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Activation, Long term AHR receptor driven direct and indirect gene expression changes leads to N/A, Hepatotoxicity, Hepatopathy, including a constellation of observable effects
Key Event Relationship Overview
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||Rick Becker (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
It is not exactly known just how sustained AHR activation leads to hepatotoxicity. Nonetheless, the constellation of different histopathological alterations included in toxic hepatopathy are highly associated with tumor formation (Simon et al. 2009).
Evidence Supporting this KER
The quantitative relationship discussed in the sustained AHR activation (MIE) page and also presented below in 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 KE#1 was also enhanced (Shimamoto et al. 2011).
Uncertainties and Inconsistencies
While the exact mechanism of how sustained AHR activation leads to toxic hepatopathy, a large number of observations lend certainty to the relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between Hepatoxicity/Hepatopathy and downstream KEs of Cellular Proliferation / Hyperplasia and Hepatocellular and Bile Duct Tumors does not appear to occur in humans; however, a comprehensive assessment of this KER in humans has not been conducted in a fashion appropriate for this AOP.
Kociba, R.J., Keyes, D.G., Beyer, J.E., Carreon, R.M., Wade, C.E., Dittenber, D.A., Kalnins, R.P., Frauson, L.E., Park, C.N., Barnard, S.D., Hummel, R.A., Humiston, C.G., 1978. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46, 279-303.
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.
Sand, S., von Rosen, D., Victorin, K., Filipsson, A.F., 2006. Identification of a critical dose level for risk assessment: developments in benchmark dose analysis of continuous endpoints. Toxicol. Sci. 90, 241-251.
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
Simon, T., Aylward, L.L., Kirman, C.R., Rowlands, J.C., Budinsky, R.A., 2009. Estimates of cancer potency of 2,3,7,8-tetrachlorodibenzo(p)dioxin using linear and nonlinear dose-response modeling and toxicokinetics. Toxicol. Sci. 112, 490-506.
Simon, T.W., Simons, S.S., Preston, R.J., Boobis, A.R., Cohen, S.M., Doerrer, N.G., Fenner-Crisp, P.A., McMullin, T.S., McQueen, C.A., Rowlands, J.C., RISK21 Dose- Response Subteam, 2014. The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events. Crit. Rev. Toxicol. 44 (Suppl. 3), 17-43.