Abstract
Polycyclic aromatic hydrocarbons (PAHs) occur naturally (bitumen and oils) and are formed during all incomplete combustions of organic materials. PAH exposure sources are manifold and include specific workplaces, ambient air, various foodstuffs, tobacco smoke and some medications. At least four members of this class of chemicals have been classified as proven or probable human carcinogens. Assessment of the exposure to PAHs with suitable methods is of importance, particularly in users of new-generation tobacco/nicotine products, which are intended to replace combustible cigarettes (CCs), a major source of non-occupational exposure to PAHs. In a clinical study comprising a period of 74 h under confinement, we investigated the exposure to naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), pyrene (Pyr) and benzo[a]pyrene (BaP) by measuring urinary monohydroxy-PAH (OH-PAH) derived from these parent compounds in habitual users of CCs, electronic cigarettes (ECs), heated tobacco products (HTPs), oral tobacco (OT), and nicotine replacement therapy products (NRTs). Non-users (NU) of any tobacco/nicotine products served as (negative) control group. Smokers exhibited the highest levels for all PAH biomarkers measured, almost all of which were significantly different from the NU and user groups of all other products investigated. CC smokers were the only group which showed a significant relationship between almost all PAH biomarkers and dose markers such as daily consumption, urinary nicotine equivalents (Nequ) and plasma cotinine (CotP). The ratios in urinary OH-PAH between CC and all other groups were dependent on the biomarker and range from < 2 to > 10. These ratios could at least partly be explained by the enzymes involved, their region-selectivity and inducibility by smoking. In conclusion, cigarette smokers (CC) were the only group, which showed product use dependent exposure to PAHs, whereas users of EC, HTP, NRT and OT were not distinguishable from NU of any tobacco/nicotine products.
Similar content being viewed by others
References
Auer R, Concha-Lozano N, Jacot-Sadowski I, Cornuz J, Berthet A (2017) Heat-not-burn tobacco cigarettes: smoke by any other name. JAMA Intern Med 177(7):1050–1052. https://doi.org/10.1001/jamainternmed.2017.1419
Benowitz NL, Peng M, Jacob P III (2003) Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharmacol Ther 74(5):468–474. https://doi.org/10.1016/j.clpt.2003.07.001
Bosilkovska M, Tran CT, de La Bourdonnaye G, Taranu B, Benzimra M, Haziza C (2020) Exposure to harmful and potentially harmful constituents decreased in smokers switching to carbon-heated tobacco product. Toxicol Lett 330:30–40. https://doi.org/10.1016/j.toxlet.2020.04.013
Buckley TJ, Waldman JM, Dhara R, Greenberg A, Ouyang Z, Lioy PJ (1995) An assessment of a urinary biomarker for total human environmental exposure to benzo[a]pyrene. Int Arch Occup Environ Heath 67:257–266. https://doi.org/10.1007/BF00409408
Buckpitt A, Boland B, Isbell M, Morin D, Shultz M, Baldwin R, Chan K, Karlsson A, Lin C, Taff A (2002) Naphthalene-induced respiratory tract toxicity: metabolic mechanisms of toxicity. Drug Metab Rev 34(4):791–820. https://doi.org/10.1081/DMR-120015694
Centers for Disease Control and Prevention (CDC) (2019) Fourth National report on human exposure to environmental chemicals, Updated Tables, January 2019. 2019 (August 8th). https://www.cdc.gov/exposurereport/index.html . Accessed 30 July 2022
Dai H, Benowitz NL, Achutan C, Farazi PA, Degarege A, Khan AS (2022) Exposure to toxicants associated with use and transitions between cigarettes, e-cigarettes, and no tobacco. JAMA Netw Open 5(2):e2147891. https://doi.org/10.1001/jamanetworkopen.2021.47891
dell’Omo M, Lauwerys RR (1993) Adducts to macromolecules in the biological monitoring of workers exposed to polycyclic aromatic hydrocarbons. Crit Rev Toxicol 23:111–126. https://doi.org/10.3109/10408449309117113
