The Influence of Aging on the Pharmacokinetics and Pharmacodynamics of Carbon Tetrachloride In Fisher-344 Rats

EPA Grant Number: GF9502084
Title: The Influence of Aging on the Pharmacokinetics and Pharmacodynamics of Carbon Tetrachloride In Fisher-344 Rats
Investigators: Schoeffner, Daniel
Institution: University of Georgia
EPA Project Officer: Michaud, Jayne
Project Period: May 1, 1995 through January 1, 2000
Project Amount: $25,344
RFA: STAR Graduate Fellowships (1995) Recipients Lists
Research Category: Fellowship - Health , Health Effects , Academic Fellowships


The objective of this study is to critically evaluate the effect that increasing age has on toxicological responses to carbon tetrachloride CCL4 in Fisher-344 (F-344) rats. The elderly represent the most rapidly growing segment of the population in the U.S. It is well recognized that the frequency of idiosyncrasies and other adverse drug reactions increases with age. If this holds true for chemicals as well, the elderly may be considered a sensitive subpopulation to environmental contamination. CCL4 is a ubiquitous environmental contaminant. CCL4 exerts its greatest influence on the liver, the kidneys, and the central nervous system. The specific three goals of this study are: 1) to determine differences in CCL4-induced hepatotoxicity among various age groups of F-344 rats; 2) to measure physiological and metabolic parameters in geriatric F-344 rats; and 3) to develop and validate PBPK and biologically-based pharmacodynamic models for CCL4. To accomplish the first goal, several distinct age groups of F-344 rats will be utilized. Three dose levels will be employed in order to assess dose-response relationships of CCL4 in the senescent rodents. CCL4 will be administered by oral gavage in an aqueous emulsion to more closely simulate ingestion of CCL4 in water. Hepatotoxicity will be assessed 24 hours post-dosing. For the second goal, physiological modeling will be required utilizing biological parameters specific to the animal in question. Allometric scaling has frequently been used when experimentation data are limited. These values will aid in the development of a physiologically-based pharmacokinetic (PBPK) model that will subsequently be used to predict blood and tissue concentrations in senescent rodents. For the third goal, a PBPK model will be developed using the experimentally determined physiological and metabolic parameters from geriatric F-344 rats. Metabolic parameters, such as Vmax and Km, can be determined by gas uptake techniques in a limited number of animals. Biological sampling will be performed to validate the model predictions. Blood and tissue samples will be taken to compare the model predictions to the actual time-course of blood and target organ tissue concentrations of parent compound and cytotoxic metabolites. In-vivo covalent binding of radiolabeled CCL4 to cellular proteins and lipids will be used as a measure of target tissue dose of cytotoxic metabolites, in order to develop and validate a dynamic model of CCL4.

Supplemental Keywords:

RFA, Health, Air, Toxics, National Recommended Water Quality, air toxics, HAPS, Susceptibility/Sensitive Population/Genetic Susceptibility, genetic susceptability, 33/50, sensitive populations, pharmacodynamics, carbon tetrachloride, pharmacokinetic models, elderly, Fisher-344 Rats, age dependent response, CCL4 responses

Progress and Final Reports:

  • 1995
  • 1996
  • 1997
  • 1998
  • Final