Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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“…with DNA-reactive agents, as shown for a variety of tissues (Butterworth et al, 1992;Cunningham, 2000;Williams et al, 2000).…”

Section: Introductionmentioning

confidence: 83%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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“…As Williams et al 50 reported that the cytotoxicity caused by injection of DEN is dose-dependent, we first performed doseresponse experiments to investigate if the loss of gp130 in hepatocytes might have a role in tumor initiation and progression. We have previously shown that the lack of gp130 promotes susceptibility to LPS-induced acute liver injury.…”

Section: 43mentioning

confidence: 99%

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

et al. 2015

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Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocytespecific gp130 knockout mice (gp130 Δhepa ) and control animals (gp130 f/f ) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130 f/f and gp130 Δhepa animals. However, gp130 Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGFdependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

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“…2-acetlaminofluorene Williams et al, 2000;Littlefield et al, 1980); dimethylnitrosamine (Peto et al, 1991); dibenzo[a,l]pyrene (Bailey et al, 2009); diethylnitrosamine (Peto et al, 1991;Williams et al, 2000)), it is still not possible to determine the nature of the relationship at human relevant exposures with confidence. For less studied chemicals, the lack of key evidence needed to make educated judgments about probable doseresponse curves (i.e.…”

Section: Page 16 Of 48mentioning

confidence: 99%

Interpretation of the margin of exposure for genotoxic carcinogens – Elicitation of expert knowledge about the form of the dose response curve at human relevant exposures

Boobis

Flari

Gosling

et al. 2013

Food and Chemical Toxicology

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Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. ABSTRACTThe general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at low levels of exposure; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty and most importantly, query the rigour of the assumption of a linear relationship.Highlights  Experts are reluctant to express views on the dose-response curve for genotoxic carcinogens *Manuscript for revision (track changes hidden) Click here to view linked ReferencesPage 2 of 48  The POD can be extrapolated first from high to low dose in animals and then to humans, or vice versa  Expert judgement was that the dose-response curve is highly non-linear at human relevant exposures  Stochastic events and the distribution of susceptibilities will contribute, to an unknown extent  Interpretation of the MOE requires consideration of MOA, species differences and human variability Keywords Dose-response function; expert judgment; genotoxic carcinogens; low dose extrapolation; margins of exposure; risk assessment

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Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

Cited by 83 publications

References 45 publications

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

Interpretation of the margin of exposure for genotoxic carcinogens – Elicitation of expert knowledge about the form of the dose response curve at human relevant exposures

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