Objectives: Inhalation of microwave popcorn butter flavorings in the workplace induces a bronchiolitis-obliterans like obstructive disease in workers, termed "popcorn workers's lung." In animal models inhalation of popcorn butter flavoring, its constituent flavoring, diacetyl (D), or diacetyl substitute, 2,3-pentanedione (2,3-P), evoke marked damage to the epithelium of upper airways and large lower airways. While the toxicity of these flavorings on airway epithelium is now acknowledged, nothing is known about the effects of D and 2,3-P on airway smooth muscle. Therefore, we investigated the pharmacological activity of D and 2,3-P on isolated airways. Methods: The isolated, perfused trachea preparation was used; this method allows separate addition of agents to the mucosal surface [intraluminal (IL) bath] or serosal surface [extraluminal (EL) bath] of the airway. Tracheas removed from anesthetized guinea pigs were mounted on holders to allow perfusion of the lumen with modified Krebs-Henseleit solution while measuring mechanical responses, i.e., change in diameter, from inlet minus outlet pressure difference (delta P; cm H2O). RESULTS. In unstimulated tracheas, or in tracheas first contracted with EL methacholine (3 times 10-7 M; EL EC50), D applied to the IL bath elicited contraction (1 - 3 mM); higher concentrations (10 - 30 mM) elicited contraction followed by relaxation. The relaxation component of the response could have been mediated by the release of epithelium-derived relaxing factor (EpDRF), which is triggered by elevations in IL osmolarity greater than 3 mosM. This possibility was investigated by adding D intraluminally to tracheas from which the epithelium had been removed, and by adding D to the EL bath. In both instances responses to D were obtained that did not differ from epitheliumcontaining tracheas following the addition of D to the IL bath. Responses to IL and EL 2,3-P mimicked those to D over the same concentration range, and were not affected by epithelium removal. Conclusions: The concentrations of D that elicit contractile responses of the trachea have been calculated through modeling to exist in the airway wall of exposed rats, and are associated with epithelial damage. D and 2,3-P are nearly identical in their activities as bronchoconstricting and bronchodilating agents in this in vitro model. The relaxant responses to the two flavorings in higher concentrations are not attributable to the elevation in osmolarity and the release of EpDRF. The results suggest that the direct effects of the two flavorings on airway smooth muscle of workers may be comparable.
Biohazards; Biological-effects; Exposure-assessment; Exposure-levels; Laboratory-testing; Lung-disorders; Lung-irritants; Microbiology; Pharmacodynamics; Pulmonary-congestion; Pulmonary-disorders; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Risk-analysis