Assessing modified risk tobacco and nicotine products: Description of the scientific framework and assessment of a closed modular electronic cigarette

Regulatory Toxicology and Pharmacology

Volumn 90, Issue , 2017, Pages 342-357

  Murphy, James ^a   Gaca, Marianna ^a   Lowe, Frazer ^a   Minet, Emmanuel ^a   Breheny, Damien ^a   Prasad, Krishna ^a   Camacho, Oscar ^a   Fearon, Ian M ^a   Liu, Chuan ^a   Wright, Christopher ^a   McAdam, Kevin ^a   Proctor, Christopher ^a  

^a BRITISH AMERICAN TOBACCO   (United Kingdom)

Author keywords

Assessment framework; Modified Risk Tobacco Products; Public health; Risk reduction; Tobacco harm reduction

Indexed keywords

GLUTATHIONE; NICOTINE; REACTIVE OXYGEN METABOLITE; NICOTINE GUM;

ARTICLE; CARDIOVASCULAR DISEASE; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL STUDY; CLOSED MODULAR ELECTRONIC CIGARETTE; CONCEPTUAL FRAMEWORK; ELECTRONIC CIGARETTE; FOOD AND DRUG ADMINISTRATION; GOVERNMENT REGULATION; HEALTH INSURANCE; HUMAN; LUNG CANCER; NONHUMAN; POPULATION RESEARCH; POSTMARKETING SURVEILLANCE; PRECLINICAL STUDY; PRIORITY JOURNAL; PUBLIC HEALTH SERVICE; RISK ASSESSMENT; RISK REDUCTION; TOBACCO; UNITED KINGDOM; UNITED STATES; AEROSOL; CHEMISTRY; EVALUATION STUDY; HARM REDUCTION; PRACTICE GUIDELINE; PROCEDURES; PUBLIC HEALTH; SMOKING; SMOKING PREVENTION; STANDARDS; TOXICITY;

AEROSOLS; ELECTRONIC NICOTINE DELIVERY SYSTEMS; GUIDELINES AS TOPIC; HARM REDUCTION; HUMANS; NICOTINE; PUBLIC HEALTH; RISK ASSESSMENT; SMOKING; SMOKING PREVENTION; TOBACCO; TOBACCO PRODUCTS; TOBACCO USE CESSATION PRODUCTS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 85029816061     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2017.09.008     Document Type: Article

References (122)

1. US Department of Health Human Services, The Health Consequences of Smoking 50 Years of Progress: a Report of the Surgeon General., 2014, US Department of Health & Human Services, Centres for Disease Control and Prevention; National centre for Chronic Disease Prevention and health promotion, office on smoking and health, Atlanta, GA.
2. Adamson, J., Thorne, D., Zainuddin, B., Baxter, A., McAughey, J., Gaça, M., Application of dosimetry tools for the assessment of e-cigarette aerosol and cigarette smoke generated on two different in vitro exposure systems. Chem. Cent. J., 10, 2016, 74.
3. AFNOR, AFNOR publishes the world's first voluntary standards for electronic cigarettes and e-liquids. 2015 http://www.afnor.org/en/news/2015/avril-2015/afnor-publishes-the-world's-first-voluntary-standards-for-electronic-cigarettes-and-e-liquids. (Accessed 20 February 2017)
4. Alderman, S.L., Song, C., Moldoveanu, S.C., Cole, S.K., Particle size distribution of e-cigarette aerosols and the relationship to Cambridge filter pad collection efficiency. Beiträge zur Tab. Int., 26, 2014, 4.
5. Ankley, G.T., Bennett, R.S., Erickson, R.J., Hoff, D.J., Hornung, M.W., Johnson, R.D., Mount, D.R., Nichols, J.W., Russom, C.L., Schmieder, P.K., Serrrano, J.A., Tietge, J.E., Villeneuve, D.L., Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem. 29 (2010), 730–741.
6. Azzopardi, D., Patel, K., Jaunky, T., Santopietro, S., Camacho, O.M., McAughey, J., Gaҫa, M., Electronic cigarette aerosol induces significantly less cytotoxicity than tobacco smoke. Toxicol. Mech. Methods 26 (2016), 477–491.
