The importance of anatomical realism for validation of physiological models of disposition of inhaled toxicants.

The goodness of fit of three PBPK models to data for inhalation uptake of 1,3-butadiene by mice from closed chambers were compared. These models included a classical flow-limited model with blood consolidated into arterial and venous compartments, a flow-limited model with implicit blood and alveolar compartments, and a model with an actual alveolar compartment and blood distributed among compartments for arterial, venous, and capillary spaces. Using physiological and biochemical parameters from the literature, all three models reproduced observed steady-state blood butadiene concentrations. However, the first two models predicted more rapid uptake of butadiene than was observed. Assumptions such as ignoring extrahepatic metabolism or reducing the ventilation rate by 75% were required to enable these models to fit the butadiene uptake data. The behavior of the third model resembled that of the other two models when the single-pass extraction ratio of butadiene for all tissues was close to 1, but the model did reproduce observed butadiene uptake when an extraction ratio of 0.5 was used. The difference in predictions of the three models was traced to smaller computed blood:tissue gradients and tissue butadiene concentrations, hence reduced rates of metabolic clearance, when the blood is distributed. These results suggest that the common assumption of flow limitation in the disposition of an inhaled gas may not always be appropriate. Because structurally different models can reproduce the same uptake data and all these models cannot be correct, the assumptions on which these models were based must be investigated experimentally to ensure that they are physiologically realistic.