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Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204
2To whom correspondence should be addressed. E-mail: jrader{at}cfsan.fda.gov.
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ABSTRACT |
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50% in subjects examined before (1995–1996) and after (1997–1998) fortification. Another analyses of samples collected between 1994 and 1999 identified a trend of increasing serum folate values from 1996 onward with values in 1998 160% of those measured in 1996. Comparisons between 1988–1994 National Health and Nutrition Examination Survey (NHANES) III data and 1999 NHANES showed increased serum and erythrocyte folate concentrations among childbearing-aged women. While recent data show improved folate status in a short period of time, much about long-term effects of the fortification program remains unknown. Interest in the effects of increased folate intakes on risk of NTDs or vascular disease needs to be balanced against concerns about masking the anemia of vitamin B-12 deficiency and the general lack of data about safety of continuous high intakes. Careful monitoring over time is necessary to determine that the program functions as intended.
KEY WORDS: • folate • fortification • folate status • serum folate • homocysteine
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDISCUSSIONCONCLUSIONLITERATURE CITED |
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,2
). This fortification was intended to assist women of childbearing age in increasing their intake of folic acid and thereby reduce their risk of a pregnancy affected by a neural tube birth defect (NTD).3
Clinical trial data that have evaluated dose-response relationships for a general population for very long periods of time are rarely available when plans are developed for a national food fortification program. For this reason, issues of safety for the general population and potential effectiveness for specific target populations must be addressed using the best available information. The level of fortification chosen for the U.S. program (i.e., 140 µg folic acid per 100 g cereal-grain product) (3
,4
) appeared to provide the best possible accommodation between competing concerns regarding effectiveness for the target population and safety for the much larger nontarget population. It was originally estimated that the U.S. folate fortification plan would add 80–130 µg folic acid/d to usual intakes of adults >19 y of age (3
,4
). The effectiveness and safety of the fortification program can be evaluated only by comparison of pre- and postfortification data, when available, and by careful postfortification monitoring. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONDISCUSSIONCONCLUSIONLITERATURE CITED |
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Prior to the availability of data that directly assessed changes in folate status following fortification, several types of studies were used to estimate the potential effects of the program. Such studies include those in which indicators of folate status [e.g., serum folate, red blood cell (RBC) folate, homocysteine (Hcy)] are measured in volunteers who have been given graded amounts of folic acid in a fortified food (e.g., breakfast cereal) for specified periods of time (5
). Such studies provide data regarding the effects of short-term exposure to a single food but do not address the effects of consuming a wide range of fortified foods for a long period of time. Thus, such short-term studies tend to underestimate the potential effects of a broad-based fortification program. In another approach, estimates of intakes that might result from a fortified food supply are derived by combining food consumption data with calculated amounts of folic acid that would be present in foods following fortification (6
). Such an approach relies on food consumption surveys that typically underestimate the amounts of food consumed. This, in turn, results in an underestimation of nutrient intakes. In addition, because food-by-food analyses are not conducted, broad assumptions must be made regarding the folate content of foods after fortification. Such approaches, while helpful in several aspects, more likely underestimate, rather than overestimate, folate intakes.
This report will review recent studies that report direct measurements of indices of folate status in individuals following fortification and compare such values with those measured in the prefortification period. Recently published data regarding the prevalence of NTDs also will be reviewed.
Effects on serum/plasma folate, RBC folate and total Hcy
Jacques et al. (7
) presented the first data that directly assessed the effects of fortification on indices of folate status. These authors measured plasma folate and total Hcy (tHcy) concentrations using blood samples from the fifth (January 1991 to December 1994) and sixth (January 1995 to August 1998) examinations of the Framingham Offspring Study cohort. Samples from the fifth and sixth examinations provided baseline and follow-up values, respectively. The cohort was divided into a study group and a control group based on the dates of their follow-up examinations. Samples were obtained from the control group before fortification (January 1995 to September 1996, 756 subjects) and from the study group after fortification (September 1997 to March 1998, 350 subjects).