Farsalinos KE, Voudris V, Poulas K (2015) E-cigarettes generate high levels of aldehydes only in ‘dry puff’ conditions. Addiction 110(8):1352–1356. https://doi.org/10.1111/add.12942
Farsalinos KE, Voudris V, Spyrou A, Poulas K (2017) E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: a replication study under verified realistic use conditions. Food Chem Toxicol 109(Pt 1):90–94. https://doi.org/10.1016/j.fct.2017.08.044
Food and Drug Administration (FDA) (2018) bioanalytical method validation—guidance for industry, https://www.fda.gov/regulatory-information/search-fdaguidance-documents/bioanalytical-method-validation-guidance-industry. Accessed 30 July 2022
Gao P, da Silva E, Hou L, Denslow ND, Xiang P, Ma LQ (2018) Human exposure to polycyclic aromatic hydrocarbons: metabolomics perspective. Environ Int 119:466–477. https://doi.org/10.1016/j.envint.2018.07.017
Goniewicz ML, Gawron M, Smith DM, Peng M, Jacob P 3rd, Benowitz NL (2017) Exposure to nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a longitudinal within-subjects observational study. Nicotine Tob Res 19:160–167. https://doi.org/10.1093/ntr/ntw160
Goniewicz ML, Smith DM, Edwards KC, Blount BC, Caldwell KL, Feng J, Wang L, Christensen C, Ambrose B, Borek N, van Bemmel D, Konkel K, Erives G, Stanton CA, Lambert E, Kimmel HL, Hatsukami D, Hecht SS, Niaura RS, Travers M, Lawrence C, Hyland AJ (2018) Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA Netw Open 1(8):e185937. https://doi.org/10.1001/jamanetworkopen.2018.5937
Hagedorn HW, Scherer G, Engl J, Riedel K, Cheung F, Errington G, Shepperd J, McEwan M (2009) Urinary excretion of phenolic polycyclic aromatic hydrocarbons (OH-PAH) in nonsmokers and in smokers of cigarettes with different ISO tar yields. J Anal Toxicol 33(6):301–309. https://doi.org/10.1093/jat/33.6.301
Hattemer-Frey HA, Travis CC (1991) Benzo-a-pyrene: environmental partitioning and human exposure. Toxicol Ind Health 7:141–157. https://doi.org/10.1177/074823379100700303
Haziza C, de La Bourdonnaye G, Skiada D, Ancerewicz J, Baker G, Picavet P, Lüdicke F (2016) Evaluation of the tobacco heating system 2.2. Part 8: 5-day randomized reduced exposure clinical study in Poland. Regul Toxicol Pharmacol 81:S139–S150. https://doi.org/10.1016/j.yrtph.2016.11.003
Herrmann K (1964) Phenols in tobacco leaves and tobacco smoke / Über die phenolischen Inhaltsstoffe des Tabaks und des Tabakrauches. Beiträge Zur Tabakforschung 2(5):159–179. https://doi.org/10.2478/cttr-2013-0071
Heudorf U, Angerer J (2001) Urinary monohydroxylated phenanthrenes and hydroxypyrene—the effects of smoking habits and changes induced by smoking on monooxygenase-mediated metabolism. Int Arch Occup Environ Heath 74:177–183. https://doi.org/10.1007/s004200000215
International Agency for Research on Cancer (IARC) (1973) Certain polycyclic aromatic hydrocarbons and heterocyclic compounds, vol 3. IARC Press, Lyon, France
International Agency for Research on Cancer (IARC) (2002) IARC monographs on the evaluation of carcinogenic risks to humans: some traditional herbal medicines, some mycotoxins, naphthalene and styrene, vol 82. IARC Press, Lyon, France
International Agency for Research on Cancer (IARC) (2004) Tobacco smoke and involuntary smoking, vol 83. IARC Press, Lyon, France
International Agency for Research of Cancer (IARC) (2010) Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures, vol 92. IARC Press, Lyon, France
Jacob J, Grimmer G, Dettbarn G (1999) Profile of urinary phenanthrene metabolites in smokers and non-smokers. Biomarkers 4:319–327. https://doi.org/10.1080/135475099230705
Jacob J, Raab G, Soballa V, Schmalix WA, Grimmer G, Greim H, Doehmer J, Seidel A (1996) Cytochrome P450-mediated activation of phenanthrene in genetically engineered V79 Chinese hamster cells. Environ Toxicol Pharmacol 1:1–11. https://doi.org/10.1016/1382-6689(95)00003-8
Jacob J, Seidel A (2002) Biomonitoring of polycyclic aromatic hydrocarbons in human urine. J Chromatogr B 778(1–2):31–47. https://doi.org/10.1016/S0378-4347(01)00467-4
