A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA adduct formation in primary hepatocytes

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.01.016· OSTI ID:21344947

Paini, Alicia ^[1]; Punt, Ans ^[1]; Viton, Florian; Scholz, Gabriele; Delatour, Thierry; Marin-Kuan, Maricel; Schilter, Benoit ^[2]; Bladeren, Peter J. van ^[1]

---

1. Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands)
2. Nestle Research Center, PO Box 44, Lausanne (Switzerland)

Estragole has been shown to be hepatocarcinogenic in rodent species at high-dose levels. Translation of these results into the likelihood of formation of DNA adducts, mutation, and ultimately cancer upon more realistic low-dose exposures remains a challenge. Recently we have developed physiologically based biokinetic (PBBK) models for rat and human predicting bioactivation of estragole. These PBBK models, however, predict only kinetic characteristics. The present study describes the extension of the PBBK model to a so-called physiologically based biodynamic (PBBD) model predicting in vivo DNA adduct formation of estragole in rat liver. This PBBD model was developed using in vitro data on DNA adduct formation in rat primary hepatocytes exposed to 1'-hydroxyestragole. The model was extended by linking the area under the curve for 1'-hydroxyestragole formation predicted by the PBBK model to the area under the curve for 1'-hydroxyestragole in the in vitro experiments. The outcome of the PBBD model revealed a linear increase in DNA adduct formation with increasing estragole doses up to 100 mg/kg bw. Although DNA adduct formation of genotoxic carcinogens is generally seen as a biomarker of exposure rather than a biomarker of response, the PBBD model now developed is one step closer to the ultimate toxic effect of estragole than the PBBK model described previously. Comparison of the PBBD model outcome to available data showed that the model adequately predicts the dose-dependent level of DNA adduct formation. The PBBD model predicts DNA adduct formation at low levels of exposure up to a dose level showing to cause cancer in rodent bioassays, providing a proof of principle for modeling a toxicodynamic in vivo endpoint on the basis of solely in vitro experimental data.

• OSTI ID: 21344947
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.01.016; PII: S0041-008X(10)00041-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
60 APPLIED LIFE SCIENCES
BIOLOGICAL MARKERS
CARCINOGENS
DNA
DNA ADDUCTS
DOSES
IN VITRO
IN VIVO
LIVER
LIVER CELLS
MEN
MUTATIONS
NEOPLASMS
RATS
SIMULATION
TOXICITY
ADDUCTS
ANIMAL CELLS
ANIMALS
BODY
DIGESTIVE SYSTEM
DISEASES
GLANDS
MALES
MAMMALS
MAN
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PRIMATES
RODENTS
SOMATIC CELLS
VERTEBRATES