As already mentioned, the ultratrace elements other than selenium and iodine are a disparate group in terms of their possible requirement or nutritional importance for human health and well-being. Although molybdenum has known essential functions, it has no unequivocally identified practical nutritional importance. The other 14 ultratrace elements discussed here have been suggested to be essential based on circumstantial evidence. This evidence is presented below along with some indication of possible requirement (extrapolated from the deficient animal intakes shown in Table 3), and some indication as to what constitutes a high intake.
A dietary deficiency of aluminum in goats reportedly results in increased abortions, depressed growth, incoordination and weakness in hind legs, and decreased life expectancy. Aluminum deficiency has also been reported to depress growth in chicks. Other biochemical actions that suggest aluminum could possibly act in an essential role include the in vitro findings that it activates the enzyme adenylate cyclase, enhances calmodulin activity, stimulates DNA synthesis in cell cultures, and stimulates osteoblasts to form bone through activating a purative G, protein-coupled cation sensing system.
If humans have a requirement for aluminum, for which there is currently no evidence, it probably is much less than 1.0 mg day-1. Aluminum toxicity apparently is not a concern for healthy individuals. Cooking foods in aluminum cook-ware does not lead to detrimental intakes of aluminum. High dietary ingestion of aluminum probably is not a cause of Alzheimer's disease. However, high intakes of aluminum through such sources as buffered analgesics and antacids by susceptible individuals (e.g., those with impaired kidney function including the elderly and low-birthweight infants) may lead to pathological consequences and thus should be avoided. For most healthy individuals, an aluminum intake of 125 mg day 1 should not lead to toxicological consequences.
Arsenic deprivation has been induced in chickens, hamsters, goats, pigs, and rats. In the goat, pig, and rat, the most consistent signs of deprivation were depressed growth and abnormal reproduction characterized by impaired fertility and elevated perinatal mortality. Other notable signs of deprivation in goats were depressed serum triacylglycerol concentrations and death during lactation. Myocardial damage was also present in lactating goats. Other signs of arsenic deprivation have been reported, including changes in mineral concentrations in various organs. However, listing all signs reported to be caused by arsenic deficiency may be misleading because studies with chicks, rats, and hamsters have revealed that the nature and severity of the signs are affected by a number of dietary and other factors. For example, female rats fed a diet that is conducive to kidney calcification have more severe calcification when dietary arsenic is low; kidney iron was also elevated. Male rats fed the same diet do not show these changes.
Other factors that affect the response to arsenic deprivation include methionine, arginine, choline, taurine, and guanidoacetic acid. In other words, the signs of arsenic deprivation were changed and generally enhanced by nutritional stressors that affected sulfur amino acid or labile methyl-group metabolism; this suggests that arsenic has a biochemical function that affects these substances. Further evidence for this suggestion is the finding that arsenic deprivation slightly increases liver S-adenosylhomo-cysteine (SAH) and decreases liver S-adenosyl-methionine (SAM) concentrations in animal models, thus resulting in a decreased SAM/SAH ratio; SAM and SAH are involved in methyl transfer. Additionally, arsenite can induce the isolated cell production of certain proteins known as heat shock proteins. The control of production of these proteins in response to arsenite apparently is at the transcriptional level, and involves changes in the methylation of core histones. It also has been shown that arsenic can increase the methylation of the p53 promoter, or DNA, in human lung cells.
