MECHANISMS OF AIRWAY REACTIVITY FOLLOWING EXPOSURE TO TOLUENE DIISOCYANATE

Toluene diisocyanate (TDI), a highly reactive chemical used as a polymerizing agent in the production of polyurethane foams and plastics, causes bronchial asthma in some individuals exposed to this chemical. The mechanism of this reaction is not known, although an interference in beta adrenergic function has been proposed. This study was designed to determine the affects of TDI on beta adrenergic receptor function using two different experimental model systems: (1) A biochemical model measured beta adrenergic-adenylate cyclase activity of frog erythrocytes; and (2) Guinea pig tracheal smooth muscle responsiveness was used to assess physiologic function following a single intratracheal instillation of TDI. Isolated tracheal smooth muscle responsiveness to cholinergic and beta adrenergic agents was also determined after inhalation of TDI vapors.;TDI inhibited isoproterenol stimulated erythrocyte adenylate cyclase activity in a dose dependent manner. Studies with fluoride, which activates adenylate cyclase independent of beta receptor stimulation also demonstrated a dose-dependent inhibition in activity by TDI, suggesting nonspecific inhibition of adenylate cyclase activity. Guinea pigs treated with a single intratracheal instillation of TDI showed no difference in tracheal smooth muscle responsiveness measured as the concentration of isoproterenol corresponding to 50% of maximum relaxation (ED50) when compared to controls, nor was there a difference in maximum relaxation. Similar results were observed following inhalation of TDI vapors (0.029 ppm) five hours per day for twenty continuous days. Significant differences in smooth muscle responsiveness was observed in studies measuring carbachol-induced contractility. The dose-effect curve of TDI exposed animals was shifted upward and to the left of control animals. The mean -log ED50 of carbachol treated strips was significantly lower than controls and developed greater maximum tension. The observed increase in maximum tension and leftward shift of the dose-effect curve for TDI exposed animals suggest direct smooth muscle alteration. This may be the result of increased cholinergic receptor number or affinity, or due to other changes in smooth muscle. In summary, the data suggests TDI induces airway hyperreactivity by producing a direct effect on airway smooth muscle.