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Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
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Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 68
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 69
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 70
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 71
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 72
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 73
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 74
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 75
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 76
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
×
Page 77
Suggested Citation:"'COPPER AND MOLYBDENUM '." National Research Council. 1974. Geochemistry and the Environment: Volume I: The Relation of Selected Trace Elements to Health and Disease. Washington, DC: The National Academies Press. doi: 10.17226/20136.
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Page 78

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Garro, F., and A. Pentschew. 1964. Neonatal hydrocephalus in the offspring of rats fed during pregnancy nontoxic amounts of tel- lurium. Arch. Physchiatr. Nervenkr. (Berlin) 206:272-280. Hubert, A. E. 1971. A sensitive method for the determination of teDurium in vegetation. In Geological Swvey research 1971. U.S. Geo1. Swv. Prof. Pap. 75~D. U.S. Government Printing Office, Washington, D.C. pp. 162-164. Mead, L. D., and W. J. Gies. 1901. Physiological and toxicological effects of tellurium compounds with a special study of their influence on nutrition. Am. J. Physiol. 5:104-149. TeUurium 61 Muehlberger, C. W., and H. H. Schrenk. 1928. The effect of the state of oxidation on the toxicity of certain elementL J. Pharm. Exp. Ther. 33:27G-271. Schroeder, H. W., and M. Mitchener. 1971. Selenium and tellurium in rats: Effect on growth, survival and tumors. J. Nutr. 101:1531- 1540. Steinberg, H. H., S.C. Massari, A. C. Miner, and R. Rink. 1942.ln- dustrial exposure to tellurium: atmospheric studies and clinical evaluation. J. Ind. Hyg. Toxicol. 24:183-192.

IX Copper and Molybdenum GEORGE K. DAVIS, Chairman Roger Jorden, Joe Kubota, Herbert A. Laitinen, Gennard Marrone, Paul M. Newberne, Boyd L. O'Dell, JohnS. Webb Copper and molybdenum are known to be essential to the survival of plants and animals. Deficiencies have been de· scribed in numerous areas, and where higher concentrations occur in soils and plants, toxic conditions have been iden· tified in ruminant animals(Ammerman, 1970; Underwood, 1971). So far as is known, molybdenum deficiency does not occur naturally, but toxicity is frequently observed among animals when molybdenum levels are high and copper levels are low. Although areas of plant or animal copper and mo· lybdenum deficiency, imbalance, and toxicity have been mapped (Hawkes and Webb, 1962), the ecosystem is sub· ject to continual change, particularly in areas of intense human activity. CHARACTERISTIC GEOCHEMISTRY Copper Copper has atomic number 29, an atomic weight of 63.546 and percentage isotopic compositions of 63Cu 69.09 and 65Cu 30.91. It occurs in nature as the native element and as Cu+ (ionic radius 0.54 A) and Cu2 + (ionic radius 0.81 A for six-fold coordination). In the Cu2 + state, it is isomor· phous with Znl+ (0.83 A), Mgl+ (0.80 A), and Fel+ (0.69 A). Copper tends to occur in sulfide deposits, and it even occurs in part as sulfides in igneous rocks. The concentration of copper in the continental crust 68 is generally given as about 50 ppm (Prat and Komarek, 1934). As indicated in Table 19, in the igneous rocks copper is concentrated in the basalts, where it tends to be richest in such ferromagnesian minerals as pyroxene and biotite. In the sedimentary cycle, copper is concentrated in the clay mineral fractions, with a slight tendency toward en· richment in clays rich in organic carbon. It is also notably concentrated in sedimentary manganese oxides (up to tenths of a percent). The data on seawater indicate that more than 99.9 per· cent of the copper carried to the ocean is precipitated, mainly with the clays, in part with manganese oxides. It is probable that much of the copper reported in sur· face waters comes from contamination with metallurgical wastes, from plating works, and from other industrial sources. On weathering, copper is likely to be more mobile under acid than under alkaline conditions; the reverse is true for molybdenum, which is particularly immobile in oxidizing, iron-rich environments (Schwarz and Mertz, 1957). Cop- per commonly tends to form organic complexes, whereas molybdenum, when mobile, probably moves for the most part as the soluble anion. Both elements, but especially copper, are likely to be fixed by organic matter. Coal, on the average, is relatively low in copper and high in molybdenum compared to productive agricultural soils,

TABLE 19 Typical Copper and Molybdenum Content in the Principal Igneous and Sedimentary Rocks Concentration, ppm Rock Type Copper Igneous Granitica,b 15 (4-30) Basaltica,b 90 (3G-160) Ultramafica,b 15 (2-100) Sedimentary Limestonea,b,c 4 Sandstonea.b 2 Shale and ctay"·b so (18-120) Black shaled 70 (2G-200) Deep sea claya,b 250 aTurekian and Wedepohl (1961). bParker ( 1967). Molybdenum 1.4 (1-(i) 1.5 (0.9-7) 0.3 0.4 0.2 2.6 10.0 (1-300) 27.0 "Wedepohl (1970). dvine, J. D., and E. B. Tourtelot, Econ. Geol., 6S, 223 ( 1970). NOTE: Usual ranges reported are shown In parentheses. which average I 5 'and 5 ppm, respectively. However, ex- tremes do exist. Ruhr Valley coal, for example, contains up to 6,000 ppm molybdenum. Molybdenum Molybdenum has atomic number 42, an atomic weight of 95 .94 and percentage isotopic compositions of 92Mo 1 5.86, 94Mo 9.12, 95Mo 15.7, 96Mo 16.5, 97Mo 9.45, 98Mo 23.75, and 10~o 9.62. It occurs in nature with valences 4+ (in the sulfide molybdenite, the commercial source) and 6+ in mo- lybdates and possibly in the 3+- and 5+-states. Its ionic radius in six-fold coordination is 0.68 A for Mo6+; molybdates are generally isostructural with the corresponding tungstates. f_W6+ has ionic radius 0.68 A.) Molybdenum is a rare element; its abundance in the con- tinental crust generally in the range of 2 ppm (Swaine, 1955). Molybdenum is rather uniformly distributed among the igneous rocks, with a slight concentration in basaltic rocks (Table 19). Molybdenum is concentrated in shales, clays, phos- phorites, coal, and petroleum. In all these materials, a marked positive correlation exists between the contents of molybdenum and organic carbon. The data on seawater indicate that more than 99.9 per- cent of the molybdenum supplied to the ocean is precipi- tated, mainly with the clays, although some is found in the hydrous manganese oxides. Man's activities contribute molybdenum to the environ- ment in metallurgical processing, phosphate