## 1 Introduction  
Human exposure to external chemical carcinogens is a well-defined cancer risk factor that accounts for about 40% of malignancies worldwide [1]. Chemical carcinogens also include pharmaceuticals and their impurities, as per the International Agency for Research on Cancer Monographs; thus, for occupational and consumer safety protection, screening for drug carcinogenicity is internationally mandated by legal requirements. In the European Union, they are defined by the ICH S2 (R1) (\"Genotoxicity testing and data interpretation for pharmaceuticals intended for human use\") [2] and ICH M3 (R2) (\"Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals\") guidelines [3] pertaining to drug products as well as by the most recent ICH M7 (R1) (\"Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk\") guideline [4] dealing with drug mutagenic impurities. These regulations remain effective for new drug substances and new drug products during their clinical development, and subsequent applications for marketing, and only in a few circumstances for post-approval submissions of marketed products. Notably, the ICH M7 (R1) guideline was not implemented until 2014. Hence, a considerable number of pharmaceuticals have remained outside its scope, based on their well-established use, leaving their potential carcinogenic impurities unverified. The accidental discovery of mutagenic N-nitrosodimethylamine impurity in well-established valsartan and ranitidine-containing products, followed by their global recall in 2018, ultimately uncovered the insufficiency of the existing procedures, prompting an immediate scientific and institutional response [5]. As a consequence, worldwide risk assessment and mutagenic impurity profiling of old pharmaceuticals has led to the withdrawal of over 1800 batches of various finished formulations, until now, including sartans, antidiabetics, antihistamines and antibiotics in the United States, only due to mutagenic contaminants [6]. Even recently, in March 2022, all batches of propranolol extended-release capsules were recalled in Canada for their contamination with mutagenic N-nitroso-propranolol [7]. This clearly illustrates the huge scale of drug carcinogenic impurities problem, warranting the need for constant safety monitoring. The postulate applies in particular to all pharmaceuticals indicated for chronic use, whose lifetime cumulative doses are the highest. Mutagenic N-nitroso compounds, besides being potential drug impurities, can also be endogenously formed from N-nitrosole drug precursors treated with nitrite in the strongly acidic environment of gastric juice. Possible sources of nitroso metabolites are amine, amide, cyanamide, guanidine, hydroxylamine, amidine, hydrazine, hydrazide, piperazine and diketopiperazine structures, which are present in a large portion of drugs, making them theoretically nitrosole [6; 8]. Drug-nitrite interaction products can easily form DNA adducts, either in the nucleus or in the mitochondria, via electrophilic interactions, which translates into their multidirectional carcinogenic potency [6]. Indeed, in a recent animal models study, reactive nitrosamines caused mutations in both nuclear and mitochondrial DNA, leading to upregulation of the beta-2-adrenergic-receptors-cholinergic-receptornicotinic-alpha-7-subunit-dependent nitrosamine canonical signaling, resulting in lung tumor growth. This was mediated by a malfunction of mitochondrial-reactive oxygen species [9]. Nitrosamines also caused aberrations in the mitochondrial electron transport chain, subunits I, II and IV, consequently affecting transmembrane electric potential and increasing oxidative stress, as an alternative cancerogenic mechanism [10]. Additionally, nitrosamines can reversively inhibit gap junction intercellular communication leading to cancer, recently confirmed by [PERSON] [11].