The safety of micronutrients – Part 3: minerals

Calcium

The uptake of orally ingested calcium (Ca2+) via the cells of the small intestine is regulated by calcitriol (the physiologically active form of vitamin D 3) and parathyroid hormone (PTH), which is synthesized in the parathyroid glands. The rate of absorption of calcium varies depending on several factors (1): after infancy it reaches greatest efficiency in puberty (approx. 60%), before falling to around 15–20% in adulthood. During the growth phase in childhood and adolescence, increased activity of bone-forming cells (osteoblasts) causes a greater amount of calcium to accumulate and be stored in the bone matrix. Maximum bone mineral mass and highest bone density are usually achieved during adolescence and young adulthood (until around the age of 30). From the age of 30 years bone density decreases continuously (by around 1% a year), even when calcium metabolism is balanced. Loss in bone mineral density due to aging is caused by an increase in the activity of bone-dissolving cells (osteoclasts), which is accompanied by increased degradation of bone tissue and release of calcium from the bone. The loss of bone mass is progressive, especially in post-menopausal women following changes in estrogen status. During pregnancy calcium absorption is increased due to the daily calcium transfer to the fetus via the placenta. In addition to increased absorption from the intestines, the greater requirements for calcium during pregnancy are met by a greater release of calcium from the skeleton (2). In nursing mothers calcium for the milk is provided entirely by increased mobilization of calcium from the bones.

Besides forming and maintaining strong bones and teeth, calcium also plays an important role in soft tissues where, amongst other things, it is involved in the function of vessels and muscles, as well as signal transmission to nerves and in cells. However, around 99% of all the calcium in the body is found in the skeletal system, including the teeth, where it is stored mainly in its bound form as undissolved calcium phosphate or hydroxyapatite. The concentration of calcium in blood serum is reciprocally related to the calcium content of bones, small intestine and kidney and is kept constant within narrow limits by a complex hormonal regulatory system: parathyroid hormone (PTH), calcitriol and the hormone calcitonin influence calcium absorption from the intestines, excretion via the kidneys and calcium release or uptake by the bones.

If serum levels of calcium fall – whether as the result of inadequate intake or due to increased losses – more PTH is produced to stimulate synthesis of the biologically active form of vitamin D3 and hence calcium absorption from the small intestine. At the bone site, PTH and activated vitamin D3 stimulate the activity of the osteoclasts, leading to resorption (breakdown) of bone substance and consequently to the release of calcium (and also phosphate) from the bone into the bloodstream. If blood levels of calcium rise (for example following increased intakes from the diet or dietary supplements), more calcitonin is synthesized and inhibits the activity of the osteoclasts on the bone and hence inhibits the dissolution of bone tissue, which in turn promotes calcium accumulation in the skeleton. At the same time the hormone stimulates renal excretion of calcium. Via these mechanisms calcitonin leads to a fall in the concentration of calcium in the serum.

High intakes of calcium can reduce the bioavailability and absorption of other minerals such as magnesium, manganese and zinc, but this has not been observed to harm health (3). There are a few hypotheses relating to the possible effects of high calcium intakes. Study results relating to the increased risk of kidney stone formation are inconclusive (4), while a potential preventive role for calcium has also been reported (5).

Results from studies into the possible connection between calcium consumption and cardiovascular disease were also inconclusive. On the one hand targeted calcium administration improved blood lipid levels (6) and lowered blood pressure (7), thus reducing the risk of developing cardiovascular disease. On the other hand, the risk for cardiovascular disease could theoretically be increased by raising the levels of calcium in the blood, since this could encourage the development of vascular calcification (hardening of the arteries) and cardiovascular disease (8). Whilst some longitudinal studies revealed no connection between targeted calcium administration and increased disease risk (9, 10), other, shorter studies indicated a heightened risk (11–13). One meta-analysis suggested that regular use of calcium preparations – whether in combination with vitamin D or not – could slightly increase the risk of heart attack or stroke (13). However, experts criticized its analytical methods and highlighted the distortion of results and unanswered questions (14, 15). One recently published, large-scale longitudinal study reported no rise in the risk of developing cardiovas-cular disease (heart attack or stroke) among women taking more than 1,000 mg calcium per day (16). Instead, a possible association between the use of calcium preparations and a lower risk of cardiovascular disease was observed. Since the results of clinical and observational studies are inconsistent the evidence for an influence of dietary supplements with calcium on the risk of developing cardiovascular disease is considered insufficient (17).