fertilization, phosphatic-detergent discharges, and in coal and oil burn- ing. Copper and Molybdenum 69 SOURCES Soil The relation between the molybdenum or copper content of the parent rock and that in the derivative soil is depen- dent on many factors, including the degree of weathering, the nature and intensity of soil formation, drainage, pH, Eh, and the amount of organic matter in the soil. The amount of clay is a key factor in the cation-exchange capacity. The movement or retention of copper or molybdenum and consequent levels found in soil are influenced by the amount of clay present, which influences the exchange capacity (Broadbent and Nakoshima, 1971; Doner and Mortland, 1969; Lailach et al., 1968); a higher pH favors molybdenum availability, whereas a lower pH favors cop- per availability. The moisture content is a key factor in microorganism activity, which influences the availability of both molybdenum and copper. The amount of copper and molybdenum in soil is therefore subject to considerable variation. Mean levels (and ranges) are 20 (I-50) ppm for copper and 0.1 (0.005-5) ppm for molybdenum (Swaine, 1955). Much higher values may be encountered in soils derived from mineralized parent material. Figures for the total soil-metal content provide no more than an indication of the possibility of deficiency or excess in plants rooted therein. Both copper and molybdenum are more available to plants as the result of microbial activity associated with impeded drainage. Copper uptake is par- ticularly low in highly organic soils, especially those with pH values above 6. Molybdenum tends to be less available in freely drained soils that are rich in iron. A better measure of the available metal content can be obtained by using ap- propriate weak extractants, such as ethylenediaminetetra- acetic acid (Eo T A) for copper and acetic acid for molyb- denum. The geographic pattern shows that copper deficiency in plants is relatively rare, predominantly affecting local areas and centered in, though not completely restricted to, soils developed on arenaceous clay-poor parents or highly organic (peat) material. Areas of copper toxicity in plants are rare, but may be encountered in mineralized areas or in areas contaminated by mining or smelting activity. Areas of molybdenum deficiency in plants are most likely to occur on acid, freely drained soils, particularly those rich in iron oxides, or on severely leached or highly arenaceous parent material. The most widespread source of molybdeniferous soils is marine black shale. Molybdenum toxicity in plants has also been reported in some granitic areas where the soils contain as little as I ppm molybdenum (Kubota and Allaway, 1972). Rather higher total contents generally seem to be necessary to achieve toxicity on shale

70 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE soils. For any given molybdenum content, organic soils and those with impeded drainage are the most toxic. Water Surface and ground waters are a potential source of imbal· ances when used for drinking or when applied to soils through irrigation or flooding. Above-normal levels of cop- per or molybdenum may be either natural or contributed by man. Present information rarely allows us to determine whether the extremes are natural and thus whether they can be controlled. A second major problem is that most imbalances are lo- calized and near their point sources. The only readily avail- able information on water concentrations of these elements is for streams draining broad regions; e.g., 104 mi2 or greater (Kopp and Kroner, 1968; Thornton et al., 1966). The ef· feet of dilution, in broad averages, is illustrated in Table 20, based on work of Hadjimarkos ( 1967), which indicates that drinking water is a minor source of copper and molybdenum, although tap-water levels as high as 580 p.g/1 of molybdenum have been found (Chappell and Jorden, 1971). Similarly de· tailed work has led to the discovery that local imbalances in cattle may result from the cattle drinking water contain· ing unusual levels of the elements (Davis, 1950). Where irrigation is practiced, the presence of high levels of copper or molybdenum in the water can be a factor in the development of toxic reactions of plants or animals. The quality criteria for irrigation water, i.e., 5 ppm molybdenum for long-term use, 50 ppm molybdenum for intermittent use, and 1 ppm copper for continuous use are in recognition of this potential effect (Federal Water Quality Administra· tion, 1968). The national impact of water-borne contribution of cop- per and molybdenum is difficult to detect, predict, or eval· uate because information is either absent or not retrievable. TABLE 20 Concentration and Daily Human Intake of Copper and Molybdenum Mean Drinking-Water Concentration, Element ppm Copper 0.029 Molybdenum 0.008 SOURCE: Hadjimarkos (1967). Plants lntake,IA8fd Percentage from Water Food Water 58 3,200 1.8 16 1,000 1.6 Although Swaine and Mitchell (1960) have indicated that the total trace element content of a soil depends in large part on that found in the parent rocks, Oertel (1961) has TABLE 21 Dry-Weight Yields and Copper Concentrations in Tobacco Grown with Different Levels of Copper in the Nutrient Culture Medium Concentration Yields, g Copper Concentration, ppm of Copper in Medium, ppm Tops Roots Tops Roots 0.02 8.6 0.7 8.8 31 0.04 8.9 0.9 8.8 61 0.08 9.4 0.8 11 87 0.16 8.8 0.9 14 ISS 0.32 3.9 0.3 17 >160 0.64 3.0 0.3 16 >160 SOURCE: Struckmeyer et al. ( 1969). demonstrated that a direct correlation is not always found. Thus, an analysis of either may be misleading insofar as the amount available to the plant is concerned. The species of plant is a major factor in determining the availability of cop- per or molybdenum to a browsing animal. Also, copper levels in plants vary with the age of the plant and between parts, such as root, stem, leaf, or seed (Beeson, 1941 ). Table 21 shows dry-weight yields and copper concentra· tions in shoots and roots of tobacco grown with different levels of copper in the nutrient culture medium (Struck- meyer et al., 1969). In general, deficiencies of copper occur in animals graz· ing on open meadows, but rarely when they are fed whole TABLE 22 Copper Concentrations in Forage Plants of Culpeper and Orange Counties, Virginia Copper Number of Concentration, ppm Plant Type Soil Belt Samples Range Mean Alfalfa Penn-Bucks 21 6.5-19.7 11.2 Tatum-Nason 4 9.8-16.2 13.5 Davidson 22 10.2-18.5 12.6 Lespedeza Penn-Bucks 12 6.o-14.2 9.8 Tatum-Nason 29 6.4-12.8 8.6 Davidson IS 6.4-13.7 9.4 Cecil 7 7.3-11.8 10.2 Red clover Penn·Bucks 3 19.5-21.0 20.0 Tatum-Nason 4 ll.S-20.5 IS.O Davidson 10 13.7-29.0 18.2 Cecil 7 IO.S-29.0 18.7 Ladino clover Penn-Bucks s 10.2-15.2 13.0 Davidson 2 12.o-12.s 12.2 Tunothy Penn-Bucks s l.S- 9.7 S.l Cecil I 6.7 6.7 Orchard grass Penn-Bucks 2 13.7-16.0 14.8 Tatum-Nason 4 8.o-1s.s 12.0 SOURCE: Price et al. (19SS).

