Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid

Folate is a water-soluble B-complex vitamin required for cell growth and division, and adequate folate intake is necessary to prevent a wide variety of health conditions. Some published studies have raised concerns about the safe use of folic acid, a synthetic form of folate, above 400 µg. In order to identify potential research needs for evaluating the safe use of folic acid at an intake level higher than the current RDA (referred to as "high intake" in this document), the National Toxicology Program (NTP) partnered with the NIH Office of Dietary Supplements (ODS) to convene an expert panel to evaluate the current state of the science.

As background material for the expert panel, published literature relevant for evaluating the potential for health effects associated with high doses of folic acid was collected and summarized. Due to the large number of published studies on folate and folic acid, screening of the literature using systematic review methodology was undertaken to transparently identify, select, and group the studies by potential health effects areas.

A steering committee of individuals knowledgeable about the folic acid health literature was formed to suggest areas where data indicate potential adverse health effects associated with high intakes or blood levels of folic acid. Four general health effect categories were identified (cancer, cognition in conjunction with vitamin B12 deficiency, hypersensitivity-related outcomes, and thyroid and diabetes related disorders). This document includes an explanation of the methods used to identify and collect the relevant literature. The human study data for these health effects were summarized and are available online and in the Supplementary Material as a resource for the expert panel. Supporting literature from relevant animal and in vitro studies are listed in Supplementary Material. This document also presents the reasoning of the steering committee as to why other health effects identified in the literature were not considered high priority areas of focus for this review.

On May 11-12, 2015, the National Toxicology Program (NTP) and Office of Dietary Supplements (ODS) convened an expert panel to identify research needs related to the safe use of high intakes of folic acid based on consideration of the state of the science. The expert panel was charged to (1) identify the areas of consistency and areas of uncertainty in the available science, (2) identify research needs based on review of the available science, and (3) propose research approaches for addressing the research needs and gaps in the available science. The Panel's recommendations did not require consensus, included minority opinions, and do not necessarily represent the opinion of NTP or ODS. This NTP Monograph includes the expert panel report as Chapter 6.0.