Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action

Susan P. Felter, Jennifer E. Foreman, Alan Boobis, J. Christopher Corton, Adriana M. Doi, Lynn Flowers, Jay Goodman, Lynne T. Haber, Abigail Jacobs, James E. Klaunig, Angela M. Lynch, Jonathan Moggs, Arun Pandiri

Research output: Research - peer-reviewArticle

Abstract

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor–alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARα MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs.

LanguageEnglish (US)
Pages1-7
Number of pages7
JournalRegulatory Toxicology and Pharmacology
Volume92
DOIs
StatePublished - Feb 1 2018

Profile

Cytotoxicity
Liver
Tumors
Rodentia
constitutive androstane receptor
Toxicology
Education
Neoplasms
Research
PPAR alpha
Cytoplasmic and Nuclear Receptors
Risk assessment
Labeling
Hazards

Keywords

  • Constitutive Androstane Receptor
  • Mode of action
  • Nongenotoxic
  • Peroxisome proliferator-activated receptor alpha (PPARα)
  • Rodent liver tumors

ASJC Scopus subject areas

  • Toxicology

Cite this

Felter, S. P., Foreman, J. E., Boobis, A., Corton, J. C., Doi, A. M., Flowers, L., ... Pandiri, A. (2018). Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action. Regulatory Toxicology and Pharmacology, 92, 1-7. DOI: 10.1016/j.yrtph.2017.11.003

Human relevance of rodent liver tumors : Key insights from a Toxicology Forum workshop on nongenotoxic modes of action. / Felter, Susan P.; Foreman, Jennifer E.; Boobis, Alan; Corton, J. Christopher; Doi, Adriana M.; Flowers, Lynn; Goodman, Jay; Haber, Lynne T.; Jacobs, Abigail; Klaunig, James E.; Lynch, Angela M.; Moggs, Jonathan; Pandiri, Arun.

In: Regulatory Toxicology and Pharmacology, Vol. 92, 01.02.2018, p. 1-7.

Research output: Research - peer-reviewArticle

Felter, SP, Foreman, JE, Boobis, A, Corton, JC, Doi, AM, Flowers, L, Goodman, J, Haber, LT, Jacobs, A, Klaunig, JE, Lynch, AM, Moggs, J & Pandiri, A 2018, 'Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action' Regulatory Toxicology and Pharmacology, vol 92, pp. 1-7. DOI: 10.1016/j.yrtph.2017.11.003
Felter, Susan P. ; Foreman, Jennifer E. ; Boobis, Alan ; Corton, J. Christopher ; Doi, Adriana M. ; Flowers, Lynn ; Goodman, Jay ; Haber, Lynne T. ; Jacobs, Abigail ; Klaunig, James E. ; Lynch, Angela M. ; Moggs, Jonathan ; Pandiri, Arun. / Human relevance of rodent liver tumors : Key insights from a Toxicology Forum workshop on nongenotoxic modes of action. In: Regulatory Toxicology and Pharmacology. 2018 ; Vol. 92. pp. 1-7
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