects of the biological importance of copper. Because of the problems of obtaining certain references, particularly manuscript reports, this review should be considered as a "critical review" of the literature. The cross-referencing scheme used in 1 2 the preparation and writing of the review provides an integration of concepts from all areas covered by the literature search. It is a review that addresses four basic questions: 1. What does copper do to organisms? 2. What are the sources of environmental copper? 3. What happens to copper once it enters the environment? 4. What are the relationships between the chemistry of copper and its biological importance? These questions translate into a series of topics that form the chapters of this review. Signature of Grant Recipient A.G. Lewis, Professor Department of Oceanography The University of British Columbia 2 3 EXECUTIVE SUMMARY The literature used in this review covers a wide range of topics. These include the importance of copper to man, the requirements for copper exhibited by organisms and the various functions or roles of copper in organisms. They include the biological effects of excess metal and the chemical conditions that help to determine the availability of copper to organisms. Metal chemistry is also a factor in the biologically important changes that occur when copper is introduced naturally or from a man-made source. From the 3,766 references used in the review, some of the highlights include: Copper plays a number of essential roles in organisms. It is found in several enzymes and Galiazzo et al. (1988) present evidence that copper acts as a regulator of the expression of major enzyme activities involved in biological oxygen activation. Wissler et al. (1987) describe a copper-containing organic that can regulate cell division and act as what the authors term a “novel type of ‘Wound-Hormone’.” Because it is a required element, copper deficiency produces physiological problems in plants and animals. Chlorosis has been reported under copper deficient conditions, for leaves of young oil palm plants (Pacheco et al., 1986; Pacheco and Tailliez, 1986) and soybean (Casanova and de Valls, 1987). Agricultural studies of alfalfa (Isaev and Khalileva, 1987), bermudagrass (Angel and Feagley, 1987), bromegrass (Horvath, 1986), clover (Nikolaeva, 1988) and a number of cereals (Anke et al., 1986; Coventry et al., 1987; Gordetskaya et al., 1987; Razuvanov, 1985; Saad et al., 1984) have shown direct benefit from copper supplementation in certain soils. Barley pollen development is highly irregular in copper-deficient plants, resulting in low and variable pollen fertility (Jewell et al., 1988). In lambs in flocks, a combination of cobalt and copper deficiency produces poor growth, depressed appetite, poor general condition, anaemia, loss of wool, serious lacrimal secretion and ataxia (Schwan et al., 1987). Tanner et al. (1988) report some of these problems in copper-deficient cattle; poor growth and anaemia appear to be common expressions of low copper status (e.g. Suttle and Jones, 1987), factors that can often be corrected with supplementation (e.g. Wittenberg and Boila, 1987). In humans, Danks (1988) comments (page 236) that "there is no longer any debate about the essential role of Cu in humans and the main effects of severe deficiency are well established, even though not all these effects can be explained adequately." However, the U.S. Food and Nutrition Board (Anonymous, 1986) questions the adequacy of data from metabolic balance studies, to establish a recommended daily allowance (RDA). In an article by Raloff (1989) it is pointed out that the new RDA guidelines by the U.S. National Research Council loosely advocate levels up to 3 mg daily. However, the author comments (page 277) that "... less than half the U.S. population consumes even 1.5 mg ... and one-third ... eat less than I mg daily, a level studies indicate can foster dozens of changes linked with heart disease, including elevated cholesterol and blood pressure." Until copper gets an RDA, Klevay (quoted in Raloff, 1989) "... argues, consumers and the food industry 'will continue to ignore copper' in labeling, research and their menus." The effect of copper deficiency on cartilage and other connective tissue is detrimental (e.g. Allen et al., 1988) and congenital copper deficiency has been associated with Sudden Infant Death Syndrome (SIDS; Reid, 1987). Deficiencies are not uncommon in older people (e.g. Gershwin and Hurley, 1987), either as a result of physiological stress or simply improper diet. Even in healthy adults, copper has been shown to affect behavioral and sleep patterns (Penland, 1988). Deficiencies can also be produced by food components that actively scavenge copper (e.g. Emsley, 1989). 3 4 There is continuing work on the chemistry and biochemistry of copper-containing drugs, not only to elucidate their structure but also to better understand the mechanism of their action and the reasons for unwanted side effects. These include drugs for blood pressure and cardiovascular problems (Adachi et al., 1988; Balman et al., 1988; Christie et al., 1988; Gross and Prohaska, 1988; Hammond et al., 1988; Peters et al., 1988; Sugiyama et al., 1986), strong metal chelating agents used to treat Wilson's disease patients (Trombetta et al., 1988), drugs used to treat inflammation (e.g. Roch-Arveiller et al., 1987; Shetty and Melethil, 1987), anticonvulsant and emetic drugs (Palm et al., 1986; Ueno et al., 1987), antitumour and antineoplastic drugs (Harrison et al., 1987; Hasinoff and Davey, 1988; Litterst, 1988) and antimicrobial agents (Ali et al., 1985; Chatterjee et al., 1988; Lambs and Berthon, 1988; Tumanov et al., 1983). The use of copper to control organism growth is important in pesticides, wood preservatives and antifouling agents. A wide variety of copper complexes have been developed as bacteriostatic agents (e.g. Fang et al., 1987) and a number of fungicides contain copper. Many of these are used to protect important plant crops or their products (Iino et al., 1987). Metal released into the environment from these agents is of concern. Copper-containing fungicides have been suggested to cause chromosomal aberrations (Osiecka, 1987) and may act as mutagenic agents. In bivalve molluscs, like the mussel Mytilus, excess copper has been shown to reduce or stop water filtration (Abel and Papathanassiou, 1986; Redpath and Davenport, 1988) and o associated with a decline in growth potential (Widdows and Johnson, 1988). One of the detrimental effects of excess copper is due to its ability to affect lipids. Excess copper may be associated with the deterioration of the lipid portion of the cell membrane and cause a change in membrane permeability (de Vos et al., 1988). The biological effect of excess copper can be reduced by organics which bind the metal. A number of organics are capable of doing this. Microorganisms and algae produce polysaccharides, many of which have the ability to bind copper (Kaplan et al., 1987b). In fact, Geesey et al. (1987) suggest that bacteria- produced acidic polysaccharides can promote deterioration of copper in aquatic environments. Many organisms produce an organic or group of organics that can bind excess metal once within the organism. The ability of organisms to adapt to changes in copper concentration is suggested by the increase in organics such as metallothionein after exposure (e.g. Steinert and Pickwell, 1988), a feature which tends to stabilize tissue metal concentrations. Metal-metal interactions can change the biological effect of copper. Carson (1988) comments that chronic copper poisoning is a problem in the sheep industry as a result of excess copper or low molybdenum in commercial feeds. It can often be rectified by increasing the concentration of molybdenum.