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DRIs
Dietary Reference IntakesDietary Reference Intakes
119-02
Allison A. Yates, PhD, RD
Procedures for Development of Tol...
Today’s Presentation
 Previous discussions/reports impacting
need to develop a new process for setting
reference values
...
Previous Reports that Set the Stage
for the Development ULs
 1983 Risk Assessment Report—U.S. NRC
 1983 Recommended Nutr...
The Concept of a Safe Intake Range
Observed level of intake
Riskofinadequacy
Riskofexcess
0.5 0.5
RDA
Average
Requirement
...
DRI Framework
 Reference values to meet variety of uses
 Concepts of reduction of risk to chronic
disease
 Reviews of o...
Why DRIs?
Conceptual Approach
 Quantitative dietary reference values need to
address multiple users and meet multiple
nee...
Observed level of intake
UL
Riskofinadequacy
Riskofexcess
0.5 0.5
RDA
AI
EAR
Increase
Relationship of the DRIs
Dietary Reference Intakes
Upper Reference Levels
Subcommittee
Uses of DRIs
Subcommittee
Standing Committee on the Scientif...
Flow Chart of DRI Activities—FNB/IOM Process
NRC REVIEW
UPPER
REFERENCE
LEVELS
SUBCOMMITTEE
DRI COMMITTEE-
Scientific
Eval...
DRIs
Dietary Reference IntakesDietary Reference Intakes
119-02
Allison A. Yates, PhD, RD
Development of Tolerable Upper
In...
DRI Funding Provided By
 United States: DHHS (Office of Disease Prevention and Health
Promotion, Food and Drug Administra...
Subcommittee on Upper Reference
Levels of Nutrients
Original Subcommittee 1995+
 IAN C. MUNRO, chair, CanTox, Inc.,
Missi...
Key Issues in the Development of a
Model for Upper Levels of Nutrients
 Safety versus risk
 Limitations of traditional m...
Characteristics of the
Concept of Safety
Safety is:
 An intellectual concept
 Not an inherent biological property
 A po...
Safety: A Point on a Continuum
+ + + +SOCIETY CULTURE POLITICS LAW ECONOMICS
UNSAFE
(0)
SAFE
(100)
222-02
SCIENCE
Definition of Risk
 Risk is defined as the probability of an
adverse effect occurring at some specified
level of exposure...
Limitations of Traditional Toxicology
Models in Use in 1994
 Focused on establishing safe intakes not
tolerable upper int...
Typical Studies Required for
Food Ingredients (Usually for Non-
Essential Additives)
 Acute toxicity - 2 species
 Sub-ch...
Calculation of Acceptable
Daily Intake (ADI)
ADI
(mg/kg bw-
man)
=
NOAEL1 (mg/kg bw-animal)
Safety Factor (usually 100)
No...
Unique Characteristics of Data on
Overconsumption of Nutrients
 Absence of dose-response data
 Few available human or an...
Problem Identified When Standard
Uncertainty Factors Used with
Essential Nutrients
US EPA’s RfD (oral reference dose) for ...
Risk Assessment Model
 Hazard Identification
 Dose-Response Assessment
 Exposure Assessment
 Risk Characterization
Ris...
DRI UL
Tolerable Upper Intake Level--Definition
The highest daily nutrient intake level that is likely
to pose no risk of ...
UL
Tolerable Upper Intake Level
Aspects Important to Consider when
Applying to Nutrients
 Limited data available due to f...
Step 1: Hazard Identification
Components
 Evidence of adverse effects in humans
 Causality
 Relevance of experimental d...
Step 2: Dose-Response Assessment
Components
 Data selection
 Identification of no-observed-adverse-effect
level (NOAEL) ...
Step 3: Uncertainty Assessment
Depends on
 Inter-individual variation in sensitivity
 Experimental animal data extrapola...
UL Calculations
Almost always based on data for adults, then
typically decreased for younger age groups
LOAEL =
Uncertaint...
Effect of Uncertainty Assessment on UL
100%
50%
RDA UL NOAEL LOAEL
100%
50%
RDA UL
NOAEL
LOAEL
RiskofAdverse
Effects
Risko...
