DAILY MAXIMUM INTAKE LIMIT IN HEALTH FUNCTIONAL FOOD ACT

Transcription

1 Comment Number 1: By the Council for Responsible Nutrition, Washington, DC, USA DAILY MAXIMUM INTAKE LIMIT IN HEALTH FUNCTIONAL FOOD ACT The Republic of Korea (ROK) proposal is in agreement with the first principle of international regulatory standards for vitamins and minerals that is, in general, maximums should be based solely on realistic safety considerations identified by nutrient-appropriate risk assessment. While abiding by this principle, it is necessary for the health benefits of consumers and for fair practices in trade to make sure that the maximums identified are not more restrictive than necessary to protect consumers against harm by excess consumption. Although several of the specific limits proposed by ROK are appropriate, others differ considerably from the results of a rigorous application of scientific risk assessment as well as from the conclusions of the FNB, SCF and EVM. CRN acknowledges that the FNB, SCF and EVM sometimes disagree, and CRN believes that it has identified the scientific issues that should allow these differences to be reconciled to the best scientific interpretation. The following evaluations and recommendations are derived by CRN using the TABD direct approach to supplement safety (Appendix I). Vitamin A (as Retinol) COMMENTS ON SPECIFIC VITAMINS AND MINERALS The FNB, SCF and CRN have identified 3,000 _g (or 10,000 IU) of retinol per day as a safe intake. These values were identified on the basis of avoidance of any identifiable risk of birth defects associated with much high intakes. Each of these reviews considered the evidence that excess retinol increases the risk of bone fractures to be inconclusive, and not a proper basis for a recommended limit. The EVM identified 3,000 _g as safe in relation to risk of birth defects, but considered the evidence on bone fragility to be persuasive and set a limit of 1,500 _g on this basis. In conclusion, the evidence on bone fragility is not generally considered persuasive. In recognition that retinol intakes from unfortified and fortified conventional foods can vary over a substantial range, a 1,500 _g (5,000 IU) maximum for supplement products is not objectionable. The 700 _g daily maximum proposed by the ROK is not justified by the scientific evidence and has the potential to be a potential technical barrier to trade. Vitamin D Although long considered one of the most toxic of the vitamins because of a history of over fortification in the late 1940s in the United Kingdom, modern clinical trial evidence shows vitamin D to have a wider margin of safety than previously believed.

2 The FNB and SCF have set UL values at 50 _g (2,000 IU). The EVM set a UL at 25 _g. CRN had previously considered 20 _g safe, but now on the basis of newer clinical trial evidence considers vitamin D safe at supplemental intakes of up to 60 _g (and possibly up to 100 _g, although the evidence at 100 _g may be insufficient to serve as the basis of policy). Vitamin D comes from the diet but is also synthesized in the skin from cholesterol metabolites. Blood levels regulate synthesis in the skin, and sun exposure cannot cause vitamin D toxicity. Thus, sun exposure is not a consideration in setting a maximum for vitamin D. The 5 _g daily maximum proposed by the ROK is arbitrarily restrictive, and is restrictive enough to be harmful to many consumers who need more vitamin D due to lack of sun exposure and aging-slowed metabolism. A daily maximum of 5 _g would be a significant and unjustified barrier to trade. Vitamin E The FNB set a UL of 1,000 mg for vitamin E. The EVM set a guidance level of 800 IU (727 mg for the form of vitamin E considered). The SCF selected the same data that the EVM used, but applied a larger uncertainty factor to set a UL of 300 mg. CRN considers the evidence for safety to be sufficient at intakes up to 1,600 IU (1,070 mg for the form tested). By any comparison, the 67 mg daily maximum proposed by the ROK is arbitrarily restrictive and could be a significant and unjustified barrier to trade. Vitamin K The FNB and SCF did not find any data that justified setting a UL for vitamin K. The EVM set a guidance level of 1,000 _g after application of large uncertainty factor to the data from a clinical trial that used 10 mg per day. CRN considers the clinical trial evidence at 10 mg intakes to be compelling because of the absence of any adverse effect at intakes up to 30 mg. By any comparison, the _g daily maximum proposed by the ROK is arbitrarily restrictive and could be a significant trade barrier. Vitamin C (ascorbic acid) The FNB set a UL at 2,000 mg, and the EVM selected 1,000 mg as the safe level. The SCF has not yet made any recommendation on vitamin C safety. CRN considers 2,000 mg to be a safe supplemental intake. The basis for these safety recommendations is the potential for osmotic diarrhea when large doses are consumed and present in the stomach and intestine at one time. Intakes from conventional foods are more distributed over the day, and would not contribute to the potential for this adverse effect. No other postulated adverse effects have been found credible by the FNB, EVM, or CRN. The mg daily maximum proposed by the ROK is unnecessarily restrictive and could pose trade barriers.

