often are less readily absorbed when they are part of a meal than when taken separately or when present in drinking water (NRC, 1989b). The opposite is true for fat-soluble vitamins whose absorption depends on fat in the diet. ULs must therefore be based on nutrients as part of the total diet, including the contribution from water. Nutrient supplements that are taken separately from food require special consideration, since they are likely to have different availabilities and therefore may present a greater risk of producing toxic effects.
The collection of scientific data for developing ULs is discussed in Chapter 2. 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. As noted in the section above on nutrient interactions, interference with nutrient bioavailability is not considered an adverse effect at this stage; rather it is considered only after more conventional adverse responses are evaluated and a tentative UL is derived.
The primary types of data used as background for identifying nutrient hazards in humans are as follows:
Human studies. Although data from controlled studies in humans are the basis for establishing nutritional requirements, the number of controlled human toxicity studies conducted in a clinical setting are, for ethical reasons, very limited and are useful for identifying only very mild and completely reversible adverse effects. Nevertheless, the available 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. Observational studies that focus on well-defined populations with clear exposures to diverse specific 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.
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 nonessential chemicals are generally less available than human data on es-