Upper Levels of Folate Intake

There are two potential problems associated with widespread enrichment of foods with folic acid or the indiscriminate use of folic acid supplements:

1. Intakes of folic acid in excess of about 5,000 [g per day antagonize the anticonvulsants used in treatment of epilepsy, leading to an increase in fit frequency (Section 10.9.6).

Table 10.4 Reference Intakes of Vitamin Bi2 (^g/day)

U.K.

EU

U.S./Canada

FAO

Age

1991

1993

1998

2001

0-3 m

0.3

0.4

0.4

4-6 m

0.3

0.4

0.4

7-9 m

0.4

0.5

0.5

0.5

10-12 m

0.4

0.5

0.5

0.5

1-3 y

0.5

0.7

0.9

0.9

4-6 y

0.8

0.9

1.2

1.2

7-8 y

1.0

1.0

1.2

1.8

Males

9-10 y

1.0

1.0

1.8

1.8

11-13 y

1.2

1.3

1.8

2.4

14-15 y

1.5

1.3

2.4

2.4

>16 y

1.5

1.4

2.4

2.4

Females

9-10 y

1.0

1.0

1.8

1.8

11-13 y

1.2

1.3

1.8

2.4

14-15 y

1.2

1.3

2.4

2.4

>16 y

1.5

1.4

2.4

2.4

Pregnant

1.5

1.6

2.6

2.6

Lactating

2.0

1.9

2.8

2.8

EU, European Union; FAO, Food and Agriculture Organization; WHO, World Health Organization. Sources: Department of Health, 1991; Scientific Committee for Food, 1993; Institute of Medicine 1998; FAO/WHO, 2001.

EU, European Union; FAO, Food and Agriculture Organization; WHO, World Health Organization. Sources: Department of Health, 1991; Scientific Committee for Food, 1993; Institute of Medicine 1998; FAO/WHO, 2001.

2. High intakes of folic acid mask the development of megaloblastic anemia from vitamin B12 deficiency and result in the development of subacute combined degeneration of the spinal cord as the first sign of deficiency (Section 10.9.3). This means that elderly people are especially vulnerable, because of atrophic gastritis. It has been suggested that vitamin B12 should be added to cereal products, as well as folate; as long as intrinsic factor secretion is unimpaired, crystalline vitamin B12 will be absorbed normally, despite atrophic gastritis.

The U.S./Canadian upper level of folic acid intake (Institute of Medicine, 1998) is set at 1,000 [g per day, which is considered to be unlikely to mask the development of megaloblastic anemia in elderly people. The United Kingdom (Department of Health, 2000) considered the number of people over age 50 who would be exposed to intakes greater than 1,000 [g per day and the number of neural tube defects that would be prevented at various levels of folic acid enrichment of flour. It was concluded that fortification at 240 /g per 100 g of flour would have a significant beneficial effect without resulting in unacceptably high intakes by any population group. After public consultation in the United Kingdom, it was decided in May 2002 not to require fortification of flour with folic acid, pending surveillance of the effects of mandatory fortification in other countries.

10.12 PHARMACOLOGICAL USES OF FOLATE AND VITAMIN B,2

The only pharmacological use of vitamin B12, other than for the treatment of deficiency or for rare children with vitamin dependency diseases affecting the binding of the coenzyme to methylmalonyl CoA mutase (Section 10.8.2), is as an antidote for cyanide poisoning. Supplements of vitamin B12 are available for strict vegetarians who might be at risk of deficiency. There is no evidence of any adverse effects of high intakes of vitamin B12.

Supplements of400 /g per day of folic acid, begun before conception, halve the risk of neural tube defect (Section 10.9.4), and similar supplements reduce the plasma concentration of homocysteine in people homozygous for the ther-molabile variant of methylene-tetrahydrofolate reductase (Section 10.3.4.2), although it is not known whether or not this will reduce their risk of cardiovascular disease. A number of manufacturers voluntarily enrich foods with folic acid. In the United States and other countries, there is mandatory enrichment of cereal products with folic acid.

It remains to be seen whether mandatory enrichment of cereal products with folic acid will reduce death from cardiovascular disease. But this, and the widespread voluntary enrichment of foods in other countries, means that intervention studies with folic acid supplements for cancer prevention are unlikely to yield useful results, because the control group will also be receiving a high intake of folic acid.

FURTHER READING

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Bailey LB and Gregory JF, 3rd (1999) Folate metabolism and requirements. Journal of

Nutrition 129, 779-82. Blakley RL (1995) Eukaryotic dihydrofolate reductase. Advances in Enzymology and Related Areas of Molecular Biology 70, 23-102. Boers GHJ (1997) Hyperhomocysteinemia as a risk factor for arterial and venous disease.

A review of evidence and relevance. Thrombosis and Haemostasis 78, 520-2. Carmel R (2000) Current concepts in cobalamin deficiency. Annual Reviews of Medicine 51,357-75.

Chanarin I and Metz J (1997) Diagnosis of cobalamin deficiency: the old and the new. British Journal ofHaematology 97, 695-700.

Chanarin I, Deacon R, Lumb M, Muir M, and Perry J (1985) Cobalamin-folate interrelations: a critical review. Blood 66, 179-89.

Choi SW and Mason JB (2000) Folate and carcinogenesis: an integrated scheme. Journal of Nutrition 130,129-32.

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D'Angelo A and Selhub J (1997) Homocysteine and thrombotic disease. Blood 90, 1-11.

Department of Health (2000) Folic Acid and the Prevention of Disease. London: The Stationery Office.

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Fenech M (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutation Research 475, 57-67.

Fitzpatrick PF (1998) The aromatic amino acid hydroxylases. Advances in Enzymology and Related Areas of Molecular Biology 74B, 235-94.

FitzpatrickPF (1999) Tetrahydropterin-dependent amino acid hydroxylases. AnnualRe-views of Biochemistry 68,355-81.

Fleming A (2001) The role of folate in the prevention of neural tube defects: human and animal studies. Nutrition Reviews 59, S13-S20; discussion S13-S20.

GluskerJP (1995) Vitamin B12 andtheB12 coenzymes. Vitamins and Hormones 50,1-76.

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References cited in the text are listed in the Bibliography.

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