@SusanFelter Once again thank you for becoming part of our community. I had opportunity to read some of your published work (‘A proposed framework for assessing risk from less-than-lifetime exposure to carcinogens’. ICH M7(R1) defined a sub-class of MIs described as the Cohort of Concern (CoC), including N-nitroso compounds. However, there is still debate about the use or not of LTL for this family of compounds when defining acceptable limits. Do you think there is even room for debate on this?
Hi Naiffer. I’m sorry it’s taken me so long to respond. I certainly think this is an appropriate topic to consider when defining acceptable limits. I saw another post where a statement was made that, “It’s my understanding that LTL approach has been rule out from N-nitrosamine because the impurity outperform the DNA repair mechanism.” Do you know what the basis for this statement is?
1 Like
I’m not sure of the original basis for the EMA decision to exclude LTL - was it only out of an abundance of caution, perhaps, in the absence of definite data (and yes, the reason cited was the risk of exceeding the repair threshold, but little if any evidence was provided)? However, from memory, the experts called in by the FDA at the public meeting in March were fairly uniform in stating that we are still comfortably below the repair threshold at the doses proposed for nitrosamines and even the higher doses for LTL - at least for smaller alkyl adducts (which are of course typically the most potent nitrosamines…), the repair enzymes are extremely abundant.
In terms of whether there is room for debate, the initial EMA position, at least, was clear; however, the science seems to indicate that the approach should be valid so I think the topic should very much be up for debate (https://doi.org/10.1016/j.yrtph.2021.104926)
1 Like
Thank you @David. This is my impression as well – the EMA position appears to be a precautionary approach (vs data-based). I think the publication by Bercu et al. provides a compelling (data-based) argument that LTL is appropriate for nitrosamines. Even with the higher doses supported by LTL, we are still talking about very low exposures compared to those associated with an increased tumor incidence in the bioassay.
1 Like
Thanks @SusanFelter. As @David pointed out the ‘exceeding the repair threshold’ has been mentioned in several forums but I personally have not seen any definite data. My overall readout from FDA’s March meeting was ‘more data is needed’. @riskscience @jbercu @fernandaw recently published a case study on NDEA, as referenced by David.