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Toxicological Sciences 59, 49-58 (2001)
Copyright © 2001 by the Society of Toxicology

Biotransformation and Toxicokinetics

Toward a Biologically Based Dose-Response Model for Developmental Toxicity of 5-Fluorouracil in the Rat: A Mathematical Construct

R. Woodrow Setzer*,1, Christopher Lau{dagger}, M. Leonard Mole{dagger}, M. Frank Copeland{dagger}, John M. Rogers{dagger} and Robert J. Kavlock{dagger}

* Experimental Toxicology Division and {dagger} Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711

Biologically based dose-response (BBDR) models comprise one way to incorporate 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 developmental toxicity. Previous work has provided data and a general mechanistic framework for the developmental toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. In this paper, a mathematical model relating maternally administered treatment with 5-FU to embryonal thymidylate synthetase inhibition and thymidylate synthetase inhibition to various measures of deoxyribonucleotide triphosphate (dNTP) pool perturbation is developed, and parameters are estimated using the data collected. The strategy used was to develop semi-empirical submodels for each of the intervening steps, and to estimate model parameters from previously described data. The models developed predict that there is no practical threshold for dNTP pool perturbation; that is, even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

Key Words: biologically based dose-response model; 5-fluorouracil (5-FU); deoxyribonucleotide triphosphate (dNTP) pool perturbation; fetal weight deficit; thymidylate synthetase (TS) inhibition.


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