It has been suggested, based upon animal data, that a possible arsenic requirement for humans eating 8.37MJ (2000kcal) would be 12-25 mgday-1; this is near the typical daily intake shown in Table 3. Because of mechanisms for the homeo-static regulation of arsenic (including methylation,
Table 3 Human body content, and deficient, typical, and rich sources of intakes of ultratrace elements
Apparent deficient intake (species)
Human body content
Typical human daily dietary intake
16G mgkg-1 (goat)
<25 mgkg 1 (chicks) <35 mgkg-1 (goat) <15 mgkg-1 (hamster) <30 mgkg-1 (rat) <0.3 mgkg-1 (chick) 0.25-0.35 mg perday
G.8mgkg-1 (goat) <5 mgkg-1 (goat) <4 mgkg-1 (rat)
< 25 mgkg 1 (goat) <25 mg day-1 (human) <30 mgkg-1 (rat)
<100 mgkg-1 (goat) <20 mgkg-1 (rat) 180 mgkg-1 (goat)
2GG-35G mg 5-2G mg
Children less than age 10 years, 2 mg Adults, 120 mg 350 mg
1-2 mg 36Gmg
7-14 mg 1GG mg
1-3 mg Nonfluoridated areas,
Baked goods prepared with chemical leavening agents (e.g., baking powder), processed cheese, grains, vegetables, herbs, tea, antacids, buffered analgesics Shellfish, fish, grain, cereal products
Food and drink of plant origin, especially noncitrus fruits, leafy vegetables, nuts, pulses, avocados, legumes, wine, cider, beer, peanut butter Grain, nuts, fish Shellfish, grains - especially those grown on high-cadmium soils, leafy vegetables Fish, tea, fluoridated water
Wheat bran, vegetables, leguminous seeds Seafood, plant foodstuffs grown under high-lead conditions
Eggs, meat, processed meat, fish, milk, milk products, potatoes, vegetables (content varies with geological origin) Milk and milk products, dried legumes, pulses, organ meats (liver and kidney), cereals, and baked goods Chocolate, nuts, dried beans and peas, grains Coffee, black tea, fruits and vegetables (especially asparague), poultry, fish Unrefined grains of high fiber content, cereal products, beer, coffee Canned foods Shellfish, mushrooms, parsley, dill seed, black pepper, some prepared foods, grains, beer, wine then excretion in urine), its toxicity through oral intake is relatively low; it is actually less toxic than selenium, an ultratrace element with a well-established nutritional value. Toxic quantities of inorganic arsenic generally are reported in milligrams. For example, reported estimated fatal acute doses of arsenic for humans range from 70 to 300 mg or about 1.0 to 4.0 mg per kg body weight.
Some forms of organic arsenic are virtually nontoxic; a 10 g per kg body weight dose of arsenobe-taine depressed spontaneous motility and respiration in male mice, but these symptoms disappeared within 1 h. Results of numerous epidemio-logical studies have suggested an association between chronic overexposure to arsenic and the incidence of some forms of cancer; however, the role of arsenic in carcinogenesis remains controversial. Arsenic does not seem to act as a primary carcinogen, and is either an inactive or extremely weak mitogen. In the USA, a standard known as a reference dose (RfD; lifetime exposure that is unlikely to cause adverse health effects) of 0.3 mgperkg body weight per day, or 21 mgday-1 for a 70 kg human, has been suggested for inorganic arsenic. Because of safety factors in the determination, the RfD for arsenic conflicts with the possible arsenic requirement; this conflict is similar to that for some other mineral elements including zinc. These conflicts are currently being addressed by nutritionists and toxicologists.
Listing the signs of boron deficiency for animal models is difficult because most studies have used stressors to enhance the response to changes in dietary boron. Thus, the response to boron deprivation varied as the diet changed in its content of nutrients such as calcium, phosphorus, magnesium, potassium, and vitamin D. Although the nature and severity of the changes varied with dietary composition, many of the findings indicated that boron deprivation impairs calcium metabolism, brain function, and energy metabolism. Studies also suggest that boron deprivation impairs immune function and exacerbates adjuvant-induced arthritis in rats. Feeding low boron to humans (<0.3 mgday-1) altered the metabolism of macrominerals, electrolytes, and nitrogen, as well as oxidative metabolism, and produces changes in erythropoiesis and hematopoiesis. Boron deprivation also altered electroencephalograms to suggest depressed behavioral activation and mental alertness, depressed psychomotor skills and cognitive processes of attention and memory, and enhanced some effects of estrogen therapy such as increases in concentrations of serum 17/-estradiol and plasma copper. Other findings suggest that boron may have an essential function. In vitro it competitively inhibits oxidoreductase enzymes, which require pyridine or flavin nucleo-tides, and enzymes such as serine proteases, which form transition state analogs with boronic acid or borate derivatives. Boron has an essential function in plants, in which it influences redox actions involved in cellular membrane transport. This latter finding supports the hypothesis that boron has a role in cell membrane function or stability such that it influences the response to hormone action, transmembrane signaling, or transmembrane movement of regulatory cations or anions. Another finding in support of this hypothesis is that boron influences the transport of extracellular calcium into and the release of intracellular calcium in rat platelets activated by thrombin.