Jacob P III, Wilson M, Benowitz NL (2007) Determination of phenolic metabolites of polycyclic aromatic hydrocarbons in human urine as their pentafluorobenzyl ether derivatives using liquid chromatography-tandem mass spectrometry. Anal Chem 79(2):587–598. https://doi.org/10.1021/ac060920l
Jerina DM, Daly JW, Witkop B, Zaltzman-Nirenberg P, Udenfriend S (1970) 1, 2-Naphthalene oxide as an intermediate in the microsomal hydroxylation of naphthalene. Biochemistry 9(1):147–156. https://doi.org/10.1021/bi00803a019
Jongeneelen FJ, Bos RP, Anzion RBM, Theuws JLG, Henderson PT (1986) Biological monitoring of polycyclic aromatic hydrocarbons. Metabolites in urine. Scand J Work Environ Health 12:137–143
Klotz K, Zobel M, Schäferhenrich A, Hebisch R, Drexler H, Göen T (2018) Suitability of several naphthalene metabolites for their application in biomonitoring studies. Toxicol Lett 298:91–98. https://doi.org/10.1016/j.toxlet.2018.07.008
Lafontaine M, Champmartin C, Simon P, Delsaut P, Funck-Brentano C (2006) 3-Hydroxybenzo[a]pyrene in urine of smokers and non-smokers. Toxicol Lett 162:181–185. https://doi.org/10.1016/j.toxlet.2005.09.019
Lafontaine M, Gendre C, Delsaut P, Simon P (2004) Urinary 3-hydroxybenzo [a] pyrene as a biomarker of exposure to polycyclic aromatic hydrocarbons: an approach for determining a biological limit value. Polycyclic Aromat Compd 24(4–5):441–450. https://doi.org/10.1080/10406630490471447
Li Z, Romanoff L, Bartell S, Pittman EN, Trinidad DA, McClean M, Webster TF, Sjödin A (2012) Excretion profiles and half-lives of ten urinary polycyclic aromatic hydrocarbon metabolites after dietary exposure. Chem Res Toxicol 25(7):1452–1461. https://doi.org/10.1021/tx300108e
Lu D, Harvey RG, Blair IA, Penning TM (2011) Quantitation of benzo[a]pyrene metabolic profiles in human bronchoalveolar (H358) cells by stable isotope dilution liquid chromatography-atmospheric pressure chemical ionization mass spectrometry. Chem Res Toxicol 24(11):1905–1914. https://doi.org/10.1021/tx2002614
Meeker JD, Barr DB, Serdar B, Rappaport SM, Hauser R (2007) Utility of urinary 1-naphthol and 2-naphthol levels to assess environmental carbaryl and naphthalene exposure in an epidemiology study. J Expo Sci Environ Epidemiol 17(4):314–320. https://doi.org/10.1038/sj.jes.7500502
Mirzababaei A, Daneshzad E, Moradi S, Abaj F, Mehranfar S, Asbaghi O, Clark CCT, Mirzaei K (2021) The association between urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) and cardiovascular diseases and blood pressure: a systematic review and meta-analysis of observational studies. Environ Sci Pollut Res Int. https://doi.org/10.1007/s11356-021-17091-4
Nan H-M, Kim H, Lim H-S, Choi JK, Kawamoto T, Kang J-W, Lee C-H, Kim Y-D, Kwon EH (2001) Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations. Carcinogenesis 22(5):787–793. https://doi.org/10.1093/carcin/22.5.787
Pelkonen O, Nebert DW (1982) Metabolism of polycyclic aromatic hydrocarbons: etiologic role in carcinogenesis. Pharmacol Rev 34:189–222
Phillips DH (1999) Polycyclic aromatic hydrocarbons in the diet. Mutat Res 443:139–147. https://doi.org/10.1016/S1383-5742(99)00016-2
Preuss R, Drexler H, Böttcher M, Wilhelm M, Brüning T, Angerer J (2005) Current external and internal exposure to naphthalene of workers occupationally exposed to polycyclic aromatic hydrocarbons in different industries. Int Arch Occup Environ Heath 78(5):355–362. https://doi.org/10.1007/s00420-004-0593-3
Preuss R, Koch HM, Wilhelm M, Pischetsrieder M, Angerer J (2004) Pilot study on the naphthalene exposure of German adults and children by means of urinary 1- and 2-naphthol levels. Int J Hyg Environ Health 207(5):441–445. https://doi.org/10.1078/1438-4639-00313
Ramsauer B, Sterz K, Hagedorn HW, Engl J, Scherer G, McEwan M, Errington G, Shepperd J, Cheung F (2011) A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of phenolic polycyclic aromatic hydrocarbons (OH-PAH) in urine of non-smokers and smokers. Anal Bioanal Chem 399(2):877–889. https://doi.org/10.1007/s00216-010-4355-7
