ToxSci Advance Access originally published online on April 15, 2003
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Toxicological Sciences 73, 301-314 (2003)
Copyright © 2003 by the Society of Toxicology
CARCINOGENICITY |
Stochastic Simulation of Hepatic Preneoplastic Foci Development for Four Chlorobenzene Congeners in a Medium-Term Bioassay
* Preclinical Development, Human Genome Sciences, Inc., Rockville, Maryland 20850;
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709;
Kalypsos, Inc., La Jolla, California 92037;
School of Pharmacy, University of Colorado Health Science Center, Denver, Colorado 80262;
¶ Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523; and
|| Department of Oncology, McArdle Laboratory for Cancer Research, Madison, Wisconsin 53706
A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase 
(GST-P) enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen for 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TECB), pentachlorobenzene (PECB), and hexachlorobenzene (HCB). Male Fisher 344 rats, eight weeks of age, were initiated with a single dose (200 mg/kg, ip) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.1 mol/kg chlorobenzene was maintained for six weeks. Partial hepatectomy was performed three weeks after initiation. Liver weight, normal hepatocyte division rates, and the number and volume of GST-P positive foci were obtained at 23, 26, 28, 47, and 56 days after initiation. A clonal growth stochastic model separating the initiated cell population into two distinct subtypes (referred to as A and B cells) was successfully used to describe the foci development data for the four chlorobenzenes. The B cells are initiated cells that display a selective growth advantage under conditions that inhibit the growth of initiated A cells or normal hepatocytes. The simulation exercise for the four chlorobenzenes indicates a positive correlation between the estimated net growth rate of B cells during the 2-week regeneration period following partial hepatectomy and final foci volume at the end of the bioassay. This observation is consistent with the sensitivity analysis of model parameters. While TECB, PECB, and HCB all significantly increased foci volume, only HCB increased normal hepatocyte proliferation. Together, these results indicate that examining effects of chemicals on regenerative responses following partial hepatectomy may be a means for understanding the carcinogenicity potential of chlorobenzene compounds.
Key Words: preneoplastic foci; simulation; liver carcinogenesis; clonal growth model; chlorobenzene.
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