Use of risk assessment in the establishment of NRVs

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1 Use of risk assessment in the establishment of NRVs Council for Responsible Nutrition - International December 1, 2012 Andrew Shao, PhD Chair, IADSA Scientific Council

2 Outline Challenges with bioactives Risk assessment (RA) as basis for maximums for essential micronutrients Application of RA to bioactive substances Rationale for establishing the UL (or HOI) before the NRV Closing remarks

3 Bioactives Isoflavones Carotenoids Anthocyanins Catechins

4 . Derived from plants Bioactives Not considered essential per se but provide health benefits Not drugs Can be considered nutritive Some more well characterized than others Lack a scientific framework on which to base recommendations

5 An appropriate scientific framework to support recommendations for bioactives should be proportionate to the risk posed by the substance the amount of evidence necessary to inform a policy recommendation should be tailored more appropriately to risk and benefit.

7 Risk Assessment Scientific process to evaluate probability and consequences of adverse effects resulting from consumption of (or exposure to) a specific amount of any substance 7

8 Risk Assessment for Nutrients Nutrient risk assessment is widely accepted Developed by IOM, then accepted and refined by EFSA, EVM, Codex, etc Regulatory maximums based on UL, not nutritional need required by Codex, European Commission, ASEAN, and many countries 8

9 What is the UL? Definition: Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population 9

10 Maximums for Vitamins and Minerals RDA based levels Countries moving to safety based levels Safety based levels

11 When UL is Not Possible No UL is set without identified of a hazard and dose-response data A major limitation of the UL for regulatory and policy applications CRN & IADSA 2004 reports used the Observed Safe Intake (OSL) method January 2006 FAO-WHO report on risk assessment defined a Highest Observed Intake (HOI) when no UL value is identified Solves the major problem of original UL method 11

12 Highest Observed Intake (HOI) Derived only when no adverse health effects have been identified. It is the highest level of intake observed or administered as reported within (a) study(ies) of acceptable quality. 12

13 HOI Risk Assessment 1. Assess data to identify any hazard (if found, use UL method) 2. Dose-response analysis to identify highest intake with sufficient data to exclude adverse effects (HOI) 3. Evaluate uncertainty 4. Select reasonable HOI

14 FLOW CHART: Evaluate data for evidence of toxicity Toxicity Dose-response assessment to identify NOAEL or LOAEL Select an uncertainty factor (UF) for data quality Calculate UL = NOAEL (or LOAEL) UF No toxicity If no evidence of toxicity, a NOAEL or LOAE cannot be set and no UL can be calculated Apply Highest Observed Intake Method (HOI) = the highest level with adequate evidence of no toxic effects use HOI instead of UL

15 Established toxicity: Classic UL method applied UL NOAEL HOI No established toxicity: HOI method applied No data range 15

16 Importance of the HOI Method: Vitamin B12 Example No established toxicity (i.e. no known hazard) US FNB, EC SCF = no UL established Absence of UL may be perceived as absence of safety data BfR (Germany) = 9 µg (3xRDA) (proposed) MEFI (France) = 3 µg (1xRDA) (proposed) UK EVM = 2000 µg Guidance Level CRN/IADSA OSL = 3000 µg Some ordinary foods contain up to 50 to 100 µg Aging decreases vitamin B12 absorption and increases dietary needs to 25 t0 100 µg or more 16

17 Safety values: Vitamin examples NUTRIENT IOM SCF-EFSA EVM 2003 CRN/IADSA 2004 (US) (EU) (UK) (supplements) Vit A, µg 3,000 3,000 1,500 bone fragility 3,000 birth defects Vit E, mg, α-te 1, IU = 540 mg 1,500 (high retinol) 3,000 (low retinol) 1,600 IU = 1,070 mg Vit C, mg 2,000 >1,000 1,000 2,000 Vit D, µg (Hathcock et al 2007) Vit B-1, mg suppl 100 Vit B-2, mg suppl 200 Vit B-6, mg (100/4) 10 (50/300x60) 100 Folic acid, µg 1,000 1,000 1,000 suppl 1,000 Vit B-12, µg ,000 3,000 17

18 Safety Values Mineral Examples NUTRIENT IOM (US) SCF- EFSA (EU) EVM 2003 (UK) Calcium, mg 2,500 2,500 1,500 suppl 1,500 Phosphorus, mg 4,000 >750 suppl 250 suppl 1,500 CRN/IADSA 2004 (supplements) Potassium, mg --* -- 3,750 w/ minor AE 1,500 (3x500) Magnesium, mg 350 free 250 free 400 suppl 400 Boron, mg Chromium, µg ,000 1,000 Copper, mg Manganese, mg total, 4 suppl 10 Selenium, µg total, 350 suppl 200 suppl (direct data) Zinc, mg suppl 30 suppl 18

19 Application to botanicals & bioactives? J. Nutr. 138: 1992S 1995S, 2008 Int Rev of Food Sci and Tech, 2008, 14-17

Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Shao A, Hathcock JN. Regul Toxicol Pharmacol. 2008 Apr;50(3):376-99. Review.

Review. Risk assessment for the carotenoids lutein and lycopene. Shao A, Hathcock JN. Regul Toxicol Pharmacol. 2006 Aug;45(3):289-98. Review. Risk assessment for coenzyme Q10 (Ubiquinone).

