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BOX 3-1 Development of Tolerable Upper Intake Levels (ULs)

Components Of Hazard Identification

  • Evidence of adverse effects in humans

  • Causality

  • Relevance of experimental data

  • Mechanisms of toxic action

  • Quality and completeness of the database

  • Identification of distinct and highly sensitive subpopulations

Components Of Dose-Response Assessment

  • Data selection

  • Identification of no-observed-adverse-effect level (NOAEL) (or lowest-observed-adverse-effect level [LOAEL]) and critical endpoint

  • Uncertainty assessment

  • Derivation of a UL

  • Characterization of the estimate and special considerations

gists generally regard any demonstrable structural or functional alteration as representing an adverse effect, some alterations may be considered to be of little or self-limiting biological importance. As noted earlier, adverse nutrient-nutrient interactions are considered in the definition of an adverse effect.

  1. Causality. As outlined in Chapter 2, the criteria of Hill (1971) are considered in judging the causal significance of an exposureeffect association indicated by epidemiological studies.

  2. Relevance of experimental data. Consideration of the following issues can be useful in assessing the relevance of experimental data:

    • Animal data. Animal data may be of limited utility in judging the toxicity of nutrients because of highly variable interspecies differences in nutrient requirements. Nevertheless, relevant animal data are considered in the hazard identification and dose-response assessment steps where applicable.

    • Route of exposure. Data derived from studies involving oral exposure (rather than parenteral exposure) are most useful for evaluating nutrients. Data derived from studies involving parenteral routes of exposure may be considered relevant if the adverse effects are systemic and data are available to permit extrapolation between routes. (The terms route of exposure and route of intake refer to how a

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