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. The primary types of data used as background for identifying nutrient hazards in humans are as follows:
Human studies. Human data provide the most relevant kind of information for hazard identification and, when they are of sufficient quality and extent, are given greatest weight. However, the number of controlled human toxicity studies conducted in a clinical setting is very limited because of ethical reasons. Such studies are generally most useful for identifying very mild (and ordinarily reversible) 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. Observational data 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. Most of the available data used in regulatory risk assessments come from controlled laboratory experiments in animals, usually mammalian species other than humans (e.g., rodents). Such data are used in part because human data on 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 Tolerable Upper Intake Levels (ULs) problematic (see below).
Six key issues that are addressed in the data evaluation of human and animal studies are the following (see Box 3-1):
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 eliciting an adverse effect in humans. Decisions regarding which observed effects are adverse are based on scientific judgments. Although toxicolo-