Animal-to-human extrapolation using compartmental models.

We have been studying how to use compartmental models to reliably extrapolate toxicological experimental results from one animal species to another with the ultimate goal of useful extrapolation to man. We have taken, as the fundamental core of our analysis, the physically necessary equations describing mass balance. These equations are the classical Fickian equations of the form VdC/dt = Q(a - v). These equations are not a complete set since they are insufficient to provide estimation of venous, arterial, or tissue concentrations with time. Therefore, the mass balance equations must be augmented with additional phenomenological relations to permit the desired calculations. Many investigators use the venous exist condition. While it is clear how to extrapolate the mass balance equations from one sized animal to another or from one species to another, it is not clear how to extrapolate the venous exit condition. In this research we have evaluated the venous exit condition by comparing it with approximate analyses of perfusion and substance diffusion in the tissue.

The association of elevated plasma cortisol and early atherosclerosis as demonstrated by coronary angiography.

To study the association of plasma cortisol and coronary atherosclerosis, we elected 71 male outpatients who had coronary angiography as part of their evaluation at our facility. Forty-eight percent of the angiograms showed no evidence of coronary artery disease (CAD), 20% showed mild CAD, and 32% showed moderate to severe CAD. We found significant correlations between elevated serial morning plasma cortisols and moderate to severe coronary atherosclerosis. Using the odds ratio, we compared plasma cortisol to the major risk factors for coronary artery disease. Plasma cortisol was second only to serum cholesterol as a discriminator in our patient population between diseased and non-diseased patients. We found a significant correlation between plasma cortisol and cholesterol, blood pressure, and smoking- the three cardinal risk factors for CAD. The highest degree of correlation was found between cortisol and cholesterol. The possible significance of the association of cortisol and the major risk factors for CAD is discussed.

Physiologically based pharmacokinetic models for the transport of trichloroethylene in adipose tissue.

In this paper we present three physiologically based pharmacokinetic (PBPK) models for the systemic transport of trichloroethylene (TCE), with a focus on the adipose, or fat tissue. TCE is a widespread environmental contaminant, and has been shown to produce toxic effects in both animals and humans. A key characteristic of TCE is its tendency to accumulate in fat tissue, which has a major impact on the overall systemic disposition of TCE. Here we use PBPK models to predict the dynamics of TCE in the various tissues and organs, including the adipose tissue. The first model utilizes the standard 'perfusion-limited' compartmental model for the fat tissue, while the second model uses a 'diffusion-limited' model to describe the transport through the adipose tissue. Both of these ODE models are based on 'well-mixed' and rapid equilibrium assumptions, and do not take into account the specific and largely heterogeneous physiology of adipose tissue. The third model we discuss is a PBPK hybrid model with an axial-dispersion type model for the adipose tissue. This PDE-based model is designed to capture key physiological heterogeneities of fat tissue, including widely varying fat cell sizes, lipid distribution, and blood flow properties. Model simulations demonstrate that this model may be well-suited to predict the experimental behavior of TCE in adipose tissue using parameter estimation techniques.