IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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assay with or without metabolic activation or in metabolically competent human lymphoblastoid
cells at either of two loci tested. In contrast, positive results were obtained in
assays for micronucleus formation, chromosomal aberrations and chromosomal recombinations
in vitro, consistent with a potential clastogenic mechanism of action. Some, but
not all, of these tests required metabolic activation for induction of genotoxicity. It is not
clear, however, which reactive naphthalene metabolite is responsible for the clastogenic,
and presumably carcinogenic, effects, as evidence for the reactivity of both naphthalene
1,2-oxide and naphthoquinone exists.
Exposure to naphthalene causes cellular injury and increases cell replication rates,
suggesting a cytotoxic mode of action. For example, intraperitoneal administration of
naphthalene produces injury (swelling, vacuolation, exfoliation, necrosis) of the tracheobronchial
epithelial Clara cells of mice but not of rats (Plopper et al., 1992a,b). In the
same study, naphthalene was also cytotoxic to the olfactory epithelium of both rats and
mice, but the effect was seen at much higher doses in mice, suggesting higher sensitivity
of the rat nose. These site and species differences in toxicity correlate well with the
higher rates of metabolism by mouse lung tissue and rat nasal tissue; metabolism in vitro
in pulmonary tissue fractions from human and non-human primates is 1–2 orders of
magnitude lower than that in rodents.
Overall, the proposed mechanism of action of naphthalene is that the higher rates of
metabolism lead to cytotoxic metabolites in mouse lung, causing increased cell turnover
and tumours. The absence of rat lung tumours is entirely consistent with this mechanism.
Significantly, the maximal rates of metabolism in human lung microsomes are about two
orders of magnitude lower than those in mice. The high rates of metabolism in rat nasal
epithelium similarly lead to tissue damage and nasal tumours; however, the etiology of
these nasal tumours, particularly the neuroblastomas, is not fully understood.
5.1 Exposure data
5. Summary of Data Reported and Evaluation
Naphthalene is a commercially important aromatic hydrocarbon which is produced
from coal tar and petroleum. It is used mainly as an intermediate in the production of
phthalic anhydride, naphthalene sulfonates and dyes and to a lesser extent as a mothrepellent.
Human exposure to naphthalene can occur during its production, in creosote
treatment of wood, in coal coking operations, during its use as an industrial intermediate,
as a result of its use as a moth-repellent, and as a result of cigarette smoking.
5.2 Human carcinogenicity data
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The only data available to the Working Group were two case series. No inference on
the carcinogenicity of naphthalene could be drawn from these.