1. DSHEA and Bioavailability Elizabeth A. Yetley, Ph.D. Ctr. Food Safety & Applied Nutrition Food and Drug Administration

2. Approach: Regulatory Applications –How has concept been applied? –General characteristics Specific questions for dietary supplements Science and research needs

3. Regulatory Applications

4. Regulatory Experience Drugs -- separate regulations Foods -- case-by-case –Safety –Labeling

5. Food Safety -- Bioavailability Safety –Food additive authorizations –GRAS status –GMPs –Infant formula quality factors

6. Safety Example: Food Additive Olestra Must add fat soluble vitamins Label information required

7. Safety Example -- GRAS GRAS -- Nutrients: Amounts not in excess of that required to produce intended effect Levels not to exceed GMPs

8. Safety Example -- Finished Products Calcium and iron supplements –Less effective than expected High doses of selenium -- low toxicity Contaminants –Mercury –Lead in calcium supplements

9. Safety Example-- Infant Formula Infant formula “Quality Factors” Statutory requirement Failure to meet --> adulteration Proposed definition:

10. Food Labeling -- Bioavailability Label information –Nutrition or Supplement Facts declarations –Claims –“Enriched” products

11. Label declarations -- History Based on analytical amounts Nutrients: –Derived from 1968 RDAs –1968 RDA’s -- some “correction” for bioavailability –FDA’s compliance method for some nutrients - - microbiological assay

12. Label declarations -- History Calorie content –May use specific Atwater factors –May use specific food factors –Correct for insoluble dietary fiber –Correct for protein indigestibility

13. Label Declarations -- History Non-nutrients: –No correction for bioavailability

14. Claims -- History Truthful and not misleading Meets regulations “More” claims: >= 10% RDI

15. Health claims -- History Calcium and osteoporosis Folic acid and neural tube defects Meet USP standards: dissolution & disintegration Calcium: “assimilable”

16. “Enriched” products -- History Nutrient -- physiologically available Level --> not result in excessive intake Nutrient -- suitable for intended purpose

17. “Enriched” products -- History Iron and Calcium “Safe and suitable”, or “Harmless and assimilable” Research –Predictive validity of animal bioassays –Identification relative bioavailability of ingredient sources

18. General principles -- History Affects both safety and effectiveness Case-by-case Physiological effects, not just absorption Linked to intended use Amounts not to exceed intended effects Not to deceive consumer

19. Current Marketed D.S. Products

20. Ingredients Vitamins and minerals Macronutrients Botanicals Amino Acids Substances intended to supplement the diet

21. Potential Bioavailability Issues Source ingredient Extraction and processing procedures Interactions -- “active” constituents Effects of “inert” ingredients/coatings… Interactions –with diet –with drugs

22. Next Steps -- Science & Research

23. Issues to be addressed Definition: What is it? Compliance (analytical) methods? Specific regulatory impacts –Safety requirements? –Label information? –GMPs?

24. Definition: Why Discuss? When to consider bioavailability? How to monitor compliance? Substantiation or documentation?

25. Definition: Absorption? Digestion? Metabolism? Excretion? Summary: Utilization?

26. Definitional Challenges? Case by case vs. general? Ingredient vs. finished product?

27. Definitional Challenges? New RDI’s based on “equivalents” –Example: Folic acid Applicability to other ingredients?

28. Definitional Challenges? New Upper Limits based on “synthetics” –Example: Folic acid Applicability to other ingredients?

29. Safety and Effectiveness Challenges How to deal with exposure levels Effectiveness Safety Safety factors for uncertainty

30. Host and Use Challenges Label information Appropriate use conditions Vulnerable populations Consumer right to know issues

31. Other Challenges Effect of processing? Effect of storage?

32. Science and Research Needs Bioavailability: High priority research need for CFSAN Definition Analytical methods Meaningfulness of measures

33. Key issue On food - drug continuum Where do dietary supplements fall relative to bioavailability?