7. Banerjee, A., Waters, D., Camacho, O.M., Minet, E., Quantification of plasma microRNAs in a group of healthy smokers, ex-smokers and non-smokers and correlation to biomarkers of tobacco exposure. Biomarkers 20:2 (2015), 123–131.
8. Banerjee, A., Haswell, L.E., Baxter, A., Parmar, A., Azzopardi, D., Corke, S., Thorne, D., Adamson, J., Mushonganono, J., Gaca, M.D., Minet, E.F., Differential gene expression using RNA-seq profiling in a reconstituted airway epithelium exposed to conventional cigarette smoke or electronic cigarette aerosols. Appl Vitro Toxicol 3:1 (2017), 84–98.
9. Bates, C., Presentation at the E-cigarette Summit. 2013.
10. Baxter, A., Thain, S., Banerjee, A., Haswell, L.E., Parmar, A., Phillips, G., Minet, E.F., Targeted omics analyses, and metabolic enzyme activity assays demonstrate maintenance of key mucociliary characteristics in long term cultures of reconstituted human airway epithelia. Toxicol Vitro 29 (2015), 864–875.
11. Berghmans, T., Ameye, L., Willems, L., Paesmans, M., Mascaux, C., Lafitte, J.J., Meert, A.P., Scherpereel, A., Cortot, A.B., CsToth, I., Dernies, T., Toussaint, L., Leclercq, N., Sculier, J.P., For the european lung cancer working party. Identification of microRNA-based signatures for response and survival for non-small cell lung cancer treated with cisplatin-vinorelbine A ELCWP prospective study. Lung Cancer 82:2 (2013), 340–345.
12. Berman, M.L., Connolly, G., Cummings, M.K., Djordjevic, M.V., Hatsukami, D.K., Henningfield, J.E., Myers, M., O'Connor, R.J., Parascandola, M., Rees, V., Rice, J.M., Shields, P.G., Providing a science base for the evaluation of tobacco products. Tob. Regul. Sci. 1 (2015), 76–93.
13. Breheny, D., Oke, O., Pant, K., Gaça, M., The comparative tumour promotion assessment of e-cigarette and cigarettes using the in vitro Bhas 42 cell transformation assay. Environ. Mol. Mutagen. 58:4 (2017), 190–198.
14. BSI, PAS 54115 Vaping products, including electronic cigarettes, formulations, e-shisha and directly-related products – Manufacture, importation, testing and labelling – Guide. 2015 http://www.bsigroup.com/en-GB/about-bsi/media-centre/press-releases/2015/july/E-cigarettes-guidance-published/. (Accessed 20 February 2017)
15. Burns, D.M., Dybing, E., Gray, N., Hecht, S., Anderson, C., Sanner, T., O'Connor, R., Djordjevic, M., Dresler, C., Hainaut, P., Jarvis, M., Opperhuizen, A., Straif, K., Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob. Control 17 (2008), 132–141, 10.1136/tc.2007.024158.
16. Campbell, J., Van Landingham, C., Crowell, S., Gentry, R., Kaden, D., Fiebelkorn, S., Loccisano, A., Clewell, H., A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites. Chemico-Biological Interact. 238:1 (2015), 102–110.
17. Cancer Research UK, Cancer mortality by age. http://www.cancerresearchuk.org/cancer-info/cancerstats/mortality/cancerdeaths/, 2014. (Accessed 20 February 2017)
18. Cancer Research UK, E-cigarettes Safer than Smoking Says Long-term Study. 2017 (online) Available at: http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2017-02-06-e-cigarettes-safer-than-smoking-says-long-term-study. (Accessed 20 February 2017)
19. Carter, L.P., Stitzer, M.L., Henningfield, J.E., O'Connor, R.J., Cummings, K.M., Hatsukami, D.K., Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol. Biomarkers Prev. 18 (2009), 3241–3262.
20. Combes, R., Scott, K., Crooks, I., Dillon, D., Meredith, C., McAdam, K.G., Proctor, C., The in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter with reduced toxicant yields. Toxicol Vitro 27 (2013), 1533–1541.
