any extrapolation of animal data to predict human response has to take into account this possibility.

Key issues that are addressed in the data evaluation of human and animal studies are listed in Box 4-1.

Evidence of Adverse Effects in Humans

The hazard identification step involves the examination of human, animal, and in vitro published evidence addressing the likelihood of a nutrient or food component eliciting an adverse effect in humans. Decisions regarding which observed effects are adverse are based on scientific judgments. Although toxicologists must consider the possibility that many demonstrable structural or functional alterations represent adverse effects with respect to nutrients, some alterations may be considered of little or self-limiting biological importance. As noted earlier, adverse nutrient-nutrient interactions are considered in the definition of an adverse effect.

Causality

The identification of a hazard is strengthened by evidence of causality. As explained in Chapter 3, the criteria of Hill (1971) are

BOX 4-1 Development of Tolerable Upper Intake Levels (ULs)

Components of Hazard Identification

  • Evidence of adverse effects in humans

  • Causality

  • Relevance of experimental data

  • Pharmacokinetic and metabolic 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 and identification of critical endpoints

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

  • Assessment of uncertainty and data on variability in response

  • Derivation of a UL

  • Characterization of the estimate and special considerations



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