Problems With Studying Extrapolation Relationships Empirically: The Case of ED50 Ratios.* K. P. Brand, University of Ottawa, Canada
Extrapolation relationships play a central role in translating experimentally derived (usually in animals) toxicity estimates into estimates more relevant to the human population. A standard approach for characterizing each extrapolation relies on ratios of pre-existing toxicity estimates. Applications of this approach have overlooked several sources of error. This paper extends previous analysis which demonstrated worrisome limits to the informativeness of benchmark dose ratios obtained from quantal data. We focus on the particular case of ED50 ratios, comparing their informativeness to the previously investigated ED10 ratios. Emerging work by Slob and co-workers, suggests that the interpretation ofED10s from quantal data is problematic, and that ED50s are a more defensible summary measure. An analysis of ED50 ratios would therefore seem particularly timely. Previous work implicated censoring as being the predominant source of bias, and suggested imputation strategies. Building on this work, we test the effectiveness of the imputation strategies on ED50 ratios using our simulation platform. Recommendations are made for future interpretations of ED50 ratios.
*Funded by the McLaughlin Centre for Population Health Risk Assessment
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