Trace elements for development

TRACE ELEMENTS. Early in the twentieth century, scientists were able to qualitatively detect small amounts of several elements in living organisms. At the time, these elements were often described as being present in “traces” or “trace amounts.” This apparently led to the term “trace elements,” which today is usually defined as mineral elements that occur in living systems in micrograms per gram of body weight or less. A majority of elements of the periodic table probably could be considered trace elements. However, the presence of most of these elements in higher animals quite likely is just a manifestation of our geochemical origin or the result of environmental exposure. Only eight trace elements are generally accepted as being essential for health and wellbeing in higher animals through the consumption of food and beverages; these are cobalt, copper, iodine, iron, manganese, molybdenum, selenium, and zinc. Persuasive evidence has recently appeared that indicates two other trace elements, boron and chromium, may also be essential; however, general acceptance of their essentiality is still lacking. Based on findings with experimental animals and lower life forms, numerous other trace elements have been suggested as being essential for higher animals including aluminum, arsenic, fluorine, lithium, nickel, silicon, and vanadium. However, conclusive evidence for essentiality, such as a defined biochemical function, is lacking for these elements. Thus, their nutritional importance remains to be determined. Of the elements mentioned, assuring the consumption of foods providing adequate amounts of iodine, iron, and zinc is of greatest practical concern for human health. Evidence is emerging, however, suggesting that the amount of cobalt (as vitamin B12), copper, selenium, boron, and chromium provided through foods should be considered a practical nutritional concern in assuring or promoting health and well-being. These eight elements will be emphasized in this review.

Physiological Roles of Trace Elements

Trace elements have several roles in living organisms. Some are essential components of enzymes where they attract substrate molecules and facilitate their conversion to specific end products. Some donate or accept electrons in reactions of reduction and oxidation, which results in the generation and utilization of metabolic energy. One trace element, iron, is involved in the binding, transporting, and releasing of oxygen in higher animals. Some trace elements impart structural stability to important biological molecules. Finally, some trace elements control important biological processes through such actions as facilitating the binding of molecules to receptor sites on cell membranes, altering the structure or ionic nature of membranes to prevent or allow specific molecules to enter or leave a cell, and inducing gene expression resulting in the formation of proteins involved in life processes.

Homeostatic Regulation of Trace Elements

The ability of the body to maintain the content of a specific substance such as a trace element within a certain range despite varying intakes is called homeostasis. Homeostasis involves the processes of absorption, storage, and excretion. The relative importance of these three processes varies among the trace elements. The homeostatic regulation of trace elements existing as positively charged cations (for example, copper, iron, zinc) occurs primarily during absorption from the gastrointestinal tract. Trace elements absorbed as negatively charged anions (for example, boron, selenium) are usually absorbed freely and completely from the gastrointestinal tract. Thus, they are homeostatically regulated primarily by excretion through the urine, bile, sweat, and breath. Storage of trace elements in inactive sites or forms is another mechanism that prevents inappropriate amounts of reactive trace elements to be present, for example, storage of iron in the form of ferritin. Release of a trace element from a storage site also can be important in preventing deficiency.


This trace element has one known function in higher animals and humans; it is a constituent of thyroid hormone (thyroxine, T4) that, after conversion to triiodothyronine (T3), functions as a regulator of growth and development by reacting with cell receptors, which results in energy (adenosine triphosphate, ATP) production and the activation or inhibition of synthesis of specific proteins.

Recognition that iodine was nutritionally important began in the 1920s when it was found that iodine prevented goiter, and increased iodine intake was associated with decreased endemic cretinism, the arrested physical and mental development caused by the lack of thyroid hormone. Today, the consequences of iodine deficiency still are a major public health problem in the world. In fact, iodine deficiency is the most prevalent global cause of preventable mental retardation. Briefly, the spectrum of iodine deficiency disorders is large and includes fetal congenital anomalies and perinatal mortality; neurological cretinism characterized by mental deficiency, deaf mutism, spastic diplegia (spastic stiffness of the limbs), and squint; psychomotor defects; goiter; and slowing of the metabolic rate causing fatigue, slowing of bodily and mental functions, weight increase, and cold intolerance.

