Step 1: “Hazard Identification” or Indicator Review and Selection

Health Outcomes and Related Conditions

1. Clarify threshold effects of calcium and vitamin D on skeletal health outcomes by life stage and for different racial/ethnic groups.

2. Elucidate inter-relationship between calcium and vitamin D, and specify independent effect(s) of each.

3. Explore causal role for vitamin D in non-skeletal health.

4. Determine the appropriateness of serum 25-hydroxyvitamin D (25OHD) as a biomarker of effect.

5. Elucidate the effect of genetic variation, including that among racial/ethnic groups, and epigenetic regulation of vitamin D on developmental outcomes.

Adverse Effects, Toxicity, and Safety

1. Develop innovative methodologies to provide for identification and assessment of adverse effects of excess calcium and vitamin D.

2. Elucidate adverse effects of long-term, high-dose calcium and vitamin D.

3. Further explore nature of vitamin D toxicity.

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).

2. Clarify 25OHD distribution in body pools including storage and mobilization from adipose tissue.

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

4. Clarify the extent to which differences exist between vitamin D₂ and vitamin D₃.

Synthesizing Evidence and Research Methodology

1. Explore enhanced methodologies for data synthesis.

2. Identify approaches to weight better potential health outcomes.

Step 2: “Hazard Characterization” or Intake-Response Assessment and Specification of DRIs