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DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY III. STATISTICAL MODELS
Citation:
Allen, B., R. Kavlock, C. Kimmel, AND E. Faustman. DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY III. STATISTICAL MODELS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/061.
Description:
Although quantitative modeling has been central to cancer risk assessment for years, the concept of do@e-response modeling for developmental effects is relatively new. he benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for det g reference doses and reference concentrations. tatistical models appropriate for representing the unique fea of developmental toxicity testing have been developed and applied. eneralizations of those models (designated the RVR, LOG, and NCTR models) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome-, and the possibility of a threshold dose below which background response rates are unaltered. he generalized models were applied to a database of 607 endpoints with significant dose-related increases @m response rate. t was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. ignificant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. itter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a B-binonmial distribution for the observations among individual fetuses. n contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. MD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected, The BMDs at the 5% level of risk were similar to no observed adverse effect levels detected by statistical tests of trend. urther examination of dose-response modeling for developmental toxicity testing is needed.