Rodgman A (2001) Studies of polycyclic aromatic hydrocarbons in cigarette mainstream smoke: identification, tobacco precursors, control of levels: a review. Beitraege Zur Tabakforschung International 19(7):361–379. https://doi.org/10.2478/cttr-2013-0724
Rodgman A, Cook LC (2009) The composition of cigarette smoke an historical perspective of several polycyclic aromatic hydrocarbons. Beitraege Zur Tabakforschung International 23(6):384–410. https://doi.org/10.2478/cttr-2013-0873
Rögner N, Hagedorn H-W, Scherer G, Scherer M, Pluym N (2021) A sensitive LC–MS/MS method for the quantification of 3-Hydroxybenzo[a]pyrene in urine-exposure assessment in smokers and users of potentially reduced-risk products. Separations 8(10):171. https://doi.org/10.3390/separations8100171
Rossbach B, Wollschläger D, Letzel S, Gottschalk W, Muttray A (2020) Internal exposure of firefighting instructors to polycyclic aromatic hydrocarbons (PAH) during live fire training. Toxicol Lett. https://doi.org/10.1016/j.toxlet.2020.05.024
Sarkar M, Liu J, Koval T, Wang J, Feng S, Serafin R, Jin Y, Xie Y, Newland K, Roethig HJ (2010) Evaluation of biomarkers of exposure in adult cigarette smokers using Marlboro Snus. Nicotine Tob Res 12(2):105–116. https://doi.org/10.1093/ntr/ntp183
Scherer G, Engl J, Urban M, Gilch G, Janket D, Riedel K (2007) Relationship between machine-derived smoke yields and biomarkers in cigarette smokers in Germany. Regul Toxicol Pharmacol 47(2):171–183. https://doi.org/10.1016/j.yrtph.2006.09.001
Scherer G, Frank S, Riedel K, Meger-Kossien I, Renner T (2000) Biomonitoring of exposure to polycyclic aromatic hydrocarbons of nonoccupationally exposed persons. Cancer Epidemiol Biomark Prev 9:373–380
Scherer G, Mutze J, Pluym N, Scherer M (2022a) Assessment of nicotine delivery and uptake in users of various tobacco/nicotine products. Curr Res Toxicol 3:100067. https://doi.org/10.1016/j.crtox.2022.100067
Scherer G, Pluym N, Scherer M (2021) Intake and uptake of chemicals upon use of various tobacco/nicotine products: can users be differentiated by single or combinations of biomarkers? Contrib Tob Nicotine Res 30(4):167–198. https://doi.org/10.2478/cttr-2021-0014
Scherer G, Scherer M, Mutze J, Hauke T, Pluym N (2022b) Assessment of the exposure to tobacco-specific nitrosamines and minor tobacco alkaloids in users of various tobacco/nicotine products. Chem Res Toxicol 35(4):684–693. https://doi.org/10.1021/acs.chemrestox.2c00020
Schober W, Pusch G, Oeder S, Reindl H, Behrendt H, Buters JT (2010) Metabolic activation of phenanthrene by human and mouse cytochromes P450 and pharmacokinetics in CYP1A2 knockout mice. Chem Biol Interact 183(1):57–66. https://doi.org/10.1016/j.cbi.2009.09.008
Sibul F, Burkhardt T, Kachhadia A, Pilz F, Scherer G, Scherer M, Pluym N (2021) Identification of biomarkers specific to five different nicotine product user groups: study protocol of a controlled clinical trial. Contemp Clin Trials Commun 22:100794. https://doi.org/10.1016/j.conctc.2021.100794
Stabbert R, Voncken P, Rustemeier K, Haussmann HJ, Roemer E, Schaffernicht H, Patskan G (2003) Toxicological evaluation of an electrically heated cigarette. Part 2: chemical composition of mainstream smoke. J Appl Toxicol 23(5):329–339. https://doi.org/10.1002/jat.924
Starski A, Kukielska A, Postupolski J (2021) Occurrence of polycyclic aromatic hydrocarbons in human diet exposure and risk assessment to consumer health. Rocz Panstw Zakl Hig 72(3):253–265. https://doi.org/10.32394/rpzh.2021.0178
Strickland P, Kang D, Sithisarankul P (1996) Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environ Health Perspect 104(Suppl 5):927–932. https://doi.org/10.1289/ehp.96104s5927
Theophilus EH, Coggins CRE, Chen P, Schmidt E, Borgerding MF (2015) Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: a one-week clinical confinement study. Regul Toxicol Pharmacol 71(2):225–234. https://doi.org/10.1016/j.yrtph.2014.12.023
