Toward a biologically based dose-response model for developmental toxicityof 5-fluorouracil in the rat: A mathematical construct

Biologically based dose-response (BBDR) models comprise one way to incorpor ate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for deve lopmental toxicity. Previous work has provided data and a general mechanist ic framework for the developmental toxicity of 5-FU when it was administere d to pregnant rats subcutaneously on gestation day 14. In this paper, a mat hematical model relating maternally administered treatment with 5-FU to emb ryonal thymidylate synthetase inhibition and thymidylate synthetase inhibit ion to various measures of deoxyribonucleotide triphosphate (dNTP) pool per turbation is developed, and parameters are estimated using the data collect ed. The strategy used was to develop semi-empirical submodels for each of t he intervening steps, and to estimate model parameters from previously desc ribed data. The models developed predict that there is no practical thresho ld for dNTP pool perturbation; that is, even minimal doses of 5-FU should r esult in some perturbation of dNTP pools. In particular, the relationship b etween dNTP pool perturbation and fetal weight deficit suggests that if the re is a biological threshold for the effect of 5-FU on fetal weight, the re sponsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest d ose examined for developmental effects in these studies).