grains (Hartmans and Bosman, 1970). Harvested dried grass is a better source of copper than the same grass consumed as fresh pasture (Ferguson et aL, 1943). Grasses tend to be lower in copper than legumes or mixtures of grasses and legumes, averaging in some cases 5 ppm for grass alone and I 5 ppm for legumes (Beeson, 1941 ). Many factors affect the copper content of plants, but soil content is probably the most important (see Table 22) (Beeson, 1941; Price et al., 1955; Reuther and Smith, 1953). Higher levels and high availability of soil copper will produce copper toxicity in plants, with disturbed iron metabolism. The metabolic role of copper appears to limit the concentration that plant tissues can tolerate before the plant is killed; this serves to limit the concentration of copper found in plant tissue other than seeds to about 20 ppm (Brown, 1961). Vegetables and Seeds Any general estimate of the copper content of the commonly consumed vegetables is difficult because these amounts vary enormously, depending partly on the copper content in the fertilizers applied. Plant leaves seldom yield more than 20 ppm, whereas seeds-particularly cereal grains-are relatively good sources of copper (Tables 23 and 24). Molybdenum is an essential component of several en- zymes, including xanthine oxidase, aldehyde oxidase, nitrate reductase, and nitrogenase. Its physiological role appears to be more critical in plants than in animals; deficiency disease has been difficult to produce in animals on molybdenum- free diets, but molybdenum is critical for plant production, and better understanding of its biochemical function in plants is needed. TABLE 23 Effects of Rate of Copper Application as Copper Sulfate on the Yield of and Copper Concentration in Cucumbers and Snapbeans Cucumbers, 1970 Snapbeans, 1969 Tissue Tissue Copper in Yield, Copper, Yield, Copper, Soil, lb/acre tons/acre ppm tons/acre ppm 0 1.95 15.1 3.65 14.3 16 7.45 12.0 4.18 13.3 48 7.86 14.1 3.70 17.3 144 6.05 18.2 3.59 22.0 432 0.41 25.2 0.86 40.3 SOURCE: Walsh, Leo M. 1971. Proceedings of the Fertilizer and Aalime Conference, Vol. 10. Soils Department, University of Wisconsin, Madison. Animals Highly variable copper concentrations are found in the tis· sues of all animal species and, except for brain copper, Copper and Molybdenum 71 TABLE24 Copper Concentrations in Representative Agricultural and Horticultural Plant Species Number Copper Content, ppm Plant or Plant of Part Analyzed Analyses Maximum Minimum Mean Alfalfa, above-ground portion cut for hay 8 IS 4 9 Barley, grain 12 41 6 16 Beans, f.eld; seed 12 16 7 11 Beets, root 15 27 6 10 Cabbage, edible portion 26 28 4 14 Carrots, roots IS 18 7 11 Cover, red, above· ground portion 41 20 6 10 Com, grain 6 17 4 8 Com, stover 16 9 2 5 Kale, edible portion 6 56 24 36 Lettuce, edible portion 45 33 3 19 Oats, grain 29 51 4 11 Oats, straw 26 54 3 11 Onions, bulb 11 24 5 12 Orange, fruit 3 22 3 10 Peas, green, edible portion 9 15 6 9 Potatoes, tubers 143 24 2 8 Soybean, above-ground portion, cut for hay 32 12 4 9 Spinach, edible portion 34 24 3 9 Tomato, fruit 51 34 8 14 Wheat, grain 108 24 4 9 Wheat, straw 24 5 1 3 SOURCE: Beeson (1941). amounts per unit body weight diminish with age. Average total body copper content of fat-free tissues from various animals is shown in Table 25. Tissues with low copper content include the prostate, thymus, thyroid, and pituitary glands; tissues with inter- mediate copper levels include spleen, pancreas, muscles, skin, and bones. Relatively high concentrations of copper are found in liver, brain, kidney, heart, and hair (Cunning- ham, 1931; Smith, 1967). In autopsy material from five human subjects who had died from accidental causes, an average of 23 mg of copper was found in the liver, heart, spleen, kidneys, brain, and blood, with 8 mg in the liver, 8 mg in brain tissue, and the remaining 7 mg distributed among the other tissues and organs (Cartwright and Win- trobe, 1964a,b). The brain appears to be the only organ in which copper concentration increases with age, approx- imately doubling from birth to maturity (Schroeder et al., 1966). The highest concentration of copper is found in the pigmented portions of the eye, particularly in the iris and choroid, where amounts up to 100 ppm (dry wt) can occur (Bowness et aL, 1952; Bowness and Morton, 1952). Serum levels may vary considerably, from 0.05 to 0.8 ppm. Molybdenum concentrations are normally very low in

72 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE TABLE 25 Average Total Body Content of Copper in Fat-Free Tissues from Various Animals Animal Type Guinea pig Rabbit Rat Pig Cat Human Copper Concentration, ppm Newborn Adult 6.9 4.0 4.3 3.2 2.9 4.7 1.5 2.0 1.9 1.9 1.7 SOURCES: Spray, C. M., and Widdowson, E. M. 1950. The effect of growth and development in the composition of mammals. Dr. J. Nutr. 4 :332. Widdowson, E. M. 1950. Chemical composi· tion of newly born mammals. Nature 166:626. animal tissues of all species, as illustrated in Table 26. The mean dietary intake of molybdenum is probably about 1 mg/d (Tipton et a/., 1966), and it is apparently of such small significance in human nutrition that its role has been studied very little. Miller eta/. (1959) did balance studies on 24 girls, 7-9 years of age, and found an average intake of 75 mg/d molybdenum, most of which appeared in the urine. The higher the protein intake, the less molyb- denum was retained. EFFECTS ON ANIMAL AND HUMAN HEALTH The essentiality of copper for plant and animal life is well established. Low-copper soils have been reported to affect plant growth and animal health in many parts of the world (Underwood, 1971 ). Some of the copper-deficiency cases reported involve simple insufficiency, but in the majority of cases, the deficiency is precipitated by interference with absorption of copper or its utilization. The interfering fac- tors most frequently involved in ruminants are molybdate and sulfate (Ferguson et al., 1938; Dick, 1953). Acute copper excesses and chronic copper toxicity in sheep have also been reported (Underwood, 1971 ). The pos· sibility that a certain level of copper in the diet did cause the toxicity depends here also on the level of molybdenum, sulfate (Dowdy and Matrone, 1968; Dick, 1953), and probably zinc and iron (Suttle and Mills, 1966). Chemistry of Copper, Molybdenum, Zinc, Sulfate, and Molybdate Consideration of certain chemical and biochemical proper- ties of the elements that interact in copper metabolism gives insight into the probable mechanism of the interac- tions. The biologically active forms of copper, either Cu+ or Cul+, are probably chelates. A favored chelate con- figuration of Cu + is tetrahedral in shape. Zn2+ also sup- ports tetrahedral chelate configurations. Both Cu + and Zn2+ are d 10 ions with similar ionic radii ligand atom pref- erences (Matrone, 1970; Hill and Matrone, 1970). Thus, it is not unreasonable to predict that Zn2+ can substitute for cu+ in some biologically active compounds of copper, ren- dering them inactive, which might explain why zinc supple- ments help to overcome copper toxicity in swine (Suttle and Mills, 1966). In the ruminant, either Mo04 alone (Dowdy and Matrone, 1968) or S04 alone (G. G. Gomez-Garcia and G. Matrone, personal communication, 1972) may induce copper deficiency. Absorption In most species, copper is absorbed mainly from the jejunum and small intestine (Underwood, 1971), although in the rat about 50 percent of the copper appears to be absorbed from the stomach (Van Campen and Gross, 1965). In humans, as much as 32 percent of the daily oral intake of 2.5 mg may be absorbed, but net absorption is about 5 percent or less, with most of the copper excreted in the bile (Underwood, 1971). Under normal physiological conditions, absorbed copper is complexed by serum albumin and transported to the liver, where it is stored and re-emerges excreted in the bile or re- leased to the blood as ceruloplasmin. Copper in ceruloplas- min is apparently not released until ceruloplasmin is broken down. Determinations of ceruloplasmin have provided a rapid method for detecting copper deficiency. Ruminant animals are particularly subject to both copper toxicity and copper-molybdenum-sulfate imbalance. Sheep are among the most sensitive animals to the effects of ele- vated dietary copper levels. In both cattle and sheep the in- teraction between copper and molybdenum is in part a function of the sulfate level. TABLE 26 Molybdenum Concentrations in Animal Tissues Animal Type Adult man Adult rat Chickens Molybdenum Concentration by Tissue, ppm (dry wt) Liver Kidney Spleen Lung Brain 3.2 1.8 3.6 1.6 1.0 4.4 0.20 0.52 0.15 0.37 0.14 0.24 Muscle 0.14 0.06 0.14 SOURCES: Tipton et al. ( 1966); Higgins, E. S., D. A. Richert, and W. W. Westerfeld. 1956. Molybdenum deficiency and tungstate inhibition studies. J . Nutr. 59:539-559.

