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Toxic effects of water-soluble vitamin

By Razak Hj. Lajis
The Sun, December 28, 1996

GENERALLY, VITAMINS FALL INTO TWO categories, namely water-soluble and fat-soluble vitamins. Vitamin C and the B vitamins are classed as water-soluble vitamins.

The B vitamins may be subdivided into two groups. Those acting as cofactors in the release of energy from food are placed in one group. This energy releasing vitamins comprise of thiamine, riboflavin, niacin, biotin and pathothenic acid. Folacin and cyanocobalamin belong to the second group. The members of this group play important roles in the formation of nucleic acids and red blood cells.

Vitamins in large doses can be used as primary therapy for certain medical conditions. While there is no doubt that these nutrients are essential to health, misconceptions about their functions and effectiveness still occur.

Vitamins are physiologically active chemicals and many have toxic effects at high doses. The group of water-soluble vitamins comprise a large number of vitamins that differ greatly in chemical structure and biological action. They are all water-soluble and can be obtained in relatively substantial amounts from the same sources, namely yeast and liver. Toxicity following acute overdose with multiple vitamin preparations is unlikely unless a massive dose has been ingested.

Vitamins are actually coenzymes that combine with a protein apoenzyme to form an enzyme. These resultant enzymes are used for metabolic functions. Most vitamins have important functions in intermediary metabolism or the special metabolism of the various organ systems. Not all vitamins can be synthesised in the body. In some instances, they are synthesised in insufficient amounts to meet normal requirement. Therefore, in such situations, vitamins must be taken in small amounts from an exogenous sources.

A number of disease states, however, may require the use of vitamins in doses exceeding the recommended nutrient intake. In some metabolic diseases, vitamins are used a therapeutic drugs rather than dietary supplements. In some cases, a dose of more than 10 times have been indicated.

This practice is described as "megavitamin therapy." Normally, it is given in amounts above the recognised biological requirements. For children, the recommended intake is an estimate of the amount of a given vitamin or mineral required to establish and maintain appropriate body stores and meet growth needs in specific age and sex categories. A brief summary of recommended daily allowances are illustrated as in table 1.

(0-12 mo)
<4 years
Adults & children > 4yrs
B1 (Thiamine) Beri-beri, inflammation of nerves Liver, unrefined cereal, grains 0.5 mg 0.7 mg 1.5 mg
B2 (Riboflavin) Inflammation of the tongue, maceration at angles of mouth Liver, milk 0.6 mg 0.8 mg 1.8 mg
B3 (Niacin) Pellagra Yeast, lean meat, liver 8 mg 9 mg 20 mg
B6 (Pyridoxine) Convulsions, hyperirritability Yeast, wheat, corn, liver 0.4 mg 0.7 mg 2.0 mg
B12 (Cyanocobalamin) Pernicious anaemia Liver, meat, eggs, milk 2 mcg 3 mcg 6 mcg
Vit. C (Ascorbic Acid) Scurvy Citrus fruits, leafy green vegetables 35 mg 40 mg 60 mg
Folates (Foloc Acid) Sprue, anaemia, neural tube defects in children of folate-deficient women leafy green vegetables 0.1 mg 0.2 mg 0.4 mg
Table 1

Water-soluble vitamins are thought to be readily excreted and therefore would cause few problems if taken in excess. There is a general impression that there is considerable margin of safety with most vitamins and that few side-effects occur even at dose levels well above the recommended daily dietary allowance (RDA).

The safety margin appears to be particularly wide for the water-soluble vitamins, especially vitamin B and C, which are rapidly excreted from the body if they are not utilised.

However, this is not always true. Acute and chronic toxicities do occur from excessive water-soluble vitamins. Toxicity from megadosing on water-soluble vitamins, although infrequent, can occur. These toxicities are more frequently associated with thiamine, niacin, pyridoxine and possibly with ascorbic acid (vitamin C).

Vitamin C is important in the formation and maintenance of connective tissue, bone, blood components and nervous tissue. Dietary sources include most fruits and vegetables, especially citrus fruits, tomatoes and cabbages. Meat and liver have little or none. Vitamin C has been widely promoted for the prevention or treatment of many conditions ranging from the common cold to cancer. Toxicity is primarily manifested as an adverse effect due to the acid nature or reducing properties of vitamin C. Diarrhoea and abdominal cramps occur with daily doses over 1g. Gas formation in the stomach or intestines may occur at dosages 3g to 30g daily, although many people tolerate these quantities.

