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

TitleHuman relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action
Publication TypeJournal Article
Year of Publication2018
AuthorsFelter S.P, Foreman J.E, Boobis A., Corton J.C, Doi A.M, Flowers L., Goodman J., Haber L.T, Jacobs A., Klaunig J.E, Lynch A.M, Moggs J., Pandiri A.
JournalRegulatory Toxicology and Pharmacology
Volume92
Pagination1-7
Date PublishedFeb
ISBN Number0273-2300
Accession Number29113941
KeywordsConstitutive Androstane Receptor, Mode of action, Nongenotoxic, Peroxisome proliferator-activated receptor alpha (PPARalpha), Rodent liver tumors
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 (PPARalpha), 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 PPARalpha 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.

Short TitleRegul. Toxicol. Pharmacol.
Alternate JournalRegulatory toxicology and pharmacology : RTP