IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

NAPHTHALENE 407
monooxygenases in the bronchiolar epithelium. Covalent binding of reactive naphthalene
metabolites to proteins in lungs of tolerant mice was similar to that in control mice
(Lakritz et al., 1996).
Male Swiss Webster mice were made tolerant by seven daily injections of 200 mg/kg
bw naphthalene. The concentration of glutathione in the terminal airways, measured 24 h
after the last injection, was 2.7-fold higher than in vehicle control mice. A challenge dose
of naphthalene (300 mg/kg bw, given on day 8) did not produce injury. However, tolerant
mice that were allowed to recover for 96 h after the seventh injection were again susceptible
to injury induced by a challenge dose, and the concentration of glutathione in the
terminal airways had declined to control values. Tolerant mice treated on day 8 simultaneously
with the challenge dose of naphthalene and buthionine sulfoximine, an inhibitor
of γ-glutamylcysteine synthetase, appeared as susceptible to injury as naphthalenechallenged
controls. These results showed that increased rates of glutathione synthesis
were critical for resistance to naphthalene toxicity in male Swiss-Webster mice (West
et al., 2000).
A 10% solution (w/v) of naphthalene in corn oil was administered by gavage to
Brown Norway rats at a dose of 0.7 g/kg bw per day for 102 days; control rats received
corn oil only. Two of the naphthalene-treated groups were given normal diet containing
one of two types of aldose reductase inhibitor at concentrations known to inhibit sugar
cataract formation in galactose-treated rats. The remaining naphthalene-treated groups
and the controls were given unmodified diet. Gradual, progressive development of zonal
opacities with decreased lens glutathione peroxidase and glutathione reductase activities
was observed in rats given naphthalene or naphthalene plus a carboxylic acid aldose
reductase inhibitor, but not naphthalene plus a hydantoin-type aldose reductase inhibitor.
These results led the authors to suggest an oxidative mechanism in naphthalene-induced
cataract formation (Tao et al., 1991). Rathbun et al. (1990) also showed the progressive
development of cataracts in Black-Hooded rats given a daily dose of 1 mL of a 10%
(w/v) solution of naphthalene in corn oil by gavage for up to 79 days, together with a
progressive loss of lens glutathione peroxidase and glutathione reductase activity, i.e.,
impairment of the defence system against oxidative damage. Holmén et al. (1999) later
demonstrated that 0.5 and 1.0 g/kg bw naphthalene given by gavage twice a week for 10
weeks causes cataractous changes in Brown Norway rats.
Male and female B6C3F 1 mice (10–11 weeks of age) were exposed by inhalation to
0, 10 or 30 ppm [0, 52 or 157 mg/m 3 ] naphthalene for 6 h per day on five days per week
for 104 weeks (Abdo et al., 1992; National Toxicology Program, 1992). Naphthalene
caused increased incidence and severity of chronic inflammation, metaplasia of the
olfactory epithelium and hyperplasia of the respiratory nasal epithelium and chronic
inflammation in the lungs of both male and female mice. In another chronic inhalation
study, male and female Fischer 344 rats were exposed to 0, 10, 30 or 60 ppm [0, 52, 157
or 314 mg/m 3 ] naphthalene for 6 h per day on five days per week for 105 weeks
(National Toxicology Program, 2000). Non-neoplastic lesions that were observed in
exposed rats at incidences greater than those in the chamber controls included atypical