Statistical Evaluation of Toxicological Experimental Design for Bayesian Model Averaged Benchmark Dose Estimation with Dichotomous Data

摘要

A method is presented to statistically evaluate toxicity study design for dose-response assessment aimed at minimizing the uncertainty in resulting Benchmark dose (BMD) estimates. Although the BMD method has been accepted as a valuable tool for risk assessment, the traditional no observed adverse effect level (NOAEL)/lowest observed adverse effective level (LOAEL) approach is still the principal basis for toxicological study design. To develop similar protocols for experimental design for BMD estimation, methods are needed that account for variability in experimental outcomes, and uncertainty in dose-response model selection and model parameter estimates. Based on Bayesian model averaging (BMA) BMD estimation, this study focuses on identifying the study design criteria that can reduce the uncertainty in BMA BMD estimates by using a Monte Carlo pre-posterior analysis on BMA BMD predictions. The results suggest that (1) as more animals are tested there is less uncertainty in BMD estimates; (2) one relatively high dose is needed and other doses can then be appropriately spread over the resulting dose scale; (3) placing different numbers of animals in different dose groups has very limited influence on improving BMD estimation; and (4) when the total number of animals is fixed, using more (but smaller) dose groups is a preferred strategy.