Hollaender award 2023: Adventures in applied genetic toxicology DOI
Rosalie K. Elespuru

Environmental and Molecular Mutagenesis, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

This work describes career "adventures" into applied research in environmental mutagenesis. Surprising and interesting results, as well publications Nature Science, may counter an assumption that is not exciting or impactful basic research. The narrative described terms of "mentors," whose advice had a lasting impact resonated many ways. Adventures included forays nitrosamine mutagenicity, nanomaterial assessment, photoactivated DNA damaging agents, p53 gene germ cell mutagenic risk, bacterial mutagenicity assays, genotoxicity phone radiation, Covid diagnostic PCR personalized cancer prevention, >25 years regulatory safety assessment at FDA. FDA review data, experiments the lab, international standards generation, collaboration with others to foster better analyses generally relation risk. As demonstrated by accidental adventures led scientific life-altering personal realizations, most critical happenings science life turn out be "random," unexpected, events. Finally, this my lifelong tripmate William Lijinsky models, it suggested "non-hypothesis driven," open-ended approach can path-breaking forefront.

Language: Английский

Re‐Evaluating Acceptable Intake: A Comparative Study of N‐Nitrosomorpholine and N‐Nitroso Reboxetine Potency DOI Creative Commons
Shaofei Zhang, Jennifer Cheung, Jakub Kostal

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

ABSTRACT Establishing regulatory limits for Drug Substance‐Related Impurities (NDSRIs) is challenging due to the limited genotoxicity and carcinogenicity data available many of these impurities, often leading conservative approaches. In this study, we evaluated genotoxic potential two structurally related nitrosamines: N‐nitrosomorpholine (NMOR) N‐nitroso reboxetine. Compared well‐studied NMOR, there little toxicological information Currently, both compounds have an acceptable intake value 127 ng/day, based on a read‐across using NMOR. While tested positive in series vitro vivo assays, found that mutagenic reboxetine was significantly lower than The benchmark dose (BMD) analysis mutagenicity supports 24,000 ng/day Computational studies, carried out quantum‐mechanical CADRE program, were consistent with outcomes, suggesting at or above 1500 comparison prediction supported by computed reactivity hydroxylation step, greater steric hindrance alpha carbons, more facile proton transfer heterolysis toward aldehyde metabolite. presented work can be used refine improve Carcinogenic Potency Categorization Approach (CPCA). It also underscores importance collaboration between authorities, pharmaceutical industry, scientific researchers address risks while avoiding overestimation certain NDSRIs.

Language: Английский

Citations

1
An Enhanced Metabolization Protocol for In Vitro Genotoxicity Assessment of N‐Nitrosamines in Mammalian Cells DOI Creative Commons
Marit E. Geijer,

A. M. Gernaat,

Nynke Moelijker

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

ABSTRACT N‐Nitrosamines (NAs) are probable human carcinogens and were detected as impurities in pharmaceuticals, which led to a concern for health. NAs require metabolic activation before they become mutagenic, not all mutagenic since their reactivity is related structure. While some potent mutagens vivo, vitro metabolization with exogenous S9 liver extract generally less efficient. an enhanced bacterial mutagenicity protocol was recently developed, uses increased concentrations of extracts, there presently improved suitable mammalian cell genotoxicity assays. Therefore, we optimized hamster extract‐based NA assessed the genotoxic potential various using ToxTracker. With this (EMP), potency N‐nitrosodimethylamine (NDMA) approximately 200‐fold compared standard exposure The EMP further validated seven additional humans commonly exposed: N‐nitrosodiethylamine (NDEA), N‐nitrosodiethanolamine (NDELA), N‐nitrosodibutylamine (NDBA), N‐nitrosofluoxetine (NF), 1‐nitrosopyrrolidine (NPYR), N‐nitrosomorpholine (NMOR), 1‐cyclopentyl‐4‐nitrosopiperazine (CPNP), two non‐mutagenic NAs: N‐nitrosobupropion (NBuPRO) N‐nitrosoproline (NPRO). Genotoxicity could be confirmed six EMP, demonstrating that cells new approach methodology (NAM) ToxTracker may have when investigating NA‐related genotoxicity.

Language: Английский

Citations

0
Tale of Three N-Nitrosamines and the Variables Needed to Assess Their Carcinogenicity In Silico Incorporated into a Single Workflow DOI
Jakub Kostal, Adelina Voutchkova‐Kostal

Chemical Research in Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

N-Nitrosamine impurities in pharmaceuticals present a considerable challenge for regulators and industry alike, where the absence of carcinogenic-potency studies has left gap that must be adequately filled to protect public health. In interim, this means balancing risk assessment with necessity continue research, development, supply pharmaceuticals. long term, we need cost-effective solution optimizes both. As if beholden Newton's Third Law, every crisis breeds an opportunity equal magnitude. Consequently, cross-industry consortia have been racing find by advancing our current science. Recent spotlight on silico tools, as fast increasingly reliable alternative vivo vitro testing. Because N-nitrosamine bioactivation lends itself uniquely quantum mechanics (QM) approaches, integration electronic-structure considerations emerged dominant approach. This signifies leap predictive toxicology, which has, much its existence, relied atomistic (quantitative) structure-activity relationships, i.e., (Q)SARs. Here validation integrated docking-QM approach within CADRE program demonstrate utility three different impurities, N-nitroso-7-monomethylamino-6-deoxytetracycline, N-nitroso-dabigatran etexilate, 1-methyl-4-nitrosopiperazine. We show combined strategy, considers bioavailability, transport, cytochrome P450 binding, reactivity, can leveraged supplement overly conservative Carcinogenic Potency Categorization Approach (CPCA) setting daily acceptable intake (AI) using defensible, highly mechanistic, quantitative drivers metabolism. To end, argue while N-nitroso-7-monomethylamino-6-deoxytetracycline 1-methyl-4-nitrosopiperazine are cohort-of-concern etexilate is not potent carcinogen (TD50 > 1.5 mg/kg/day), contrasting CPCA-derived AI. Lastly, discuss how tool broader landscape QM methods CPCA into single harmonized strategy carcinogenicity impurities.

