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often limited due to ethical concerns. Creative approaches using an array of methodologies developed in other fields need to be adapted for nutritional use and incorporated into the approach for studying adverse effects of nutrients in vitro and in vivo using relevant animal models.

  1. Elucidate adverse effects of long-term, high-dose calcium and vitamin D. The question of nutrient safety should not be a secondary aspect of study design nor can the failure to detect adverse effects as part of a study not designed for that purpose be considered an adequate assessment of safety. Dedicated studies are needed to assess adverse health effects related to long-term, high dose (although not necessarily “toxic”) levels of calcium and vitamin D.

  2. Further explore the nature of vitamin D toxicity. Although toxicity is not the most appropriate goal for setting ULs, a better understanding of the timing, doses, and mechanisms associated with vitamin D toxicity (hypervitaminosis D) would be beneficial to understanding the impact of vitamin D on the human body. Of particular import is information about the metabolic fate and dynamics of high doses of vitamin D. The identification and use of animal models (particularly large animal models) would be especially helpful. Also needed is an understanding of how weight loss in obese individuals might affect vitamin D status and adverse outcomes (e.g., bariatric surgery patients).

Research Needs Related to Basic Physiology and Molecular Pathways

  1. Examine the influence of calcium and phosphate on the regulation of vitamin D activation and catabolism through parathyroid hormone and fibroblast-like growth factor 23 (FGF23). Identify pathways that regulate vitamin D activation and catabolism through parathyroid hormone and FGF23 in order to understand the influence of calcium and phosphate intake on vitamin D regulation.

  2. Clarify 25OHD distribution in body pools including storage and mobilization from adipose tissue. Understanding the distribution, storage, and mobilization of 25OHD in body pools would enhance the understanding regarding relationships among exposure to vitamin D from intake or endogenous synthesis, circulation serum levels of 25OHD, and health outcomes. The role of storage compartments and factors important to the mobilization of vitamin D is noticeably lacking.

  3. Evaluate the nature and significance of extra-renal production of calcitriol for health outcomes. Determining the significance of extra-renal production of calcitriol for health outcomes is essential

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