{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:29:12Z","timestamp":1788384552372,"version":"build-2803163510"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse (NIDA) of the National Institutes of Health","award":["R01DA051005"],"award-info":[{"award-number":["R01DA051005"]}]},{"name":"National Institute on Drug Abuse (NIDA) of the National Institutes of Health","award":["P008078601"],"award-info":[{"award-number":["P008078601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>sugars, added or naturally present in cigarette tobacco, have been reported to contribute to the harmful properties of cigarettes by enhancing smoke palatability, appeal, and potentially toxicity and addictiveness. In this study, 13C sugars were used to better understand the specific impact of added sugars on smoke composition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>[13C]-isotope-labeled sugars were added to cigarettes. Different concentrations, sugars (fructose, glucose, sucrose, and a mixture) were tested with 8 cigarette brands, with different design characteristics such as length, filter ventilation, and sugar content. Cigarettes were machine-smoked (using International Organization for Standardization and World Health Organization Intense regimes), and the resulting samples were subjected to untargeted and targeted analyses (for volatile organic compounds, polycyclic aromatic hydrocarbons (PAHs), aldehydes, tobacco-specific nitrosamines, and nicotine).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The presence of 13C in 5 furans, pyranone, and 1 compound of unknown chemical identity showed that additional amounts of these compounds were directly formed from the decomposition of sugars. Up to 58% of 5-hydroxymethylfuran originated from 13C sugars. Moreover, sugars were direct precursors of 4 out of the 5 aldehydes tested, although the 13C-labeled fraction of aldehydes was much smaller (up to 2%). No evidence for the direct formation of PAHs was found, but the addition of sugars was nevertheless found to impact the levels of unlabeled PAHs, TSNAs, and nicotine, presumably by altering the burning process of the experimental cigarettes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Added sugars to cigarette tobacco contribute to the formation of harmful and flavored components in smoke, including furans and aldehydes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications<\/jats:title>\n                    <jats:p>Based on our findings on sugars as precursors of harmful and flavored compounds, we propose to ban the addition of sugars to cigarettes and other combustible tobacco products. Imposing maximum allowable levels on sugars that are naturally present in tobacco could also be considered, as they also lead to harmful compounds and impart a flavor.<\/jats:p>\n                    <jats:p>This study adds to the body of evidence that sugars present in cigarette tobacco are precursors of harmful and flavored constituents of cigarette smoke. Regulation of sugars, such as banning added sugars and setting limits on natural sugars, may serve to protect public health.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ntr\/ntag053","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:05:04Z","timestamp":1773831904000},"page":"1402-1411","source":"Crossref","is-referenced-by-count":1,"title":["Stable isotope labeling reveals that sugars are direct precursors to several toxicants and flavorings in cigarette smoke"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1129-262X","authenticated-orcid":false,"given":"Wouter F","family":"Visser","sequence":"first","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walther N M","family":"Klerx","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans W J M","family":"Cremers","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan G W","family":"Lensen","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Dings","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roelina","family":"Hoving","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilbert J","family":"de Ruijter","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Boer","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u00f6mi","family":"Weibolt","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max J","family":"van Alphen","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-8944","authenticated-orcid":false,"given":"Irina","family":"Stepanov","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences, School