Micronutrients 1231 Vitamins

For vitamins, health risks are traditionally associated with deficiencies. If a large intake range is considered, there is the risk of toxicity (see Figure 12.2). As far as the margin between physiological need and toxic dose is concerned, two groups of vitamins are distinguished: the lipophilic vitamins (vitamins A, D, E, and K) and the water-soluble vitamins (vitamin C, biotin, niacin, pantothenic acid, and folate, and the vitamins B). For the first group the margin may be relatively narrow, for the latter very wide.

Excessive vitamin intake can lead to a variety of toxic effects. In a number of cases, vitamin-induced toxicity is well-known. In other cases, vitamins are only slightly toxic or rather harmless. Although the vitamin content of the diet usually does not lead to toxic effects, it will be of increasing importance to take care of the standards set for vitamin intake in view of the recent trend of vitamin supplementation and fortification. In addition, vitamins are more and more used in processed food as naturally occurring antioxidants instead of synthetic antioxidants.

Also, long-term consumption of high doses of vitamins may be hazardous, even though they are rapidly eliminated. The lipophilic vitamins A and D pose the highest risk, as they can accumulate in the body.

12.3.1.1 Lipophilic vitamins

Vitamins are illustrative examples of body-oriented substances with their specific functions in organisms. It is mainly through the mechanisms underlying these functions that at high intake levels vitamins may be toxic to the organism (hypervitaminosis). Therefore, this section studies the toxicity of the lipophilic vitamins (A, D, E, and K) in relation to their intake, preceded by brief descriptions of their physiological functions.

Vitamin A represents a group of substances necessary for reproduction, cellular differentiation, and proliferation of epithelia, growth, integrity of the immune sytem, and normal eye sight. Retinal, formed from retinol, is involved in the so-called visual cycle. In this cycle, the retinal pigment rhodopsin (visual purple) is bleached on exposure to light. Next, a stimulus is sent to the rods in the retina. The bleaching of visual purple enables the human eye to see at night. In case of vitamin A deficiency, one of the symptoms is night blindness.

The large group of retinoids comprises naturally occurring substances with some vitamin A activity, such as retinol, retinaldehyde, and retinoic acid, and a large number of synthetic, structurally-related substances with or without vitamin A activity. In foods of animal origin, vitamin A is present as retinyl ester. The sources richest in vitamin A are fish liver oils. Further, considerable amounts are also present in fortified whole milk and eggs.

Food consumption data showed that the average daily dietary intake by adult men is about 1500 |g retinol equivalents (RE). The RDA for vitamin A is 1000 |g RE. If consumed

vitamin A intake |g/kg body wt/day

Figure 12.5 Response of a typical mucous epithelium to vitamin A intake (scheme at the top), and clinical symptoms of altered cell function as a result of vitamin deficiency as well as of vitamin A toxicity (bottom curve). Source: Int. Vit. A Consultative Group, Nutrition Foundation, 1980.

in very high doses, vitamin A causes, either acutely or chronically, a large number of adverse effects, including headache, vomiting, diplopia, alopecia, dryness of the mucous membranes, desquamation, bone abnormalities, and liver damage (see Figure 12.5).

Any toxic effects usually result from continuous high daily intake. High intakes of 15 times the RDA can be reached by consuming large amounts of liver or fish liver oils, and food with vitamin A supplements. A high incidence (>20%) of spontaneous abortions and birth defects, including malformations of the cranium, face, heart, thymus, and central nervous system, has been observed in fetuses of women who ingested therapeutic doses of 500 to 1500 |g/kg body weight of 13-cis retinoic acid during the first 3 month of pregnancy. High daily doses of retinyl esters or retinol may cause similar abnormalities.

The mechanisms underlying vitamin A toxicity are very complex, as a sequence of events is triggered. The main toxic effects are related to its function in differentiation and proliferation of cells. The kinetic behavior of vitamin A is largely determined by binding to blood proteins and receptor proteins, and by cellular transport. High intake of vitamin A (hypervitaminosis A) may result in saturation of protein binding which may lead to membrane damage (by free vitamin A).

Vitamin D is necessary for normal bone growth and mineral homeostasis. Exposure of the skin to ultraviolet light catalyzes the synthesis of vitamin D3 (cholecalciferol) from

7-dehydrocholesterol. Another major form, vitamin D2 (ergocalciferol), is formed from ergosterol in plants on exposure to ultraviolet light.

