Folic Acid and Safety Patrick J. Stover, PhD Cornell University

1. Folic Acid and Safety Patrick J. Stover, PhD Cornell University

2. 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.

3. Folate and Pathology Folate-Associated Pathologies Metabolic Disruption Biochemical Markers Hypomethylated DNA Elevated homocysteine S-adenosylmethionine(vitamin deficiency; SNPs) Thymidylate (vitamin deficiency; SNPs) Purines - Cancer- CVD- Demyelination- NTDs - Anemia - Cognitive decline Increased uracil in DNA Decreased DNA synthesis Decreased DNA synthesis & reduced cell division Anemia

4. 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

5. Masking Vitamin B12 deficiency Megaloblastic Anemias – hypersegmented neutrophils • Results from vitamin B-12 deficiency • Impaired DNS synthesis • Diagnostic indicator of B-12 deficiency

6. 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 degeneration • Paresthesias • Gait ataxia • Memory 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

7. 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

8. Impairment of Zn absorption • No 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)

9. 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

10. 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 AEDs • increase 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 patients • Fertile women treated with phenytoin require folic acid to maintain normal serum folate (Berg et al. J. Am. Diet. Assoc. 95:352-6 1995).