Inhalation of
naphthalene causes olfactory epithelial nasal
tumors in rats (but not in mice) and benign lung
adenomas in mice (but not in rats). The limited available human data have not identified an association between
naphthalene exposure and increased respiratory
cancer risk. Assessing
naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of
naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of
naphthalene to the
epoxide, followed by GSH depletion, cytotoxicity, chronic
inflammation, regenerative
hyperplasia, and
tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose-response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for
naphthalene-induced rat nasal
tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions.