What additional question(s) would you like to ask your fellow panelists for discussion (please be sure to phrase your response in the form of a question)?
Results
(5 Answers)
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Expert 5
1. How strong Is the evidence that upon metabolic saturation that the parent compound is producing the cytotoxicity? -
Expert 6
which molecular mechanism do you consider explaining the cytotoxicity of 1,4-D?do you think that TRPV1 activation with opening of a calcium-channel may represent a possible mechanism?what's your view when cytotoxicity in the nasal mucosa is 'explained' mechanistically as 'irritation'?is the statement 'no indication for cytotoxicity' made in USEPA documents at certain occasions misleading? -
Expert 4
It might be helpful to have the panel consider the relative priority of additional studies to increase confidence in the hypothesized mode of action - i.e., what, if any, constitute highest priorities for follow up work?. -
Expert 2
1. What do you believe will be appropriate means to elucidate the contribution of ongoing other liver injuries to the oncogeneic consequences of 1,4 DX?
2. How might spatiotemporal methods help provide correlations in the transcriptomic perturbations and effector phosphoproteins in tissues at various time points?
3. Would single-cell analyses over a time course proffer avenues for helping dissect the landscape of genetic and epigenetic consequences? -
Expert 3
Would it be useful for further refinements in PBPK model(s) for improving confidence of likely human doses that as which DX metabolic saturation occurs (can this be even done given induction response)?
Experts have proposed several questions for discussion, primarily focusing on mechanisms of cytotoxicity, metabolic processes, and research priorities related to 1,4-D/DX.
There appears to be convergent interest in understanding the mechanistic basis of cytotoxicity, with Expert 5 questioning evidence for the parent compound's role in cytotoxicity upon metabolic saturation, Expert 6 specifically inquiring about molecular mechanisms (including TRPV1 activation), and Expert 2 suggesting advanced methods to investigate liver injuries and transcriptomic changes.
Regarding research priorities, Expert 4 directly asks about prioritizing additional studies to increase confidence in the hypothesized mode of action, while Expert 3 focuses on PBPK model refinements to better understand metabolic saturation in humans.
Expert 6 uniquely raises concerns about potential misleading statements in USEPA documents regarding cytotoxicity indications, suggesting some critical examination of regulatory assessments.