Idealized
Benefit/Risk Curve
Probabilitythatstipulated
intakeisinadequatefora
randomlyselectedindividual
Probabilitythatst...
Importance of Knowing Distributions
for Dietary Recommendations
Frequency
Requirement Adverse Effects
Intake
Distribution
...
Distributions for Dietary
Recommendations—Possibly
Overlapping Distributions
Frequency
Requirement Idealized
Adverse Effec...
Example of Overlapping Requirements Distribution with
Distribution of Adverse Effects: Caries Experience and
Dental Fluoro...
Example:
Establishing a UL For Folate
UL Adverse Effects from
1998 B-Vitamin Report
Nutrient Adverse Effect NN(L)OAEL UF Adult UL/d
Niacin1
Flushing L = 50 mg 1...
UL for Folate
Dose Response Assessment
Adverse Effect Selection
 Possible adverse effects in the literature
— Neurologica...
UL for Folate
Dose Response Assessment
Identification of NOAEL (or LOAEL)
 Supplemental folate ≥ 5 mg/d ~100 reported cas...
UL for Folate
Dose Response Assessment
Uncertainty Assessment
 UF chosen was 5
 Why so high when there is dose-response
...
UL for Folate
Calculations
All adults
LOAEL (Masking B-12 deficiency) 5 mg/day
UF 5
===
1 mg/day = UL
Example:
Establishing a UL For β-Carotene
Why Not a UL for -Carotene?
 Supplemental -carotene increased the risk
of lung cancer in two major trials (doses used
2...
Plasma -Carotene Concentrations in
Large Population Studies
U.S. 5th to 95th%
0.09–0.9
(5–49)
“Threshold”
>0.4 mol/L
(>2...
Supplemental -Carotene and Lung
Cancer Risk
Report conclusion: “Based on evidence that -
carotene supplements have not b...
Example:
Establishing a UL For Vitamin A
Adverse Effects Considered in
Setting the Upper Level for Vitamin A
 Bone mineral density
 Liver toxicity
 Teratogenici...
Upper Levels for Vitamin A
Women of reproductive age
NOAEL (teratogenicity) = 4,500 μg/day = 3,000 μg/day
UF 1.5
All other...
Tolerable Upper Intake Levels for
Vitamin A (µg/day)
Life Stage UL
0–6 mo 600
7–12 mo 600
1–3 y 600
4–8 y 900 (same as RDA...
Example:
Establishing a UL For Iron
Adverse Effects Considered for
Setting the Upper Level for Iron*
 Gastrointestinal distress
 Impaired zinc absorption
 ...
Critical Points in Establishing Useful
ULs
 Integrate nutrient requirements analysis with evaluation
of adverse effects--...
93
56
44
31
14
12
8
5
5
5
5
3
2
2
2
0 20 40 60 80 100
Vitamin E
Magnesium
Vitamin A
Vitamin C
Vitamin B6
Zinc
Folate
Coppe...
Synthesis Report Submitted as
CRD 1 for Codex Committee on
Nutrition and Foods for Special
Dietary Uses in 1998
All DRI re...
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Nutrient Risk Assessment and Upper Intake Levels - USA_2015

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Expert Consultation on Nutrient Risk Assessment for Determination of Safe Upper Levels for Nutrients held on 4th December, 2015 by International Life Sciences Institute, India.

