substance enters the body, for example, by ingestion, injection, or dermal absorption. These terms should not be confused with form of intake, which refers to the medium or vehicle used, e.g., supplements, food, and drinking water.)
Duration of exposure. Consideration needs to be given to the relevance of the exposure scenario (e.g., chronic daily dietary exposure versus short-term bolus doses) to dietary intakes by human populations.
Mechanisms of toxic action. Knowledge of molecular and cellular events underlying the production of toxicity can assist in dealing with the problems of extrapolation between species and from high to low doses. It may also aid in understanding whether the mechanisms associated with toxicity are those associated with deficiency. In the case of the B vitamins, knowledge of the biochemical sequence of events resulting from toxicity and deficiency is still incomplete, and it is not yet possible to state with certainty the extent to which these sequences share a common pathway.
Quality and completeness of the database. The scientific quality and quantity of the database are evaluated. Human or animal data are reviewed for suggestions that the substances have the potential to produce additional adverse health effects. If suggestions are found, additional studies may be recommended.
Identification of distinct and highly sensitive subpopulations. The ULs are based on protecting the most sensitive members of the general population from adverse effects of high nutrient intake. For some nutrients, however, there may be distinct subgroups that have extreme sensitivities that do not fall within the range of sensitivities expected for the general population. The UL for the general population may not be protective for these subgroups. As indicated earlier, the extent to which a distinct subpopulation will be included in the derivation of a UL for the general population is an area of judgment to be addressed on a case-by-case basis.
The process for deriving the UL is described in this section and outlined in Box 3-1. It includes selection of the critical data set, identification of a critical endpoint with its NOAEL (or LOAEL), and assessment of uncertainty.