BMDL vs TD50 Consideration When? How?

This question comes to me via direct message, a really interesting one. I would ask our Toxicologist to help us understand a bit more about the topic and divergency.

Cases where a AI of nitrosamine impurity cannot be derived by SAR/read-across approach, and when the nitrosamine exposure occurs in plasma or liver, BMDL10 value based on TGR assay can be used to calculate AI instead of TD50 value.
We were wondering if this control option using BMDL has been already discussed within nitrosamine regulator working group in the interest of harmonisation.

Although both ICH M7 guideline and EMA guidance ‘Procedure under article 5(3) of regulation EC (No) 726/2004’ mentioned that the use of BMDL would be possible as an alternative methods for TD50, all the AIs of nitrosamines published by EMA and FDA until now have been based on TD50 or derived using SAR/read-across approach, which imply that international regulatory experts prefered to use default approach (EMA 18 ng/day, FDA 26.5 ng/day) if there was no adequate surrogate with robust carcinogenicity data for read-across approach.

Considering the above, we would like to ask if BMDL approach is now actually considered as an possible option for nitrosamine AI by international regulators

@AndyTeasdale @conudel @MichaelBurns @SusanFelter @ASrinivasan @David Thanks for all your help!

I think that a toxicologist should talk about the acceptability of the technical aspects. Bu all I can say is hte a transgenic mice assay should be acceptable to the agencies for data poor nitrosamilnes. However, the sponsor needs to discuss with the Agency in question before starting an elaborate transgenic mice study.

From a scientific perspective it makes sense to be able to model the data from a TGR study to derive a BMDL10. If the agencies are accepting the TGR as a valid in vivo assay to de-risk a nitrosamine, when the TGR is clearly negative, it makes sense that the results show the nitrosamine to be positive the data from this TGR should be valid to use in a BMD model. If the study is designed properly with enough doses levels allowing for a robust BMD calculation, then the BMDL10 should be able to be used as the point of departure to calculate an AI. Hopefully soon we will know if the agencies will accept this method to derive a compound specific AI for a nitrosamine that lack carci data.


@conudel Thanks for sharing this information…

@conudel & @Naiffer_Host, Could you arrange one online video session on this topic?