Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study

Budinsky, R. A., Schrenk, D., Simon, T., Van den Berg, M., Reichard, J. F., Silkworth, J. B., Aylward, L. L., Brix, A., Gasiewicz, T., Kaminski, N., Perdew, G., Starr, T. B., Walker, N. J. and Rowlands, J. C. (2014) Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Critical Reviews in Toxicology, 44 1: 83-119. doi:10.3109/10408444.2013.835787


Author Budinsky, R. A.
Schrenk, D.
Simon, T.
Van den Berg, M.
Reichard, J. F.
Silkworth, J. B.
Aylward, L. L.
Brix, A.
Gasiewicz, T.
Kaminski, N.
Perdew, G.
Starr, T. B.
Walker, N. J.
Rowlands, J. C.
Title Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study
Journal name Critical Reviews in Toxicology   Check publisher's open access policy
ISSN 1040-8444
1547-6898
Publication date 2014-01-01
Year available 2013
Sub-type Critical review of research, literature review, critical commentary
DOI 10.3109/10408444.2013.835787
Open Access Status Not yet assessed
Volume 44
Issue 1
Start page 83
End page 119
Total pages 37
Place of publication Philadelphia, PA, United States
Publisher Taylor & Francis
Language eng
Abstract Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.
Keyword Dioxin
Dose-response assessment
Human relevance framework
Key events
Liver cancer
Mode of action
Modulating factors
TCDD
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 25 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 24 Mar 2016, 21:26:43 EST by System User on behalf of Learning and Research Services (UQ Library)