Based on available studies, the European Food Safety Authority (EFSA) decided to define total tolerable upper intake levels (UL) for calcium from all sources (diet and dietary supplements) as 2,500 mg per day for adults (18). The US Institute of Medicine defined ULs for children from 9 to 18 years as 3,000 mg calcium per day, for adults from 19 to 50 years as 2,500 mg per day and for adults from the age of 70 years as 2,000 mg daily (19).

Magnesium

Magnesium plays an important role in energy metabolism. It also supports nervous system function and contributes to muscle and bone health. Magnesium consumed in the diet is absorbed via the small intestine. With a large supply of magnesium the transport mechanism becomes saturated and the percentage of magnesium absorbed falls. Conversely, low magnesium intakes or a deficiency results in a greater rate of absorption from the intestine: if blood concentrations of magnesium are low, larger amounts of parathyroid hormone and calcitriol, the active form of vitamin D 3, are released and stimulate increased absorption of magnesium from the small intestine (20). Under normal circumstances the rate of absorption is between
35 and 55%, but it can rise to 75% or fall to 25%, depending on the amount of magnesium ingested.

Around 95% of the total magnesium in the body is intracellular (found in the body’s cells). Of this, 50–70% (in bound form) is stored in the bones (21). Around 28% of the magnesium in the cells is located in muscles and the remainder in soft tissue. Only 5% of the magnesium in the body is found in extracellular fluid and less than 1% in serum and the fluid between the cells. Only free magnesium (Mg2+) is biologically active. Free extracellular magnesium concentrations are kept constant within a very narrow range with the aid of a complex hormonal regulatory system, which controls absorption from the small intestine, excretion via the kidneys and the exchange with stores in the skeleton (22). If serum levels of magnesium drop, parathyroid hormone and calcitriol stimulate magnesium reabsorption and inhibit renal excretion of magnesium. In the event of an excess of magnesium, more of the hormone calcitonin is produced, which stimulates magnesium excretion via the kidneys and reduces reabsorption; the latter can also be lowered by a high intake of calcium. In this way, even very high intakes of magnesium can be excreted via the kidneys (23).

Whilst there are no indications that large amounts of orally ingested magnesium (up to 10 mg magnesium per kg body weight daily) cause damage to health in healthy persons (24), neurological disorders have been observed in people with impaired renal function and increased sensitivity to magnesium-containing medicines (25). Based on the observation that long-term consumption of large doses of magnesium can lead to mild to moderate diarrhea, the US Institute of Medicine decided to define a tolerable upper intake level for adults of a total of 350 mg magnesium per day from dietary supplements and medication (26), while the European Commission’s Scientific Committee on Food set the UL at 250 mg per day (27).

Potassium

Potassium is involved in the transmission of electrical impulses to nerve and muscle cells and in the synthesis of proteins and breakdown of carbohydrates. Potassium is absorbed in the small intestine and absorption is very little affected by the amount of potassium ingested. Total potassium levels in the body are around
40–50 mmol/kg body weight (1 mmol K+ corresponds to 39.1 mg) and depend on physique, age and sex (28). Potassium is located primarily (98%) within cells. Cell potassium concentrations vary with the type of tissue and are an expression of its metabolic activity: muscle cells contain the highest proportion of this mineral (60%), followed by red blood cells (8%), liver cells (6%) and other tissue cells (4%). Distribution of potassium between the inside and outside of cells is regulated by the hormones insulin, aldosterone and catecholamines. When serum potassium levels of potassium are high, these hormones stimulate potassium transport into the cells, leading to a rapid fall in extracellular potassium concentrations. Conversely, a low level of potassium in serum (hypokalemia) leads to inhibition of potassium transport into the cells – mediated by a drop in hormone levels – and consequently to a rise in extracellular potassium concentrations. Potassium balance is closely linked to magnesium metabolism. Hence a magnesium deficit, for example, reduces potassium absorption in the small intestine.

Excess amounts of potassium in the body are excreted mainly via the kidneys. In cases of chronic potassium overload and impaired renal function, more potassium is excreted in the feces. Raised blood potassium values, which are usually the result of renal insufficiency, lead to a lowering of the membrane potential of nerve and muscle cells, which can give rise to generalized muscular weakness (e.g., “heavy legs” and breathing difficulties) as well as to paresthesia of the hands and feet (29). Since no side effects occurred in several studies with healthy subjects with high potassium intakes, both the US Institute of Medicine (30) and the European Food Safety Authority (31) decided not to define tolerable upper intake levels. The EFSA noted that in healthy adults regular intakes of potassium in the diet which do not normally exceed 5 to 6 grams per day, plus a daily intake of 3 grams of potassium chloride from dietary supplements are not harmful to health.