Although homeostatic mechanisms allow for a substantial tolerance to high intakes of iodine, iodine-induced hyperthyroidism has been recognized for nearly two centuries. People who have had a marked iodine deficiency and are then given high amounts of iodine as part of a preventative program are at risk of getting hyperthyroidism with clinical signs including weight loss, tachycardia, muscle weakness, and skin warmth.

Iodide, an anion, is rapidly and almost completely absorbed from the stomach and upper gastrointestinal (GI) tract. Most other forms of iodine are changed in the GI tract to iodide and completely absorbed. When thyroid hormone is ingested, about 80 percent is absorbed without change; the rest is excreted in the feces. Absorbed iodide circulates in the free form; it does not bind to proteins in blood. Iodide is rapidly removed from circulation by the thyroid and kidney. Urinary excretion is a major homeostatic mechanism. If iodine intake has been adequate, only about 10 percent of absorbed iodide appears in the thyroid, the rest appears in the urine. However, if iodine status is inadequate, a much higher percentage, up to 80 percent, can appear in the thyroid. The thyroid gland is essentially the only storage site for iodine, where it appears mostly as mono-and diiodotyrosine and T4, with a small amount of T3.

The recommended intakes of iodine for various age and sex groups are shown in Table 1, which shows that the recommended dietary allowance (RDA) for adults is 150 >g/day. Iodized salt has been the major method for assuring adequate iodine intake since the 1920s. Other sources of iodine are seafood and foods from plants grown on high-iodine soils.


This trace element is a component of molecules that transport oxygen in blood. Numerous enzymatic reactions involving oxidation and reduction (redox) use iron as the agent through which oxygen is added, hydrogen is removed, or electrons are transferred. The classes of enzymes dependent on iron for activity include the oxidoreductases, exemplified by xanthine oxidase/dehydrogenase; monooxygenases, exemplified by the amino acid oxidases and cytochrome P450; dioxygenases, exemplified by amino acid dioxygenases, lipoxygenases, peroxidases, fatty acid desaturases, and nitric oxide synthases; and miscellaneous enzymes such as aconitase.

Among the trace elements, iron has the longest and best described history. By the seventeenth century, a recognized treatment for chlorosis, or iron deficiency anemia, was drinking wine containing iron filings. Despite the extensive knowledge about its treatment and prevention, and the institution of a variety of effective interventions, iron deficiency is the primary mineral deficiency in the United States and the world today. The physiological signs of iron deficiency include anemia, glossitis (smooth atrophy of tongue surface), angular stomatitis (fissures at the angles of the mouth), koilonychia (spoon nails), blue sclera, lethargy, apathy, listlessness, and fatigue. Pathological consequences of iron deficiency include impaired thermoregulation, immune function, mental function, and physical performance; complications in pregnancy, including increased risk of premature delivery, low birth weight, and infant mortality; and possibly increased risk of osteoporosis.

Concerns have been expressed about high intakes of iron being a health issue. This has come about through epidemiologic observations associating high dietary iron or high body iron stores with cancer and coronary heart disease. Further experimental studies, however, are required to confirm whether the high intakes of iron increase the risk for these diseases. The toxic potential of iron arises from its biological importance as a redox element that accepts and donates electrons to oxygen that can result in the formation of reactive oxygen species or radicals that can damage cellular components such as fatty acids, proteins, and nucleic acids. Antioxidants are enzymes or molecules that prevent the formation of oxygen radicals or convert them to nonradical products. When not properly controlled by antioxidants, reactive oxygen damage can lead to premature cell aging and death. An iron overload disease known as hereditary hemochromatosis is caused by a defective regulation of iron transport with excessive iron absorption and high transferrin (transport form) iron in plasma. Clinical signs appear when body iron accumulates to about 10 times normal and include cirrhosis, diabetes, heart failure, arthritis, and sexual dysfunction. Hemochromatosis also increases the risk for hepatic carcinoma. The treatment for hereditary hemochromatosis is repeated phlebotomy.

