Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Sustained AhR Activation leading to Rodent Liver Tumours||KE||Strong|
|Mammalia sp. AVB-2011||Mammalia sp. AVB-2011||Strong||NCBI|
Level of Biological Organization
How this Key Event works
As defined in NTP (2006a), toxic hepatopathy consists of a constellation of different histological observations including, but not limited to, hepatocyte hypertrophy, multinucleated hepatocytes, inflammation, pigmentation, steatosis, portal fibrosis, bile duct cysts, cholangiofibrosis, mitochondrial injury, necrosis, fibrosis, and porphyria, as well as bile duct and oval cell hyperplasia (Boverhof et al., 2005; Chang et al., 2005; Hailey et al., 2005; Jones and Greig, 1975; NTP, 2006a; NTP, 2006b; NTP, 2006c; NTP, 2006d; NTP, 2006e; NTP, 2006f; Walker et al., 2006; Simon et al., 2009). In this AOP, Hepatotoxicity/Hepatopathy is distinguished from Cellular Proliferation/Hyperplasia as the histological observations that comprise toxic hepatopathy but without bile duct hyperplasia and oval cell hyperplasia.
How it is Measured or Detected
As noted, Hepatotoxicity/Hepatopathy includes the histologically observed effects that comprise toxic hepatopathy save the proliferative effects. Necrosis and inflammation are not observed after 52 weeks of DLC administration but occur during the second year of treatment and are observed at the 2-year termination of the NTP cancer bioassays. Necrosis and inflammation are observed at lower doses than those at which tumors were observed (Hailey et al., 2005). Damage to hepatocytes and cytotoxicity are common features of these histopathological changes. This provides empirical support for the hypothesis that regenerative repair may be a contributor to the proliferative response and the adverse effects observed at the higher TCDD dosages.
Evidence Supporting Taxonomic Applicability
The relationship of this constellation of organ-level effects to hepatocellular cancer is well established in mammalian species; for example, steatosis and nonalcoholic steatohepatitis increase the risk of liver cancer in humans and rodents (Ip and Wang, 2014; Nakamura and Terauchi, 2013). Sustained AHR activation induces steatosis and could act in a similar fashion.
Boverhof, D.R., Burgoon, L.D., Tashiro, C., Chittim, B., Harkema, J.R., Jump, D.B., Zacharewski, T.R., 2005. Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-Mediated hepatotoxicity. Toxicol. Sci. 85, 1048-1063.
Chang, H., Wang, Y.J., Chang, L.W., Lin, P., 2005. A histochemical and pathological study on the interrelationship between TCDD-induced AhR expression, AhR activation, and hepatotoxicity in mice. J. Toxicol. Environ. Heal. A. 68, 1567-1579.
Hailey, J.R., Walker, N.J., Sells, D.M., Brix, A.E., Jokinen, M.P., Nyska, A., 2005. Clas- sification of proliferative hepatocellular lesions in harlan sprague-dawley rats chronically exposed to dioxin-like compounds. Toxicol. Pathol. 33, 165-174.
Ip, B.C., Wang, X.-D., 2014. Non-alcoholic steatohepatitis and hepatocellular carci- noma: implications for lycopene intervention. Nutrients 6, 124-162.
Jones, G., Greig, J.B., 1975. Pathological changes in the liver of mice given 2,3,7,8-tetrachlorodibenzo-p-dioxin. Experientia 31, 1315-1317.
Nakamura, A., Terauchi, Y., 2013. Lessons from mouse models of high-fat diet- induced NAFLD. Int. J. Mol. Sci. 14, 21240-21257.
NTP, 2006a. NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser. 4-232.
NTP, 2006b. NTP toxicology and carcinogenesis studies of 2,3,4,7,8- Pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1-198.
NTP, 2006c. NTP toxicology and carcinogenesis studies of 3,3',4,4',5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser. 4-246.
NTP, 2006d. NTP technical report on the toxicology and carcinogenesis studies of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 4-168.
NTP, 2006e. NTP toxicology and carcinogenesis studies of a binary mixture of 3,3' ,4,4' ,5-Pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) and 2,20,4,40,5,50-Hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1-258.
NTP, 2006f. NTP toxicology and carcinogenesis studies of a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6), 2,3,4,7,8- pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4), and 3,3',,4,4' ,5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (Gavage studies). Natl. Toxicol. Program Tech. Rep. Ser. 1-180.
Simon, T., Aylward, L.L., Kirman, C.R., Rowlands, J.C., Budinsky, R.A., 2009. Estimates of cancer potency of 2,3,7,8-tetrachlorodibenzo(p)dioxin using linear and nonlinear dose-response modeling and toxicokinetics. Toxicol. Sci. 112, 490-506.
Walker, N.J., Wyde, M.E., Fischer, L.J., Nyska, A., Bucher, J.R., 2006. Comparison of chronic toxicity and carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 2-year bioassays in female Sprague-Dawley rats. Mol. Nutr. Food Res. 50, 934-944.