Toxicology of Industrial Compounds

136 PULMONARY HYPERREACTIVITY TO INDUSTRIAL POLLUTANTS
isocyanate, damage of the airways is characterized by a steep concentrationresponse
curve. Based on acute 45-min exposure of rats the threshold for
respiratory tract irritation is approximately 1 mg m −3 . Exposures equaling
this concentration were tolerated without exposure-related effects, whether
exposure occurred singly for 45-min or repeatedly for 2 weeks. Marginal
effects were observed at 4 mg m −3 , all effects, including mortality, were
produced at 7 mg m −3 . This demonstrates that selection of appropriate
exposure concentrations appears to be most critical in the rat model. The
assessment of diagnostic sensitivity of the methods used to probe damage
to the respiratory tract demonstrated that respiratory function data, blood
gas measurements, and BALF analysis facilitate a meaningful interpretation
of the effects observed and are important adjuncts to common inhalation
toxicological studies on rats to describe quantitatively the diseased state of
the lung.
The guinea-pig model is experimentally less demanding and therefore can
suitably be used as a screening test for respiratory sensitization, as far as
the limitations of this model are taken into account. Studies on guinea-pigs
demonstrate that elicitation of respiratory hypersensitivity is
challengeconcentration dependent and that the concentrations used should
slightly exceed the threshold concentration for irritation to maximize the
magnitude of the response. However, sensitization by inhalation may
increase the susceptibility to irritant stimuli and thus confounds the
selection of the most appropriate concentration for challenge. The
combined approach of evaluating several breathing parameters, e.g.
respiratory rate, flow- and volume-derived parameters, during both the
hapten (free or conjugated) and the ACh challenge provides a promising
method to distinguish specific and nonspecific hypersensitivity responses.
Furthermore, it is critically important to assess the respiratory irritant
potency of the compound under investigation. For potent irritant
substances such as volatile isocyanates, challenge with the haptenprotein
conjugate minimizes the likelihood to confound specific hypersensitivity
responses with those evoked merely by irritation. Taking all imponderable
factors into consideration, it appears that the guinea-pig intradermalinduction
inhalation-challenge protocol is adequately susceptible to identify
potent respiratory tract sensitizers. However, if the airway inflammation
related features of asthma are the endpoints of primary interest other
animal models appear to be more appropriate.
References
BARNES, P.J., BARANIUK, J.N. and BELVISI, M.G., 1991a, Neuropeptides in the
respiratory tract (Part II). Am. Rev. Respir. Dis., 144, 1391–9.