Underwood (1971) has provided a review of copper and molybdenum in the nutrition of animals, citing research that illustrates species differences, environmental effects, changes due to husbandry practices, and the interaction of various nutrients and dietary constituents. Copper toxicity occurs in all species but is a special prob- lem in ruminant animals. The consumption of plants with environmentally caused high copper content, and such hus- bandry practices as feeding copper supplements, combined with the condition of restricted elimination of absorbed copper, have caused toxic reactions in ruminant animals. Monogastric animals, such as swine and poultry, can tol- erate much higher levels of dietary copper than ruminants before exhibiting toxic symptoms, provided that the diet also includes adequate zinc, iron, and protein. The dietary level of naturally occurring or synthetic chelates can also be an important factor. The nutritional requirements of different species of animals for copper is similar in the presence of adequate sulfate and in the absence of molybdenum and is probably less than 5 ppm of the diet. However, as the level of molyb- denum in the diet of the ruminant animal increases, the amount of sulfate necessary for the copper-molybdenum interaction increases. Monogastric animals are much more tolerant of increased molybdenum levels in the diet. Other factors that influence the animal dietary require- ment as well as the tolerance for copper include sex and stage of maturity, dietary history, the presence of special compounds such as certain plant alkaloids in the feed, water composition, and genetic variation. In acute or clinical situations, when assessing the influ- ence of copper and molybdenum in the geochemical en- vironment on animal health and disease, alterations in the metabolism that may be associated with the environmental abnormalities must be considered. Changes of this kind that might be observed include severe digestive disorders, failure of connective-tissue formation, changed bone structure, achromotrichia, vascular changes, alteration in blood trans- port of metabolic compounds, organ-function failure, abnormal-element concentration in tissues, distorted growth patterns, and failure of maintenance and reproduction. In the more common chronic or marginal changes that indicate influence of the geochemical environment, such less defmitive changes in health as reduced growth and poor lactation and reproductive performance may be the only effects observed other than response to remedial procedures. Molybdenum toxicity in animals appears to be mainly confmed to animals grazing on plants grown over poorly drained granitic alluvium and black shale. Widespread stream-sediment sampling in England and Wales has indi- cated that the disorder may be far more prevalent and more significant economically at the subclinical level; the same situation could exist elsewhere (Webb et al., 1968; Webb and Atkinson, 1965; Thornton et al., 1969). In practice, molybdenum toxicity demonstrates itself as a copper de- Copper and Molybdenum 73 ficiency when adequate sulfate is present; the mechanism of this apparent interaction is not well understood. The essentiality of molybdenum in animal metabolism is under- stood even less well. Functions General Enzymatic Function The essential trace elements, with a few minor exceptions (notably iodine), function as components of vital enzyme systems. Many of the metallo- enzymes are known (O'Dell and Campbell, 1971 ), but many are doubtless unrecognized. Because copper and molybde- num are essential for both plants and animals, there is good reason to believe that they both exert as yet unrecognized biocatalytic functions. Less is known about the mechanism by which toxicity is manifest when these or other elements are consumed in excess. One of the most promising ap- proaches appears to be the examination of enzyme systems that might logically be inhibited by specific metal ions. To delineate the system for study, work must first be done with intact animals or plants. In some instances, the metal ion is chelated directly by the apoenzyme to form the active enzyme; in others it must be chelated by a specific organic molecule, such as a por- phyrin or corrin ring. As it is only the chelated or enzymat- ically bound metal in a tissue or cell that is catalytically active, a measure of total metal content may not be a valid indicator of function-even though it is the only feasible measurement available to date. Eventually, a method needs to be found for assaying tissues for catalytic function rather than simply for trace element content. Physiological Functions Copper has several important physiological functions that are commonly defined by pathological characteristics of the deficiency state. The best-known pathologies are anemia, the central-nervous- system disorder, neonatal ataxia (swayback) in lambs, and failure of pigmentation of hair, wool, and feathers. The im- portance of copper in connective-tissue metabolism has received increased attention in recent years (Underwood, 1971 ). Failure of cross linking of the connective-tissue proteins-collagen and elastin-results in defective bones as well as cardiovascular disorders, including spontaneous rupture of the aorta. The anemia of copper deficiency appears to result from faulty iron metabolism, and recent work implicates ceru- loplasmin, the chief copper protein in plasma. Ceruloplas- min is an oxidase that catalyzes, among other things, the oxidation of ferrous to ferric iron. It has been termed fer- roxidase and is postulated to aid in iron mobilization (Osaki eta/., 1966; Ragan eta/., 1969). Whether this totally ex- plains the role of copper in hemoglobin synthesis is not clear. Copper plays a vital role in the biosynthesis of com- pounds that serve to cross link polypeptide chains in both

