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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-95/112, 1994.
Description:
Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. Recently, statistical models appropriate for developmental toxicity testing have been developed and applied (Rai and Van Ryzin, 1985; Kupper et al. 1986; and Kodell et al., 1991). Those models (designated the RVR, LOG, and NCTR models respectively) account for the correlations among individual fetuses, the potential for litter size to affect the probability of adverse outcome, and the possibility of a threshold dose. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. The models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. Litter size appeared to be a significant covariable for predicting response rates. The ability of the LOG model to fit the data was largely due to method of accounting for litter size. A threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD 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 that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to NOAEL's determined by statistical tests of trend.