tween intake and the extent of the toxic response known to be most relevant to humans. Data on bioavailability are considered and adjustments in expressions of dose-response are made to determine whether any apparent differences in response can be explained.

• The critical data set documents the route of exposure and the magnitude and duration of the intake. Furthermore, the critical data set documents the NOAEL (or LOAEL).

A nutrient can produce more than one toxic effect (or endpoint), even within the same species or in studies using the same or different exposure durations. The NOAELs and LOAELs for these effects will ordinarily differ. The critical endpoint used to establish a UL is the adverse biological effect exhibiting the lowest NOAEL (e.g., the most sensitive indicator of a nutrient’s toxicity). Because the selection of uncertainty factors (UFs) depends in part on the seriousness of the adverse effect, it is possible that lower ULs may result from the use of the most serious (rather than most sensitive) endpoint. Thus, it is often necessary to evaluate several endpoints independently to determine which one leads to the lowest UL.

For some nutrients, there may be inadequate data on which to develop a UL. The lack of reports of adverse effects following excess intake of a nutrient does not mean that adverse effects do not occur. As the intake of any nutrient increases, a point (see Figure 3-2) is reached at which intake begins to pose a risk. Above this point, increased intake increases the risk of adverse effects. For some nutrients and for various reasons, there are inadequate data to identify this point or even to estimate its location.

Because adverse effects are almost certain to occur for any nutrient at some level of intake, it should be assumed that such effects may occur for nutrients for which a scientifically documentable UL cannot now be derived. Until a UL is set or an alternative approach to identifying protective limits is developed, intakes greater than the Recommended Dietary Allowance or Adequate Intake should be viewed with caution.

The absence of sufficient data to establish a UL points to the need for studies suitable for developing them.

Several judgments must be made regarding the uncertainties and thus the uncertainty factor (UF) associated with extrapolating from