Language: Английский

Citations

0
HESI GTTC Ring Trial: Concordance between Ames and Rodent Carcinogenicity Outcomes for N-Nitrosamines (NAs) with Rat and Hamster Metabolic Conditions DOI Creative Commons
Joel P. Bercu, Alejandra Trejo‐Martin,

Connie L. Chen

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 105835 - 105835

Published: April 1, 2025

A multi-sector study (i.e., Ring Trial) was designed to improve the in vitro detection of N-nitrosamine (NA)-associated mutagenicity by optimizing bacterial reverse mutation Ames) assay protocol and testing various conditions on sensitivity specificity for prediction rodent carcinogenicity. total 29 NAs 3 N-nitroso drug-like compounds from different structural classes carcinogenicity outcomes were tested (two independent laboratories per compound) across 5 strains using a 30-minute pre-incubation protocol. To evaluate impact metabolic activating systems (MASs), included use 10 or 30% liver S9 fractions prepared rats hamsters pretreated with inducers enzymatic activity. Results indicate that E. coli Salmonella typhimurium detecting single base pair mutations, coupled MASs containing hamster S9s most sensitive (90%) identifying are carcinogens. Regarding MAS combinations, highest rat (93%), but has low (45%), good laboratory agreement Ames calls (91%). DMSO water considered suitable solvents, except small-molecular weight alkyl NAs. These results will support harmonized NAs, giving high confidence negative result.

Language: Английский

Citations

0
Comparative DNA damage induced by eight nitrosamines in primary human and macaque hepatocytes DOI
Ji‐Eun Seo, Xiaobo He, Matthew Bryant

et al.

Chemico-Biological Interactions, Journal Year: 2025, Volume and Issue: unknown, P. 111538 - 111538

Published: May 1, 2025

Language: Английский

Citations

0
The latest advances on the formation, exposure level and control strategies of nitrosamines in meat, poultry and fish products DOI
Mengjing Guo, Yanping Xian, Xiaojuan Zhao

et al.

Food Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 144837 - 144837

Published: May 1, 2025

Language: Английский

Citations

0
Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells DOI
Xilin Li, Yuan Le, Xiaoqing Guo

et al.

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: unknown, P. 105730 - 105730

Published: Oct. 1, 2024

Language: Английский

Citations

3
Resolution of Historically Discordant Ames Test Negative / Rodent Carcinogenicity Positive N-nitrosamines using a Sensitive, OECD-aligned Design DOI Creative Commons

Dean N Thomas,

John W. Wills,

Mark Burman

et al.

Mutagenesis, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

The in vitro Bacterial Reverse Mutation (Ames) Test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that certain members this chemical class outcomes Ames did not correlate with their associated rodent carcinogenicity outcomes. This has resulted negative an OECD aligned alone (standard or enhanced) no longer being considered sufficient by regulatory authorities to assess potential carcinogenic risk NAs if present as impurities drug products. Consequently, extensive follow-up vivo testing can be required characterise and genotoxic NA (i.e., beyond defined ICH M7 guideline non-NA impurities). We previously demonstrated alkyl-nitrosamines detected appropriately designed, identified those conditions contributed most assay sensitivity. design was used seven NAs, i.e. (methyl(neopentyl)nitrosamine, N-methyl-N-nitroso-2-propanamine, N-nitrosodiisopropylamine, bis(2-methoxyethyl)nitrosoamine, N-nitroso-N-methyl-4-fluoroaniline, dinitrosoethambutol, (R,R)- mononitrosocaffeidine) were reported Tests but positive studies. All mutagenic test therefore these compounds should discordant (false negatives) respect correlation carcinogenicity. These results confirm sensitivity detection provides further support its pivotal placement within framework assessment pharmaceuticals limit risk. In addition, we 1-cyclopentyl-4-nitrosopiperazine, indicates it could serve a suitable control provide confidence class.

Language: Английский

Citations

2
Hollaender award 2023: Adventures in applied genetic toxicology DOI
Rosalie K. Elespuru

Environmental and Molecular Mutagenesis, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

This work describes career "adventures" into applied research in environmental mutagenesis. Surprising and interesting results, as well publications Nature Science, may counter an assumption that is not exciting or impactful basic research. The narrative described terms of "mentors," whose advice had a lasting impact resonated many ways. Adventures included forays nitrosamine mutagenicity, nanomaterial assessment, photoactivated DNA damaging agents, p53 gene germ cell mutagenic risk, bacterial mutagenicity assays, genotoxicity phone radiation, Covid diagnostic PCR personalized cancer prevention, >25 years regulatory safety assessment at FDA. FDA review data, experiments the lab, international standards generation, collaboration with others to foster better analyses generally relation risk. As demonstrated by accidental adventures led scientific life-altering personal realizations, most critical happenings science life turn out be "random," unexpected, events. Finally, this my lifelong tripmate William Lijinsky models, it suggested "non-hypothesis driven," open-ended approach can path-breaking forefront.

Language: Английский

Citations

0