PROCESS OF BUILDING BIOLOGICALLY BASED DOSE-RESPONSE MODELS FOR DEVELOPMENTAL DEFECTS

The problem of developing biologically-based dose-response models is addressed for predicting the prevalence of birth defects at low doses of toxic chemicals administered during pregnancy. To illustrate the process of incorporating biological information, a model is postulated to predict the prevalence of cleft palate for a chemical that reduces embryonic/fetal growth, which results in inadequate palatal cells for closure. Experimental bioassay data examining the prevalence of cleft palate in mice exposed to the herbicide 2,4,5-T are used to illustrate the process. With the limited data available, it is necessary to assume a model for cell growth and the relationship between the cell growth rate parameter and dose of 2,4,5-T. Also, a relationship between cleft palate prevalence and growth is assumed and then checked with experimental data. The purpose of the paper is not to provide a universal biologically based dose-response model for cleft palate, but rather to demonstrate the extent, and type of information and data required. It remains to be seen if the form of the model is appropriate for chemicals that primarily produce embryo/fetal malformations or death via reduced or delayed cellular growth.