Folic-Acid Fortification of Flour and Increased Rates of Colon Cancer

Zosia Chustecka

April 24, 2009

April 15, 2009 — Data from Chile show that there has been an increase in the rate of colorectal cancer since 2000, when the government introduced a mandatory program of fortification of wheat flour. A similar increase was reported in the United States and Canada in the late 1990s, after the introduction of folic-acid fortification there.

The aim of folic-acid fortification is to reduce neural tube defects, a result of folate deficiency during pregnancy and, in this, the programs have been successful. In Chile, these complications were reduced by 40% in 1 year.

But could the downside be an increase in the risk for colorectal cancer?

The latest data, published online February 2 in the European Journal of Gastroenterology & Hepatology, suggest that it might be. Sandra Hirsch, MD, MSc, and colleagues from the University of Chile, in Santiago, analyzed hospital-discharge data for two 4-year periods — before folic-acid fortification (1992–1996) and after (2001–2004) — and found a significant increase in reported cases of colon cancer. The increase was 162% in people 45 to 64 years and 190% in people 65 to 79 years.

Most other diseases showed no consistent patterns of change, they note. There was a small increase in breast cancer, smaller than that seen for colon cancer, but the authors note that this could probably be attributed to 2 programs for breast cancer introduced in 2000, one for early detection and the other guaranteeing universal access to treatment.

The researchers acknowledge that there could be other explanations for the finding, such as the rise in obesity (which increased from 19.7% in 1997 to 22% in 2003). However, Dr. Hirsch pointed out to Medscape Oncology that there were no changes in the hospital-discharge data for cardiovascular disease during that time.

"Our data provide new evidence that a folate-fortification program could be associated with an additional risk of colon cancer," Dr. Hirsch and colleagues conclude.

One problem with this study is that it uses indirect data for the incidence of colon cancer, say critics. There are no cancer registries in Chile, so the researchers used the diagnosis indicated on hospital-discharge forms as a proxy for disease incidence.

This is an important limitation of the study, said Reinhold Stockbrugger, MD, one of the editors of the European Journal of Gastroenterology & Hepatology. "Discharge rates are influenced by healthcare politics, increasing access to healthcare for new strata of the population with increased cancer risk, and so forth," he comments in a press release issued by the Journal.

"This study provides only a weak indirect indication of a causal relationship between folate enrichment and colorectal cancer," Dr. Reinhold said. However, he added that the finding is "similar to that reported in the United States and Canada."

Those data appeared nearly 2 years ago (Cancer Epidemiol Biomarkers Prev. 2007; 16:1325-1329), in a study by Joel Mason, MD, and colleagues from the Jean Mayor US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, in Boston, Massachusetts. That study used incidence data from nationwide cancer registries and showed significant increases in colorectal cancer rates in both the United States and Canada.

Folic-acid fortification began in the United States in 1996 and in Canada in 1997, and became mandatory in both countries in 1998, Dr. Mason and colleagues note. Concurrently, both countries experienced "abrupt reversals" of the downward trend in colorectal cancer incidence that they had enjoyed. In the United States, rates started to increase in 1996 and peaked in 1998; in Canada, rates began to rise in 1998 and peaked in 2000. Both rates have continued to exceed pre-1996/97 levels.

At the time, Dr. Mason and colleagues stressed that the observations did not prove a causal link, and they emphasized the "very compelling body of scientific evidence that has accrued over the past 15 years that indicates that supplemental folic acid protects against neural tube defects."

Walter Willet, MD, DrPH, an expert on diet, nutrition, and cancer from Harvard School of Public Health, in Boston, Massachusetts, told Medscape Oncology: "I am quite certain that we are not causing an epidemic of colorectal cancer with folic acid fortification of flour." He pointed out that mortality rates from this cancer are continuing to decline steadily, and that, at the time the increase in incidence was noted in the United States, there had been an increase in colonoscopy. In addition, Dr. Willet pointed out, folic acid reduces the incidence of neural tube defects, and there is evidence that it is protective against stroke.

Total Amount of Folic Acid Important?

Dr. Mason and colleagues also note that there is evidence that "habitually high intakes of dietary folate are protective against colorectal cancer." They suggest, however, that the pharmaceutical form of folate (i.e., folic acid, which is used in fortification of foods and in vitamin tablets) might act differently than dietary folate, and they note that there is literature to suggest that a high intake of folic acid can accelerate the growth of established neoplasma. Adding substantial quantities of folic acid to the food supply in the mid-1990s might have facilitated the transformation of colorectal adenomas (which are found in 35% to 50% of Americans) into larger cancers, they suggest.

In the United States, folic acid was added to flour at a concentration of 140 μg/100 g (compared with 150 μg/100 g in Canada and 220 μg/100 g in Chile). But Dr. Mason and colleagues note that many breakfast cereals are fortified and that many Americans take vitamin supplements that include folic acid at a dose of 400 μg per pill.

In an interview with Medscape Oncology, Dr. Mason said that the new data from Chile "contribute to this concern that the total amount of folic acid present in the food stream can potentially contribute to an increase in certain types of cancer." However, he also said that the Chilean data are "weak in some regard," in that they rely on a surrogate end point of hospital-discharge data rather than cancer-incidence data.

Another recent publication has added to the concern about folic acid and cancer, he noted. New data from the Aspirin/Folate Polyp Prevention Study, published last month (J Natl Cancer Inst. 2009;101:432-435), show a 3-fold increase in prostate cancer among men who took the folate supplement, compared with men who took placebo.

This is cancer in a different organ, and the folic acid was in a supplement rather than in fortified foodstuff, but this observation "contributes to the concern," Dr. Mason commented. "There is a real concern that there are certain types of cancers common in the older population that are in an indolent phase of slow development, but their development may be accelerated by too much folic acid," Dr. Mason said. One example is the colorectal adenoma, "which sits in the colon for a decade before it evolves into a cancer, as far as anyone can tell." A second example is dysplastic prostatic nodules, which are seen in most men when they reach 70 to 90 years of age; the majority of these do not become clinically significant, and these men die of other causes, he added.

"In both situations, these are indolent precancerous lesions, which, with a bit of tweaking, might be pushed over the edge to evolve into clinically significant cancer," Dr. Mason said.

Is folic acid one of the factors that could push an indolent lesion into cancer?

"We cannot prove causality," Dr. Mason said, "but this is highly biologically plausible." This is a "smoldering concern," but at the moment there are not enough data to lead to any changes in the current policy of folic-acid fortification in those countries that have already implemented it, Dr. Mason said. But the matter is being debated, particularly by countries around the world (and the European Union) that are considering whether or not to implement such a policy. Dr. Mason recently took part in a meeting of experts in Sweden to discuss these matters, and has written a comprehensive review of the issue (Nutr Rev. 2009,67;206-212).

It is not just a question of folic-acid fortification of food, however; there is also the issue of folic-acid supplementation, such as in multivitamin pills. Dr. Mason noted that recent data from the US Centers for Disease Control suggest that 70% to 80% of the general adult population has detectable levels of folic acid in the blood, but "under more natural conditions, folic acid would not even be present in the blood."

Dr. Mason said he is attracted to the proposal that has been suggested in the United Kingdom, namely that, if folic-acid fortification goes ahead, there should be a reduction in the folic-acid component of vitamin and other supplement products. The dose of folic acid would need to be cut quite dramatically, he suggested, from the current 400 μg in a daily tablet to around 50 to 100 μg.

The researchers have disclosed no relevant financial relationships.

Eur J Gastroenterol Hepatol. Published online before print February 2, 2009. Abstract


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