Thresholds vary among members of the general population (NRC, 1994). For any given adverse effect, if the distribution of thresholds in the population could be quantitatively identified, it would be possible to establish ULs by defining some point in the lower tail of the distribution of thresholds that would protect some specified fraction of the population. However, data are not sufficient to allow identification of the distribution of thresholds for the B vitamins or choline. The method for identifying thresholds for the general population described here is designed to ensure that almost all members of the population will be protected, but it is not based on an analysis of the theoretical distribution of thresholds. By using the model to derive the threshold, however, there is considerable confidence that the threshold, which becomes the UL for nutrients, lies very near the low end of the theoretical distribution and is the end representing the most sensitive members of the population. For some nutrients there may be subpopulations that are not included in the general distribution because of extreme or distinct vulnerabilities to toxicity. Such distinct groups, whose conditions warrant medical supervision, may not be protected by the UL.
When possible, the UL is based on a no-observed-adverse-effect level (NOAEL), which is the highest intake (or experimental oral dose) of a nutrient at which no adverse effects have been observed in the individuals studied. If there are no adequate data demonstrating a NOAEL, then a lowest-observed-adverse-effect level (LOAEL) may be used. A LOAEL is the lowest intake (or experimental oral dose) at which an adverse effect has been identified. The derivation of a UL from a NOAEL (or LOAEL) involves a series of choices about what factors should be used to deal with uncertainties. Uncertainty factors are applied in an attempt to deal both with gaps in data and with incomplete knowledge regarding the inferences required (e.g., the expected variability in response within the human population). The problems of both data and inference uncertainties arise in all steps of the risk assessment. A discussion of options available for dealing with these uncertainties is presented below and in greater detail in Appendix J.
A UL is not in itself a description of human risk. It is derived by application of the hazard identification and dose-response evaluation steps (steps 1 and 2) of the risk assessment model. To determine whether populations are at risk requires an intake assessment (step 3, evaluation of their intakes of the nutrient) and a determination of the fractions of those populations, if any, whose intakes exceed the UL. In the intake assessment and risk characterization steps (steps 3 and 4; described in the respective nutrient chapters),