An analysis of both human and animal data has resulted in the suggestion by a World Health Organization (WHO) publication that an acceptable safe range of population mean intakes of boron for adults could well be 1.0-13 mgday-1. In other words, 1.0 mg probably covers any requirement and 13 mg will not lead to any toxicological consequences. However, the US and Canada concluded in 2002 that there was still insufficient evidence to establish a clear biological function for boron in humans, so no recommended dietary intake was set for those countries. Boron has a low order of toxi-city when administered orally. Toxicity signs in animals generally occur only after dietary boron exceeds 100 mgg-1. The low order of toxicity of boron for humans is shown by the use of boron as a food preservative between 1870 and 1920 without apparent harm. It was reported in 1904 that when doses equivalent to more than 0.5 g of boric acid were consumed daily, disturbances in appetite, digestion, and health occurred. It was concluded in this report that this quantity of boron per day was too much for an average person to receive regularly. The upper limit (UL) for the US and Canada has been set at 20mgday-1 based on extrapolation from animal studies.
It has been reported that a dietary deficiency of bromide results in depression of growth, fertility, hematocrit, hemoglobin, and life expectancy, and increases in milk fat and spontaneous abortions in goats. Other biological actions that suggest bromine could possibly act in an essential role include the findings that bromide alleviates growth retardation caused by hyperthyroidism in mice and chicks, and insomnia exhibited by many hemodia-lysis patients has been associated with bromide deficit.
If humans have a requirement for bromide, which has not yet been shown to be the case, based on deficient intakes for animals it is probably no more than 1.0 mg day-1. Bromine ingested as the bromide ion has a low order of toxicity; thus bromine is not of toxicological concern in nutrition.
Deficiency of cadmium reportedly depresses growth of rats and goats. Other in vitro biochemical actions that suggest cadmium could possibly act as an essential element include the finding that it has transforming growth factor activity and stimulates growth of cells in soft agar.
If humans have a requirement for cadmium, which is still uncertain, based on deficient intakes for animals it is probably less than 5 mgday-1. Although cadmium may be an essential element at these extremely low amounts, it is of more concern because of its toxicological properties. Cadmium has a long half-life in the body and thus high intakes can lead to accumulation, resulting in damage to some organs, especially the kidney. The toxicological aspects of cadmium have been discussed earlier (See: xx).
Reported unequivocal or specific signs of fluoride deficiency are almost nonexistent. A study with goats indicated that a fluoride deficiency decreases life expectancy and caused pathological hisrology in the kidney and endocrine organs. Most of the evidence accepted as showing a need for fluoride comes from studies in which it was orally administered in pharmacological doses. Pharmacological doses of fluoride have been shown to prevent tooth caries, improve fertility, hematopoiesis and growth in iron-deficient mice and rats, prevent phosphorus-induced nephro-calcinosis, and perhaps prevent bone loss leading to osteoporosis.
