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TOWARD A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROURACIL IN THE RAT: A MATHEMATICAL CONSTRUCT
Citation:
Setzer, R W., C S. Lau, M L. Mole, F. M. Copeland, J M. Rogers, AND R J. Kavlock. TOWARD A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROURACIL IN THE RAT: A MATHEMATICAL CONSTRUCT. TOXICOLOGICAL SCIENCES 59:49-58, (2001).
Description:
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 (Shuey et al. 1993). Previous work (Lau et al. 2000) 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 dose to embryonal thymidylate synthetase inhibition, and thymidylate synthetase inhibition to various measures of deoxyribonucleotide (dNTP) pool perturbation, is developed and parameters 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 the dose-response data described in a companion paper (Lau et al , 2000). 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 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).