Doses of 8g for three to seven days can cause accumulation of uric acid in the urine with kidney stones. Megadoses can also result in the increased excretion of urine containing calcium oxalate crystals, oxalate being the major metabolite of vitamin C. Daily ingestion of greater than 2g may also increase the risk of kidney stones.

Although large doses of vitamin C can be tolerated without significant toxicity in the majority of people, it should be avoided in those with a history of kidney stones or other risk factors for stone development. Most people can tolerate a daily intake of 10 to 100 times the recommended nutrient intake without toxicity symptoms.

Vitamin C has been thought to be a safe drug when given in normal therapeutic doses to patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, but there have been reports of haemolysis associated with large doses. In one incident, two boys were reported to suffer from haemolysis after a substantial consumption of vitamin C through their lemon-flavoured soft-drink. It was found that the vitamin C content of the drink was 1,000 mg per 200ml glass.

The boys took two to three glasses of the drinks and thus consumed approximately 3 gm to 4gm vitamin C each in 4 - 6 hours. Although it was that vitamin C could substitute for reduced glutathione in the body and act as a scavenger for toxic oxygen radicals, higher serum ascorbate levels will lead to oxidative haemoglobin breakdown and haemolysis. The effect is more prominent in those suffering from G-6-PD deficient individuals given 1.5g vitamin C orally.

As for thiamine (Vitamin B1), there appears to be a large margin of safety before toxicity develops, particularly when it is administered orally. The only established therapeutic value of thiamine is in the treatment or the prophylaxis of thiamine deficiency.

Pregnancy increases thiamine requirements slightly. There appears to be little toxicity from excess thiamine until daily intake approaches several grams. Unless the disease being treated is the direct result of a deficiency, there is no reason to expect thiamine to act beneficially. However, thiamine may be used as a dietary supplement if it is believed that insufficient amounts are being absorbed. Such conditions may occur in cases of chronic diarrhoea. In this case, prophylactic administration of thiamine may prevent the development of deficiency symptoms.

Thiamine has been used as a therapeutic agent for unrelated conditions such as ulcerative colitis and decreased gastrointestinal osmotic tension. Thiamine has also been used to stimulate the appetite. The therapeutic oral dose is 10 mg daily for several weeks until all evidence of deficiency disappears. The toxic oral dose is approximately 40 times higher and is apparently unrelated to its role as vitamin.

Doses of greater than 5 mg/day for four to five weeks have been reported to cause headache, irritability, insomnia, rapid pulse and weakness. Taking 10g daily for about three weeks has resulted in toxic effects on the nervous system and cardiovascular system.

Riboflavin (vitamin B2) acts as a coenzymes in tissue respiration and oxidation. Like thiamine, riboflavine is used in expending energy. A minimum intake of 1 mg/day is recommended. The normal requirement is usually met from dietary sources. Riboflavine is found in large amounts in liver, kidney, wheat bran, yeast and peas. Therapeutic doses range from 2 mg to 15 mg daily. Riboflavine consumed in megadoses does not appear to have any toxic effects.

Niacin (vitamin B3) is the term used to describe nicotinic acid and nicotinamide, a component of co-enzymes involved in metabolic processes through-out the body. The active form of the vitamin is nicotinamide. Niacin activity is measured in niacin equivalent (NE), which is equal to 1 mg of niacin. Both forms of niacin are water-soluble. Good sources are liver, kidney and other meats. It is also present in fish, legumes and wheat germ. Milk , eggs and fruits are normally poor sources of niacin. The recommended daily dietary allowance of niacin is 20 mg or less. Therapeutic doses of 100 mg to 500 mg/day have been used to treat pellagra. For prophylactic purposes, doses of 25 mg/day are recommended.

Nia cin causes the release of histamine, which results in flushing of the face, neck and chest soon after administration, and the effects last for about 20 minutes. The effect is more frequently seen at doses of 3g or greater but may be produced with as little as 100mg.

