Salmonella typhimurium TA100 and TA1535 and E. coli WP2 uvrA are highly sensitive to detect the mutagenicity of short Alkyl-N-Nitrosamines in the Bacterial Reverse Mutation Test

Bringezu, Frank; Simon, Stephanie

doi:10.1016/j.toxrep.2022.02.005

Cited by 16 publications

(20 citation statements)

References 31 publications

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“…A recent retrospective analysis has found that an Ames test conducted in accordance with the OECD 471 guidelines is highly sensitive for identifying the carcinogenic potential of N -nitrosamines . Consistent with this, in a contemporary investigation, Bringezu and Simon demonstrated the in vitro mutagenicity of several short chain N -alkyl- N -nitrosamines (e.g., NDMA, NDEA, N -nitrosodipropylamine, and NDBA) following the OECD 471 protocol (i.e., employing 4 Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537) and an E. coli strain (WP2 uvrA ), applying both plate incorporation and preincubation protocols, and a phenobarbital/β-naphthoflavone-induced rat liver S9 fraction for the conduct of the Ames assay. For NDMA, the investigators reported that the preincubation protocol was required, as no clear positive response was detected with the plate incorporation protocol.…”

Section: Genotoxicity Assaysmentioning

confidence: 95%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

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The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence in all medicinal products. In the absence of rodent carcinogenicity data for novel N-nitrosamines derived from aminecontaining APIs, a conservative class limit of 18 ng/day (based on the most carcinogenic N-nitrosamines) or the derivation of acceptable intakes (AIs) using structurally related surrogates with robust rodent carcinogenicity data is recommended. The guidance has implications for the pharmaceutical industry given the vast number of marketed amine-containing drugs. In this perspective, the rate-limiting step in N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation to yield DNA-reactive diazonium or carbonium ion intermediates, is discussed with reference to the selection of read-across analogs to derive AIs. Risk-mitigation strategies for managing putative N-nitrosamines in the preclinical discovery setting are also presented.

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Section: Genotoxicity Assaysmentioning

confidence: 95%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

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“…55,57 As well as ensuring that the sensitivity of the test is maximized, the use of several strains with and without S9 allows the association of mechanism of action with a positive result. The most sensitive Salmonella strain for the small-molecule dialkyl N-nitrosamines is TA1535, 58,59 with some signal in TA100 and E. coli WP2 uvrA (all with S9); 59 however, the aromatic N-nitroso compounds are sensitive to TA98 and TA100 with and without S9, a strain profile that is comparable to that of the aromatic amines. 60 As discussed above, this is an important piece of evidence in determining that this subclass follows a different mechanism.…”

Section: α-Hydroxy or -Alkoxymentioning

confidence: 98%

“…The “strain profile” mentioned is the combination of strains and metabolic activation that are sensitive to a particular compound and, due to the different mutations required for histidine/tryptophan production in different strains, can provide valuable mechanistic insight. , As well as ensuring that the sensitivity of the test is maximized, the use of several strains with and without S9 allows the association of mechanism of action with a positive result. The most sensitive Salmonella strain for the small-molecule dialkyl N -nitrosamines is TA1535, , with some signal in TA100 and E. coli WP2 uvrA (all with S9); however, the aromatic N -nitroso compounds are sensitive to TA98 and TA100 with and without S9, a strain profile that is comparable to that of the aromatic amines .…”

Section: N-nitroso Compound Subclassesmentioning

confidence: 99%

Drawing a Line: Where Might the Cohort of Concern End?

Ponting

Foster

2023

Org. Process Res. Dev.

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The definitions of the chemical classes in the Cohort of Concern (CoC) by Kroes and co-workers are based on broad structural alerts, in particular for N-nitroso compounds�for which the alert consists essentially of the N−N�O substructure without further refinement. Recent pharmaceutical recalls have focused on the presence of dialkyl N-nitrosamine impurities, some of which are exceptionally potent carcinogens�2 orders of magnitude more potent than the pharmaceutical Threshold of Toxicological Concern (TTC), 1.5 μg/day. However, the class of "N-nitroso compounds" is potentially significantly broader. This Perspective looks at the N-nitroso compounds that are at the edges of the cohort, where changes in mechanism, metabolic activation potential, stability, or indeed toxicity data lead to questions about whether these compounds should be classed as CoC. The critical mechanism of action, metabolic α-hydroxylation leading to a diazonium ion, is presented, along with the pathways by which Nnitroso compounds that are not dialkyl N-nitrosamines can lead to comparable DNA adducts.

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“…The general view is that there is insufficient data to conclude that such Nitrosamines are of lower concern, despite recent publications, in the view of industry at least, demonstrating this, both in terms of in silico evaluation of carcinogenicity data and repeat Ames tests, 11,12 on simple dialkyl N-Nitrosamines. 13 In the apparent absence of such proof this has led to proposals relating to higher acceptable intakes (AIs) routinely being challenged. Indeed, recent guidance updates, 9,14 have in several instances reinforced this, many limits still being based on highly conservative and simplistic read across to the limits set for NDEA/NDMA, 26.5 ng/96 ng/day, respectively, or 18 ng/ day in Europe.…”

Section: ■ N-nitrosaminesmentioning

confidence: 99%

“…Are they mutagenic/carcinogenic? The general view is that there is insufficient data to conclude that such Nitrosamines are of lower concern, despite recent publications, in the view of industry at least, demonstrating this, both in terms of in silico evaluation of carcinogenicity data and repeat Ames tests, , on simple dialkyl N-Nitrosamines . In the apparent absence of such proof this has led to proposals relating to higher acceptable intakes (AIs) routinely being challenged.…”

Section: N-nitrosaminesmentioning

confidence: 99%