Balchem Corporation - Comment

30 January 2008 Division of Dockets Management HFA-305 Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, Room 1061 Rockville, MD 20852 In re: Food Labeling: Revision of Reference Values and Mandatory Nutrients Docket Number FDA-2008-0040 Dear Sir or Madam: The following comments are apropos to Question 17 (Are there other micronutrients that should be of public health concern? Please be specific in describing what, if any, other micronutrients are of public health concern.) and Footnote (g) of Table 2 (Dietary Reference Intakes, Recommended Intakes for Individuals, Vitamins): ?[T]here are few data to assess whether a dietary supply of choline is needed at all stages of the life cycle and it may be that the choline requirement can be met by endogenous synthesis at some of these stages.? In fact, in the decade since the publication of the Dietary Reference Intake for choline (IOM, 1998), there has been significant research detailing choline metabolism and its associated genetics in both human and animal systems, indicating that choline deficiency is an increasingly important issue in human nutrition, at many life stages. Deficiency can have serious physiological repercussions (Fischer et al., 2007), including hepatosteatosis (fatty liver), organ dysfunction and muscle damage, though it is preventable and reversible. Deficiency can be the result of curtailed de novo synthesis of choline in the body or an individual?s dietary habits, and these two factors are intertwined. Endogenous production of choline depends on the activity of key enzymes and ready availability of appropriate biochemical precursors (which may come from the diet) for enzyme-mediated metabolic reactions. If an individual possesses a particular polymorph (alternate form) of a gene encoding an enzyme important in choline metabolism, and this gene product is underexpressed (resulting in reduced enzyme activity), this individual may very readily enter a deficient state, perhaps even with only a small change in diet. Individuals may choose to minimize the presence of foods that are naturally good sources of choline (e.g. egg yolks, liver, etc.) in their diets for reasons as diverse as low palatability or high collateral levels of cholesterol. They may turn to more highly processed products that are fortified instead. In this instance, choline content claims and labeling with a relevant Daily Value (DV) will be particularly important. Non-dietary factors may be important in driving endogenous choline synthesis, as well. For example, estrogen status appears to have an effect on genes related to choline metabolism. In a recent study, it was shown that men and post- menopausal women are especially prone to exhibit physiological problems associated with choline deficiency (Fischer et al., 2007). It has been shown that estrogen induces expression of the gene for phosphatidylethanolamine N- methyltransferase (PEMT), an enzyme that regulates de novo synthesis of choline (Resseguie et al., 2007). Specific polymorphs to this, and/or other enzymes, can make an individual more susceptible to choline deficiency and associated organ dysfunction (daCosta et al., 2006). In light of this research, which points to potential choline deficiency in a low estrogen state, the suggested intake of choline for postmenopausal women and adult men requires re-evaluation, and adjustment upward. Another important element contributing to choline deficiency is choline?s role as one of the methyl donors involved one-carbon metabolism. Underexpression of the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme that controls availability of methyl-tetrahydrofolate (MTHF) as a methyl donor, results in depletion of an organism?s endogenous choline store, as choline must be consumed in methyl-donation reactions in place of MTHF (Schwahn et al., 2003). Certain polymorphs of a gene encoding a related enzyme, 5,10- methylenetetrahydrofolate dehydrogenase (MTHFD1), appear to affect methyl- group availability for the PEMT reaction, and may reverse the protective effect of estrogen on the endogenous choline store (Kohlmeier et al., 2005). The frequency of polymorphism in these genes has been shown to be significant within the US population (e.g. Wilcken et al., 1996, Kohlmeier et al., 