3 Vitamin B1 (thiamin) The FNB and SCF found no evidence of hazard at any level on human consumption, and therefore did not set UL values. The EVM set a guidance level (but not a UL) at 100 mg per day. Intakes from conventional foods are inconsequential in safety evaluation. CRN considers the 25 mg daily maximum proposed by the ROK to be arbitrarily restrictive and not needed to protect the public health. Although no harm from excess has been identified at any level, the data are sufficient to support a daily maximum of 100 mg as safe and therefore not objectionable as a trade barrier. Vitamin B2 (riboflavin) The FNB and SCF found no evidence of hazard at any level on human consumption, and therefore did not set UL values. The EVM set a guidance level (but not a UL) at 40 mg per day. Intakes from conventional foods are inconsequential in safety evaluation. CRN considers the 12 mg daily maximum proposed by the ROK to be arbitrarily restrictive and not needed to protect the public health. The evidence that riboflavin should have a lower maximum than that for thiamin comes from misinterpretation of data related to injected riboflavin. Although no harm from excess has been identified at any level, the data are sufficient to support a daily maximum of 200 mg as safe and therefore not objectionable as a trade barrier. Vitamin B6 (pyridoxine) Official scientific opinion on the safety of this vitamin varies greatly. The FNB set a UL of 100 mg. The SCF UL is 25 mg. The EVM UL is 10 mg. Previously, the CRN safety value for this vitamin was 200 mg, but the new evaluation is that 100 mg is the highest intake that can confidently considered safe. Intakes from conventional foods range only up to 4 mg. CRN considers the 49.5 mg daily maximum proposed by the ROK to be somewhat unnecessarily restrictive, and recommends that it be revised to 100 mg. With that maximum, intakes from conventional foods are not an important consideration. Folic Acid The FNB, SCF, EVM and CRN have all identified 1,000 _g of folic acid as a safe intake. Because of the inefficient conversion of the complex folates in food to free folic acid, food folates are not an important consideration in the evaluation of folic acid. CRN considers the 250 _g daily maximum proposed by the ROK to be arbitrarily restrictive and to carry a strong potential to be an unjustified barrier to trade. Vitamin B12 The FNB and EVM found no evidence of hazard from any level of vitamin B12 and did not set a UL value. The EVM set a guidance level at 2,000 _g, considering this to be the highest level at which the evidence for safety is sufficient. CRN considers the evidence for safety to be sufficient up to intakes of 3,000 _g.

