Exploration of potential susceptibility of the older rodent population to two solvents using physiologically based pharmacokinetic (PBPK) transport models

摘要

The goal of this work was to use PBPK models to determine differences in distribution of two chemicals by taking into account physiological differences due to aging. A standard allometric scaling technique was evaluated and compared with the actual physiological measurements obtained in the older (24 month) F344 rat. This rodent species is commonly utilized in experiments designed to determine toxicity to environmental contaminants. Using physiological data across several adult mammalian species, modelers in the past have extrapolated to humans using an empirical allometric power equation of the from: COchemical boundsK(BW)~(75), where CO(cardiac output) is the physiological input parameter being scaled, K is a constant and BW is the body weight of the species in question. The question arises as to whether this same equation can be used to extrapolate within a given experimental species accounting for changes with age. Using this hypothesis, it can be assumed that the rat's K value for any given parameter is independent of age. Our goal was to test this hypothesis using PBPK models and computer simulations.