Among nonusers of B-vitamin supplements, mean plasma folate increased from 4.6 µg/L among individuals examined before fortification to 10.0 µg/L in individuals examined after implementation of fortification (P < 0.001). In nonusers of supplements, the prevalence of plasma folate values <3 µg/L fell from 22.0% among those examined before fortification to 1.7% among individuals examined after fortification. Jacques et al. (7
) also reported that the mean tHcy concentration decreased from 10.1 to 9.4 µmol/L during this same time (P < 0.001) and the prevalence of high Hcy concentrations (i.e., 13 µmol/L) decreased from 18.7 to 9.8%. The authors concluded that fortification of enriched cereal-grain products with folic acid was associated with a substantial improvement in the folate status of the middle-aged and older adults participating in the study (7
).
Lawrence et al. (8
) reviewed computer-stored data for serum folate in >98,000 blood samples submitted to Kaiser Permanente’s Southern California Endocrinology Laboratory between 1994 and 1998. These authors found that the median prefortification serum folate value in 1994 of 12.6 µg/L increased gradually during the transition period between initiation of fortification in 1996 and full implementation in 1998 to 18.7 µg/L (8
). Serum folate levels continued to increase in 1999, and levels in many of the 1999 samples could not be assessed because they exceeded the maximal value of 20.0 µg of folate per liter using the method to measure serum folate in the clinical laboratory (9
).
The U.S. Centers for Disease Control and Prevention reported recently that the mean RBC (erythrocyte) folate level in women aged 15–44 y participating in the 1988–1994 National Health and Nutrition Examination Survey (NHANES) that was conducted prior to folic acid fortification was 181 µg/L (95% confidence interval (CI), 177–185 µg/L) and had increased 74% to 315 µg/L (95% CI, 289–314 µg/L) in those participating in the 1999 NHANES (10
). Comparison of median serum folate and RBC folate levels obtained several years prior to and 1 y following full implementation of folic acid fortification showed two- to threefold increases. Increases of this magnitude occurred across all groups of women 15–44 y of age (i.e., in pregnant vs. nonpregnant women, supplement users vs. nonsupplement users). Thus, these changes are likely due to fortification of the national food supply (10
).
The most recent data examining changes in folate status in the U.S. following fortification are those of Caudill et al. (11
). These authors examined folate status in healthy nonpregnant Southern California women (18–45 y of age) following folic acid fortification. Their study was of cross-sectional design in which a fasting blood sample was obtained from socioeconomically advantaged (n = 85; >200% federal poverty level 1999) and disadvantaged (n = 50; 
200% federal poverty level 1999) women in Southern California. Women were excluded from participation if they were smokers, pregnant, lactating, consuming supplements containing folic acid within the past 12 mo or taking medication known to interfere with folate metabolism or had a history of chronic disease. The women were recruited from January 1999 through December 1999.
Serum and RBC folate (mean ± SD) for socioeconomically advantaged (54 ± 18 and 1387 ± 329 nmol/L, respectively) and disadvantaged women (41 ± 18 and 1172 ± 342 nmol/L, respectively) greatly exceeded the levels deemed acceptable for serum folate (
13.6 nmol/L) and RBC folate (906 nmol/L), which are associated with very low risk of NTD. Values for plasma tHcy for both groups combined (5.5 ± 1.7 µmol/L) were within the lower limit of the normal range and indicative of adequate folate status. Caudill et al. (11
) concluded that, following folic acid fortification of the food supply, women of childbearing age were achieving positive folate balance and RBC folate concentrations associated with reduced risk of NTD. The data of Caudill et al. (11
) indicate that economically disadvantaged women were benefiting from the fortification. It is clear that fortification is reaching at least some segments of lower income, minority women of childbearing age. Moreover, 78% of the socioeconomically disadvantaged women had RBC values >906 nmol/L and none had elevated Hcy levels (11
).
Caudill et al. (11
) noted that the high concentrations of folate in RBCs and serum indicated that the fortification program was delivering more than the 100 µg folic acid/d originally estimated (12
). Caudill et al. (11
) assessed total dietary folate intakes and found them to be 100–200 µg/d higher than nationwide prefortification intakes. Caudill et al. (11
) compared their own data with data provided by studies of Daly et al. (13
) in women consuming 100, 200 or 400 µg folic acid/d in addition to usual dietary intakes for 6 mo. Caudill et al. (11
) noted that the median RBC folate concentration for all women in their study was 1246 nmol/L and that this value, compared with responses to folic acid observed by Daly et al. (13
), suggested that the fortification program was delivering an additional 200–400 µg folic acid/d.