Absorption from the GI tract is the primary homeostatic mechanism for iron. Dietary iron exists generally in two forms, heme and non-heme, that are absorbed by different mechanisms. Heme iron is a protoporphyrin molecule containing an atom of iron; it comes primarily from hemoglobin and myoglobin in meat, poultry, and fish. Non-heme iron is primarily inorganic iron salts provided mainly by plant-based foods, dairy products, and iron-fortified foods. Heme iron is much better absorbed and less affected by enhancers and inhibitors of absorption than non-heme iron. Iron absorption is regulated by mucosal cells of the small intestine, but the exact mechanisms in the regulation have not been established. Both iron stores and blood hemoglobin status have a major influence on the amount of dietary iron that is absorbed. Under normal conditions, men absorb about 6 percent and menstruating women absorb about 13 percent of dietary iron. However, with severe iron deficiency anemia (functionally deficient blood low in hemoglobin), absorption of non-heme iron can be as high as 50 percent. Iron loss from the body is very low, about 0.6 mg/day. This loss is primarily by excretion in the bile and, along with iron in desquamated mucosal cells, eliminated via the feces. Menstruation is a significant means through which iron is lost for women. It should be noted, however, that nonphysiological loss of iron resulting from conditions such as parasitism, diarrhea, and enteritis account for half of iron deficiency anemia globally. Excess iron in the body is stored as ferritin and hemosiderin in the liver, reticuloendothelial cells, and bone marrow.

The recommended intakes of iron for various age and sex groups are shown in Table 1, which shows that the RDA for adult males and postmenopausal women is 8 mg/day; and that for menstruating adult women is 18 mg/day. Meat is the best source of iron, but iron-fortified foods (cereals and wheat-flour products) also are significant sources.


This trace element is the only one that is found as an essential component in enzymes from all six enzyme classes. Over 50 zinc metalloenzymes have been identified. Zinc also functions as a component of transcription factors known as zinc fingers that bind to DNA and activate the transcription of a message, and imparts stability to cell membranes.

Signs of zinc deficiency in humans were first described in the 1960s. Although it is generally thought that zinc deficiency is a significant public health concern, the extent of the problem is unclear because there is no well-established method to accurately assess the zinc status of an individual. The physiological signs of zinc deficiency include depressed growth; anorexia (loss of appetite); parakeratotic skin lesions; diarrhea; and impaired testicular development, immune function, and cognitive function. Pathological consequences of zinc deficiency include dwarfism, delayed puberty, failure to thrive (acrodermatitis enteropathica infants), impaired wound healing, and increased susceptibility to infectious disease. It has also been suggested that low zinc status increases the susceptibility to osteoporosis and to pathological changes caused by the presence of excessive reactive oxygen species or free radicals.

Zinc is a relatively nontoxic element. Excessive intakes of zinc occur only with the inappropriate intake of supplements. The major undesirable effect is an interference with copper metabolism that could lead to copper deficiency. Long-term high zinc supplementation can reduce immune function and high-density lipoprotein (HDL)-cholesterol (the “good” cholesterol). These effects are seen only with zinc intakes of 100 mg/day or more.

A primary homeostatic mechanism for zinc is absorption from the small intestine. Absorption involves a carrier-mediated component and a nonmediated diffusion component. With normal dietary intakes, zinc is absorbed mainly by the carrier-mediated mechanism. Although absorption can be modified by a number of factors, about 30 percent of dietary zinc is absorbed. The efficiency of zinc absorption is increased with low zinc intakes. The small intestine has an additional role in zinc homeostasis through regulating excretion through pancreatic and intestinal secretions. After a meal, greater than 50 percent of the zinc in the intestinal lumen is from endogenous zinc secretion. Thus, zinc homeostasis depends upon the reabsorption of a significant portion of this endogenous zinc. Intestinal conservation of endogenous zinc apparently is a major mechanism for maintaining zinc status when dietary zinc is inadequate. The urinary loss of zinc is low and generally not markedly affected by zinc intake.

