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ToxSci Advance Access originally published online on June 12, 2003
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Toxicological Sciences 75, 192-200 (2003)
Copyright © 2003 by the Society of Toxicology

RISK ASSESSMENT

Biologically Motivated Computational Modeling of Chloroform Cytolethality and Regenerative Cellular Proliferation

Yu-Mei Tan, Byron E. Butterworth1, Michael L. Gargas2 and Rory B. Conolly3

CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709

ABSTRACT

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodents. As such, events related to cytotoxicity are the driving force for cancer induction. In this paper we extended an existing physiologically based pharmacokinetic (PBPK) model for chloroform to describe a plausible mechanism linking the hepatic metabolism of chloroform to hepatocellular killing and regenerative proliferation. The key aspects of this mechanism are (1) the production of damage at a rate proportional to the rate of metabolism predicted by the PBPK model, (2) the saturable repair of the damage, (3) the stimulation of the cell death rate by damage, and (4) the stimulation of the cell division rate as a function of the difference between the control and exposed numbers of cells. This extension allows the 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 concentrations and exposure durations 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 the 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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