Abstract 4021: The evaluation of carcinogenicity evidence of dibenzanthracenes

Abstract

Abstract Dibenzanthracenes (DBAs) are identified as carcinogens and are on the California Proposition 65 list. DBAs are five-ring polycyclic aromatic hydrocarbons (PAHs). This chemical group consists of three isomers: DB[a,c]A, DB[a,h]A, and DB[a,j]A. DBAs are products of the incomplete combustion or pyrolysis of organic matter and can be formed during high temperature cooking. They are air pollutants present in engine exhaust, tobacco and marijuana smoke, and may also contaminate soil and water. DB[a,h]A is a well-studied International Agency for Research on Cancer (IARC) Group 2A carcinogen, whereas fewer studies relevant to carcinogenicity have been conducted with DB[a,c]A and DB[a,j]A. Carcinogenicity evidence from multiple data streams was integrated in the hazard identification of this chemical group. These data streams include animal cancer bioassays, mechanistic studies and other relevant data, including high-throughput studies (e.g., ToxCast), toxicogenomic studies, and information from quantitative structure-activity relationship (QSAR) models. Structure activity comparisons across the three DBAs and related carcinogenic PAHs served to bridge the data gaps for the two less studied isomers. The results of our analyses showed that each of the DBAs share similar biological activities in animals: all induce tumors in mice, are mouse skin tumor initiators, form DNA adducts, are genotoxic, and form metabolites that are also genotoxic and initiators of mouse skin tumors. All three DBAs activate the aryl hydrocarbon receptor (AhR) in reporter gene assays, and DB[a,h]A and DB[a,c]A have been shown to bind to the AhR. In addition to strong evidence of genotoxicity, other carcinogenic mechanisms are likely also operative, including receptor activation (e.g., AhR), immune suppression, altered cell proliferation, apoptosis, and cell cycle regulation. There are strong structure-activity similarities among the DBAs and several carcinogenic 4-, 5- and 6-ring PAHs, including benzo[a]pyrene and dibenzo[a,h]pyrene. In addition, DB[a,c]A and DB[a,j]A were predicted to be mutagenic and carcinogenic in several QSAR models, including VEGA, Lazar and OECD QSAR Toolbox. Integration of the evidence from these multiple data streams resulted in the identification of the DBAs as a chemical group as carcinogens. Citation Format: Feng Tsai, Jennifer C. Hsieh, Gwendolyn Osborne, Martha Sandy. The evaluation of carcinogenicity evidence of dibenzanthracenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4021.