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Event: 1171

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Increase, Clonal Expansion of Altered Hepatic Foci

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. The short name should be less than 80 characters in length. More help
Increase, Clonal Expansion of Altered Hepatic Foci

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Cell term

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Organ term

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

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
PPARalpha-dependent liver tumors in rodents KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. 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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help
  • More than 40 years ago, cancer biologists pounced on the Darwinian principles of mutation, selection, and clonal expansion to explain cancer evolution. The occurrence of altered clones of cells in the livers of animals was revealed by enzyme histochemistry with a resulting plethora of different types of clones including those positive for gamma-glutamyltranspeptidase (GGT), placental glutathione transferase and negative for APTase and glucose-6-phosphase (Glauert et al. 1986; Pitot, 1990; Scherer, 1987)

    Mathematical models of clonal formation were developed soon after suffered from non-identifiability of parameters (Moolgavkar & Lubeck 2003; Connolly & Andersen 1991; Cox & Huber 2007). More recently, an examination of a clonal expansion model of cancer suggested a widely accepted model of clonal expansion appeared biologically implausible when compared to a model based on the concept of dysregulated hyperplasia (Bogen 2014).

    Notwithstanding the vagaries of understanding and modeling early events in cancer pathogenesis, altered hepatic foci representing clones of presumably premalignant cells have been demonstrably observed as a precursor of rodent liver tumors. Oval cells are similar to fetal hepatoblasts and bipotential in that they can differentiate into either hepatocytes or cholantiocytes (Grompe 2013). primary oval cells from rats treated with PPARa activators differentiated into basophilic cells, similar to those in pre-neoplastic basophilic clones observed in chronic studies of PPARa activators (Kaplanski et al. 2000; Marsman & Popp, 1994).  Continued activation of PPARα is necessary for focal enlargement and the formation of tumors (Grasl-Kraupp et al. 19931a, b, c; Isenberg et al. 1997; Corton et al. 2014).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Clonal expansion of altered hepatic foci is measure histologically as changes in the number of foci per volume of liver tissue or volume fraction of the liver (Marsman & Popp 1994; Isenberg et al. 1997; Kuwata et al. 2016)

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

The occurrence and growth of altered hepatic foci have been measured primarily rodents as part of initiation-promotion studies or two-year bioassays (Dragan et al. 1991; Hendrich et al. 1987; Pitot et al. 1989).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Conolly, R. B., & Andersen, M. E. (1991). Biologically based pharmacodynamic models: tools for toxicological research and risk assessment. Annu Rev Pharmacol Toxicol, 31, 503-523.

Corton, J. C., Cunningham, M. L., Hummer, T. B., Lau, C, Meek, B, Peters, JM, Popp, JA, Rhomberg, L, Seed, J., & Klaunig, J. E. (2014). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol, 44(1), 1-49.

Cox, L. A., & Huber, W. A. (2007). Symmetry, identifiability, and prediction uncertainties in multistage clonal expansion (MSCE) models of carcinogenesis. Risk Anal, 27(6), 1441-1453.

Dragan, Y. P., Rizvi, T., Xu, Y. H., Hully, J. R., Bawa, N., Campbell, H. A. et al. (1991). An initiation-promotion assay in rat liver as a potential complement to the 2-year carcinogenesis bioassay. Fundam Appl Toxicol, 16(3), 525-547.

Glauert, H. P., & Pitot, H. C. (1986). Influence of dietary fat on the promotion of diethylnitrosamine-induced hepatocarcinogenesis in female rats. … of the Society for Experimental Biology ….

Grasl-Kraupp B, Huber W, Just W, et al. (1993a). Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin. Carcinogenesis, 14, 1007–12.

Grasl-Kraupp B, Huber W, Timmermann-Trosiener I, Schulte-Hermann R. (1993b). Peroxisomal enzyme induction uncoupled from enhanced DNA synthesis in putative preneoplastic liver foci of rats treated with a single dose of the peroxisome proliferator nafenopin. Carcinogenesis, 14, 2435–7

Grasl-Kraupp B, Waldhor T, Huber W, Schulte-Hermann R. (1993c). Glutathione S-transferase isoenzyme patterns in different subtypes of enzyme-altered rat liver foci treated with the peroxisome proliferator nafenopin or with phenobarbital. Carcinogenesis, 14, 2407–12

Grompe, M. (2009). Adult Liver Stem Cells.  In Essentials of Stem Cell Biology (pp. 285-298). Elsevier.

Hendrich, S., Campbell, H. A., & Pitot, H. C. (1987). Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis, 8(9), 1245-1250.

Isenberg JS, Kolaja KL, Ayoubi SA, et al. (1997). Inhibition of WY 14 643-induced hepatic lesion growth in mice by rotenone. Carcinogenesis, 18, 1511–9

Kaplanski, C., Pauley, C. J., Griffiths, T. G., Kawabata, T. T., & Ledwith, B. J. (2000). Differentiation of rat oval cells after activation of peroxisome proliferator-activated receptor alpha43. Cancer Res, 60(3), 580-587.

Kuwata, K., Inoue, K., Ichimura, R., Takahashi, M., Kodama, Y., & Yoshida, M. (2016). Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice. Food Chem Toxicol, 88, 75-86.

Marsman, D. S., & Popp, J. A. (1994). Biological potential of basophilic hepatocellular foci and hepatic adenoma induced by the peroxisome proliferator, Wy-14,643. Carcinogenesis, 15(1), 111-117.

Moolgavkar, S. H., & Luebeck, E. G. (2003). Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer, 38(4), 302-306.

Pitot, H. C., Campbell, H. A., Maronpot, R., Bawa, N., Rizvi, T. A., Xu, Y. H. et al. (1989). Critical parameters in the quantitation of the stages of initiation, promotion, and progression in one model of hepatocarcinogenesis in the rat. Toxicol Pathol, 17(4 Pt 1), 594-611; discussion 611.

Pitot, H. C., Dragan, Y., Xu, Y. H., & Pyron…, M. (1990). Role of altered hepatic foci in the stages of carcinogenesis. Progress in clinical ….

Scherer, E. (1987). Relationship among histochemically distinguishable early lesions in multistep-multistage hepatocarcinogenesis. Mouse Liver Tumors.