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3 A Model for the Development of Tolerable Upper Intake Levels
Pages 60-81

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From page 60...
... Many inclivicluals are self-meclicating with nutrients for curative or treatment purposes. It is beyond the scope of this report to aciciress the possible therapeutic benefits of higher nutrient intakes that may offset the potential risk of adverse effects.
From page 61...
... However, it is possible to develop intake levels that are unlikely to pose risk of adverse health effects for most members of the general population, including sensitive inclivicluals. For some nutrients, these intake levels pose a potential risk to subpopulations with extreme or distinct vulnerabilities.
From page 62...
... Scientific information about various adverse effects t and their relationships to intake levels varies greatly among nutrients and clepencis on the nature, comprehensiveness, and quality of available ciata. The uncertainties associated with the unavoidable problem of extrapolating from the circumstances uncler which ciata are clevelopeci (e.g., in the laboratory or clinic)
From page 63...
... Risk assessment is subject to two types of scientific uncertainties: those related to ciata and those associated with inferences that are required when directly applicable ciata are not available (NRC, 1994~. 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.
From page 64...
... · Derivation of Tolerable Upper Intake Level (UL) 1 Intake Assessment Evaluation of the range and the distribution of human intakes of the nutrient or the food component ~ r 1 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 adverse effects.
From page 65...
... · Step 3. Intake assessment evaluates the distribution of usual total ciaily nutrient intakes for members of the general population.
From page 66...
... of a nutrient at which no adverse effects have been observed in the inclivicluals stuclieci. This is iclentifieci for a specific circumstance in the hazard identification and close-response assessment steps of the risk assessment.
From page 67...
... A discussion of other aspects of the risk characterization that may be useful in judging the public health significance of the risk and in risk management decisions is provicleci in the final section of this chapter, "Risk Characterization." APPLICATION OF THE RISK ASSESSMENT MODEL TO NUTRIENTS This section provides guidance for applying the risk assessment framework (the moclel) to the derivation of Tolerable Upper Intake Levels (ULs)
From page 68...
... As intake increases above the UL, the risk of adverse effects increases. If adverse effects have been associated with total intake, ULs are baseci on total intake of a nutrient from food, water, and supplements.
From page 69...
... 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 declines in lean body mass and with cleclines in renal and liver function that occur with aging; sensitivity changes in clirect 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.
From page 70...
... Some nutrients may be less readily absorbed when part of a meal than when consumed separately. Supplemental forms of some nutrients may require special consideration if they have higher bioavailability and therefore may present a greater risk of producing adverse effects than equivalent amounts from the natural form found in food.
From page 71...
... 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.
From page 72...
... Decisions about which observed effects are adverse are baseci on scientific jucigments. Although toxicologists generally regard any demonstrable structural or functional alteration as representing an adverse effect, some alterations may be consiclereci to be of little or self-limiting biological importance.
From page 73...
... Pharmacokinetic and Metabolic Data When available, ciata regarding the rates of nutrient absorption, distribution, metabolism, and excretion may be important in clerivation of Tolerable Upper Intake Levels (ULs)
From page 74...
... Identification of Distinct and Highly Sensitive Subpopu;lations The ULs are based on protecting the most sensitive members of the general population from adverse effects of high nutrient intake. Some highly sensitive subpopulations have responses (in terms of incidence, severity, or both)
From page 75...
... Selecting the critical ciata set includes the following considerations: · Human ciata, when acloquate to evaluate adverse effects, are preferable to animal ciata, although the latter may provide useful supportive information. · In the absence of appropriate human ciata, information from an animal species with biological responses most like those of humans is most valuable.
From page 76...
... 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.
From page 77...
... Because ciata are generally available regarding intakes of nutrients in human populations, the data on nutrient toxicity may not be subject to the same uncertainties as are data on nonessential chemical agents. The resulting UFs for nutrients and food components are typically less than the factors of 10 often applied to nonessential toxic substances.
From page 78...
... When ciata are lacking on chronic exposures, scientific judgment is necessary to cletermine whether chronic exposure is likely to leaci to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter cluration)
From page 79...
... As noted earlier, in cases where the Tolerable Upper Intake Level pertains only to supplement use and floes not pertain to usual food intakes of the nutrient, the assessment is clirecteci at supplement intakes only. RISK CHARACTERIZATION As clescribeci earlier, the question of whether nutrient intakes create a risk of adverse effects requires a comparison of the range of nutrient intakes Food, supplements, and other sources or supplements alone, depending upon the basis for the Tolerable Upper Intake Level tUL]
From page 80...
... 1. the fraction of the population consistently consuming the nutrient at intake levels in excess of the UL; 2.
From page 81...
... Twenty-sixth report of the Joint FAD/WHO Expert Committee on Food Additives. WHO Technical Report Series, No.


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