74 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE elastin and collagen. The critical reaction is the oxidation of the epsilon carbon of lysine residues held in peptide linkage. Such reactions are catalyzed by amine oxidases. Some of the amine oxidases are known to be copper metal- loenzymes, and lysyl oxidase is postulated to be copper- dependent. It has not yet been isolated and characterized, but work on this matter should receive high priority. The significance of the biogenic amines in mental health is just beginning to unfold. These amines are catalyzed by amine oxidase, and if these oxidases are copper-dependent, copper deficiency might play a role in mental health. This aspect of copper as a biocatalyst should be investigated. Dietary Sources of Copper and Molybdenum The best animal sources of dietary copper are liver and brain. Shellfish yield relatively high levels of copper and are considered a good source (Underwood, 1971 ); oysters and soft clams contain the highest levels (300-400 ppm). Milk is generally a poor source, though some samples ex- amined have contained as much as 600 p.g/1. The molybdenum content of food varies greatly. In gen- eral, legumes, cereal grains, leafy vegetables, and liver and kidney are good sources, whereas fruits, root and stem veg- etables, muscle meats, and dairy products are among the poorest (Beeson, 1941; Price eta/., 1955; Dick, 1956). Molybdenum is concentrated to some extent in the outer layers of grain, which are now removed during flour-milling; refined grain products are therefore poor sources for mo- lybdenum, and copper appears to be lost in even greater quantities during the same process. When molybdenum is present in higher than normal levels in soils, plants may take up amounts that are toxic for animals. This situation has been particularly well described in the United Kingdom and is interrelated with the presence of copper and sulfate (Ferguson et al., 1943; Dick, 1953; Underwood, 1971). Irrigation Floodwater Molybdenum deficiency in plants in the United States appears to result from soil acidity. The spectrum of molyb- denum content with a given species may be quite wide, ranging from below one to several hundred parts per million. Molybdenum functioning as a requirement for nitrogen- ftxing organisms may favor legume production. However, molybdenum requirements of plants have not been char- acterized beyond meeting these requirements of micro- organisms. Excretion The major proportion of the copper consumed by man is excreted in the feces even though it is first absorbed. Ex- cretion into the intestine is accomplished by the biliary system (Cartwright and Wintrobe, 1964a). Biliary copper is poorly absorbed, probably because it is bound to a spe- cific protein that impairs absorption (Farrer and Mistilis, 1967). Molybdenum is excreted primarily in the urine, prob- ably as the molybdate anion (Scaife, 1956). Sulfate in- creases urinary excretion of molybdenum, presumably by interfering with membrane transport. The mechanism of this postulated antagonism is unknown and deserves study. MOLYBDENUM AND COPPER POLLUTION The distribution of disorders related to excess and deficiency of copper and molybdenum in the United States has recently been reviewed by Kubota and Allaway ( 1972). Imbalances of these elements can be traced to the effects of weathering, causing variations in plant uptake from soil; they may also be induced by industrial pollution. One method by which these imbalances may reach plants, animals, or man is il- lustrated in Figure 8, although numerous additional ele- Drinking Water FIGURE 8 Flow diagram showing water, recycled wastes, and air sources of copper and molybdenum.

ments and routes may exist. In specific cases of known im- balances, all elements should be evaluated in a more detailed manner. The current fad for recycling waste (animal wastes, sew· age solids and liquids, channel dredging and industrial wastes) to the land offers very real possibilities of unwit- tingly creating imbalances in organisms. Because such wastes are commonly high in trace element concentration (Davis, 1950; Patterson, 1971), they may directly alter crop production (Alvin J. Ohlrogge, personal communica- tion, 1971) or indirectly affect the consumers. In swine production, one very real potential threat to human health is in the proposal that swine feed be sup- plemented with 250 ppm copper. Ohlrogge has estimated that such a practice, combined with recycling of swine manure, would lead to the application of 6 lb copper per acre per year, or a total increase of some 1.6 X I 0 7 lb copper per year for the state of Indiana alone. An illustration of the pattern that might develop from feeding high-level copper diets to swine was prepared for the U.S. Food and Drug Administration, and a portion of that report follows. Manure characteristics are shown in Table 27. The results of Benne et aL ( 1961 ), indicate that swine manure is 75 percent water, and will furnish 10 lb nitrogen, 2.8 lb phosphorus, and 7.6 lb potassium per ton. Corn grain (ISO bu/acre) would be expected to remove 135, 22, and 30 lb/acre of nitrogen, phosphorus, and potassium, respec- tively. The total nitrogen required by a 150-bu/acre corn crop (grain plus stover) is about 200 lb/acre. Thus the maximum rate for pig manure would be 200/10, or 20 tons/acre, which would contain 5 tons of dry matter. If we assume that the manure contains copper concentrations up to 750 ppm, then this treatment would add 7.5 lb of copper per acre per year. It has been estimated, based on the expected feed intake of swine (Committee on Animal Nutrition, 1968), that 3-6 lb copper per acre would result from manure applied at 20-40 tons/acre, using the copper supplementation. From the above data, if the manure were used as a source Copper and Molybdenum 15 TABLE 27 Characteristics of Manure from Growing Finishing Pigs Daily Waste Production Animal Animal Solids and Liquids Wet Solids Only Age, weeks Weight,lb (ft3 ) (gal) (ft3 ) Ob) 6-9 40 0.06 0.5 0.04 2.4 9-13 100 0.13 1.0 0.1 5.9 13-18 150 0.21 1.7 0.15 8.8 18-23 210 0.30 2.2 0.2 12.0 SOURCE: Table 1. 1969. Handlin& swine manure. Aaric. Eng. Dig. (Iowa State Univenity) 11:1-4. e Midwest Plan Service, 1969. NOTE: Fertilizer content of a ton of manure Ia about 10 lb of nl· trogen, 3 lb of phosphorus, 8 lb of potauium. The above fiaurea are median values for undiluted fresh manure without bedding. of nitrogen for corn grain production, the buildup would be as shown in Table 28. In areas where rainfall is not sufficient for leaching of excess potassium and other salts, the swine manure could not be used as a source of nitrogen for more than 3-10 years. This assumption is based on the continuous produc- tion of corn grain and a maximum potassium concentra- tion of 5 percent saturation of soils cation exchange capacity (cEc) with the range of CEC being 10 to 30 milli- equivalents (meq) per 100 g. With leaching of potassium, the removal of stover or the inclusion of alfalfa in the ro- tation, the buildup of potassium would be much less. Leaching would decrease sodium and potassium much more rapidly than copper, as is shown in the following tabulation: looding dUTation (yr) for CtlfXICity of which 20 ton/aae/yr CEC• copper of manure could be 10il texture (meq/100g) (lb/acre) applied if it supplied 3lbCu 6lbCu sand 1-3 32-96 1~32 5-16 loam 3-{; 96-192 32-{;4 16-32 silty loam 6-10 192-320 64-100 32-{;4 •cation exchange capacity measured with ammonium acetate at pH7. TABLE 28 Buildup of Minerals in Soil from Pig Manure Used as a Source of Nitrogen for Corn Grain Production Amount by Element, lb/acre Added/Removed Nitrogen Phosphorus Added with manure (20 tons per acre) 200 56 Removed by 1 SO bu com 135 22 Buildup (excess pounds per acre per year) 65 34 SOURCE: Dale Baker, personal communication, 1971. Potassium 152 30 122 With Various Copper Levels Low Medium High 3 O.o7 3 6 0.07 6 1.5 O.o7 1.5

