A BIOLOGICALLY-BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICOLOGY

The methods currently used to evaluate the risk of developmental defec ts in humans from exposure to potential toxic agents do not reflect bi ological processes in extrapolating estimated risks to low doses and f rom test species to humans. We develop a mathematical model to describ e aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can b e incorporated into the model includes timing and rates of dynamic cel l processes such as differentiation, migration, growth, and replicatio n. The dose-response models produced can explain patterns of malformat ion rates as a function of both dose and time of exposure, resulting i n improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain developmen t in rats.