The recommended intakes of zinc for various age and sex groups are shown in Table l, which shows that the RDA for adult males is 11 mg/day and for adult females is 8 mg/day. The best food sources for zinc are red meats, organ meats (for example, liver), shellfish, nuts, whole grains, and legumes. Many breakfast cereals are fortified with zinc.

Cobalt (Vitamin B12)

Ionic cobalt is not an essential nutrient for humans. Cobalt is an integral component of vitamin B12, which is an essential nutrient for nonruminant animals and humans. Vitamin B12 is a cofactor for two enzymes, methionine synthase which methylates homocysteine to form methionine, and methylmalonyl coenzyme A (CoA) mutase which converts L-methylmalonyl CoA, formed by the oxidation of odd-chain fatty acids, to succinyl CoA.

In the nineteenth century, a megaloblastic anemia (functionally deficient blood containing primitive large red blood cells) was identified that was invariably fatal and thus called pernicious anemia. The first effective treatment for this disease was 1 pound of raw liver daily. In 1948, the anti–pernicious anemia factor (vitamin B12) in liver was isolated and found to contain 4 percent cobalt. Vitamin B12 deficiency most commonly arises when there is a defect in vitamin B12 absorption caused by such factors as atrophic gastritis,Helicobacter pylori infection, and bacteria overgrowth resulting from achlorohydria and intestinal blind loops. Because vitamin B12 only comes from foods of animal origin, absolute vegetarianism will lead to deficiency in vitamin B12 after 5 to 10 years. The physiological signs of severe vitamin B12 deficiency are megaloblastic anemia, spinal cord demyelination, and peripheral

Recommended Dietary Allowances for Selected Trace Elements Established by the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences (see bibliography).
  Recommended Dietary Allowance
  Copper (μg/day) Iodine (μg/day) Iron (μg/day) Selenium (μg/day) Vitamin B12 (cobalt) (μg/day) Zinc (μg/day)
0–6 months
7–12 months 11 3
1–3 years 340 90 7 20 0.9 3
4–8 years 440 90 10 30 1.2 5
9–13 years 700 120 8 40 1.8 8
14–18 years 890 150 11 M/15 F 55 2.4 11 M/9 F
19–50 years 900 150 8 M/18 F 55 2.4 11 M/9 F
51 years and greater 900 150 8 55 2.4 11 M/8 F
18 years or less 1,000 220 27 60 2.6 13
19–50 years 1,000 220 27 60 2.6 11
18 years and less 1,300 290 10 70 2.8 14
19–50 years 1,300 290 9 70 2.8 12
Abbreviations: F, female; M, male.

neuropathy. The pathological consequences of deficiency include pernicious anemia, memory loss, dementia, an irreversible neurological disease called subacute degeneration of the spinal cord, and death. Recently, mild vitamin B12 deficiency has been cited as a cause of high circulating homocysteine, which has been associated with an increased risk for cardiovascular disease. Vitamin B12 is essentially nontoxic. Doses up to 10,000 times the minimal daily adult human requirement do not have adverse effects.

Vitamin B12 absorption is a relatively complex process. Digestion by the saliva and acid environment of the stomach releases vitamin B12 from food, then it is bound to a haptocorrin called R protein that carries it into the duodenum. A binding protein, called intrinsic factor, released by gastric parietal cells binds vitamin B12after the stomach acid is neutralized in the duodenum, and digestive enzymes remove the R binder from the vitamin. The intrinsic factor–bound vitamin B12 is carried to a specific receptor in the ileum called cubilin and internalized by receptor-mediated endocytosis. Because vitamin B12 is water-soluble, excessive intakes are efficiently excreted in the urine.

The recommended intakes for vitamin B12 for various age and sex groups are shown in Table l, which shows that the RDA for adults is 2.4 >g/day. Food sources of vitamin B12 are of animal origin and include meats, dairy products, and eggs. Fortified cereals have also become a significant source of vitamin B12.


