To prevent Neural Tube Defects (NTDs) the Food and Drug Administration (FDA), USA implemented mandatory folic acid fortification of flour. This commenced in January 1998. The fortification level was set at 140 μg/100 g flour supplying ~100 μg daily to the average American. This amount was selected on the basis that it would not result in intakes in excess of 1 mg (upper safe daily limit) by any population group. Doubt has been cast on the actual level of fortification however and recent calculations have shown that the level of folic acid fortification is likely to have been over twice the amount mandated [1
] with average intakes ranging from 215 to 240 μg/day.
The Centers for Disease Control (CDC) supported the fortification strategy but because this level fell short of the target to supply 400 μg to all women of childbearing age, they considered increasing the level to 350 μg and even 700 μg/100 g, which would supply approximately 2.5 and 5 times more folic acid respectively [2
] The primary concern with these higher levels of fortification is that certain segments of the population will be exposed to amounts of folic acid greater than 1000 μg/day and that this may have adverse effects.
After much deliberation by the relevant authorities in the UK folic acid will be added to bread in the UK within a year. In addition the Republic of Ireland have opted for mandatory fortification, which will be fully implemented in the next year.
Research to date suggests that the enzymatic reduction and methylation of folic acid during its absorption in the intestine or its first pass through the liver is dose-dependent. Hence oral folic acid above certain threshold doses saturates the normal intestinal absorptive mechanisms and results in unmetabolised folic acid in serum as well as the normal metabolite 5-methyltetrahydrofolate. This has been demonstrated at oral doses in the region of 200 μg [3
] and 266 μg [4
]. In a more recent paper it was shown that repeated consumption of physiological amounts of folic acid lead to the accumulation of unmetabolised folic acid in serum [5
]. It has also been demonstrated that passive consumption of folic acid in foodstuffs by pregnant women leads to the appearance of unmetabolised folic acid in foetal cord blood [6
]. While these studies examined the acute serum response to folic acid, none have investigated the effect after a prolonged period of exposure to the vitamin.
Folic acid has the potential to mask the early haematological manifestations of pernicious anaemia. This has been demonstrated experimentally [7
] and clinically [11
]. Other safety considerations of excess folic acid consumption highlighted by the FDA [16
] include potential unknown risks for pregnant women, and persons on anti-epileptic and anti-folate medication. The FDA also noted the uncertainties regarding the effects of chronic exposure in children, whose requirements for folate are lower than those of adults. Furthermore evidenced based [17
] and hypothetical concerns include the potential to promote cancer [19
] and the recent hypothesis that exposure of the foetus to excess folic acid may favour the selection of the Methylentetrahydrofolate polymorphism, associated with a range of debilitating illnesses [21
To date no studies have examined the effect of long-term consumption of folic acid on unmetabolised folic acid in serum. The accumulation of folic acid after consumption of fortified bread repeatedly over only one 8-hour period [5
] provides justification for this. In this paper we examined unmetabolised folic acid appearance after consumption of folic acid for a prolonged period. The three levels selected to be tested were in the region of that already implemented in the mandatory US fortification programme and the two higher levels considered by the CDC.