Phosphorus

After calcium, phosphorus is quantitatively the most common mineral in the body and is an essential building block of organic compounds (carbohydrates, proteins, lipids, nucleic acids and vitamins) and of inorganic compounds (e.g., calcium phosphate). Phosphorus plays a central role in cellular energy generation and storage, signal transmission and bone and tooth mineralization (32). Moreover it is an important component of cell membranes (as a component of phospholipids) and genetic material (DNA and RNA). Food is generally not rich in phosphorus, although industrially processed foods like meat products and sausages, bread and bakery goods, cola-containing and fizzy drinks can have a comparatively high phosphate content. As a rule, dietary supplements do not contain large amounts and therefore only contribute to a minor extent to the supply of phosphorus to the body (33). Phosphorus from animal-source foods is usually more bioavailable (over 60%) than phosphorus from plant-source foods (up to 50%).

After ingestion phosphorus is absorbed preferentially in the small intestine. Its rate of absorption is higher in the growth phase than in adulthood (34). Whereas calcium and iron inhibit phosphate absorption, it is enhanced by calcitriol, the physiologically active form of vitamin D. Over 85% of absorbed phosphate is found in compounds with calcium, in the form of calcium phosphate or hydroxylapatite, in the skeleton and teeth (35). Ten to 15% are located in other tissues such as brain, liver and muscles, in the form of energy-rich phosphate compounds (adenosine triphosphate, ATP), phosphocreatine (supplies energy to muscle tissue) and phospholipids. Around 60–80% of phosphates are excreted via the kidneys and 20–40% in the feces. Phosphate metabolism is regulated via parathyroid hormone, activated vitamin D3 and calcitonin, which influence phosphate release and uptake into the bones, phosphate absorption in the gut and phosphate excretion via the kidneys. Hormonal regulation of the phosphate metabolism enables it to adjust to varying phosphate intakes and make relatively large amounts of phosphate tolerable. Unlike the serum concentration of calcium, which is kept constant within relatively tight limits, phosphate balance is not strictly regulated.

Studies have shown that higher intakes of phosphorus (from 800 mg to 2,000 mg a day) do not significantly lower blood calcium levels, regardless of calcium intake (36). The common assumption that high intakes of phosphorus in carbonated drinks could contribute to a loss of calcium and hence to an increased risk for the development of osteoporosis has so far not been substantiated by studies (37). Whilst the European Food Safety Authority decided, on the basis of available studies, not to define tolerable upper intake levels for phosphorus (38), the US Institute of Medicine set a UL of 4 grams per day for adults (39).

Iron

Iron occurs in food in two forms: as heme iron in meat (Fe2+) and as the somewhat less utilizable non-heme iron (Fe3+) in all other foods. The bioavailability of (non-heme) iron from the diet can be enhanced by concomitant ingestion of vitamin C and/or vitamin A, whereas excessive intakes of other metal ions (e. g., zinc, copper and manganese) can strongly inhibit iron absorptionthrough the formation of complexes (40). Iron is absorbed mainly from the small intestine. After absorption iron is either bound in the form of ferritin (a protein that stores iron) or carried in the plasma to cells and tissues with the aid of a transport protein (transferrin). Around 80% of the iron in the body is present as a component of active biological compounds: most of it is needed to produce hemoglobin (41) – the oxygen transporter in the red blood cells (erythro-cytes) – and only a small part is used to synthesize myoglobin (which stores oxygen in muscle tissue) or for the mitochondrial respiratory chain and iron-dependent enzymes (42). About 20% of the iron reserves are found bound to protein (as ferritin) in the organs of storage, in particular liver, spleen, intestinal mucosa and bone marrow. The amount of stored iron regulates the absorption of non-heme iron, whilst the more readily absorbed heme iron is taken up regardless of nutritional status. Blood ferritin levels provide a reliable measure of nutritional iron status.

Because there are no regulated excretion mechanisms for iron, excessive intakes of iron in the diet cannot be compensated by increased excretion. Some studies conclude that substantially raised ferritin levels lead, in the long term, to an increase in the risk of atherosclerosis and heart attacks (43, 44). Many other trials come to very different conclusions, however (45-47). Based on the oxidative activity of iron and the possible negative influence of oxidative stress on the incidence of bowel cancer precursors, the hypothesis was formed that high intakes of iron could contribute to the risk for bowel cancer (48). However, no such effect has been observed by any study as yet (49). Isolated cases have been reported of children under 3 years who have accidentally consumed more than 900 mg iron in high-dose preparations and subsequently suffered gastrointestinal side effects (50).

