Confidence Level for the Product of Uncertainty Factors. D. W. Gaylor, R. L. Kodell, and J. J. Chen, National Center for Toxicological Research, FDA, Jefferson, AR 72079
A reference dose (RfD) is an estimate of daily exposure to a potentially toxic substance for a human population, including sensitive subgroups, that is likely to be without appreciable risk of deleterious health effects during a lifetime. The RFD is calculated by dividing a no or low-observed-adverse-effect-level (NOAEL or LOAEL) or a benchmark dose (BD), corresponding to a measurable low level of risk, by a series of uncertainty factors: UA to account for greater sensitivity of humans than animals, UH to account for sensitive subgroups, US when only subchronic data are available, and UL when a LOAEL or BD is used. The RfD is the NOAEL, LOAEL, or BD divided by (UA*UH*US*UL). Commonly, a maximum default value of 10 is used for each source of uncertainty with smaller values used when justified. Various authors have compiled databases for each of these uncertainty factors and noted that each tend to be lognormally distributed. Using these databases to estimate the mean and standard deviation of the logarithm for each of these uncertainty factors, it is possible to obtain an approximate confidence limit for their product (UA*UH*US*UL). It is shown that the conventional use of default factors provides at least 95% confidence for most situations.
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