Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (2005) / 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 50-72
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From page 50... ...
The setting of a UL does not indicate that nutrient intakes greater than the Recommended Dietary Allowance (RDA) or Adequate Intake (AI)
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From page 51... ...
However, it is possible to develop intake levels that are unlikely to pose risks of adverse health effects for most members of the general healthy population, including sensitive individuals. For some nutrients, these intake levels may pose a risk to subpopulations with extreme or distinct vulnerabilities.
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From page 52... ...
It was concluded, however, that the current state of scientific understanding of toxic phenomena in general, and nutrient toxicity in particular, is insufficient to support the development of such a model. Scientific information about various adverse effects and their relationships to intake levels varies greatly among nutrients and depends on the nature, comprehensiveness, and quality of available data.
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From page 53... ...
. Data uncertainties arise during the evaluation of information obtained from the epidemiological and toxicological studies of nutrient intake levels that are the basis for risk assessments.
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From page 54... ...
Intake Assessment Evaluation of the range and the distribution of human intakes of the nutrient or the food component 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 55... ...
• Step 3. Intake assessment evaluates the distribution of usual total daily nutrient intakes for members of the general population.
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From page 56... ...
. UFs are used to make inferences about the threshold dose of substances for members of a large and diverse human population using data on adverse effects obtained in epidemiological or experimental studies.
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From page 57... ...
to the derivation of Tolerable Upper Intake Levels (ULs) for nutrients.
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From page 58... ...
Because the consumption of balanced diets is consistent with the development and survival of humankind over many millennia, there is less need for the large uncertainty factors that have been used for the risk assessment of nonessential chemicals. In addition, if data on the adverse effects of nutrients are available primarily from studies in human populations, there will be less uncertainty than is associated with the types of data available on nonessential chemicals.
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From page 59... ...
Consideration of Variability in Sensitivity The risk assessment model outlined in this chapter is consistent with classical risk assessment approaches in that it must consider variability in the sensitivity of individuals to adverse effects of nutrients or food components. A discussion of how variability is dealt with in the context of nutritional risk assessment follows.
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From page 60... ...
Some nutrients may be less readily absorbed when they are 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.
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From page 61... ...
adverse effects. 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.
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From page 62... ...
All these advantages of animal data, however, may not always overcome the fact that species differences in response to chemical substances can sometimes be profound, and any extrapolation of animal data to predict human response needs to take into account this possibility. Key issues that are addressed in the data evaluation of human and animal studies are described below (see Box 3-1)
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From page 63... ...
to dietary intakes by human populations. Pharmacokinetic and Metabolic Data When available, data regarding the rates of nutrient absorption, distribution, metabolism, and excretion may be important in the derivation of Tolerable Upper Intake Levels (ULs)
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From page 64... ...
Thus, if there are significant pharmacokinetic and metabolic data over the range of intakes that meet nutrient requirements, and if it is shown that this pattern of pharmacokinetic and metabolic data does not change in the range of intakes greater than those required for nutrition, it may be possible to infer the absence of toxic risk in this range. In contrast, an alteration of pharmacokinetics or metabolism may suggest the potential for adverse effects.
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From page 65... ...
Selecting the critical data set includes the following considerations: • Human data, when adequate to evaluate adverse effects, are preferable to animal data, although the latter may provide useful supportive information. • In the absence of appropriate human data, information from an animal species with biological responses most like those of humans is most valuable.
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From page 66... ...
Until a UL is set or an alternative approach to identifying protective limits is developed, intakes greater than the Recommended Dietary Allowance or Adequate Intake should be viewed with caution. The absence of sufficient data to establish a UL points to the need for studies suitable for developing them.
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From page 67... ...
Because data 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.
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From page 68... ...
A UF to account for the uncertainty in extrapolating animal data to humans is generally applied to the NOAEL when animal data are the primary data set available. While a default UF of 10 is often used to extrapolate animal data to humans for nonessential chemicals, a lower UF may be used because of data showing some similarities between the animal and human responses (NRC, 1994)
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From page 69... ...
UL = Tolerable Upper Intake Level; NOAEL = no-observed-adverse-effect level; LOAEL = lowest-observedadverse-effect level; RDA = Recommended Dietary Allowance. Figure 3-3, when using the same critical endpoint there is a greater level of uncertainty in setting the UL based on a LOAEL as compared with a NOAEL.
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From page 70... ...
As noted earlier, in cases where the Tolerable Upper Intake Level pertains only to supplement use and does not pertain to usual food intakes of the nutrient, the assessment is directed at supplement intakes only. RISK CHARACTERIZATION As described earlier, the question of whether nutrient intakes create a risk of toxicity requires a comparison of the range of nutrient intakes (food, supplements, and other sources or supplements alone, depending on the basis for the Tolerable Upper Intake Level [UL]
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From page 71... ...
the fraction of the population consistently consuming the nutrient at intake levels in excess of the UL, 2. the seriousness of the adverse effects associated with the nutrient, 3.
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From page 72... ...
Thus, the significance of the risk of excessive nutrient intake cannot be judged only by reference to Figure 3-4, but requires careful consideration of all of the above factors. Information on these factors is contained in this report's sections describing the bases for each of the ULs.
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