After reviewing the available studies, the US Institute of Medicine decided to set a tolerable upper intake level for iron of 45 mg per day in total from all sources for adults (51). Above these doses gastrointestinal side effects (e.g., constipation) might be expected. The European Food Safety Authority described the data available as insufficient to define a UL (52).

Selenium

The trace element selenium occurs in protein-rich animal-source foods (fish, meat, offal and eggs) and also in plant-source foods (e.g., pulses, nuts and fungi) in the form of selenium-containing amino acids (seleno-cysteine and selenomethionine). Inorganic selenium compounds play a role primarily in dietary supplements and medicines. Orally ingested selenium is absorbed via the small intestine. The rate of absorption depends on the type, quantity and source of the ingested selenium compounds and on interactions between them and other food ingredients (e.g., sulfur and heavy metals. The selenium status of the individual does not influence absorption (53). After absorption, selenium is transported in the bloodstream to the liver, where it accumulates in proteins while producing selenoproteins P (SeP). These are transported in the bloodstream to tissues. The highest concentrations are found in the liver, kidneys, heart, spleen, brain, gonads (especially testes), erythrocytes and thrombocytes. However, because of its greater overall weight, the skeletal musculature contains the largest proportion of selenium, with 40–50% of selenium reserves found here. Whereas selenium in cells such as erythrocytes, immune cells and thrombocytes functions as an essential component of many enzymes and proteins (e.g., the antioxidant glutathione peroxidases), outside the cells it is bound to plasma proteins (selenoprotein P, beta-globulin and albumin).

Selenomethionine from the diet can be unspecifically incorporated into proteins in place of the sulfur-containing amino acid methionine, whilst selenocysteine is available for incorporation into the peptide chain of selenium-dependent proteins and enzymes. Inorganic selenite and selenate are used as precursors for the synthesis of selenocysteine. Selenium is excreted primarily via the kidneys; excretion depends on both the selenium status of the individual and on oral intakes. In contrast to other trace elements, like iron, copper and zinc, whose balance is controlled mainly via absorption from the small intestine, selenium is regulated above all by excretion via the kidneys, and in the case of excessive selenium, through respiration (54).

Some observational and intervention studies provided evidence that increased intakes of selenium could help reduce the risk of developing some forms of cancer (55-57) and type 2 diabetes (58). More recent clinical studies investigated these possible associations in greater depth (including in combination with other micro-nutrients): In the SELECT study daily consumption of 200 micrograms of selenomethionine (around 4 times the recommended amount) alone and in combination with vitamin E led to no reduction in the risk for prostate cancer (59). The SU.VI.MAX study revealed that targeted consumption of selenium in combination with vitamins C and E as well as beta-carotene and zinc had no influence on the incidence of chronic diseases such as cancer, diabetes or cardiovascular disease as compared with placebo (60). In this instance, participants with normal blood levels of prostate-specific antigen (one parameter in the diagnosis of prostate carcinoma) appeared to experience a significant reduction for the risk of prostate cancer, while subjects with raised antigen values demonstrated a slight increase in risk (61). This latter could not be observed in the SELECT study (59, 62). Some of the study results relating to a possible association between selenium intakes and the risk for type 2 diabetes are contradictory. Whereas some trials indicated a preventive effect (58, 63), some indicated rather the opposite (64).

Based on the available studies the US Institute of Medicine decided to set the tolerable upper intake levels for selenium in adults at 400 micrograms per day in total from all sources (65). The European Commission’s Scientific Committee on Food defined a UL for adults of 300 micrograms per day in total (66).

Zinc

In humans, zinc, along with iron, is one of the quantitatively most important trace elements. Zinc occurs in foods from animal and plant sources mostly as zinc2+ bound to amino acids or proteins. The rate of absorption of zinc in the small intestine is on average between 15 and 40%, and depends on nutritional status, physiological requirements and the presence or absence of certain nutritional elements. Vitamin C, some of the amino acids and proteins of animal origin encourage uptake, while large amounts of calcium as well as iron and copper inhibit absorption (67). Quantitatively, the greatest proportion of zinc is found in muscles (60%) and bones (20–30%). The trace element is also found in many other cells of tissues and organs, where it functions as an important component and/or cofactor of many enzymes, in particular from the oxidoreductase and hydrolase groups. Zinc is involved in amino acid metabolism and in protein and nucleic acid synthesis. Only around 0.8% of the total body pool of zinc is located in the blood. In contrast to iron, organisms do not have large reserves of zinc, so that a continuous intake of zinc in the diet is essential. Zinc is excreted primarily via the bowels in the feces. As oral intake increases, so does zinc excretion in the feces.