Prior to the report of Caudill et al. (11
), only two studies had investigated the effects of folic acid fortification on folate status (7
–9
). The post-folic acid fortification status observed by Caudill et al. (11
) is more comparable to that reported from Lawrence and colleagues (8
,9
) than to that reported by Jacques et al. (7
), possibly due to differences in geographic location of the participants and/or the fact that folic acid fortification had been in effect longer when Caudill et al. (11
) carried out their study.
Folate status indicators in residents of Ontario, Canada.
Canada began its mandatory fortification of all flour and some corn and rice products with folic acid in November 1998. Ray et al. (14
) evaluated folate and vitamin B-12 status in Ontario, Canada, following this fortification. They also studied the role of plasma Hcy in the assessment of vitamin B-12 deficiency because plasma Hcy has been reported to be useful in the evaluation of patients with suspected vitamin B-12 or folate deficiencies. These authors performed a retrospective cross-sectional study using a community database of all Ontario samples analyzed by a laboratory that was a major provider of diagnostic laboratory services in Canada. All consecutive single-patient samples for plasma Hcy collected between January 1 and September 30, 1999, were included, as well as corresponding RBC folate and serum B-12 concentrations. A total of 711 samples were evaluated; the mean age of all subjects was 58.4 y (95% CI, 57.4–59.4). Ray et al. (14
) reported that concentrations of serum folate and RBC folate were much higher than expected. The geometric mean serum folate level in all subjects was 34.5 nmol/L (15.2 µg/L; 95% CI, 34.1–37.8 nmol/L; 15.0–16.7 µg/L) and the geometric mean RBC folate value was 956.8 nmol/L (422.2 µg/L; 95% CI, 932.1–982.2 nmol/L; 411.3–433.5 µg/L). The geometric mean tHcy value was 8.8 µmol/L (95% CI, 8.5–9.2). These data are in agreement with those of Jacques et al. (7
) and Lawrence et al. (8
,9
), who have reported significant increases in serum folate levels in the general U.S. population.
Ray et al. (14
) noted that, in their data set, a plasma Hcy >15 µmol/L did not discriminate between cobalamin concentrations below versus those above 120 pmol/L. Thus, their study could not validate the accuracy of plasma Hcy in the evaluation of vitamin B-12 deficiency. The authors expressed concern that, given the inability to detect mild vitamin B-12 deficiency using indicators such as plasma Hcy and considering the substantial growth in the older segments of the Canadian population, occult vitamin B-12 deficiency could become a common disorder.
Changes in birth prevalence of NTDs.
The intent of the fortification plan was to assist women in increasing their folate intake during their childbearing years. Honein et al. (15
) reported the results of a study designed to evaluate the impact of folate fortification on birth prevalence of NTDs. The authors carried out a national study of birth certificate data for live births to women in 45 U.S. states and the District of Columbia between January 1990 and December 1999. The authors assumed that nearly all pregnancies from October 1998 through December 1999 were exposed to the folic acid-fortified food supply. The authors found that the birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100,000 live births (0.038%) before fortification to 30.5 per 100,000 live births (0.031%) after fortification. This represented a 19% decline in birth prevalence of NTDs. The authors noted that, while this decline was temporally associated with the fortification of cereal-grain products, other factors may also have contributed to the decline.
The postfortification environment
Elevated Hcy has been identified as an independent risk factor for cardiovascular and cerebrovascular disease. Because increased folate intakes are associated with decreases in Hcy levels, some investigators have hypothesized that increased folate intake will reduce mortality from vascular disease and have proposed increases in the fortification level to achieve a "maximal" reduction in serum Hcy levels (see Ref. 16
). However, elevated Hcy is not a specific indication of inadequate intake of folate. It can be caused by dietary insufficiencies of vitamin B-12 (14
), vitamin B-6 or riboflavin (17
) or by conditions such as renal failure. Clinical trials to evaluate whether elevated Hcy is a causal factor for cardiovascular disease or a result of the disease itself are not yet completed. While it is known that treatment with a combination of folic acid, vitamin B-6 and vitamin B-12 will reduce elevated Hcy in most cases, there is no evidence to date that such treatment will reduce clinical events. A number of clinical trials are currently in the field (see Ref. 18
).