Copper is a cofactor for a number of oxidase enzymes including lysyl oxidase, ferroxidase (ceruloplasmin), dopamine beta-monooxygenase, tyrosinase, alpha-amidating monooxygenase, cytochrome C oxidase, and superoxide dismutase. These enzymes are involved in the stabilization of matrixes of connective tissue, oxidation of ferrous iron, synthesis of neurotransmitters, bestowal of pigment to hair and skin, assurance of immune system competence, generation of oxidative energy, and protection from reactive oxygen species. Copper also regulates the expression of some genes.

Although copper is a well-established essential trace element, its practical nutritional importance is a subject of debate. Well-established pathological consequences of copper deprivation in humans have been described primarily for premature and malnourished infants and include a hypochromic, normocytic, or macrocytic anemia; bone abnormalities resembling scurvy by showing osteoporosis, fractures of the long bones and ribs, epiphyseal separation, and fraying and cupping of the metaphyses with spur formation; increased incidence of infections; and poor growth. The consequences of the genetic disorder Menkes’ disease (copper deficiency caused by a cellular defect in copper transport) in children include “kinky-type” steely hair, progressive neurological disorder, and death. Other consequences have been suggested based upon findings from epidemiological studies, and animal and short-term human copper deprivation experiments; these include impaired brain development and teratogenesis for the fetus and children, and osteoporosis, ischemic heart disease, cancer, increased susceptibility to infections, and accelerated aging for adults.

Copper toxicity is not a major health issue. The ingestion of fluids and foods contaminated with high amounts of copper can cause nausea. Because their biliary excretion pathway is immature, accumulation of toxic amounts of copper in the liver could be a risk for infants if intake is chronically high; this apparently caused cases of childhood liver cirrhosis in India.

Intestinal absorption is a primary homeostatic mechanism for copper. Copper enters epithelial cells of the small intestine by a facilitated process that involves specific copper transporters, or nonspecific divalent metal ion transporters located on the brush-border surface. Then the copper is transported to the portal circulation where it is taken up by the liver and resecreted in plasma bound to ceruloplasmin. Transport of copper from the liver into the bile is the primary route for excretion of endogenous copper. Copper of biliary origin and nonabsorbed dietary copper are eliminated from the body via the feces. Only an extremely small amount of copper is excreted in the urine. The absorption and retention of copper varies with dietary intake and status. For example, the percentages of ingested copper absorbed were 56 percent, 36 percent, and 12 percent with dietary intakes of 0.8, 1.7, and 7.5 mg/day, respectively. Moreover, tissue retention of copper is markedly increased when copper intake is low.

The recommended intakes for copper for various ages and sex groups are shown in Table 1, which shows that the RDA for adults is 900 >g/day. The best sources of copper are legumes, whole grains, nuts, organ meats (for example, liver), seafood (for example, oysters, crab), peanut butter, chocolate, mushrooms, and ready-to-eat cereals.


Selenium is a component of enzymes that catalyze redox reactions; these enzymes include various forms of glutathione peroxidase, iodothyronine 5<-deiodinase, and thioredoxin reductase.

Although selenium was first suggested to be essential in 1957, this was not firmly established until a biochemical role was identified for selenium in 1972. The first report of human selenium deficiency appeared in 1979; the subject resided in a low-selenium area and was receiving total parenteral nutrition (TPN) after surgery. The subject and other selenium-deficient subjects on TPN exhibited bilateral muscular discomfort, muscle pain, wasting, and cardiomyopathy. Subsequently, it was discovered that Keshan disease, prevalent in certain parts of China, was prevented by selenium supplementation. Keshan disease is a multiple focal myocardial necrosis resulting in acute or chronic heart function insufficiency, heart enlargement, arrhythmia, pulmonary edema, and death. Other consequences of inadequate selenium include impaired immune function and increased susceptibility to viral infections. Selenium deficiency also can make some nonvirulent viruses become virulent.

Recently, however, not only selenium deficiency, but effects of supranutritional intakes of selenium have become of great health interest. Several supplementation trials have indicated that selenium has anticarcinogenic properties. For example, one trial with 1,312 patients supplemented with either 200 >g selenium/day or with a placebo found the selenium treatment was statistically associated with reductions in several types of cancer including colorectal and prostate cancers.