In the long term, ingestion of high doses of zinc (50–150 mg a day) has been associated with a negative influence on biomarkers (e.g., immune cells and HDL cholesterol). Theoretically, this could promote the development of diseases (68, 69). Moreover, interactions between zinc preparations and antibiotics as well as between zinc and folic acid have been reported (70). More recent studies have been unable to confirm the latter (71). The US Institute of Medicine considered a possible inhibition of copper uptake and copper-containing enzymes when defining the tolerable upper intake level for zinc, and set a UL of 40 mg per day in total for adults (72). The European Commission’s Scientific Committee on Food took account of the potential impairment to copper provision by setting a UL for adults of 25 mg per day (73).

Iodine

The amounts of iodine in the diet vary greatly, depending mainly on iodine concentrations in soil and water. Salt-water fish and shellfish are among the richest sources of iodine. If cows and poultry are given the appropriate feed, milk and dairy products and eggs can also be rich in iodine. Other foods, in particular plant-source foods, contribute only a small proportion of iodine to the diet, because in many places the soil is very iodine-depleted. To ensure a sufficient supply of dietary iodine the use of table salt fortified with iodine is often recommended. Iodine in the diet is absorbed from the small intestine and enters the bloodstream as inorganic iodide or iodate or in its organically bound form. From there it is transported to the thyroid gland (80%) and other tissues (muscles, gallbladder, pituitary gland, salivary glands) (74). As an essential component of thyroid hormone, iodine is indispensable for maintenance of normal thyroid function (75). Excessive intakes of nitrate in the diet (e.g., from spinach, radish or drinking water) inhibit active iodine transport to the thyroid gland. With the aid of selenium-dependent deiodinases some iodide is released from the cells of the thyroid gland and other tissues and is available to the organism. This trace element is excreted primarily in the urine.

Whilst healthy adults could readily tolerate daily intakes of up to 2,000 micrograms a day, in people who were hypersensitive to iodine because of an iodine deficiency, intakes of anything over 200 micrograms a day were associated with hyperthyroidism (75). The European Commission’s Scientific Committee on Food set a tolerable upper intake level of 600 micrograms a day in total for healthy adults (76), although the US Institute of Medicine considered a UL of 1,100 micrograms per day to be acceptable for healthy adults (77).

Other minerals

Chromium, which occurs in many foods, usually in its trivalent form (Cr3+), is involved in the metabolism of carbohydrates, lipids and proteins through an influence on insulin activity after uptake via the intestine (78). As yet no side effects have been observed after targeted administration of chromium. In clinical studies, dietary supplementation with chromium picolinate in doses of up to 1,000 micrograms per day did not cause any side effects (79). The US Institute of Medicine found that the available data did not allow definition of a tolerable upper intake level for chromium (80). The European Food Safety Authority noted that, based on in-vitro trials, high doses of chromium picolinate could cause damage to DNA, and defined a UL for adults of 250 micrograms of chromium per day from all sources (81).

Copper, which occurs in foods mainly in its bound form as Cu+ and Cu2+, is absorbed in the small intestine and then carried in the bloodstream to the cells, where it acts as a component of various enzymes (e.g., oxidases) and is involved, inter alia, in the binding of iron to transferrin. Whilst vitamin C and some amino acids promote the uptake of copper in the gut, high intakes of calcium, phosphate, zinc and iron can substantially reduce absorption (82). The highest concentrations of copper are found in the liver (15%) and brain (10%), followed by heart and kidneys. Around 80% of excess copper is excreted into bile and eliminated in the feces. Toxic effects from acute oral ingestion of large amounts of copper have been described as reversible (83), whereas long-term consumption of high doses could cause irreversible damage. Based on available studies, the European Commission’s Scientific Committee on Food defined a tolerable upper intake level for adults of 5 milligrams of copper per day from all sources (84). The US Institute of Medicine set a corresponding UL of 10 milligrams per day (85).