Determinants of plasma tHcy.
It is well recognized that folate status is a determinant of mild hyperhomocysteinemia in the general population, in coronary disease patients and in renal transplant patients (Ref. 19
and references therein). Renal disease renders individuals somewhat refractory to the effect of folic acid supplementation on fasting tHcy. Bostom et al. (19
) hypothesized that improved folate status secondary to fortification would have a more limited impact on the prevalence of mild hyperhomocysteinemia in renal transplant patients versus coronary artery disease patients. Bostom et al. (19
) evaluated fasting tHcy levels in a series of 86 stable renal transplant patients and 175 coronary artery disease patients. The subjects were examined between October 1997 and October 1998. All were either nonusers of supplements containing folic acid, vitamin B-6 or vitamin B-12 or refrained from use of such supplements for 6 wk. Bostom et al. (19
) observed that the geometric mean fasting tHcy levels were 8.0% higher (15.6 vs. 8.3 µmol/l; P < 0.001) and the prevalence of fasting tHcy > 12 µM was markedly increased (69.8 vs. 10.9%, P < 0.001) in the renal transplant patients. The authors concluded that in the era of folate-fortified cereal-grain products, hyperhomocysteinemia is much more common in stable renal transplant patients than in coronary artery disease patients. This finding suggests that renal transplant patients may be a preferable population for controlled trials that seek to evaluate the hypothesis that lowering tHcy levels will reduce cardiovascular disease outcomes (19
).
Jacques et al. (20
) examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in nearly 2000 men and women, aged 28–82 y, from the fifth examination cycle of the Framingham Offspring Study (1991 and 1994). These authors found that tHcy was associated with plasma folate, vitamin B-12 and pyridoxal phosphate (PLP). Among nonusers of dietary supplements, dietary folate, vitamin B-6 and riboflavin were associated with tHcy (P for trend < 0.01). These new data confirmed the importance of previously recognized determinants of fasting tHcy and suggested that intakes of other dietary factors (e.g., vitamin B-6 and riboflavin) also influence circulating tHcy concentrations. The finding of an association between dietary vitamin B-6 and Hcy is also supported by recent work of McKinley et al. (17
).
Hcy can be remethylated to methionine in reactions requiring vitamin B-12, folate and riboflavin as cofactor, cosubstrate and prosthetic group, respectively (17
), or can undergo a transsulfuration reaction to form cysteine. The transsulfuration reaction is dependent upon PLP and is catalyzed by cystathionine ß-synthase (EC 4.2.1.22). Vitamin B-6 has been used for many years to treat homocystinuria caused by cystathionine ß-synthase deficiency (21
). Its role in the treatment of mild hyperhomocysteinemia is still not clear. While some data suggest that physiologic doses of vitamin B-6 have little or no significant Hcy-lowering effect, it is possible that the effect has been missed because of much greater effects of folic acid, vitamin B-12 or both.
McKinley et al. (17
) investigated the effect of low-dose vitamin B-6 supplementation on fasting tHcy concentrations in healthy elderly persons after exclusion of those deficient in vitamin B-12 and after optimization of folate and riboflavin status. This study, while not carried out in the U.S., is relevant to the situation here because it measured effects on Hcy in folate-replete individuals, such as are now found in the U.S. population consuming folate-fortified foods. Subjects in this study were recruited in Northern Ireland between January and April 1998. Twenty-two healthy elderly persons (aged 63–80 y) were given supplements of 1.6 mg vitamin B-6 for 12 wk in a randomized double-blind placebo-controlled trial after repletion with folic acid (400 µg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk). Results showed that folic acid supplementation lowered fasting Hcy by 19.6% (P < 0.001). There was a significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation and this led to a further significant 7.5% reduction in plasma Hcy. Such data, which show that low-dose vitamin B-6 lowers plasma tHcy in folate- and riboflavin-replete subjects, suggest that programs focused on the reduction in hyperhomocysteinemia also need to consider the role of vitamin B-6 status. These interesting new data also suggest that, in a folate-replete population, simply increasing folate levels may not necessarily result in further decreases in Hcy if vitamin B-6 status is less than adequate.