of Public Health, University of Minnesota , Minneapolis, MN 55455 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5310-9064","authenticated-orcid":false,"given":"Reinskje","family":"Talhout","sequence":"additional","affiliation":[{"name":"Centre for Health Protection, National Institute for Public Health and the Environment , Postbus 1, 3720 BA, Bilthoven ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"2026072301020950000_ref1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1093\/ntr\/ntac222","article-title":"Sugars and sweeteners in tobacco and nicotine products: Food and Drug Administration's regulatory implications","volume":"25","author":"Rezk-Hanna","year":"2023","journal-title":"Nicotine Tob Res"},{"key":"2026072301020950000_ref2","first-page":"412","article-title":"Influence of additives on cigarette related health risks. Contributions to","volume":"25","author":"Klus","year":"2012","journal-title":"Tob Res"},{"key":"2026072301020950000_ref3","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3109\/10408444.2011.650789","article-title":"Scientific assessment of the use of sugars as cigarette tobacco ingredients: a review of published and other publicly available studies","volume":"42","author":"Roemer","year":"2012","journal-title":"Crit Rev Toxicol"},{"key":"2026072301020950000_ref4","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/j.fct.2006.06.016","article-title":"Sugars as tobacco ingredient: effects on mainstream smoke composition","volume":"44","author":"Talhout","year":"2006","journal-title":"Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association"},{"key":"2026072301020950000_ref5","first-page":"265","volume-title":"Tobacco: Production, Chemistry and Technology","author":"Leffingwell","year":"1999"},{"key":"2026072301020950000_ref6","first-page":"381","article-title":"Effect of sugar content on acetaldehyde yield in cigarette smoke","author":"Cahours","year":"2014","journal-title":"Beitr\u00e4ge zur Tabakforschung \/ Contributions to Tobacco Research"},{"key":"2026072301020950000_ref7","article-title":"Evaluation of competitive cigarettes","author":"Newson","year":"1975","journal-title":"Liggett & Myers"},{"key":"2026072301020950000_ref8","volume-title":"A Summary Developed with Input from Batco, Batcf, Souza Cruz, & B&W. Brown & Williamson","author":"Gordon","year":"1992"},{"key":"2026072301020950000_ref9","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1021\/tx020069f","article-title":"Acetaldehyde in mainstream tobacco smoke: formation and occurrence in smoke and bioavailability in the smoker","volume":"15","author":"Seeman","year":"2002","journal-title":"Chem Res Toxicol"},{"key":"2026072301020950000_ref10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S0008-6215(00)82540-9","article-title":"Tobacco additives and cigarette smoke. Part I. Transfer of d-glucose, sucrose, and their degradation products to the smoke","volume":"17","author":"Gager","year":"1971","journal-title":"Carbohydr Res"},{"key":"2026072301020950000_ref11","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.ijheh.2016.09.002","article-title":"Oxidative and inert pyrolysis on-line coupled to gas chromatography with mass spectrometric detection: on the pyrolysis products of tobacco additives","volume":"219","author":"Paschke","year":"2016","journal-title":"Int J Hyg Environ Health"},{"key":"2026072301020950000_ref12","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1093\/ntr\/ntz203","article-title":"Aldehyde and volatile organic compound yields in commercial cigarette mainstream smoke are mutually related and depend on the sugar and humectant content in tobacco","volume":"22","author":"Pennings","year":"2020","journal-title":"Nicotine Tob Res"},{"key":"2026072301020950000_ref13","first-page":"61","article-title":"Effect of adding sugar to burley tobacco on the emission of aldehydes in mainstream tobacco smoke tobacco regulatory science","author":"Cheah","year":"2018"},{"key":"2026072301020950000_ref14","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/08958370304461","article-title":"Evaluation of relationships between mainstream smoke acetaldehyde and \"tar\" and carbon monoxide yields in tobacco smoke and reducing sugars in tobacco blends of U.S. commercial cigarettes","author":"Seeman","year":"2003","journal-title":"Inhal