Promotion of liver GST-P foci by a chemical mixture of hexachlorobenzene (HCB) and 3,3',4,4',5-pentachlorobiphenyl (PCB126): integration of computer modeling and biology of clonal growth.
Lu-Y; Lohitnavy-M; Reddy-M; Lohitnavy-O; Eickman-E; Ashley-A; Xu-Y; Yang-R
Toxicologist 2006 Mar; 90(1):435
The objectives of this study were two-fold: (1) evaluating carcinogenic potential of a mixture of two persistent pollutants, HCB and PCB126, in an initiation/promotion bioassay involving the development of glutathione S-transferase form (GSTP) liver foci; and (2) integrating computer modeling with the biology of foci growth in the bioassay. The 8-week bioassay involved initiation with diethylnitrosamine on day 0, two-thirds partial hepatectomy on day 21, and daily oral gavage of HCB+PCB126 mixture from day 14 in young male F344 rats. The animals were sacrificed on days 20, 24, 28, 47, and 56. The mixture treatment significantly increased GST-P foci area and number in the liver, indicating the carcinogenic potential of this mixture. Our biologically based computer model was developed to simulate the occurrence and evolution of initiated GST-P cells in the liver over time. The initiated cells were partitioned into A and B subpopulations with the same division rate but different death rates. Each subpopulation was further categorized into single cells, mini- (2-12 cells), medium (13-400 cells), and large foci (>400 cells) with different growth kinetics. For the first time, our model quantitatively analyzed the effects of the size of foci on their growth kinetics. The model outputs on relative foci volume, foci number/cm3 liver, and size distribution were consistent with the experimentally derived data. This study is part of our continuing development of a predictive tool for carcinogenic potential of chemical mixtures by integrating computer modeling with biology of foci development. The predictive power of such biologically based modeling will increase as more data are available and quantitative correlation can be drawn between chemical properties and critical model parameters.
Models; Computer-models; Pollutants; Laboratory-animals; Animals; Animal-studies; Simulation-methods; Quantitative-analysis; Liver-disorders; Carcinogenicity; Carcinogenesis; Carcinogens; Chemical-properties
The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California
Colorado State University - Fort Collins