Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Cyp2E1 Activation Leading to Liver Cancer||AdverseOutcome|
Key Event Description
Liver cancer is among the most common forms of cancer and the second leading cause of cancer death. It is more prevalent in males than females; however, prevalence has been increasing in both genders over the last two decades (Ellison, L.F., Wilkins, K. 2012). Hepatocellular carcinoma (HCC) is a primary cancer of the hepatocytes that is typically a progression from the benign hepatocellular adenoma (HCA). The most common risk factor for developing hepatocellular carcinoma is chronic liver injury and inflammation (caused by persistent infection, fatty liver disease, or chemical exposure). This disease is almost always lethal in the absence of extreme intervention measures (e.g., surgery, liver transplant).
How It Is Measured or Detected
- In animal models, the presence of HCA and HCC are measured histologically following the two-year rodent bioassay, which is conducted according to OECD Test Guideline 451 (OECD 2009).
- In humans, liver cancer is detected by abdominal CT scan followed by biopsy and pathological examination. Symptoms of liver cancer include: jaundice, abdominal pain, nausea, and liver dysfunction. Liver cancer is more common in patients with risk factors that include: viral hepatitis, non-viral hepatitis, chronic alcoholism, obesity leading to steatohepatitis, cirrhosis, and liver fluke infection (Bonder and Afdhal 2012, Paradis 2013, Venkatesh, et al. 2014).
Domain of Applicability
Hepatocellular carcinoma occurs in many vertebrate species including birds, fish, and mammals such as humans.
Regulatory Significance of the Adverse Outcome
Any cancer endpoint is considered to be adverse from a regulatory perspective. Substances causing cancer are regulated such that the general population is not exposed to levels that exceed the carcinogenic dose. The standard assay for carcinogens is the two-year rodent bioassay, which is conducted by the National Toxicology Program in the U.S.A. (https://ntp.niehs.nih.gov/). The International Agency on Research on Cancer (IARC; https://www.iarc.fr/) categorizes substances based on available evidence pointing to their ability to cause cancer in humans and/or animals.
Bonder, A., Afdhal, N., 2012. Evaluation of liver lesions. Clin. Liver Dis. 16, 271-283.
Ellison, L.F., Wilkins, K., 2012. Canadian Trends in Cancer Prevalence. Health Reports 23.
OECD, 2009. OECD Guideline for the Testing of Chemicals: Carcinogenicity Studies (Test Guideline 451).
Paradis, V., 2013. Histopathology of hepatocellular carcinoma. Recent Results Cancer Res. 190, 21-32.
Venkatesh, S.K., Chandan, V., Roberts, L.R., 2014. Liver masses: a clinical, radiologic, and pathologic perspective. Clin. Gastroenterol. Hepatol. 12, 1414-1429.