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Titolo:
Toward a biologically based dose-response model for developmental toxicityof 5-fluorouracil in the rat: A mathematical construct
Autore:
Setzer, RW; Lau, C; Mole, ML; Copeland, MF; Rogers, JM; Kavlock, RJ;
Indirizzi:
US EPA, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA US EPA Res Triangle Pk NC USA 27711 & Dev, Res Triangle Pk, NC 27711 USA US EPA, Reprod Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA US EPA Res Triangle Pk NC USA 27711 & Dev, Res Triangle Pk, NC 27711 USA
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 1, volume: 59, anno: 2001,
pagine: 49 - 58
SICI:
1096-6080(200101)59:1<49:TABBDM>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLACENTAL-TRANSFER; KINETIC-MODEL; CHEMOTHERAPY; METABOLISM;
Keywords:
biologically based dose-response model; 5-fluorouracil (5-FU); deoxyribonucleotide triphosphate (dNTP) pool perturbation; fetal weight deficit; thymidylate synthetase (TS) inhibition;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Setzer, RW US EPA, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab,Off Res & Dev, Mail Drop 74, Res Triangle Pk, NC 27711 USA US EPA Mail Drop 74 Res Triangle Pk NC USA 27711 , NC 27711 USA
Citazione:
R.W. Setzer et al., "Toward a biologically based dose-response model for developmental toxicityof 5-fluorouracil in the rat: A mathematical construct", TOXICOL SCI, 59(1), 2001, pp. 49-58

Abstract

Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used forrisk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has beenused 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 poolperturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

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Documento generato il 24/01/20 alle ore 13:12:04