MODELING FETAL DEATH AND MALFORMATION IN DEVELOPMENTAL TOXICITY STUDIES

We review approaches to dose-response modeling and risk assessment for binary data from developmental toxicity studies. In particular, we fo cus on jointly modeling fetal death and malformation and use a continu ation ratio formulation of the multinomial distribution to provide a m odel for risk. Generalized estimating equations are used to account fo r clustering of animals within litters. The fitted model is then used to calculate doses corresponding to a specified level of excess risk. Two methods of arriving at a lower confidence limit or Benchmark dose are illustrated and compared. We also discuss models based on single b inary end points and compare our approach to a binary analysis of whet her or not the animal was 'affected' (either dead or malformed). The m odels are illustrated using data from four developmental toxicity stud ies in EG, DEHP, TGDM, and DYME conducted through the National Toxicol ogy Program.