{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:16:21Z","timestamp":1793222181826,"version":"4.5.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    There is significant regulatory and economic need to distinguish analytically between tobacco-derived nicotine (TDN) and synthetic nicotine (SyN) in commercial products. Currently, commercial e-liquid and oral pouch products are available that contain tobacco-free nicotine, which could be either extracted from tobacco or synthesized. While tobacco products that contain TDN are regulated by FDA Center for Tobacco Products, those with SyN are currently not in the domain of any regulatory authority. This regulatory difference provides an economic incentive to use or claim the use of SyN to remain on the market without submitting a Premarket Tobacco Product Application. TDN is ~99.3% (\n                    <jats:italic>S<\/jats:italic>\n                    )-nicotine, whereas SyN can vary from racemic (50\/50 (\n                    <jats:italic>R<\/jats:italic>\n                    )\/(\n                    <jats:italic>S<\/jats:italic>\n                    )) to \u2265 99% (\n                    <jats:italic>S<\/jats:italic>\n                    )-nicotine, i.e., chemically identical to the tobacco-derived compound. Here we report efforts to distinguish between TDN and SyN in various samples by characterizing impurities, (\n                    <jats:italic>R<\/jats:italic>\n                    )\/(\n                    <jats:italic>S<\/jats:italic>\n                    )-nicotine enantiomer ratio, (\n                    <jats:italic>R<\/jats:italic>\n                    )\/(\n                    <jats:italic>S<\/jats:italic>\n                    )-nornicotine enantiomer ratio, and carbon-14 (\n                    <jats:sup>14<\/jats:sup>\n                    C) content. Only\n                    <jats:sup>14<\/jats:sup>\n                    C analysis accurately and precisely differentiated TDN (100%\n                    <jats:sup>14<\/jats:sup>\n                    C) from SyN (35\u201338%\n                    <jats:sup>14<\/jats:sup>\n                    C) in all samples tested.\n                    <jats:sup>14<\/jats:sup>\n                    C quantitation of nicotine samples by accelerator mass spectrometry is a reliable determinate of nicotine source and can be used to identify misbranded product labelled as containing SyN. This is the first report to distinguish natural, bio-based nicotine from synthetic, petroleum-based nicotine across a range of pure nicotine samples and commercial e-liquid products.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0267049","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T13:50:15Z","timestamp":1649944215000},"page":"e0267049","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":32,"title":["Analysis and differentiation of tobacco-derived and synthetic nicotine products: Addressing an urgent regulatory issue"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9933-9877","authenticated-orcid":true,"given":"Andrew G.","family":"Cheetham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Plunkett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preston","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Hilldrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie G.","family":"Coffa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5335-0886","authenticated-orcid":true,"given":"Stan","family":"Gilliland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Eckard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"pone.0267049.ref001","unstructured":"Family Smoking Prevention and Tobacco Control Act of 2009, Pub. L. No. 111\u201331 (June 22, 2009)."},{"key":"pone.0267049.ref002","year":"2020"},{"key":"pone.0267049.ref003","unstructured":"Puff Bar: Homepage 2021 [cited December 20, 2021]. Available from: https:\/\/puffbar.com."},{"issue":"7","key":"pone.0267049.ref004","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1021\/acs.chemrestox.1c00192","article-title":"Determination of (R)-(+)- and (S)-(-)-Nicotine Chirality in Puff Bar E-Liquids by (1)H NMR Spectroscopy, Polarimetry, and Gas Chromatography-Mass Spectrometry","volume":"34","author":"AK Duell","year":"2021","journal-title":"Chem Res Toxicol"},{"issue":"39","key":"pone.0267049.ref005","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.15585\/mmwr.mm7039a4","article-title":"Notes from the Field: E-Cigarette Use Among Middle and High School Students\u2014National Youth Tobacco Survey, United States, 2021","volume":"70","author":"E Park-Lee","year":"2021","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"pone.0267049.ref006","year":"2021"},{"key":"pone.0267049.ref007","year":"2021"},{"key":"pone.0267049.ref008","year":"2021"},{"key":"pone.0267049.ref009","unstructured":"Firms Embrace Synthetic Nicotine After FDA Rejections 2021 [cited December 20, 2021]. Available from: https:\/\/vaporvoice.net\/2021\/08\/31\/vapor-companies-eye-synthetic-nicotine-after-marketing-denials\/."},{"key":"pone.0267049.ref010","article-title":"Denied FDA Authorization, Vaping Companies Start to Explore Loopholes.","author":"A. Norcia","year":"2021","journal-title":"Filter Magazine."