P OSSIBLY E SSENTIAL U LTRA T RACE E LEMENTS

Circumstantial evidence often is used to contend that an element is essential. This evidence generally fi ts into four categories.

These are:

1. Dietary deprivation in some animal model consistently results in a changed biological function, body structure, or tissue composition that is preventable or reversible by an intake of an apparent physiological amount of the element in question.

2. The element fi lls the need at physiological concentrations for a known in vivo biochemical action to proceed in vitro.

3. The element is a component of known biologically important molecules in some life form.

4. The element has an essential function in lower forms of life.

TABLE 8.9

Biochemical, Clinical and Nutritional Aspects of Iodine

Biological Function Iodine has only one function; it is a component of thyroid hormones. However, thyroid hormones have an impact on a wide range of metabolic and developmental functions

Signs of Defi ciency

Biochemical Decreased plasma or serum thyroxine (T4) and triiodothyronine (T3), and urinary iodine, and increased plasma or serum thyroid stimulating hormone (TSH) and cholesterol

Physiological Decreased basal metabolic rate; increased heart rate, size, stroke volume and output; reduced muscle mass and delayed skeletal maturation; abnormal production of glial cells and myelinogenesis; and goiter

Pathological Consequences of Defi ciency

Established The spectrum of iodine defi ciency disorders is large and includes fetal congenital anomalies and perinatal mortality

Neurological cretinism characterized by mental defi ciency, deaf mutism, spastic diplegia and squint

Psychomotor defects

Fatigue and slowing of bodily and mental functions

Weight increase and cold intolerance caused by slowing of the metabolic rate Predisposing Factors for Defi ciency Residence in an area with low soil iodine and treatment with lithium

Recommended Intakes

Prevention of defi ciency RDAs (and AIs) set by the Food and Nutrition Board³ for iodine (μg/day) are: infants age 0–0.5 year, (110), and age 0.5–1 year, (130); children age 1–8 years, 90, and age 9–13 years, 120; males age ≥ 14 years, 150;

females ≥14 years, 150, pregnant, 220, and lactating, 290

Therapeutic or benefi cial Iodized oil, in which the fatty acids are chemically modifi ed by iodination, slowly releases iodine over a period of months or years in the body. In populations with a high prevalence of severe iodine defi ciency disorders (goiter incidence 30% or more), 1 ml of iodized oil containing 480 mg of iodine administered orally or by injection is a therapeutic measure for long term protection against iodine defi ciency. An oral iodine dose as potassium iodide or iodate of 30 mg monthly or 8 mg biweekly has been found to be an effective prophylaxis for iodine defi ciency Food Sources Iodized salt has been the major method for assuring adequate iodine intake since the 1920s. Other sources are sea

foods and foods from plants grown on high-iodine soils

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TABLE 8.10

Biochemical, Clinical and Nutritional Aspects of Molybdenum

Biological Function In humans, three molybdoenzymes have been identifi ed; these are aldehyde oxidase, xanthine oxidase/dehydrogenase and sulfi te oxidase in which molybdenum exists as a small nonprotein factor containing a pterin nucleus.

Molybdoenzymes oxidize and detoxify various pyrimidines, purines and pteridines; catalyze the transformation of hypoxanthine to xanthine and xanthine to uric acid; and catalyze the conversion of sulfi te to sulfate

Signs of Defi ciency

Biochemical A patient on total parenteral nutrition exhibited hypermethioninemia, hypouricemia, hyperoxypurinemia, hypouricosuria, and low urinary sulfate excretion

Patients with inborn errors of molybdenum cofactor synthesis exhibited increased plasma and urine sulfi te, sulfate, thiosulfate, S-sulfocysteine, taurine, and xanthine; increased serum S-sulfonated transthyretin; and decreased urine and serum uric acid

Physiological Total parenteral nutrition patient: mental disturbances progressing to coma. Genetic errors patients: seizures, failure to thrive, and brain atrophy/lesions

Pathological Consequences of Defi ciency

Established Patients with inborn errors of molybdenum cofactor synthesis: mental retardation, dislocated lenses, and death at early age

