Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (2005) / Chapter Skim
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4. A Model for the Development of Tolerable Upper Intake Levels
4. A Model for the Development of Tolerable Upper Intake Levels
Pages 84-106
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From page 84... ...
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 85... ...
ULs are useful because of the increased interest in, and availability of, fortified foods, the increased use of dietary supplements, and the growing recognition of the health consequences of excesses, as well as inadequacies of nutrient intakes. ULs are based on total intake of a nutrient from food, water, and supplements if adverse effects have been associated with total intake.
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From page 86... ...
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 87... ...
. 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 88... ...
· 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 89... ...
The risk is generally expressed as the fraction of the exposed population, if any, having nutrient intakes (Step 3) in excess of the estimated UL (Steps 1 and 2)
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From page 90... ...
. UFs are used to make inferences about the threshold dose of substances for members of a large and diverse human population from data on adverse effects obtained in epidemiological or experimental studies.
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From page 91... ...
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. There is no evidence to suggest that nutrients consumed at the recommended intake (the Recommended Dietary Allowance or Adequate Intake)
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From page 92... ...
For example, sensitivity increases with declines in lean body mass and with the declines in renal and liver function that occur with aging; sensitivity changes in direct relation to intestinal absorption or intestinal synthesis of nutrients; sensitivity increases in the newborn infant 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. During pregnancy, the increase in total body water and glomerular filtration results in lower blood levels of water-soluble vitamins dose for dose, and therefore results in reduced susceptibility to potential adverse effects.
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From page 93... ...
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 since they 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 94... ...
Nutrient supplements that are taken separately from food require special consideration because they are likely to have different bioavailabilities and therefore may represent a greater risk of producing adverse effects. STEPS IN THE DEVELOPMENT OF THE TOLERABLE UPPER INTAKE LEVEL Hazard Identification Based on a thorough review of the scientific literature, the hazard identification step outlines the adverse health effects that have been demonstrated to be caused by the nutrient.
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From page 95... ...
The effects of chronic exposures can be identified in far less time than they can with the use of epidemiological methods. 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 this possibility into account.
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From page 96... ...
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 derivation of Tolerable Upper Intake Levels (ULs)
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From page 97... ...
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 98... ...
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 99... ...
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. At intakes above the UL, the risk of adverse effects increases.
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From page 100... ...
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 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 101... ...
· Subchronic NOAEL to predict chronic NOAEL. When data are lacking on chronic exposures, scientific judgment is necessary to determine whether chronic exposures are likely to lead to adverse effects at lower intakes than those producing effects after subchronic exposures (exposures of shorter duration)
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From page 102... ...
Insufficient Evidence of Adverse Effects The scientific evidence relating to adverse effects of nutrient excess varies greatly among nutrients. The type of data and evidence of causation used to derive ULs have been described earlier in this chapter, but such data and evidence are simply unavailable for some nutrients.
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From page 103... ...
, (2) data relating to adverse effects were available (e.g., amino acids)
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From page 104... ...
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 (from food, supplements, and other sources, or from supplements alone, depending upon the basis for the Tolerable Upper Intake Level [UL]
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From page 105... ...
1. the fraction of the population consistently consuming the nutrient at intake levels in excess of the UL, 2.
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From page 106... ...
1996. Trace Elements in Human Nutrition and Health.
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