76 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE A thorough analysis offorms, levels, availability, release, and uptake from recycled waste desperately needs evalua- tion before widespread adoption of the practice of feeding high levels of copper to swine leads to irreversible damage. Atmospheric Fallout High levels of copper and molybdenum from atmospheric fallout, causing plant injury, have occurred (Patterson, 1971; Cannon and Anderson, 1971 ); the levels are usually highest near smelting operations. The potential danger to human health of this fallout should be investigated. Water Pollution The operation of a desalination plant often produces an ef· fluent that is hot, hypersaline, lowered in pH, and period· ically contains above-normal concentrations of copper (Robert C. Harriss, personal communication, 1971 ). Nu- merous studies have been made concerning the effects of copper on freshwater fishes (Kellerman, 1912; Marsh and Robinson, 1910; Titcomb, 1914). Copper is toxic to fishes in soft fresh waters at concentrations between 0.01 and 0.02 ppm (Powers, 1917; Jones, 1938, 1939; Pickering and Henderson, 1964). In their review of the literature, Doudo· roff and Katz (1953) concluded that in natural fresh waters, copper sulfate concentrations below 0.025 ppm as copper are not acutely toxic for most common fish species; how- ever, extensive variations in copper sensitivity occur among different species. Marine invertebrates such as Nereis have been found to have a short-term threshold for copper toxicity of around 0.10 ppm (Raymont and Shields, 1964). Deschiens (1968) examined the effect of molluscicides (chiefly, CuCh) on zoophytic groups that constitute the food supply for certain fishes. Arthur and Leonard ( 1970) found no effect on fish from copper solutions ranging from 8 to 14.8 mg/1 after 6 weeks in soft water. After an additional 9 weeks, newly hatched amphipods grew to adulthood only in solutions equal to or less than 4.6 mg/1. Hueck and Adema (1968) studied the effects of copper on algae and daphniae in an artificial ecosystem. Using flowing water bioassays, Hazel and Meith ( 1970) found that eggs of the Chinook salmon could withstand 0.08 mg/1 of copper-about half the thresh· old for fry, which showed acute toxicity at 0.04 mg/1. A level of 0.02 mg/1 inhibited growth and caused increased fry mortality. Pippy and Hare ( 1969) found that copper and zinc pollution in the Miramichi River in New Brunswick, combined with higher water temperatures, caused increased bacterial growth (Aeromonas lique[aciens), which in turn caused disease in Atlantic salmon and suckers. Overall, how· ever, little information is available on the ecological effects of copper on various aquatic systems, especially in marine areas. Relatively few studies of the effects of chronic exposure of aquatic organisms to copper have been performed. Mount ( 1968) found that fathead minnows (Pimephales promelas Rafmesque) exposed to copper for 11 months did not suffer impaired growth or reproduction at 3-7 percent of the 96· hour TLm (the concentration of the chemical in water that will kill 50 percent of the test animals in 96 h). Mount and Stephan ( 1969) found a maximum acceptable toxic con· centration of copper on the basis of growth, reproduction, and survival for the fathead mirmow between 0.13 and 0.22 of the 96-hour TLm value at an EDT A hardness of 30 mg/1 as CaC03 • This was 0.03-0.08 of the 96-hour T L m at a hardness of 200 mg/1. Fish in copper concentrations of 0.0145 and 0.0058 ppm showed no adverse symptoms with respect to the above process. Sprague et al. (1964), studying the effects of copper on salmon parr, found an incipient lethal level (ILL) of0.048 ppm in water, but discovered that fish avoided concentrations ofO.OS ILL . Field· avoidance thresholds range up to 0.43 ILL . Raymont and Shields (1964) found that there was little difference in the toxicity to fish of various cupric com- pounds in water, leading the authors to conclude that the cupric ion itself is the toxic agent. This conclusion is sup- ported by the fact that copper toxicity is greatly reduced by applications of EDTA. Nielsen and Wium-Anderson (1970) later contended that copper usually did not occur in ionic form in nature because the natural concentrations of copper, if in ionic form, would seriously limit photo- synthetic activity and growth of unicellular algae. They thought that copper was probably complexed into organic matter, such as polypeptides, and was therefore not poisonous to algae. However, they suggested that much of the copper in subsurface ocean areas was present in ionic form . Numerous investigators (Greenberg, 1942; Hassall, 1963; Mandelli, 1960; Nielsen et aL, 1969; Arthur and Leonard, 1970; Erickson eta/ .• 1970) have demon· strated the toxicity of copper to phytoplankton, the degree of toxicity being a function of the species tested , the chem- ical form of the copper, the temperature, and the salinity. Concentrations as small as 6 pg/1 can inhibit photosynthe· sis in some species. In fact, L. Kamp-Nielsen (personal communication, 1970) has demonstrated that in certain species of algae, ionic copper is as toxic as mercury. RECOMMENDATIONS FOR RESEARCH 1. Gaps in knowledge of the metabolism and metabolic function .>f copper and molybdenum that should be filled include the effects of copper accumulation by the liver. Although there is no true storage organ for copper, the con· centration in liver correlates positively with dietary intake (Underwood, 1971) and is also influenced by other dietary factors, most notably by Mo04 and so4 ions, which tO· gether decrease copper concentration in the liver. In the

