IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

NAPHTHALENE 401
induction in DBA/2 mice after treatment with naphthalene or its metabolites 1,2- or 1,4naphthoquinone
suggests that these mice may be unable to convert the latter into free
radical intermediates.
Spiro-(2,7-difluorofluorene-9,4′-imidazoline)-2′,5′-dione (ALØ1576) is an aldose
reductase inhibitor that can prevent the development of naphthalene-induced cataracts in
rats. This action is believed to involve inhibition of the reduction of naphthalene
dihydrodiol to 1,2-dihydroxynaphthalene (Xu et al., 1992; Lou et al., 1996). Male rats
of five strains (4–5 weeks of age), including two pigmented (Long-Evans and Brown
Norway) and three albino (Sprague-Dawley, Wistar and Lewis) strains, were given
naphthalene by gavage at 500 mg/kg bw per day for three days, then 1000 mg/kg bw per
day for up to six weeks. Each experiment included groups treated with vehicle alone
(control), naphthalene, naphthalene plus ALØ1576 or ALØ1576 alone. The aldose
reductase inhibitor was given at 10 mg/kg bw per day by gavage one hour before the
naphthalene feeding. Naphthalene induced cataracts in all five strains. During administration
of naphthalene, whole-lens glutathione levels were 20–30% lower than those of
controls. After four weeks of administration, an almost 20-fold increase in the content of
protein–glutathione mixed disulfides was observed in the lenses. ALØ1576 completely
prevented all morphological and chemical changes in the lenses of naphthalene-treated
rats (Xu et al., 1992). To determine whether pigmentation is required for naphthaleneinduced
cataract formation, Murano et al. (1993) studied the progression of cataracts in
Brown Norway and Sprague-Dawley rats that had received an oral dose of naphthalene
(1000 mg/kg bw) every other day for six weeks. The changes in the lens were qualitatively
similar in the two strains, but the cataract progressed more uniformly and more
rapidly in the Brown Norway rats.
An intraperitoneal injection of 0.05–2.0 mmol/kg bw naphthalene in corn oil in
C57BL/6J mice (weighing 15–20 g) caused a specific bronchiolar lesion characterized
by a dilation of Clara cells with loss of apical projections. The Clara cells later became
exfoliated from large areas of the bronchioles. After loss of the Clara cells, abnormalities
appeared on the surface of the ciliated cells and, within 48 h after administration of
naphthalene, there was rapid division of the remaining cells. The repopulated Clara cells
were distributed randomly in the bronchioles, with gradual re-establishment of the
classic canal-like pattern (Mahvi et al., 1977).
Intraperitoneal injection of 200–375 mg/kg bw naphthalene in male Swiss Webster
mice produced highly selective necrosis of the bronchiolar epithelial cells but no necrosis
in the kidney or liver. This pulmonary damage was more severe when the mice were
pretreated with diethyl maleate (which depletes glutathione) and less severe after pretreatment
with piperonyl butoxide (which inhibits CYP enzymes). In contrast, treatment
with SKF 525A (another CYP inhibitor) before treatment with naphthalene had no effect
on naphthalene-induced pulmonary damage. Intraperitoneal injection of 25–600 mg/kg
bw [ 14 C]naphthalene resulted in covalent binding of naphthalene-derived radioactivity to
tissue macromolecules, with the highest levels of binding in lung, liver and kidney. The
level of binding corresponded with rapid depletion of glutathione in both the lung and