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Nutrient Risk Assessment and Upper Intake Levels - USA_2015

  1. 1. DRIs Dietary Reference IntakesDietary Reference Intakes 119-02 Allison A. Yates, PhD, RD Procedures for Development of Tolerable Upper Intake Levels for Nutrients 1994-2004
  2. 2. Today’s Presentation  Previous discussions/reports impacting need to develop a new process for setting reference values  Overview of US/Canada DRI Process  In-depth look at steps in developing ULs  Examples of UL derivation
  3. 3. Previous Reports that Set the Stage for the Development ULs  1983 Risk Assessment Report—U.S. NRC  1983 Recommended Nutrient Intakes—Health & Welfare, Canada  1991 UK Dietary Reference Values Report— COMA  1994 Risk Assessment of Essential Elements Report—ILSI 143-01
  4. 4. The Concept of a Safe Intake Range Observed level of intake Riskofinadequacy Riskofexcess 0.5 0.5 RDA Average Requirement 198-01 Safe Range of Intake 1.0 1.0 Upper Safe Deficient Adapted from Health and Welfare, Canada, 1983; 1991 UK Report, COMA
  5. 5. DRI Framework  Reference values to meet variety of uses  Concepts of reduction of risk to chronic disease  Reviews of other food components  In-depth rationale for functional end points used  Open dialog with interested groups  Estimates of upper limits of intake 143-01
  6. 6. Why DRIs? Conceptual Approach  Quantitative dietary reference values need to address multiple users and meet multiple needs —Labeling —Limits for fortification —Assessing adequacy of diets of population groups  One number can’t do it all if a science-based approach is to be followed 142-02
  7. 7. Observed level of intake UL Riskofinadequacy Riskofexcess 0.5 0.5 RDA AI EAR Increase Relationship of the DRIs
  8. 8. Dietary Reference Intakes Upper Reference Levels Subcommittee Uses of DRIs Subcommittee Standing Committee on the Scientific Evaluation of Dietary Reference Intakes Panels Ca, Vitamin D, Phosphorus, Mg, F Folate, B12, Other B Vitamins, Choline Vitamins C and E, Se, ß-carotene and Other Carotenoids Vitamins A and K, As, B, Cr, Cu, Fe, I2, Mn, Mo, Ni, Si, V, Zn Energy and Macronutrients Electrolytes, Water [Other Food Components] 10 years, $US ~7.5 M
  9. 9. Flow Chart of DRI Activities—FNB/IOM Process NRC REVIEW UPPER REFERENCE LEVELS SUBCOMMITTEE DRI COMMITTEE- Scientific Evaluation of DRIs NUTRIENT GROUP PANEL(S) SCIENTIFIC AND USER COMMUNITIES Reports Released Recommends Appointments to Panel and Guides Forwards Drafts Solicits Nominees Input USES OF DRIs SUBCOMMITTEE 1) Holds Workshops and Meetings 2) Develops Scientific Basis for Nutrient Needs and Sets Tentative Reference Values, Including EARs, Variances, RDAs, AIs, and ULs Forwards Drafts Forwards Drafts Develops Guidelines for use with Emphasis on Policy, Guidance & Education 158-01
  10. 10. DRIs Dietary Reference IntakesDietary Reference Intakes 119-02 Allison A. Yates, PhD, RD Development of Tolerable Upper Intake Levels for Nutrients 1994-2004 DRI Reports 1997-2004
  11. 11. DRI Funding Provided By  United States: DHHS (Office of Disease Prevention and Health Promotion, Food and Drug Administration, Centers for Disease Control and Prevention, and NIH); USDA; U.S. Army  Health Canada  NGOs: the Dannon Institute; International Life Sciences Institute  the DRI Corporate Donors’ Fund: Daiichi Fine Chemicals; Kemin Foods; M&M/Mars; Mead Johnson Nutritionals; Nabisco Foods Group; Natural Source Vitamin E Association; Roche Vitamins; U.S. Borax; and Weider Nutritional Group 223-02