McKay et al. (22
) determined whether a multivitamin/multimineral supplement formulated to contain 100% daily value (DV) would further lower Hcy and improve vitamin status in elderly adults already consuming a folic acid-fortified diet. McKay et al. (22
) carried out a randomized double-blind placebo-controlled trial with 80 healthy free-living men and women aged 50–87 y with total plasma Hcy concentrations 8 Fmol/L. The participants were recruited in the greater Boston area between October 1997 and January 1999 (i.e., during the transition to full compliance with the fortification regulations and during their first full year in effect). The participants received either a multivitamin/mineral supplement formulated at 100% of the DV for folic acid, vitamin B-6 and vitamin B-12 or placebo for 56 d while consuming their usual diets. The authors reported that, after the 8-wk treatment, subjects taking the multivitamin/multimineral supplement had significantly higher B-vitamin status and lower Hcy concentrations than did controls (P < 0.01). Plasma folate, PLP and vitamin B-12 concentrations increased 42, 37 and 14%, respectively, in the supplemented group. The mean Hcy concentrations decreased 9.6% (P < 0.001). Regression analysis indicated that only the increase in folate status was responsible for the Hcy-lowering effect. The authors suggested that their results indicated that supplemental folate intake via multivitamins may provide further benefit in increasing vitamin status and in lowering plasma Hcy even in those consuming folate-fortified food.
It is noteworthy that the data from McKay et al. (22
) show that the supplementation reduced the prevalence of suboptimal folate status (i.e., plasma folate <15 nmol/L; < 6.6 µg/L) from 15 to 5%. We noted earlier that Jacques et al. (7
) reported that among nonusers of supplements the prevalence of plasma folate values <3 µg/L (<6.8 nmol/L) fell from 22% among those examined before fortification to 1.7% among individuals examined after fortification. Among users of dietary supplements, the prevalence of plasma folate values <3 µg/L fell from 0.9% before fortification to essentially 0.0% after fortification. These findings may suggest that had the study population of McKay et al. (22
) been exposed to fortification for a longer period of time the additional supplemental folate would have had less effect than was observed.
Future considerations
While it is clear that the current U.S. fortification program has brought about a rapid improvement in folate status, the U.S. Institute of Medicine (IOM) (23
) has expressed concern about potential adverse effects of high doses of folic acid in specific subgroups of the population (e.g., individuals treated with anticonvulsants and anti-folate therapeutics such as methotrexate) (23
). In addition, there are no data regarding the effects of long-term exposure of, e.g., young children to several times their daily recommended intake (DRI) for folic acid. This is of some importance because the DRI for children is 200–300 µg/d and the IOM (23
) has established a tolerable upper limit of folic acid intake of 300 µg/d for children aged 1–3 y and 400 µg/d for those aged 4–8 y. Estimates of folic acid intakes in several U.S. population groups suggest that some people may be consuming intakes that approach or exceed the IOM’s upper limit for folic acid (6
). These authors estimated postfortification intakes in different population groups including children, using data from two national food consumption surveys with corrections to reflect the required levels of folic acid added to foods. Their estimates derived from this study suggested that 15–25% of children between the ages of 1 and 8 y may have intakes of folic acid in excess of the tolerable upper limit of 300 (1–3 y) or 400 (4–8 y) µg folic acid/d. Data on the effect of the fortification program on folate status of young children have not yet been reported.
