Upstream eventActivation, Long term AHR receptor driven direct and indirect gene expression changes
Formation, Hepatocellular and Bile duct tumors
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Sustained AhR Activation leading to Rodent Liver Tumours||non-adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Replacement of liver cells normally occurs by hepatocyte replication (Paku et al, 2001). However, KE#2 may produce sufficient liver damage that stem cell replication also contributes to hepatocyte replacement (Alison, 2005). KE#3, hyperplasia/proliferation likely includes both hepatocytes and liver stem cells. In humans, liver damage from a range of stressors (e.g., alcohol consumption) is relation to tumor development and, in general, increased stem cell replication appears to be associated with tumor formation (Tomasetti and Vogelstein, 2015).
Evidence Supporting this KER
The quantitative relationship discussed in the MIE page and also presented on the KER page for MIE --> KE#2 is common to dioxin-like chemicals (NTP, 2006a, 2006b, 2006c, 2006d, 2006e, 2006f). Note the two plots on the left of the figure on the KER page for MIE --> KE#2 show the relationship between the MIE and the AO. Liver tumors in rodents occur with sustained activation of the AHR (NTP, 2006a, 2006b, 2006c, 2006d, 2006e, 2006f; Shimamoto et al. 2011).
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). The AO of liver tumors occurs toward the end of the lifespan and requires an MIE level of around 100 pbb-weeks.
Uncertainties and Inconsistencies
A large body of evidence cited throughout this AOP supports the relationship between the MIE and AO.
Quantitative Understanding of the Linkage
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|
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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This relationship occurs in rodents and possibly other animals but not in humans.
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.