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Select Committee on Agriculture Minutes of Evidence


Memorandum submitted by Professor H F Woods, Chairman of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (E44)

ABOUT THE COMMITTEE ON TOXICITY

  The Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) is a committee of independent experts which advises the Chief Medical Officer (CMO) and, through him, the Government on the risks associated with the exposure of the general public to chemicals used in everyday life.

  Committee members are appointed by the CMO as independent scientific and medical experts on the basis of their special skills and knowledge. They are appointed for fixed time periods, generally three years, and are eligible for reappointment at the end of their terms. Members are appointed from a range of scientific specialities, including toxicology, pharmacology, pathology, epidemiology and nutrition. Where necessary, specialised advice outside of the Committee's area of expertise can be obtained from other advisory committees, such as the Committee on the Medical Aspects of Food and Nutrition Policy (COMA), and the Committees on Mutagenicity and on Carcinogenicity, and by co-opting experts or forming working groups to consider specific issues. The terms of reference of the Committee are at Annex A. A list of members, as of March 1998, is attached at Annex B.

WORKING PRACTICES

  The usual way in which a committee review is conducted is that the secretariat conducts a search of the specialised medical, scientific and toxicological databases. If appropriate, information is obtained from manufacturers and other interested parties and the secretariat will then critically assess the relevant data and prepare a paper for the Committee. This normally consists of a covering paper in which the available data are summarised, the most important points highlighted and questions presented for the Committee to address, and appendices giving detailed summaries of the studies reviewed, including the methodology and results. Typically, critical papers which report the Lowest Observed Adverse Effect Level (LOAEL) or No Observed Adverse Effect Level (NOAEL) are attached as appendices. All other papers will be circulated to members if requested.

  After an assessment of all the available relevant data, the Committee identifies the critical studies from which to determine safe doses. It is important to recognise that it is the nature of risk assessment that the review of the totality of the data leads to the use of one or two critical studies to identify the LOAEL and/or NOAEL. Often risk assessments for chemicals are based on extrapolations from studies using laboratory animals. Greater weight is attached to evidence from studies in humans, where available, as there are sometimes uncertainties about whether effects observed in animals are relevant to man. Safety margins are applied to the NOAEL or LOAEL to determine safe levels. When animal data are used it is accepted practice to use a factor of 10 to allow for inter-species differences and a further factor of 10 for inter-individual variations, ie to allow for possible differences due to age, sex, diet, disease, ethnicity etc. An additional safety factor may be used if there are special circumstances that give rise to a cause for concern, eg if the hazard is unduly severe or if a LOAEL rather than NOAEL is used as the starting point for determination of a safe dose. These safety margins are widely used by the international toxicology community, including the World Health Organization.

MEMBERS' INTERESTS

  It is inevitable that many experts will have gained experience by applying scientific and toxicological skills to address questions of a commercial nature, as researchers working in universities and research institutes are encouraged to seek financial support for research from a wide range of organisations. Considerable efforts are made to avoid or document potential conflicts of interest, so that the impartiality of the Committee's advice is not called into question. Members are reminded of the requirement to declare interests (a) on appointment; (b) each year for inclusion in the annual report and (c) at the start of every meeting and again at the beginning of each relevant agenda item.

  If a member declares an interest in a topic under discussion, he or she may, at the discretion of the Chairman, be allowed to take part in the discussion. However, where an interest is considered to be too close to the topic under discussion, members can be excluded from the discussion and the decision making process.

  The procedures used in determining interests are published in the Committee's Annual Report, as is a complete list of the interests declared by members. A copy of the list for 1996, with procedures for declaring interests, is attached at Annex C.

OPENNESS

  An annual report of the Committee is published, together with those of its sister committees, the Committee on Carcinogenicity and the Committee on Mutagenicity. These reports provide a summary of the Committee's advice on the topics considered throughout the year and a list of members' interests.

  In addition, it is now usual practice for any statement on a specific topic to be made available from the secretariat and on the internet. Statements vary in length, but will usually provide a summary of the evidence considered, the critical studies and the committee's advice.

  At present, committee papers are usually marked "For Members' Use Only" and are not made more widely available, although this procedure is currently under review. In the case of vitamin B6, since information was provided by the dietary supplements industry and nutritional therapist interests on an "in confidence" basis, the paper was marked "In Confidence".

  The public (and interested parties) have had access to our statement on vitamin B6 but have not had the opportunity to see the full extent of the data considered by the Committee. I am firmly of the opinion that this has not helped public understanding of the rigour with which we went about our task.

