{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:34:52Z","timestamp":1791999292987,"version":"4.4.0"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Detection of N-nitrosamines (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed drugs, otherwise known as NA Drug Substance-Related Impurities (NDSRIs). The Ames test is used to assess the mutagenic potential of drug impurities, including NAs. Concerns over the sensitivity of the Ames test, as recommended in Organization for Economic Co-operation and Development Test Guideline 471, in predicting the rodent carcinogenic potential of NAs has prompted optimization of several test parameters used for detecting the mutagenicity of NAs (e.g. methods used for metabolic activation and the selection of tester strains). In order to discuss optimal Ames test conditions for the evaluation of NAs, including NDSRIs, the Office of New Drugs in the US Food and Drug Administration\u2019s Center for Drug Evaluation and Research and the Health and Environmental Sciences Institute\u2019s Genetic Toxicology Technical Committee co-organized and co-sponsored a workshop entitled \u201cNitrosamines: Ames Data Review and Method Development Workshop\u201d. The workshop featured five sessions addressing charge questions pertinent to the Ames test conditions and performance through the presentation of data and panel discussions. This report outlines the key takeaway points from the workshop.<\/jats:p>","DOI":"10.1093\/mutage\/geag011","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:48:55Z","timestamp":1770986935000},"page":"225-236","source":"Crossref","is-referenced-by-count":2,"title":["Nitrosamine Ames Data Review and Method Development: proceedings of a US FDA\/HESI workshop"],"prefix":"10.1093","volume":"41","author":[{"given":"Aisar","family":"Atrakchi","sequence":"first","affiliation":[{"name":"US Food and Drug Administration\/Center for Drug Evaluation and Research , Silver Spring, MD 20993 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6726-7227","authenticated-orcid":false,"given":"Raechel","family":"Puglisi","sequence":"additional","affiliation":[{"name":"Health and Environmental Sciences Institute , Washington, DC 20005 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6780-4721","authenticated-orcid":false,"given":"Joel","family":"Bercu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Nonclinical Safety and Pathobiology , Foster City, CA 94404 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cheung","sequence":"additional","affiliation":[{"name":"Pfizer Research, Development, and Medical , Groton, CT 06370 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-3325","authenticated-orcid":false,"given":"Andreas","family":"Czich","sequence":"additional","affiliation":[{"name":"Sanofi, R&D Translational Medicine Preclinical Safety , Frankfurt D-69526 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-7509","authenticated-orcid":false,"given":"Roland","family":"Froestchl","sequence":"additional","affiliation":[{"name":"BfArM (Federal Institute for Drugs and Medical Devices), Licensing 2, Unit Pharmaceutical Biotechnology, Genetic and Reproductive Toxicology , Bonn 53175 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Davis-Bruno","sequence":"additional","affiliation":[{"name":"US Food and Drug Administration\/Center for Drug Evaluation and Research , Silver Spring, MD 20993 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6244-1774","authenticated-orcid":false,"given":"Robert H","family":"Heflich","sequence":"additional","affiliation":[{"name":"U.S. Food and Drug Administration\/National Center for Toxicological Research , Jefferson, AR 72079 \u00a0","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8207-5035","authenticated-orcid":false,"given":"Tetyana","family":"Kobets","sequence":"additional","affiliation":[{"name":"New York Medical College , Department of Pathology, Microbiology and Immunology, 40 Sunshine Cottage Road, Valhalla, NY 10595 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9232-6041","authenticated-orcid":false,"given":"Timothy J","family":"McGovern","sequence":"additional","affiliation":[{"name":"US Food and Drug Administration\/Center for Drug Evaluation and Research , Silver Spring, MD 20993 ,","place":["United States"]},{"name":"White Oak Regulatory Tox, LLC , Crownsville, MD 21032 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1533-7664","authenticated-orcid":false,"given":"Anthony","family":"Lynch","sequence":"additional","affiliation":[{"name":"GSK, Genetic & Investigative Toxicology , Stevenage, SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Selby","sequence":"additional","affiliation":[{"name":"GSK, Genetic & Investigative Toxicology , Stevenage, SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4388-370X","authenticated-orcid":false,"given":"Maik","family":"Schuler","sequence":"additional","affiliation":[{"name":"Pfizer Research, Development, and Medical , Groton, CT 06370 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela De Oliveira","family":"Silveira","sequence":"additional","affiliation":[{"name":"Lhasa Limited , Leeds , Canal Wharf, Leeds LS11 5PS,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6805-3526","authenticated-orcid":false,"given":"Alisa","family":"Vespa","sequence":"additional","affiliation":[{"name":"Pharmaceutical Drugs Directorate, Health Canada , Ottawa, ON, K1A 0K9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6108-9908","authenticated-orcid":false,"given":"Rhys","family":"Whomsley","sequence":"additional","affiliation":[{"name":"European Medicines Agency , Domenico Scarlattilaan 6, 1083 HS Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3704-9866","authenticated-orcid":false,"given":"Connie L","family":"Chen","sequence":"additional","affiliation":[{"name":"Health and Environmental Sciences Institute , Washington, DC 20005 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,14]]},"reference":[{"key":"2026062711112544600_ref1","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/J.CHEMOSPHERE.2018.07.098","article-title":"Critical review of major sources of human exposure to N-nitrosamines","volume":"210","author":"Gushgari","year":"2018","journal-title":"Chemosphere"},{"key":"2026062711112544600_ref2","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1080\/19440049.2019.1649472","article-title":"Literature compilation of volatile N-nitrosamines in processed meat and poultry products - an update","volume":"36","author":"Lee","year":"2019","journal-title":"Food Addit Contam Part A Chem