Although fluoride is not generally considered an essential element in the classical sense for humans, it still is considered a beneficial element. Because of this, in the US-Canada, the AI has been set, on the basis of reducing dental caries without adverse effects, at: 0.01 mg day-1 for infants 0-6 months; 0.5 mg for 6-12 months; 0.7 mg for 1-3 years; 1 mg for 4-8 years; 2mg for 9-13 years; 3mg for 1418 years; 3mg for women and 4mg for men. These intakes provide amounts of fluoride that will give protection against dental caries and generally not result in any consequential mottling of teeth; they should not be considered intakes that are needed to prevent a nutritional deficiency of fluoride. Chronic fluoride toxicity through excessive intake mainly through water supplies and industrial exposure has been reported in many parts of the world. Chronic toxicity resulting from the ingestion of water and food providing in excess of 2.0 mg day-1 is manifested by dental fluorosis or mottled enamel ranging from barely discernible with intakes not much above 2.0 mg day-1 to stained and pitted enamel with much higher amounts. Crippling skeletal fluorosis apparently occurs in people who ingest 10-25mgday-1 for 7-20 years. The UL (mg per day) is 0.7 mg for 0-6 months, 0.9 mg for 7-12 months, 1.3 mg for 1-3 years, and 2.2 mg for 4-8 years, and 10 mg for all older age groups including pregnant and lactating women.
A low germanium intake has been found to alter bone and liver mineral composition and decrease tibial DNA in rats. Germanium also reverses changes in rats caused by silicon deprivation, and is touted as having anticancer properties because some organic complexes of germanium can inhibit tumor formation in animal models.
If humans have a requirement for germanium, based on animal deprivation studies, it is probably less than 0.5 mg day-1. The toxicity of germanium depends upon its form. Some organic forms of germanium are less toxic than inorganic forms. Inorganic germanium toxicity results in kidney damage. Some individuals consuming high amounts of organic germanium supplements contaminated with inorganic germanium have died from kidney failure. Although germanium has long been believed to have a low order of toxicity because of its diffusible state and rapid elimination from the body, until more knowledge is obtained about the intakes at which germanium becomes toxic, they probably should not greatly exceed those found in a typical diet. An intake of no more than 5.0 mg day-1 would meet any possible need for germanium and most likely will be below the level found to have toxicological consequences.
A large number of findings have come from one source that suggests that a low dietary intake of lead is disadvantageous to pigs and rats. Apparent deficiency signs found include: depressed growth; anemia; elevated serum cholesterol, phospholipids and bile acids; disturbed iron metabolism; decreased liver glucose, triacylglycerols, LDL-cholesterol and phospholipids; increased liver cholesterol; and altered blood and liver enzymes. A beneficial action of lead (2 mgg-1 versus 30ngg-1 diet) is that it alleviates iron deficiency signs in young rats.
If humans have a requirement for lead, which has not yet been demonstrated to be the case, it is probably less than 30 mg day-1 based on animal deprivation studies. Although lead may have beneficial effects at low intakes, lead toxicity is of more concern than lead deficiency. Lead is considered one of the major environmental pollutants because of the past use of lead-based paints and the combustion of fuels containing lead additives. The toxicological aspects of lead are discussed elsewhere (See: xx).
Lithium deficiency reportedly results in depressed fertility, birthweight, and life span, and altered activity of liver and blood enzymes in goats. In rats, lithium deficiency apparently depresses fertility, birthweight, litter size, and weaning weight. Other in vitro biochemical actions suggesting that lithium could possibly act as an essential element include the stimulation of growth of some cultured cells, and having insulinomimetic action. Lithium is best known for its pharmacological properties; it is used to treat manic-depressive psychosis. Its ability to affect mental function perhaps explains the report that incidence of violent crimes is lower in areas with high-lithium drinking water.
If humans have a requirement for lithium, based on animal deprivation studies it is probably less than 25 mg day-1, which is much less than the usual dietary intake (see Table 3). Lithium is not a particularly toxic element, but the principal disadvantage in the use of lithium for psychiatric disorders is the narrow safety margin between therapeutic and toxic doses. About 500 mg lithium per day is needed to raise serum concentrations to be effective in these disorders; this is close to the concentration where mild toxicity signs of gastrointestinal disturbances, muscular weakness, tremor, drowsiness, and a dazed feeling begin to appear. Severe toxicity results in coma, muscle tremor, convulsions, and even death.