Whereas some plant-source foods (e.g., wholegrain cereals, rice, green leafy vegetables, fruits, and tea leaves) contain large amounts of manganese, the manganese content of animal-source foods tends to be very low. Manganese (Mn2+ and Mn3+) absorbed from the small intestine is transported to the liver and thence to many tissues. In the human organism manganese plays an important role as a specific component of certain enzymes like the antioxidant superoxide dismutase (86). No specific storage proteins are known for manganese, although the trace element accumulates in some tissues, like the brain, when ingested in large amounts. Here, Mn3+ in particular can have toxic effects after long-term intake of high doses (for example in people who inhale manganese particles at work over many years or who have consumed dietary supplements containing manganese) (87). But apart from these extreme cases, the regulation of manganese absorption ensures that excessive amounts are not absorbed after oral ingestion (88). Due to a lack of available data on safety, the European Commission’s Scientific Committee on Food decided not to define a tolerable upper intake level for manganese (89). Based on the results of clinical studies (90), the US Institute of Medicine set a UL for adults of 11 milligrams of manganese in total per day (91).

1. Abrams S. A. et al. Calcium and magnesium balance in 9-14-y old children. Am J Clin Nutr. 1997; 66: 1172–1177.
2. Oliveri B. et al. Mineral and bone mass changes during pregnancy and lactation. Nutrition. 2004; 20: 235–240.
3. Greger J. L. Nutrient interactions. In: Bodwell C. D., Erdman J. W. Jr., eds. Effect of Variations in Dietary Protein, Phosphorus, Electrolytes and Vitamin D on Calcium and Zinc Metabolism. New York: Marcel Dekker. 1988; 205–227.
4. Heaney R. P. Calcium supplementation and incident kidney stone risk: a systematic review. J Am Coll Nutr. 2008; 27(5):519–527.
5. Curhan G. C. et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993; 328:833–838.
6. Reid I. et al. Effects of calcium supplementation on serum lipid concentrations in normal older women: a randomized controlled trial. Am J Med. 2002; 112:343–347.
7. Griffith L. et al. The influence of dietary and non-dietary calcium supplementation on blood pressure: an updated meta-analysis of randomized controlled trials. Am J Hypertens. 1999; 12(1 Pt 1):84–92.
8. Foley R. N. et al. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2008; 156:556–563.
9. Bostick R. et al. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999; 149:151–161.
10. Xiao Q. et al. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP Diet and Health Study. JAMA Intern Med. 2013; 1–8.
11. Pentti K. et al. Use of calcium supplements and the risk of coronary heart disease in 52–62-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas. 2009; 63:73–78.
12. Li K. et al. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012; 98:920–925.
13. Bolland M. J. et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011; 342:d2040.
14. Bockman R. S. et al. The Challenges of the Single Micronutrient Study: Commentary on Calcium Supplements and Cardiovascular Events. Position paper of the ASBMR Professional Practice Committee. Washington, DC: American Society for Bone and Mineral Research. 2011.
15. Nordin B. E. et al. The calcium scare: what would Austin Bradford Hill have thought? Osteoporosis Int. 2011; 22:3073–3077.
16. Paik J. M. et al. Calcium supplement intake and risk of cardiovascular disease in women. Osteoporos Int. 2014; 25(8):2047–2056.
17. Heaney R. P. et al. Review of Calcium Supplements and Cardiovascular Disease Risk. Adv Nutr. 2012; 3:763–771.
18. European Food Safety Authority. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA); Scientific Opinion on the Tolerable Upper Intake Level of Calcium. EFSA J. 2012; 10(7):2814–2844.
19. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press. 2010.
20. Saris N. E. et al. Magnesium. An update on physiological, clinical and analytical aspects. Clin. Chem. Acta. 2000; 294:1–26.
21. Elin R. J. The assessment of magnesium status in humans. In: Metal Ions in Biological Systems. Vol. 26: Compendium on Magnesium and its Role in Biology, Nutrition, and Physiology. Sigel H., Sigel A. (Eds.) Marcel Dekker, Inc., New York , Basel. 1990; p. 579–596.
22. Fleet J. C. and Cashman K. D. Magnesium. In: Present Knowledge in Nutrition. Eight Edition. Bowman B.A., Russell R.M. (Eds.). 2001.
23. Shils M. E. Magnesium. In: Shils M. E., Olson J. A., Shike M., Ross C. A., eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lea and Febiger. 1999; 169–192.
24. Durlach J. et al. Magnesium and therapeutics. Magnesium Res. 1994; 7:313–328.
