Based upon your preferred MOA(s) documented in your response Question 1 for rodent liver tumors, is the MOA also applicable for human health risk assessment (please explain your answer)?

Answer Explanations

• Possibly applicable

  Expert 5
  In the case of a cytotoxic MOA , in theory these same key events and biological processes seen in rodents would also function in humans.  Thus in theory a cytotoxic DX MOA might apply to humans.  However  any hepatotoxicity in humans would be for short-
  term since the exposure would be discountinued once liver injury was detected.  Even if  chronic human exposure would occur the doses as noted in the occupational exposure studies woudl not be sufficient to induce chronic hepatic toxicity needed to invoke a regenerative hepatic hyperplastic response. The epidemiological data on DX exposure to humans did not show an increae in liver tumors. 
• Likely applicable

  Expert 6
  There is no reason to believe that the MOA for hepatic effects is fundamentally different between humans and rodents. However, there remains some uncertainty as long as the molecular events leading to cytotoxicity/cell death have not been fully elucidated. It appears inadequate, however, to base the idea of a non-thresholded MOA on the lack of a full understanding of the molecular mechanism leading to cytotoxicity.  
• Applicable,

  Expert 4
  Qualitative relevance of the hypothesized mode of action in humans cannot be precluded based on evidence that humans lack some mechanistic element known to be necessary for the rodent tumourigenic response. Hepatotoxicity associated with cyp 2E1 induction in humans has been observed following exposure to high doses of other toxicants .  However, there are a number of factors which may contribute to quantitative variations in response in humans for the hypothesized key events including, for example, the distribution and activity of cyp 2E1 and the relative sensitivity of tissue response to cyp 2E1 induction.  If possible, the development of a sufficiently robust (verified) PBK model to address quantitative variations in the induction of cyp 2E1 by 1,4-DX would be helpful to estimate the sustained levels of human exposure anticipated to result in similar response in humans to that observed in studies in rodents. These are likely very high, with the practical implication that the probability of 1,4-DX causing cancer in humans is likely negligibly low (or zero).  
• Likely applicable

  Expert 2
  This requires careful study of high-risk subgroups, not just healthy subjects. 
• Possibly applicable

  Expert 1
  Possibly applicable as long as MOA is considered and a threshold based extrapolation is used.
• Not applicable

  Expert 3
  Given that the MoA action is high-dose specific and requiring of metabolic saturation, and that such doses are extremely unlikely to be encountered under any reasonable human chronic exposure scenario, this tumor response can be considered as "quantitatively not relevant" to human cancer based on the application of conventional MoA framework analyses.