Targeted Mechanistic Evidence Synthesis to Inform Evidence Integration Decisions on the Potential Human Carcinogenicity of Naphthalene Exposure - Poster
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Animal and in vitro studies published over the past 20 years on naphthalene have provided mechanistic information implicating several biological processes in the development of naphthalene-induced tumor formation. Multiple modes of action (MOAs) for naphthalene-induced carcinogenesis have been proposed, including genotoxicity, cytotoxicity, and sustained regenerative cell proliferation. While these proposed MOAs may differ in specific key events, the formation of naphthalene toxic metabolite and the biological relevance of these toxic metabolites to humans has emerged as a key component in answering the question of applicability of carcinogenic risk to humans. Here, concurrent with the broad systematic review of health effects related to naphthalene exposure, specific aims within the mechanistic analysis were used to: (1) integrate the available evidence for the formation of each toxic metabolite in human, and (2) determine the biological plausibility that each of these key metabolites could be generated in human tissue and increase human oncogenic risk. Mechanistic studies were identified by tagging studies during screening of the broad literature search focused on the potential human health impacts associated with napthalene exposure. There is a great deal of similarity between the rodent and human naphthalene metabolism pathways; however, the activity of the enzymes involved in naphthalene metabolism and therefore the number of metabolites and stereoisomers of the produced metabolites may differ between rodents to humans. For the specific question of metabolic relevance, we used a well-established metabolic pathway for napthalene as a scaffold and then evaluated the availability of studies that addressed the applicability of this metabolic pathway to humans. Studies that had deficiencies in reporting critically important study details (e.g., missing experimental exposure details) were excluded. The evidence for each study was summarized in a tabular format that described study details, supporting evidence, and opposing evidence. Using the metabolic pathway as a framework, results from included studies were then integrated to determine the human relevance of each naphthalene metabolite. This case study is useful to highlight approaches for conducting a targeted mechanistic analysis to answer key questions during evidence integration in a systematic review. In addition, this case study can help identify strategies to present the concept of biological plausibility in structured frameworks for evidence integration. Disclaimer: The findings and conclusions in this abstract have not been formally disseminated by the U.S. EPA and should not be construed to represent any agency determination or policy.