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Relationship: 1518


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Sustained proliferation leads to Liver Cancer

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Cyp2E1 Activation Leading to Liver Cancer non-adjacent Moderate Not Specified Francina Webster (send email) Open for citation & comment WPHA/WNT Endorsed

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

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

Life Stage Applicability

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

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Every time a cell divides, there is a small chance that a mutation might occur. Because hepatocytes are polyploid, there is an increased rate of error-prone division due to multipolar mitotic spindles, which can result in aneuploidy in daughter cells (Stanger 2015). The risk for mutation is further increased when these cells are under stress (e.g., by a chemical exposure or increased oxidative stress). While it is generally understood that increased cellular proliferation is a predisposing factor to chemical carcinogenesis— ‘sustained proliferative signaling’ is one of the Hallmarks of Cancer (Hanahan and Weinberg 2000, Hanahan and Weinberg 2011) and IARC identifies altered cell proliferation as a key characteristic of a carcinogen (Smith, et al. 2015)—the exact mechanism for how one leads to the other is not altogether clear. There will be many steps in between observations of overt cellular proliferation leading to hepatocellular carcinoma. Thus, we describe this as an indirect KER with the hopes that additional empirical data to support the intervening steps will be available in the future, and that these additional KE(R)s can be developed at that time.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help


It is broadly accepted that pro-proliferative signaling is activated in an attempt to compensate for increases in cell death (Stanger 2015). Increased hepatocyte proliferation on a background of polyploidy, elevated cell death and oxidative DNA damage has the effect of increasing the likelihood of fixing harmful mutations, which are necessary for malignant transformation (Celton-Morizur and Desdouets 2010, Shi and Line 2014).  However, the precise mechanistic processes defining this relationship have not been mapped out.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Not all cases where there is sustained cellular proliferation produce tumours (some simply regenerate the liver to its healthy form). For instance Barash et al. (2010) demonstrate that increased background levels of inflammation and genomic instability are required for the progression from sustained cellular proliferation following PHx to tumourigenesis. Therefore, it is clear that malignant transformation must be accompanied by some sort of abnormal cellular signaling or impaired homeostasis. It is well understood that ‘context’ plays an important, albeit poorly understood, role in malignant transformation (Bissell and Hines 2011). More work is needed in this field to determine the additional modifying factors that predict whether a chemical that induces hepatocellular proliferation will cause cancer.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Any species that has a liver.


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


Barash, H., Gross, E.R., Edrei, Y., Ella, E., Israel, A., Cohen, I., Corchia, N., Ben-Moshe, T., Pappo, O., Pikarsky, E., Goldenberg, D., Shiloh, Y., Galun, E., Abramovitch, R., 2010. Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks. Proc. Natl. Acad. Sci. U. S. A. 107, 2207-2212.

Bissell, M.J., Hines, W.C., 2011. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320-329.

Celton-Morizur, S., Desdouets, C., 2010. Polyploidization of liver cells. Adv. Exp. Med. Biol. 675, 123-135.

Golden, R.J., Holm, S.E., Robinson, D.E., Julkunen, P.H., Reese, E.A., 1997. Chloroform mode of action: implications for cancer risk assessment. Regul. Toxicol. Pharmacol. 26, 142-155.

Hanahan, D., Weinberg, R.A., 2000. The hallmarks of cancer. Cell 100, 57-70.

Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646-674.

Moser, G.J., Foley, J., Burnett, M., Goldsworthy, T.L., Maronpot, R., 2009. Furan-induced dose–response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology 61, 101-111.

NTP, 2004. NTP Technichal Report on the Toxicology and Carinogenesis Studies of Urethane, ethanol, and urethane/ethanol in B6C3F1 Mice (drinking water studies). NTP-TR-510.

NTP, 1977. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity. NTP-TR-3.

NTP, 1976. Report of the Carcinogenesis Bioassay of Chloroform (CAS No. 67-66-3). TR-001.

Shi, J.-., Line, P.-., 2014. Effect of liver regeneration on malignant hepatic tumors. World J. Gastroenterol. 20, 16167-16177.

Smith, M.T., Guyton, K.Z., Gibbons, C.F., Fritz, J.M., Portier, C.J., Rusyn, I., DeMarini, D.M., Caldwell, J.C., Kavlock, R.J., Lambert, P., Hecht, S.S., Bucher, J.R., Stewart, B.W., Baan, R., Cogliano, V.J., Straif, K., 2015. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ. Health Perspect.

Solt, D.B., Cayama, E., Tsuda, H., Enomoto, K., Lee, G., Farber, E., 1983. Promotion of liver cancer development by brief exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or carbon tetrachloride. Cancer Res. 43, 188-191.

Stanger, B.Z., 2015. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 77, 179-200.

Templin, M.V., Jamison, K.C., Sprankle, C.S., Wolf, D.C., Wong, B.A., Butterworth, B.E., 1996. Chloroform-induced cytotoxicity and regenerative cell proliferation in the kidneys and liver of BDF1 mice. Cancer letters 108, 225-231.