US Department of Health and Human Services (2010) How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease. A report of the surgeon general. National Library of Medicine Cataloging in Publication, Rockville, MD, USA
Van Rooij JGM, Veeger MMS, Bodelier-Bade MM, Scheepers PTJ, Jongeneelen FJ (1994) Smoking and dietary intake of polycyclic aromatic hydrocarbons as sources of interindividual variability in the baseline excretion of 1-hydroxypyrene in urine. Int Arch Occup Environ Heath 66:55–65. https://doi.org/10.1007/BF00386580
Vondráček J, Machala M (2020) The role of metabolism in toxicity of polycyclic aromatic hydrocarbons and their non-genotoxic modes of action. Curr Drug Metab. https://doi.org/10.2174/1389200221999201125205725
Waldman JM, Lioy PJ, Greenberg A, Butler JP (1991) Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the total human environmental exposure study (THEES). J Expo Anal Environ Epidemiol 1:193–225
Wang Y, Wong LY, Meng L, Pittman EN, Trinidad DA, Hubbard KL, Etheredge A, Del Valle-Pinero AY, Zamoiski R, van Bemmel DM, Borek N, Patel V, Kimmel HL, Conway KP, Lawrence C, Edwards KC, Hyland A, Goniewicz ML, Hatsukami D, Hecht SS, Calafat AM (2019) Urinary concentrations of monohydroxylated polycyclic aromatic hydrocarbons in adults from the U.S. Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013–2014). Environ Int 123:201–208. https://doi.org/10.1016/j.envint.2018.11.068
Wilhelm M, Hardt J, Schulz C, Angerer J, Agency HBCotGFE (2008) New reference value and the background exposure for the PAH metabolites 1-hydroxypyrene and 1-and 2-naphthol in urine of the general population in Germany: basis for validation of human biomonitoring data in environmental medicine. Int J Hyg Environ Health 211(3–4):447–453. https://doi.org/10.1016/j.ijheh.2007.09.002
Wilson AS, Davis CD, Williams DP, Buckpitt AR, Pirmohamed M, Park BK (1996) Characterisation of the toxic metabolite (s) of naphthalene. Toxicology 114(3):233–242. https://doi.org/10.1016/S0300-483X(96)03515-9
Yang M, Koga M, Katoh T, Kawamoto T (1999) A study for the proper application of urinary naphthols, new biomarkers for airborne polycyclic aromatic hydrocarbons. Arch Environ Contam Toxicol 36(1):99–108. https://doi.org/10.1007/s002449900447
Zevin S, Benowitz NL (1999) Drug interactions with tobacco smoking. Clin Pharmacokinet 36(6):425–438. https://doi.org/10.2165/00003088-199936060-00004
Acknowledgements
The authors would like to thank Filip Sibul for helping organize and monitor the conductance of the clinical study. We thank Janina Mütze and Michael Sprenzel for conducting the analyses for OH-PAHs and Nequ in urine as well as cotinine in plasma.
Funding
This study was funded with a grant from the Foundation for a Smoke-Free World (FSFW) (Grant number: 2018/03), a US nonprofit 501(c) (3) private foundation. FSFW had no role in the planning and execution of this study, data analysis and publication of the results. The Foundation accepts charitable gifts from PMI Global Services Inc. (PMI); under the Foundation’s Bylaws and Pledge Agreement with PMI, the Foundation is independent from PMI and the tobacco industry.
Author information
Authors and Affiliations
Contributions
Conceptualization, MS, GS and NP; formal analysis, NR; writing—original draft preparation, GS; writing—review and editing, NP, MS; supervision, MS, NP; project administration, MS; funding acquisition, MS and NP. All authors have read and agreed to the published version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Scherer, G., Scherer, M., Rögner, N. et al. Assessment of the exposure to polycyclic aromatic hydrocarbons in users of various tobacco/nicotine products by suitable urinary biomarkers. Arch Toxicol 96, 3113–3126 (2022). https://doi.org/10.1007/s00204-022-03349-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03349-4