Selenium is a relatively toxic element; Intakes averaging 1.2 mg/day can induce changes in nail structure. Chronic selenium intakes over 3.2 mg/day can result in the loss of hair and nails, mottling of the teeth, lesions in the skin and nervous system, nausea, weakness, and diarrhea.

Selenium, which is biologically important as an anion, is homeostatically regulated by excretion, primarily in the urine but some also is excreted in the breath. Selenate, selenite, and selenomethionine are all highly absorbed by the GI tract; absorption percentages for these forms of selenium are commonly found to be in the 80 to 90 percent range.

The recommended intakes for selenium are shown in Table 1, which shows that the RDA for adults is 55 >g/day. Food sources of selenium are fish, eggs, and meat from animals fed abundant amounts of selenium and grains grown on high-selenium soil.


Recent findings with this trace element suggest that it may be of nutritional importance, although a clearly defined biochemical function for boron in higher animals and humans has not been defined. It has been hypothesized, however, that boron has a role in cell membrane function that influences the response to hormones, transmembrane signaling, or transmembrane movement of regulatory cations or anions. Human studies suggest that a low boron intake can impair cognitive and psychomotor function and the inflammatory response, as well as increasing the susceptibility to osteoporosis and arthritis.

About 85 percent of ingested boron is absorbed and excreted in the urine shortly after ingestion. Because boron homeostasis is regulated efficiently by urinary excretion, it is a relatively nontoxic element. A tolerable upper level intake of 20 mg/day was determined for boron by the Food and Nutrition Board of the United States National Academy of Sciences.

An analysis of both human and animal data by a World Health Group suggested that an acceptable safe range of population mean intakes for boron for adults could be 1 to 13 mg/day. Foods of plant origin, especially fruits, leafy vegetables, nuts, pulses, and legumes are rich sources of boron.


A naturally occurring biologically active form of chromium called chromodulin has been described that apparently has a role in carbohydrate and lipid metabolism as part of a novel insulin-amplification mechanism. Chromodulin is an oligopeptide that binds four chromic ions and facilitates insulin action in converting glucose into lipids and carbon dioxide.

The nutritional importance of chromium is currently a controversial subject. Chromium deficiency has been suggested to impair glucose tolerance, which could eventually lead to diabetes. Supranutritional chromium supplementation (1,000 >g/day) has been found beneficial for some cases of type II diabetes. Supplements containing supranutritional amounts of chromium in the picolinate form have been promoted as being able to induce weight loss and to increase muscle mass. However, most ergogenic (work output) oriented studies have found chromium picolinate supplementation to be ineffective for increasing muscle mass, strength, and athletic performance, and there are no data from well-designed studies to support the claim that chromium picolinate supplementation is an effective weight loss modality. Chromium in the +3 valence state is a relatively nontoxic element.

Chromium homeostasis is regulated by intestinal absorption, which is low. Estimates of absorption range from less than 0.5 to 2 percent. Absorbed chromium is excreted in the urine.

The Food and Nutrition Board of the United States Academy of Sciences determined that there was not sufficient evidence to set an estimated average requirement of chromium. Therefore, an adequate intake was set based on estimated mean intakes. The adequate intake for young males was set at 35 >g/day, and that for young females was set at 25 >g/day. Some of the best food sources of chromium are whole grains, pulses, some vegetables (for example, broccoli and mushrooms), liver, processed meats, ready-to-eat cereals, and spices.


It is likely that not all the essential mineral elements for humans have been identified. Moreover, numerous biochemical functions for trace elements most likely remain to be identified. Thus, the full extent of the pathological consequences of marginal or deficient intakes of the trace elements has not been established. Furthermore, some trace elements such as selenium, fluoride, and lithium in supranutritional amounts are being found to have therapeutic or preventative value against disease. Thus, the determination of the importance of trace elements for human health and well-being should be considered a work in progress with some exciting advances likely in the future.


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