It was all about the babies. A decade ago, when the U.S. required flour, bread and pasta to be fortified with folic acid, health experts believed it would help prevent devastating birth defects such as spina bifida.
There's no question that it worked. As many as 1,000 newborns a year in the United States - and many more elsewhere - have been spared so-called neural tube defects because their mothers got a crucial infusion of folic acid before they even knew they were pregnant.
But now some scientists are asking whether there have been unforeseen trade-offs for the population as a whole - including thousands of additional colon cancer cases each year, a somewhat smaller bump-up in prostate cancer, and an increase in cognitive impairment among the elderly.
"The existing science at the time this decision was made showed the benefits and not any significant risk," said Dr. Joel Mason, director of the Vitamins and Carcinogenesis Laboratory at the U.S. Department of Agriculture's Human Nutrition Research Center at Tufts University. "What has evolved is, there's an increasing level of concern that it might be harming some segments of the population."
The renewed debate comes at a time when activists in the United States are pushing to increase the amount of folic acid in fortified foods, under the theory that if some is good, then more is better.
It also comes as the United Kingdom has put on hold its effort to require folic acid fortification. Scientists there are considering new research suggesting a possible downside to adding folic acid to the national diet.
Not everyone is convinced there even is a debate. The benefits of folic acid have been clearly proved, they say, and if anything, women of childbearing age need more folic acid than fortified foods provide. Proponents say that in addition to deterring birth defects, folic acid might prevent some cancers, strokes and cardiovascular disease.
And any potential downsides, they argue, are unproven.
Dr. Walter Willett, chairman of the department of nutrition at the Harvard School of Public Health, said time will show that there are more benefits to folic acid than previously known - and not that it causes cancer.
Though scientists don't fully understand how folic acid works, they believe that it assists in the formation of the building blocks of DNA, stimulating cell growth, preventing damage and helping DNA to replicate.
In normal tissue, it helps cells to divide and grow and proliferate. In cells where cancer is just beginning, folic acid is believed to have the same effect - causing fast-growing cancer cells to reproduce even more rapidly.
Chemically, folic acid is the synthetic form of folate, a member of the vitamin B family. Green leafy vegetables, dried beans and nuts are among the foods naturally rich in folate. But before flour-based products were fortified, dietary supplements were among the only ways that women of child-bearing age could ensure an intake of 400 micrograms a day - the dosage believed to prevent birth defects.
Not enough women did it on their own, which is why the U.S. turned to fortification. Today, some breakfast cereals alone contain 400 micrograms of folic acid per serving. Even so, the March of Dimes, a national advocacy group devoted to reducing birth defects, is considering petitioning the Food and Drug Administration to increase the amount of folic acid required in fortified foods.
The concept of fortification isn't new. One of the earliest successful efforts was the addition of iodine to salt in 1924 to prevent goiter and other symptoms of severe iodine deficiency.
Vitamin D was first added to milk in the 1930s to prevent rickets. When folic acid in flour and bread became mandatory in 1998, those staples had long been fortified with thiamin, niacin and riboflavin.
Dr. Frank Witter, a professor of gynecology and obstetrics at Johns Hopkins, said fortification isn't enough by itself. Some women still don't get the necessary folic acid. But he would not advocate an increase in fortification levels.
"We have to strike a balance," he said. "Even water, there's a downside for too much and a downside for too little. The fortification is probably at an adequate level. [But] you can't really count on any fortification process to completely correct a problem."
A study published last summer by Tufts' Mason and his colleagues suggested a possible link between folic acid fortification and U.S. and Canadian colorectal cancer rates, which are no longer declining as quickly as they once were.
Since the introduction of mandatory folic acid fortification in those two countries, an expected drop in colon cancer rates has shown an uptick, translating to as many as 15,000 extra cases of colon cancer in the U.S. annually and 1,500 in Canada - cases that researchers say might not have occurred without folic acid.
Mason said that while his study is not definitive, its conclusions are not theoretical, either. In the 1940s, when leukemia patients got large doses of folic acid, their cancer growth accelerated. This prompted Dr. Sidney Farber and others to try antifolates for the treatment of childhood leukemia - now considered the birth of chemotherapy.
If there's a 10 percent chance that his concerns about folic acid are valid, Mason said, "I don't think we can afford to take that 10 percent chance." He said he doesn't think the U.S. should stop fortification until more evidence is collected, but that the United Kingdom should wait.
Some folic acid researchers are starting to see the nutrient as a double-edged sword. When it's given to someone with no polyps or tumors, it might prevent their formation. But in patients with growths so small that they're undetectable, folic acid could speed up cancer development, said Dr. Cornelia Ulrich, a researcher at the Fred Hutchinson Cancer Research Center in Seattle.
By age 60, she said, about 30 percent of the population has polyps that could potentially grow faster with folic acid. "We've known for a while that cancer actually likes folate," she said. "There may be this dual effect."
Ulrich said she's not worried about current U.S. fortification levels because flour and pasta account for only a small percentage of the folic acid in many bodies.
She is more concerned about supplements taken by older adults and by cancer patients. Fortified health bars and drinks can provide even more folic acid, adding up to potentially problematic levels.
"There can be groups who easily can have 1 milligram of folic acid a day, usually health-conscious people who think they are doing themselves good," she said.
And while research is slim, she added, "there's reason to believe taking a folic acid supplement could do harm."
Dr. Young-In Kim, a nutrition expert at the University of Toronto who has studied folic acid in animals, said fortification places too many people at risk. He wants to see large-scale fortification suspended while officials target young women with messages about getting enough folic acid.
"We need to carefully consider whether we've done the right thing," he said. "This was the largest human experiment ever done, putting the entire population of the U.S. and Canada on high doses of folic acid."
Willett, the Harvard nutritionist, said it could take another decade or more for the impact of folic acid fortification to be known. But based on what is known, he is optimistic that the many upsides of folic acid will be affirmed.
"Given the overall picture, if there is any negative impact, it is counterbalanced by other positive trends," he said. "I think we've done something that overall is beneficial, and we won't know the full balance of benefits, or possible adverse effects, for many years. But overall the picture looks good."
Still, he added, "Any time you do anything that's beneficial, you take some chance of unintended harm. Almost anything you do in a complex system - and human systems are complex - perturbs something else. Biology is very complicated. There are often unintended consequences, good and bad."
Folic Acid Facts
What it is
A member of the vitamin B family, folic acid is the synthetic form of the nutrient folate.
Where it's found
Occurs naturally in green leafy vegetables, fruits and nuts. Found in fortified flours, breads and pasta. Highest concentrations are typically found in nutritional supplements.
Prevention of birth defects such as spina bifida; also might prevent some cancers, stroke and cardiovascular disease.
Might accelerate development of pre-cancerous growths, particularly in the colon, into cancer. Also might increase rate of cognitive impairment in older people.