21. CORESTA, Routine Analytical Machine for E-Cigarette Aerosol Generation and Collection – Definitions and Standard Conditions. 2015 https://www.coresta.org/sites/default/files/technical_documents/main/CRM_81.pdf. (Accessed 20 February 2017)
22. Costigan, S., Meredith, C., An approach to ingredient screening and toxicological risk assessment of flavours in formulations. Regul. Toxicol. Pharmacol. 72:2 (2015), 361–369.
23. Cravo, A.S., Bush, J., Sharma, R., Martin, C., Craige, S., Walele, T., A randomised, parallel group study to evaluate the safety profile of an electronic vapour product over 12 weeks. Regul. Toxicol. Pharmacol. 81:Suppl. 1 (2016), S1–S14.
24. Crooks, I., Scott, K., Dalrymple, A., Dillon, D., Meredith, C., The combination of two novel tobacco blends and filter technologies to reduce the in vitro genotoxicity and cytotoxicity of prototype cigarettes. Regul. Toxicol. Pharmacol. 71 (2015), 507–514.
25. Cunningham, F.H., Fiebelkorn, S., Johnson, M., Meredith, C., A novel application of the margin of exposure approach: segregation of tobacco smoke toxicants. Food Chem. Toxicol. 49 (2011), 2921–2933.
26. Cunningham, F., Fiebelkorn, S., Dillon, D., Meredith, C., Tools for the prioritisation of tobacco smoke toxicants: an overview. Rec. Adv. Tob. Sci. 38 (2012), 21–31.
27. Cunningham, A., Slayford, S.J., Vas, C., Gee, J., Costigan, S., Prasad, K., Development, validation and application of a device to measure e-cigarette users’ puffing topography. Sci. Rep., 6, 2016, 35071.
28. D'Ruiz, C.D., Graff, D.W., Robinson, E., Reductions in biomarkers of exposure, impacts on smoking urge and assessment of product use and tolerability in adult smokers following partial or complete substitution of cigarettes with electronic cigarettes. BMC Public Health, 16, 2016, 543, 10.1186/s12889-016-3236-1.
29. Dautzenberg, B., Bricard, D., Real-time characterisation of e-cigarette use: the one million puffs study. J. Addict. Res. Ther., 6, 2015, 229.
30. Dittrich, D.J., Fiebledorn, R.T., Bevan, M.J., Rushforth, D., Murphy, J.J., Ashley, M., McAdam, K.G., Liu, C., Proctor, C.J., Approaches for the Design of Reduced Toxicant Emission Cigarettes, vol. 3, 2014, Springer Plus, 374.
31. European Food Safety Authority (EFSA), EFSA/WHO International Conference with Support of ILSI Europe on Risk Assessment of Compounds that Are Both Genotoxic and Carcinogenic. 2006.
32. European Medicines Agency, Guideline on Similar Biological Medicinal Products. 2014 Committee for Medicinal Products for Human Use (CHMP)/437/04 Rev 1.
33. European Medicines Agency, Guideline on the Qualification and Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation EMA/CHMP/458101/2016. 2016.
34. European Parliament and the Council of the European Union Tobacco Products Directive., (2014). 2014/40/EU. http://ec.europa.eu/health/tobacco/docs/dir_201440_en.pdf. (Accessed 20 February 2017).
35. European Pharmacopeia., (2016). https://www.edqm.eu/sites/default/files/index9-1_e.pdf (Accessed 20 February 2017).
36. Farmen, R.H., Newland, K.E., Nachi, R., Kafonek, C.J., Islam, R., The analysis of isotopically labelled propylene glycol in e-cigarettes. 2014, Coresta congress ST72 https://www.coresta.org/sites/default/files/abstracts/2014_ST72_Farmen.pdf. (Accessed 20 February 2017)
37. th Meeting, 2014 https://celerion.com/wordpress/wp-content/uploads/2015/01/Celerion_2014-TSRC_Propylene-Glycol.pdf. (Accessed 20 February 2017)
38. Farsalinos, K.E., Polosa, R., Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review. Ther. Adv. Drug Saf. 5:2 (2014), 67–86.
