The European food safety authority (EFSA) last evaluated vitamins and minerals for safety in 2006 and set a so-called Tolerable Upper Intake Level (UL) for each micronutrient, provided sufficient data were available. This UL reflects the maximum safe level of a micronutrient that will not cause adverse effects when taken daily from all sources for a lifetime.
| The maximum safe daily intake for synthetic folic acid is 1,000 µg (equivalent to 1,670 to 2,000 µg folate equivalents).The maximum safe daily intake for synthetic folic acid is mathematically equivalent to 5 times the EU recommended daily intake (Nutrient Reference Value, NRV). |
The above safe daily intake limit applies to adults 19 years of age and older, as well as pregnant and lactating women, and takes into account only synthetic folic acid from dietary supplements and fortified foods. Legislation has approved only synthetic folic acid in the form of pteroylglutamic acid (PGA) and calcium L-methylfolate for use in dietary foods, dietary supplements, and fortified foods. The synthetic form of folic acid was chosen for reasons of stability and better absorption and is used in all preparations available on the market. Synthetic folic acid is almost completely absorbed in the intestine, while dietary folates are only absorbed to about 50%. Accordingly, the intake recommendation of the DGE indicates so-called folate equivalents (FÄ), where 1 µg FÄ = 1 µg dietary folate = 0.5 to 0.6 µg synthetic folic acid. That is, a safe maximum daily intake of 1,000 µg of synthetic folic acid would be equivalent to 1,670 to 2,000 µg of dietary folate. The data of the NVS II (National Nutrition Survey II, 2008) on the daily intake of folic acid from dietary supplements indicate that an unintentional exceeding of an amount of 1,000 µg of synthetic folic acid is unlikely. The so-called LOAEL (Lowest Observed Adverse Effect Level) – the lowest dose of a substance at which adverse effects were just observed – is 5 mg (= 5,000 µg) of synthetic folic acid per day. Accordingly, the lowest dose at which adverse effects were just observed is 25 times greater than the NRV value and 5 times greater than the safe daily intake level (Tolerable Upper Intake Level; UL). For folic acid from natural sources (dietary folate), no adverse side effects of excessive intake have been observed to date. Due to the high undersupply of folic acid in the German population, an excessive intake of the vitamin via the conventional diet is not to be expected anyway. Adverse effects of excessive folic acid intake
With intake of extremely high amounts of synthetic folic acid around 15 mg (equivalent to 25 to 30 mg folate equivalents), insomnia (sleep disturbances), agitation, hyperactivity, nausea (nausea), meteorism (flatulence), impaired taste sensation and allergic reactions such as pruritus (itching), erythema (extensive reddening of the skin) and urticaria (hives) have been observed. Intake of 5 mg of synthetic folic acid per day or more may mask vitamin B12 deficiency, i.e., hematological symptoms identical in vitamin B12 and folic acid deficiency, such as megaloblastic anemia (anemia caused by vitamin B12 deficiency or, less commonly, folic acid deficiency), are improved due to folic acid intake, whereas neurological symptoms of vitamin B12 deficiency cannot be prevented. The diagnosis of nervous system dysfunction due to vitamin B12 deficiency may therefore be hampered if folic acid intake is excessive at the same time. In epileptics, an amount of synthetic folic acid in excess of 1,000 µg may have a seizure-inducing effect. In addition, synthetic folic acid in these amounts accelerates the breakdown of antiepileptic drugs in the liver and may thereby weaken the antiepileptic effect. On the other hand, these drugs reduce the absorption of folates and folic acid in the intestine. Furthermore, interactions (interactions) of folic acid and dietary folates and the drug methotrexate (a folic acid antagonist/counteractant to folic acid) are discussed in rheumatism and cancer patients. However, a daily intake of 1,000 µg of synthetic folic acid (equivalent to 1,670 to 2,000 µg of folate equivalents) does not appear to affect the efficacy of methotrexate.There is even evidence that higher doses of folic acid can reduce the side effects of rheumatism or cancer therapy (chemotherapy). A study by Figueiredo et al. indicates a positive relationship between folic acid and prostate carcinoma (prostate cancer). An intake of 1 mg of synthetic folic acid daily in addition to dietary intake of natural folates tripled the risk of prostate cancer over a 10-year period (9.7% vs. 3.3%). Animal studies also showed a link between folic acid and the development of colon adenomas (glandular growths of the colon; 70-80% of all colorectal polyps are adenomas, which as neoplasms (new formations) carry a malignant potency, i.e. they can degenerate malignantly). Here, megadoses to rats resulted in progression of premalignant lesions (40 mg to 5 g of synthetic folic acid per kg of diet). Colon adenomas can arise from the lesions and, under certain conditions, represent a potential precursor to carcinoma (precancerous lesion).However, it should be noted that in human studies, high doses of synthetic folic acid above the Tolerable Upper Intake Level (UL) resulted in a significant reduction in the recurrence of distant adenomas. Numerous smaller intervention studies support this protective (protective) effect of moderately increased amounts of synthetic folic acid. The effect of folic acid on the development of colon carcinoma (colorectal cancer) is quantity dependent. Both extremely high amounts of synthetic folic acid and a deficiency of folic acid were associated with an increased risk of colon carcinoma in animal studies.Based on several human studies, moderately increased amounts of synthetic folic acid are also considered protective in this context. In a study of 88,756 women, intake of more than 400 µg of synthetic folic acid per day, over a 15-year period, was associated with a 75% lower risk of colon cancer compared to women who did not take synthetic folic acid in the form of supplements.The negative effects described above are only possible if the safe maximum daily intake of synthetic folic acid from supplements is deliberately exceeded. As mentioned at the outset, increased intake of folic acid from natural sources (dietary folate) does not pose a risk of undesirable side effects.
