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Relationship: 875

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

Activation, Long term AHR receptor driven direct and indirect gene expression changes leads to Alterations, Cellular proliferation / hyperplasia

Upstream event

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

Activation, Long term AHR receptor driven direct and indirect gene expression changes

Downstream event

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

Alterations, Cellular proliferation / hyperplasia

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
Sustained AhR Activation leading to Rodent Liver Tumours	non-adjacent	High	High	Allie Always (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 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

Both the development of altered hepatic foci, which are preneoplastic lesions, and the highly proliferative environment induced in the liver by Hepatoxicity/Hepatopathy induce cell proliferation. Replacement of liver cells normally occurs by hepatocyte replication (Paku et al, 2001). However, Hepatoxicity/Hepatopathy may produce sufficient liver damage that stem cell replication also contributes to hepatocyte replacement (Alison, 2005). In general, increased stem cell replication appears to be associated with tumor formation (Tomasetti and Vogelstein, 2015).

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

The quantitative relationship discussed in the Sustained AHR Activation (MIE) page and also presented on the KER page for Sustained AHR Activation --> Hepatotoxicity/Hepatopathy is common to dioxin-like chemicals (NTP, 2006a, 2006b, 2006c, 2006d, 2006e, 2006f). In addition, rats fed indole-3-carbinol for eight weeks in an initiation-promotion medium term assay showed the development of oxidative stress, likely due to induction of CYP1A and other phase I enzymes. The development of AHF, here noted as Changes in Cellular Growth Homeostasis / Apoptosis was also enhanced (Shimamoto et al. 2011).

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

Many two-year bioassays of dioxin-like chemicals showed both sustained AHR activation measured by CYP induction as well as an extensive proliferative/regenerative response in the liver (NTP, 2006a, 2006b, 2006c, 2006d, 2006e, 2006f).

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

While the exact mechanism of how sustained AHR activation leads to a strong hepato-proliferative response, a large number of observations lend certainty to the relationship.

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

Figure 4: Indirect key event relationships. Sustained AHR activation was identified as the MIE and determined as the product of fractional AHR activation measured by CYP1A1 induction and time in weeks. The frequency of histopathology and tumors observed in rats in the NTP bioassays was plotted against sustained AHR activation. A) Relationships between the MIE and aspects of KE2 (hepatopathy and hyperplasia; all response shown as filled circles). B) Relationships between the MIE and the two tumor types representing the adverse outcome (AO) (responses shown as an X). The Hill coefficients, BMD21 and TDV21 values are shown in the table below. The values shown as open circles in the two plots in B show tumor responses in animals in the stop-exposure group that were exposed to the maximum DLC concentration for 31 weeks (see text for discussion). In each plot in B, three values, one each for TCDD, 4-PeCDF and PCB-126, are shown for the stop-exposure experiments and only two are not obscured by the other responses. The numerical ESA50 values are the half-maximal level of sustained AHR activation similar to an EC50 and described in the text.

The quantitative KER linking the sustained AHR activation to Hepatotoxicity/Hepatopathy is shown in Fig. 4 at the left. Indirect key event relationships. Sustained AHR activation was identified as the MIE and determined as the product of fractional AHR activation measured by CYP1A1 induction and time in weeks. The frequency of histopathology and tumors observed in rats in the NTP bioassays was plotted against sustained AHR activation. A) Relationships between the MIE and aspects of Hepatotoxicity/Hepatopathy and Cellular Proliferation / Hyperplasia; all response shown as filled circles). B) Relationships between the MIE and the two tumor types representing the adverse outcome (AO) (responses shown as an X). The Hill coefficients, BMD21 and TDV21 values are shown in the table below. The values shown as open circles in the two plots in B show tumor responses in animals in the stop-exposure group that were exposed to the maximum DLC concentration for 31 weeks. In each plot in B, three values, one each for TCDD, 4-PeCDF and PCB-126, are shown for the stop-exposure experiments and only two are not obscured by the other responses. The numerical ESA50 values are the half-maximal level of sustained AHR activation similar to an EC50 and described in the text.Using methods described in Simon et al. (2014), the transitional dose values of the sustained AHR activation index based on a 21% response level are shown in the table below Here, the transitional dose value is the projection from the 21% response level to the background response level using the slope of the dose-response at this same 21% response level (Sand et al., 2006; Simon et al., 2014). While not definitive thresholds, transitional dose values based on the 21% response level can be used as an approximation of a threshold. As noted, toxic hepatopathy includes a constellation of effects and the transitional dose value has the lowest value of the three effects representing the Hepatotoxicity/Hepatopathy and the Cellular Proliferation / Hyperplasia.

Hill Model parameters and Transitional Dose Values (TDV) for Hepatotoxicity/Hepatopathy, Cellular Proliferation / Hyperplasia and the occurrence of Hepatocellular and Bile Duct Tumors based on the Quantitative Measure of the MIE or Sustained AHR Activation in ppb-weeks

Endpoint	Hill Coeff.	Kd in SAA units	BMD21 in SAA units	TDV21 in SAA units
KE#3
Bile duct hyperplasia	2.28	87.05	48.7	43.0
Oval cell hyperplasia	7.44	91.2	76.3	73.6

ESA50 (Fig. 4) is similar to an EC50 - it is the effective level of sustained AHR activation necessary to achieve a 50% response. As described, the level of sustained AHR activation can be calculated by multiplying the fractional level of AHR activation measured by CYP1A1 induction by the number of weeks of dosing. Bile duct hyperplasia occurs at a higher level of sustained AHR activation and oval cell hyperplasia at an even higher level (Fig. 5A, middle and bottom plots). The dose-response for oval cell hyperplasia is much steeper than the other two histopathological effects that comprise KE#3. Although speculative, this higher level of sustained AHR activation needed for bile duct hyperplasia may be the reason why Kociba et al. (1978) failed to observe bile duct tumors whereas they were observed in NTP (2006a). Possibly, the distinction between the two studies may be that dosage regimen (diet vs. gavage) or changes in the Sprague-Dawley strain over time. In the rats used in Kociba et al. (1978), the degree of sustained AHR activation needed for promotion of bile duct tumors may not have been achieved.

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

This relationship occurs in rodents and possibly other animals but not in humans.

References

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

Alison, M.R., 2005. Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev. 1, 253-260.

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.

Paku, S., Schnur, J., Nagy, P., Thorgeirsson, S.S., 2001. Origin and structural evolution of the early proliferating oval cells in rat liver. Am. J. Pathol. 158, 1313-1323.

Shimamoto, K., Dewa, Y., Ishii, Y., Kemmochi, S., Taniai, E., Hayashi, H., Imaoka, M., Morita, R., Kuwata, K., Suzuki, K., Shibutani, M., Mitsumori, K., 2011. Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine. Toxicology. 283, 109-17.

Tomasetti, C., Vogelstein, B., 2015. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81.