ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg078
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Preclinical Development, Human Genome Sciences, Inc. Rockville, MD 20850
* To whom correspondence should be addressed. E-mail: raymond.yang{at}colostate.edu.
A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase
© 2003 Society of Toxicology
Carcinogenity
Stochastic Simulation of Hepatic Preneoplastic Foci Development for Four Chlorobenzene Congeners in a Medium-Term Bioassay
2 CIIT Centers for Health Research, Six Davis Drive, Research Triangle Park, NC 27709
3 Aeomica Disease Profiling Group, Amersham Plc., 929 E. Arques Ave., Sunnyvale, CA 94085
4 School of Pharmacy, University of Colorado Health Science Center, Denver, CO 80262
5 Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Department of Environmental Health, Colorado State University, Fort Collins, CO 80523
6 Department of Oncology, McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706
Abstract 
(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, 8 weeks of age, were initiated with a single dose (200 mg/kg, i.p.) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.1 mol/kg chlorobenzene was maintained for 6 weeks. Partial hepatectomy was performed 3 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 that the model parameter value for the net growth rate of B cells during the 2-week regenerative period following partial hepatectomy is correlated with 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, but 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.
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