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

R. A. Budinsky, D. Schrenk, T. Simon, M. Van Den Berg, J. F. Reichard, J. B. Silkworth, L. L. Aylward, A. Brix, T. Gasiewicz, N. Kaminski, Gary H. Perdew, T. B. Starr, N. J. Walker, J. C. Rowlands

Research output: Contribution to journalReview article

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)83-119
Number of pages37
JournalCritical Reviews in Toxicology
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2014

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Aryl Hydrocarbon Receptors
Dioxins
Toxicity
Liver
Tumors
Chemical activation
Neoplasms
Chemical Safety
Cell Proliferation
Liver Neoplasms
Carcinogens
Toxicology
Cell proliferation
Homeostasis
Rats
Apoptosis
Ligands
Education
Tissue
Growth

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Budinsky, R. A., Schrenk, D., Simon, T., Van Den Berg, M., Reichard, J. F., Silkworth, J. B., ... 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. https://doi.org/10.3109/10408444.2013.835787
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, Gary H. ; Starr, T. B. ; Walker, N. J. ; Rowlands, J. C. / Mode of action and dose-response framework analysis for receptor-mediated toxicity : The aryl hydrocarbon receptor as a case study. In: Critical Reviews in Toxicology. 2014 ; Vol. 44, No. 1. pp. 83-119.
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Budinsky, RA, Schrenk, D, Simon, T, Van Den Berg, M, Reichard, JF, Silkworth, JB, Aylward, LL, Brix, A, Gasiewicz, T, Kaminski, N, Perdew, GH, Starr, TB, Walker, NJ & Rowlands, JC 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, vol. 44, no. 1, pp. 83-119. https://doi.org/10.3109/10408444.2013.835787

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, Gary H.; Starr, T. B.; Walker, N. J.; Rowlands, J. C.

In: Critical Reviews in Toxicology, Vol. 44, No. 1, 01.01.2014, p. 83-119.

Research output: Contribution to journalReview article

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T2 - The aryl hydrocarbon receptor as a case study

AU - Budinsky, R. A.

AU - Schrenk, D.

AU - Simon, T.

AU - Van Den Berg, M.

AU - Reichard, J. F.

AU - Silkworth, J. B.

AU - Aylward, L. L.

AU - Brix, A.

AU - Gasiewicz, T.

AU - Kaminski, N.

AU - Perdew, Gary H.

AU - Starr, T. B.

AU - Walker, N. J.

AU - Rowlands, J. C.

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