Do you agree that any of the MOAs listed above (other than direct genotoxicity) is indicative of a threshold dose-response relationship, in general (not specific to 1,4-DX)?

Answer Explanations

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  Expert 5

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	1	0	0	0
  Oxidative stress	1	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	1	0	0	0
  Other (please explain)

  Since the MOAs listed above are biological/pharmacological  processes, by definition agents that interact with these processes will exhibit a dose response and hence a threshold. This is the basis for pharmacology and toxicology.   I can also argue that genetox whether direct or indirect is also dose response and threshold dependent.  
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  Expert 6

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	1	0	0	0
  Oxidative stress	1	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	1	0	0	0
  Other (please explain)	1	0	0	0

  see above for a possible role of other receptors... TRPV1 etc...?
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  Expert 4

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	0	1	0	0
  Proliferative regeneration induced by cytotoxicity	1	0	0	0
  Oxidative stress	0	1	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	0	1	0	0
  Other (please explain)

  Generally, threshold approaches may be considered appropriate where mutation resulting from direct interaction with DNA is not an early, influential key event but rather, occurs following precursor events for which it is assumed that there is a threshold of exposure below which the effect will not occur.   Depending on the nature and temporal sequence of the key events in the documented mode of action and associated empirical evidence, then, dose-response analysis for indirect genotoxicity could be based on a threshold approach where key events may include cytotoxicity/proliferative regeneration, oxidative stress and/or activation of nuclear receptors and associated transcription factors (i.e., those which do not induce tumours through a mutagenic mode of action). Variations in interpretation result not so much from fundamental disagreement with this premise which is captured in existing regulatory guidance, but rather, I believe, on consensus on what constitutes adequate evidence that a chemical is acting via a hypothesized mode of action.
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  Expert 2

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	0	0	1	0
  Oxidative stress	0	0	1	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	0	0	1	0
  Other (please explain)	1	0	0	0

  The processes for oncogenesis have not been sufficiently addressed so far. The contribution of oncogenic clones other than injured hepatocytes has not been revealed. The role of factors suggested in the above response to 1.3 will need examination. 
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  Expert 1

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	1	0	0	0
  Oxidative stress	1	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	1	0	0	0
  Other (please explain)

  High Dioxane exposure at metabolic saturation produces/generates ROS via CYP2E1, cytotoxicity via ROS in liver causing regenerative cell proliferation are threshold based MOA and therefore risk assessments should be threshold based
  
  ROS DNA damage leading to mutation is a threshold based MOA.
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  Expert 3

  	Yes	It depends	No	I cannot answer
  Indirect genotoxicity	1	0	0	0
  Proliferative regeneration induced by cytotoxicity	1	0	0	0
  Oxidative stress	1	0	0	0
  Activation of nuclear receptors and associated transcription factors (e.g., CAR/PXR)	1	0	0	0
  Other (please explain)	1	0	0	0

  The data suggest all of the listed MoAs are secondary to a threshold-driven saturation of DX metabolism.  If very high-dose DX is somehow causing an as yet unidentified high-dose specific MoA (recent transcriptomic data provides no evidence, however of such an unidentified MoA), this would still be threshold-dependent on TK saturation.