This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 139

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

N/A, Hepatotoxicity, Hepatopathy, including a constellation of observable effects

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
	Liver Diseases	occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Sustained AhR Activation leading to Rodent Liver Tumours	KeyEvent	Undefined (send email)	Open for citation & comment	Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Mammalia sp. AVB-2011	Mammalia sp. AVB-2011	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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.

References

List of the literature that was cited for this KE description. More help

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.