Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

Abstract

Sulfoxafl or, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifi cally, hepatocellular adenomas and carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies. Sulfoxafl or is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver tumors: (1) CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specifi city for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular hypertrophy and hyperplasia, absence of liver eff ects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or PPAR activation), and indicate that the identifi ed rodent liver tumor MoA for sulfoxafl or would not occur in humans. In this case, sulfoxafl or is considered not to be a potential human liver carcinogen.

Crosstalk between Receptor and Non-receptor Mediated Chemical Modes of Action in Rat Livers Converges through a Dysregulated Gene Expression Network at Tumor Suppressor Tp53

“…Furthermore, the doses of the chemicals administered are of a single concentration and duration albeit the MTD and so essentially the preserved gene networks that we discovered are not dynamic in nature. It is important to emphasize that the gene modules described here are a starting point for MOA characterization and greater nuance will likely be required to characterize mechanistic processes associated with specific receptors (e.g., PPAR-α vs. AhR; LeBaron et al, 2014 ; Becker et al, 2015 ) or chemicals with mixed MOAs. An illustration of such nuance was shown in a recent study in which clear subgroups of chemicals in the RM class of compounds was observed (De Abrew et al, 2015 ).…”

Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action

“…The postulated MOA is similar to that of certain other nongenotoxic agents which are CAR activators. 17,19,[29][30][31][32][33] Furthermore, multiple alternative MOAs have been excluded. Overall, these data strongly support that the postulated MOA for metofluthrin-and momfluorothrin-produced rat hepatocellular tumours is mediated by CAR activation.…”

“…As mentioned above, numerous publications have mentioned that the CARmediated MOA is qualitatively not relevant to humans, based on the lack of the key event of an increased cell proliferation in hepatocellular tumorigenesis induced by the prototypic CAR activator PB. 15,17,19,20,[29][30][31][32][33][36][37][38][39] A cultured human hepatocyte study…”

Biphasic hCAR Inhibition-Activation by Two Aminoazo Liver Carcinogens

“…Normally phosphorylated and complexed with heat shock protein 90 (HSP90) and cytosolic CAR retention protein (CCRP) in cytosol, CAR can become activated, e.g., in mice by binding to a ligand, such as 1,4-bis [2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or in mice or humans by being dephosphorylated via phenobarbital-mediated recruitment of protein phosphatase 2 (PP2A), after which CAR translocates to the nucleus where it heterodimerizes with nuclear receptor RXR and then interacts with promoter complexes of target genes that regulate many physiological processes including lipid metabolism, glucose metabolism, hormonal regulation, cell growth, wound healing, and apoptosis [1][2][3][4][5][6][7]. CAR is thought to promote liver tumors in some rodents by stimulating downstream (e.g., CYP2b, Wisp, FoxM1, cMyc) receptors, multidrug transporters and resistance genes, and related epigenetic modifications (e.g., regions of altered DNA methylation) and microRNA dysregulation (e.g., miR-182 and miR-802 upregulation and miR-122 downregulation) that facilitate hepatocellular proliferation and associated shifts in energy and growth-directed metabolism [2,5,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], particularly when coupled with -catenin activation [23].…”