39. Farsalinos, K.E., Spyrou, A., Stefopoulos, C., Tsimopoulou, K., Kourkoveli, P., Tsiapras, D., Kyrzopoulos, S., Poulas, K., Voudris, V., Nicotine absorption from electronic cigarette use: comparison between experienced consumers (vapers) and naïve users (smokers). Sci. Rep., 5, 2015, 11269.
40. Fearon, I.M., Acheampong, D.O., Bishop, E., Modification of smoke toxicant yields alters the effects of cigarette smoke extracts on endothelial migration: an in vitro study using a cardiovascular disease model. Int. J. Toxicol. 31 (2012), 572–583.
41. Fearon, I.M., Eldridge, A., Gale, N., Shepperd, C.J., McEwan, M., Camacho, O.M., Nides, M., McAdam, K., Proctor, C., E-cigarette nicotine delivery: data and learnings from pharmacokinetic studies. Am. J. Health Behav. 41:1 (2016), 16–32.
42. Food and Drug Administration, Guidance for industry modified risk tobacco product applications. Draft Guid., 2012 http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM297751.pdf. (Accessed 20 February 2017)
43. Food and Drug Administration, DEPARTMENT of HEALTH and HUMAN SERVICES (2012). 77 FR 20034-Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke; Established List. Federal Register, vol 77, 2012 Issue 64 (April 3, 2012).
44. Food and Drug Administration, Deeming Tobacco Products to Be Subject to the Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products and Required Warning Statements for Tobacco Products. 2016 To be published in Federal Register 5 October 2016 http://federalregister.gov/a/2016-10685. (Accessed 20 February 2017)
45. Fowles, J., Dybing, E., Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob. Control 12 (2003), 424–430.
46. Garcia-Perez, I., Lindon, J.C., Minet, E.F., Application of CE–MS to a metabonomics study of human urine from cigarette smokers and non-smokers. Bioanalysis 6 (2014), 2733–2749.
47. Gilbert, HA., (1965). Smokeless non tobacco cigarette. Patent US3200819.
48. Goniewicz, M.L., Knysak, J., Gawron, M., Kosmider, L., Sobczak, A., Kurek, J., Prokopowicz, A., Jablonska-Czapla, M., Rosik-Dulewska, C., Havel, C., Jacob, P.I., Benowitz, N., Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob. Control 23 (2014), 133–139.
49. Goniewicz, M.L., Smith, D.M., Peng, M., Jacob, P. III, Benowitz, N.L., Exposure to nicotine and selected toxicants in cigarette smokers who switched to electronic cigarettes: a longitudinal within-subjects observational study. Nicotine Tob. Res. 19:2 (2017), 160–167.
50. Gregg, E., Williamson, J., Proctor C, ‘Reilly, D., A proposed framework for PREP assessment. Proceedings of the Annual Meeting of the Society for Research on Nicotine and Tobacco, 2008.
51. Gregg, E.O., Minet, E., McEwan, M., Urinary biomarkers of smokers’ exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach. Biomarkers 18:6 (2013), 467–486.
52. Hajek, P., Etter, J.F., Benowitz, N., Eissenberg, T., McRobbie, H., Electronic cigarettes: review of use, content safety, effects on smokers and potential for harm and benefit. Addiction 109 (2014), 1801–1810.
53. Han, S.G., Pant, K., Bruce, S.W., Gairola, C.G., An assay method for the prediction of tumor promoting potential of chemicals by the use of Bhas 42 cells. Mutat. Res. 557:2 (2004), 191–202.
54. Haswell, L.E., Thorne, D., Richter, A., Hewitt, K., Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: a potential model of goblet cell hyperplasia. Toxicol Vitro 24 (2010), 981–987.
55. Haswell, L.E., Papadopoulou, E., Newland, N., Shepperd, C.J., Lowe, F.J., A cross-sectional analysis of candidate biomarkers of biological effect in smokers, never-smokers and ex-smokers. Biomarkers 19:5 (2014), 356–367.