  12. 12. Subcommittee on Upper Reference Levels of Nutrients Original Subcommittee 1995+  IAN C. MUNRO, chair, CanTox, Inc., Mississauga, Ontario  WALTER MERTZ, Retired, USDA, Beltsville, MD  RITA B. MESSING, Minnesota Dept of Health  SANFORD A. MILLER, Georgetown University, Washington, DC  SUZANNE P. MURPHY, University of California, Berkeley  JOSEPH V. RODRICKS, The Life Sciences Consultancy, Arlington VA  IRVIN H. ROSENBERG, USDA & Tufts University, Boston  STEVE L. TAYLOR, Univ. of Nebraska, Lincoln  ROBERT H. WASSERMAN, Cornell University, Ithaca, NY Additional Members 1999-2004  G. HARVEY ANDERSON, University of Toronto  GEORGE C. BECKING, Phoenix OHC, Kingston, Ontario  ELAINE FOUSTMAN, University of Washington, Seattle  SUZANNE HENDRICH, Iowa State University, Ames  RENATE D. KIMBROUGH, Institute for Evaluating Health Risks  HARRIS PASTIDES, University of South Carolina, Columbia  JOHN A. THOMAS, San Antonio  GARY M. WILLIAMS, New York Medical College 219-03
  13. 13. Key Issues in the Development of a Model for Upper Levels of Nutrients  Safety versus risk  Limitations of traditional models  Unique characteristics of nutrients  Sparse documentation of adverse effects of chronic overconsumption  Coordinating the work of the nutrient review panels with the subcommittees 220-02
  14. 14. Characteristics of the Concept of Safety Safety is:  An intellectual concept  Not an inherent biological property  A point on a continuum 221-02 UK DRV Report in 1991 had used the term “Upper Safe Level of Intake”
  15. 15. Safety: A Point on a Continuum + + + +SOCIETY CULTURE POLITICS LAW ECONOMICS UNSAFE (0) SAFE (100) 222-02 SCIENCE
  16. 16. Definition of Risk  Risk is defined as the probability of an adverse effect occurring at some specified level of exposure  Risk assessment is a scientific exercise, not influenced by value judgments  Risk management = approaches to take to mitigate identified risk --- not part of risk assessment 223-02
  17. 17. Limitations of Traditional Toxicology Models in Use in 1994  Focused on establishing safe intakes not tolerable upper intake levels  Reliance on animal data  Most involved the concept of establishing an Acceptable Daily Intake (ADI) ---somewhat equivalent to other terms such as US EPA’s Oral Reference Dose (RfD) or US ATSDR’s Minimum Risk Level (MRL) 224-02
  18. 18. Typical Studies Required for Food Ingredients (Usually for Non- Essential Additives)  Acute toxicity - 2 species  Sub-chronic toxicity - 2 species  Multi-generation studies  Teratology studies  Long-term/carcinogenicity studies - 2 species  Absorption, distribution, metabolism and excretion studies  Genotoxicity studies - in vitro / in vivo 225-01 e.g., NAS report, Risk Assessment in the Federal Government: Managing the Process, 1983 (The “Red Book”)
  19. 19. Calculation of Acceptable Daily Intake (ADI) ADI (mg/kg bw- man) = NOAEL1 (mg/kg bw-animal) Safety Factor (usually 100) Note: Safety Factor designed to compensate for: a) Animal to man extrapolation b) Intrahuman sensitivities (children, elderly, gender) c) Differences in test population size 226-01 1No Adverse Effect Level
  20. 20. Unique Characteristics of Data on Overconsumption of Nutrients  Absence of dose-response data  Few available human or animal chronic studies  Few surveillance studies to establish NOAEL  Available databases have concentrated on supplement intake, but not total  Significant differences in bioavailability, particularly for trace elements 227-01
  21. 21. Problem Identified When Standard Uncertainty Factors Used with Essential Nutrients US EPA’s RfD (oral reference dose) for zinc for children was less than the 1989 RDA for zinc for young boys
  22. 22. Risk Assessment Model  Hazard Identification  Dose-Response Assessment  Exposure Assessment  Risk Characterization Risk Management 231-01
  23. 23. DRI UL Tolerable Upper Intake Level--Definition The highest daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population. As intake increases above the UL, the potential risk of adverse effects may increase(s). The UL is not a recommended level of intake and is not a level that is desirable to attain. 228-04 NOTE: Words in italics added in later DRI reports
