Evidence for a recommended dietary allowance for vitamin C from pharmacokinetics: A comment and analysis

The current recommended dietary allowance (RDA) for vitamin C, as proposed by the Food and Nutrition Board/National Research Council in 1980 and reconfirmed in 1989, is 60 mg daily for nonsmoking adult males. Levine et al. [Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., et al. (1996) Proc. Natl. Acad. Sci. USA 93, 3704–3709], based on a study of vitamin C pharmacokinetics in seven healthy men, have now proposed that the RDA should be increased to 200 mg daily. I have examined, in brief, the experimental and conceptual bases for this new recommendation and its implications for public health and nutrition policy and programs. Using, for illustrative purposes only, data extracted from each of two recent dietary surveys of noninstitutionalized adult males living in households in the Netherlands and the United States, it is predicted that the prevalence of intakes inadequate to meet the individual’s own requirement would be about 96% or 84%, respectively, if the criteria of adequacy used for derivation of the 200 mg RDA are accepted. Depending upon the particular average requirement value for ascorbic acid that might be derived from their data, the proposal by Levine et al. would mean a desirable increase in mean intakes in these two populations by as much about 2- to 3-fold. Hence, before an action of this kind is to be recommended, an answer must be sought to the question whether current experimental data including the criteria selected (saturation kinetics) are adequate to establish a new set of requirements for vitamin C, which then carry such profound policy implications. This will require critical assessment of all of the available evidence emerging from laboratory, clinical, and epidemiological studies to determine whether it provides a sufficient rationale for accepting criteria of vitamin C adequacy such as those proposed by Levine et al. and the requirement estimates so derived.

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.

Determinants of the recommended dietary allowance (RDA) for vitamin C include the relationship between vitamin C dose and steady-state plasma concentration, bioavailability, urinary excretion, cell concentration, and potential adverse effects. Because current data are inadequate, an in-hospital depletion-repletion study was conducted. Seven healthy volunteers were hospitalized for 4-6 months and consumed a diet containing <5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at seven daily doses of vitamin C from 30 to 2500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the current RDA of 60 mg daily was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1000 mg daily. Neutrophils, monocytes, and lymphocytes saturated at 100 mg daily and contained concentrations at least 14-fold higher than plasma. Bioavailability was complete for 200 mg of vitamin C as a single dose. No vitamin C was excreted in urine of six of seven volunteers until the 100-mg dose. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1000 mg of vitamin C daily compared to lower doses. Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value.

Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia

Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR). The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism. Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise. Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR II, these mice develop progressive alopecia from the age of 4 weeks.