Pathogenetic role of alveolar surfactant depleted by phosgene: Biophysical mechanisms and peak inhalation exposure metrics

Abstract

In contrast to water-soluble respiratory tract irritants in their gas phase, the physicochemical properties of ‘hydrophilicity’ vs. ‘lipophilicity’ are the preponderant factors that dictate the site of major retention of the gas at the portal of entry. The lipophilic physical properties of phosgene gas facilitate retention in the alveolar region lined with amphipathic pulmonary surfactant (PS). The relationship between exposure and adverse health outcomes is complex, may vary over time, and is dependent on the biokinetics, biophysics, and pool size of PS relative to the inhaled dose of phosgene. Kinetic PS depletion is hypothesized to occur as inhalation followed by inhaled dose-dependent PS depletion. A kinetic model was developed to better understand the variables characterizing the inhaled dose rates of phosgene vs. PS pool size reconstitution. Modeling and empirical data from published evidence revealed that phosgene gas unequivocally follows a concentration x exposure (C × t) metric, independent of the frequency of exposure. The modeled and empirical data support the hypothesis that the exposure standards of phosgene are described best by a C × t time-averaged metric. Modeled data favorably duplicate expert panel-derived standards. Peak exposures within a reasonable range are of no concern.