56. Haswell, L.E., Fields, W.R., Cortes, L., Croteau, P., McIntosh, L., Mohareb, F., Chelsky, D., Phillips, G., Gaça, M., Camacho, M., A Targeted Proteomic Comparison of Human Induced Sputum from Smokers and Non Smokers. 2016, Society of Toxicology Abstract #3041.
57. Haswell, L.E., Baxter, A., Banerjee, A., Verrastro, I., Mushonganono, J., Adamson, J., Thorne, D., Gaça, M., Minet, E., Reduced biological effect of e-cigarette aerosol compared to cigarette smoke evaluated in vitro using normalized nicotine dose and RNA-seq-based toxicogenomics. Sci. Rep., 7, 2017, 888.
58. Health Canada, Determination of “tar” nicotine and carbon monoxide in mainstream tobacco smoke. Health Can. Method T-115, 1999 http://edge.rit.edu/edge/P10056/public/Health%20Canada%20Nicotine. (Accessed 20 February 2017)
59. Hill, A., Camacho, O., A System Dynamics approach to assess the impact of launching a new nicotine product on population health outcomes. Regul. Toxicol. Pharmacol. 86 (2017), 265–278.
60. Hughes, J.R., Hatsukami, D., Signs and symptoms of tobacco withdrawal. Arch. Gen. Psychiatry 43 (1986), 289–294.
61. ICCVAM, Interagency Coordinating Committee on the Validation of Alternative Methods “In Vitro Cytotoxicity Test Methods for Estimating Starting Doses for Acute Oral Systematic Toxicity Testing”. 2006, National Institute of Health (NIH) publication No. 07–4519.
62. Institute for In Vitro Sciences., (2017). http://www.iivs.org/. (Accessed 20 February 2017).
63. Institute of Medicine, IOM, Scientific Standards for Studies on Modified Risk Tobacco Products. 2012, The National Academies Press, Washington, DC.
64. Iskandar, A.R., Gonzalez-Suarez, I., Majeed, S., Marescotti, D., Sewer, A., Xiang, Y., Leroy, P., Guedj, E., Mathis, C., Schaller, J.-P., Vanscheeuwijck, P., Frentzel, S., Martin, F., Ivanov, N.V., Peitsch, M.C., Hoeng, J., A framework for in vitro systems toxicology assessment of e-liquids. Toxicol. Mech. Methods 26:6 (2017), 392–416.
65. Kaluarachchi, M.R., Boulangé C.L., Garcia-Perez, I., Lindon, J.C., Minet, E.F., Multiplatform serum metabolic phenotyping combined with pathway mapping to identify biochemical differences in smokers. Bioanalysis 8 (2016), 2023–2043.
66. Kramer, A., Green, J., Pollard, J. Jr., Tugendreich, S., Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30 (2014), 523–530.
67. Kulasekaran, A., Proctor, C., Papadopoulou, E., Shepperd, C.J., Guyer, R., Gandek, B., Ware, J.E. Jr., Preliminary evaluation of a new German translated tobacco quality of life impact tool to discriminate between healthy current and former smokers and to explore the effect of switching smokers to a reduced toxicant prototype cigarette. Nicotine Tob. Res. 17:12 (2015), 1456–1464.
68. Lowe, F., Fearon, I., Camacho, O., Minet, E., Murphy, J., A framework for the assessment of reduced risk tobacco and nicotine products. Rec. Adv. Tob. Sci., 2015, 51–82.
69. Lowe, F., Luettich, K., Talikka, M., Hoang, V., Haswell, L., Hoeng, J., Gaça, M., Development of an adverse outcome pathway for the onset of hypertension by perturbation of endothelial nitric oxide bioavailability and oxidative stress. Appl. vitro Toxicol 3:1 (2017), 131–148.
70. Luettich, K., Talikka, M., Lowe, F., Haswell, L., Park, J., Gaça, M., Hoeng, J., The adverse outcome pathway for oxidative stress-mediated EGFR activation leading to decreased lung function. Appl. vitro Toxicol 3:1 (2016), 99–109.
