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In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200μg/kg rat/day) for 4 weeks and receiving either vehicle or CDDO-Im (three times weekly), one week prior to and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared to a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N7-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P positive foci increased substantially (0% to 13.8%) over the 4 weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.

Cadmium is a transition metal and an ubiquitous environmental and industrial pollutant. Laboratory animal studies and epidemiological studies have shown that exposure to cadmium is associated with various organ toxicities and carcinogenic effects. Several national and international regulatory agencies have classified cadmium compounds as carcinogenic to humans. In 2012, International Agency for Research on Cancer (IARC) reviewed the relevant information on cadmium exposure and concluded that there is sufficient evidence in humans for the carcinogenicity of cadmium and its compounds. However, the underlying molecular mechanism(s), especially for the carcinogenicity, are unknown. The mechanisms proposed for carcinogenicity include aberrant gene expression, induction of oxidative DNA damage, stimulation of cell proliferation, malignant cell transformation, inhibition of DNA damage repair, inhibition of apoptosis and epigenetic mechanisms including alteration of DNA methylation. Studies have shown that due to the slow elimination, cadmium is a cumulative toxicant and past exposures could result in toxic effect of the residual metal. To better understand the mechanisms of cadmium carcinogenicity we have reviewed in vitro experimental and in vivo animal studies focused on the proposed mechanisms of carcinogenicity as well as epidemiological evidence on carcinogenicity in lung and kidney following cadmium exposure. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views and/or policies of the U.S. EPA Citation Format: Raghu G. Nath, BR Sonawane, SV Vulimiri, YS Lin. Mechanisms of cadmium carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2738. doi:10.1158/1538-7445.AM2015-2738

The development of short-term or accelerated cancer bioassays using genetically modified (GM) animals that exhibit high sensitivity to chemically induced cancers and that act through mode(s) of action relevant to humans continues to be an important focus of research. However, to date only a few GM mouse models such as the Trp53+/−, the Tg.AC and the rasH2 models have effectively been evaluated to substitute for the two-year rodent cancer bioassays. Whether these models provide an acceptable replacement for the conventional rodent cancer bioassay for assessing human cancer risks is the subject of ongoing debate. The objective of this study was to evaluate the current status of the use of GM mice for accelerated cancer bioassays in assessing the potential human health risks associated with exposure to carcinogenic agents. We compared the published data from the GM bioassays with results obtained using the National Toxicology Program's conventional 2-year mouse cancer bioassay presently used in human cancer risk assessment. The results demonstrate a moderate success for these GM models to distinguish carcinogens from non-carcinogens. Although the GM models are less efficient in detecting rodent carcinogens, they are more consistent in identifying non-carcinogens. Our analysis also shows that there continue to be concerns about the assay design and protocols used for the GM models, including issues related to sample size, study duration, genetic instability, and reproducibility. Additional issues of concern include specific toxicity pathway-dependent effects, and differences in the potential carcinogenic mechanisms operating in GM and non-GM animals, topics that still need to be investigated. In addition, the dose-responses of the GM models can vary substantially from those seen in conventional cancer bioassays. Overall, we conclude that the existing GM mouse models are of value for hazard identification, but are of limited use for dose-response analysis with currently used study designs. Hence, until these models are thoroughly validated using more robust study designs and the dose-response issues adequately addressed, caution should be exercised when using the current GM models to assess the carcinogenic risks of chemicals to humans. Disclaimer: The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency or the National Institute of Environmental Health Sciences. Citation Format: David A. Eastmond, Suryanarayana V. Vulimiri, John E. French, Babasaheb Sonawane. An evaluation of the use of genetically modified mouse models in human cancer risk assessment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1561. doi:10.1158/1538-7445.AM2013-1561