Risk of adverse effects 1.5 0 DRI Concept DRI Concept EAR RDA UL 1.5 0 Observed level intake Risk of inadequacy
Tolerable Upper Intake Level The highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population Not a recommended level of intake Not a level that is desirable to attain
Deriving an Upper Level 1) Critical Data Set 2) Identify Critical Toxic Effect (End Point) NOAEL vs. LOAEL 3) Derivation of an Uncertainty Factor (typically less than 10)
UL = NOAEL or LOAEL UF
Sources of Uncertainty 1) Interindividual Variation 2) Animal to Human Extrapolations 3) Short Term vs. Chronic Exposures 4) Use of a LOAEL instead of a NOAEL 5) Small numbers 6) Severity UF = 1-10
DRI Schematic EAR RDA UL NOAEL LOAEL Risk of Toxicity Intake
CH 2 OH Vitamin A (Retinol) β-carotene Vitamin B 6 (Pyridoxine) Zn (crystral structure)
Example: Adverse Effects Considered in Setting North American UL for Vit.. A Bone mineral density Liver toxicity Teratogenicity (women of reproductive age) Bulging fontanel (infants)
Daily Dietary intake of Retinol Associated Variable with Risk for Hip Fracture Retinol Intake 0.5 mg/d 1.0 0.51-1.0 mg/d 0.92 1.01-1.5 mg/d 1.34 >1.5 mg/d 2.05 Per category 1.33 p =.006 Continuous per mg 1.68 p =.004 (Melhus et al. Ann Intern Med 1998) Multivariate Analysis (OR)
Relative Risk (RR) of Hip Fracture by Quintiles of Retinol Intake from Food and Supplements Among Postmenopausal Women in the Nurses Health Study, 1980-1998 Postmenopausal Hormone Users Postmenopausal Hormone Non-users Quintiles of Retinol Multivariate Multivarite (µg/d) RR (95%CI) RR (95%CI) 1 (<500) 1.00 (Referent) 1.09 (0.67-1.78) 2 (500-849) 0.95 (0.52-1.72) 1.44 (0.89-2.33) 3 (850-1299) 0.87 (0.47-1.61) 1.43 (0.87-2.36) 4 (1300-1999) 1.29 (0.71-2.32) 1.66 (0.99-2.78)* 5 ( 2000) 1.26 (0.68-2.33) 2.52 (1.48-4.31) (Feskanich et al., JAMA 2000)
Freudenheim (AJCN, 1986) 1) 4 year longitudinal study in 84 pre and postmenopausal women 2) Range of dietary intake of vitamin A over 3 years- 2-3 mg/day 3) No consistent relationship between vitamin intake and change in bone mineral content (arm bones) HoutKooper (J Nutr,, 1995) 1) 18 month longitudinal study in 66 premenopausal women 2) Mean vitamin A intake from diet = 1.2mg/day 3) Positive slopes between TB-BMD BMD and vitamin A intake
Upper Levels for Vitamin A (US) 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 *Rothman NEJM, 1995 (EU NOAEL = 3000 μg/day via regression curve)
Author Ballew, et al 2001 Promislow,, et al 2002 Renjmark,, et al 2004 Opotansky,, et al Am J Med, 2004 Lim, et al Osteoporos Int,, 2004 Wolf, et al AJCN, 2005 Penniston,, et al AJCN, 2006 Other Studies Study NHANES III (cross sectional) Rancho Bernardo (prospective cohort) Danish OPS (nested case control) NHANES I (prospective cohort) 1WHS (prospective cohort) WHI (cross sectional) Wisconsin (case control) Result RE not associated with BMD Vitamin A intake above RDA associated with decreased BMD (700-900ug) No effect of vitamin A intake on BMD or fracture risk (<500ug - >1500ug) Both high and low serum vitamin A associated with hip fracture No evidence between vitamin A intake and fracture (<1500ug - >3000ug) No relation of diet intake or serum vitamin A with BMD (Mean = 700ug) RE not elevated in osteoporatic normal women
Maggio,, et al J Clin Endocrinol Metab (88); 1523-27, 27, 2003 150 women > 60y (Italy)- 75 with osteoporosis; 75 without. Serum retinol was positively correlated with bone mass in osteoporotic population.