Niacin has been proposed for the treatment of schizophrenia and has been used to treat certain types of hyperlipidaemia. When used in megadoses of 3g/day in adults (over 100 times the recommended dose), niacin has been found to cause flushing in 92% of patients. It has been demonstrated that daily doses of about 3 g are sufficient to result in hepatotoxicity.

This appears to be dose-related. Liver toxicities may result in symptoms of jaundice. Some people may develop ulcer. Cholestatic jaundice has also been reported as a result of long-term ingestion of niacin. Other common gastrointestinal effects include abdominal pain, nausea and diarrhoea.

Pyridoxine is also known as vitamin B6. The requirement for pyridoxine increases with the amount of protein in the diet. The average adult's minimal requirement for pyridoxine is about 1.25mg/day in individuals ingesting 100g of protein per day. A level of 2.0 mg per day is recommended in adults. The recommended dietary allowance is 2.5mg/day in pregnancy. The same level is recommended during lactation. Actually, spontaneous vitamin B6 deficiency due to dietary insufficiency rarely occurs. The best sources of vitamin B6 are liver, kidney, milk, legumes, yeast and certain vegetables.

In man, convulsions have been reported to occur when very high levels of pyridoxine were administered intravenously. Most people can consume up to 20 mg per day without any adverse effects. However, some individuals who take several grams daily for prolonged period of time may experience severe peripheral neuropathies.

Pyridoxine has also been reported to interfere with some medications, rendering the drugs less effective. High doses of pyridoxine has been associated with ulcers.

Cyanocobalamine or vitamin B12 administration is only indicated when deficiency occurs. Deficiency of vitamin B12 may be caused by inadequate dietary intake, defective intestinal requirements or impaired utilisation in the tissues.

Vitamin B12 deficiency due to increase requirements is normally seen in pregnancy. A number of cases were reported to occur mainly in vegetarians who avoided all dairy products and eggs. It is also often associated with severe general malnutrition.

The daily requirement for vitamin B12 is about 2 to 6 mcg. Approximately 2,000 to 3,000 mcg of vitamin B12 are stored in the body. This amount provides enough supply for quite long time before deficiency arises. Therefore, for an individual who has a well balanced diet and no history of malabsorption, there seems no reason whatsoever for an additional vitamin B12 supplements. Foods in the human diet that contain vitamin B12 are essentially those of animal origin. It can be obtained form liver, seafood, meat, eggs and milk.

Vitamin B12 has not been found in plant tissues. No serious toxic effects have been successfully demonstrated even with doses far in excess of the therapeutic range.

Various forms of these vitamins are available as multi-vitamin preparations. Many are marketed for the relief of stress or as a supplement and tonic for active lifestyles. Despite all these claims, there is little proof that the unusual high dose of vitamins above the normal food intake is necessary.

Although abnormal amounts of vitamins are advertised as necessary for dealing with everyday stress, there is little evidence to support this. The use of vitamin preparations are indicated only in treating conditions such as deficiency states, malabsorption, prolonged illness, renal failure, alcoholism, dialysis and genetic disease.

VitaminDoseDuration of IntakeSigns and symptoms
Vitamin C
(Ascorbic Acid)
3 to 30g Days to years Diarrhoea, gas in the stomach or intestines, kidney stones
Vitamin B1 Several grams Weeks Headache, weakness, irritability, trembling, tachycardia, hypotension
Vitamin B2   Single dose Yellow discoloration of urine
Vitamin B3
(Niacin, nicotinamide,
Nicotinic Acid)
100mg to 3g Single dose to months Flushing, hypotension, headache, abdominal pain, diarrhoea, peptic ulcer, liver toxicity, skin rash, hyperuricemia, hyperglycemia, arrhythmia
Vitamin B6 50mg to 6g Months Ataxia, decreased sensations, headache, depression, tiredness
Table 2

Although vitamins are generally perceived as harmless substances, they have defined toxicities in large doses. The best safeguards against vitamin toxicity are to ingest vitamins as food and to eat as wide a variety of foods as possible. There are no reports of vitamin deficiencies developing in people eating well-balanced diets.

Instant solutions to health problems by sticking to unprofessional megavitamin therapy is inappropriate, ineffective, costly and may be dangerous.

The writer is a pharmacist at the National Poison Centre, Universiti Sains Malaysia, Penang.

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