REPRODUCIBILITY OF THE DOSE-RESPONSE CURVE OF STEROID-INDUCED CLEFT-PALATE IN MICE

Pregnant CD-1 mice were exposed to cortisone acetate at doses ranging from 20 to 100 mg/kg/day on days 10-13 by oral and intramuscular route s. Multiple replicate assays were conducted under identical conditions to assess the reproducibility of the dose-response curve for cleft pa late. The data were fitted to the probit, logistic, multistage or Armi tage-Doll, and Weibull dose-response model separately for each route o f exposure. The curves were then tested for parallel slopes (probit an d logistic models) or coincidence of model parameters (multistage and Weibull models). The 19 replicate experiments had a wide range of slop e estimates, wider for the oral than for the intramuscular experiments . For all models and both routes of exposure the null hypothesis of eq uality of slopes was rejected at a significant level of p < 0.001. For the intramuscular group of replicates, rejection of slope equality co uld in part be explained by not maintaining a standard dosing regime. The rejection of equivalence of dose-response curves from replicate st udies showed that it is difficult to reproduce dose-response data of a single study within the limits defined by the dose-response model. Th is has important consequences for quantitative risk assessment, public health measures, or development of mechanistic theories which are typ ically based on a single animal bioassay.