42nd Annual meeting of the Society of Toxicology (SOT) location:Salt Lake City, Utah, US date:9-13 March 2003
Aim: Occupational asthma is the principal cause of work-related respiratory disease in the industrial world. In the absence of satisfactory models for predicting the potential of low molecular weight chemicals to cause asthma, we have attempted to produce immunologically mediated respiratory responses in mice using toluene diisocyanate (TDI), a known respiratory sensitizer.
Methods: BALB/C mice received TDI (20 µl per ear, 0.3 or 3% solution) or vehicle (acetone/olive oil) on each ear for three consecutive days. On day 7 the mice received a dermal boost of TDI (20 µl per ear, 0.3 or 3% solution). On day 10, they were intranasally challenged with TDI (0.1%, 10 µl per nostril) or vehicle. Lung function was monitored by whole body plethysmography for 40 min after intranasal challenge, and bronchial reactivity to methacholine (0, 10, 25, 50 and 100 mg/ml) was assessed 24 h later. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) and histology.
Results: Mice sensitized with TDI, boosted with TDI and challenged with TDI did not show a different breathing pattern after intranasal challenge compared to the control. One day later they did not show an increased reactivity to methacholine. However, mice that been “sensitized” with the vehicle and then “boosted” with TDI (0.3% or 3%), experienced marked bronchoconstriction immediately after the intranasal challenge with 0.1% TDI. 24 h later they had pronounced bronchial hyperreactivity and pulmonary inflammation [20% and 40% neutrophils; 1.5% and 2% eosinophils in BAL, for boosts with 3% and 0.3%]. Dry and wet lung weight were also significantly higher in this group compared to the control. Histologic examination revealed a minor influx of eosinophils round the blood vessels.
Conclusion: We have been partially successful in our attempt to develop a model of chemical-induced asthma. The role of dermal sensitization and subsequent dermal boosting is proving to be one of the critical factors, the mechanisms of which remain to be explored.