Topic of the Month

The safety of micronutrients – Part 2: water-soluble vitamins

September 1, 2014

Insufficient and excessive consumption of nutrients can both increase the risk of damage to health. As intake is increased, the risk of developing a harmful nutrient deficiency falls until the intake reaches an amount that is regarded as adequate (recommended daily amount). Above this amount (tolerable upper intake level or UL) toxic effects may be seen that once more increase the risk of damage to health. How the body reacts to the consumption of specific micronutrients depends on the dosage and on the consumer’s baseline nutrient status. If nutrient levels are already high, increasing consumption is likely to increase the risk of toxicity. With vitamins as with all nutrients: more is not always better. This also applies to water-soluble vitamins, although these do not accumulate in the body to the same degree as the fat-soluble vitamins (see also The safety of micronutrients – Part 1: fat-soluble vitamins).

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The water-soluble vitamins include the B-vitamins and vitamin C. Since only limited amounts of these substances can be stored in the body they have to be ingested regularly. Due to the small reserves in the body, the recommended blood levels of water-soluble vitamins are maintained for only a few weeks if intake is insufficient. If excessive amounts are consumed, absorption by the small intestine is reduced and most of the vitamin is excreted via the kidneys. A single large dose is therefore not particularly beneficial. Vitamin B12 is an exception to this rule. It is stored in significant amounts in the liver. The relatively large body reserves and the low turnover of vitamin B12 explain why a vitamin B12 deficiency only becomes clinically apparent after some years. Water-soluble vitamins are usually precursors or elements of coenzymes which are essential for numerous metabolic processes.

Vitamin C

A little vitamin C (ascorbic acid) is absorbed by the mucus membranes of the mouth when it is taken orally, but most is absorbed by the small intestine. If the amount of vitamin C consumed is increased, the activity of the vitamin C transport proteins gradually decreases and consequently the rate of uptake falls (1). Hence around 80–90% of an oral dose of 180 mg/day are utilized by the body; with a dose of 1,000 mg/day the rate falls to around 65–75%, with 3,000 mg/day uptake is about 40% and with a 12,000 mg dose only around 16% of the vitamin C is absorbed (2). Because human beings do not possess a special store for ascorbic acid, excess intakes are either not absorbed or are excreted in the feces (stools) and/or renally (via the kidneys) (3). Vitamin C in blood plasma is transported to various tissues – primarily brain, adrenal glands, the lens of the eye and leucocytes – where it can help protect cell components against oxidative damage. The vitamin is also needed for the production of collagen and ensures that bone, skin, blood vessels, the nervous system and the immune system function normally.

It is assumed that vitamin C does not cause permanent damage to health even when large doses are taken orally. Apart from diarrhea and other gastrointestinal side effects, which can occur with intakes of 3 g per day or more, no reliable evidence has been found for numerous other supposedly undesirable effects. Reports that consuming large amounts of vitamin C over a long period of time could lead to low blood vitamin C levels due to a rebound effect (4) have not been confirmed (5). Equally, evidence for increased formation of kidney stones (calcium oxalate and uric acid stones) in people who took more than 1 g of ascorbic acid per day (6); raised levels of uric acid elimination (7); oxidative effects mediated by iron (8); excessive absorption and release of iron (8) or destruction of vitamin B12 (9) and of tooth enamel (10) does not appear to be reliable (5).

While the US Institute of Medicine (5) defined a UL of 2,000 mg vitamin C for adults, the European Food Safety Authority (11) decided not to set a tolerable upper intake level. The Authority described a daily intake of 1,000 mg ascorbic acid in addition to normal consumption from the diet as harmless.