The evidence for the essentiality of molybdenum is substantial and conclusive. Molybdenum functions as a cofactor in enzymes that catalyze the hydroxylation of various substrates. Aldehyde oxidase oxidizes and detoxifies various pyrimidines, purines, pteridines, and related compounds. Xanthine oxidase/dehydrogenase catalyzes the transformation of hypoxanthine to xanthine, and xanthine to uric acid. Sulfite oxidase catalyzes the transformation of sulfite to sulfate. Attempts to produce molybdenum deficiency signs in rats, chickens, and humans have resulted in only limited success, and no success in healthy humans.
Deficiency signs in animals are best obtained when the diet is supplemented with massive amounts of tungsten, an antagonist of molybdenum metabolism. Nonetheless, reported deficiency signs for goats and pigs are depressed food consumption and growth, impaired reproduction characterized by increased mortality in both mothers and offspring, and elevated copper concentrations in liver and brain. A molybdenum-responsive syndrome found in hatching chicks is characterized by a high incidence of late embryonic mortality, mandibular distortion, anophthalmia, and defects in leg bone and feather development. The incidence of this syndrome was particularly high in commercial flocks reared on diets containing high concentrations of copper, another molybdenum metabolism antagonist.
Examples of nutritional standards that have been set for molybdenum are the current US-Canada recommendations, which are the following: Adequate Intake for infants aged 0-0.5 years, 2 mg and aged 0.5-1 years, 3 mg; RDA for children 1-3 years, 17 mg; 4-8 years, 22 mg; 9-13 years, 34 mg; 1418 years, 43 mg; women from 19->70 years, 34 mg; and men aged 19->70 years, 45 mg. The recommended intake is 50 mgday-1 in pregnancy and lactation. These values were set using balance data in adults with extrapolation to the other groups. Usual dietary intakes are substantially higher than these recommendations. Large oral doses are necessary to overcome the homeostatic control of molybdenum; thus, it is a relatively nontoxic nutrient. The UL for children 1-3 years is 300 mg, for 4-8 years, 600 mg, and 9-13 years, 1100 mg. For adolescents the UL is 1700 mg, and for adults, 2000 mg, including pregnant and lactating women, based on doses that caused reproductive damage in animals.
Based on recent studies with rats and goats, nickel deprivation depresses growth, reproductive performance and plasma glucose, and alters the distribution of other elements in the body, including calcium, iron, and zinc. As with other ultratrace elements, the nature and severity of signs of nickel deprivation are affected by diet composition. For example, vitamin B12 status affects signs of nickel deprivation in rats, and the effects suggest that vitamin B12 must be present for optimal nickel function. The nickel function also may involve folic acid because an interaction between these two affected the vitamin B12 and folic acid-dependent pathway of methionine synthesis from homocysteine. Nickel might function as a cofactor or structural component in specific metalloenzymes in higher organisms because such enzymes have been identified in bacteria, fungi, plants, and invertebrates. These nickel-containing enzymes include urease, hydrogenase, methylcoenzyme M reductase, and carbon monoxide dehydrogenase. Moreover, nickel can activate numerous enzymes in vitro.
Based on a lack of human studies, no recommended intake levels have been set for humans. Life-threatening toxicity of nickel through oral intake is unlikely. Because of excellent homeostatic regulation, nickel salts exert their toxic action mainly by gastrointestinal irritation and not by inherent toxi-city. Based on extrapolation from animal studies, the UL has been set for the US and Canada at the following doses of soluble nickel salts: 1-3 years, 0.2 mg; 4-8 years, 0.3 mg; 9-13 years, 0.6 mg; and all adolescents and adults, 1 mg.
Rubidium deficiency in goats reportedly results in depressed food intake and life expectancy, and increased spontaneous abortions. If rubidium is required by humans, the requirement probably would be no more than a few hundred micrograms per day, based on animal data. Rubidium is a relatively nontoxic element and thus is not of toxicolo-gical concern from the nutritional point of view.
