Folic acid and colorectal cancer: Chilean study adds to concerns

By Stephen Daniells

- Last updated on GMT

Related tags: Folic acid

Rates of colorectal cancer may have increased in Chile since introduction of mandatory folic acid fortification, says a new study.

According to findings published in The European Journal of Gastroenterology & Hepatology​ the South American country is the third to report an apparent increase in colorectal cancer since the introduction of mandatory fortification.

“Our data provide new evidence that a folic acid fortification program with 220 micrograms of synthetic folic acid per 100 g of wheat flour could be associated with an additional risk of colon cancer,”​ wrote the researchers, led by Dr. Sandra Hirsch and colleagues of University of Chile, Santiago.

“Thus, we need to evaluate this finding to determine the amount of folic acid necessary to prevent neural tube defects and to minimize possible new adverse effects.”

According to the Chilean data, a "temporal relationship"​ between folic acid supplementation and colorectal cancer was observed, said Hirsch and her co-workers, with cancer risk increased by 162 per cent in people aged 45 to 64 and by 190 per cent in people aged 65 to 79.

Other possible explanations for the rise in colon cancer in Chile may include rising obesity and other risk factors.

Commenting independently on the study, Dr Reinhold Stockbrugger, one of the journal’s editors said: "This study provides only a weak, indirect indication of a causal relationship between folate enrichment and colorectal cancer, though similar to that reported in the U.S. and Canada."

Contradictory results

Over 30 case-control and prospective cohort studies have reported that increased intakes of folate may reduce​ the risk of colorectal cancer by 40 to 60 per cent. Similar risk reductions have also been reported for the lesion that precedes the cancer, the adenomatous polyp.

The Chilean study coincides with a review paper published in the April issue of Nutrition Reviews​. Joel Mason from USDA Human Nutrition Research Center on Aging at Tufts University addressed the Janus effect of folate on colorectal health.

“Under most circumstances, adequate intake of folate appears to assume the role of a protective agent against cancer, most notably colorectal cancer,”​ wrote Dr Mason. “However, in select circumstances in which an individual who harbours a pre-cancerous or cancerous tumour consumes too much folic acid, the additional amounts of folate may instead facilitate the promotion of cancer.”

The complex links between folate and cancer have created a “global dilemma”​, said Dr Mason, with regards to instituting folic acid fortification programs in other countries.

Unquestionable benefits

Folate is found in foods such as green leafy vegetables, chick peas and lentils, and an overwhelming body of evidence links has linked folate deficiency in early pregnancy to increased risk of neural tube defects (NTD) - most commonly spina bifida and anencephaly - in infants.

This connection led to the 1998 introduction of public health measures in the US and Canada, where all grain products are fortified with folic acid - the synthetic, bioavailable form of folate.

Preliminary evidence indicates that the measure is having an effect with a reported 15 to 50 per cent reduction in NTD incidence. In Chile, the measure has been associated with a 40 per cent reduction in NTDs. Parallel measures in European countries, including the UK and Ireland, are still on the table.

Last month a Food Safety Authority of Ireland (FSAI) working group stated there would be no public health benefit from mandatory folic acid fortification, but a final determination would be made at the end of the year when more data would be available.

Folic acid versus folate

“The fact that folic acid, which is not a naturally occurring form of the vitamin, is used by food and pharmaceutical industries for fortification and supplementation is potentially of importance,”​ wrote Mason.

On passage through the intestinal wall, folic acid is converted to 5-methyltetrahydrofolate, the naturally circulating form of folate. However, some studies have suggested that oral doses of folic acid in high doses may overwhelm this conversion pathway, leading to measurable levels of folic acid in the blood.

“There has been some concern that this oxidized, non-substituted form of folate might feasibly be detrimental because it is not a naturally occurring co-enzymatic form of the vitamin,”​ said Mason.

"When this folic acid intake is added to that which appears in voluntarily fortified foods such as ready-to-eat breakfast cereals plus the additional quantity that is now consumed in the form of mandatory cereal grain fortification, it should come as no surprise that a large percentage of the population has detectable quantities of un-metabolized folic acid circulating chronically in the bloodstream."

Maximising the benefits, minimising the risks

In an editorial in the October 2006 issue of Gut​ (Vol. 55, pp.1461-1466) Dr Y-I Kim of the University of Toronto called mandatory folic acid fortification "probably the most important science drive intervention in nutrition and public health in decades"​.

But given that certain segments of the population may benefit less and may even experience adverse effects, he said that wavering over fortification "should not be construed as public health malpractice but should be regarded as public health prudence"​.

"The design of cogent public health policies that effectively optimise health for many while presenting no or minimal risk to others, must often occur in the absence of complete information," ​added Dr Mason. "However, we are nevertheless obliged to deliberate with as much of an in-depth understanding as the existing science allows."

Sources: The European Journal of Gastroenterology & Hepatology​ doi: 10.1097/MEG.0b013e328306ccdb "Colon cancer in Chile before and after the start of the flour fortification program with folic acid" Authors: S. Hirsch, H. Sanchez, C. Albala, M.P. de la Maza, G. Barrera, L. Leiva, D. Bunout

Nutrition Reviews​ April 2009, Volume 67, Issue 4, Pages 206-212"Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons"​Author: J.B. Mason

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