25. Flink E. B. Magnesium deficiency and magnesium toxicity in man. In: Prasad A. S., ed. Trace Elements in Human Health and Disease. Vol. 2. New York: Academic Press. 1976; 1–22.
26. Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press. 1997.
27. European Commission, Scientific Committee on Food (EC SCF). Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Magnesium. European Commission, SCF/CS/NUT/UPPLEV/54 Final Report. Brussels. 2001.
28. He Q. et al. Total body potassium differs by sex and race across adult age span. Am J Clin Nutr. 2003; 78: 72–77.
29. McLaren D. S. Clinical manifestations of human vitamin and mineral disorders: a resume. In: Shils M. E., Olson J. A., Shike M., Ross C. A., eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lea and Febiger. 1999; 485–503.
30. Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium Chloride, and Sulfate. Washington, DC: National Academy Press. 2004.
31. European Food Safety Authority (EFSA). Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the tolerable upper intake level of potassium. EFSA J. 2005; 193:1–19.
32. Knochel J. P. Phosphorus. In: Shils M. E., Olson J. A., Shike M., Ross C. A., eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lea and Febiger. 1999; 157–167.
33. Bailey R. L. et al. Dietary supplement use is associated with higher intakes of minerals from food sources. Am J Clin Nutr. 2011; 94:1376–1381.
34. Garg A. N. and Anderson J. J. B. Phosphorus. In: Encyclopedia of Food Sciences and Nutrition. Second Edition. Caballero B., Trugo L. C., Finglas P. M. (Eds.) Elsevier Science Ltd., Oxford. 2003; 4532–4546.
35. Knochel J. P. Phosphorus. In: Shils M. E., Shike M., Ross A. C., Caballero B., Cousins R. J., eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins. 2006; 211–222.
36. Arnaud C. D. and Sanchez S. D. Calcium and phosphorus. In: Ziegler E. E., Filer L. J., eds. Present Knowledge of Nutrition. 7th ed. Washington, DC: ILSI Press. 1996; 245–255.
37. Heaney R. P. The calcium-phosphate connection. Alternative Ther Women’s Health. 2002; 4:75–77.
38. European Food Safety Authority. Tolerable Upper Intake Levels for Vitamins and Minerals. Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission Related to the Tolerable Upper Intake Level of Phosphorous. 2006; 447–460.
39. Institute of Medicine. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press. 1997; 146–189.
40. Collings R. et al. The absorption of iron from whole diets: a systematic review. Am J Clin Nutr. 2013; 98:65–81.
41. Fairbanks V. F. Iron in medicine and nutrition. In: Shils M. E., Olson J. A., Shike M., Ross C. A., eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lea and Febiger. 1999; 193–221.
42. Yip R. and Dallman P. R. Iron. In: Ziegler EE, Filer LJ, eds. Present Knowledge of Nutrition. 7th ed. Washington, DC: ILSI Press. 1996; 277–292.
43. Zhang W. et al. Associations of dietary iron intake with mortality from cardiovascular disease: the JACC study. J Epidemiol. 2012; 22:484–493.
44. Salonen J. T. et al. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992; 86:803–811.
45. Avni T. et al. Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis. Eur J Heart Fail. 2012; 4:423–429.
46. Kaldara-Papatheodorou E. E. et al. Anemia in heart failure: should we supplement iron in patients with chronic heart failure? Pol Arch Med Wewn. 2010; 120(9):354–360.
47. Danesh J. and Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies. Circulation. 1999; 99:852–854.
48. Tseng M. et al. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol. 1996; 144:1005–1014.
49. Zhang X. et al. A prospective study of intakes of zinc and heme iron and colorectal cancer risk in men and women. Cancer Causes Control. 2011; 22:1627–1637.
50. Chang T. P. and Rangan C. Iron poisoning: a literature-based review of epidemiology, diagnosis, and management. Pediatr Emerg Care. 2011; 27:978–985.
51. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.
52. European Food Safety Authority. Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission Related to the Tolerable Upper Intake Level of Iron. EFSA J. 2004; 125:1–34.
53. Rayman M. P. Selenium and human health. Lancet. 2012; 379:1256–1268.
54. Barceloux D.G. Selenium. J Toxicol Clin Toxicol. 1999; 37: 145–172.
55. Russo M. W. et al. 1997. Plasma selenium levels and the risk of colorectal adenomas. Nutr Cancer. 1997; 28:125–129.
56. Patterson B. H. and Levander O. A. Naturally occurring selenium compounds in cancer chemoprevention trials: a workshop summary. Cancer Epidemiol Biomarkers Prev. 1997; 6:63–69.
57. Young K. L. and Lee P. N. Intervention studies on cancer. Eur J Cancer Prev. 1999; 8:91–103.