Anal Control Expo Risk Assess"},{"key":"2026062711112544600_ref3","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1021\/ACS.OPRD.3C00100\/ASSET\/IMAGES\/LARGE\/OP3C00100_0007.JPEG","article-title":"The nitrosamine \u201cSaga\u201d: lessons learned from five years of scrutiny","volume":"27","author":"Nudelman","year":"2023","journal-title":"Org Process Res Dev"},{"key":"2026062711112544600_ref4","volume-title":"Guidance for Industry | M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk","author":"FDA","year":"2023"},{"key":"2026062711112544600_ref5","volume-title":"CDER Nitrosamine Impurity Acceptable Intake Limits","author":"FDA","year":"2023"},{"key":"2026062711112544600_ref6","volume-title":"Nitrosamine Impurities in Medications: Guidance; Appendix 3: Enhanced Ames Assay Test Conditions","author":"Health Canada","year":"2022"},{"key":"2026062711112544600_ref7","volume-title":"Enhanced Ames Test Conditions for N-Nitrosamines; Appendix 3 to Questions and Answers for Marketing Authorisation Holders\/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726\/2004 Referral on Nitrosamine Impurities in Human Medicinal Products","author":"EMA","year":"2024"},{"key":"2026062711112544600_ref8","doi-asserted-by":"publisher","first-page":"105835","DOI":"10.1016\/J.YRTPH.2025.105835","article-title":"HESI GTTC ring trial: concordance between Ames and rodent carcinogenicity outcomes for N-nitrosamines (NAs) with rat and hamster metabolic conditions","volume":"161","author":"Bercu","year":"2025","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref9","doi-asserted-by":"crossref","first-page":"503855","DOI":"10.1016\/j.mrgentox.2025.503855","article-title":"A comparative analysis of select P450 enzymes in uninduced and PB\/BNF-induced hamster and rat liver S9","volume":"902","author":"Evans","year":"2025","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"key":"2026062711112544600_ref10","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1093\/mutage\/gead033","article-title":"Ames test study designs for nitrosamine mutagenicity testing: qualitative and quantitative analysis of key assay parameters","volume":"39","author":"Thomas","year":"2024","journal-title":"Mutagenesis"},{"key":"2026062711112544600_ref23","author":"Londenberg","year":"2025"},{"key":"2026062711112544600_ref11","doi-asserted-by":"publisher","DOI":"10.1016\/J.YRTPH.2024.105709","article-title":"Optimizing the detection of N-nitrosamine mutagenicity in the Ames test","volume":"153","author":"Heflich","year":"2024","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref12","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3123\/JEMSGE.32.53","article-title":"Inhibitory effect of dimethyl sulfoxide on the mutagenicity of Promutagens in the Ames test","volume":"32","author":"Hakura","year":"2010","journal-title":"Genes Environ"},{"key":"2026062711112544600_ref13","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/S0090-9556(25)08435-1","article-title":"Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase","volume":"22","author":"Masubuchi","year":"1994","journal-title":"Drug Metab Dispos"},{"key":"2026062711112544600_ref14","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2023.105410","article-title":"Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays","volume":"141","author":"Li","year":"2023","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref15","doi-asserted-by":"publisher","first-page":"105730","DOI":"10.1016\/J.YRTPH.2024.105730","article-title":"Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells","volume":"154","author":"Li","year":"2024","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref16","doi-asserted-by":"publisher","DOI":"10.1002\/EM.22618","article-title":"Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential","volume":"65","author":"Cheung","year":"2024","journal-title":"Environ Mol Mutagen"},{"key":"2026062711112544600_ref17","doi-asserted-by":"publisher","DOI":"10.1007\/S00204-024-03859-3","article-title":"Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide","volume":"98","author":"Gandhi","year":"2024","journal-title":"Arch Toxicol"},{"key":"2026062711112544600_ref18","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1002\/EM.22338","article-title":"Mutation as a toxicological endpoint for regulatory decision-making","volume":"61","author":"Heflich","year":"2020","journal-title":"Environ Mol Mutagen"},{"key":"2026062711112544600_ref19","doi-asserted-by":"publisher","DOI":"10.1016\/J.YRTPH.2024.105681","article-title":"N-nitrosamine impurity risk assessment in pharmaceuticals: utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP","volume":"152","author":"Powley","year":"2024","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref20","doi-asserted-by":"publisher","DOI":"10.1016\/J.YRTPH.2024.105672","article-title":"Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine","volume":"152","author":"Jolly","year":"2024","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref21","doi-asserted-by":"publisher","DOI":"10.1016\/J.YRTPH.2022.105245","article-title":"Genotoxicity evaluation of a valsartan-related complex N-nitroso-impurity","volume":"134","author":"Glowienke","year":"2022","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026062711112544600_ref22","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2026.106051","article-title":"Ames concordance with the In vivo transgenic rodent (TGR) mutation assay for NDSRIs and relative In vivo TGR potency with exemplar nitrosamines","volume":"30","author":"Jolly","journal-title":"Regul Toxicol Pharmacol"}],"container-title":["Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/mutage\/advance-article-pdf\/doi\/10.1093\/mutage\/geag011\/66901525\/geag011.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mutage\/article-pdf\/41\/4\/225\/66901525\/geag011.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mutage\/article-pdf\/41\/4\/225\/66901525\/geag011.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T15:11:37Z","timestamp":1782573097000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mutage\/article\/41\/4\/225\/8483857"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,14]]},"references-count":23,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2,14]]},"published-print":{"date-parts":[[2026,6,27]]}},"URL":"https:\/\/doi.org\/10.1093\/mutage\/geag011","relation":{},"ISSN":["0267-8357","1464-3804"],"issn-type":[{"value":"0267-8357","type":"print"},{"value":"1464-3804","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,2,14]]}}}