4 By any comparison, the 60 _g daily maximum proposed by the ROK is arbitrarily restrictive and a potential trade barrier. Niacin (nicotinic acid and nicotinamide) Niacin raises complex issues because it occurs in two forms with different effects, and one of the effects of nicotinic acid is dubious as an adverse reaction. In addition to these issues, slow release formulations have a two-fold greater potential for adverse effects than do immediate release formulations. Nicotinic acid The FNB, SCF and EVM have set UL values for nicotinic acid on the basis of its skin-flushing effect. These values are 35 mg, 10 mg, and 17 mg, respectively. CRN considers this effect not to qualify as a hazard and therefore not to be a proper basis of a UL value for supplements. If the label provides a warning that the skin flushing may occur, this effect is more properly described as a nuisance, rather than as a hazard. CRN believes that the proper basis for a regulatory maximum for nicotinic acid is the potential for liver toxicity at much higher intakes. Even if the flushing effect is considered so undesirable that it should qualify as a hazard and the basis of a UL, the FNB, SCF and EVM have misinterpreted the data that support the doseresponse evaluation for this effect. The clinical data they relied upon involved administration of single bolus doses of nicotinic acid on an empty stomach, a circumstance that encourages high plasma concentrations of nicotinic acid for a short period. Taking nicotinic acid with food or as a slow release formulation greatly decreases the potential for it to cause flushing. CRN recommends a maximum of 500 mg nicotinic acid for conventional (immediate) release nicotinic acid products and 250 mg for slow release products, provided that the label carries a warning that this effect is very uncomfortable, although not dangerous. CRN recommends that all products exceeding 35 mg carry such a warning on the label. The 14 mg daily maximum proposed by the ROK is arbitrarily restrictive and carries the potential to be a trade barrier. Nicotinamide Inexplicably, the FNB UL applies to both nicotinic acid and nicotinamide, although the latter does not have the effect selected as the basis of the UL. For nicotinamide, the SCF has identified a UL of 900 mg and the EVM identified 500 as the supplemental UL. CRN considers these levels to be more restrictive than justified to assure safety. CRN considers 1,500 mg of nicotinamide to be safe, and is pleased that the ROK has recommended a separate maximum for this form of niacin at this level. CRN recommends that the ROK set this maximum at 1,500 mg per day for adults. Pantothenic Acid The FNB and SCF did not set a UL for pantothenic acid because they could not find any evidence of hazard to justify it. The EVM could not establish a UL but set a guidance level at 200 mg. CRN considers 1,000 mg as a safe level for supplements and finds conventional food sources to be trivial in comparison.

5 The 30 mg daily maximum proposed by the ROK is arbitrarily restrictive and would be an unjustified trade barrier. Biotin The FNB and SCF did not set a UL for biotin because of the absence of evidence of adverse effects. The EVM set a guidance level of 900 _g, after application of a 10-fold uncertainty factor. CRN considers the direct evidence for safety to be sufficient at intakes up to 2,500 _g. The 501 _g daily maximum proposed by the ROK is arbitrarily restrictive, and could be used as an unjustified trade barrier. Calcium The FNB set a UL for total calcium of 2,500 mg and the EVM set a UL for supplemental calcium of 1,500 mg. Considering intakes from conventional foods, these UL values are compatible. The SCF has not yet review calcium safety. CRN identifies 1,500 mg of supplemental calcium as a safe level. In comparison, the 700 mg daily maximum proposed by the ROK is arbitrarily restrictive, and could pose a trade barrier. Magnesium Scientific opinion on the safety of magnesium varies considerably. The FNB set a UL of 350 mg for free salts of magnesium (not the magnesium naturally occurring in foods). The SCF used the same data but applied a larger uncertainty factor to set a UL for free magnesium of 250 mg. In contrast, the EVM set a UL of 400 mg for supplemental magnesium. CRN considers supplemental magnesium levels of 400 mg to be safe, and total magnesium intakes of 700 mg to be safe. In comparison, the 220 mg daily maximum proposed by the ROK is restrictive and could be a trade issue. Potassium The FNB and SCF have not set UL values for potassium. The EVM set a surprisingly high UL of 3,700 mg. Although that high level may be safe for intake from conventional foods, which means distribution throughout the day, intake of potassium salts as bolus dose supplements could have adverse effects (gastrointestinal and neuromuscular) at that level. CRN recommends a maximum supplemental potassium level of 500 mg per occasion and 1,500 mg per day. The 3,500 mg daily maximum proposed by the ROK is excessive for supplemental potassium. It certainly would not pose a trade barrier, and its appropriateness is a purely domestic issue for the ROK. Chromium

