Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Toward a biologically based dose-response model for developmental toxicityof 5-fluorouracil in the rat: Acquisition of experimental data
Autore:
Lau, C; Mole, ML; Copeland, MF; Rogers, JM; Kavlock, RJ; Shuey, DL; Cameron, AM; Ellis, DH; Logsdon, TR; Merriman, J; Setzer, RW;
Indirizzi:
US EPA, Natl Hlth & Environm Effects Res Lab, Reprod Toxicol Div, Res Triangle Pk, NC 27711 USA US EPA Res Triangle Pk NC USA 27711 ol Div, Res Triangle Pk, NC 27711 USA US EPA, Natl Hlth & Environm Effects Res Lab, Expt Toxicol Div, Res Triangle Pk, NC 27711 USA US EPA Res Triangle Pk NC USA 27711 ol Div, Res Triangle Pk, NC 27711 USA Dupont Merck Pharmaceut Co, Newark, DE USA Dupont Merck Pharmaceut Co Newark DE USA k Pharmaceut Co, Newark, DE USA Mantech Environm Sci, Res Triangle Pk, NC USA Mantech Environm Sci Res Triangle Pk NC USA Sci, Res Triangle Pk, NC USA
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 1, volume: 59, anno: 2001,
pagine: 37 - 48
SICI:
1096-6080(200101)59:1<37:TABBDM>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
COLON-CARCINOMA-CELLS; DOUBLE-STRAND BREAKS; MOUSE FM3A CELLS; THYMIDYLATE SYNTHASE; MESSENGER-RNA; DEOXYRIBONUCLEOSIDE TRIPHOSPHATES; 2-DIMENSIONAL ANALYSIS; GROWTH-INHIBITION; MATERNAL EXPOSURE; THYMIDINE KINASE;
Keywords:
mammalian developmental toxicity; BBDR modeling; 5-fluorouracil; thymidylate synthetase inhibition; dNTP imbalance; limb dysmorphogenesis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Lau, C US EPA, Natl Hlth & Environm Effects Res Lab, Reprod Toxicol Div, Mail Drop 67, Res Triangle Pk, NC 27711 USA US EPA Mail Drop 67 Res TrianglePk NC USA 27711 e Pk, NC 27711 USA
Citazione:
C. Lau et al., "Toward a biologically based dose-response model for developmental toxicityof 5-fluorouracil in the rat: Acquisition of experimental data", TOXICOL SCI, 59(1), 2001, pp. 37-48

Abstract

Biologically based dose-response (BBDR) models represent an emerging approach to improving the current practice of human health-risk assessment. The concept of BBDR modeling is to incorporate mechanistic information about a chemical that is relevant to the expression of its toxicity into descriptive mathematical terms, thereby providing a quantitative model that will enhance the ability for low-dose and cross-species extrapolation. Construction of a BBDR model for developmental toxicity is particularly complicated by the multitude of possible mechanisms. Thus, a few model assumptions were made. The current study illustrates the processes involved in selecting the relevant information for BBDR modeling, using an established developmental toxicant, 5-fluorouracil (5-FU), as a prototypic example. The primary BBDR model for 5-FU is based on inhibition of thymidylate synthetase (TS) and resultant changes in nucleotide pools, DNA synthesis, cell-cycle progression, and somatic growth. A single subcutaneous injection of 5-FU at doses rangingfrom 1 to 40 mg/kg was given to pregnant Sprague-Dawley rats at gestational day 14; controls received saline. 5-FU was absorbed rapidly into the maternal circulation, and AUC estimates were linear with administered doses. Wefound metabolites of 5-FU directly incorporated into embryonic nucleic acids, although the levels of incorporation were low and lacked correlation with administered doses. On the other hand, 5-FU produced dose-dependent inhibition of thymidylate synthetase in the whole embryo, and recovery from enzyme inhibition was also related to the administered dose. As a consequence of TS inhibition, embryonic dTTP and dGTP were markedly reduced, while dCTPwas profoundly elevated, perhaps due to feedback regulation of intracellular nucleotide pools. The total contents of embryonic macromolecules (DNA and protein) were also reduced, most notably at the high doses. Correspondingly, dose-related reductions of fetal weight were seen as early as GD 15, and these deficits persisted for the remainder of gestation. These detailed dose-response parameters involved in the expression of 5-FU developmental toxicity were incorporated into mathematical terms for BBDR modeling. Such quantitative models should be instrumental to the improvement of high-to-low dose and cross-species extrapolation in health-risk assessment.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/07/20 alle ore 18:09:52