Vitamin B1

Vitamin B1 (thiamine) is found in low concentrations in both plant-source and animal-source foods and is absorbed by the gut via a dose-dependent mechanism. As intake increases, the percentage of thiamine absorbed decreases: only around 50% of a 1 mg intake and as little as 33% of a 5 mg intake are absorbed (12). In all, a maximum of 8–15 mg vitamin B1 can be absorbed per day. Once absorbed, thiamine is carried to the liver with the blood cells, and from there is transported through the bloodstream to the target organs and tissues – in particular cardiac muscle, kidney, brain and skeletal muscles – to meet their requirements. There it is taken up primarily by the mitochondria, where it participates in energy and carbohydrate metabo-lism. Alcohol (ethanol) suppresses the activation (phosphorylation) of thiamine, so that alcoholics are at increased risks of thiamine deficiency. The total amount of vitamin B1 in the body of healthy people is
25–30 mg, around 40% of which is found in the muscles. The limited capacity of the body to store this
B vitamin, together with its high rate of turnover, make it necessary to consume it daily in sufficient amounts to meet demand, especially when vitamin B1 requirements are raised due to increased metabolic activity. This might be after exercise or heavy physical work, during pregnancy and breastfeeding, or due to chronic alcohol abuse or fever (12). When large doses of vitamin B1 are taken, once the tissues are saturated the vitamin is excreted almost completely via the kidneys.

No side effects have been detected, even after oral doses of several hundred milligrams of vitamin B1. For this reason, neither the US Institute of Medicine (13) nor the European Commission’s Scientific Committee on Food (14) has defined tolerable upper intake levels. In one clinical study dietary supplementation with
100 mg thiamine hydrochloride was identified as safe (15).

Vitamin B2

Vitamin B2 (riboflavin) is synthesized from plants and microorganisms, enters animal organisms via the food chain and is found in many foodstuffs. The rate of absorption of riboflavin after consumption of physiological dosages is on average between 50 and 60% (16). After uptake of vitamin B2 via the small intestine it is converted, primarily in liver, kidney and heart, into coenzyme forms – flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) – which are involved in many reduction and oxidation reactions of energy, carbohydrate, protein and lipid metabolism. The body’s ability to store riboflavin is limited. In adult humans about 123 mg vitamin B2 is retained in the kidneys.

In studies, orally ingested riboflavin showed no toxic effects up to a dose of 400 mg per day (17). Neither the US Institute of Medicine (18) nor the European Commission’s Scientific Committee on Food (19) has defined tolerable upper intake levels for riboflavin.

Niacin

Vitamin B3 (niacin) occurs as nicotinic acid (primarily in plant tissue such as cereals and coffee beans) or as nicotinamide (primarily in animal organisms in the form of the coenzymes NAD and NADP). The rate of absorption of niacin from the small intestine is most influenced by the dietary composition: whilst it is almost 100% for animal-source foods, absorption from cereal products is only around 30%. Once absorbed, niacin, mainly in the form of nicotinic acid, is carried by the blood to the liver, where it is converted to the coenzymes NAD and NADP. These coenzymes play an elementary role in many reduction and oxidation (redox) reactions of the energy and amino acid metabolism systems and in the detoxification of medicinal drugs (20). Apart from the liver, erythrocytes and other tissues are involved to some extent in the storage of niacin in the form of NAD(P). Excess niacin is not stored in the body but excreted, primarily via the kidneys.

Adequate adult intakes for the synthesis of NAD and NADP are 15 to 18 mg nicotinic acid per day, but daily doses over 50 mg can have acute vasodilatory effects (blushing). Doses of up to 3 g daily (21) – used to treat disorders of the fat metabolism system – can cause chronic liver damage. In contrast, doses of up to
6 g of nicotinamide were not associated with any side effects (22). In dietary supplements, the better tolerated buffered nicotinic acid, which is released slowly, is used as well as nicotinic acid and nicotinamide.

The US Institute of Medicine (23) defined the combined upper tolerable intake levels (UL) of nicotinic acid and nicotinamide for adults as 35 mg per day. The European Commission’s Scientific Committee on Food (24) set a UL for adults of 10 mg/day for nicotinic acid and 900 mg/day for nicotinamide.

