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Relationship: 1514

Title

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

Hepatocytotoxicity leads to Sustained proliferation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Hepatocytotoxicity

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Sustained proliferation

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	adjacent	High	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

Sex	Evidence
Mixed	Moderate

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

Hepatocytes are typically quiescent, with only about 1-2% turnover. However, under cytotoxic conditions, the liver has a remarkable ability to replace dead or dying cells through induction of cellular proliferation to create new liver cells and maintain homeostasis. Indeed, following surgical resection or chemically induced injury, the liver is able to activate cell division and regenerate itself.

The liver replaces dead cells via two main pathways: (1) hypertrophy and division of existing cells; or (2) proliferation of a population of facultative stem cells, called biliary epithelial cells (BECs), located at the Canals of Hering (in zone 1 where canaliculi join and drain into the main bile duct). Facultative stem cells are functional, differentiated cells that will dedifferentiate in response to tissue damage, thereby becoming a population of progenitor cells that can redifferentiate to replace multiple lost cell types. In a process known as ductal expansion, BECs dedifferentiate into oval cells, which then redifferentiate into hepatocytes or BECs in order to regenerate damaged liver tissue. Liver cell proiferattion and regeneration has been extensively reviewed (Mao, et al. 2014, Stanger 2015, Yanger and Stanger 2011).

On a molecular level, how liver cell proliferation occurs is less completely understood. Molecular signals that are released from dying cells trigger proliferation of existing cells. Important players include the transcription factors AP-1 (particularly the c-Jun monomer) and NF-kappaB, both of which are not normally expressed in adult liver, but are up-regulated following partial hepatectomy and are required for hepatic regeneration.

Liver cellular proliferation has been well studied in mice, rats, and zebrafish (Cox and Goessling 2015, Goessling and Sadler 2015), which are all systems that are thought to work in a similar way to human livers (Kwon, et al. 2015). Liver regeneration can be observed following partial hepatectomy. Methods for 2/3 partial hepatectomy have been described (Mitchell and Willenbring 2008, Mitchell and Willenbring 2014).

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

Strong. The liver is well known to regenerate itself following chemical or surgical injury. It is widely accepted that significant cytotoxicity to the liver leads to cellular proliferation (Forbes and Newsome 2016). If this occurs during chronic exposure these effects would persist or be sustained.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Strong. That chronic hepatotoxicity leads to persistant proliferation/sustained proliferation has been widely reported for a number of liver toxicants (as well as surgical resection of the liver). This is a very data-rich field. Below we summarize a few examples of the empirical data supporting this relationship.

Furan is a rodent hepatocarcinogenic chemical that is proposed to operate through a mode of action involving cytotoxicity followed by cellular proliferation (Fransson-Steen, et al. 1997, Moser, et al. 2009). In support of the relationship between hepatotoxicity and persistant proliferation/sustained proliferation, mice and rats exposed to dose ranges of furan present with cytotoxicity at lower doses than the doses at which they present regenerative proliferation. Mice exposed to a dose range of 0, 0.5, 1, 2, 4, 8 mkd had significant levels of liver cytotoxicity (measured by serum ALT) beginning at 1 mkd, and significant levels of cellular proliferation (measured by BrdU incorporation) at 8 mkd (Moser, et al. 2009). F344 rats exposed to 0-16 mkd furan showed significant increases in cell death starting at 2-4 mkd, and proliferation at 8-16 mkd (Ding, et al. 2012). Cytotoxicity also begins at earlier time points than proliferation. Cell death and proliferation were also measured in male Sprague-Dawley rats exposed to 30 mkd furan over a three month time course. Apoptosis was detected after one day, whereas proliferation began to occur after three days (Hickling, et al. 2010).

Male Wistar rats treated with a single, necrogenic dose of thioacetamide had serum AST levels of approximately 500, 2250, 1900 and 500 IU/L serum at 12, 24 (peak), 48 and 72 hours post-exposure; levels were restored to normal after 96 hours. Levels of cellular proliferation followed closely after, and peaked at 48 hours; thereby demonstrating a temporal concordance between cytotoxicity and cellular proliferation (Bautista, et al. 2010). Rats exposed to thioacetamide presented with hepatotoxicity (increased ALT) beginning at 24 hours post-exposure followed by increased cellular proliferation at 36 hours post-exposure (samples were taken over the following time-course: 6, 12, 24, 36, 48, 72 and 96 hours); thereby demonstrating a temporal concordance between cytotoxicity and cellular proliferation (Mangipudy, et al. 1995).

