Toxicological Sciences 57, 32-42 (2000)
Copyright © 2000 by the Society of Toxicology
Carcinogenicity |
Analysis of Rat Liver Foci Growth with a Quantitative Two-Cell Model after Treatment with 2,4,5,3',4'-Pentachlorobiphenyl
,1
* Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden;
Chemical Industry Institute of Toxicology, Six Davis Drive, Research Triangle Park, North Carolina 27709; and
AstraZeneca, R&D Södertälje, Safety Assessment, S-151 85, Södertälje, Sweden
A biologically based, quantitative foci-growth model was used to analyze the effect of 20 and 52 weeks treatment with 2,4,5,3',4'-pentachlorobiphenyl (PCB118) on the development of enzyme-altered foci in rat liver initiated with partial hepatectomy and diethylnitrosamine. Hepatocyte proliferation was examined and the data were used in the selection of division rates for the computer simulations of foci growth. The bromodeoxyuridine-labeling index in foci was generally larger than in nonfocal tissue. A strong correlation was found between foci occurrence and proliferation in focal as well as nonfocal tissue, suggesting that cytotoxicity and regenerative proliferation are involved in the foci growth caused by PCB118. The foci growth model adequately simulated the foci data when certain assumptions were introduced. Given the general view that PCB118 is a nonmutagenic compound, the foci data could not be modeled assuming one homogenous cell population, but was adequately fitted assuming two separate initiated cell populations that respond differently to the promotion stimulus. Other assumptions were a selective growth advantage for initiated cells during and shortly after the initiation treatment, and a transient increase of proliferation in focal hepatocytes at the first PCB administration in the higher dose groups. The model predicted an increased rate of focal cell death, at high doses, to adequately fit the foci data. These assumptions are supported by experimental data for other carcinogens, indicating the importance of studying cell kinetics in heterogeneous subpopulations of initiated cells in PCB-induced hepatocarcinogenesis.
Key Words: polychlorinated biphenyl (PCB); 2,4,5,3',4'-pentachlorobiphenyl; tumor promotion; cell proliferation; quantitative foci growth model; altered hepatic foci.
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