Fortified foods (e.g., margarine), milk, eggs and butter are the major sources of vitamin D. The daily vitamin D intake is estimated at 2 |g of cholecalciferol for adults. Presumably, vitamin D pools in the body are replenished in most people by regular exposure to sunlight. The RDA for vitamin D is 5 |g of vitamin D3 for adults and 10 |g for young adults. Vitamin D is potentially toxic, especially for young children. The effects of excessive vitamin D intake include hypercalcemia and hypercalciuria, leading to deposition of calcium in soft tissues, and irreversible renal damage (nephrocalcinosis) and cardiovascular damage. Although the toxic dose has not been established for all ages, hypervitaminosis D in young children has been related to the consumption of as little as 45 |g vitamin D3 per day.

Vitamin E is the collective name for an important group of natural products: the tocopherols. There are four members: a, p, y and 5, differing from each other in the number and position of the methyl groups attached to the chroman ring, or the saturated carbon side chain. The major and most potent form of vitamin E is a-tocopherol.

The tocopherol content of food (vegetable oils, wheat germ, nuts, green leafy vegetables) varies greatly. During storage and processing large amounts may be lost. The intake of vitamin E is estimated at about 10 mg per day, which is also the RDA. Compared to the other lipophilic vitamins, vitamin E is relatively nontoxic when taken orally. High intake may result in symptoms associated with the pro-oxidant action of vitamin E. Most adults appear to tolerate oral doses of 100 to 800 mg per day.

Vitamin K is necessary for the maintenance of normal blood coagulation. The vitamin is found in green leafy vegetables. Even if large amounts of vitamin K were ingested over a long period of time, no toxic effects were reported. However, administration of a substance structurally related to vitamin K, menadione, may result in hemolytic anemia, hyperbilirubinemia, and kernicterus in the newborn. The underlying mechanism is believed to involve interaction with sulfhydryl groups.

12.3.1.2 Hydrophilic vitamins To this group belong vitamin C, biotin, niacin, pantothenic acid, folate and the vitamins B: thiamin (Bj), riboflavin (B2), vitamin B6 and vitamin B12. Relatively large amounts of these vitamins can be ingested without adverse consequences. They are rapidly excreted from the body, as they are water soluble.

Daily intakes of the antioxidant vitamin C (L-ascorbic acid) up to 1 g did not lead to toxic effects. The harmless use of vitamin C is also shown by Figure 12.2. There is a relatively wide margin between the RDA and the toxic dose. If high doses were taken over a long period of time, however, vitamin C appeared to induce toxic effects. Well-known adverse effects after doses as high as 1 g or more are gastrointestinal disturbances such as diarrhea, nausea, and abdominal cramps. Increased peristalsis, resulting from a direct osmotic effect on the intestine, is believed to be the cause. Occasionally, these effects are attributed to sensitization associated with urticaria, edema, and skin rashes. Toxic effects following high doses of vitamin C usually disappear within one or two weeks. They can be prevented by using buffered solutions of vitamin C or by intake after meals.

Thiamin, as thiamin pyrophosphate, is a co-enzyme required for oxidative decarboxylation of a-keto acids and for transketolase in the pentose phosphate pathway. It occurs in considerable amounts in germs of grains, peas, and nuts, and in yeast. Even at very high doses, oral intake of thiamin does not lead to toxic effects; it is rapidly excreted into the urine. Following parenteral or intravenous administration of thiamin, a variety of toxic effects have been reported, but usually only at doses several hundred times higher than the RDA.

Niacin, another hydrophilic vitamin is nicotinic acid. A derivative of this acid, nicotinamide, functions in the body as a component of two cofactors: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin is found in the liver, kidneys, meat and fish, and wheat bran, in the germs of grains, and in yeast. High doses of nicotinic acid, but not of nicotinamide, may lead to vascular dilatation, or flushing.

Vitamin B6 occurs in two forms: pyridoxal phosphate and pyridoxine (or pyridoxol). Pyridoxal phosphate is the metabolically active form of the vitamin. It serves primarily as a cofactor in transamination reactions. Vitamin B6 is found in kidneys, liver and eggs. The acute toxicity of vitamin B6 is low. Toxic effects have not been observed in man following an intravenous dose of 200 mg or oral doses of more than 200 or 300 mg. If taken in gram quantities for months or years, however, vitamin B6 can cause ataxia and severe sensory neuropathy.

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