IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

B6C3F 1 mice given a single intraperitoneal injection of naphthalene (Cho et al., 1994b;
Tsuruda et al., 1995).
4.5 Mechanistic considerations
NAPHTHALENE 415
Mechanistic studies conducted in experimental animals and tissues using a variety of
approaches have attempted to determine the modes of action of naphthalene with respect
to its toxicity and carcinogenicity. Such studies can provide insights into the relevance
of the rodent tumours (lung tumours in female but not male mice, and nasal tumours in
male and female rats) in predicting the carcinogenic response in humans.
In general, mice appear to be more susceptible to lung tumour induction by epoxides
and epoxide-forming chemicals than rats (Melnick & Sills, 2001). Thus inhalation of
ethylene oxide, 1,3-butadiene, isoprene and chloroprene induced lung tumours in mice
but not in rats (Lynch et al., 1984; National Toxicology Program, 1984; Snellings et al.,
1984; National Toxicology Program, 1987; Owen et al., 1987; Melnick et al., 1994;
National Toxicology Program, 1998, 1999; Melnick & Sills, 2001). The determinants
underlying the susceptibility of the mouse lung towards tumour formation may rely in
part on toxicokinetic considerations, but toxicodynamic determinants probably also play
a role. If naphthalene 1,2-oxide is responsible for the lung tumours observed in mice,
species differences in response at this organ may be due to a combination of higher rates
of naphthalene 1,2-oxide production in the Clara cells of the mouse lung, and, possibly,
a greater susceptibility of the mouse lung to epoxide-induced carcinogenesis (National
Toxicology Program, 2000).
4.5.1 Interspecies differences in toxicokinetics and metabolism of naphthalene
The initial step in naphthalene metabolism involves the formation of a 1,2-epoxide
and this process is a key step in the generation of cytotoxic metabolites. Substantial differences
in both the rates of epoxide formation and the stereochemistry of the epoxides
formed are observed between target tissues (mouse lung and olfactory epithelium, rat
olfactory epithelium) and non-target tissues (rat and hamster lung, hamster olfactory epithelium).
The rates of metabolism in lung microsomes from humans and non-human
primates are very similar and are 10–100-fold lower than in lung microsomes from
rodents. CYP2F in mouse lung is important in the local metabolism of naphthalene and
this is likely to be a critical determinant in naphthalene-induced cytotoxicity in the
mouse.
4.5.2 Interspecies differences in toxicodynamics and mode of action of
naphthalene
There is no evidence for mutagenic activity of naphthalene in the most widely used
genotoxicity assays. For example, naphthalene was not mutagenic in the Salmonella