DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY .3. STATISTICAL-MODELS

Although quantitative modeling has been central to cancer risk assessm ent for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endp oints for determining reference doses and reference concentrations. St atistical models appropriate for representing the unique features of d evelopmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, hi. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. How e, J. Chen, and D. Gaylor. 1991, Risk Anal. 11, 583-590). Generalizati ons of those models (designated the RVR, LOG, and NCTR models, respect ively) account for the correlations among observations in individual f etuses or implant within litters; the potential for variables other th an dose, such as litter size, to affect the probability of adverse out come; and the possibility of a threshold dose below which background r esponse rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in r esponse rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model ap pearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility wi th respect to the representation of the dependence of response probabi lity on litter size, a trait not shared by the other two models. Litte r size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assumin g a beta-binomial distribution for the observations among individual f etuses. In contrast, a threshold dose parameter did not appear to be n ecessary to adequately describe the observed dose-response patterns. B MD estimates (corresponding to 5% additional risk) from all three mode ls were similar to one another and to BMDs estimated from other, gener ic dose-response models (not specifically designed for developmental t oxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse e ffect levels determined by statistical tests of trend. Greater emphasi s on and further examination of dose-response modeling for development al toxicity testing are needed; biologically based approaches that con sider the continuum of developmental effects induced in such tests sho uld be encouraged. (C) 1994 Society of Toxicology.