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Editorials |
1 From the Jean Mayer US Department of Agriculture Human Nutrition Research Center, Tufts University, Boston.
See corresponding article on page 198.
2 Reprints not available. Address correspondence to IH Rosenberg, Jean Mayer USDA Human Nutrition Research Center, Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: Rosenberg{at}hnrc.tufts.edu.
As we lurch toward the end of the 20th century, it may be worth remembering that the youngest of our vitamins, vitamin B-12, is just over 50 y old and the next youngest, folic acid, is only a few years older. In 1945, the synthesis of pteroylglutamic acid was accomplished at Lederle Laboratories after pteroyltriglutamate had been isolated by the same laboratory 2 y earlier. In the race to isolate, purify, and then synthesize folic acid, many different substances with a similar growth-promoting potential for microorganisms and with the capability of reducing macrocytic anemia were candidates for vitamin status. Of the lessons to be learned from that era of discovery of vitamins, spanning much of the first half of this century, one is that folic acid, or folate, comes in many forms or vitamers with different reduction states in the pteroyl moiety and different numbers of glutamates in the 
-linked side chain. When the synthesis of pteroylglutamic acid provided abundant amounts of pure folic acid for study and therapy, it was known that the bulk of folates in food and in the diet was in more complicated polyglutamated forms with a range of bioavailabilities. Still, it was convenient to use the pure synthetic substance for studies of absorption and metabolism of folate and eventually as a form of the vitamin used in supplements and as an additive to the food supply.
The study by Lewis et al (1) in this issue of the Journal shows how important the synthetic form of folic acid has become in our food supply and in food and nutrition policy. By simply including in their estimates of folate intakes the amounts of folate that had been added to food as a result of the Food and Drug Administration (FDA) mandate that, by January 1998, all enriched flour and grain products be fortified with folic acid, these authors showed how much greater these estimates were than estimates not taking into account this source of folate. The success of the FDA's recent mandate can now be assessed with Lewis et al's modeled data with the observation that from 83% to 97% of the population in Lewis et al's 6 sex and age groups were meeting or exceeding the estimated average requirement of folate as set in the recent report of the Institute of Medicine (IOM) (2).
This success may be "virtual" because folate intakes were estimated and not actually measured and the folate estimates themselves "virtual" because a large proportion was synthetic folic acid. Given the abundance of synthetic folic acid in the food supply, especially that in fortified grain and cereal products, it may be tempting to overemphasize the contribution of crystalline or synthetic folic acid and diminish the importance of naturally occurring folate in food in meeting our nutritional needs and preventing disease. This would be a mistake. The use of the concept of dietary folate equivalents in the recent IOM report was an effort to account for the apparent differences in bioavailability between crystalline monoglutamyl folate ingested with or without food and polyglutamyl forms of folate that predominate naturally in food and require an additional digestive step to become bioavailable. In calculating dietary folate equivalents, a bioavailability correction factor is used to account for the 40% difference in bioavailability between crystalline folic acid and naturally occurring folate in food. Time will tell whether this correction factor will strike the appropriate middle ground to deal with the complexity of the many forms of folate in the food supply. The study by Lewis et al indicates the usefulness of the concept of dietary folate equivalents, but also the complexity of calculating the unit and the tendency for the unit to be misinterpreted. For example, there is a misconception that crystalline folic acid is superior to food folate in other ways than just its modestly higher absorption efficiency. We must recognize, however, that despite the different bioavailabilities of and the use in research of synthetic folic acid and supplements to document protection or prevention of disease, folate is folate in biological interactions and the bulk of folate intake should continue to come from foods naturally rich in folate.
Sir William S Gilbert wrote in Pirates of Penzance"When constabulary duty's to be done, a policeman's lot is not a happy one." In this case, a regulator's lot is not an easy one. The FDA deserves our congratulations for arriving at sound recommendations for folate food fortification despite challenging circumstances. They remained vigilant and based their findings on sound science. Although I referred to the success of the FDA as "virtual" (perhaps even virtuous) because their folate intake estimates are based on dietary assessments and modeling and not on actual measurements, evidence from the Framingham Heart Study population, studied before and after mandated folate fortification (3), corroborates Lewis et al's findings. In that study, Jacques et al showed that blood folate concentrations increased and homocysteine concentrations decreased postfortification commensurate with Lewis et al's estimates of satisfactory folate intakes. The FDA seems to have done a good job in selecting the amounts of folate for food fortification. There is still a need to determine the effect of food fortification with folate on the incidence of neural tube defects. The incidence of neural tube defects was one of the driving forces behind folate fortification. Certainly, programs are needed to improve folate intakes in populations with lower than adequate intakes, especially females of childbearing age. However, it appears that real progress is being made in the challenging task to safely meet the folate needs of the entire population.
REFERENCES
This article has been cited by other articles:
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  C. M. Ulrich and J. D. Potter Folate supplementation: too much of a good thing? Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 189 - 193. [Full Text] [PDF]
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 I. H Rosenberg Science-based micronutrient fortification: which nutrients, how much, and how to know? Am. J. Clinical Nutrition, August 1, 2005; 82(2): 279 - 280. [Full Text] [PDF]
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