absence of sulfate, molybdenum accumulates. Abnormally high levels of copper accumulate in the liver when man is afflicted with such diseases as cirrhosis, yellow atrophy of the liver, tuberculosis, carcinoma, and hepatolenticular degeneration (Wilson's disease), and inherited metabolic disorder (Underwood, 1971 ). 2. A program designed to monitor major watersheds and tributary streams for copper and molybdenum content should be established. The information obtained would indicate locations where abnormal levels of these elements might be expected and would make it possible to assess the human and animal intake from water. 3. Molybdenum function in metabolic pathways of plants and animals is still not well understood, and the sub- ject merits research support. Because microorganism nitro- gen fiXation appears to be molybdenum-dependent, and because this process is a major factor in the production of plant proteins, a better understanding of molybdenum ac- tion is important. 4. The interaction of copper, molybdenum, and sulfate is recognized as important in evaluating the impact of en- vironmental levels of these nutrients. The mechanism of the interaction, however, remains uncertain and merits strong research support. The basic metabolic pathways may be essential to explaining the suggested relationships to diseases as wide-ranging as cardiovascular disease, dental caries, and cancer. 5. Many instances have been reported of inadequate methodology for assessing chronic subchemical deficiencies. Intensive research into improved methods of evaluating the metabolic status of plants and animals with respect to cop- per and molybdenum is recommended. 6. Many gaps exist in knowledge of the cycling and re- cycling of copper and molybdenum from production source to ultimate sink. The environmental budget of these ele- ments is woefully incomplete. Research into the sources, movement in the biosphere, and ultimate deposit is impor- tant and should be supported. 7. Certain environmental danger points have been rec- ognized, and these merit special research. They include the effects on freshwater streams and marine waters of copper and molybdenum from discharges associated with such human activities as mining, manufacturing, smelting, and recycling animal waste and sewage effluents. Buildup of these elements in soils as a result of applying fertilizers, manures, and sewage effluents needs defmitive study. The effects of atmospheric fallout from discharges from burning fuel, especially coal and other fossil fuels, also need special study. REFERENCES Ammerman, C. B. 1970. Recent developments in cobalt and copper in ruminant nutrition : A review. J. Dairy Sci. 53 :1097. Copper and Molybdenum 77 Arthur, J. W., and E. N. Leonard. 1970. Effects of copper on Gam- marus pseudolimnaeus, Physa integra, and Ozmpeloma decisum in soft water. J. Fish. Res. Board Can. 27:1277. Beeson, K. C. 1941. The mineral composition of crops with particu- lar reference to the soils in which they were grown. U.S. Dept. of Agric. Misc. Publ. No. 369. 164 pp. Benne, E. J., S. L. Tisdale, and W. L. Nelson. 1961. Soil fertility and fertilizers. Mich. Agric. Exp. Stn. Circ. No. 291. Bowness, J. M., and R. A. Morton. 1952. Distribution of copper and zinc in eyes of fresh-water fishes and frogs. Occurrence of metals in melanin fractions from eye tissues. Biochem. J. 51 :53(}-535. Bowness, J. M., R. A. Morton, M. H. Shaker, and A. L. Stubbs. 1952. Distribution of copper and zinc in mammalian eyes. Occurrence of metals in melanin fractions from eye tissues. Biochem. J. 51 :521-530. Broadbent, F. E., and T. Nakashima. 1971. Effect of added salts on nitrogen mineralization in three California soils. Soil Sci. Soc. Am. Proc. 35:457460. Brown, J. C. 196l.lron chlorosis in plants. Adv. Agron. 13 :329- 369. Cannon, H. L., and B. M. Anderson. 1971. The geochemist's involvo- ment with the pollution problem. In Environmental geochem- istry in health and disease, H. L. Cannon and H. C. Hopps 1 eds). Geol. Soc. Am. Mem. No. 123. Geological Society of America, Boulder, Colo. pp. 155-177. Cartwright, G. E., and M. M. Wintrobe. 1964a. Copper metabolism in normal subjects. Am. J. Clin. Nutr. 14:224-232. Cartwright, G. E., and M. M. Wintrobe. 1964b. The question of copper deficiency in man. Am. J. Clin. Nutr. 15:94-110. Olappell, W. R., and R. M. Jorden. 1971. Molybdenum in the en- vironment: A report to the National Science Foundation. Uni- versity of Colorado, Boulder. Committee on Animal Nutrition. 1968. Nutrient requirements of swine. No. 2 in Nutrient requirements of domestic animals (6th revised ed.). NAS Publ. No. 1599. National Academy of Sciences, Washington, D.C. 69 pp. Cunningham, I. J. 1931. CXLI Some biochemical and physiological aspects of copper in animal nutrition. Biochem. J. 25 :1267-1294. Davis, G. K. 1950. The influence of copper on the metabolism of phosphorus and molybdenum. In Symposium on copper metab- olism, W. D. McElroy and B. Glass I eds) . Johns Hopkins Uni- versity Press, Baltimore, Md. pp. 216-229. Deschiens, R. 1968. Control of the effect of chemical molluscicides of freshwater zoophytic associations. C.R. (Acad. Sci., Paris) Ser. D:266. Dick, A. T. 1953. Effect of inorganic sulfate on the excretion of molybdenum in sheep. Aust. Vet. J. 29:18. Dick, A. T. 1956. Molybdenum in animal nutrition. Soil. Sci. 81 :229. Doner, H. E., and M. M. Mortland. 1969. Benzene complexes with copper (II) montmorillonite. Science 166:1406-1408. Doudoroff, P., and M. Katz. 1953. Critical review of literature on the toxicity of industrial wastes and their components to fish. II. The metals, as salts. Sewage Ind. Wastes 25(7) :802-839. Dowdy, R. P., and G. Matrone. 1968. Copper-molybdenum inter- action in sheep and chicks. J. Nutr. 95:191-196. Erickson, S. J., N. Lackie, and T. E. Maloney. 1970. A screening technique for estimating copper toxicity to estuarine phyto- plankton. J. Water Pollut. Control Fed. 42:27(}-278. Farrer, P. A., and S. P. Mistilis. 1967. Absorption of exogenous and endogenous biliary copper in the rat. Nature 213:291. Federal Water Quality Administration. 1968. Water quality criteria: Report of the National Technical Advisory Committee to the Secretary of the Interior. U.S. Government Printing Office, Washington, D.C.

