Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats.

Physiologically based pharmacokinetic (PBPK) models developed from gas uptake experiments have been used to estimate metabolic parameters for volatile organic compounds. Due to the potential application of PBPK models to estimate metabolic bioactivation constants in humans, it is important to understand the complex nature of these models and the resulting estimates. Adult male F344 rats (165-205 g) were individually exposed to carbon tetrachloride (CCl4) in gas uptake systems. Three rats at each concentration were exposed for 6 hr to initial concentrations of 25, 100, 250, and 1000 ppm CCl4. Partition coefficient determinations were performed by the vial equilibration technique and used as model inputs. Computer optimizations with the means of each initial chamber concentration at each time point resulted in an estimate of Vmax of 0.11 mg/hr (Vmaxc = 0.37 mg/hr/kg) and Km of 1.3 mg/liter. To determine the effect of individual animal variation in Vmax, optimizations were also performed with the mean +/- SD, resulting in Vmax estimates of 0.09 and 0.12 mg/hr, respectively. Similar analysis resulted in Km estimates of 0.98 and 1.58 mg/liter. The results of the sensitivity analysis were concentration dependent for CCl4. These results show Vmax and Km to be most accurately detected at lower initial chamber concentrations. Results of the sensitivity analysis at the lowest concentration established the following model input hierarchy: blood to air partition > fat partition and fat volume fraction > slowly perfused partition, ventilation rate, cardiac output, fat blood flow percentage > liver blood flow percentage and slowly perfused blood flow percentage. Further sensitivity analysis determined Vmax and Km to be highly correlated when using gas uptake technology and point to the need to an independent estimate for either constant. In summary, the application of sensitivity analysis to PBPK modeling resulted in an increased understanding of factors governing the estimation of metabolic parameters.

A physiologically based pharmacokinetic model for chloropentafluorobenzene in primates to be used in the evaluation of protective equipment against toxic gases.

Chloropentafluorobenzene (CPFB) has been proposed as an innocuous simulant for the uptake of toxic gases. Exposure to CPFB in a training exercise could be inferred afterwards from a measurement of CPFB in expired breath. To understand the relationship between exposure and measurement, we have developed a physiologically-based pharmacokinetic (PB-PK) model for CPFB in primates. To test the model, inhalation exposures were conducted on anesthetized rhesus monkeys. CPFB concentration in expired breath was measured during and after exposure. Simulations of CPFB uptake and clearance agreed with experimental measurements in seven of eight monkeys. A human version of the model was used to simulate exposures consisting of a single breath or a few breaths. By showing a measurable CPFB concentration in expired breath after several hours of clearance, simulations with the human model indicated the suitability of CPFB as a simulant for toxic gases.

Functional localization of avian intrapulmonary CO2 receptors within the parabronchial mantle.

To determine the location of avian intrapulmonary CO2 receptors, we changed the CO2 stimulus at different regions within the parabronchial mantle and measured the resulting changes in breathing pattern. Three procedures were used to vary the CO2 stimulus: (1) reverse the direction of pulmonary perfusion; (2) stop pulmonary ventilation while maintaining perfusion; and (3) stop pulmonary perfusion while maintaining ventilation. Right and left lungs of adult, anesthetized White Leghorn type chickens were independently, unidirectionally ventilated. The right lung was used to maintain the bird while the left pulmonary artery and vein were cannulated and connected to an extracorporeal gas exchanger, thereby isolating this lung's perfusion. The innervation to both lungs remained intact. When left pulmonary perfusion was reversed, the bird's breathing pattern remained unchanged. The change in breathing pattern that resulted from stopping left pulmonary ventilation was the same during forward perfusion (pulmonary artery to pulmonary vein) as during backward perfusion (pulmonary vein to pulmonary artery). The change in breathing pattern that resulted from stopping forward perfusion was the same as that resulting from stopping backward perfusion. The results indicate that CO2 receptors are not concentrated on the peripheral side of the parabronchial mantle, where venous blood would influence tham, or on the luminal side of the mantle, where arterialized blood would influence them. The CO2 receptors are either distributed symmetrically between the peripheral and luminal sides of the mantle or located in the epithelial lining of the parabronchial lumen.

Theory of gas exchange in the avian parabronchus.

To understand the distribution of oxygen and carbon dioxide in the avian lung, a theoretical treatment of gas exchange in the parabronchus of the avian lung is described. The model is modified after Zeuthen (1942). In addition to bulk flow through the parabronchial lumen, diffusion through the air spaces of both the parabronchial lumen and air capillaries is treated. The relationship of PO2 and PCO2 within the blood capillaries, air capillaries, and parabronchial lumen to parabronchial blood flow and ventilation is graphically shown. The results indicate that the variations of PO2 and PCO2 along an air capillary are less than one torr under resting conditions. Removal of diffusion resistance within the air space of the air capillaries increases calculated parabronchial gas exchange by less than 0.1% at rest. At high or resting ventilation rates the partial pressure profile along the parabronchial lumen calculated considering bulk flow only agrees well with the profile calculated considering bulk flow and axial diffusion, but as the ventilation rate decreases there is increasingly large disagreement. Forward diffusion of O2 toward the parabronchus reduces pre-parabronchial PO2 and backward diffusion of CO2 from the parabronchus increases PCO2. Neglecting diffusion within the air spaces of both the lumen and the air capillaries increases calculated parabronchial gas exchange by less than 2% (CO2) or 6% (O2) at rest.