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TOWARDS A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROUACIL IN THE RAT: A MATHEMATICAL CONSTRUCT
Citation:
Setzer, R W., C S. Lau, M L. Mole, M. F. Copeland, J M. Rogers, AND R J. Kavlock. TOWARDS A BIOLOGICALLY BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROUACIL IN THE RAT: A MATHEMATICAL CONSTRUCT. Presented at SOT, San Francisco, CA, March 25 - 29, 2001.
Description:
CREATING A BIOLOGICALLY-BASED DOSE-RESPONSE MODEL FOR DEVELOPMENTAL TOXICITY OF 5-FLUOROURACIL IN THE RAT. R W Setzer1, C Lau2, M L Mole2, M F Copeland2, J M Rogers2 and R J Kavlock2. 1ETD, 2RTD, NHEERL, ORD, US EPA, Research Triangle Park, NC, USA.
Biologically based dose-response (BBDR) models are a way to incorporate mechanistic information into dose-response assessment. 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. 1994). 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. Here we develop a mathematical model relating maternally administered dose to embryonal thymidylate synthetase (TS) inhibition, and thymidylate synthetase inhibition to various measures of deoxyribonucleotide (dNTP) pool perturbation, and estimate parameters and the uncertainty of subsequent predictions using the previously collected data. The strategy used was to develop semi-empirical submodels for 5-FU pharmacokinetics, 5-FU metabolism and TS inhibition, and nucleotide pool perturbation, and to estimate model parameters from the dose-response data described in Lau et al (2000). Even for the relatively simple models described here, not all parameters could be uniquely estimated using data from dose-response and time-course studies, and some values had to be assigned based on plausible guesses. The models developed predict that 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. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.)