Please indicate your confidence rating on the weight of evidence supporting/refuting the potential mode of action for the carcinogenic effects of 1,4-DX in the rat peritoneal mesothelioma? (-5=strong refuting evidence, 0=lack of or equivocal evidence, +5=strong supporting evidence)

Answer Explanations

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  Expert 4

  	-5	-4	-3	-2	-1	0	1	2	3	4	5	I cannot answer
  Direct genotoxicity	0	0	0	1	0	0	0	0	0	0	0	0
  Indirect genotoxicity	0	0	0	0	0	0	0	1	0	0	0	0
  Proliferative regeneration induced by cytotoxicity	0	0	0	0	0	1	0	0	0	0	0	0
  Oxidative stress	0	0	0	0	0	1	0	0	0	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR, PXR)	0	0	0	0	0	1	0	0	0	0	0	0
  Other (please explain)

  I'm not aware of an hypothesized MOA or relevant associated data for rat peritoneal mesotheliomas.  It's possible that the mode of action is mediated through indirect genotoxicity based on observation in a relatively robust dataset in both in vitro and in vivo assays that 1,2-DX is not mutagenic and only weakly genotoxic with responses being positive generally only in the presence of toxicity.  However, the lack of hypothesis for an MOA and additional supporting data based on mechanistic studies precludes informed response to the question, in my view.
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  Expert 2

  	-5	-4	-3	-2	-1	0	1	2	3	4	5	I cannot answer
  Direct genotoxicity	1	0	0	0	0	0	0	0	0	0	0	0
  Indirect genotoxicity	0	0	0	0	0	0	0	0	0	0	1	0
  Proliferative regeneration induced by cytotoxicity	0	0	0	0	0	0	0	0	0	0	1	0
  Oxidative stress	0	0	0	0	0	0	0	0	0	0	1	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR, PXR)	0	0	0	0	0	1	0	0	0	0	0	0
  Other (please explain)	0	0	0	0	0	1	0	0	0	0	0	0

  The possibility of mutagenesis in additional cell populations emerging after damage in the initial susceptible cell populations.   
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  Expert 3

  	-5	-4	-3	-2	-1	0	1	2	3	4	5	I cannot answer
  Direct genotoxicity	1	0	0	0	0	0	0	0	0	0	0	0
  Indirect genotoxicity	0	0	0	0	0	1	0	0	0	0	0	0
  Proliferative regeneration induced by cytotoxicity	0	0	0	0	0	1	0	0	0	0	0	0
  Oxidative stress	0	0	0	0	0	1	0	0	0	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR, PXR)	1	0	0	0	0	0	0	0	0	0	0	0
  Other (please explain)	0	0	0	0	0	0	1	0	0	0	0	0

  It highly likely this tumor response is not mediated through direct genotoxicity or activation of nuclear receptors as evidenced by experimental evidence in liver (i.e., if not genotoxic and not a NR-activator in liver, unlikely to be so in other organs.  Alternative MoAs including indirect genotoxicity, proliferative regeneration induced by cytotoxicity have not been directly examined for this tissue response.  However, it has been appropriately and importantly noted that peritoneal mesotheliomas have only been observed in F344 rats, a rat strain that is uniquely sensitive to essentially a 100% incidence of testis Leydig cell tumors.  Cook et al. (1999) has concluded that of 7 hypothesized MoAs for rat LCTs, 2 are likely qualitatively not relevant to humans and the remaining 5 are substantially quantitatively not human relevant.  These observations can be coupled to the review conclusions that mechanistic links between LCTs and tunica vaginalis/peritoneal mesotheliomas are plausible for the non-fibrous rodent carcinogen, acylamide (Haber et al., Reg.Tox. Pharmacol. 53: 134-149, 2009).  Although far from a complete MoA, when coupled with the metabolic saturation hypothesis, it suggests the peritoneal mesotheliomas are also likely driven by a non-genotoxic and high-dose specific threshold MoA. 
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  Expert 6

  	-5	-4	-3	-2	-1	0	1	2	3	4	5	I cannot answer
  Direct genotoxicity	1	0	0	0	0	0	0	0	0	0	0	0
  Indirect genotoxicity	0	0	0	0	0	0	0	0	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	0	0	0	0	0	0	0	1	0	0	0	0
  Oxidative stress	0	0	0	0	0	0	0	1	0	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR, PXR)	0	0	0	0	0	0	0	1	0	0	0	0
  Other (please explain)	0	0	0	0	0	0	0	1	0	0	0	0

  The rat peritoneal mesothelioma is frequently seen as an adverse outcome elicited by carcinogens of various types. This type of tumor is rare in humans. The natural history of this type of tumors is not entirely clear (see my response to the next question). 
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  Expert 5

  	-5	-4	-3	-2	-1	0	1	2	3	4	5	I cannot answer
  Direct genotoxicity	0	0	0	0	0	0	0	0	0	0	0	1
  Indirect genotoxicity	0	0	0	0	0	0	0	0	0	0	0	1
  Proliferative regeneration induced by cytotoxicity	0	0	0	0	0	0	0	0	0	0	0	1
  Oxidative stress	0	0	0	0	0	0	0	0	0	0	0	1
  Activation of nuclear receptors and associated transcription factors (e.g., CAR, PXR)	0	0	0	0	0	0	0	0	0	0	0	1
  Other (please explain)

  The issue of  the Mode of Action of rat peritoneal mesothelioma induction by 1,4 DX is unresolved in my opinion.  Each tumor type/site that is linked to exposure to a chemical agent should be evaluated for its own mode of action. It is not appropriate to apply the MOA for the liver tumors to the other tuor types seen here without experimental evidence to show that simialr Key events are occuring in these other two tissues as seen in the liver.  This does not preclude that if a specific mode of action is defined in one target site  (ie cytotoxicity in the liver) that a similar mode of action could be applied to another target organ.  However,  in this case, there is a lack of sufficent data on the peritoneal mesothelioma induction by 1,4 DX to define the 1,4 DX mode of action.  The data gaps are too great for this tumor type to make an assessment.    Published studies have linked  carbon and asbestos to the induction of mesothelioma ( Reamon-Buettner SM, Rittinghausen S, Klauke A, Hiemisch A, Ziemann C. Malignant peritoneal mesotheliomas of rats induced by multiwalled carbon nanotubes and amosite asbestos: transcriptome and epigenetic profiles. Part Fibre Toxicol. 2024 Jan 31;21(1):3. doi: 10.1186/s12989-024-00565-x. PMID: 38297314; PMCID: PMC10829475.)  Oxidative stress  (Fiorilla I, Martinotti S, Todesco AM, Bonsignore G, Cavaletto M, Patrone M, Ranzato E, Audrito V. Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma. Cells. 2023 Aug 11;12(16):2048. doi: 10.3390/cells12162048. PMID: 37626858; PMCID: PMC10453755.) appears to be important in the induction of mesotheliomas, linking the finding of 1,4 DX in the liver.