Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis

Abstract

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.

Keywords: Cytotoxicity; dose–response; genotoxicity; hazard identification; human equivalent concentrations; human relevance; risk assessment; site concordance.

Figure 1.

The seven key aspects of the Hypothesis-Based Weight-of-Evidence (HBWoE) approach.

Figure 2.

Proposed scheme for naphthalene metabolism and reactive metabolites (adapted from ATSDR 2005). CYP450 = Cytochrome P450 Enzyme(s); GSH = Reduced Glutathione; SG = Glutathione.

Figure 3.

Amount of naphthalene metabolized in rat and human dorsal olfactory, ventral respiratory, lung, and liver tissue per inhaled dose in accordance with the hybrid CFD–PBPK model for naphthalene (Campbell et al. 2014).

Figure 4.

Two-year (NTP 2000) vs 90-day (Dodd et al. 2012) metabolized dose–response in male and female rats following naphthalene exposure via inhalation (BMR of 10% extra risk for the 0.95 lower confidence limit on the BMD). Figures show the best-fit curve. See supplemental material for all modeling results. (A) Male rat respiratory epithelial hyperplasia dose–response from 2-year study (Logistic); (B) male rat respiratory epithelial hyperplasia dose–response from 90-day study (Weibull); (C) female rat olfactory epithelial hyperplasia dose–response from 2-year study (Log-Logistic with NO FIT); (D) female olfactory epithelial hyperplasia dose–response from 90-day study (Log-Logistic).