Suggested Increased susceptibility to cancer⁹⁰

Predisposing Factors for Defi ciency A high sulfur amino acid intake may increase the need for molybdenum Recommended Intakes

Prevention of defi ciency RDAs (and AIs) set by the Food and Nutrition Board³ for molybdenum (μg/day) are: infants age 0–0.5 year, (2), and age 0.5–1 year, (3); children and adolescents age 1–3 years, 17, age 4–8 years, 22, age 9–13 years, and age 14–18 years, 43; adults, 45; pregnant and lactating females, 50

Therapeutic or benefi cial None have been proposed

Food Sources Milk and milk products, pulses, organ meats (e.g., liver and kidney), cereals, baked goods

TABLE 8.11

Biochemical, Clinical and Nutritional Aspects of Selenium

Biological Function Selenium is a component of enzymes that catalyze redox reactions; these enzymes include various types of glutathione peroxidases, iodothyronine 5’-deiodinases, and thioredoxin reductases

Signs and Symptoms of Defi ciency

Biochemical Decreased plasma and erythrocyte selenium, plasma selenoprotein P and erythrocyte glutathione peroxidase Physiological Bilateral muscular discomforts, muscle pain, dry fl aky skin, and wasting

Pathological Consequences of Defi ciency

Established In the presence of other contributing factors, Keshan disease, a multiple focal myocardial necrosis resulting in acute or chronic heart function insuffi ciency, heart enlargement, arrhythmia, pulmonary edema, and death; other consequences include impaired immune function and increased susceptibility to viral infections

Suggested Increased susceptibility to certain types of cancer; Kashin-Beck disease, an endemic osteoarthritis; and mood disturbances^93,94 Recommended Intakes

Prevention of defi ciency RDAs (and AIs) set by the Food and Nutrition Board² for selenium (μg/day) are: infants age 0–0.5 year, (15), and age 0.5–1 year, (20) children age 1–3 years, 20, age 4–8 years, 30; and age 9–13 years, 40; males age ≥14 years, 55;

females age ≥14 years, 55, and lactating, 70

Therapeutic or benefi cial A supplement of 200 μg/day of selenium was found to have cancer protective effects Food Sources Fish, eggs, and meat from animals fed luxuriant selenium, grains grown on high-selenium soil

An element is considered to have strong circumstantial support for essentiality if all four types of evidences exist for it. There is strong circumstantial evidence for the essentiality of arsenic, nickel, silicon, and vanadium; thus, they are considered possibly essential ultra trace elements.

Arsenic

In addition to the information in Table 8.12, other fi ndings, supporting arsenic essentiality, are that arsenic can activate some enzymes and enhance DNA synthesis by unsensitized and phytohemagglutinin-stimulated human lymphocytes in vitro.

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170 Handbook of Nutrition and Food

Interestingly, although arsenic is considered to be carcinogenic, it has recently been found to be effective in the treatment of acute promyelocytic leukemia⁹⁵ and cancer risk is decreased in populations that drink water containing small amounts of arsenic.⁹⁶ Hypothesized explanations for the decreased risk range from arsenic having an essential function that protects against oxidative damage and DNA repair inhibition to it having a hormetic effect. Hormesis is a process in which a low dose of a substance stimulates a response that is benefi cial, because it protects against adverse actions that are induced by mechanisms similar to toxic doses of the substance. The information in Table 8.12 primarily comes from reviews by Nielsen.^58,97

Nickel

By 1984, extensive signs of nickel deprivation had been reported for six animal species. Unfortunately, many of the reported signs may have been misinterpreted manifestations of pharmacologic actions, because nickel was provided in relatively high amounts to supplemented controls in some experiments. Thus, many of the early reported nickel deprivation fi ndings are not shown in Table 8.13. Recent animal experiments have shown that nickel is benefi cial, if not essential, for optimal reproduc-tive function, bone composition and strength, energy metabolism, and sensory function. Additional evidence supporting the possible essentiality of nickel is that it is essential for some lower forms of life, where it participates in hydrolysis and redox enzyme reactions, regulates gene expression, and stabilizes certain structures. Interestingly, the substrates or products for all the nickel-requiring enzymes are dissolved gases: hydrogen, carbon monoxide, carbon dioxide, methane, oxygen, and ammonia.

