Toxicology of Industrial Compounds

134 PULMONARY HYPERREACTIVITY TO INDUSTRIAL POLLUTANTS
breathing parameters upon acetylcholine and hapten or conjugate challenge
significantly enhance the diagnostic sensitivity of the guinea-pig model.
From studies using single, brief high level aerosol or dust exposures for the
induction of animals it can be concluded that previous high level exposures
evoke bronchial hyperresponsiveness upon challenge at lower hapten
concentrations when compared with intradermally sensitized animals.
However, guinea-pigs sensitized intradermally to the volatile PI
demonstrated remarkable immediate-type respiratory reactions only upon
challenge with the conjugate and not with slightly irritant concentrations
of the free PI. To study if phenyl isocyanate is capable of inducing a
reactive airway or an asthma like syndrome, the subsequently described rat
model was used.
The rat model
This animal model focuses on the induction of airway inflammation which
comprises most of the characteristic features of asthma. It has been stated
that respiratory hypersensitivity should depend on two separate factors:
first, the degree of allergic airways, and second, the sensitivity to
bronchoconstrictive mediators. Increasing evidence suggests that the
eosinophils play a critical role in the pathogenesis of asthma and of other
non-allergic hyperresponsive airway diseases. For the induction of the
asthmatic state male rats were exposed for 2 consecutive weeks by
inhalation (5 h day −1 , 5 days week −1 ). The target concentrations of phenyl
isocyanate were chosen on the basis of a single 45-min exposure study
which suggested that approximately 1 mg m −3 air is the irritant threshold
concentration for ‘any’ duration of exposure. The 2 week repeated
inhalation study was designed to assess the functional, bio chemical and
morphological signs of phenyl isocyanate induced lung disease and their
regression during an observation period of approximately 2 months.
The most characteristic features of asthma comprise an increased influx
of eosinophilic granulocytes into the tissue of the airways, secretory cell
hyper-plasia and metaplasia, smooth muscle hypertrophy and hyperplasia,
epithelial desquamation, airway hyperresponsiveness, and eventually partial
occlusion of the airway lumen with mucus and cellular debris. The
formation of mucus plugs is a regular feature of asthma and accounts for
most of the clinical, biochemical and physiological abnormalities.
Histopathological evaluation of the respiratory tract indicated a
bronchiolitis obliterans and smooth muscle hypertrophy in rats exposed to
approximately 7 mg m −3 air, whereas only minimal effects were found
following 4 mg m −3 air. Lung function measurements revealed that some rats
were hyperresponsive to an ACh-stimulus. As shown in Figure 9.2, also the
increase in shunt blood (Q s/Q t) anddecrease in forced expiratory flow rates
(MMEF) as well as mucus products (sialomucins), polymorphonuclear