Respiratory Toxicology Group
Investigation of bronchiolitis obliterans caused by diacetyl inhalation
The Respiratory Toxicology Group group is investigating the role of inhaled diacetyl in recent cases of obliterative bronchiolitis (OB) in microwave popcorn plant workers. Diacetyl is used to impart a buttery flavor to foods and is a major component of artificial butter flavorings used in microwave popcorn. Because inhalation toxicity data for diacetyl are not available, a safe worker exposure limit has not been established. The group is investigating the effects of repeated exposure to diacetyl vapors on mice and rats to establish a dose-response and a no-effect-level that can be used by regulatory agencies. Although OB is a rare environmental disease, it is a major component of lung transplant rejection. There is no effective treatment for this usually fatal disease. Research on the pathogenesis of OB has been limited, because a good animal model of OB does not exist. An animal model of OB is being developed using diacetyl-exposed rats and mice. This animal model will allow investigation of the pathogenesis of this disease and may provide methods for early detection, treatment and prevention.
Mechanisms of indium and other metals in lung and pleural toxicity
Indium phosphide (InP) is a metal compound used in the microelectronics industries. Inhalation of InP particles can occur when workers are grinding and shaping components containing InP. In a chronic inhalation study in mice, InP was highly toxic and carcinogenic for the lung, and also caused serosal fibrosis with adhesions throughout the pleural cavity, hyperplasia of the pleural mesothelium and inflammation of heart arteries. Although fibers (e.g. asbestos) are known to cause lesions in the pleural mesothelium, pleural effects are uncommon after inhalation of a non-fibrous particulate. The objective of these studies is to investigate how InP causes pleural hyperplasia and inflammation of the heart arteries in B6C3F1 mice. The RT group has demonstrated that InP causes a pronounced and long-term perturbation in pleural cavity dynamics after a single instillation into the lungs. This change in the pleural cell dynamics may play a role in the etiology of pleural fibrosis. The instillation of soluble indium chloride or other metal salts into the mouse lung are being investigated to determine if this pleural response is unique to indium or is a general response of the pleura to metal particulates in the lung. Preliminary results indicate that pleural cavity parameters can be altered long after lung parameters have returned to baseline. If the pleural effects are caused by factors released from the injured lung, then it is possible that cardiovascular effects of InP may be due to factors transported from the lung to the heart via the pleural fluid.