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AbstractThe benchmark dose (BMD) approach is increasingly used as a preferred approach for dose–effect analysis, but standard experimental designs are generally not optimized for BMD analysis. The aim of this study was to evaluate how the use of unequally sized dose groups affects the quality of BMD estimates in toxicity testing, with special consideration of the total burden of animal distress. We generated continuous dose–effect data by Monte Carlo simulation using two dose–effect curves based on endpoints with different shape parameters. Eighty‐five designs, each with four dose groups of unequal size, were examined in scenarios ranging from low‐ to high‐dose placements and with a total number of animals set to 40, 80, or 200. For each simulation, a BMD value was estimated and compared with the "true" BMD. In general, redistribution of animals from higher to lower dose groups resulted in an improved precision of the calculated BMD value as long as dose placements were high enough to detect a significant trend in the dose–effect data with sufficient power. The improved BMD precision and the associated reduction of the number of animals exposed to the highest dose, where chemically induced distress is most likely to occur, are favorable for the reduction and refinement principles. The result thereby strengthen BMD‐aligned design of experiments as a means for more accurate hazard characterization along with animal welfare improvements.

AbstractIncreasingly, dose‐response data are being evaluated with the benchmark dose (BMD) approach rather than by the less precise no‐observed‐adverse‐effect‐level (NOAEL) approach. However, the basis for designing animal experiments, using equally sized dose groups, is still primed for the NOAEL approach. The major objective here was to assess the impact of using dose groups of unequal size on both the quality of the BMD and overall animal distress. We examined study designs with a total number of 200 animals distributed in four dose groups employing quantal data generated by Monte Carlo simulations. Placing more animals at doses close to the targeted BMD provided an estimate of BMD that was slightly better than the standard design with equally sized dose groups. In situations involving a clear dose‐response, this translates into fewer animals receiving high doses and thus less overall animal distress. Accordingly, in connection with risk and safety assessment, animal distress can potentially be reduced by distributing the animals appropriately between dose groups without decreasing the quality of the information obtained.