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

Acknowledgements

The authors would like to thank Daniel Skall, a Gradient employee, for his efforts in finalizing the dose–response modeling analysis. The authors gratefully acknowledge the extensive comments from five anonymous reviewers selected by the Editor. These comments were most helpful in revising the manuscript.

Declaration of interest

The authors’ affiliation during the course of this work is as shown on the first page. All authors, other than Dr. Marc Nascarella, are currently affiliated with Gradient, a private environmental consulting firm. Dr. Nascarella's current affiliation is with the Massachusetts Department of Public Health. This paper was prepared with financial support to Gradient from the Naphthalene Research Committee (NRC). The NRC is a group of companies and organizations that produce or use naphthalene-containing materials and/or products. The work reported in the paper was conducted during the normal course of employment by Gradient. The NRC was given the opportunity to comment on the manuscript. The authors retained final decision-making, and have the sole responsibility for the writing and contents of this paper. The views and opinions expressed are not necessarily those of the NRC.

Supplementary material available online

Supplementary Tables and plots to be found online at http://informahealthcare.com/doi/abs/10.3109/10408444.2015.1061477.