Preparatory work for the update of the tolerable upper intake levels for folic acid/folate
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Abstract
The aim was to collect and appraise scientific evidence that could be used to derive an upper intake level for folic acid/folate. Five systematic reviews of the literature were conducted to identify evidence to i) characterize the dose‐response curve between plasma/serum (P/S) folate and dietary folate intake expressed as dietary folate equivalents (DFE) in adults, and to assess the relationship between ‘high’ folate (intake/biomarkers) in humans with low B12 status and the ii) development of neuropathy and iii) cognitive impairment or dementia, and risk of iv) colorectal adenomas and colorectal cancer (CRC) and v) and prostate cancer. Narrative reviews were also performed. The linear meta‐regression model P/S folate (nmol/L) = 6.0 + 0.034*DFE/d (95% confidence interval, CI; 0.027‐0.040), R2 = 0.68, based on 22 studies and 60 data points could be used to predict mean P/S folate (and 95% CI) based on DFE intake. In view of the paucity of data, no comprehensive uncertainty analysis and evidence integration were performed for effects of ‘high’ folate intake on neuropathy, cognitive function/dementia. Comprehensive uncertainty analyses and evidence integration for a detrimental effect at high folate intake/status were performed for folic acid interventions and development of colorectal adenomas, for P/S folate from observational studies in relation to CRC incidence, and for total folate intake from observational studies in relation to prostate cancer incidence. The folic acid interventions were few (n = 4) and revealed both beneficial and detrimental effects on adenoma recurrence. For CRC the meta‐analyses on P/S folate indicated no association, but the risk estimates in the highest folate exposure groups were compared to levels indicating folate inadequacy or deficiency, thus, the research question could not be adequately addressed. For prostate cancer incidence too few studies with mixed results prevented any clear conclusion on total folate intake and risk of prostate cancer.