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Human Relevance of Rodent Liver Tumors: Key Insights from a Toxicology Forum Workshop on Nongenotoxic Modes of Action

Felter, S and Foreman, J and Boobis, A and Corton, C and Doi, A and Flowers, L and Goodman, J and Haber, L and Jacobs, A and Klaunig, J and Lynch, A and Moggs, Jonathan and Pandiri, A (2017) Human Relevance of Rodent Liver Tumors: Key Insights from a Toxicology Forum Workshop on Nongenotoxic Modes of Action. Regulatory toxicology and pharmacology, 92. pp. 1-7. ISSN PMID: 29113941

Official URL: PMID: 29113941

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 thress MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs.

Item Type: Article
Keywords: non-genotoxic carcinogenesis, mode of action, mechanism, human relevance, rodent tumours
Date Deposited: 28 Nov 2017 00:45
Last Modified: 28 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/33452

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