A physiologically based pharmacodynamic analysis of hepatic foci within a medium-term liver bioassay using pentachlorobenzene as a promoter and diethylnitrosamine as an initiator.
A stochastic clonal growth model for describing quantitative changes in size and number of putative preneoplastic lesions was modified to analyze the time-course information of cell proliferation and glutathione S-transferase pi (GST-P) foci within a medium-term bioassay. The study used F344 rats and a single initiating event using diethylnitrosamine (200 mg/kg ip) at Week 0. After a 2-week recovery period, chemical treatment began by gavage administration of pentachlorobenzene (PeCB; 100 micromol/kg/day, 7 days/week) in a corn oil vehicle and continued for 6 weeks. One week after beginning gavage dosing, a two-thirds partial hepatectomy was performed and the animals were serially euthanized at 48, 120, 168, 624, and 840 h postsurgery, which corresponds to 216, 288, 336, 792, and 1008 h following the beginning of PeCB treatment, respectively. For analysis, two types of models were evaluated for describing the time-course changes in GST-P foci. First, a sequential model describing the transformation of normal cells into a homogenous initiated cell population (i.e., one-cell model). Second, a two-cell model that describes a heterogeneous foci population by splitting the initiated cell population into two distinct types. In our study, the one-cell model was unable to adequately represent the time-course data for changes in both size and number of foci. In contrast, the two-cell model, which was parameterized to describe a negative selection mechanism, produced adequate simulations of both the size and number of foci. This model-based analysis suggested that the differences between PeCB-treated and untreated animals were primarily in parameters involving the rates of cell death.
Thomas
R S
RS
Center for Environmental Toxicology and Technology, Colorado State University, Fort Collins, Colorado 80523-1680, USA.
Conolly
R B
RB
Gustafson
D L
DL
Long
M E
ME
Benjamin
S A
SA
Yang
R S
RS
D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D002273:Carcinogens / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000633:toxicity*; D002999:Clone Cells; D003043:Cocarcinogenesis; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004357:Drug Synergism; D005659:Fungicides, Industrial / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D002273:Carcinogens; D002722:Chlorobenzenes; D005659:Fungicides, Industrial; C003060:pentachlorobenzene; D005982:Glutathione Transferase; D004128:Dimethylnitrosamine