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Key Event Title
Tumorigenesis, Hepatocellular carcinoma
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Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Mutagenic MOA for Cancer 2||AdverseOutcome||Agnes Aggy (send email)||Open for citation & comment||EAGMST Under Review|
Key Event Description
The AO final key event results from the processes that occur in the earlier series of key events, which for AFB1 is a mutagenic MOA—the AFB1 induction of mutations in critical cancer genes that alter the phenotype of the mutant cell and set the stage for that cell to progress to a pre-neoplastic lesion and ultimately an HCC. The biological processes described in this AO, however, are not specific to a mutagenic MOA—nor necessarily demonstrated for AFB1 exposure, but occur in development of HCC from all MOAs for HCC. Thus the final key events (AHF and HCC) represent the final stages of the pathway that leads to HCC from a mutagenic MOA or other MOAs.
Hepatocellular carcinoma (HCC) is a cancer of hepatocytes, and this disease is almost always lethal in the absence of extreme intervention measures (e.g., surgery, liver transplant). A number of factors are associated with HCC including AFB1 exposure, infection with hepatitis virus (HBV), and alcohol use. A common etiologic feature of HCC, whether produced by AFB1 intoxication, HBV, cirrhosis or something else, is the presence of oxidative damage in the liver. (Ravinayagam et al., 2012 Int J Hepatol; Kim et al., 2011 J Ginseng Res).
AFB1 produces specific pro-mutagenic adducts that are believed to lead to a mutation in the p53 gene, which affects its functioning. P53 is generally considered to be a tumor suppressor gene involved in cell cycle regulation and initiation of apoptosis. When applied in vitro to hepatocytes, AFB1 produced cellular swelling, bleb formation, and lysis. These effects may be due to lipid peroxidation affecting the cell membrane from the downstream dialdehyde metabolite of the AFB1 epoxide metabolites. (Mathijs et al., 2009, 2010) This damage is reflective of oxidative stress, a known contributor to HCC (Ravinayagam et al., 2012 Int J Hepatol; Kim et al., 2011 J Ginseng Res). As discussed elsewhere in this AOP, the Nrf2-Keap1 anti-oxidant response induced by a number of chemoprotective agents can be quite effective in preventing HCC [3-8], even in the presence of a significant burden of N7- AFB1-G adducts.
The cellular damage produced by exposure to AFB1 likely leads to chronic inflammation, also a contributor to tumor progression. (Ellinger-Ziegelbauer et al., 2004) Heme oxygenase-1 (HO-1) breaks down heme to bilirubin and biliverdin that have anti-oxidant and anti-inflammatory activities (Keum et al., 2006; Caballero et al 2004) , thus countering the inflammatory response. The induction of HO-1 is part of the Nrf2-Keap1 anti-oxidant response.
From a systems biology and biochemistry perspective, the presence of oxidative stress and inflammation, although not specific only to AFB1 exposure, are strong contributors to cancer progression.(Ohnishi et al., 2013; Zheng et al., 2013; Higgs et al., 2014).
How It Is Measured or Detected
Hepatocellular carcinoma is detected in humans by clinical examination confirmed by pathological examination, and in laboratory test species by pathological examination.
Domain of Applicability
Hepatocellular carcinoma occurs in many vertebrate species including birds, fish, and mammals such as humans.
Regulatory Significance of the Adverse Outcome
Although not specifically used EPA for regulatory determinations vis-à-vis AFB1, HCC has been used as an adverse endpoint in many hazard assessments that can be used as input to risk management decisions. The U.S. EPA Integrated Risk Information System (IRIS database) contains 111 instances wherein HCC has been considered in hazard assessment of environmental contaminants. For example, HCC in rats formed part of the weight of evidence in categorizing polychlorinated biphenyls as probable human carcinogens. These tumors, combined with other liver tumors, also formed the basis for quantitative dose-response assessment for cancer induced by polychlorinated biphenyls by the oral route.(USEPA, 2014).
Given that AFB1 can be a contaminant in both human food and animal feed, FDA has established allowable limits. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/foodadvisorycommittee/ucm428947.pdf
Caballero F, Meiss R, Gimenez A, Batlle A, Vazquez E (2004) Immunohistochemical analysis of heme oxygenase-1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. Int J Exp Pathol 85: 213-222.
Higgs MR, Chouteau P, Lerat H (2014) 'Liver let die': oxidative DNA damage and hepatotropic viruses. J Gen Virol 95: 991-1004.
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Ohnishi S, Ma N, Thanan R, Pinlaor S, Hammam O, et al (2013) DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid Med Cell Longev 2013: 387014.
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U.S. EPA IRIS, (2014) available at http://www.epa.gov/iris/subst/0294.htm#woe
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