},{"key":"pone.0267049.ref011","author":"MR Zeller","year":"2021"},{"key":"pone.0267049.ref012","article-title":"Some Vaping Companies Are Turning to Synthetic Nicotine to Outsmart the FDA","author":"J. Ducharme","year":"2021","journal-title":"Time"},{"key":"pone.0267049.ref013","article-title":"Synthetic nicotine: Unregulated and increasingly popular","author":"KE Foley","year":"2022","journal-title":"Politico"},{"key":"pone.0267049.ref014","article-title":", inventor; Next Generation Labs, LLC, assignee. Process for the preparation of (R, S)-nicotine","author":"M Arnold","year":"2017"},{"key":"pone.0267049.ref015","article-title":"inventors; NJOY, LLC, assignee. Synthesis and resolution of nicotine","author":"B Willis","year":"2017"},{"key":"pone.0267049.ref016","article-title":"inventors; Divi\u2019s Laboratories, Ltd, assignee","author":"MKP Divi","year":"2013"},{"key":"pone.0267049.ref017","article-title":"inventors; Zanoprima Lifesciences Limited, assignee","author":"R McCague","year":"2021"},{"key":"pone.0267049.ref018","article-title":"Synthetic nicotine has arrived","author":"SE Jordt","year":"2021","journal-title":"Tob Control"},{"key":"pone.0267049.ref019","author":"ASTM International","year":"2021"},{"key":"pone.0267049.ref020","volume-title":"Advances in food authenticity testing","author":"G. Downey","year":"2016"},{"key":"pone.0267049.ref021","first-page":"77","volume-title":"Comprehensive Analytical Chemistry","author":"C Rodrigues","year":"2013"},{"key":"pone.0267049.ref022","unstructured":"Next Generation Labs. Authenticity Case Study: HiLIQ\u2014NTN \u201cNon Tobacco Nicotine\u201d: Next Generation Labs, LLC; 2021 [cited December 20, 2021]. Available from: http:\/\/www.nextgenerationlabs.com\/wp-content\/uploads\/2017\/02\/1-NGL_HiLiq_authenticity_Report_FINAL.pdf."},{"key":"pone.0267049.ref023","unstructured":"United States Pharmacopeial Convention. United States Pharmacopeia and National Formulary (USP 29-NF 24): Nicotine. 2020. Available from: https:\/\/online.uspnf.com\/uspnf\/document\/1_GUID-3D851985-2C16-408D-99E1-F241A9767168_4_en-US."},{"issue":"1","key":"pone.0267049.ref024","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3390\/ijerph110100202","article-title":"Toxic metal concentrations in cigarettes obtained from U.S. smokers in 2009: results from the International Tobacco Control (ITC) United States survey cohort","volume":"11","author":"RV Caruso","year":"2013","journal-title":"Int J Environ Res Public Health"},{"issue":"Suppl_2","key":"pone.0267049.ref025","doi-asserted-by":"crossref","first-page":"i47","DOI":"10.1136\/tc.2009.030163","article-title":"Cigarettes sold in China: design, emissions and metals","volume":"19","author":"RJ O\u2019Connor","year":"2010","journal-title":"Tob Control."},{"issue":"1\u20134","key":"pone.0267049.ref026","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s10661-010-1827-3","article-title":"Assessment of carcinogenic heavy metal levels in Brazilian cigarettes","volume":"181","author":"GF Viana","year":"2011","journal-title":"Environ Monit Assess"},{"key":"pone.0267049.ref027","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.talanta.2017.12.060","article-title":"A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their carcinogenic E\/Z-(R,S)-tobacco-specific nitrosamine metabolites","volume":"181","author":"G Hellinghausen","year":"2018","journal-title":"Talanta"},{"issue":"46","key":"pone.0267049.ref028","doi-asserted-by":"crossref","first-page":"11586","DOI":"10.1021\/jf303681u","article-title":"Variable nornicotine enantiomeric composition caused by nicotine demethylase CYP82E4 in tobacco leaf","volume":"60","author":"B Cai","year":"2012","journal-title":"J Agric Food Chem"},{"issue":"51","key":"pone.0267049.ref029","doi-asserted-by":"crossref","first-page":"42804","DOI":"10.1074\/jbc.M112.413807","article-title":"Enantioselective demethylation of nicotine as a mechanism for variable nornicotine composition in tobacco leaf","volume":"287","author":"B Cai","year":"2012","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0267049.ref030","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/(SICI)1520-636X(1999)11:1<82::AID-CHIR14>3.0.CO;2-C","article-title":"Enantiomeric composition of nornicotine, anatabine, and anabasine in tobacco","volume":"11","author":"DW Armstrong","year":"1999","journal-title":"Chirality"},{"issue":"1\u20132","key":"pone.0267049.ref031","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jchromb.2008.01.034","article-title":"Enantiomeric analysis of anatabine, nornicotine and anabasine in commercial tobacco by multi-dimensional gas chromatography and mass spectrometry","volume":"865","author":"B Liu","year":"2008","journal-title":"Journal of Chromatography B"},{"issue":"7","key":"pone.0267049.ref032","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/(SICI)1520-636X(1998)10:7<587::AID-CHIR6>3.0.CO;2-#","article-title":"Enantiomeric composition of nicotine in smokeless tobacco, medicinal products, and commercial reagents.","volume":"10","author":"DW Armstrong","year":"1998","journal-title":"Chirality"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267049","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T13:50:36Z","timestamp":1649944236000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267049"}},"subtitle":[],"editor":[{"given":"Charles Michael","family":"Greenlief","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,4,14]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0267049","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2022-4g4bt","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,14]]}}}