Dose‐response Modelling of Growth for Developmental Toxicity

Abstract

A biologically-based dose-response model for predicting developmental malformation effects from exposure to a toxic substance during pregnancy is developed. The biological basis of this model arises from the expectation of exponential growth in rodents during gestation, and the exponential growth rate assumed to be reduced by dose raised to a power when a toxic substance is administered during gestation. The prenatal foetal weight is used as a biomarker to link the incidence of cleft palate to the dose level. A dose-response growth model for prenatal foetal weight as a function of both time and dose is established. This dose-response function is then combined with a dose-response function between the incidence of cleft palate and the prenatal foetal weight to form a dose-response function between the cleft palate and dose. Two experiments, a dexamethasone (DEX) exposure in rats and a 2,4,5-trichlorophenoxyacetic (2,4,5-T) acid exposure in mice, were conducted for purpose of checking the models empirically and for demonstration of modelling process. The proposed dose-response growth model for prenatal foetal weight fits adequately to both experimental data, but the model from prenatal foetal weight and incidence of cleft palate combined seems inadequate to describe the relationship between the dose and incidence of cleft palate fully.