  24. 24. UL Tolerable Upper Intake Level Aspects Important to Consider when Applying to Nutrients  Limited data available due to few human studies  Depending on clinical significance of observed adverse effects, uncertainty factor used will vary  Observed effects may vary depending on form of intake 229-03
  25. 25. Step 1: Hazard Identification Components  Evidence of adverse effects in humans  Causality  Relevance of experimental data  Mechanism of toxic action  Quality and completeness of the data base  Identification of distinct and highly sensitive subpopulations 232-01
  26. 26. Step 2: Dose-Response Assessment Components  Data selection  Identification of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse- effect level (LOAEL) and critical endpoint  Uncertainty assessment  Derivation of a UL  Characterization of the estimate and special considerations 233-01
  27. 27. Step 3: Uncertainty Assessment Depends on  Inter-individual variation in sensitivity  Experimental animal data extrapolated to humans  LOAEL used in absence of NOAEL  Sub-chronic NOAEL used to predict chronic NOAEL 234-01
  28. 28. UL Calculations Almost always based on data for adults, then typically decreased for younger age groups LOAEL = Uncertainty Factor == UL
  29. 29. Effect of Uncertainty Assessment on UL 100% 50% RDA UL NOAEL LOAEL 100% 50% RDA UL NOAEL LOAEL RiskofAdverse Effects RiskofAdverse Effects Increasing Intake 230-03
  30. 30. Idealized Benefit/Risk Curve Probabilitythatstipulated intakeisinadequatefora randomlyselectedindividual Probabilitythatstipulated intakeisexcessivefora randomlyselectedindividual 0 1.0 1.0 0 Increasing Intake 235-01
  31. 31. Importance of Knowing Distributions for Dietary Recommendations Frequency Requirement Adverse Effects Intake Distribution XEAR RDA XIntake Amount Consumed Pop. Index AI 197-02 SuS. Murphy, 2015
  32. 32. Distributions for Dietary Recommendations—Possibly Overlapping Distributions Frequency Requirement Idealized Adverse EffectsIntake Distribution XEAR RDA XIntake Amount Consumed Pop. Index AI 197-02 SuS. Murphy, 2015 Actual Adverse Effects
  33. 33. Example of Overlapping Requirements Distribution with Distribution of Adverse Effects: Caries Experience and Dental Fluorosis Index Versus Fluoride Concentration of Drinking Water 0 1 2 3 4 5 6 7 8 0 1 2 3 2 1 CariesExperienceperChild FluorosisIndex Water [F], ppm 236-02 NOAEL?
  34. 34. Example: Establishing a UL For Folate
  35. 35. UL Adverse Effects from 1998 B-Vitamin Report Nutrient Adverse Effect NN(L)OAEL UF Adult UL/d Niacin1 Flushing L = 50 mg 1.5 ~35 mg Vitamin B6 Sensory neuropathy N = 200 mg 2.0 100 mg Folate1 Neuropathy in B12- deficient individuals L = 5 mg 5.0 1,000 µg Choline Vitamin B12 Hypotension, fishy body odor None identified as of concern L = 7.5 g 2.0 3.5 g --- 1 From supplements only 360-03
  36. 36. UL for Folate Dose Response Assessment Adverse Effect Selection  Possible adverse effects in the literature — Neurological damage in Vitamin B-12 deficient individuals — General toxicity: mental changes, sleep disturbances ,and GI effects of 15 mg/d — Increased cancer of oropharynx and hypopharynx and total cancer rates – epidemiological study — Hypersensitivity – rare, 1 mg/d — Intestinal zinc malabsorption
  37. 37. UL for Folate Dose Response Assessment Identification of NOAEL (or LOAEL)  Supplemental folate ≥ 5 mg/d ~100 reported cases  ≤ 5 mg/d (0.33 to 2.5 mg/d), only 8 well- documented  Folate supplementation maintained patients in remission of pernicious anemia symptoms  Background intake of folate from food was not specified in reports
  38. 38. UL for Folate Dose Response Assessment Uncertainty Assessment  UF chosen was 5  Why so high when there is dose-response data available? — Due to severity of neurological complications — Complications are irreversible — Only have LOAEL, not NOAEL  Not higher than 5 as have uncontrolled observations of millions of people exposed to 1/10th the LOAEL without reported harm