Toxicol"},{"key":"2026072301020950000_ref15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2478\/cttr-2013-0742","article-title":"Some studies of the effects of additives on cigarette mainstream smoke properties. II. Casing materials and humectants","volume":"20","author":"Rodgman","year":"2002","journal-title":"Beitr\u00e4ge zur Tabakforschung International\/Contributions to Tobacco Research"},{"key":"2026072301020950000_ref16","article-title":"Opinion on additives used in tobacco products (opinion 1)","author":"SCENIHR","year":"2016","journal-title":"European Commission, Scientific Committees"},{"key":"2026072301020950000_ref17","volume-title":"Tobacco Additives: Cigarette Engineering and Nicotine Addiction","author":"Bates","year":"1999"},{"key":"2026072301020950000_ref18","article-title":"Chemical factors influencing the addictiveness and attractiveness of cigarettes in New Zealand 2001","author":"Fowles"},{"key":"2026072301020950000_ref19","doi-asserted-by":"crossref","DOI":"10.3390\/molecules25071734","article-title":"Carbohydrates-key players in tobacco aroma formation and quality determination","volume":"25:","author":"Bano\u017ei\u0107","year":"2020","journal-title":"Molecules."},{"key":"2026072301020950000_ref20","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1136\/tobaccocontrol-2014-051943","article-title":"A study of pyrazines in cigarettes and how additives might be used to enhance tobacco addiction","volume":"25","author":"Alpert","year":"2016","journal-title":"Tob Control"},{"key":"2026072301020950000_ref21","first-page":"1885","article-title":"Sugar content of the tobacco and pH of the smoke in relation to lung cancer risks of cigarette smoking","volume":"48","author":"Elson","year":"1972","journal-title":"J Natl Cancer Inst"},{"key":"2026072301020950000_ref22","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/j.fct.2004.04.002","article-title":"Effects of temperature, atmosphere and pH on the generation of smoke compounds during tobacco pyrolysis","volume":"42","author":"Torikai","year":"2004","journal-title":"Food Chem Toxicol"},{"key":"2026072301020950000_ref23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.chroma.2017.07.079","article-title":"An isotope dilution ultra high performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of sugars and humectants in tobacco products","volume":"1514","author":"Wang","year":"2017","journal-title":"J Chromatogr A"},{"key":"2026072301020950000_ref24","volume-title":"Tobacco and Tobacco Products \u2014 Atmosphere for Conditioning and Testing","author":"ISO 3402","year":"2023"},{"key":"2026072301020950000_ref25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2155-9872.1000219","article-title":"Simple determination of sugars in cigarettes","volume":"5","author":"Jansen","year":"2014","journal-title":"Journal of Analytical & Bioanalytical Techniques"},{"key":"2026072301020950000_ref26","volume-title":"Tobacco and Tobacco Products \u2014 Draw Resistance of Cigarettes and Pressure Drop of Filter Rods \u2014 Standard Conditions and Measurement","author":"ISO 6565:2015","year":"2015"},{"key":"2026072301020950000_ref27","volume-title":"Cigarettes \u2014 Determination of Ventilation \u2014 Definitions and Measurement Principles","author":"ISO 9512:2019","year":"2019"},{"key":"2026072301020950000_ref28","volume-title":"Routine Analytical Cigarette-Smoking Machine\u2014Definitions and Standard Conditions","author":"ISO4387:2000","year":"2000"},{"key":"2026072301020950000_ref29","volume-title":"Routine Analytical Cigarette-Smoking Machine \u2014 Definitions and Standard Conditions","author":"ISO 3308:2012","year":"2012"},{"key":"2026072301020950000_ref30","article-title":"TobLabNet SOP 1 - standard operating procedure for intense smoking of cigarettes","author":"Organization WH","year":"2012"},{"key":"2026072301020950000_ref31","article-title":"TobLabNet SOP 9 - standard operating procedure for determination of volatile organics in mainstream cigarette smoke under ISO and intense smoking conditions","author":"Organization WH","year":"2018"},{"key":"2026072301020950000_ref32"},{"key":"2026072301020950000_ref33","article-title":"TobLabNet SOP 8 - standard operating procedure for determination of aldehydes in mainstream cigarette smoke under ISO and intense smoking conditions","author":"Organization WH","year":"2018"},{"key":"2026072301020950000_ref34","volume-title":"Application Note 