1.8
Is there anything in the review material that you would like to bring to the panels' attention or raise for discussion, if not presented in a charge question above?
Results
(6 Answers)
Several experts identified topics they would like to bring to the panel's attention regarding 1,4-D/1,4-DX research. Three main themes emerged:
- Molecular mechanisms of toxicity: Expert 6 suggested discussing molecular events leading to cytotoxicity of 1,4-D, while Expert 4 expressed interest in exploring early key events in liver tumor induction.
- Methodological concerns: Expert 2 highlighted limitations in oncogenesis assays and questioned conclusions about "regenerative response." Expert 1 pointed out that some in vivo genotoxicity data did not comply with OECD guidelines, specifically regarding dosing and exposure times.
- Mode of Action (MoA) analysis: Expert 3 suggested enhancing the MoA analysis with better characterization of cytotoxicity versus mitogenicity contributions, while questioning whether additional studies are necessary given metabolic saturation concerns.
Only Expert 5 indicated no additional topics for discussion.
Summary Generated by AI
Answer Explanations
- Yes (please explain)Expert 6I suggest that the panel exchanges ideas on the molecular events leading to cytotoxicity of 1,4-D.
- Yes (please explain)Expert 4I'd be interested in input of panel members on the potential early key events (and extent of associated support) for the hypothesized mode of induction of liver tumours by 1,4-DX based on recent studies.
- Yes (please explain)Expert 2The limitations of assays in the published studies and databases for oncogenesis involving cell subsets other than hepatocytes. The erroneous conclusions for "regenerative response" based on nucleotide tracers for DNA synthesis that cannot distinguish between DNA repair or cell hypertrophy and polyploid genome duplications vs. actual cell division.
- Yes (please explain)Expert 1In vivo genotoxicity data were not in compliance with OECD guidelines for genotoxicity assessment - exceeding doses and exposure times 4 weeks vs 16 weeks Gi et al.
Roy et al exceeds top dose for a 5 day exposure of 1000 mg/kg/day the lowest dose was 1500 mg/kg/day (OECD 474).
Gi et al. was 16 weeks mutagenicity test with only top dose of 5000 ppm producing a 2 fold marginal response - (OECD 488 is a 4 week exposure) - Yes (please explain)Expert 3The overall MoA analysis might be enhanced with a more refined characterization of the relatively contributions of cytotoxicity versus mitogenicity. However, as counterbalance, such studies may not be warranted simply on basis that metabolic saturation rules out a need for detailed characterization of subsequent events given evidence they do not occur in absence of metabolic saturation and human exposures are well below such saturation (is more evaluation of actual worst-case but reasonable human exposures required to support this contention?).
Expert 2