Pantothenic acid

Up to 50 to 95% of the vitamin B5 (pantothenic acid) found in plant and animal tissues is in the form of coenzyme A and 4‘-phosphopantetheine, an essential element of fatty acid synthesis. Once absorbed by the gut the vitamin is transported to the target tissues and taken up by the cells. Whilst no specific storage organs are known for vitamin B5, high tissue concentrations can be found in cardiac muscle, kidneys, adrenal glands and liver. Coenzyme A acts as a universal acyl group carrier in energy metabolism (ATP synthesis). 4'-phosphopantetheine produces a functional group of fatty acid synthase, a multi- enzyme complex for the synthesis of saturated fatty acids (25). Excess pantothenic acid is mainly excreted via the kidneys, in urine.

The toxicity of pantothenic acid is thought to be very low. In studies, intakes of 10 g per day over several weeks were well tolerated. Neither the US Institute of Medicine (26) nor the European Food Safety Authority (27) has defined tolerable upper intake levels for pantothenic acid.

Vitamin B6

Vitamin B6 is occurs widely in plant-source foods (mainly as pyridoxine) and in animal-source foods (mainly as pyridoxal). Moreover, bacteria in the intestines are capable of synthesizing vitamin B6 and thus increasing the amounts of pyridoxine available. Vitamin B6 consumed in the diet is absorbed from the whole length of the small intestine and carried first to the liver, whence it is transported to peripheral tissues like the muscles (28). There, in the form of pyridoxal-5'-phosphate, it is involved as a coenzyme in numerous enzymatic reactions of the carbohydrate, lipid, amino acid and neurotransmitter metabolism systems. If intake is adequate, the total body stores of vitamin B6, mostly in the form of enzyme -bound pyridoxal-5'-phosphate, are around 100 mg, divided between muscle tissue and liver. Excess ingested vitamin B6 is excreted via the kidneys.

The results of some studies provided evidence that targeted administration of pyridoxine in doses over
100 mg daily could, in the long term, lead to neurological disorders such as signs of paralysis, problems with the sense of temperature or numbness in the extremities (29, 30). One controversial study reported cases of women who had taken 50 mg pyridoxine or even less over a period of almost three years in food supple-ments who complained of neurological disturbances (31). Other studies did not observe such symptoms. Based on current data, the US Institute of Medicine (32) has defined an tolerable upper intake level (UL) for adults of 100 mg pyridoxine per day, whilst the European Commission’s Scientific Committee on Food (33) defined a UL of 25 mg per day for adults.

Biotin

Vitamin B7 (biotin) can be synthesized by many fungus and plant species, as well as by the bacteria in the human gut. The latter is of minor importance for provision with this vitamin, because it is mainly absorbed by the small intestine, while the bacteria are found in the large intestine. After absorption it is carried through the bloodstream to the cells of the target tissues, where it acts as coenzyme in a number of carboxylase reactions (introduction of COOH groups) in the amino acid metabolism system and in the biosynthesis of fatty acids (34).

Biotin appears to have very low toxicity: neither injections and oral administration of 10 mg biotin daily for six months to small children (35), nor injections of 20 mg in adults (36) led to any kind of side effects. Consequently neither the US Institute of Medicine (37) nor the European Commission’s Scientific Committee on Food (38) has defined an tolerable upper intake level for vitamin B7.

Folic acid

Vitamin B9 occurs in animal-source and plant-source foods as folate, as well as in the form of synthetically manufactured folic acid which is added to foods, food supplements and medicines. In comparison with the natural folate compounds folic acid is highly stable and as pure substance is almost fully absorbed, while the folate compounds found in food have only around 50% bioavailability. Naturally occurring folates can also be manufactured synthetically: the bioavailability of 5-methyltetrahydrofolate corresponds to that of folic acid. The dietary folate equivalent (DFE) is calculated from the different absorption rates: 1 µg DFE = 1 µg of dietary folate, 1 µg of dietary folate = 0.5 µg of folic acid, 1 µg of folic acid = 2 µg of dietary folate or 2 µg DFE (39).