5991-2125EN: Carbonyl-DNPH Derivatives in Indoor and In-Car Air by UHPLC and Triple Quadrupole LC\/MS","author":"Fu","year":"2018"},{"key":"2026072301020950000_ref35","volume-title":"TobLabNet SOP 5 - Standard Operating Procedure for Determination of Benzo[a]Pyrene in Mainstream Cigarette Smoke under ISO and Intense Smoking Conditions","author":"Organization WH","year":"2015"},{"key":"2026072301020950000_ref36","volume-title":"TobLabNet SOP 3 - Standard Operating Procedure for Determination of Tobacco-Specific Nitrosamines in Mainstream Cigarette Smoke under ISO and Intense Smoking Conditions","author":"Organization WH","year":"2014"},{"key":"2026072301020950000_ref37","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1021\/acs.chemrestox.4c00550","article-title":"Sugars in tobacco products: toxicity Research and implications for tobacco product regulation","volume":"38","author":"Stepanov","year":"2025","journal-title":"Chem Res Toxicol"},{"key":"2026072301020950000_ref38","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/cssc.201902887","article-title":"Thermal cracking of sugars for the production of glycolaldehyde and other small oxygenates","volume":"13","author":"Schandel","year":"2020","journal-title":"ChemSusChem."},{"key":"2026072301020950000_ref39","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3390\/ijerph8020613","article-title":"Hazardous compounds in tobacco smoke","volume":"8","author":"Talhout","year":"2011","journal-title":"Int J Environ Res Public Health"},{"key":"2026072301020950000_ref40","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.fct.2004.03.014","article-title":"Subacute (28-day) toxicity of furfural in Fischer 344 rats: a comparison of the oral and inhalation route","volume":"42","author":"Arts","year":"2004","journal-title":"Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association"},{"key":"2026072301020950000_ref41","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/jat.2550110508","article-title":"Inhalation toxicity of furfural vapours: an assessment of biochemical response in rat lungs","volume":"11","author":"Gupta","year":"1991","journal-title":"J Appl Toxicol"},{"key":"2026072301020950000_ref42","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1007\/BF01701132","article-title":"Pathological and biochemical alterations induced by inhalation of furfural vapor in rat lung","volume":"47","author":"Mishra","year":"1991","journal-title":"Bull Environ Contam Toxicol"},{"key":"2026072301020950000_ref43","volume-title":"Acute Exposure Guideline Levels for Selected Airborne Chemicals","author":"National Research Council","year":"2008"},{"key":"2026072301020950000_ref44","volume-title":"Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels","author":"National Research Council","year":"2010"},{"key":"2026072301020950000_ref45","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/0192623313482526","article-title":"A 28-day gavage toxicity study in male Fischer 344 rats with 2-methylfuran","volume":"42","author":"Gill","year":"2014","journal-title":"Toxicol Pathol"},{"key":"2026072301020950000_ref46","doi-asserted-by":"crossref","first-page":"113365","DOI":"10.1016\/j.fct.2022.113365","article-title":"Toxicity, genotoxicity, and carcinogenicity of 2-methylfuran in a 90-day comprehensive toxicity study in gpt delta rats","volume":"168","author":"Kuroda","year":"2022","journal-title":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association."},{"key":"2026072301020950000_ref47","article-title":"Flavor-Base 10 - tobacco version 2015","author":"Leffingwel & Associates"}],"container-title":["Nicotine &amp; Tobacco Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ntr\/advance-article-pdf\/doi\/10.1093\/ntr\/ntag053\/67389368\/ntag053.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ntr\/article-pdf\/28\/8\/1402\/67389368\/ntag053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ntr\/article-pdf\/28\/8\/1402\/67389368\/ntag053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:02:19Z","timestamp":1784782939000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ntr\/article\/28\/8\/1402\/8527521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,3,18]]},"published-print":{"date-parts":[[2026,7,22]]}},"URL":"https:\/\/doi.org\/10.1093\/ntr\/ntag053","relation":{},"ISSN":["1469-994X"],"issn-type":[{"value":"1469-994X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,3,18]]}}}