July 13, 2007 Since the institution of nationwide folic acid fortification of enriched grains in the mid 1990s, the number of infants born in the United States and Canada with neural tube defects has declined by 20 percent to 50 percent. Concurrent with the institution of fortification, however, the rate at which new cases of colorectal cancer were diagnosed in men and women increased, report researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University.
Joel Mason, MD, director of the USDA HNRCA's Vitamins and Carcinogenesis Laboratory, and colleagues analyze the temporal association between folic acid fortification and the rise in colorectal cancer rates, and present their resulting hypothesis in an article in the July issue of Cancer Epidemiology Biomarkers & Prevention.
"Nationwide fortification of enriched grains is generally considered one of the greatest advances in public health policy," says Mason, who is also an associate professor at the Friedman School of Nutrition Science and Policy at Tufts. "But since the time that the food supply in North America was fortified with folic acid, we have been experiencing four to six additional cases of colorectal cancer for every 100,000 individuals each year compared to the trends that existed before fortification.
"Our analysis suggests that this increase is not explained by chance or by increased cancer screening. Therefore, it is important to analyze risks and benefits of fortification, and encourage scientific debate in countries that are considering instituting or enhancing folic acid fortification."
Mason and colleagues analyzed data from national cancer registries, one in the United States and another in Canada. The US data were derived from the nationwide Surveillance Epidemiology and End Results (SEER) registry that publishes cancer occurrence rates and survival data, covering approximately 26 percent of the population. The Canadian data were obtained from Canadian Cancer Statistics, an annual publication by the Canadian Cancer Society and the National Cancer Institute of Canada.
In 1996 and 1998, there were abrupt reversals in the 15-year downward trends in colorectal cancer rates in the United States and Canada, respectively. Since peaking in 1998 in the United States and in 2000 in Canada, the rates have not returned to their earlier levels. Although folic acid fortification of enriched grains -- including bread, cereal, flour, rice, and pasta -- did not become mandatory until 1998, large food companies began voluntary fortification in 1996, first in the United States and later in Canada.
Folic acid is the synthetic form of folate, a B vitamin that is essential for cell growth. After intestinal absorption, folic acid is converted to methyltetrahydrofolate, found naturally in foods such as leafy green vegetables, legumes and citrus fruits. "The body's response to folic acid appears to be complex," says Mason. "While fortification of the food supply is clearly beneficial for women of child-bearing age and their offspring, it is possible that it may, coincidentally, be linked to the increase in colorectal cancer rates. Our report is intended to create a foundation upon which to further explore that possibility."
As Mason and colleagues note, there is a compelling body of scientific evidence suggesting that habitually high intakes of dietary folate are protective against colorectal cancer. Mason explains, however, that "There are several reasons why we may have inadvertently created the opposite effect with folic acid fortification. First, folate's pivotal role in DNA synthesis also makes it a potential growth factor for cancerous or pre-cancerous cells, and when administered in large quantities to individuals who unknowingly harbor cancer cells, it could paradoxically enhance cancer development.
The addition of substantial quantities of folic acid into the foodstream may have facilitated the transformation of benign growths into cancers, or small cancers into larger ones," he says. "Second, the fact that a synthetic form of folate is used for fortification may be important," suggests Mason. "As the total amount of folic acid ingested increases, the mechanism that converts folic acid to methyltetrahydrofolate can become saturated. The leftover folic acid in the circulation might have detrimental effects, as it is not a natural form of the vitamin."
At a time when many countries are debating whether or not to institute or enhance folic acid fortification, Mason and colleagues urge caution and debate. "We must examine the effects of folic acid fortification on the population as a whole, which includes better defining the nature of the relationship between folic acid fortification and colorectal cancer," says Mason. "Improved monitoring and further research in this field is important to our understanding of the long-term public health effects of fortification."
Reference: Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. Cancer Epidemiology Biomarkers & Prevention. 2007 (July); 16(7):1-5. "A Temporal Association between Folic Acid Fortification and a Rise in Colorectal Cancer Rates May be Illuminating Important Biological Principles: a Hypothesis."
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