Simulation-based assessment of model selection criteria during the application of benchmark dose method to quantal response data

BACKGROUND: To employ the benchmark dose (BMD) method in toxicological risk assessment, it is critical to understand how the BMD lower bound for reference dose calculation is selected following statistical fitting procedures of multiple mathematical models. The purpose of this study was to compare the performances of various combinations of model exclusion and selection criteria for quantal response data. METHODS: Simulation-based evaluation of model exclusion and selection processes was conducted by comparing validity, reliability, and other model performance parameters. Three different empirical datasets for different chemical substances were analyzed for the assessment, each having different characteristics of the dose-response pattern (i.e. datasets with rich information in high or low response rates, or approximately linear dose-response patterns). RESULTS: The best performing criteria of model exclusion and selection were different across the different datasets. Model averaging over the three models with the lowest three AIC (Akaike information criteria) values (MA-3) did not produce the worst performance, and MA-3 without model exclusion produced the best results among the model averaging. Model exclusion including the use of the Kolmogorov-Smirnov test in advance of model selection did not necessarily improve the validity and reliability of the models. CONCLUSIONS: If a uniform methodological suggestion for the guideline is required to choose the best performing model for exclusion and selection, our results indicate that using MA-3 is the recommended option whenever applicable.