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

LeBaron, Matthew J.; Geter, David R.; Rasoulpour, Reza J.; Gollapudi, B. Bhaskar; Thomas, Johnson; Murray, Jennifer; Kan, Hayato; Wood, Amanda J.; Elcombe, Cliff; Vardy, A. E.; McEwan, Jillian; Terry, Claire; Billington, Richard

doi:10.1016/j.taap.2013.04.009

Cited by 27 publications

(23 citation statements)

References 28 publications

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“…The impact of CAr humanization on hepatic effects of PB has been addressed in different publications; after short-term PB treatment, Huang et al (2005) show DNA synthesis in livers of humanized CAr mice (hCAr; in some of the experiments cited in the following, mice with humanized CAr and PXr were used, but are referred to as hCAr in the following for the sake of clarity) after treatment with PB. By contrast, results from another study indicate that hCAr does not support the hyperplastic response (ross et al 2010) and a slight but significant increase in hepatocellular proliferation was observed in wild type (WT) but not hCAr mice after administration of sulfoxaflor (leBaron et al 2013). The reason for these discrepant findings is still unclear.…”

mentioning

confidence: 95%

Liver cell proliferation and tumor promotion by phenobarbital: relevance for humans?

Braeuning

2014

Arch Toxicol

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mentioning

confidence: 95%

Liver cell proliferation and tumor promotion by phenobarbital: relevance for humans?

Braeuning

2014

Arch Toxicol

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“…In CARKO/PXRKO animals treated with the same carcinogenic dietary concentration of sulfoxafl or (750 ppm), no evidence of CAR (or PXR) activation was noted, either through gene expression or liver enzyme activity. Importantly, as detailed in LeBaron et al (2013), a molecular comparison of the CD-1 and C57/Bl6 mouse strains demonstrated similar responsiveness to sulfoxafl or as these strains are known to be diff erentially responsive to CAR activators. In animals with hCAR/hPXR, sulfoxafl or-treatment induced quantitatively less CAR activation compared to wild-type mice; however, the PXR-associated response in hCAR/hPXR mice was equal to or greater than the induction noted in wild-type mice.…”

Section: Summary Of Sulfoxafl or Rodent Liver Tumor Moa Datamentioning

confidence: 85%

“…As predicted from the knowledge gained from the MoA data, the chronic/carcinogenicity dietary studies in mice and rats identifi ed increased incidence of hepatocellular tumors (adenomas and carcinomas). The detailed MoA evaluation responsible for the rodent liver eff ects, including tumors, was recently published and is the source of the primary data (LeBaron et al 2013), although a summary of the relevant toxicity and MoA data are presented below. In this paper, the relevance to humans of the proposed MoA for rodent liver tumors was analyzed using the HRF approach , and the advantages and disadvantages of this proactive MoA investigation are discussed.…”

Section: Historymentioning

confidence: 99%

“…These studies are presented in detail in LeBaron et al (2013) and are briefl y summarized here. Although liver tumors were seen in both sexes of mice and in male rats, the data presented will be limited to males, as male mice and rats were more sensitive to the liver eff ects of sulfoxafl or.…”

Section: Summary Of Sulfoxafl or Rodent Liver Tumor Moa Datamentioning

confidence: 99%

“…As detailed in LeBaron et al (2013) and qualitatively summarized in Table 2, in mice exposed to a tumorigenic dose of 750 ppm liver gene expression analysis indicated a clear, CARmediated response to sulfoxafl or ( Cyp2b10 ; 54.8-fold or 56.5-fold after 7 or 90 days of treatment, respectively), with a minor contribution of PXR ( Cyp3a11 ; 2.7-fold or 2.8-fold after 7 or 90 days of treatment, respectively). Similar CAR activation was noted at 500 ppm after 7 days (42.1-fold) and 300 ppm after 28 days (61.7-fold).…”

Section: Summary Of Sulfoxafl or Rodent Liver Tumor Moa Datamentioning

confidence: 99%

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

LeBaron

Gollapudi

Terry³

et al. 2014

Critical Reviews in Toxicology

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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.

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Concurrent evaluation of general, immune, and genetic toxicity endpoints as part of an integrated testing strategy

Schisler

Sura

Visconti

et al. 2014

Environ and Mol Mutagen

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Integrated testing strategies involve the assessment of multiple endpoints within a single toxicity study and represent an important approach for reducing animal use and streamlining testing. The present study evaluated the ability to combine general, immune, and genetic toxicity endpoints into a single study. Specifically, this study evaluated the impact of sheep red blood cell (SRBC) immunization, as part of the T-cell dependent antibody response (TDAR) assay, on organ weights, micronuclei (MN) formation (bone marrow and peripheral blood), and the Comet assay response in the liver of female F344/DuCrl rats treated with cyclophosphamide (CP) a known immunosuppressive chemical and genotoxicant. For the TDAR assay, treatment with CP resulted in a dose-dependent decrease in the antibody response with a suppression of greater than 95% at the high dose. Injection with SRBC had no impact on evaluated organ weights, histopathology, hematology, and clinical chemistry parameters. Analysis of MN formation in bone marrow and peripheral blood revealed a dose-dependent increase in response to CP treatment. Injection with SRBC had no impact on the level of MN in control animals and did not alter the dose response of CP. There was a slight increase in liver DNA damage in response to CP as measured by the Comet assay; however, injection with SRBCs did not alter this endpoint. Overall these data provide strong support for the concurrent assessment of general, immune, and genetic toxicology endpoints within a single study as part of an integrated testing strategy approach.

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

Cited by 27 publications

References 28 publications

Liver cell proliferation and tumor promotion by phenobarbital: relevance for humans?

Liver cell proliferation and tumor promotion by phenobarbital: relevance for humans?

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

Concurrent evaluation of general, immune, and genetic toxicity endpoints as part of an integrated testing strategy

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