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ToxSci Advance Access originally published online on March 16, 2005
Toxicological Sciences 2005 85(2):1033-1040; doi:10.1093/toxsci/kfi144
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Toxicological Sciences vol. 85 no. 2 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

A Comparison of Ratio Distributions Based on the NOAEL and the Benchmark Approach for Subchronic-to-Chronic Extrapolation

Bas G. H. Bokkers*,1 and Wout Slob*,{dagger}

* Institute for Risk Assessment Sciences (IRAS), P.O. Box 80176, 3508 TD Utrecht, The Netherlands, and {dagger} National Institute of Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands

Received November 18, 2004; accepted March 10, 2005

One approach to derive a data-based assessment factor (AF) for subchronic-to-chronic extrapolation is to determine ratios between the NOAELsubchronic and NOAELchronic for the same compounds. Instead of using ratios of NOAELs, the distribution can also be estimated by ratios of subchronic and chronic Benchmark Doses (or Critical Effect Doses, CEDs, for continuous data). In this study 314 dose-response datasets on body weights and liver weights of mice and rats were selected providing dose-response information after both subchronic and chronic exposure. NOAEL ratios could be derived in only 68 of these datasets, while CED ratios could be derived in 189 datasets. When only the (53) datasets suitable for both approaches were evaluated the variation of the CED ratio distribution (GSD [geometric standard deviation]: 2.9) was smaller than the one of the NOAEL ratio distribution (GSD: 3.3). After correcting for the estimation error of the individual CED ratios the GSD of the CED distribution decreased to 2.3. The geometric means (GMs) of the NOAEL and CED distributions were similar (1.2 and 1.6, respectively). Comparing the NOAEL distribution based on all 68 datasets suitable for deriving NOAEL ratios with the CED distribution based on the 189 ratios suitable for deriving CED ratios resulted in similar GMs (1.5 and 1.7, respectively), but the GSDs differed considerably (5.3 and 2.3 respectively). It is concluded that usage of the CED approach results in less wide distributions. Furthermore, a larger fraction of available datasets is useful to inform the ratio distribution. This results in more accurate, and less conservative distributions of AFs in general compared to the distributions based on NOAEL ratios that have been proposed so far.

Key Words: benchmark dose; NOAEL; critical effect dose; subchronic-to-chronic extrapolation; assessment factor; extrapolation factor.


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[Abstract] [Full Text] [PDF]


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