6 The FNB and SCF did not find appropriate data to serve as the basis for a UL value for chromium. The EVM did not find evidence of adverse effects in humans but extrapolated from animal data on chromic chloride to set a guidance level of 10 mg (10,000 _g). Although the publication that the EVM relied upon used both chromic chloride and chromium picolinate, which gave the same benign outcomes, the EVM excluded the picolinate form from its recommendation. In contrast, CRN recommends a chromium limit of 1,000 _g for all nutritionally useful form of chromium, based on human clinical trials with chromium picolinate. In comparison, the 50 _g daily maximum proposed by the ROK is arbitrary and extremely restrictive, and would likely pose significant trade barriers. Copper The FNB and EVM set UL and guidance levels at 10 mg. The SCF used a larger uncertainty factor to set a UL of 5 mg. CRN identifies 9 mg as safe. Copper intakes are generally below 1.5 mg from foods. The 1.5 mg daily maximum proposed by the ROK is arbitrarily and unnecessarily restrictive, and could be a significant barrier to trade. Iodine The FNB set a UL for total iodine at 1,100 _g. The EVM set the UL at 940 _g total intake and 500 _g for supplemental iodine. The SCF has not yet considered this element. CRN considers 1,000 _g total and 500 _g supplemental iodine to be safe. In comparison, the 75 _g daily maximum proposed by the ROK is arbitrarily restrictive and would pose a significant unjustified trade barrier. Iron The FNB set a UL for iron at 45 mg, based on the gastrointestinal irritation that can occur when iron supplements are taken on an empty stomach. The SCF has not yet offered an opinion on the safety of iron. The EVM guidance level for supplemental iron is 17 mg, based on the lower end of a range of uncertainty that was further corrected by an uncertainty factor of 3. CRN considered the same data that FNB reviewed but concluded that iron supplements are likely to be taken with food rather than on an empty stomach. CRN therefore identifies 65 mg as a safe level for iron supplements. In comparison, the 15 mg daily maximum proposed by the ROK is restrictive and could create a significant trade barrier. Manganese The FNB set its UL for manganese at 11 mg. The SCF deemed the data too uncertain to set a UL for this trace element. The EVM set a total manganese UL at 12 mg but declared food and water sources to be so variable that it set the supplemental UL at 4 mg. CRN considers the evidence on supplemental manganese to be sufficient to show safety at 10 mg.

7 In comparison, the 2.0 mg daily maximum proposed by the ROK is quite restrictive and could create significant barriers to trade. Molybdenum The FNB and SCF set UL values at 2,000 _g and 600 _g, respectively. In contrast, the EVM set a UL for total intake at 450 _g total manganese, but concluded that supplemental molybdenum should not be considered safe at any level. CRN considers the evidence sufficient to show that 350 _g of supplemental molybdenum is a safe level. In contrast, the 25 _g daily maximum proposed by the ROK is arbitrarily and unnecessarily restrictive. It would pose a significant trade barrier. Selenium The FNB set a UL for total selenium intake at 400 _g. The SCF reviewed the same human epidemiological data but interpreted them differently and applied a different uncertainty factor to derive a UL of 300 _g for total intake. In contrast, CRN concludes from direct human clinical trial data with 200 _g of supplemental selenium that this level is safe as a supplement. In comparison, the 50 _g daily maximum proposed by the ROK for supplemental selenium is arbitrary and excessively restrictive beyond that necessary to achieve safety. Moreover, there is considerable epidemiological evidence that intakes above 100 _g reduce the risk of certain cancers and this is confirmed by a long-term clinical trial at 200 _g of supplement. The 50 _g proposed maximum would pose a significant and unjustified trade barrier. Zinc The FNB and SCF set UL values of 40 mg and 25 mg, respectively. The EVM set a supplemental UL at 25 mg. The EVM correctly attributes the evidence relied upon by the FNB, SCF and EVM as relating to supplemental, not total, amounts of zinc. The EVM selected an arbitrary uncertainty factor of 2 and derived their supplemental UL of 25 mg. CRN identifies 30 mg as a safe supplemental level of zinc. In comparison, the 15 mg daily maximum proposed by the ROK is unnecessarily restrictive and could create significant trade barriers.