2005). Health status, specifically pregnancy and lactation, affects choline metabolism as well. Pregnancy can induce deficiency in a mother because of the high choline requirements of the fetus and placenta (Zeisel et al., 1995), in spite of the apparent protective effects of estrogen. Scientific data on the importance of choline for the development of the fetal brain is well established (e.g. Li et al., 2004, Meck & Williams, 2003, Zeisel, 2006), and new data has emerged on its benefits for prevention of neural tube defects and orofacial clefts (Shaw et al., 2004, Shaw et al., 2006). Choline?s nutritional importance for infants is well- recognized, as it is a requisite component of infant formulas. However, in light of this new data on gestational trends in endogenous choline supply, the recommended intake of choline for pregnant and lactating women should be re- evaluated and adjusted upward. Choline content of foods will be of value to a major portion of the consumer population because of a previously underappreciated tendency toward deficiency. As such, a food?s choline content and DV should be made more prominent on its label. A set of Daily Values (DV) should be determined for choline, based on data that takes into account the significant genetic heterogeneity that exists with respect to choline metabolism in the general population, as well as the needs incurred in different life stages. Thank you for your consideration of our comments. Sincerely, Kristine V. Lukasik, Ph.D. Balchem Corporation References da Costa, K.A., Kozyreva, O.G., Song, J., Galanko, J.A., Fischer, L.M. Zeisel, S.H. 2006. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 20:1336-1344. Fischer, L.M., daCosta, K.A., Kwock, L., Stewart, P.W., Lu, T.S., Stabler, S.P., Allen, R.H., Zeisel, S.H. 2007. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J. Clin. Nutr. 85(5):1275-1285. Institute of Medicine (IOM). 1998. Choline. In: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B(6), Folate, Vitamin B(12), Pantothenic Acid, Biotin, and Choline. A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, National Academy of Sciences (NAS). Institute of Medicine (IOM). National Academy Press (NAP); Washington, DC. Kohlmeier, M., da Costa, K., Fischer, L.M., Zeisel, S.H. 2005. Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. PNAS 102(44):16025 ? 16030. Li, Q., Guo-Ross, S., Lewis, D.V., Turner, D., White, A.M., Wilson, W.A., Swartzwelder, H.S. 2004. Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol. 91:1545-1555. Meck, W.H., Williams, C.L. 2003. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci. Biobehav. Rev. 27:385?399. Resseguie, M. Song, J. Niculescu, M.D., da Costa, K.A., Randall, T.A., Zeisel, S.H. 2007. Phosphatidylethanolamine N??-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J. 21:2622-2632. Schwahn, B.C., Zhoutao, C. ; Laryea, M.D., Wendel, U., Lussier-Cacan, S., Genest, J., Mar, M-H., Zeisel, S.H., Castro, C. Garrow, T. Rozen, R. 2003. Homocysteine-betaine interactions in a murine model of 5,10- methylenetetrahydrofolate reductase deficiency. FASEB J.17(3): 512-514. Shaw, G.M. Carmichael, S.L., Laurent, C., Rasmussen, S.A. 2006. Maternal nutrient intakes and risk of orofacial clefts. Epidemiology 17:285-291. Shaw, G.M., Carmichael, S.L., Yang, W., Selvin, S., Schaffer, D.M. 2004. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am. J. Epidemiol. 160:102?109. Wilcken, D., Wang, X., Sim, A., McCredie, R. 1996. Distribution in healthy and coronary populations of the methylene tetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler. Thromb. Vasc. Biol. 16:878-882. Zeisel, S.H. 2006. Fetal origins of memory: The role of dietary choline in optimal brain development. J. Pediatr. 149:S131-136. Zeisel, S.H., Mar, M-H., Zhou, Z., da Costa, K.A. 1995. Pregnancy and lactation are associated with diminished concentrations of choline and its metabolites in rat liver. J. Nutr. 125:3049-3054. Kristine Lukasik, Balchem Corporation - The following comments are apropos to Question 17 (Are there other micronutrients that should be of public health concern? Please be specific in describing what, if any, other micronutrients are of public health concern.) and Footnote (g) of Table 2 (Dietary Reference Intakes, Recommended Intakes for Individuals, Vitamins)....