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Relationship: 1517

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 Liver Cancer

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

Liver Cancer

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

Cell death by necrosis and necroptosis produces DAMPs that trigger inflammation. Inflammation is widely considered to be an important risk factor that sets the stage for malignant transformation; however, mechanistically, it is unclear how it does so.

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

Moderate.

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

Moderate.

Empirical evidence broadly supports the notion that cytotoxicity occurs at doses lower than those that cause liver cancer, and at early time points. A few examples are shown below.

F344 rats exposed for 13 weeks to furan (0-60 mkd, gavage) showed a dose dependent increase in degeneration and necrosis of hepatocytes beginning at 8 mkd and 15 mkd, in males and females, respectively. A second group of rats (exposed to 0-8 mkd furan) was studied at nine months, fifteen months, and two years. After nine months, degeneration and necrosis were observed in the hepatocytes of all animals in the 4 and 8 mkd groups. After fifteen months, these endpoints were significantly increased in all animals (male and female) of each dose group. After two years, rats developed hepatocellular adenomas and carcinomas beginning at 4 mkd in male and female rats (NTP 1993). Thus, cytotoxicity precedes cancer and occurs at similar doses and the empirical evidence is concordant with a relationship between cytotoxicity and cancer.

In a study conducted by the NTP (1993), B6C3F1 mice (male and female) were exposed for 13 weeks to the hepatocarcinogen furan (0, 4, 8, 15, 30,60 mkd, gavage; n=10 per group) (nine male and four female mice exposed to 60 mkd died before the end of the study). Toxic lesions were seen in the liver at all doses and severity increased with dose, bile duct hyperplasia and cholangiofibrosis were observed at 30 and 60 mkd (NTP 1993). A two year study was conducted using a lower dose range (0, 4, 8, 15 mkd). Kaplan Meier survival curves showed a dose-dependent decrease in survivorship with increasing dose of furan. There was a dose dependent increase in hepatocellular adenoma and carcinoma in male and female mice (NTP 1993).

Empirical evidence supporting an underlying mechanism relating to inflammation as a mitigating factor in this relationship is less clear. Inflammation in response to furan exposure occurs in mice at around the same dose as cytotoxicity and increases in a dose and time dependent manner (Fransson-Steen, et al. 1997, Moser, et al. 2009, NTP 1993). Inflammation is accompanied by an increase of circulating inflammatory markers (Wang, et al. 2014), and changes in inflammation-associated gene expression (Jackson, et al. 2014). In Moser et al. (2009) mild inflammation arose at very low doses (0.5 mkd), was moderate at 1 mkd, and was marked at 4mkd; whereas hepatocellular adenomas and carcinomas were not observed until 4 and 8 mkd, respectively.

Most recently, the relationship between chemically induced hepatocellular carcinoma and inflammation was outlined in an award-winning article that was published in the journal Carcinogenesis: The 2016 Carcinogenesis Award Winners “Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2” (Karin and Dhar 2016). Studies in which diethylnitrosamine (DEN, a liver carcinogen) was given to male mice demonstrated that induction of hepatocellular carcinoma is dependent upon induction of inflammation. A liver myeloid cell-specific ablation of IKK-beta was sufficient to inhibit DEN-dependent carcinogenesis, whereas its deletion in hepatocytes enhanced carcinogenesis (Maeda, et al. 2005). The latter was due to an increase in cell death, which caused a subsequent increase of the cytokine and tumour protomtor interleukin 6 (IL-6) (Maeda, et al. 2009). IL-6 is known to be inhibited by estrogen, which could account for the higher prevalence of hepatocellular carcinoma in males (Naugler, et al. 2007). IL-6 has been described as a “wolf in sheep’s clothing” and is thought to be an important link between inflammation and cancer (Naugler and Karin 2008). IL1-alpha released from dying hepatocytes is another important promoter of hepatocellular carcinoma (Sakurai, et al. 2008).

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

This relationship appears to be valid for toxicants that produce moderate levels of cytotoxicity. Acetaminophen is a Cyp2E1 substrate that produces extremely high levels of hepatotoxicity. Acetaminophen does not cause liver cancer because death by liver failure occurs before cancer can develop.

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

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

References

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

Brenner, C., Galluzzi, L., Kepp, O., Kroemer, G., 2013. Decoding cell death signals in liver inflammation. J. Hepatol. 59, 583-594.

Elsharkawy, A.M., Mann, D.A., 2007. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46, 590-597.

Finkin, S., Pikarsky, E., 2011. NF-kappaB in liver cancer: the plot thickens. Curr. Top. Microbiol. Immunol. 349, 185-196.

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.

Jackson, A.F., Williams, A., Recio, L., Waters, M.D., Lambert, I.B., Yauk, C.L., 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol. Appl. Pharmacol. 274, 63-77.

Kaczmarek, A., Vandenabeele, P., Krysko, D.V., 2013. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209-223.

Karin, M., 2009. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect. Biol. 1.

Karin, M., 2006. Nuclear factor-kappaB in cancer development and progression. Nature 441, 431-436.

Karin, M., Dhar, D., 2016. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37, 541-546.

Luedde, T., Kaplowitz, N., Schwabe, R.F., 2014. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765-783.e4.

Luedde, T., Schwabe, R.F., 2011. NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nature Reviews Gastroenterology and Hepatology 8, 108-118.

Maeda, S., Hikiba, Y., Sakamoto, K., Nakagawa, H., Hirata, Y., Hayakawa, Y., Yanai, A., Ogura, K., Karin, M., Omata, M., 2009. Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression. Hepatology 50, 1851-1860.

Maeda, S., Kamata, H., Luo, J.L., Leffert, H., Karin, M., 2005. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990.

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.

Naugler, W.E., Karin, M., 2008. The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol. Med. 14, 109-119.

Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., Karin, M., 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124.

Pikarsky, E., Ben-Neriah, Y., 2006. NF-kappaB inhibition: a double-edged sword in cancer? Eur. J. Cancer 42, 779-784.

Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., Ben-Neriah, Y., 2004. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466.

Sakurai, T., He, G., Matsuzawa, A., Yu, G.Y., Maeda, S., Hardiman, G., Karin, M., 2008. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer. Cell. 14, 156-165.

Vainer, G.W., Pikarsky, E., Ben-Neriah, Y., 2008. Contradictory functions of NF-kappaB in liver physiology and cancer. Cancer Lett. 267, 182-188.

Vallabhapurapu, S., Karin, M., 2009. Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693-733.

Wang, E., Chen, F., Hu, X., Yuan, Y., 2014. Protective effects of apigenin against furan-induced toxicity in mice. Food Funct. 5, 1804-1812.

Wang, J., Huang, Q., Chen, M., 2003. The role of NF-kappaB in hepatocellular carcinoma cell. Chin. Med. J. (Engl) 116, 747-752.