Evaluation of the benchmark dose method for dichotomous data: model dependence and model selection.
The benchmark dose (BMD) method was evaluated using the USEPA BMD software. Dose-response data on cleft palate and hydronephrosis for a number of related polyhalogenated aromatic compounds were obtained from the literature. According to chi(2) test statistics, each dichotomous USEPA model failed to adequately describe only 1 of 12 cleft palate data sets. For hydronephrosis, the models were discriminated to a higher extent according to global goodness-of-fit. NOAELs for cleft palate corresponded to BMDLs (the approximate lower confidence limit on the BMD) for extra risks in the range of 5% or below. Model dependence of the BMDL estimate was more pronounced at lower levels of benchmark response (BMR). A BMR of 5% (extra risk) is recommended for cleft palate since model differences at this level were limited for all data. In addition, at BMRs of 5-10% the BMDL for all models was little affected by the specified confidence limit size (in the 90-99% range). For BMDL determination a conservative model selection approach was applied. At the suggested level of BMR (5%) this procedure resulted in use of the same model (multistage model) for the cleft palate endpoint in general. Akaike's information criterion (AIC) was considered for comparison between models. Determination of appropriateness of use of such methods in dose-response applications requires further analysis.
Sand
Salomon
S
Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, 17177 Stockholm, Sweden. salomon.sand@imm.ki.se
Filipsson
Agneta Falk
AF
Victorin
Katarina
K
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D019985:Benchmarking / Q000379:methods*; D002972:Cleft Palate / Q000139:chemically induced; D003198:Computer Simulation; D004147:Dioxins / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006869:Hydronephrosis / Q000139:chemically induced; D015233:Models, Statistical; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D018570:Risk Assessment / Q000379:methods; D013723:Teratogens / Q000633:toxicity; D014481:United States; D014484:United States Environmental Protection Agency
D004147:Dioxins; D013723:Teratogens