COT CONSIDERATION OF VITAMIN B6

First consideration

  The Committee was asked in 1995 to review the toxicity of vitamin B6 following concerns expressed by the Consumers' Association regarding the high level of vitamins and minerals in dietary supplements in general, and of vitamin B6 products in particular.

  The secretariat conducted a detailed search of the scientific and medical literature and also wrote to Solgar, the manufacturer of a high dose supplement which was highlighted by the Consumers' Association, informing them of the review and inviting the submission of relevant information. This letter was copied to the Health Food Manufacturers' Association.

  As noted above, although all relevant data were assessed, it is the nature of risk assessment that the review of the totality of data leads to the use of one or two critical studies for the determination of safe doses. In humans, the lowest reported adverse effect level was 50 mg/day. This was reported by Dalton and Dalton (1987) who investigated women attending a clinic for premenstrual tension.

  Those 172 women who had serum B6 levels above the normal assay range were divided into two groups: those who complained of neurological symptoms and those who did not, this latter group acted as internal controls. Although there was no difference in the mean age or mean daily B6 intake of these two groups there was a significantly longer period over which the group with neurological symptoms had been taking vitamin B6. The authors suggest that the duration of vitamin B6 exposure appears to have been a significant factor in the development of neurological symptoms. This is particularly important since individuals taking dietary supplements may take them for very long periods.

  The Dalton study also reported that three months after stopping vitamin B6 supplementation 55 per cent reported partial recovery and by six months all had completely recovered. Seven women who inadvertently did not stop taking vitamin B6 continued to complain of symptoms. Three women who started taking 50 mg vitamin B6 daily again (to correct for low vitamin B6 serum levels) complained of symptoms within one month.

  The critical animal study was a 100+ day study in dogs published by Phillips et al (1978). Pyridoxine hydrochloride (Vitamin B6) was administered orally (0, 50 or 200 mg/kg/day) to three groups of female beagles (four control, and five per treatment group). Four of the five animals in the high dose group showed signs of ataxia (clumsiness) and loss of balance after 45 days of treatment, whilst the fifth showed clinical signs after 75 days. Histological examination of tissues at termination in this group showed damage to the nervous system with bilateral loss of myelin and axons in the dorsal funiculi and loss of fibres in the dorsal roots. Animals in the low dose group showed no clinical signs but histological examination revealed loss of myelin in the dorsal nerve roots in all five dogs. These effects on the nervous system are comparable with the symptoms in humans and it is clear that the low dose group show a less severe form of the damage seen in the high dose group. This is therefore only a LOAEL.

  The Committee unanimously agreed with the Scientific Committee for Food (which advises the European Commission) that intakes of more than 50 mg vitamin B6 per day must be regarded as potentially harmful. Bearing in mind that the Reference Nutrient Intake (RNI) for vitamin B6 was on average 1.2 mg/day for females and 1.4 mg/day for males, the Committee agreed that the daily intake of vitamin B6 from dietary supplements should not exceed 10 mg. This would allow intakes several times that necessary to meet nutritional requirements, but would ensure a safety factor of five below levels reported to be harmful in humans. (A factor of five is less than is normally used as noted above, since a factor of 10 is often used to allow for inter-individual variation). Members noted that neurotoxicity due to vitamin B6 administration takes a number of months to develop and therefore any advice issued should reflect the fact that it was prolonged administration of high levels of vitamin B6 which carried a toxicological risk.

  Since adequate human data were available, the Committee agreed that it was not necessary to consider the animal toxicity data on vitamin B6, although members observed that extrapolation from these data gave a potential "safe level" very close to that derived from the human data.

Second consideration

  The Committee were asked to advise on the toxicity of vitamin B6 for a second time in 1997 when it became apparent that interested parties were concerned that the Committee may not have taken important information into account in its earlier assessment. The secretariat invited interested parties to submit relevant information for consideration by the Committee.

  Much of the information submitted for consideration by the Committee concerned reports of beneficial effects attributed to vitamin B6. It should be noted that papers reporting beneficial effects often do not state whether adverse effects were investigated or reported. The literature included full papers, letters, short communications and reviews. Much of the literature referred to treatment of specific diseases, where patients would be expected to take licensed medicinal products rather than dietary supplements. The information supplied did not include any adequate studies of the safety of long term administration of vitamin B6 in humans.

  On the basis of its review of the additional literature, the Committee endorsed its earlier recommendation that the maximum daily intake of vitamin B6 from dietary supplements should not exceed 10 mg. A statement was agreed and this was passed to the Food Advisory Committee (FAC) to consider what action should be taken on the sale of vitamin B6 dietary supplements. A copy of the Statement is attached at Annex D.

