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?

Answer Explanations

• Yes (please explain)

  Expert 6
  I suggest that the panel exchanges ideas on the molecular events leading to cytotoxicity of 1,4-D.
• Yes (please explain)

  Expert 4
  I'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 2
  The 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 1
  In 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 3
  The 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?).