The gene expression function of nickel also involves the diffusion of oxygen and hydrogen into the cell. The information in Table 8.13 primarily comes from reviews by Nielsen,58,80,97,98 and Eder and Kirchgessner.⁹⁹

Silicon

In addition to the information in Table 8.14, other fi ndings supporting silicon essentiality include its localization in the active growth areas, or osteoid layer, and within the osteoblasts of bone in young experimental animals; its consistent presence in collagen and glycosaminoglycan fractions from several types of connective tissues; and its increased intake associated with increased cortical bone mineral density in men and premenopausal women. Also, orthosilicic acid at physiological concentra-tions was found to stimulate collagen type I synthesis in human osteoblast-like cells and enhance osteoblast differentiation in culture. The information in Table 8.14 primarily comes from reviews by Nielsen,58,80,97,98 and Carlisle.¹⁰⁰

TABLE 8.12

Arsenic: Biological Function in Lower Forms of Life, Defi ciency Signs in Animals, and Speculated Importance and Postulated Adequate Intake for Humans

Biological Function in Lower Forms of Life

A biochemical function for arsenic has not been identifi ed in lower forms of life. But, the bacterium Chrysiogenes arsenatis reduces As⁵⁺ to As³⁺ to gain energy for growth. There are enzymes in higher animals and humans that methylate arsenic with S-adenosylmethionine as the methyl donor. Arsenite methytransferase methylates arsenite to monomethylarsenic acid, which is methylated by monomethylarsenic acid methyltransferase to yield dimethylarsinic acid, the major form of arsenic in urine

Possible Biological Function in Humans

Arsenic possibly has a function involving the utilization of labile methyl groups arising from methionine, and thus infl uencing the function of systems dependent upon or regulated by methyl incorporation

Defi ciency Signs in Selected Experimental Animals

Goat Depressed growth and serum triglycerides; abnormal reproduction characterized by impaired fertility and elevated perinatal mortality; and death during lactation with myocardial damage

Pig Depressed growth and abnormal reproduction characterized by impaired fertility and elevated perinatal mortality Rat Depressed growth and hepatic putrescine, spermidine, spermine and S-adenosylmethionine

Elevated hepatic S-adenosylhomocysteine Abnormal reproduction

Speculated Importance for Humans Defi cient intakes may increase the risk for some types of cancers

Predisposing Factors for Defi ciency Stressors that affect the utilization of the labile methyl group including high dietary arginine and taurine, and low dietary methionine and choline

Stressors that affect arsenic metabolism including low dietary zinc and high dietary selenium Postulated Adequate Intake for

Humans

Based on the hypothesized requirements for experimental animals, 12–25 μg/day may be benefi cial or adequate for humans

Food Sources Shellfi sh, fi sh, grains, and cereal products

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TABLE 8.13

Nickel: Biological Function in Lower Forms of Life, Defi ciency Signs in Animals, and Speculated Importance and Postulated Adequate Intake for Humans

Biological Function in Lower Forms of Life

In lower forms of life, nickel has been identifi ed as an essential component of seven different enzymes: urease, hydrogenase, carbon monoxide dehydrogenase, methyl-S-coenzyme-M reductase, Ni-superoxide dismutase, glyoxalase I, and acireductone dioxygenase. Nickel has been reported to be required for the hydrogenase gene to be expressed in Bradyrhizobium japonicum

Possible Functions in Humans Nickel may have a function affecting signaling by a gaseous molecule (e.g., carbon monoxide) or regulated by cyclic guanosine monophosphate channels

Intracellular calcium ion signaling by affecting a calcium channel or receptor Enzyme reactivity or gene expression requiring a gaseous molecule Defi ciency Signs in Selected Experimental Animals

Goat Depressed growth, hematocrits, and reproductive performance

Pig Depressed growth, and altered distribution and proper functioning of zinc and calcium

Rat Depressed growth

Altered iron metabolism, brain and erythrocyte fatty acid composition, long bone shape, taste preference to saccharin, and eye mitochondrial morphology

