"Safe upper limits" for nutritional supplements: one giant step backward - Editorials

Townsend Letter for Doctors and Patients, Oct, 2003 by Alan R. Gaby

In May, 2003, the "Expert Group on Vitamins and Minerals" (EVM), an advisory group originally commissioned in 1988 by the then Ministry of Agriculture, Fisheries and Food, and subsequently reporting to the Food Standards Agency in England, published a report that set "Safe Upper Limits" (SULs) for the doses of most vitamin and mineral supplements. The establishment of SULs was based on a review of clinical and epidemiological evidence, as well as animal research and in vitro studies. For those nutrients for which the available evidence was judged insufficient to set an SUL, the EVM instead established "Guidance Levels," which were to be considered less reliable than SULs.

This writer's analysis of the EVM report reveals that the dose limits were set inappropriately low for many vitamins and minerals; well below doses which have been used by the public for decades with apparent safety. While the release of this 360-page document would be of little import, were it to be used solely as a manifesto for the pathologically risk-averse, preliminary indications are that it could be used very actively to support the arguments of those who are seeking to ban the over-the-counter sale of many currently available nutritional supplements. If the report is used that way, then the public health could be jeopardized.

On May 30, 2002, the European Union adopted Directive 2002/46/EC, which established a framework for setting maximum limits for vitamins and minerals in food supplements. The EVM report is seen by the UK government as the basis for its negotiating position in the process of setting these pan-European limits.

The apparent anti-nutritional-supplement, anti-self-care bias that permeated the process of setting safety limits is evident both in the way in which the SUL was defined and in the fact that the benefits of nutritional supplements were purposely ignored. The SUL was defined as the maximum dose of a particular nutrient "that potentially susceptible individuals could take daily on a life-long basis, without medical supervision in reasonable safety." In other words, it is the highest dose that is unlikely to cause anyone any harm, ever, under any circumstance. Furthermore, the EVM was specifically instructed not to consider the benefits of any of the nutrients, and not to engage in risk/ benefit analysis. (1)

There is little or no precedent in free societies for restricting access to products or activities to levels that are completely risk-free. Aspirin causes intestinal bleeding, water makes people drown, driving a car causes accidents, and free speech may offend the exquisitely offendable. Politicians and bureaucrats do not seek to ban aspirin or water or driving or free speech, because their benefits outweigh their risks. For vitamins and minerals, however, some authorities seem to believe that unique safety criteria are needed.

Moreover, the government's instructions to disregard the many documented benefits of nutritional supplements introduced a serious bias into the evaluation process. As the EVM acknowledged, determining safety limits involves an enormous degree of uncertainty and a fairly wide range of possible outcomes. The committee might have established higher safety limits than it did, had it been told to weigh benefits against risks. The government's instructions appeared to be an implicit directive to err on the side of excluding doses that are being used to prevent or treat disease. And that is what the EVM did, often by making questionable interpretations of the data, and doing so in what appears to have been an arbitrary and inconsistent manner.

Riboflavin Guidance Level

A typical example of the EVM's dubious approach to establishing safety limits is its evaluation of riboflavin. The committee acknowledged that no toxic effects have been reported in animals given an acute oral dose of 10,000 mg/ kg of body weight, or after long-term ingestion of 25 mg/kg/day (equivalent to 1,750 mg/day for a 70-kg human). Moreover, in a study of 28 patients taking riboflavin for migraine prophylaxis, a dose of 400 mg/day for 3 months did not cause any adverse effects. Despite a complete absence of side effects at any dose in either humans or animals, the EVM set the Guidance Level for riboflavin at 40 mg/ day. That level was established by dividing the 400 mg/day used in the migraine study by an "uncertainty factor" of 10, to allow for variability in the susceptibility of human beings to adverse effects.

A more appropriate conclusion regarding riboflavin would have been that no adverse effects have been observed at any dose, and that there is no basis at this time for establishing an upper limit. If the EVM's recommendation is used to limit the potency of riboflavin tablets to 40 mg, then migraine sufferers will have to take 10 pills per day, in order to prevent migraine recurrences. (2)

Vitamin B6 Safe Upper Limit

Similar reasoning led to an SUL of 10 mg/day for vitamin B6, even though this vitamin has been used with apparent safety, usually in doses of 50 to 200 mg/day, to treat carpal tunnel syndrome, premenstrual syndrome, asthma, and other common problems. The SUL for vitamin B6 was derived from an animal study, in which a dose of 50 mg/kg of body weight/day (equivalent to 3,000 mg/day for a 60-kg person) resulted in neurotoxicity. The EVM reduced that dose progressively by invoking three separate "uncertainty factors:" 1) by a factor of 3, to extrapolate from the lowest-observed-adverse-effect-level (LOAEL) to a no-observed-adverse-effect-level (NOAEL); 2) by an additional factor of 10, to account for presumed inter-species differences; and 3) by a further factor of 10 to account for inter-individual variation in humans. Thus, the neurotoxic dose in animals was reduced by a factor of 300, to a level that excludes the widely used 50- and 100-mg tablets.