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

4. Biological effects of increased folate intake. The following concerns, new and old, have been raised in the literature: 1.Masking Vitamin B12 deficiency (pernicious anemia). 2.Impairment of Zn absorption (Hansen et al, 2001) 3.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: 1.Masking Vitamin B12 deficiency (pernicious anemia). 2.Impairment of Zn absorption (Hansen et al, 2001) 3.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 65 Zn 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: 1.Masking Vitamin B12 deficiency (pernicious anemia). 2.Impairment of Zn absorption (Hansen et al, 2001) 3.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).