In general (not specific to 1,4-DX) do you agree that metabolic saturation might be an appropriate key event to base cancer dose-response modeling on (i.e., as the point of departure)?

Answer Explanations

• Yes

  Expert 5
  It appears that at the point of metabolic saturation and above, the parent compound induced liver toxcity as evidenced by liver serum enzymes and histopath that correlated with liver tumor induction.  This would be the first key event. 
• Yes

  Expert 6
  As soon as no cytotoxic or even genotoxic metabolite can be identified and the evidence indicates that the parent compound is the cytotoxic agent, saturation must be a key event if it is a precondition for the occurrence of substantial amounts of the parent compound,e, g., in blood.
• No

  Expert 4
  Though metabolic saturation appears to be an important determinant of dose-response for 1,4-DX, its description as a key event (KE) is inconsistent with convention  for MOA and AOPs. KEs are measurable biological (toxicodynamic) changes that are essential to progression along an AOP/MOA. The conditions under which progression can be expected (i.e., quantitation) are described not in KEs, but in the key event relationships (KERs) that link upstream to downstream KEs. Quantitation is characterized by PBK and PD models (the latter characterizes quantitative relationships in KERs linking KEs). The first key event in the hypothesized mode of action for 1,4-DX is likely best described as induction of cyp 2E1 with estimation of quantitative variations between and within species for this key event being critically important for human relevance, dose response analysis and quantitative risk estimation. If possible, additional refinement of the existing PBK models taking into account the analysis on which EPA (2013) concluded that they were inadequate for application in their assessment might be helpful. 
• No

  Expert 2
  The experimental data so far have involved healthy humans and animals. The dimorphic nature of liver cancers with the greater susceptibility of females is essentially unexplained - this requires additional investigation of the contribution of sex hormones in oncogenic cell activations as well as their role in the regulation of transcriptional controls. The findings of 1,4-DX  showing more tumorigenesis for females is the reverse of viral hepatic oncogenesis producing greater susceptibility of males for liver cancers, which results from the dimorphic regulation of HNF4a transcription factor and its effects on multiple downstream targets. The contribution of additional "hits" for oncogenesis - it's generally agreed that hepatic carcinogenesis is a multistep process involving a combination of genetic mutations - needs elucidation for subgroups at greater risk for liver cancers, e.g., those with obesity, hepatic steatosis, various metabolic syndromes, and bearers of variant alleles predisposing to progressive liver injury or deficits in liver repair.        
• No

  Expert 1
  Metabolic saturation leading to parent compound accumulation triggering liver effects although important is not a considered a cancer key event as per IARC. The resulting effects are key events - proliferation, cytotoxicity ROS are cancer key events 
• Yes

  Expert 3
  It is clear (with one exception of female mouse liver tumors at 66 mg/kg/day, requiring further investigation?) that rodent liver tumors are all high-dose associated with likely TK-saturating conditions that result in dose-disproportionate increases in parent DX and accompanying compensatory cyp2e1 induction.  Absent this early key early event, subsequent MoA key events are also absent, e.g., at sub-saturating doses postulating ensuing KEs are not present.