71. MacKay, J., Eriksen, M., Shafey, O., The Tobacco Atlas. second ed., 2006 http://www.cancer.org/aboutus/globalhealth/cancerandtobaccocontrolresources/the-tobacco-atlas. (Accessed 20 February 2017)
72. Margham, J., McAdam, K.G., Forster, M., Liu, C., Wright, C., Mariner, D., Proctor, C., Chemical composition of an e-cigarette aerosol – a quantitative comparison with cigarette smoke. Chem. Res. Toxicol. 29 (2016), 1662–1678.
73. Maunders, H., Patwardhan, S., Phillips, J., Clack, A., Richter, A., Human bronchial epithelial cell transcriptome: gene expression changes following acute exposure to whole cigarette smoke in vitro. Am J Physiology - Lung Cell. Mol. Physiology 292:5 (2007), L1248–L1256.
74. McNeill, A., Munafò M.R., Reducing harm from tobacco use. J. Psychopharmacol. 27 (2012), 13–18.
75. McNeill, A., Brose, L.S., Calder, R., Hitchman, S.C., Hajek, P., McRobbie, E-cigarettes: an Evidence Update a Report Commissioned by Public Health England., 2015 https://www.gov.uk/government/publications/e-cigarettes-an-evidence-update. (Accessed 20 February 2017)
76. McQuillan, K., Carr, T., Taylor, M., Bishop, E., Fearon, I.M., Examination of the use of human sera as an exposure agent for in vitro studies investigating the effects of cigarette smoking on cellular cardiovascular disease models. Toxicol Vitro 29 (2015), 856–863.
77. Murphy, J., Assessing the risk of e-cigarettes, 21, 2017, Pan European Networks: Government, 52–55.
78. National centre for 3Rs, National Centre for the Replacement, Refinement and Reduction of Animals in Research. 2017 https://www.nc3rs.org.uk/the-3rs. (Accessed 16 June 2017)
79. st Century: a Vision and a Strategy. 2007, The national academies press, Washington DC, 10.17226/11970.
80. Neilson, L., Mankus, C., Thorne, D., Jackson, G., DeBay, J., Meredith, C., Development of an in vitro cytotoxicity model for aerosol exposure using 3D reconstructed human airway tissue; application for assessment of e-cigarette aerosol. Toxicol Vitro 29:7 (2015), 1952–1962 http://dx.doi.org/10.1016/j.tiv.2015.05.018. (Accessed 20 February 2017)
81. Nutt, D.J., Phillips, L.D., Balfour, D., Curran, H.V., Dockrell, M., Foulds, J., Fagerstrom, K., Letlape, K., Milton, A., Polosa R,·Ramsey, J., Sweanor, D., Estimating the harms of nicotine-containing products using the MCDA approach. Eur. J. Addict. Res. 20:5 (2014), 218–225.
82. OECD, Test No. 471: Bacterial Reverse Mutation Test, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. 1997, OECD Publishing.
83. OECD, Test No, 476. In Vitro Mammalian Cell Gene Mutation Test, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. 1997, OECD Publishing.
84. OECD, Test No. 487. In Vitro Mammalian Cell Micronucleus Test, OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. 2010, OECD Publishing.
85. OECD, Organisation for Economic Co-operation and Development “Guidance Document on the in Vitro BHAS 42 Cell Transformation Assay” ENV/JM/Mono(2016) 1 Series on Testing & Assessment, No. 231. 2016, OECD Publishing.
86. Polosa, R., Morijaria, J.B., Caponnetto, P., Caruso, M., Campagna, D., Amaradio, M.D., Ciampi, G., Russo, C., Fisichella, A., Persisting long term benefits of smoking abstinence and reduction in asthmatic smokers who have switched to electronic cigarettes. Discov. Med. 21:114 (2016), 99–108.
87. Polosa, R., Morijaria, J.B., Caponnetto, P., Prosperini, U., Russo, C., Pennisi, A., Bruno, C.M., Evidence for harm reduction in COPD smokers who switch to electronic cigarettes. Respir. Res., 17(1), 2016, 166.
88. Poussin, C., Laurent, A., Peitsch, M.C., Hoeng, J., De Leon, H., Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells. Toxicology 339 (2016), 73–86.
