An integrated approach for prospectively investigating a mode-of-action for rodent liver effects.

Abstract

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end points to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen.

• Authors: Matthew J LeBaron, David R Geter, Reza J Rasoulpour, B Bhaskar Gollapudi, Johnson Thomas, Jennifer Murray, H Lynn Kan, Amanda J Wood, Cliff Elcombe, Audrey Vardy, Jillian McEwan, Claire Terry, Richard Billington
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 270 Issue 2 Pg. 164-73 (Jul 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23607986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013. Published by Elsevier Inc.

Chemical References

• Insecticides
• Pyridines
• Sulfur Compounds
• RNA
• sulfoxaflor
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP2B1

Topics

• Animals
• Cell Proliferation (drug effects)
• Cytochrome P-450 CYP1A1 (metabolism)
• Cytochrome P-450 CYP2B1 (metabolism)
• Dose-Response Relationship, Drug
• Female
• Insecticides (administration & dosage, toxicity)
• Liver (drug effects, enzymology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Microsomes, Liver (drug effects, enzymology, metabolism)
• Prospective Studies
• Pyridines (administration & dosage, toxicity)
• RNA (chemistry, genetics)
• Rats
• Rats, Inbred F344
• Real-Time Polymerase Chain Reaction
• Sulfur Compounds (administration & dosage, toxicity)
• Toxicity Tests (methods)