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ToxSci Advance Access published online on May 5, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh155
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received January 21, 2004
Accepted April 20, 2004

Respiratory Toxicology

Respiratory Response to Toluene Diisocyanate Depends on Prior Frequency and Concentration of Dermal Sensitization in Mice

Jeroen A. J. Vanoirbeek 1, Maciej Tarkowski 2, Jan L. Ceuppens 3, Erik K. Verbeken 4, Benoit Nemery 1*, Peter H. M. Hoet 1

1 Pneumology (Lung Toxicology), KULeuven, Leuven, Belgium
2 Pneumology (Lung Toxicology), KULeuven, Leuven, Belgium; Institute of Occupational Medicine, Department of Immunotoxicology, Lodz, Poland
3 Experimental Immunology, KULeuven, Leuven, Belgium
4 Pathology, KULeuven, Leuven, Belgium

* To whom correspondence should be addressed. E-mail: ben.nemery{at}med.kuleuven.ac.be.


  Abstract

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 verified that dermal sensitization prior to intranasal challenge influences the respiratory response using toluene diisocyanate (TDI), a known respiratory sensitizer. BALB/c mice received TDI or vehicle (acetone/olive oil) on each ear on three consecutive days (day 1, 2 and 3; 0.3% or 3% TDI) or only once (day 1; 1% TDI). On day 7 the mice received similar dermal applications of vehicle of the same concentration of TDI as before ("boost"). On day 10, they received an intranasal dose of TDI (0.1%) or vehicle. Ventilatory function was monitored by whole body plethysmography for 40 min after intranasal application, and reactivity to inhaled methacholine was assessed 24 h later. Pulmonary inflammation was assessed by bronchoalveolar lavage and histology. Mice that received an intranasal dose of TDI without having received a prior dermal application of TDI did not exhibit any ventilatory response or inflammatory changes compared to vehicle controls. In contrast, mice that had received prior application(s) of TDI, even if only on day 7, exhibited ventilatory responses, compatible with bronchoconstriction, immediately after intranasal application with TDI; enhanced methacholine responsiveness 24 h later, and pulmonary inflammation characterized by neutrophils. This was, however, not the case in mice that received the highest dermal amount of TDI (3% on day 1, 2 and 3). These findings suggest that respiratory response to TDI depend on prior frequency and concentration of dermal sensitization in mice.

Key Words: occupational asthma, animal model, diisocyanates, BALB/c mice, dermal sensitization, whole body plethysmography, BALF .


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