BOX 2 Development of Tolerable Upper In take Levels (ULs)
Components of Hazard Identification
- Evidence of adverse effects in humans
- 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
- in the form of case reports or anecdotal evidence are used for developing hypotheses that can lead to knowledge of causal associations. Sometimes a series of case reports, if it shows a clear and distinct pattern of effects, may be reasonably convincing on the question of causality.
- Animal studies. The majority of the available data used in regulatory risk assessments comes from controlled laboratory experiments in animals, usually mammalian species other than humans (for example, rodents). Such data are used in part because human data on food-derived substances, particularly nonessential chemicals, are generally very limited. Because well-conducted animal studies can be controlled, establishing causal relationships is generally not difficult. However, cross species differences make the usefulness of animal data for establishing ULs problematic (see below).
Key issues that are addressed in the data evaluation of human and animal studies are the following:
- 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 generally regard any demonstrable structural or functional alteration to represent an adverse effect, some alterations may be considered of little or self-limiting biological importance.