Diminished sperm quantity and movement Impaired brightness discrimination

Decreased long bone strength and circulating thyroid hormone concentration

Increased urinary excretion of nitrate/nitrite and phosphorus

Sheep Depressed growth, total serum protein, erythrocyte counts, ruminal urease activity, total hepatic lipids, and cholesterol

Altered tissue distribution of copper and iron

Speculated Importance for Humans Defi cient intakes may impair sensory functions and bone strength

Predisposing Factors for Defi ciency Stressors that affect labile methyl metabolism (e.g., folic acid, vitamin B6 and vitamin B12 defi ciencies, low dietary protein, and homocysteine supplementation)

Affect iron metabolism (e.g., iron defi ciency) Affect signaling (e.g., high dietary sodium chloride) Postulated Adequate Intake for

Humans

Based on hypothesized requirements for animals, 25–35 μg/day may be benefi cial or adequate for humans Food Sources Nuts, pulses, grains, and chocolate

Vanadium

There is no question that vanadium is a bioactive element. Its ability to selectively inhibit protein tyrosine phosphatases at sub-micromolar concentrations probably explains the broad range of effects that relatively high (supranutritional or pharmacologic) intakes have on cellular regulatory cascades. Protein tyrosine phosphatase inhibition is thought to be the basis for vanadium having insulin-like actions at the cellular level and stimulating cellular proliferation and differentiation. Nutritional intakes may also affect phosphorylation/dephosphorylation such that a regulatory cascade is altered. This may be the basis for the observations that vanadium deprivation altered the response to low and high dietary iodine, impaired reproduction, and induced abnormal bone morphology in experimental animals. The information suggesting vanadium is essential for humans shown in Table 8.15, as well as being essential for some lower forms of life, primarily comes from reviews by Nielsen,58,80,97,98,101,102

Marzan and McNeill,¹⁰³ and Hulley and Davison.¹⁰⁴

OTHER ELEMENTSWITH BENEFICIALOR BIOLOGICAL ACTIONS

There are several elements that have limited circumstantial evidence suggesting that they may be essential. This evidence is generally limited to a few gross benefi cial effects or apparent signs of defi ciency in one or two animal species observed by one or two research groups. Therefore, these elements do not have widespread support for being possibly essential. However, some of these elements have benefi cial pharmacological actions (fl uoride and lithium), and others may eventually be found to be of some importance from the nutritional point of view. Elements that fi t in this category include aluminum, bromine, cadmium, fl uorine, germanium, lead, lithium, rubidium, and tin. The information in Table 8.16 comes from reviews by Nielsen^80,97,105 and Anke et al.^106–110

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172 Handbook of Nutrition and Food

TABLE 8.14

Silicon: Biological Function in Lower Forms of Life, Defi ciency Signs in Animals, and Speculated Importance and Postulated Adequate Intake for Humans

Biological Function in Lower Forms of Life

Silicon has a structural role in some primitive classes of organisms including diatoms (unicellular microscopic plants), radiolarians, and some sponges. Diatoms have an absolute requirement for silicon as monomeric silicic acid for normal cell growth. The diatom, Cylindrotheca fusiformis, has fi ve transporter genes that tightly control silicon uptake and use in cell wall formation

Possible Biological Function in Humans

Silicon may be involved in the interaction between a macromolecule and a cell resulting in changes in cell synthetic activity or cytokine secretion such that it affects wound healing, immune function, and cartilage composition and ultimately calcifi cation

Defi ciency Signs in Experimental Animals

Chick Skulls with a more primitive type of bone and structural abnormalities associated with depressed collagen content; long bone abnormalities characterized by defective endochondral bone growth associated with depressed contents of articular cartilage, water, hexosamine, and collagen

Rat Increased humerus hexose; decreased humerus hydroxyproline, femur alkaline and acid phosphatase and plasma ornithine aminotransferase activity (a key enzyme in collagen synthesis)

Increased urinary helical peptide (collagen breakdown product) excretion Speculated Importance for