Kelly et al. (24
) noted that the effect of in vivo chronic exposure of adult and fetal cells to the synthetic form of folic acid has never been investigated at the population level. In a study that examined the acute appearance of unmetabolized folic acid in serum in response to the consumption of fortified foods, these authors reported that subjects on a 5-d regimen of fortified cereal and bread (in addition to their usual diet) had a threshold intake of 266 µg folic acid per meal at which unaltered folic acid appeared in the serum. While Kelly et al. (24
) suggested that the increased intakes resulting from the current U.S. fortification would be unlikely to lead to the repeated acute appearance of unmetabolized folic acid in serum because the fortified foods are likely to be consumed at more than one sitting per day, these authors noted that, on the basis of their results, compliance with recommendations for women of childbearing age to take 400 µg folic acid/d to reduce the risk of NTDs would most likely result in repeated appearance of folic acid in the maternal and fetal circulation for many consumers.
The issue of potential adverse effects of excess folate in individuals with untreated vitamin B-12 deficiency remains unresolved. In such individuals, the anemia of vitamin B-12 deficiency may be temporarily corrected or masked by excess folate, with a return to normal hematopoiesis. However, the concern remains that, in some patients, the neuropathy that occurs as a consequence of vitamin B-12 deficiency will progress or will develop for the first time in the presence of normal hematologic indices. The neuropathy, if untreated, may not be reversible by subsequent treatment with vitamin B-12. Thus, careful surveillance will be required to determine whether there is a change in the natural history of vitamin B-12 deficiency (e.g., an increase in the presentation of vitamin B-12 deficiency neuropathy in the absence of anemia).
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONDISCUSSIONCONCLUSIONLITERATURE CITED |
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There is much we still do not know about the long-term effects of this program. When considering a fortification program, it must be recognized that inadequate intakes among "low" consumers (those at whom the fortification program is directed) may not be remedied simply by increasing the level of a fortificant in the general food supply, because inadequate intakes may occur as a result of dieting, poor choices of food, etc. However, it is clear that increases in concentrations of a nutrient in the food supply are always accompanied by increases among "high" consumers whose intakes may already be high (e.g., because of use of dietary supplements, etc.). The effectiveness of a fortification program for low consumers and safety for high consumers are always competing concerns.
Additional efforts will be needed to monitor the safety and effectiveness of the folate fortification program. Such efforts include continued determinations of the folate content of foods and studies involving the stability and bioavailability of folate in foods. Studies need to be undertaken to determine the impact of the fortification on indicators of folate status in specific subgroups of the population, including those who might be at risk of excess intakes. Careful monitoring over time will be necessary to ensure that the folic acid fortification program is functioning as intended and that it does not have unintended consequences.
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FOOTNOTES |
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3 Abbreviations used: CI, confidence interval; DRI, daily recommended intake; DV, daily value; Hcy, homocysteine; IOM, U.S. Institute of Medicine; NHANES, National Health and Nutrition Examination Survey; NTD, neural tube birth defect; PLP, pyridoxal phosphate; RBC, red blood cell; tHcy, total Hcy.
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LITERATURE CITED |
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1. Department of Health and Human Services, Public Health Service, Food and Drug Administration (DHHS/PHS) (1996) Food standards: amendment of the standards of identity for enriched cereal-grain products to require the addition of folic acid: final rule (21 CFR Parts 136, 137 and 139). Fed. Regist. 61:8781-8797.
2. Department of Health and Human Services, Public Health Service, Food and Drug Administration (DHHS/PHS) (1996) Food additives permitted for direct addition to food for human consumption: folic acid (folacin): final rule (21 CFR Part 172). Fed. Regist. 61:8797-8807.
3. Department of Health and Human Services, Public Health Service, Food and Drug Administration (DHHS/PHS) (1993) Food standards: amendment of the standards of identity for enriched cereal-grain products to require the addition of folic acid: proposed rule. Fed. Regist. 58:53305-53312.
4. Department of Health and Human Services, Public Health Service, Food and Drug Administration (DHHS/PHS) (1993) Health claims and label statements: folate and neural tube defects. Fed. Regist. 58:53254-53295.
5. Malinow, M. R., Duell, P. B., Hess, D. L., Anderson, P. H., Kruger, W. D., Phillipson, B. E., Gluckman, R. A., Block, P. C. & Upson, B. M. (1998) Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N. Engl. J. Med. 338:1009-1015.
6. Lewis, C. J., Crane, N. T., Wilson, D. B. & Yetley, E. A. (1999) Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am. J. Clin. Nutr. 70:198-207.
