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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 ULs.

Uncertainty Assessment

Several judgments must be made regarding the uncertainties and thus the UF associated with extrapolating from the observed data to the general population (see Appendix L). Applying a UF to a NOAEL (or LOAEL) results in a value for the derived UL that is less than the experimentally derived NOAEL, unless the UF is 1.0. The greater the uncertainty, the larger the UF and the smaller the resulting UL. This is consistent with the ultimate goal of the risk assessment: to provide an estimate of a level of intake that will protect the health of virtually all members of the healthy population (Mertz et al., 1994).

Although several reports describe the underlying basis for UFs (Dourson and Stara, 1983; Zielhuis and van der Kreek, 1979), the strength of the evidence supporting the use of a specific UF will vary. The imprecision of the UFs is a major limitation of risk assessment approaches and considerable leeway must be allowed for the application of scientific judgment in making the final determination. Because data are generally available regarding intakes of nutrients in human populations, the data on nutrient toxicity may not be subject to the same uncertainties as are data on nonessential chemical agents. The resulting UFs for nutrients and food components are typically less than the factors of 10 often applied to nonessential toxic substances. The UFs are lower with higher quality data and when the adverse effects are extremely mild and reversible.

In general, when determining a UF, the following potential sources of uncertainty are considered and combined in the final UF:

  • Interindividual variation in sensitivity. Small UFs (close to 1) are used to represent this source of uncertainty if it is judged that little



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