Humans

Defi cient intakes may impair bone growth and remodeling, wound healing, and immune function Predisposing Factors for

Defi ciency

Stressors that affect the metabolism of silicon including high dietary fi ber and aluminum

Stressors that affect the utilization of silicon including wounds (tooth extraction), conditions causing an immune or infl ammatory response (e.g., arthritis), and low dietary calcium

Postulated Adequate Intake for Humans

Based on animal fi ndings and human urinary excretion data, suggested benefi cial or adequate intakes for humans range from 5 to 25 mg/day. On the basis of weak balance data, a silicon intake of 30 to 35 mg/day was suggested for athletes, which was 5 to 10 mg higher than that suggested for nonathletes

Food Sources Unrefi ned grains of high fi ber content and cereal products

TABLE 8.15

Vanadium: Biological Function in Lower Forms of Life, Defi ciency Signs in Animals, and Speculated Importance and Postulated Adequate Intake for Humans

Biological Function in Lower Forms of Life

Vanadium is an essential cofactor for some nitrogenases that reduce nitrogen gas to ammonia in bacteria, and for bromoperoxidase, 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

Possible Biological Function in Humans

Vanadium may have a role that promotes phosphorylation and/or inhibits dephosphorylation such that a regulatory cascade is altered

Defi ciency Signs in Selected Experimental Animals

Goat Depressed milk production and life span; increased rate of spontaneous abortion; death, sometimes preceded by convulsions, between ages 7 and 91 days; skeletal deformations in the forelegs; and thickened forefoot tarsal joints

Rat Increased thyroid weight and thyroid weight/body weight ratio, decreased erythrocyte glucose-6-phosphate dehydrogenase, and altered response to high and low dietary iodide

Speculated Importance for Humans Low intakes may impair thyroid hormone metabolism and proper bone development

Predisposing Factors for Defi ciency Stressors of thyroid or iodine metabolism and factors that reduce vanadium absorption including high dietary iron, aluminum hydroxide, and chromium

Postulated Adequate Intake for Humans

Based on animal data, a daily dietary intake of 10 μg probably would be adequate for humans. Pharmacologic doses used to experimentally treat diabetes have been in the range of 40 to 50 mg vanadium/day in the form of vanadyl sulfate, sodium orthovanadate, and organic complexes such as bis(maltoalto)oxovanadium (IV). It should be noted that the Food and Nutrition Board³ has set a tolerable upper intake level (UL) of 1.8 mg vanadium/day for male adults

Food Sources Shellfi sh, mushrooms, prepared foods, whole grains

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SUMMARY

Except for iodine and iron, the full extent of the pathological consequences of marginal or defi cient intakes of the trace and ultra trace elements has not been established. In addition, it is quite likely that not all the essential mineral elements for humans have been identifi ed, and the mechanisms for the benefi cial effects of many bioactive mineral elements have not been clearly defi ned.

Thus, it is diffi cult to tabulate trace mineral defi ciency signs and symptoms for humans. The tables in this section are works in progress, and the presented data can rapidly change because of ongoing research. However, fi ndings to date indicate that many trace and ultra trace minerals are of more practical nutritional concern than currently acknowledged.

REFERENCES

1. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, National Academy Press, Washington, DC, 1997, Chapters 6 and 8.

2. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids, National Academy Press, Washington, DC, 2000, Chapter 7.

3. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc, National Academy Press, Washington, DC, 2001, Chapters 6–13.

4. <http://www.MyPyramid.gov> accessed 3/16/06

5. Eckhert, C.D., Rowe, R.I., J. Trace Elem. Exp. Med., 12: 213; 1999.

6. Fort, D.J. et al., Biol. Trace Elem. Res., 90: 117; 2002.

7. Nielsen, F.H., J. Trace Elem. Exp. Med., 9: 215; 1996.

TABLE 8.16

Reported Defi ciency Signs in Experimental Animals and Usual Human Dietary Intakes of Apparently Bioactive Benefi cial Mineral Elements

Goat: Depressed growth and insemination success, increased

Goat: Depressed growth and insemination success, increased

In document Handbook of Nutrition and Food (Page 187-196)