7. Jacques, P. F., Selhub, J., Bostom, A. G., Wilson, P. W. & Rosenberg, I. H. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 340:1449-1454.
8. Lawrence, J. M., Petitti, D. B., Watkins, M. & Umekubo, M. A. (1999) Trends in serum folate after food fortification. Lancet 354:915-916.[Medline]
9. Lawrence, J. M., Chiu, V. & Petitti, D. B. (2000) Fortification of foods with folic acid (Letter to Editor). N. Engl. J. Med. 343:970.
10. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention (DHHS/PHS) (2000) Folate status in women of childbearing age: United States, 1999. MMWR Morb. Mortal. Wkly. Rep. 49:962-965.[Medline]
11. Caudill, M. A., Thia Le, M. S., Moonie, S. A., Setareh Torabian Esfahani, M. S. & Cogger, E. A. (2001) Folate status in women of childbearing age residing in Southern California after folic acid fortification. J. Am. Coll. Nutr. 20:129-134.
12. Crane, N. T., Wilson, D. B., Cook, D. A., Lewis, C. J., Yetley, E. A. & Rader, J. I. (1995) Evaluating food fortification options: general principles revisited with folic acid. Am. J. Public Health 85:660-666.
13. Daly, S., Mills, J. L., Molloy, A. M., Conley, M., Lee, , Young, J., Kirke, P. N., Weir, D. G. & Scott, J. M. (1997) Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350:1666-1669.[Medline]
14. Ray, J. G., Cole, D. E. C. & Boss, S. C. (2000) An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise?. Clin. Biochem. 33:337-343.[Medline]
15. Honein, M. A., Paulozzi, L. J., Mathews, T. J., Erickson, J. D. & Wong, L-Y. C. (2001) Impact of folic acid fortification of the U.S. food supply on the occurrence of neural tube defects. J. Am. Med. Assoc. 285:2981-2986.
16. Wald, D. S., Bishop, L., Wald, N. J., Law, M., Hennessy, E., Weir, D., McPartlin, J. & Scott, K. (2001) Randomized trial of folic acid supplementation and serum homocysteine levels. Arch. Intern. Med. 161:695-700.
17. McKinley, M. C., McNulty, H., McPartlin, J. M., Strain, J. J., Pentieva, K., Ward, M., Weir, D. G. & Scott, J. M. (2001) Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am. J. Clin. Nutr. 73:759-764.
18. Spence, J. D., Howard, V. J., Chambless, L. E., Malinow, M. R., Pettigrew, L. C., Sampfer, M. & Toole, J. F. (2001) Vitamin intervention for stroke prevention (VISP) trial: rationale and design. Neuroepidemiology 20:16-25.[Medline]
19. Bostom, A. G., Gohh, R. Y., Liaugaudas, G., Beaulieu, A. J., Han, H., Jacques, P. F., Dworkin, L., Rosenberg, I. H. & Selhub, J. (1999) Prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients after fortification of cereal grain flour with folic acid. Atherosclerosis 145:221-224.[Medline]
20. Jacques, P. F., Bostom, A. G., Wilson, P. W. F., Rich, S., Rosenberg, I. H. & Selhub, J. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am. J. Clin. Nutr. 73:613-621.
21. Mudd, S. H., Skovby, F., Levy, H. L., Pettigrew, K. D., Wilcken, B., Pyeritz, R. E., Andria, G., Boers, G. H., Bromberg, I. L., Cerone, R., Fowler, B., Gröbe, H., Schmidt, H. & Schweitzer, L. (1985) The natural history of homocystinuria due to cystathionine ß-synthase deficiency. Am. J. Hum. Genet. 37:1-31.[Medline]
22. McKay, D. L., Perrone, G., Rasmussen, H., Dallal, G. & Blumberg, J. B. (2000) Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet. J. Nutr. 130:3090-3096.
23. Institute of Medicine, National Academy of Sciences (1998) Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline 1998 National Academy Press Washington, DC. .
24. Kelly, P., McPartlin, J., Goggins, M., Weir, D. G. & Scott, J. M. (1997) Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am. J. Clin. Nutr. 65:1790-1795.
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