Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998) / Chapter Skim
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3 A Model for the Development of Tolerable Upper Intake Levels
3 A Model for the Development of Tolerable Upper Intake Levels
Pages 41-57
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From page 41... ...
The term adverse effect is clefineci as any significant alteration in the structure or function of the human organism (Klaassen et al., 1986) or any impairment of a physiologically important function, in accordance with the definition set by the joint World Health Organization, Food and Agriculture Organization of the United Nations, and International Atomic Energy Agency Expert Consultation in Trace Elements in Human Nutrition and Health (WHO, 1996~.
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From page 42... ...
A MODEL FOR THE DERIVATION OF TOLERABLE UPPER INTAKE LEVELS The development of a mathematical model for deriving the Tolerable Upper Intake Level (UL) was rejected for reasons clescribeci elsewhere (IOM, 1997~.
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From page 43... ...
Data uncertainties arise cluring the evaluation of information obtained from the epiclemiological and toxicological studies of nutrient intake levels that are the basis for risk assessments. Examples of inferences include the use of ciata from experimental animals to estimate responses in humans and the selection of uncertainty factors to estimate inter- and intraspecies variabilities in response to toxic substances.
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· Step 3. Intake assessment evaluates the distribution of usual total ciaily nutrient intakes for members of the general population.
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From page 45... ...
· Derivation of Tolerable Upper Intake Level (UL) Intake Assessment Evaluation of the range and the distribution of human intakes of the nutrient or the food component 1 Risk Characterization · Estimation of the fraction of the population, if any, with intakes greater than the UL · Evaluation of the magnitude with which these excess intakes exceed the UL FIGURE 3-1 Risk assessment model for nutrient toxicity.
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From page 46... ...
It is cleriveci by application of the hazard identification and close-response evaluation steps (steps 1 and 2) of the risk assessment model.
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The UL is the highest level of tinily nutrient intake 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 risk of adverse effects increases.
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Physiological changes and common conditions associated with growth and maturation that occur cluring an incliviclual's lifespan may influence sensitivity to nutrient toxicity. For example, sensitivity increases with cleclines in lean body mass and with declines in renal and liver function that occur with aging; sensitivity changes in direct relation to intestinal absorption or intestinal synthesis of nutrients; in the newborn infant sensitivity is also increased because of rapid brain growth and limited ability to secrete or biotransform toxicants; and sensitivity increases with decreases in the rate of metabolism of nutrients.
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The model clescribeci below accounts for normally expected variability in sensitivity but excludes subpopulations with extreme and distinct vulnerabilities. Such subpopulations consist of inclivicluals neecling medical supervision; they are better served through the use of public health screening, prociuct labeling, or other incliviclualizeci health care strategies.
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Observational studies that focus on welldefined populations with clear exposures to a range of nutrient intake levels are useful for establishing a relationship between exposure and effect. Observational ciata in the form of case reports or anecdotal evidence are used for developing hypotheses that can leaci to knowledge of causal associations.
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Data derived from studies involving parenteral routes of exposure may be consiclereci relevant if the adverse effects are systemic and ciata are available to permit extrapolation between routes. (The terms route of exposure and route of intake refer to how a
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· Duration of exposure. Consideration needs to be given to the relevance of the exposure scenario (e.g., chronic daily dietary exposure versus short-term bolus doses)
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. The derivation of a UL based on the most sensitive endpoint will ensure protection against all other adverse effects.
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The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals in the general population.
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· Subchronic NOAEL to predict chronic NOAEL. When ciata are lacking on chronic exposures, scientific judgment is necessary to determine whether chronic exposure is likely to leaci to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter cluration)
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Characterization of the Estimate and Special Considerations ULs are cleriveci for various life stage groups by using relevant databases, NOAELs and LOAELs, and UFs. Where no ciata exist for NOAELs or LOAELs for the group under consideration, extrapolations from data in other age groups and/or animal data are made on the basis of known differences in body size, physiology, metabolism, absorption, and excretion of the nutrient.
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Prepared in collaboration with the Food and Agriculture Organization of the United Nations and the International Atomic Energy Agency. Geneva: WHO.
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