COMMENTS

  Since publication of our advice, I have been made aware of a number of critical comments about the Committee's consideration of vitamin B6. These criticisms, including those of Professor Beckett and the "Vitamin B6 Scientific Task Group", have been the subject of comment by members of the Committee. We are clear that we have not seen any evidence that would convince us that there is a need to alter our advice, and we have every confidence that our conclusions are justified given the evidence available to us.

  I would like to make the following observations in response to some specific criticisms summarised in italics below:

Vitamin B6 has been consumed at dosages up to 200 mg daily by millions of people over several decades without any significant hazards emerging.

  The Committee would welcome the opportunity of evaluating the scientific and clinical credibility of the data that gave rise to this statement. Before undertaking our second review of vitamin B6, the Committee sought information from those active in marketing or recommending the use of vitamin B6 dietary supplements as to the availability of such data; nothing was sent that would support such a statement.

The Committee based its advice on a study by Dalton and Dalton which has been discredited by other scientists

  As noted above, although all relevant data were assessed, it is the nature of risk assessment that the review of the totality of data leads to the use of one or two critical studies for the determination of safe doses. Overall it is clear that there is an inverse relationship in animals and humans between intake and time to adverse effects. The safety of long-term intake of low doses of vitamin B6 has not been adequately studied. Nevertheless we reviewed all the available data before producing our advice.

  In humans, the lowest reported adverse effect level was 50 mg/day reported by Dalton and Dalton. In animals, the critical study was the study in beagles reported by Phillips et al. The Committee recognised the deficiencies in the Dalton and Dalton study in its statement. In view of these limitations, this study would not have been used by itself to derive a numerical recommended intake, if this were the only information available. The data of the Dalton and Dalton study are weak but consistent with an inverse relationship between dose and duration to effect in humans and serve to suggest a possible bottom limit to the relationship between dose, duration and time to adverse effects. The Committee would have been remiss to ignore the Dalton and Dalton study given the other data on dose, duration and time to adverse effects in both animals (dogs and rats) and humans.

The use of large safety factors is inappropriate, especially for essential nutrients

  Safety factors are used in regulatory toxicology to allow for species differences and human variability. The use of safety factors for xenobiotics but not for essential nutrients is an unscientific distinction which is difficult to justify providing that the resulting recommended intake is nutritionally adequate. This is clearly the case for vitamin B6 since the recommended maximum intake from dietary supplements is about seven times the Reference Nutrient Intake (about 1.2 mg/day for women and 1.4 mg for men. The RNI is that amount of a nutrient that is enough to meet the nutritional needs of almost all healthy people, even those with high needs).

  A factor of five was used to derive safe intake levels from the level of 50 mg which has been reported to be harmful in humans. It is reassuring that the standard safety factors applied to the animal data lead to the derivation of a safe level that is similar to that derived from human studies. Both the animal and the human data suggest a dose of 10 mg is safe for the general population, including susceptible groups such as the elderly, pregnant and sick.

The COT advice ignored the benefits of vitamin B6 in treating conditions such as the Pre-Menstrual Syndrome

  The Committee on Toxicity advised on the safe use of vitamin B6 as a dietary supplement, not on its medicinal use. Much of the information supplied by interested parties that we considered referred to the use of vitamin B6 to treat specific clinical conditions. Assessment of the safety of medicines requires a balance between risks and benefits—and this is a matter for the Committee on Safety of Medicines. Our advice concerned the safe use of vitamin B6 sold as a dietary supplement.

  It is interesting to note that the authors who are cited as providing evidence of no reported effects of vitamin B6 at doses up to 200 mg/day are all presumably physicians who were monitoring the progress and well-being of their patients. This is exactly the situation which will obtain in the UK under the new guidelines for General Sales List, Pharmacy, and Prescription Only levels. Patients will not be prevented from obtaining daily doses in excess of 10 mg but they will obtain these under supervision of a pharmacist (up to 49 mg) or a doctor (above 50 mg). Given the hazard/risk profile of high doses of vitamin B6 it is not unreasonable to propose that treatment of a clinical condition with a compound with well defined toxicity and a poorly defined long-term dose-response relationship should be subject to medical supervision.

Members may have been influenced by their interests with the pharmaceutical companies

  This is a highly spurious allegation, without foundation, which I reject. As Chairman I have every confidence in the rigour and independence of the advice of the committee.

8 April 1998


 
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