Folic Acid and Safety

Patrick J. Stover, PhD Cornell University

Biological effects of elevated folate intake(< 1 mg/day)

There are no demonstrated toxicities or harmful effects resulting from folate intakes currently achieved by the US population, although some may be achieving intakes > 1mg/day without supplement use.

-There are essentially no data on safety (Shane, B Am. J. Clin. Nutr. 2003.)

Unintended consequences to vulnerable populations is the primary concern.

The mechanisms whereby impaired folate metabolism increases risk for NTDs are not known, nor are the mechanisms whereby folate protects against NTDs.

Folate and PathologyMetabolic DisruptionBiochemical MarkersFolate-Associated PathologiesS-adenosylmethionine (vitamin deficiency; SNPs)

Thymidylate(vitamin deficiency; SNPs)

PurinesHypomethylated DNAElevated homocysteine

Decreased DNA synthesis & reduced cell division- Cancer - CVD - Demyelination - NTDs- Anemia- Cognitive declineAnemiaIncreased uracil in DNADecreased DNA synthesis

Biological effects of increased folate intake.

The following concerns, new and old, have been raised in the literature:

Masking Vitamin B12 deficiency (pernicious anemia).Impairment of Zn absorption (Hansen et al, 2001)Decreasing the effectiveness of drug therapy (Quinlivan and Gregory, 2002).-cancer- anticonvulsants

Masking Vitamin B12 deficiencyMegaloblastic Anemias hypersegmented neutrophils Results from vitamin B-12 deficiency Impaired DNS synthesis Diagnostic indicator of B-12 deficiency

Causes of Vitamin B-12 deficiency (20% of elderly)

Abnormal gastric events (acid/enzymes) Deficient intrinsic factor (parietal cell destruction) Malabsorption syndromes Diet

B-12 associated Neurological symptoms - Posterolateral spinal cord degenerationParesthesiasGait ataxiaMemory loss

Folic acid at elevated intakes (> 1mg/day) masks B-12 deficiency- induced hematological abnormalities w/o rescuing irreversible neurological symptoms.

Masking Vitamin B12 deficiency

Biological effects of increased folate intake.

The following concerns, new and old, have been raised in the literature:

Masking Vitamin B12 deficiency (pernicious anemia).Impairment of Zn absorption (Hansen et al, 2001)Decreasing the effectiveness of drug therapy (Quinlivan and Gregory, 2002).-cancer-anticonvulsants

Impairment of Zn absorptionNo long term study (human and animal) has indicated adverse effects of folic acid supplements on Zn balance (Butterworth and Tamura, Am. J. Clin. Nutr.50:353-8 1989)Folic acid (.350-1 mg/day) has been shown to affect Zn excretion, absorption in some but not in other studies.Fortification of white bread did not affect 65Zn absorption in young women (22-33y) at low and high zinc content (Hansen et al. Am J. Clin. Nutr. 74:125-9, 2001)

Biological effects of increased folate intake.

The following concerns, new and old, have been raised in the literature:

Masking Vitamin B12 deficiency (pernicious anemia).Impairment of Zn absorption (Hansen et al, 2001)Decreasing the effectiveness of drug therapy (Quinlivan and Gregory, 2002).-cancer -anticonvulsants

Decreasing the effectiveness of antifolate therapy There is no direct evidence, nor is it known, if folic acid supplements negate the effects of antifolate or antiepileptic drugs (Butterworth & Tamura,1989).

Cancer suggested without evidence.Antiepileptic drugs (AEDs) (valproate, carbamazepine, phenytoin)1/250 newborns exposed to AEDsincrease risk for spina bifida; risk for major malformation is 7-10% (Yerby, Epilepsia, 44:33-40, 2003)phenytoin (other AEDs?) decreases folate levels in 50% of epileptic patientsFertile women treated with phenytoin require folic acid to maintain normal serum folate (Berg et al. J. Am. Diet. Assoc. 95:352-6 1995).