BIOLOGICAL MODELING OF 5-FLUOROURACIL DEVELOPMENTAL TOXICITY

A biologically-based dose-response (BBDR) model is a mathematical desc ription of the biological events leading to expression of a toxic resp onse. As an alternative to current approaches in non-cancer risk asses sment, such models will reduce uncertainty in that they will provide a more comprehensive description of toxicity. We are involved in constr uction of a BBDR model for the developmental toxicity of 5-fluorouraci l (5-FU) in the rat using multiple approaches. First, to identify crit ical events in the pathogenesis of 5-FU developmental toxicity, thymid ylate synthetase (TS) inhibition and alterations in cell cycle kinetic s and growth were examined in embryos following maternal administratio n of 5-FU on day 14 of gestation. A dose-related decline in TS activit y was observed within I h; however, maximal inhibition and recovery we re similar at 10, 20 and 40 mg/kg. Dose-dependent cell cycle alteratio ns were observed within 4 h after exposure and were maximal at 8 h. Hi ndlimb growth reduction was observed 24 h after exposure to 40 mg/kg, but not at lower doses. At term hindlimb defects were observed at dose s above 30mg/kg. An integrated dose-response model for hindlimb defect s was derived from empirical relationships among these events. The res ultant dose-response somewhat over-predicted the developmental toxicit y of 5-FU, although results of a Monte Carlo simulation indicated that these data were not incompatible with model predictions. Overall, the results suggest that TS inhibition is a key component of the mechanis m of 5-FU developmental toxicology, but the model does not capture all of the critical events in the induction of hindlimb defects. A prelim inary mechanistic model for the inhibition of embryonic TS, DNA synthe sis and cell cycle following maternal exposure to 5-FU, independently derived from literature data to further examine the potential role of this pathway in its developmental toxicity, predicted a dose-response for TS inhibition and DNA synthesis that closely reflected the observe d patterns. These results further suggest that TS inhibition, resultan t deficits in DNA synthesis and cell cycle perturbations represent a c ritical mechanistic pathway in the developmental toxicity of 5-FU.