20 Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Shao A, Hathcock JN. Regul Toxicol Pharmacol Apr;50(3): Review. Risk assessment for glucosamine and chondroitin sulfate. Hathcock JN, Shao A. Regul Toxicol Pharmacol Feb;47(1): Review. Risk assessment for carnitine. Hathcock JN, Shao A. Regul Toxicol Pharmacol Oct;46(1):23-8. Review. Risk assessment for the carotenoids lutein and lycopene. Shao A, Hathcock JN. Regul Toxicol Pharmacol Aug;45(3): Review. Risk assessment for coenzyme Q10 (Ubiquinone). Hathcock JN, Shao A. Regul Toxicol Pharmacol Aug;45(3): Review. Risk assessment for creatine monohydrate. Shao A, Hathcock JN. Regul Toxicol Pharmacol Aug;45(3): Review. Establishing HOI first informs risk and provides guidance for setting potential NRVs

21 Ingredient Risk Assessment Values for Bioactive Substances HOI (OSL) Carnitine 2,000 mg (LCAR equivalents) Chondroitin (as sulfate) 1,200 mg Coenzyme Q10 1,200 mg Creatine (monohydrate) 5.0 g Glucosamine (chloride or sulfate) 2,000 mg Lutein 20 mg Lycopene 75 mg Arginine 20 g Glutamine 14 g Taurine 3 g Based on human data, RCTs > 1 week Many studies at higher doses, but with many limitations (e.g. small n, uncontrolled, etc )

PlantLIBRA (PLANT food supplements: Levels of Intake, Benefit and Risk Assessment) Aims to foster the safe use of food supplements containing plants or botanical preparations, by increasing

22 PlantLIBRA (PLANT food supplements: Levels of Intake, Benefit and Risk Assessment) Aims to foster the safe use of food supplements containing plants or botanical preparations, by increasing science-based decisionmaking by regulators and food chain operators. To develop, validate and disseminate data and methodologies for risk and benefit assessment and implement sustainable international cooperation. 4 continents and 25 partners, involving academics, public research institutions, Small- and Medium-Sized Enterprises, industry and nonprofit organizations

23 Estimation of health guidance values from clinical studies Application of the Observed Safe Level concept (Hathcock and Shao 2008) used for vitamins and minerals to PFS. The Observed Safe Level is defined as the highest intake with convincing evidence of safety based on data from clinical studies. Case study: EGCG from C. sinensis (L.) Kuntze, leaves, dried green tea extract Studies: RCTs in WP2 from UMIL and UBA Procedure: Arrangement of the clinical trials in decreasing order of intake of a substance, Identification of the trials with no adverse effects reported, Selection downward until the dataset is judged strong enough to justify the application of Uncertainty Factor = 1.0 PLANTLIBRA WP leaders meeting Rome, September 18 th 2012 Slide courtesy of Antonella Guzzon, Hylobates

24 Challenges with Codex Establishing NRVs Varying recommended intakes from different delegate countries Differences in age-gender groups Differences in basis for recommendations Application to a broad population (36 mo+) Lack of data in key areas (safety, children) on which to base recommendations In some cases, selected NRV can be perilously close to the UL for that nutrient

25 . US IOM Dietary Reference Intake framework for essential nutrients Safe intake range Kennedy, Am J Clin Nutr 2006;83:410S-414S

26 Too close for comfort: NRVs and ULs Current US Daily Values (from US FDA) vs. UL (from US IOM) Nutrient DV* UL Niacin 20 mg 15 mg Folate 400 µg 400 µg Iodine 150 µg 300 µg Magnesium 400 mg 350 mg Zinc 15 mg 12 mg Selenium 70 µg 30 µg Copper 2 mg 3 mg Manganese 2 mg 3 mg *US DV applies to individuals age 4+ and based on RDA UL for 4 8 yrs

27 Consequences of NRVs and UL being too close In some cases the DV approaches or even exceeds the UL Tends to be more frequent with children Subpopulation with less available and relevant data Values selected by extrapolation Can pose policy and regulatory constraints, e.g. for maximums Important for bioactives for which recommended or optimal intakes are elusive Establishing UL (or HOI) first provides more practical guidance (and political cover)

28 How close are we to establishing recommended intakes for bioactives?

29 Case Studies* Vitamin D Lutein/zeaxanthin Isoflavones Functional category Essential nutrient Defined bioactive Bioactive mixture Analytical methods (+++) (+++) (++) Pharmacokinetic/ bioavailability & metabolism (+++) (++) (++) Role/biologic plausibility (+++) (+++) (++) Good status marker Serum 25(OH)D 3 (+++) Macular pigment density (+++) Serum isoflavones (+) Observational studies link to relevant health outcome Bone (+++) Cancer (+) CVD (+) AMD (++) Cataracts (+) Bone (++) Prospective RCTs Bone density (+++) Fracture risk (+++) Macular pigment (++) Visual function (+) Cognitive function (+) Bone density (+/-) Hot flashes (++) Safety Established UL Recommended OSL Mixed, no consensus (+++) (++) (+/-) *Adapted from the proceedings of the symposium Assessing the effects of bioactives in humans: Establishing the framework for an evidence-based approach. Federation for Advancement of the Societies for Experimental Biology. Washington, DC: FASEB, 2011.

30 Closing Remarks Establishing NRVs for bioactives faces many challenges Establishing UL (or HOI) first provides more practical guidance (and political cover) To avoid confusion and subsequent concerns of approaching or exceeding UL UL (or HOI) should be based on accepted principles of risk assessment These can be applied to both essential nutrients and bioactive substances

31 Thank You! IADSA Secretariat Rue de l Association, Brussels Belgium Tel: Fax: secretariat@iadsa.be

Micronutrient Risk Assessment Safety of Fortified Foods and Supplements

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