IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

NAPHTHALENE 403
were exfoliated and necrotic. In contrast, no effect was observed on Clara cells or ciliated
cells of terminal bronchioles in rats treated with up to 1600 mg/kg bw naphthalene. Only
minor changes in Clara cells at some terminal bronchioles were observed in hamsters
dosed with 800 mg/kg bw naphthalene. The nasal cavity showed specific injury in the
olfactory epithelium in a dose- and species-dependent manner, with rats being the most
sensitive species (Plopper et al., 1992a). A morphometric comparison of changes in the
epithelial population of the terminal bronchioles and lobar bronchi showed that Clara
cells and ciliated cells in mice were affected by treatment with naphthalene, while the
bronchiolar epithelium of rats and hamsters was insensitive to this treatment (Plopper
et al., 1992b). In a companion study, Buckpitt et al. (1992) demonstrated that the stereochemistry
of the epoxidation of naphthalene may be important in the target tissue (lung)
and species selectivity (mouse) of naphthalene toxicity (see Section 4.1.2(b)).
Female FVB/n mice (2–4 months of age) were given an intraperitoneal injection of
0, 50, 100 or 200 mg/kg bw naphthalene in corn oil and killed at various time points to
investigate the phenotypic changes in airway epithelial cells after acute Clara cell injury.
Clara cell cytotoxicity from naphthalene resulted in the exfoliation of epithelial cells
containing CC10 protein, a Clara cell secretory protein. This exfoliation occurred at the
same time (24 h after treatment) as a reduction in the levels of mRNA for CC10 and
CYP2F monooxygenase. The mRNA for cyclin-dependent kinase 1 (CDK1), a marker of
cell cycling, was detected in a large number of cells in and around the bronchioles and
terminal bronchioles 48 h after treatment with naphthalene. The airways were re-populated
with immature epithelial cells lacking normal levels of CC10 mRNA and overexpressing
the mRNA for surfactant protein B. At 72 h after injection of naphthalene, a
reduction in the number of CDK1 mRNA-positive cells was observed, except at the
airway bifurcations, where increased expression of mRNA CDK1 was observed relative
to the 48-h time point. The results suggest that the repair of acute airway epithelial cell
injury induced by naphthalene occurs in overlapping stages, beginning with clearance of
dead cells followed by the proliferative re-population of injured areas and maturation of
newly re-populated regions (Stripp et al., 1995).
Naphthalene (300 mg/kg bw) was administered intraperitoneally to male FVB/n
mice (7–9 weeks of age) 36–72 h before intraperitoneal administration of [ 3 H]thymidine
(20 Ci/mmol) at a dose of 2.5 μCi/kg bw. Lungs were removed five days after treatment.
Naphthalene toxicity resulted in pulmonary neuroendocrine-cell hyperplasia, which was
characterized by increased numbers of neuroepithelial bodies without significant
changes in the number of isolated pulmonary neuroendocrine cells and with increased
[ 3 H]thymidine labelling of cells that produce calcitonin gene-related peptide, a marker of
neuroendocrine cells. These results suggest a key role of neuroendocrine cells in the
reparative process of airway epithelial cell renewal after naphthalene-induced injury in
mice (Stevens et al., 1997). Five days after an intraperitoneal injection of naphthalene
(300 mg/kg bw) to male FVB/n mice (12–14 weeks of age), an abundance of pulmonary
neuroendocrine cells and neuroepithelial bodies was observed along the main axial
pathway of the right middle lobe of the lung. Calcitonin gene-related peptide was used