B6C3F1 mice were exposed to 0, 34, 90, 138, or 277 mg/kg/day of chloroform for 4 days or for 5 days/week for 3 weeks. Hepatic necrosis was observed to be elevated above control in all dose groups at both time points. Cellular proliferation (by labelling index, BrdU incorporation) in the liver increased in a dose-dependent manner at both time points (4 days and 3 weeks), but were first significantly increased above control levels at 34 mg/kg bw (4 day group) or 138 mg/kg bw (3 week group). These data demonstrate the temporal concordance between cytotoxicity and cellular proliferation of hepatocytes; the trend is particularly clear at the 3 week time-point (Larson, et al. 1994).

The temporal concordance between cytotoxicity and cellular proliferation has also been well documented following exposure to carbon tetrachloride (Benson and Springer 1999, Doolittle, et al. 1987, Eschenbrenner and Miller 1946, Lee, et al. 1998, Nakata, et al. 1985).

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

We are not aware of any instance in which significant amounts of hepatotoxicity (in genetically normal livers) would not lead to cellular proliferation.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Unable to determine.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

This KER is relevant for sustained or persistent exposures.

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

Relevant to any species with a liver.

References

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

Bautista, M., Andres, D., Cascales, M., Morales-Gonzalez, J.A., Sanchez-Reus, M.I., 2010. Effect of gadolinium chloride on liver regeneration following thioacetamide-induced necrosis in rats. Int. J. Mol. Sci. 11, 4426-4440.

Benson, J., Springer, D., 1999. Improved risk estimates for carbon tetrachloride. Final Report. Project No., 54940. DE-FC04-96AL76406.

Ding, W., Petibone, D.M., Latendresse, J.R., Pearce, M.G., Muskhelishvili, L., White, G.A., Chang, C.-., Mittelstaedt, R.A., Shaddock, J.G., McDaniel, L.P., Doerge, D.R., Morris, S.M., Bishop, M.E., Manjanatha, M.G., Aidoo, A., Heflich, R.H., 2012. In vivo genotoxicity of furan in F344 rats at cancer bioassay doses. Toxicol. Appl. Pharmacol. 261, 164-171.

Doolittle, D.J., Muller, G., Scribner, H.E., 1987. Relationship between hepatotoxicity and induction of replicative DNA synthesis following single or multiple doses of carbon tetrachloride. J. Toxicol. Environ. Health 22, 63-78.

Eschenbrenner, A.B., Miller, E., 1946. Liver necrosis and the induction of carbon tetrachloride hepatomas in strain A mice. J. Natl. Cancer Inst. 6, 325-341.

Forbes, S.J., Newsome, P.N., 2016. Liver regeneration - mechanisms and models to clinical application. Nat. Rev. Gastroenterol. Hepatol. 13, 473-485.

Fransson-Steen, R., Goldsworthy, T.L., Kedderis, G.L., Maronpot, R.R., 1997. Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice. Toxicology 118, 195-204.

Hickling, K.C., Hitchcock, J.M., Oreffo, V., Mally, A., Hammond, T.G., Evans, J.G., Chipman, J.K., 2010. Evidence of oxidative stress and associated DNA damage, increased proliferative drive, and altered gene expression in rat liver produced by the cholangiocarcinogenic agent Furan. Toxicol. Pathol. 38, 230-243.

Larson, J.L., Wolf, D.C., Butterworth, B.E., 1994. Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage. Fundamental and applied toxicology : official journal of the Society of Toxicology 23, 537-43.

Lee, V.M., Cameron, R.G., Archer, M.C., 1998. Zonal location of compensatory hepatocyte proliferation following chemically induced hepatotoxicity in rats and humans. Toxicol. Pathol. 26, 621-627.

Mangipudy, R.S., Chanda, S., Mehendale, H.M., 1995. Tissue repair response as a function of dose in thioacetamide hepatotoxicity. Environ. Health Perspect. 103, 260-267.

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.

Nakata, R., Tsukamoto, I., Miyoshi, M., Kojo, S., 1985. Liver regeneration after carbon tetrachloride intoxication in the rat. Biochem. Pharmacol. 34, 586-588.

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