Evaluation of the uncertainty factor for subchronic-to-chronic extrapolation: statistical analysis of toxicity data

Abstract

For the extrapolation of a subchronic no-observed-adverse-effect level (NOAEL) to a chronic NOAEL an uncertainty factor of 10 is routinely applied. We evaluated this uncertainty factor by statistically analyzing a database comprising 149 oral NOAEL(subchronic)/NOAEL(chronic) ratios. Since any database forms only a limited sample of all existent chemicals, we believe that estimation errors should be taken into account. Therefore, in addition to the 95th percentile (P95) of the ratio distribution, we calculated the 95% confidence interval (CI) of this percentile. The geometric mean (GM), geometric standard deviation (GSD), P95, and CI were 1.7, 5.6, 29, and 20-46, respectively. These data do not support a lowering of the uncertainty factor as has been suggested by others. Furthermore, we analyzed the LOAEL/NOAEL ratio for subacute, subchronic, and chronic toxicity studies. However, the size of the LOAEL/NOAEL ratio only depends on the spacing between doses of the studies reviewed. Therefore, though the results may be considered supportive for an uncertainty factor of 10, we believe that there is no justification for the use of such a factor. Instead, we recommend the use of dose-response modeling which would make LOAEL-to-NOAEL extrapolation redundant.