Risks of folic acid fortification
In the Netherlands, women who wish to become pregnant are advised to take folic acid supplements during the time period prior to and following conception, in order to limit the chance of neural tube defects occurring in the embryo. It has emerged that this advice is still insufficiently followed. Another possible way to improve the intake of folate by women who wish to become pregnant is to make available food products fortified with folic acid. However, the fortification of foods with folic acid is not permitted in the Netherlands. In this report, a committee from the Health Council of the Netherlands discusses the risks that are possibly associated with an increase in intake of folic acid due to fortification of food products with folic acid. On the basis of this evaluation an acceptable upper limit for daily intake has been proposed.
Folate plays an important role in amino acid and protein metabolism as well as in the formation of DNA and RNA. Folate occurs naturally in foods such as green vegetables and citrus fruits in the reduced form, mostly as a polyglutamate, from which the glutamate units are deconjugated in the jejunum. Vitamin supplements and fortified food products usually contain a synthetic form of folate: pteroylmonoglutamic acid (PMG, folic acid). Upon absorption in the ileum, PMG is reduced to the physiologically active form of folate, but unmetabolized PMG is also found in serum. Pteroylmonoglutamic acid rarely occurs naturally in foods.
Risks
PMG has already been used in medical practice for several decades. A study of the literature reveals that a systematic toxicological evaluation of PMG is lacking. The most described risk of an increased intake of PMG is the correction of the hematological, but not the neurological, abnormalities resulting from vitamin B12 deficiency. As a consequence of this correction the aforementioned abnormalities are not observed in time. Nowadays, a vitamin B12 deficiency is, however, diagnosed by determination of the vitamin B12 level in serum. Therefore, an increased intake of PMG shouldn’t be a problem any more in the detection of a vitamin B12 deficiency. However, this depends upon doctors being far more aware of the possibility that the patient has a vitamin B12 deficiency and that a measurement of the vitamin B12 level in the serum is more quickly taken.
Furthermore, it is possible that in people with a vitamin B12 deficiency, an increased intake of PMG can mask the symptoms associated with the deficiency and thereby delay the moment at which the patient reports to the doctor with complaints.
In the literature from the period in which vitamin B12 had not yet been discovered as a vitamin, there are several descriptions of patients with pernicious anaemia who received PMG and were observed to experience a more rapid progression of neurological symptoms. On the other hand, a variable progression of pernicious anaemia is also described in people who had not received PMG. However, this has not been the subject of any rigorous research. The risk of inducing or exacerbating the neurological abnormalities by increasing the intake of PMG cannot, therefore, be excluded. Furthermore, it has been suggested such an effect of PMG may also occur in people with a marginal vitamin B12 status. It is not known at what dose this effect possibly occurs. Indications exists that in the Netherlands about 25% of the elderly have a mild vitamin B12 deficiency.
Certain drugs such as methotrexate directly influence folate metabolism. It has been shown that increasing the intake of PMG does not reduce the effect of methotrexate, although there are indications that its toxicity is reduced. Furthermore, there are indications that an increase in the intake of PMG used epilepsy patients under treatment can increase the number of epileptic fits. The Committee is of the opinion that it is the responsibility of the attending physician to discuss this with the patient and to adjust the treatment regimen accordingly.
The involvement of folate in the synthesis of DNA clarifies why drugs with an anti-folate effect inhibit tumor growth. Yet on the other hand, epidemiological studies have shown that a higher folate intake appears to be associated with a lower incidence of cancer at various sites, including colon cancer. This is explained by the role of folate, inter alia, in the methylation of DNA, which is an important process for gene regulation.
There are no convincing indications that PMG has an adverse effect on the bioavailability of zinc and the zinc status.
Hypersensitivity towards PMG has been reported on an incidental basis but in the Committee’s opinion, this is an extremely rare occurrence.
Acceptable upper limit for daily intake
Adverse effects due to an increase in folate intake as described in the literature have only been related to PMG, the synthetic form of folate. Little is known about the contribution of folate from food to these effects. In the Netherlands, food provides about 250 mg of folate per day, of which 50 to 70% is absorbed. This intake from food is relatively small compared with the intake of PMG from vitamin supplements and, in some countries, fortified food products. Furthermore, PMG from supplements and fortified food products is absorbed far more readily than folate from food. Therefore, the Committee considers it justifiable to relate the acceptable upper limit of daily intake of folate solely to PMG and not to the combined total of PMG plus folate from food.
Although a systematic toxicological evaluation of PMG has not been made, the Committee expects that the risk from direct toxicity of PMG for amounts of less than 5 mg per day is small: large scale randomized studies have not revealed any adverse effects. An uncertainty factor of five has been applied, in view of the uncertainty with regard to the very serious neurological abnormalities being introduced as result of an increased intake of PMG in people with a serious vitamin B12 deficiency. This results in an acceptable upper limit of 1 mg of PMG per day. Until results of adequate research have proven the contrary, the Committee considers the possible neurotoxic effect of PMG to be a potential risk for subjects with a marginal vitamin B12 status. Therefore, to be on the safe side, this group should not be exposed to extra PMG. For children and adolescents, the Committee recommends that the limit shall be related to the metabolic bodyweight.
Fortification of food products
Taking into consideration the existing uncertainties concerning the risk for people with mild vitamin B12 deficiency of taking PMG, the Committee advises that the fortification of food products should for the time being be limited to those foods which are specifically aimed at the target group (women who wish to become pregnant). Fortified food products should only be introduced in conjunction with the appropriate advice and labelling. This will prevent the concomitant use of folic acid supplements and folic acid fortified food products, which would result in the upper limit being exceeded repeatedly.
It is not impossible that this recommendation will need to be reviewed once further insights have been obtained into the possible positive effects of extra folic acid on homocysteine metabolism and accordingly the prevention of cardiovascular diseases.
Finally the Committee argues that the consequences of introduction of folic acid fortified food products should be accompanied by post launch monitoring, so that it can be ascertained whether these products are indeed used by the target group and if there occur any unexpected adverse effects.