78 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE Ferguson, W. S., A. H. Lewis, and S. J. Watson. 1938. Molybdenum in nutrition of milking dairy cows. Nature 141 :SS3. Ferguson, W. S., A. H. Lewis, and S. J. Watson. 1943. The teart pat- tures of Somerset: (I) the cause and cure of teart ness. J. Agric. Sci. 33:44-S I. Greenberg, S. S. 1942. Inhibitory effects of inorganic components on photosynthesis in Chlore/111. Am. J. Bot. 29:121-127. Hadjimarkos, D. M. 1967. Effect of trace elements on dental caries. J. Pediatr. 70:967-969. Hartmans, J., and M. S. M. Bosman. 1970. Differences in the copper status of grazing and housed cattle and their biochemical back- grounds. In Trace element metabolism in animals, C. F. Mills (edJ. Proceedings of the World Association for Animal Pro- duction/International Biological Programme International Sympo- sium, Aberdeen, Scotland, 1969. E. &. S. Livingstone, Edin- burgh. (Also, Williams and Wilkins Co., Baltimore, Md.) Hassall, K. A. 1963. Uptake of copper and its physiological effect on Chlore/111 vulgaris. Physiol. Plant 16:323-332. Hawkes, H. E., and J. S. Webb. 1962. Geochemistry in mineral ex- ploration. Harper and Row, New York. 415 pp. Hazel, C. R., and S. J. Meith. 1970. Bioassay of king salmon eggs and sac fry in copper solutions. Calif. Fish Game 56 :77-140. Hill, C. H., and G. Matrone. 1970. Otemical parameters in the study of in vivo and in vitro interactions of transition elements. Fed. Proc. 29:1474-1481. Hueck, H. J., and D. Adema. 1968. Toxicological investigations in an artificial ecosystem. A progress report on copper toxicity toward algae and daphniae. Helgolander Wiss. Meeresunters. 17:188. Jones, J . R. E. 1938. The relative toxicity of lead, zinc, and copper to the stickleback (Gasterosteus aculeatus L.) and the effect of calcium on the toxicity of lead and zinc salts. J. Exp. Bioi. IS : 394-407. Jones, J. R. E. 1939. The relations between the electrolytic solution pressures of the metals and their toxicity to the stickleback (Gasterosteus aculeatus L.). J. Exp. Bioi. 16:425-437. Kellerman, K. F. 1912. The rational use of disinfectants and algi- cides in municipal water supplies. Eighth Int. Congr. Appl. Otem. Orig. Commun. 26:241-245. Kopp, J. F., and R. C. Kroner. 1968. Trace metals in waters of the United States: a five-year summary of trace metals in rivers and laltes of the United States (October 1, 1962-September 30, 196 7). U.S. Department of Interior, Federal Water Pollution Control Administration, Cincinnati, Ohio. 32 pp. and 16 ap- pendices. Kubota, J., and W. H. Allaway. 1972. Geographic distribution of trace element problems in the United StateL In Micronutrients in agriculture. Soil Science Society of America, Inc. Madison, Wise. pp. S2S-SS4 . Lailach, G. E., J. D. Thompson, and G. W. Brindley. 1968. Ab- sorption of pyrimidines, purines and nucleosides by Co-. NC, eu-, and Fe (III) montmorillonite (Oay~rganic studies XIII). Oay Miner. 16:295-301. Mandelli, E. F. 1960. The inhibitory effects of copper on marine phytoplankton. Cont. Mar. Sci. 14:47-57. Marsh, M. C., and R. K. Robinson. 1910. The treatment of fish- cultural waters for the removal of algae. Bull. Bur. Fish. 28 (part 11):871-890. Matrone, G. 1970. Biochemistry and mechanisms of action of trace elements. Proceedings of the Eighth International Nutritional Congress, 1969. Excerpt& Med. (Amsterdam) pp. 171-175. Miller, R. F ., N. 0. Price, and R. W. Engel. 1959. The microelement (Zn, Mn, Cu, Mo, and Co) balance of 7-9 year old girb. Fed. Proc. 18:538. Mount, D. I. 1968. Otronic toxicity of copper to fathead minnows (Pimephaler promellls Rafinesque). Water Res. 2:215 . Mount, D. 1., and C. E. Stephan. 1969. Otronic toxicity of copper to the fathead minnow (Pimephalell promellls) in soft water. J. Fish. Res. Board Can. 26 :2449. Nielsen, E. S., L. Kamp-Nielsen, and S. Wium-Anderson. 1969. The effects of deleterious concentrations of copper on the photosynthesis of Chlore/111 pyrenoidolll. Physiol. Plant 22:1121-1133. Nielsen, E. S., and S. Wium-Anderson. 1970. Copper ions as poison in the sea and in freshwater. Int. J. Life Oceans Coastal Waters 6(2):93. O'Dell, B. L., and B. J. Campbell. 1971. Trace elements: Metabo- lism and metabolic function. In Comprehensive biochemistry, M. Florkin and E. H. Stotz (edsJ . Elsevier, Amsterdam. Vol. 21. pp. 179ff. Oertel, A. C. 1961 . Relation between trace element concentrations in soil and parent material. J. Soil Sci. 12: 119. Osaki, S., D. A. Johnson, and E. Frieden. 1966. Possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J. Bioi. Otem. 241:2746. Parker, R. L. 1967. Composition of the earth's crust. In Data of geo- chemistry, M. Fleischer (edJ. U.S. Geol. Surv. Prof. Pap. No. 44G-D. U.S. Government Printing Office, Washington, D.C. pp. 1-19. Patterson, J. B. E. 1971. Metal toxicities arising from industry. In Trace elements in soils and crops. Tech. Bull. No. 21. HMSO, Ministry of Agriculture, Fisheries, and Food, London. pp. 193- 207. Pickering, Q. H., and C. Henderson. 1964. The acute toxicity of some heavy metals to different species of warm water fisheL Proceedings of the Nineteenth Industrial Waste Conference, Part II. Eng. Ext. Ser. 117:578-591. Pippy, J. H., and G. M. Hare. 1969. Relationship of river pollution to bacterial infection in salmon (Sil/mo 11111lr) and suckers (Castastomus commersont). TranL Am. Fish. Soc. 98:685. Powers, E. G. 1917. The goldfish (CaraSJius carrmiur) as a test ani- mal in the study of toxicity. W. Bioi. Monogr. 4:127-193. Prat, S., and K. Komarek. 1934. Inheritance of resistance to copper (Found 3.25% Cu in the ash of Melandrium rilvestres growing on soils of 1-33% CuJ Sb. Masaryk. Akad. Pr. 8(8): 1-16. Price, N. 0., W. N. Linkows, and R. W. Engel. 1955. Minor element content of forage plants and soilL J . Agric. Food Otem. 3:226- 229. Ragan, H. A., S. Nacht, G. R. Lee, C. R. Bishop, and G. E. Cart- wright. 1969. Effect of ceruloplasmin on plasma iron in copper- deficient twine. Am. J. Physiol. 217:1320. Raymont, J. E. G., and J. Shields. 1964. Toxicity of copper and chromium in the marine environment. Adv. Water Pollut. Res. 3:275-318. Reuther, W., and P. F. Smith. 1953. Effects of high copper content of sandy soil on growth of citrus seedlings. Soil Sci. 75:219-224. Scaife, J. F. 1956. The action of molybdenum on some copper en- zymes. New Zealand J. Sci. Tech. (Section A) 38:285-298. Schroeder, H. A., A. P. Nason, I. H. Tipton, and J. J. Balassa. 1966. Essential trace metals in man: copper. J. Chronic Dis. 19: 1007. Schwarz, K., and W. Mertz. 1957. A glucose tolerance factor and its differentiation from factor 3. Arch. Biochem. Biophys. 72:515. Smith, H. 1967. The distribution of antimony, arsenic, copper and zinc in human tissue. J. Forensic Sci. Soc. 7(2):97-102. Sprague, J. B., P. F. Eison, and R. L. Saunders. 1964. Sublethal copper-zinc pollution in a salmon river-a field and laboratory study. In Proceedings of the Second International Conference I ....

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