A Temporal Association between Folic Acid Fortification and a Rise in Colorectal Cancer Rates May be Illuminating Important Biological Principles: a Hypothesis

Authors: Mason, Joel; DICKSTEIN, AARON - TUSM MEDICAL SCHOOL; Jacques, Paul; HAGGARTY, PAUL - ROWETT INST ABERDEEN UNIV; Selhub, Jacob; Dallal, Gerald; Rosenberg, Irwin

Submitted to: Cancer Epidemiology Biomarkers and Prevention
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/30/2007
Publication Date: 8/1/2007
Citation: Mason, J.B., Dickstein, A., Jacques, P., Haggarty, P., Selhub, J., Dallal, G., Rosenberg, I. 2007. A temporal association between folic acid fortification and a rise in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiology Biomarkers and Prevention. 16:1.

Interpretive Summary: Nationwide fortification of uncooked cereal grains with folic acid began in the U.S. and in Canada in the mid-1990s. This was done to reduce the occurrence of some types of birth defects, and it was quite effective in this regard. However, the institution of fortification was also associated with a significant increase in the rate of colorectal cancer in each country. We have done analyses on nationwide databases for each country to demonstrate the latter effect on colorectal cancer rates and we also provide data to suggest that the increase is not ascribable to increases in cancer screening. Since prior studies in humans and animals indicate that excess doses of folic acid can increase the appearance of cancers among those individuals who already harbor cancerous or precancerous cells, we hypothesize that the institution of folic acid fortification in North America in the mid-1990s may be partly, or wholly, responsible for this rise in colorectal cancer rates.

Technical Abstract: Nationwide fortification of enriched uncooked cereal grains with folic acid began in the U.S. and Canada in 1996 and 1997, respectively, and became mandatory in 1998. The rationale was to reduce the number of births complicated by neural tube defects. Concurrently, the U.S. and Canada experienced abrupt reversals of the downward trend in colorectal cancer (CRC) incidence that the two countries had enjoyed in the preceding decade: absolute rates of CRC began to rise in 1996 (U.S.) and 1998 (Canada), peaked in 1998 (U.S.) and 2000 (Canada) and have continued to exceed the pre-1996/97 trends by 4-6 additional cases/100,000 individuals. In each country the rise in CRC incidence from the pre-fortification trend falls significantly outside of the downward linear fit based on non-parametric 95% confidence intervals. The statistically significant rise in rates is also evident when the data for each country are analyzed separately for men and women. Changes in the rate of colorectal endoscopic procedures do not appear to account for this rise in CRC incidence. These observations alone do not prove causality but are consistent with folate’s known effects on existing neoplasms, as demonstrated in both pre-clinical and clinical studies. We therefore hypothesize that the institution of folic acid fortification may have been wholly or partly responsible for the observed rise in CRC rates in the mid-1990s. Further work is needed to definitely establish the nature of this relationship. In the meantime, deliberations regarding the institution or enhancement of fortification programs should be undertaken with these considerations in mind. This communication highlights a temporal association between folic acid fortification of enriched cereal grains in the U.S. A. and Canada and an increase in the incidence of colorectal cancer (CRC) in these two countries. The possibility that folic acid fortification was causally responsible for this rise in CRC incidence is consistent with the known biological functions of folate and with several pre-clinical and clinical observations that are briefly reviewed in this paper. However, the observations and integration of knowledge presented here merely create a hypothetical foundation upon which further research will be required to determine whether true causality exists.