Vitamin A (UK; EU) UK- Evidence base considered inadequate to establish an UL (Rothman biased). Intakes greater than 1500 μg/day may be inappropriate. No vitamin A supplements if pregnant. EU- UL = 3000 μg/day (LOAEL for teratogenicity- no U.F. as other studies show true threshold probably higher). Covers risk of hepatoxicity.
Upper Levels for Vitamin A (US) 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 *Rothman NEJM, 1995 (EU NOAEL = 3000 μg/day via regression curve)
Problems with Infants/Children 56% WIC infants (4-5 5 months old) eating above UL (600 RAE/d) for vitamin A Life stage Criterion RDA UL 0-6 mo Breast milk 400 600 7-12 mo Extrap up 500 600 1-3 y Both extrap 300 600 4-8 y Both extrap 400 900 9-13 y Both extrap 600 1700
Study ATBC (ATBC Cancer Prevention Group, 1994) Intervention Trials: β-carotene and Lung Cancer 1 Study Population 29.133 50-69 yr. Duration: 6 yr Daily Dose 20 mg β- carotene and/or 50 mg vitamin E Results 18% lung cancer in smokers CARET (Omenn et al, 1996) 18,254 smokers and asbestos workers, 45-69 yr Duration: 4 yr 30 mg β- carotene and 25,000 IU retinol 25% lung cancer 1 primary Prevention Randomized, Double-Blind, Placebo-Controlled
Beta Carotene UL North America None established No dose response Data conflicting Britain Based on ATBC (ferret) LOAEL = 20 mg/day, UF = 3, UL = 7 mg/day EU None established No dose response Formulation differences
Study Design Ferret β-carotene Non- β-carotene Smoking n=6 Non-Smoking n=6 Smoking n=6 Non-Smoking n=6 6 months Sacrificed
The central and excentral cleavage mechanismfor converting β-carotene to retinoids ß-Carotene Central Cleavage Excentric Cleavage ß-apo-Carotenals Retinyl Esters ß-apo-Carotenoic Acids Retinol Retinal Retinoic Acid
Oxidized Products 1) Induce P450 enzymes 2) Binding of smoke derived carcinogens to DNA
Low dose B carotene has no carcinogenic effect
Vitamin B6- UL North America 1) Based on Bernstein and Lobitz (neurologic exam) 2) UL- 200mg/day (NOAEL) 2 = 100mg/day as pyridoxine. UF based on small amount of data on doses under 200mg Britain 1) Based on Phillips, et al study of ataxia in dogs 2) UL- 3000mg/day (LOAEL) 300 = 10mg/day. UF based on use of LOAEL, interspecies variation, and interindividual variation United Kingdom 1) Based on Dalton et Dalton study (neurological symptoms) 2) UL- 100mg/day (LOAEL) 4 = 25mg/day. UF based on deficiencies of data base
Zinc- UL North America 1) Based on Yadrick,, et al study ESODismutase at 60mg (total intake) 2) UL- 60mg (LOAEL) 1.5 (UF) = 40mg/day; UF due to interindividual variation and use of a LOAEL Britain 1) Based on Yadrick,, et al study (ESOD) 2) UL- 50mg (LOAEL) 2 = 25mg/day. UF due to use of LOAEL European Union 1) Based on Davies, et al and Milne, et al studies (balance) 2) UL- 50mg (NOAEL) 2 = 25mg/day. UF due to small number of subjects and short duration
Data Gaps Lack of defined critical endpoints associated with status (vitamin A) Lack of biomarkers to use to define chronic disease (B carotene) Lack of long term studies (B6) Lack of knowledge as to which systems dysfunction with excess (Zn) Lack of dose response data (all) Lack of uniform rules as to how to apply UFs (all)