Are we not controlling this then by applying very low limits for NMOR in medicines, intrinsically applying a precautionary principle for the protection of human health and considering already that NMOR can introduce tumors?
Where scientific uncertainty would exist, this is surely compensated by low limits and other protective elements applied in international guidance.
I believe my original answer addresses this already.
What phototreatment was proven to do is generate the alpha-hydroxy nitrosamine from the nitrosamine (as usual such metabolites can be O-conjugated). The alpha-hydroxy nitrosamine metabolite is exactly what the focus is of the call for review. Replacing metabolic activation with photoactivation to get the same type of metabolite of concern doesnât make the metabolite itself different in potency and where the enzyme-mediated activation is considered very likely in a mutagenicity risk assessment like in the case of NMOR an alternative way to the same type of risk doesnât change the mutagenicity risk assessment for the type of exposure that is the focus of nitrosamine contamination in medicines? Though I understand you want to link the activation subtype to the tumor site of interest and the subtype of cancer pathogenesis at risk (while also linking with specific gene mutations causable by certain nitrosamine metabolisations and linked with skin cancer), I donât see concerns being raised in literature on the currently applied MoE linked to diversification of (understanding of) pathogenesis scenarios?
Note that over the years research has also been done on the relevance of using liver enzymes in the Ames test where for a certain group of mutagens (including nitrosamines) liver was not the most relevant tumor site, allowing investigations to diversify where needed, supported by specificity investigations on the Ames test for nitrosamines. The fact that we still use liver enzymes predominantly indicates that it is the activation effect that matters, not if it would be the exact same catalyst casing that activation in vivo (even when it would be non-enzymatic).
The anticipated metabolism of the N-nitrosamine (and the cytochrome P450 enzymes most likely involved) is surely considered when mutagenicity testing on nitrosamines is designed.
It is not so exceptional to test also mutagenicity of metabolites instead of mutagenicity of the impurity or to design mutagenicity testing around alternative activation mechanisms (though the in vivo balance between toxification and detoxification has to be considered), but considering the available (in vivo) data on NMOR that was used for acceptable daily intake development and the principle of a very low LCR for extrapolating data, I donât see something that is missed at the moment or an indication that the degree of nitrosamine alpha-hydroxylation activation that can be reached in vivo based on enzymes is much lower than based on photo-effects and also missed fully in in vivo studies and not governed in the conservative approaches to AI setting?
That perspective could have been different of course if totally different/new metabolites of concern are seen upon applying alternative activation introducers, depending on the in vivo relevance of such activations. For example if an NDSRI would be EAT negative with and without S9, the API Ames test negative upon photo-activation without S9 and the NDSRI Ames test positive upon photo-activation, whereas in vitro irradation of NDSRI gives showable new metabolites with a nitroso metabolisation link. (NPIP, NMOR, NPYR donât match that trend.)
Generally, enzyme use in testing also serves detoxification and direct and indirect mutagenicity are assessed together for new nitrosamines. Insights in cytochrome P450 enzyme binding of nitrosamines can be helpful. For non-environmental exposure scenarios, the irradiation effect if any will never be naked from the enzyme effects or overall ADME (and enzymatic/non-enzymatic NDSRI detoxification potential)?
An integrated exposure risk assessment for nitrosamines would not only be focusing on the intake of multiple medicines, but also on diet, air, soil,⊠and is not evident to achieve. At the same time full integration requires in depth insights on in vivo nitrosation and in vivo detoxification balances. Note that limits for nitrosamines in medicines are typically much tighter than regulated for food or tobacco products.
An increase is carcinogenesis understanding is always welcome, but from this particular research I donât see a significant diversification compared to existing considerations in medicines risk assessment or causal proof for the link between skin cancer incidence and the intake of specific nitrosamines via specific medicines?
The guidance for mutagenicity risk assessment for nitrosamines took quite some research to develop and publish and seems at a point where it is reflecting a industry and regulators agreement of what is a conservative way to protect human health, considering that nitrosamine cancer risk are indeed not a myth, but structure dependent.