Most of the signs of silicon deficiency in chickens and rats indicate aberrant metabolism of connective tissue and bone. For example, chicks fed a silicon-deficient diet exhibit structural abnormalities of the skull, depressed collagen content in bone, and long-bone abnormalities characterized by small, poorly formed joints and defective endochondral bone growth. Silicon deprivation can affect the response to other dietary manipulations. For example, rats fed a diet low in calcium and high in aluminum accumulated high amounts of aluminum in the brain; silicon supplements prevented the accumulation. Also, high dietary aluminum depressed brain zinc concentrations in thyroidectomized rats fed low dietary silicon; silicon supplements prevented the depression. This effect was not seen in nonthyroidectomized rats. Other biochemical actions suggest that silicon is an essential element. Silicon is consistently found in collagen, and in bone tissue culture has been found to be needed for maximal bone prolylhydroxylase activity. Silicon deficiency decreases ornithine aminotransferase, an enzyme in the collagen formation pathway, in rats. Finally, silicon is essential for some lower forms of life in which silica serves a structural role and possibly affects gene expression.
Much of the silicon found in most diets probably occurs as aluminosilicates and silica from which silicon is not readily available. Owing to lack of evidence for a biological role for silicon in humans, no recommended intakes have been set. Silicon is essentially nontoxic when taken orally. Magnesium trisilicate, an over-the-counter antacid, has been used by humans for more than 40 years without obvious deleterious effects. Other silicates are food additives used as anticaking or antifoaming agents.
A dietary deficiency of tin has been reported to depress growth, response to sound, and feed efficiency, alter the mineral composition of several organs, and cause hair loss in rats. Additionally, tin has been shown to influence heme oxygenase activity and has been associated with thymus immune and homeostatic functions.
Owing to lack of data no recommended intakes have been set for tin. Inorganic tin is relatively non-toxic. However, the routine consumption of foods packed in unlacquered tin-plated cans may result in excessive exposure to tin, which could adversely affect the metabolism of other essential trace elements including zinc and copper. Because 50mgday-1 of tin was found to affect zinc and copper metabolism, routine intakes near this amount probably should be avoided.
Vanadium-deprived goats were found to exhibit an increased abortion rate and depressed milk production. About 40% of kids from vanadium-deprived goats died between days 7 and 91 of life with some deaths preceded by convulsions; only 8% of kids from vanadium-supplemented goats died during the same time. Also, skeletal deformations were seen in the forelegs, and forefoot tarsal joints were thickened. In rats, vanadium deprivation increases thyroid weight and decreases growth. Other biochemical actions support the suggestion that vanadium could possibly act in an essential role. In vitro studies with cells and pharmacological studies with animals have shown that vanadium has: insulin-mimetic properties; numerous stimulatory effects on cell proliferation and differentiation; effects on cell phosphorylation-dephosphory-lation; effects on glucose and ion transport across the plasma membrane: and effects on oxidation-reduction processes. Some algae, lichens, fungi, and bacteria contain enzymes that require vanadium for activity. The enzymes include nitrogenase in bacteria, and bro-moperoxidase, iodoperoxidase, and chloroperoxidase in algae, lichens, and fungi, respectively. The haloperoxidases, catalyze the oxidation of halide ions by hydrogen peroxide, thus facilitating the formation of a carbon-halogen bond. The best known haloper-oxidase in animals is thyroid peroxidase. Vanadium deprivation in rats affects the response of thyroid per-oxidase to changing dietary iodine concentrations. Since a functional role for vanadium has not been determined in humans no recommended intakes have been set.
Vanadium can be a relatively toxic element. Green tongue, cramps and diarrhea, and neurological effects have occurred in humans ingesting vanadium salts. Based on renal damage in animals, the UL for adults is 1.8 mg vanadium salts per day, with insufficient data to set a UL for other age groups.
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