Benchmark dose and the three Rs. Part I. Getting more information from the same number of animals

Abstract

Evaluating dose–response data using the Benchmark dose (BMD) approach rather than by the no observed adverse effect (NOAEL) approach implies a considerable step forward from the perspective of the Reduction, Replacement, and Refinement, three Rs, in particular the R of reduction: more information is obtained from the same number of animals, or, vice versa, similar information may be obtained from fewer animals. The first part of this twin paper focusses on the former, the second on the latter aspect. Regarding the former, the BMD approach provides more information from any given dose–response dataset in various ways. First, the BMDL (= BMD lower confidence bound) provides more information by its more explicit definition. Further, as compared to the NOAEL approach the BMD approach results in more statistical precision in the value of the point of departure (PoD), for deriving exposure limits. While part of the animals in the study do not directly contribute to the numerical value of a NOAEL, all animals are effectively used and do contribute to a BMDL. In addition, the BMD approach allows for combining similar datasets for the same chemical (e.g., both sexes) in a single analysis, which further increases precision. By combining a dose–response dataset with similar historical data for other chemicals, the precision can even be substantially increased. Further, the BMD approach results in more precise estimates for relative potency factors (RPFs, or TEFs). And finally, the BMD approach is not only more precise, it also allows for quantification of the precision in the BMD estimate, which is not possible in the NOAEL approach.

Keywords:

• BMD approach
• combined analysis
• dose–response analysis
• precision
• PROAST
• NOAEL approach
• three Rs

Acknowledgements

The author is grateful to Drs. Peter Bos, Theo Vermeire, Bas Bokkers and Jos Bessems for critically reading the manuscript and providing valuable comments.

Declaration of interest

The author’s affiliation is as shown on the cover page. The author has sole responsibility of for the writing and content of the paper. This work was supported by the Netherlands Ministry of Health, Welfare and Sport.

Notes

¹It should be noted, however, that the calculation of confidence intervals in situations where the number of parameters in the dose–response model is larger than the number of dose groups still needs technical refinement in current BMD software packages.