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ToxSci Advance Access originally published online on May 5, 2004
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Toxicological Sciences 80, 258-267 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.

Application of a Statistical Dynamic Model Investigating the Short-Term Cellular Kinetics Induced by Riddelliine, a Hepatic Endothelial Carcinogen

Marjo V. Smith*,1, Abraham Nyska{dagger} and Chris Portier{dagger}

* Constella Health Sciences, 2605 Meridian Parkway, Durham, North Carolina 27713 and {dagger} National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27713

Received December 15, 2004; accepted April 20, 2004

In recent studies, riddelliine, a pyrrolizidine alkaloid, was found to increase rates of replication and apoptosis and induce hemangiosarcoma in the liver of rats and mice. To analyze DNA replication and apoptosis data taken from the same animals, we have developed a predictive mathematical model for describing BrdU labeling and apoptotic processes. The model allows the incorporation of simple diurnal patterns in cellular kinetics and is applied to data on hepatocytes and endothelial cells taken from riddelliine exposed rats. Predictions from the model were used with multivariable nonlinear regression techniques to estimate replication and apoptotic rate constants for both cell types and all treatment groups. Hypothesis tests were used with the predicted rates to separate the competing effects of riddelliine on replication and apoptosis of hepatocytes and endothelial cells as well as compare replication rates between cell types. That estimated replication rates were found to be significantly higher for endothelial cells supports the supposition of induction of hemangiosarcoma by riddelliine in the liver.

Key Words: riddelliine; mathematical model; cellular kinetics; hemangiosarcoma.


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