Folic Acid – What Dose is Safe?
The question over fortification and supplementation with the synthetic form – monoglutamate folic acid in isolation has been brought up in context international interest in food fortification and some confusion regarding supplement recommendations.
Folic acid supplementation, the synthetic form of folate has been thrown a curve ball in the last few years because of its apparent association with an increase in colorectal cancer. In particular three papers have been flagged up; the first is by Cole and his colleagues and the second by Mason and the third by Hirsch.
The first paper describes the results of a randomised trial of folic acid in the prevention of colonic adenoma (a type of benign colon tumour that can become malignant), where the subjects had previously had adenomas removed. In this paper the results have been incorrectly interpreted. The study does not show that folic acid supplementation poses a cancer hazard, it relates to adenomas not carcinomas – the malignant form. The actual incidence of adenomas in those who were supplemented vs. those who were not are virtually identical in the following two 3-4 year follow ups. The relative risks were 1.04 (p=0.58) and 1.13 (p=0.23).
The 1mg a day of folic acid neither increased nor decreased the risk of additional colorectal adenoma. The only small area of potential risk is in the subset of patients that had three or more, and due to the small numbers involved (13 placebo and 30 supplemented) there is a significant chance of incorrect results, especially when there was no risk increase in those who had 2 removed. Another study using similar strategies by Logan showed no increase in adenoma risk.
Masons paper suggests a temporal association (Two or more events that occur around the same time but are unrelated, chance occurrences) between folic acid fortification and an increase in colon cancer in the USA and Canada.
The data does not support this interpretation: Colorectal cancer declined in the USA and Canada until 1995 and 1996 respectively. Yet mandatory folic acid fortification was in place Jan1 1998 in the States and about 12 months later for Canada, so colorectal cancer rates had started to rise before fortification. Interestingly screening in these countries as elsewhere tends to increase the reported incidences, but the morbidity from cancer of the colon did not rise.
The third paper shows highest rate ratio between the two periods for colon cancer in the group aged 45-64 years (162% risk increase) and in the 65-79 years (190% risk increase). However, there could be a host of other explanation for the increase in colon cancer risk between these two periods, including obesity and dietary changes both factors associated with increased risk of colon cancer.
There are over 30 papers showing that folic acid may reduce the incidence of cancer one recent paper following over 5000 people for 8 years in Uruguay with folate supplementation concluded: Our results not only confirm earlier findings of decreased risk of colorectal and oesophageal cancers with a high dietary folate intake but also suggest decreased risk of several other cancers.
There is also evidence daily use of folic acid-containing multivitamins for greater than 5 years can decrease the risk of colon cancer by almost 50% in women with a family history of colon cancer.
A 2009 review published in the British Journal of Cancer by Hubner and Houlston from the Royal Marsden Hospital in London looked at the evidence concerning the efficacy and safety of folate as a potential chemopreventive agent for colorectal cancer. The authors explain that there are likely to be two opposing roles of folate in colorectal cancer. Higher doses of folate, particularly the food forms, are thought to provide a consistent reduction in risk, especially where precancerous lesions in the gut have yet to be present. However, particularly if neoplastic lesions in the gut have already formed, high doses of folate, particularly the synthetic form, may increase the risk of cancer.
The author’s state supported by other evidence, that high doses of the synthetic form may overrun the conversion pathway to the circulating form (5-MTHF), causing un-metabolised folic acid to run into the bloodstream. This oxidised form may then be responsible for increased risk of colorectal cancer among those with precancerous lesions.
Indicating that there remains some controversy in the decision to strike folic acid out of the supplementation loop based on increased risk or precautionary principles.
Folic acid is safe when used in doses less than 1000 mcg per day.
Concerns over its safety as an isolated nutrient become apparent when levels of 800mcg-1200mcg are consumed for 3-10 years. This may be accidentally achieved, where fortified foods along with B complex’s and multivitamin and mineral supplements are consumed. There seems less convincing evidence that folate is a problem, suggesting that the metabolic conversion from folic to folate may produce intermediate conversions that influence pre cancerous cells, but this remains an area of controversy.
Synthetic folic acid, used in isolation is the Problem
Synthetic folic acid, in its oxidized, monoglutamate form, is the ‘pharmaceutical’ folate form used in the vast majority of multivitamin and multi vitamin/mineral products. It is currently recommended both for pregnant women, and for women planning pregnancy, specifically to prevent the birth defect, spina bifida. Most UK GPs recommend supplement levels of 400 micrograms for women of childbearing age, with higher levels for women at particular risk of giving birth to an infant with the condition.
Additionally, some people (up to 10% of the population) lack the enzyme required to convert folic acid to the circulating polyglutamate form (5-methyl tetrahydrofolate or 5-MTHF) and so will not benefit from folic acid supplementation. These people require either supplements containing 5-MTHF or sufficient natural folate from their food.
When folic acid supplements are used in isolation, vitamins B1, B2, and B3 may not be present in adequate amounts to enable metabolic recycling of the folate in the body. Excessive amounts of folic acid can prevent diagnosis of vitamin B12 deficiency (pernicious anaemia), by masking blood-related symptoms.
 Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group.Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9. View Abstract
 Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1325-9. View Abstract
 Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol. 2009 Apr;21(4):436-9. View Abstract
 Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR; ukCAP Trial Group. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology. 2008 Jan;134(1):29-38. Epub 2007 Oct 10 View Abstract
 Aune D, Deneo-Pellegrini H, Ronco AL, Boffetta P, Acosta G, Mendilaharsu M, De Stefani E. Dietary folate intake and the risk of 11 types of cancer: a case-control study in Uruguay. Ann Oncol. 2010 Jul 19.View Abstract
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