89. Proctor, C.J., Lessons from clinical studies using biomarkers of exposure to assess toxicant exposure. Presentation at Biomarkers of Tobacco Exposure: a Public Workshop, 2015 Washington DC, 3rd-4th Aug 2015.
90. Proctor, C.J., Utility of Biomarkers of Biological Effect as End-points for the Disease Relevant Assessment of Novel Tobacco and Nicotine Products as Potentially Reduced Risk Products Presentation at Biomarkers of Biological Effect. 2016 A public workshop Session 5 FDA/CTP Scientific Workshop Washington 5th April 2016.
91. Proctor, C.J., Shepperd, C.J., McAdam, K., Eldridge, A., Meredith, C., Integrating chemical, toxicological and clinical research to assess the potential of reducing health risks associated with cigarette smoking through reducing toxicant emissions. Rec. Adv. Tob. Sci., 2014, 1–34 68th Tobacco Science Research Conference.
92. Puntmann, V.O., How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgrad. Med. J. 85:1008 (2009), 538–545.
93. Rabe, K.F., Beghé B., Luppi, F., Fabbri, L.M., Update in chronic obstructive pulmonary disease 2006. Am. J. Resp. Crit. Care 175:12 (2007), 1222–1232.
94. Rawlinson, C., Martin, S., Frosina, J., Wright, C., Chemical characterisation of aerosols emitted by electronic cigarettes using thermal desorption - gas chromatography - time of flight mass spectrometry. J Chromatogr. A 1497 (2017), 144–154.
95. Robinson, J., (1930). Electric vaporizer. US patent US1775947.
96. Rodgman, A., Perfetti, T.A., The Chemical Components of Tobacco and Tobacco Smoke. 2013, CRC Press, New York.
97. Roemer, E., Schramke, H., Weiler, H., Buettner, A., Kausche, S., Weber, S., Berges, A., Stueber, M., Muench, M., Trelles-Sticken, E., Pype, J., Kohlgrueber, K., Voelkel, H., Wittke, S., Mainstream smoke chemistry and in vitro and in vivo toxicity of the reference cigarettes 3R4F and 2R4F. Beiträge zur Tab. Int. 25:1 (2012), 12–30.
98. Royal College of Physicians, Nicotine without Smoke-tobacco Harm Reduction. 2016, Royal College of Physicians.
99. Schaller, J.-P., Keller, D., Poget, L., Pratte, P., Kaelin, E., McHugh, D., Cudazz, G., Smart, D., Tricker, A.R., Gautier, L., Yerly, M., Reis Pires, R., Le Bouhellec, S., Ghosh, D., Hofer, I., Garcia, E., Vanscheeuwijck, P., Maeder, S., Evaluation of the tobacco heating system 2.2. Part 2: chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol. Regul. Toxicol. Pharmacol. 81 (2016), S27–S47.
100. Schmidt, C.W., Signs of the times: biomarkers in perspective. Environ. Health Perspect. 114 (2006), A700–A705.
101. Shahab, L., Goniewicz, M.L., Blount, B.C., Brown, J., McNeill, A., Alwis, K.U., Feng, J., Wang, L., West, R., Nicotine, carcinogen, and toxin exposure in long-term e-cigarette and nicotine replacement therapy users: a cross-sectional study. Ann. Int. Med., 2017, 10.7326/M-16-1107.
102. Shepperd, C.J., Eldridge, A.C., Camacho, O.M., McAdam, K., Proctor, C.J., Meyer, I., Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes. Regul. Toxicol. Pharmacol. 66 (2013), 147–162.
103. Shepperd, C.J., Newland, N., Eldridge, A., Graff, D., Mayer, I., A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes. BMC Public Health, 13, 2013, 690.
104. Shepperd, C.J., Newland, N., Eldridge, A., Haswell, L., Lowe, F., Papadopoulou, E., Camacho, O., Proctor, C.J., Graff, D., Meyer, I., Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes. Regul. Toxicol. Pharmacol. 72 (2015), 273–291.
105. Slayford, S.J., Frost, B.E., A device to measure a smoker's puffing topography and real-time puff-by-puff “tar” delivery. Beiträge zur Tabakforschung/Contributions Tob. Res. 26 (2014), 74–84.
