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ToxSci Advance Access published online on June 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg152
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 26, 2003; accepted May 9, 2003
© 2003 Society of Toxicology

Risk Assessment

Biologically Motivated Computational Modeling of Chloroform Cytolethality and Regenerative Cellular Proliferation

Yu-Mei Tan 1, Byron E. Butterworth 1, Michael L. Gargas 1, and Rory B. Conolly 1*

1 CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, NC USA

* To whom correspondence should be addressed. E-mail: rconolly{at}ciit.org.


  Abstract

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodents. As such, events related to cytotoxicity are the driving force for cancer induction. In this study, we extended an existing physiologically based pharmacokinetic (PBPK) model for chloroform to describe a plausible mechanism linking hepatic metabolism of chloroform to hepatocellular killing and regenerative proliferation. The key aspects of this mechanism are (1) production of damage at a rate proportional to the rate of metabolism predicted by the PBPK model, (2) saturable repair of the damage, (3) stimulation of the cell death rate by damage, and (4) stimulation of the cell division rate as a function of the difference between control and exposed numbers of cells. This extension allowed simulation of the labeling index and comparison with labeling index data. Data from a previously published chloroform inhalation study with female B6C3F1 mice that determined cytolethality and regenerative cellular proliferation following exposures of varying concentration and exposure duration were used for model calibration. Both threshold and low-dose linear linkages between chloroform-induced damage and cell death rate provided visually good fits to the labeling index data after formal optimization of the adjustable parameters, and there was no statistical difference between the fits of the two models to the data. Biologically motivated computational modeling of chloroform-induced cytolethality and regenerative proliferation is a necessary step in quantitative evaluation of the hypothesis that chloroform-stimulated cell proliferation predicts the rodent tumor response.

Key Words: Chloroform, Physiologically based pharmacokinetic (PBPK) model, Pharmacodynamic (PD), Regenerative cellular proliferation, Inhaled chloroform cytolethality, Labeling index (LI), Liver .


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