58. Rajpathak S. et al. Toenail selenium and cardiovascular disease in men with diabetes. J Am Coll Nutr. 2005; 24:250–256.
59. Lippman S. M. et al. The effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009; 301:39–51.
60. Herzberg S. et al. The SU.VI.MAX Study: a randomized, placebo- controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335–2342.
61. Meyer F. et al. 2005. Antioxidant vitamin and mineral supplementation in the SU.VI.MAX trial. Int J Cancer. 2005; 116:182–186.
62. Hurst R. et al. 2012. Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr. 2012; 96:111–122.
63. Park K. et al. Toenail selenium and incidence of type 2 diabetes in U.S. men and women. Diabetes Care. 2012; 35:1544–1551.
64. Bleys J. et al. Selenium and diabetes: more bad news for supplements. Ann Intern Med. 2007; 147:271–272.
65. Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press. 2000.
66. European Commission, Scientific Committee on Food (EC SCF). Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Selenium. European Commission, SCF/CS/NUT/UPPLEV/25 Final Report, Brussels. 2000.
67. Cousins R. J. Zinc. In: Ziegler E. E., Filer L. J., eds. Present Knowledge of Nutrition. 7th ed. Washington, DC: ILSI Press. 1996; 293–306.
68. Chandra R. K. Excessive intake of zinc impairs immune responses. JAMA. 1984; 252:1443–1446.
69. Black M. R. et al. Zinc supplementation and serum lipids in adult white males. Am J Clin Nutr. 1988; 47:970–975.
70. Simmer K. et al. Are iron-folate supplements harmful? Am J Clin Nutr. 1987; 45:122–125.
71. Kauwell G. P. et al. Zinc status is not adversely affected by folic acid supplementation and zinc intake does not impair folate utilization in human subjects. J Nutr. 1995; 125:66–72.
72. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.
73. European Commission, Scientific Committee on Food. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Zinc. European Commission, SCF/CS/NUT/UPPLEV/62 Final. Brussels. 2003.
74. Freake H. C. Iodine. In: Biochemical and Physiological Aspects of Human Nutrition. Stipanuk M.H. (Ed.) W.B. Saunders Company, Philadelphia, London, New York, St. Louis, Sydney, Toronto. 2000; 33:761–781.
75. Hetzel B. S. and Clugston G. A. Iodine. In: Shils M. E., Olson J. A., Shike M., eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lea and Febiger. 1999; 253–264.
76. European Commission, Scientific Committee on Food. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Iodine. European Commission, SCF/CS/NUT/UPPLEV/26 Final Report. Brussels. 2002.
77. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.
78. do Canto O. M. et al. Chromium 3 metabolism in diabetic patients. In: Kinetic models of trace element and mineral metabolism. Subrananian K. N., WastneyM. E. (Eds.) CRC Press, Boca Raton, FL. 1995; 205–219.
79. Broadhurst C. L. and Domenico P. Clinical studies on chromium picolinate supplementation in diabetes mellitus: a review. Diabetes Technol Ther. 2006; 8(6):677–687.
80. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.
81. European Food Safety Authority. Safety of trivalent chromium as a nutrient added for nutritional purposes to foodstuffs for particular nutritional uses and foods intended for the general population (including food supplements). EFSA J. 2010; 8(12):1882.
82. Harris E. D. Copper. In: O’Dell B. L., Sunde R. A., eds. Handbook of Nutritionally Essential Mineral Elements. New York: Marcel Dekker. 1997; 231–275.
83. Aaseth J. and Norseth T. Copper; In: Friberg, L. et al. (Hrsg.). Handbook on the Toxicology of Metals, Volume II, Elsevier. 1986.
84. European Commission, Scientific Committee on Food. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Copper. European Commission, SCF/CS/NUT/UPPLEV/57 Final Report. Brussels. 2003.
85. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.
86. Malecki E. A. and Greger J. L. Manganese protects against heart mitochondrial lipid peroxidation in rats fed high levels of polyunsaturated fatty acids. J Nutr. 1996; 126:27–33.
87. Keen C. L. et al. Nutritional and toxicological aspects of manganese intake: an overview. In: Mertz W, Abernathy CO, Olin SS, eds. Risk Assessment of Essential Elements. Washington, DC: ILSI Press. 1994; 221–236.
88. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Manganese. 2012.
89. European Commission, Scientific Committee on Food. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Manganese. European Commission, SCF/CS/NUT/UPPLEV/21 Final Report. Brussels. 2000.
90. Greger J. L. Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers. Neurotoxicology. 1999; 20:205–212.
91. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. 2001.