106. Smith, M.R., Clark, B., Lüdicke, F., Schaller, J.P., Vanscheeuwijck, P., Hoeng, J., Peitsch, M.C., Evaluation of the tobacco heating system 2.2. Part 1: description of the system and the scientific assessment program. Reg. Tox. Pharm. 81 (2016), S17–S26.
107. Stratton, K., Shetty, P., Wallace, R., Bondurant, S., Committee to Assess the Science Base for Tobacco Harm Reduction; Board on Health Promotion and Disease Prevention; Institute of Medicine. Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. 2001, National Academy Press, Washington, DC.
108. Sturla, S.J., Boobis, A.R., Fitzgerlad, R.E., Hoeng, J., Kavlock, R.J., Schirmer, K., Whealan, M., Wilks, M.F., Peitsch, M.C., Systems Toxicology: from basic research to risk assessment. Chem. Res. Toxicol. 27 (2014), 314–327.
109. Taylor, M., Carr, T., Oke, T., Jaunky, T., E-cigarette aerosols induce lower oxidative stress in vitro when compared to tobacco smoke. Toxicol. Mech. Methods 26:6 (2016), 465–476.
110. th December 2016).
111. Teichert, A., Brossard, P., Felber Medlin, L., Sandalic, L., Franzon, M., Wynne, C., Laugesen, M., Lüdicke, F., Evaluation of nicotine pharmacokinetics and subjective effects following use of a novel nicotine delivery system. Nicotine Tob. Res., 2017, 1–8, 10.1093/ntr/ntx093.
112. Thorne, D., Crooks, I., Hollings, M., Seymour, A., Meredith, C., Gaҫa, M., The mutagenic assessment of electronic-cigarettes and tobacco smoke using the Ames assay in strains TA98 and TA100. Mutat. Res. 812 (2016), 29–38.
113. Thorne, D., Larard, S., Baxter, A., Meredith, C., Gaҫa, M., The comparative in vitro assessment of e-cigarette and cigarette smoke aerosols using the γH2AX assay and applied dose measurements. Tox Lett. 265 (2017), 170–178.
114. Unverdorben, M., von Holt, K., Winkelmann, B.R., Smoking and atherosclerotic cardiovascular disease: Part II: role of cigarette smoking in cardiovascular disease development. Biomarkers Med. 3 (2009), 617–653.
115. US Department of Health & Human Services, How tobacco smoke causes disease: the biology and behavioural basis for smoking–attributable disease: a report of the surgeon general. Surg. General, 2010, 351–434.
116. Vansickel, A.R., Weaver, M.F., Eissenberg, T., Clinical laboratory assessment of the abuse liability of an electronic cigarette. Addiction 107:8 (2012), 1493–1500.
117. Villeneuve, D.L., Crump, D., Garcia-Reyero, N., Adverse outcome pathway (AOP) development I: strategies and principles. Toxicol. Sci. 142:2 (2014), 312–320.
118. Walele, T., Sharma, G., Savioz, R., Martin, C., Williams, J., A randomised, crossover study on an electronic vapour product, a nicotine inhalator and a conventional cigarette. Part A: Pharmacokinetics. Regul. Toxicol. Pharmacol. 74 (2016), 187–192.
119. Walele, T., Sharma, G., Savioz, R., Martin, C., Williams, J., A randomised, crossover study on an electronic vapour product, a nicotine inhalator and a conventional cigarette. Part B: safety and subjective effects. Regul. Toxicol. Pharmacol. 74 (2016), 193–199.
120. Weitkunat, E., Lee, P.N., Baker, G., Sponsielle-Wang, Z., González-Zuloeta Ladd, A.M., Lüdicke, F., A novel approach to assess the population health impact of introducing a modified risk tobacco product. Regul. Toxicol. Pharmacol. 72:1 (2017), 89–93.
121. World Health Organisation, GLOBOCAN: estimated cancer incidence mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx, 2012 Accessed 1st September 2017.
122. Winkelmann, B.R., von Holt, K., Unverdorben, M., Smoking and atherosclerotic cardiovascular disease: Part I: atherosclerotic disease processes. Biomarkers Med. 3 (2009), 411–428.