After uptake from the small intestine and transport in the bloodstream to the liver, vitamin B9 in its biologically active form, tetrahydrofolate, acts as a coenzyme in the cells of the target tissue. There it functions as receiver and donor of C1 units (methyl groups and formyl groups), in particular in protein and nucleic acid metabolism. Cell systems with a high rate of division, like blood and epithelial cells, have high concentrations of folate. Total body levels of folate in humans are 5–10 mg, of which half is located in the liver, as the main organ of storage (40). Because of the limited body reserves, serum levels of vitamin B9 can only be maintained for 3–4 weeks when the diet does not contain folate. Excess vitamin B9 is excreted via the kidneys.

No harmful effects have been confirmed for high intakes of folates from food or of folic acid from dietary supplements or fortified foods (41). The following have been discussed as theoretical side effects of long-term high-dose supplementation with folic acid:

  1. Targeted folic acid intakes of 5 mg or more per day could prevent the occurrence of changes to blood cells that, in some patients, are the first signs of vitamin B12 deficiency. These changes could therefore remain undiscovered until the body starts to show signs of serious neurological damage (42). However, studies indicate that changes to blood are not completely disguised by folic acid (43).
  2. According to some studies, high intakes of folic acid could impair the utilization and function of zinc in people with a low zinc status (44). More recent studies did not reveal any such effects, however (45).
  3. No causal effect has been substantiated for the suspected reduced effectiveness of anti-epileptic drugs with high doses of folic acid (up to 30 mg per day) reported by some studies (42).
  4. Trials with animals indicate that adequate intakes of folic acid appear to counteract the incidence of tumors, whilst high doses of folic acid could stimulate the growth of cancer precursors (46). Clinical trials were not able to confirm such effects. In the USA and Canada an increase in the incidence of some types of cancer was reported just at the time when foods began to be fortified with folic acid, leading to speculation about a possible connection, although subsequently the cancer rates fell again. A meta-analysis of 13 randomized controlled studies investigated whether dietary supple-mentation with up to 40 mg of folic acid per day over a period of up to 7.4 years raised or lowered the risk of cancer compared to placebo (47). The analysis did not reveal any difference with regard to the incidence of cancer: bowel, lung, breast and prostate cancer or other forms of cancer were equally frequent in the folic acid and in the placebo groups.

Since folic acid is used in many countries to fortify food, consumers should take care that they do not exceed the upper tolerable intake levels in the long term if they consume these products and also take additional folic acid in the form of dietary supplements, as well as ingesting it with the normal diet. Based on current studies, both the US Institute of Medicine (48) and the European Commission’s Scientific Committee on Food (49) have defined the tolerable upper intake levels for adults as 1 mg folic acid per day.

Vitamin B12

Vitamin B12 (cobalamin) is synthesized exclusively by certain microorganisms in the gut flora. In humans the vitamin B12 produced by the gut flora is not sufficiently utilizable, so we are reliant on an additional intake of this B vitamin from foods containing meat. After absorption from the small intestine the vitamin is carried in the bloodstream to the cells of the target tissue. As a cofactor it is above all needed for cell division (DNA synthesis), the production of red blood cells, and the protective covering of nerve fibers (myelin sheath), as well as for the uptake of folic acid by cells (50). Further, vitamins B12, B6 and B9 are involved in the control of blood homocysteine levels. High concentrations of this amino acid in the blood have been associated with an increased risk for cardiovascular disease.

Vitamin B12 is the only water-soluble vitamin stored in appreciable amounts in the body. The main storage organ for vitamin B12 is the liver, which stores around 60% of cobalamin reserves. About 30% is found in skeletal muscle, while the remainder is distributed throughout other tissues like heart and brain. The relatively high body reserves (2 to 5 mg) and the low rate of turnover explain why vitamin B12 deficiency only becomes clinically apparent after some years. Hence vegetarians only exhibit signs of a deficiency after 5–6 years, despite a diet low in cobalamin. As the oral intake of vitamin B12 increases, the amount absorbed falls and the proportion of the vitamin excreted via the kidneys rises.

No undesirable side effects have been observed with oral administration or injection of large doses of vitamin B12 (e.g., 1.000 micrograms per day for a year). Neither the US Institute of Medicine (51) nor the European Food Safety Authority (52) has defined tolerable upper intake levels.

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