Comments for Event:1753

On January 18, 2021 03:09

This MoA sounds plausible. However I would like to request consideration if ROS are really the start of the cascade (MIE). ROS certainly play a role in carcinogenicity, their association to increased risk of cancer has been demonstrated several times. However the question remains if they are the causative agent (start of the cascade) or play a cascade-amplifying role (i.e.: result from local destructive processes and cause further damage).  Future research on AOPs (mechanistic studies, QSAR) and regulatory interpretation will require an exact definition what is causative and what is an associated event. IF MIEs are too generic, they will unlikely lead to clarity. I am not familiar with the data behind this AOP and thus do not mean to be a criticise this AOP, however propose to review the data again to establish if the measurability of ROS is the (first and only) MIE starting the cascade, or if underlying processes (local cytotoxicity, immune system activation...) lead to increased levels of ROS, thereby making this an associated event and biomarker.

The reason for this request is that redox cyclers like paraquat (who are constantly generating ROS), when given orally over lifetime, do not cause this specific type of cancer in rodents.