Occupational exposure to butter flavoring vapors (BFV) is associated with significant pulmonary injury. The goal of the current study was to characterize inhalation dosimetric patterns of diacetyl and butyric acid, two components of BFV, and to develop a hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) to describe these patterns. Uptake of diacetyl and butyric acid vapors, alone and in combination, was measured in the upper respiratory tract of anesthetized male Sprague-Dawley rats under constant velocity flow conditions and the uptake data were used to validate the CFD-PBPK model. Diacetyl vapor (100 or 300 ppm) was scrubbed from the airstream with 76-36% efficiency at flows of 100-400 ml/min. Butryic acid (30 ppm) was scrubbed with >90% efficiency. Concurrent exposure to butyric acid resulted in a small but significant reduction of diacetyl uptake (36 vs. 31%, p < 0.05). Diacetyl was metabolized in nasal tissues in vitro, likely by diacetyl reductase, an enzyme known to be inhibited by butyric acid. The CFD-PBPK model closely described diacetyl uptake; the reduction in diacetyl uptake by butyric acid could be explained by inhibition of diacetyl reductase. Extrapolation to the human via the model suggested that inspired diacetyl may penetrate to the intrapulmonary airways to a greater degree in the human than in the rat. Thus, based on dosimetric relationships, extrapulmonary airway injury in the rat may be predictive of intrapulmonary airway injury in humans. Butyric acid may modulate diacetyl toxicity by inhibiting its metabolism and/or altering its inhalation dosimetric patterns.