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The UK's Food Standards Agency recently recommended mandatory folic acid fortification of some foods. Nicholas Wald and Godfrey Oakley argue that it's a safe effective way of preventing spina bifida and anencephaly—but Richard Hubner and colleagues say that more research into the harms is needed
Mandatory fortification with folic acid aims to increase intake of folate in women during early pregnancy and to reduce neural tube defects in their babies. The case for mandatory fortification is strengthened by the purported association of increased intake of folate with reduced incidence of cancer, thus benefiting the whole population. But new data suggest that folate supplements may paradoxically have cancer promoting effects, enhancing the development and progression of undiagnosed premalignant and malignant lesions.
Folate metabolism is complex and influences several crucial pathways, including DNA synthesis and methylation, aberrations of which play a major role in carcinogenesis. Altered folate metabolism may disrupt these processes, providing mechanisms through which both folate deficiency and supplementation could influence cancer risk. This relation may be further complicated by using synthetic folic acid in supplements and fortification: its effects on folate metabolism are not identical to those of natural folates.1
Epidemiological studies have found that high folate intake is associated with a reduced risk of cancers of the breast, lung, pancreas, oesophagus, stomach, cervix, and in particular of the colorectum.2 But recent studies have challenged this widely accepted notion, and doubts over the validity of the epidemiological evidence have emerged. For example, a large Swedish cohort study found an increased risk of colorectal cancer in people with high plasma concentrations of folate,3 and a meta-analysis of cohort studies investigating folate intake and breast cancer risk reported no effect.4 The inverse relation in some studies of colorectal cancer and folate intake may have been confounded by dietary and lifestyle factors, in particular fibre intake, and in some instances adjustment for such confounders abolished the apparent association between folate intake and colorectal cancer risk.5 In addition, the validity of food frequency questionnaires (used in many studies to assess folate intake) has been questioned.6
Some studies have indicated that folate from foods may have a different effect than folic acid from supplements. A cohort study of 25000 postmenopausal women reported that although folate from food was not associated with risk of breast cancer, high total folate intake, mainly from folic acid supplementation, significantly increased risk by 32%.7 Similarly a meta-analysis of cohort studies investigating folate intake and colorectal cancer risk reported a significant reduction in risk in people with high intake of folate from food—but the association was close to null when folate was obtained from both diet and folic acid supplements.8
A neoplastic clone of cells has enhanced growth compared to the surrounding normal tissue. This attribute is exploited by chemotherapeutic drugs, including anti-folate drugs such as methotrexate and 5-fluorouracil, which inhibit folate metabolism enzymes, interrupting DNA synthesis and inhibiting growth of tumours. Conversely, extra folate could promote tumour growth by allowing increased DNA synthesis.
Evidence that timing of folic acid supplementation may be crucial in determining its effects on colorectal carcinogenesis comes from two genetic mouse models of colorectal cancer.9 10 In both models, if intervention was started before lesions developed, moderate folate deficiency enhanced the development of cancer and folic acid supplementation suppressed it—but once a preneoplastic lesion was present, supplementation promoted tumour growth. These studies have led to the hypothesis that in normal epithelial cells folate deficiency promotes neoplastic transformation, which can be avoided by folic acid supplementation, whereas supplementation promotes the growth of existing preneoplastic and neoplastic tissue. Although animal models of colorectal cancer have important differences from the human disease that warrant caution in extrapolation from these observations, recent randomised intervention trials in humans have lent support to this hypothesis.11 12 13
The aspirin-folate polyp prevention study recruited 1021 people who had colorectal adenoma removed at colonoscopy, randomised to intervention with folic acid (1 mg/day) or placebo, and it assessed polyp recurrence by colonoscopy at three and six years.11 The mean number of recurrent colorectal adenomas per subject was increased by folic acid supplementation (rate ratio 1.44; 95% confidence interval 1.03 to 2.02), as was the incidence of advanced colorectal adenoma with high malignant potential (1.31; 0.90 to1.89). A plausible explanation for these results is that folic acid supplementation promoted the growth of pre-existing aberrant crypt foci or small adenomas that had been missed at initial colonoscopy. If this effect of folic acid is genuine it is of major public health concern since more than 25% of people aged over 50 harbour asymptomatic colorectal adenomas.14
Folic acid supplements combined with other B vitamins result in lowered plasma homocysteine concentrations, and several large scale randomised intervention studies have investigated the use of such supplements in preventing cardiovascular disease. A meta-analysis of these studies showed that lowered plasma homocysteine may not prevent ischaemic heart disease (pooled rate ratio 0.96; 0.81 to 1.13).15 The two largest trials provided data on cancer incidence: patients randomised to folic acid supplements were 22% more likely to develop cancer in the Norwegian vitamin trial,12 and 36% and 21% more likely to develop colorectal cancer and prostate cancer in the heart outcomes prevention evaluation 2 trial.13 Although these increases were not statistically significant, cancer incidence was a secondary end point for which both trials were severely underpowered.
The level of exposure to folic acid resulting from fortification may be crucial, and the low level exposure associated with fortification could be insufficient to result in any cancer promoting effects. Levels of intake after fortification are hard to predict, however, and the increased folate intake in the US population since fortification has been twice what was originally anticipated.16
Reducing neural tube defects is clearly a worthy aim, but further investigation of the potential cancer promoting effects of varying levels of exposure to folic acid in susceptible people is desirable before mandatory fortification starts.
Funding: RAH has a clinical research training fellowship from Cancer Research UK.
Competing interests: None declared.