Targeted Mechanistic Evidence Synthesis to Inform Evidence Integration Decisions on the Potential Human Carcinogenicity of Naphthalene Exposure
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Animal and in vitro studies published since the 1998 IRIS Toxicological Review of 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, it became evident early in the process of this assessment that naphthalene toxic metabolite formation and the biological relevance of these toxic metabolites to humans were a key component in answering the question of applicability of carcinogenic risk to humans. Specific aims within the broad systematic review of the health effects of naphthalene exposure were to first to integrate the available evidence for the formation of each toxic metabolite in human and second to determine the biological plausibility that each of these key metabolites could be generated in human tissue and increase human oncogenic risk. Mechanistic studies relevant to this specific aim were identified in several ways: (1) tagging studies during screening of the broad literature search focused on the potential human health impacts associated with napthalene exposure; (2) performing “backward” searches on recent assessments by other governmental agencies and peer-reviewed review articles; and (3) performing “forward” searches to identify articles that cited the tagged studies during screening. 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 as a result from rodents to humans. For the specific question of metabolic relevance, we used the 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 to was captured using a structured table that summarizes study details, supporting evidence, and opposing evidence. Using the metabolic pathway as a framework, the captured evidence was then integrated to determine the human relevance of each naphthalene metabolite. This case study is useful to highlight approaches for conducting a very targeted mechanistic analysis to answer key questions during evidence integration. In addition, this case study can help identify strategies to present the concept of biological plausibility in structured frameworks for evidence integration. 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.