Based upon your preferred MOA(s) indicated in your response to Question 1, how applicable is that MOA across the other target organs and tumor types seen in the rodent cancer bioassays?

Answer Explanations

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  Expert 5

  	Applicable	Likely applicable	Possibly applicable	Not applicable
  Mouse hepatocellular carcinoma	1	0	0	0
  Rat nasal cavity squamous cell carcinoma	0	0	1	0
  Rat peritoneal mesothelioma	0	0	1	0

  In the case of the rat nasal cavity,  cytotoxicity appears to be in play in the induction of tumors by chemicals.  There is a literature base showing a role for cytotoxicity as a MOA for the nasal tumors.   To link the lesions seen with DX as a metabolic saturation MOA resulting in cytotoxicity in the nasal cavity requres futher evaluation.   I am less convinced that a MOA for DX and rat peritoneal mesothelioma has been established. A quick review in pubmed and the NTP site on the terms  "Rat peritoneal mesothelioma" and "chemcials that induced  Rat peritoneal mesothelioma" revealed that most studies have linked fibers (asbestos, carbon nanotubes, glass wool) to the mesothelioma formation.    Athough positive finding of  Rat peritoneal mesothelioma were reported for a number of chemical compounds.  To me it is not clear if there is a defined MOA of the  Rat peritoneal mesotheliomas.     
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  Expert 6

  	Applicable	Likely applicable	Possibly applicable	Not applicable
  Mouse hepatocellular carcinoma	1	0	0	0
  Rat nasal cavity squamous cell carcinoma	0	1	0	0
  Rat peritoneal mesothelioma	0	0	1	0

  Studies in liver are convincing for the MOA as discussed above. For the other tumors less data are available, for the nasal cavity cytotoxicity findings make a similar MOA likely, for the mesothelioma it is more difficult. Rat mesothelioma is a quite common cancer in certain rodent strains. It can be elicited by both genotoxic and non-gentoxic agents. Its relevance for humans is doubtful (Maronpot, 2016). Tumors of the processus vaginalis peritonei are extremely rare in humans.
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  Expert 4

  	Applicable	Likely applicable	Possibly applicable	Not applicable
  Mouse hepatocellular carcinoma	0	1	0	0
  Rat nasal cavity squamous cell carcinoma	0	0	1	0
  Rat peritoneal mesothelioma	0	0	1	0

  There's a fair bit of supporting information for the hypothesized mode of action for the mouse liver tumours, with the most recent mechanistic data having been collected in this species, principally as a basis to investigate the seemingly discrepant lack of observation of anticipated hepatic effects in the mouse prior to induction of tumours in the Japanese carcinogenesis bioassay (See response to 1.1 which addresses both species). While it is conceivable that the nasal squamous cell carcinomas and peritoneal mesotheliomas in rats may be induced by a similar mode of action given their observation at high doses and the nature of the evidence on the genotoxicity of 1.4-DX, the information available is inadequate to permit meaningful conclusion on modes of action for induction of these tumours as reflected in the review references identified for this poll.  For example, Health Canada (2018) concluded that insufficient data exist to allow for the assessment of the MOA for tumour types other than the liver. US EPA additionally elaborated that while there is some evidence consistent with a hypothesized mode of action for the nasal squamous cell carcinomas through induction of cyp 2E1, cytotoxicity and regenerative proliferation, there are discordant observations which seemingly, have not been investigated further and limit confidence. These include supporting observation that Cyp2E1 was inducible in rat nasal mucosa following acute oral administration of 1,4-dioxane by gavage or drinking water (Nannelli et al., 2005).  Cell proliferation prior to tumour induction was also observed following 1,4-dioxane exposure in both a 2-year inhalation study in male rats (1,250 ppm)  (Kasai et al., 2009) and a 2-year drinking water study in male (274 mg/kg-day) and female rats (429 mg/kg-day). However, there was no evidence of cytotoxicity in the nasal cavity (Kasai et al., 2009).  U.S. EPA (2013) further notes that there are no data available concerning any hypothesized MOA by which 1,4-DX produces peritoneal mesotheliomas in rats and none was identified in the review references for this poll.
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  Expert 2

  	Applicable	Likely applicable	Possibly applicable	Not applicable
  Mouse hepatocellular carcinoma	1	0	0	0
  Rat nasal cavity squamous cell carcinoma	0	0	1	0
  Rat peritoneal mesothelioma	0	0	1	0

  The contribution of oxidative stress and DNA damage in restricting the growth of some cell populations and promoting the compensatory proliferation of other subpopulations with susceptibility during the growth or proliferation phases to genetic mutations will likely apply to multiple organs.  
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  Expert 3

  	Applicable	Likely applicable	Possibly applicable	Not applicable
  Mouse hepatocellular carcinoma	1	0	0	0
  Rat nasal cavity squamous cell carcinoma	0	0	1	0
  Rat peritoneal mesothelioma	0	0	1	0

  Rat nasal cancer appears to strongly driven by a direct-contact irritation proliferation response (i.e., inhalation direct contact, and data showing drinking water nasal effects associated with substantial splashing of water directly into nasal cavity.  Unsure of peritoneal mesothelioma.