Animal studies have shown that vitamin B6 is neurotoxic, causing peripheral neuropathy, with ataxia, muscle weakness, and loss of balance in dogs given 200 mg ofpyridoxine per kg of body weight for 40 to 75 days, and the development of a swaying gait and ataxia within 9 days at a dose of300 mg per kg body weight (Phillips et al., 1978; Krinke et al., 1980). At the lower dose of 50 mg per kg of body weight, there are no clinical signs of toxicity, but histologically there is loss of myelin in dorsal nerve roots. At higher doses, there is widespread neuronal damage, with loss of myelin and degeneration of sensory fibers in peripheral nerves, the dorsal columns of the spinal cord, and the descending tract of the trigeminal nerve. The clinical signs of toxicity after 200 to 300 mg of vitamin B6 per kg of body weight regress within 3 months after withdrawal of these massive doses, but sensory nerve conduction velocity, which decreases during the development of the neuropathy, does not recover fully (Schaeppi andKrinke, 1982).
In 1983, sensory neuropathy was reported in seven patients who had been taking between 2,000 to 7,000 mg of pyridoxine/day for several months (Schaumburg et al., 1983). On withdrawal of the vitamin supplements, there was considerable recovery of neuronal function, although there was residual nerve damage in some patients.
There has been one report of the development, within 2 years, of sensory neuropathy in an infant with vitamin B6 -dependent seizures treated with 2,000 mg per day, but over the following 16 years, the neuropathy did not progress (McLachlan and Brown, 1995). However, most reports of patients with vitamin B6 dependency diseases (Section 9.4.3) do not mention sensory neuropathy. One study has reported electrophysiological and neurological examination of 17 homocystinuric patients who had been treated with 200 to 500 mg of vitamin B6 per day for 10 to 24 years; there was no evidence of neuropathy (Mpofu et al., 1991).
None of the studies in which there has been objective neurological examination has shown any evidence of sensory nerve damage at intakes of vitamin B6 below 200 mg per day. Most have shown adverse effects only at considerably higher levels of intake.
Studies with cells in culture show a cytotoxic effect of vitamin B6. This may be from the formation of cytotoxic products when the vitamin is subjected to ultraviolet irradiation and may not be relevant in vivo (Maeda et al., 2000).
18.104.22.168 Upper Levels of Vitamin B6 Intake Although there is no doubt that vitamin B6 is neurotoxic in gross excess, there is considerable controversy over the way in which toxicological data have been translated into limits on the amounts that may be sold freely as nutritional supplements. This appears to have been achieved by the application of standard toxicology safety margins, and taking as the upper safe limit of intake 1% of the no adverse effect level. Whereas this is appropriate for setting limits on additives and contaminants, it can be argued that it is not appropriate as a basis for setting limits on a nutrient; for many nutrients, an upper limit of intake established in this way would be below the average requirement to prevent deficiency.
There is little evidence that intakes of up 200 to 500 mg of vitamin B6 per day for prolonged periods are associated with any adverse effects. The U.S.
Food and Nutrition Board set a tolerable upper level for adults of 100 mg per day (Institute of Medicine, 1998); the European Union (Scientific Committee on Food, 2000) set 25 mg per day.
Supplements ofvitaminB6 rangingfrom25to500mgperdayhavebeenrecom-mended for treatment of a variety of conditions in which there is an underlying physiological or biochemical mechanism to justify their use, although in most cases there is little evidence of efficacy.
Some reports have shown vitamin B6 to be effective in suppression of lactation, although others have shown no difference from placebo. Because the vitamin suppresses the increase in prolactin induced by treatment with the dopamine receptor antagonist pimozide, and because lactation is also suppressed by the dopamine agonist bromocriptine, it has been suggested that it acts to stimulate dopaminergic activity in the hypothalamus. However, it is more likely that its action is by reduction in target tissue responsiveness to the steroid hormones that stimulate prolactin secretion. High doses of vitamin B6 are also effective in controlling tardive dyskinesia induced by neuroleptic drugs (Lerner et al., 2001).
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