API

Relationship: 875

Title

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

Upstream event

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

Downstream event

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Alterations, Cellular proliferation / hyperplasia

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Sustained AhR Activation leading to Rodent Liver Tumours non-adjacent High High

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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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 Supporting this KER

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Biological Plausibility

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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

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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

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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.

Quantitative Understanding of the Linkage

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Figure 4 alt text
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

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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

References

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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.