  39. 39. UL for Folate Calculations All adults LOAEL (Masking B-12 deficiency) 5 mg/day UF 5 === 1 mg/day = UL
  40. 40. Example: Establishing a UL For β-Carotene
  41. 41. Why Not a UL for -Carotene?  Supplemental -carotene increased the risk of lung cancer in two major trials (doses used 20 mg/d; 30 mg/d + vit. A)  However, the data are conflicting with a third major trial (dose 50 mg/every other day) reporting no adverse effects with up to 12 years intervention  Therefore, conflicting data did not allow determination of a UL 466-01
  42. 42. Plasma -Carotene Concentrations in Large Population Studies U.S. 5th to 95th% 0.09–0.9 (5–49) “Threshold” >0.4 mol/L (>20g/dL) 1.9 (100) 5.6 (300) 3.8 (200) 7.5 (400) Linxian (15 mg/day) PHS (50 mg every other day) CARET (30 mg/day) ATBC (20 mg/day) Blood -carotene concentration µmol/L (µg/dL) 468-03
  43. 43. Supplemental -Carotene and Lung Cancer Risk Report conclusion: “Based on evidence that - carotene supplements have not been shown to confer any benefit…and may cause harm in certain subgroups (possible lung cancer risk in smokers), it is concluded that -carotene supplements are not advisable, other than as a provitamin A source and for the prevention and control of vitamin A deficiency in at-risk populations.” 467-02
  44. 44. Example: Establishing a UL For Vitamin A
  45. 45. Adverse Effects Considered in Setting the Upper Level for Vitamin A  Bone mineral density  Liver toxicity  Teratogenicity (women of reproductive age)  Bulging fontanel (infants)
  46. 46. Upper Levels for Vitamin A Women of reproductive age NOAEL (teratogenicity) = 4,500 μg/day = 3,000 μg/day UF 1.5 All other adults LOAEL (liver toxicity) = 14,000 μg/day = 3,000 μg/day UF 5
  47. 47. Tolerable Upper Intake Levels for Vitamin A (µg/day) Life Stage UL 0–6 mo 600 7–12 mo 600 1–3 y 600 4–8 y 900 (same as RDA for adult male) 9–13 y 1,700 14–18 y 2,800  19 y 3,000 Preg, Lact See age group
  48. 48. Example: Establishing a UL For Iron
  49. 49. Adverse Effects Considered for Setting the Upper Level for Iron*  Gastrointestinal distress  Impaired zinc absorption  Cardiovascular disease  Cancer UL = LOAEL (gastrointestinal = 70 mg/day  45 mg/day UF distress) 1.5 *May not protect individuals with hemochromatosis
  50. 50. Critical Points in Establishing Useful ULs  Integrate nutrient requirements analysis with evaluation of adverse effects---can’t be isolated activities—and must involve both nutritionists and toxicologists  Evaluate existence of food and supplement intake data to assure that adequate exposure (intake) estimates exist for relevant sub-population groups  Dietary guidance needs to reflect varied population needs as well as potential adverse effects—depends on the seriousness of the adverse effects  Risk managers determine how to incorporate risk assessment into policy—Final Dietary Guidelines, label values, etc.
  51. 51. 93 56 44 31 14 12 8 5 5 5 5 3 2 2 2 0 20 40 60 80 100 Vitamin E Magnesium Vitamin A Vitamin C Vitamin B6 Zinc Folate Copper Phosphorus Thiamin Iron Protein Selenium Niacin Riboflavin Nutrient Percent of inadequate intakes in U.S. compared to nutrient requirements, using individual DRI EARs to determine prevalence of inadequacy; WWEIA intake surveys now include estimates from supplements as well as food to allow comparison with ULs 21st Century Paradox in the U.S.: Overnutrition & Malnutrition What We Eat in America, NHANES Percent of Population WWEIA 2001-2002, 1 day, 1+ y FSRG/ARS/USDA
  52. 52. Synthesis Report Submitted as CRD 1 for Codex Committee on Nutrition and Foods for Special Dietary Uses in 1998 All DRI reports are downloadable on National Academies Press website: www.nap.edu Search term: DRI Also, 2015 Dietary Guidelines for Americans Advisory Committee Report from February 2015 available online; final 2015 Dietary Guidelines Report not yet available

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