Do you feel that metabolic saturation of the parent 1,4-DX compound is a molecular initiating event (MIE) in any of the MOAs listed above?

Answer Explanations

• Yes

  Expert 5
  Although widely accepted in our discipline,  I remain uncomfortable with the term MIE. I view this as the first key event in the MOA.  There is an assumption that the "MIE" is the most important determinant and if this step is identified it is the mechanism of the observed carcinogenciity.  This approach does not take into account the mutistage, multistep process of the carcinogenesis process.  Each of the Key events that follow this first key event exhibit dose response characteristics.  Therefore while the first key event  - "MIE" - starts the process subsequent key events need to be triggered for the eventual formation of the tumors.  Given my bias on the terminaology, I concur that the  evidence points to the metabolic saturation as the first key event.  
• Yes

  Expert 6
  The evidence for the role of the parent compound in cytotoxicity, and for the key role of cell death and regenerative proliferation in cancer development by 1,4-DX strongly indicate that metabolic saturation allowing the occurrence of substantial amounts of the parent compound is in fact a molecular initiating event in the MOA. 
• No

  Expert 4
  By convention, as above, the molecular initiating event is best described as cyp 2E1 induction. If possible, studies in cyp2E1 deficient or null animals would be extremely helpful in examining the essentiality of this key event for 1.4-DX.  This would lend additional support to its hypothesized relevance as the critically important, limiting key event in the hypothesized MOA.  As above, refinement of the PBK models, if possible, to address EPA concerns would also be helpful.
  
  
• Yes

  Expert 2
  The initiation of oxidative stress and subsequent genomic damage that would produce hepatic growth arrest is likely an early event in the oncogenic process. 
• No

  Expert 1
  Metabolic saturation in my mind leads to MIE but is not a MIE itself.
• Yes

  Expert 3
  See previous comment.