A critical assessment of the scientific basis, and implementation, of regulations for the safety assessment and marketing of innovative tobacco-related products

ATLA Alternatives to Laboratory Animals

Volumn 43, Issue 4, 2015, Pages 251-290

  Combes, Robert D ^a   Balls, Michael ^b  

^a C/O FRAME ^*  (United Kingdom)

^b RUSSELL AND BURCH HOUSE   (United Kingdom)

Author keywords

Addiction; Cost benefit analysis; E cigarettes; FDA; Harm reduction; Hazard and risk; In vitro modelling of disease; Integrated testing; Modified risk tobacco products; New products; Old exempted products; Recommendations; Respiratory toxicity; Substantial equivalence; Tobacco regulations

Indexed keywords

ADVERSE EFFECTS; ANIMAL; ANIMAL WELFARE; COST BENEFIT ANALYSIS; FOOD AND DRUG ADMINISTRATION; HUMAN; LEGISLATION AND JURISPRUDENCE; MARKETING; RISK ASSESSMENT; SAFETY; TOBACCO; UNITED STATES;

ANIMAL WELFARE; ANIMALS; COST-BENEFIT ANALYSIS; HUMANS; MARKETING; RISK ASSESSMENT; SAFETY; TOBACCO PRODUCTS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 84953343458     PISSN: 02611929     EISSN: 26323559     Source Type: Journal    
DOI: 10.1177/026119291504300406     Document Type: Review

References (248)

1. Anon. (2009). Types of Tobacco Products. Atlanta, GA, USA: Centre for Disease Control. Available at: http://www.ct.gov/dph/lib/dph/hems/tobacco/tobacco-products.pdf (Accessed 22.07.15).
2. Stanfill, S.B. & Stepanov, I. (2014). A global view of smokeless tobacco products. In Smokeless Tobacco and Public Health: A Global Perspective, pp. 71-114. Bethesda, MD, USA: National Cancer Institute and Centers for Disease Control and Prevention, US Department of Health and Human Services.
3. Britton, J. & Bogdanovica, I. (2014). Electronic Cigarettes, 30pp. A report commissioned by Public Health England. London, UK: Public Health England. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment-data/file/311887/Ecigarettes-report.pdf (Accessed 02.09.15).
4. Brandon, T.H., Goniewicz, M.L., Hanna, N.H., Hatsukami, D.K., Herbst, R.S., Hobin, J.A., Ostroff, J.S., Shields, P.G., Toll, B.A., Tyne, C.A., Viswanath, K. & Warren, G.W. (2015). Electronic cigarettes: Review of use, content, safety, effects on smokers and potential for harm and benefit. British Dental Journal 218, 19.
5. Anon. (2012). Modified Risk Tobacco Product Applications, 47pp. Silver Spring, MD, USA: FDA, Centre for Tobacco Products. Available at: http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM297751.pdf (Accessed 22.07.15).
6. Anon. (2011). Harms of Smoking and Health Benefits of Quitting. National Cancer Institute Fact Sheet, 7pp. Bethesda, MD, USA: National Cancer Institute.
7. Campbell, D. (2014). E-cigarettes can help smokers quit or cut down heavily, say researchers. The Guardian, 17 December. Available at: http://www.theguardian.com/society/2014/dec/17/e-cigarettessmokers-quit-vaping (Accessed 26.03.15).
8. Anon. (2012). Tell FDA: No Animal Testing for Tobacco Products. Available at: www.allcreatures.org/alert/alert-20120516-2.html(Acc essed 26.03.15).
9. Anon. (2015). Smoking Experiments on Animals, 2pp. PETA, Animals Used for Experimentation Factsheet. Norfolk, VA, USA: People for the Eth - ical Treatment of Animals.
10. Solyst, J. (2011). Applying regulatory science concepts to risk-based decisions under the new US Tobacco Control Act. The John Liner Review 24, 24-33.
11. Anon. (2012). Modified Risk Tobacco Product Applications, 47pp. Guidance for Industry. Silver Spring, MD, USA: Food and Drug Administration. Available at: http://www.fda.gov/downloads/TobaccoProducts/Labeling/UCM297751.pdf (Accessed 02.09.15).
12. Anon. (2015). New Tobacco Product Review and Evaluation. Guidance for Industry. Silver Spring, MD, USA: Food and Drug Administration. Available at: http://esp.fda.gov/TobaccoProducts/Labeling/ProductsIngredientsComponents/TobaccoProductReviewEvaluation/default.htm (Accessed 02.09.15).
13. Weiner, S. (2010). The Family Smoking Prevention and Tobacco Control Act: An Early Evaluation, 30pp. Massachusetts, MA, USA: Harvard Law School. Available at: http://nrs.harvard.edu/urn-3:HUL.InstRepos:8591097 (Accessed 07.07.15).
14. Anon. (2015). AACR, ASCO, Two Leading U.S. Cancer Organizations, Call for Regulation of Ecigarettes and Other Electronic Nicotine Delivery Systems, 2pp. Philadelphia, PA, USA: American Association for Cancer Research.
15. Rom, O., Pecorelli, A., Valacchi, G. & Reznick, A.Z. (2014). Are E-cigarettes a safe and good alternative to cigarette smoking? Annals of the New York Academy of Sciences [doi: 10.1111/nyas.12609 2014].
16. Anon. (2014). Countries vindicate cautious stance on e-cigarettes. Bulletin of the World Health Organisation 92, 856-857.
17. Furber, A. (2105). Electronic cigarettes: Reasons to be cautious. Thorax 70, 307-308.
18. Lerner, C.A., Sundar, I.K., Watson, R.M., Elder, A., Jones, R., Done, D., Kurtzman, R., Ossip, D.J., Robinson, R., McIntosh, S. & Rahman, I. (2015). Environmental health hazards of e-cigarettes and their components: Oxidants and copper in e-cigarette aerosols. Environmental Pollution 198C, 100-107.
19. Anon. (2015). Issue Snapshot on Deeming: Regul - Ating Additional Tobacco Products, 1pp. Silver Spring, MD, USA: FDA Centre for Tobacco Prod - ucts. Available at: http://www.fda.gov/downloads/TobaccoProducts/NewsEvents/UCM397724.pdf (Accessed 22.07.15).
20. Anon. (2014). Electronic Cigarettes (Also Known as Vapourisers), 12pp. ASH briefing. London, UK: Action on Smoking and Health. Available at: http://www.ash.org.uk/files/documents/ASH-715.pdf(Accessed02.09.15).
21. O'Connor, R.J. (2012). Postmarketing surveillance for "modified-risk" tobacco products. Nicotine & Tobacco Research 14, 29-42.
22. Weitershausen, J. (2014). Grandfathered Tobacco Products [Webinar presentation], 21pp. Silver Spring, MD, USA: FDA Centre for Tobacco Products. Available at: http://www.fda.gov/downloads/TobaccoProducts/ResourcesforYou/BreakTheChain/UCM420769.pdf (Accessed 22.07. 15).
23. Miller, H.I. (1999). Substantial equivalence. Its uses and abuses. Nature Biotechnology 17, 1042- 1043.
24. Anon. (2015). Demonstrating the Substantial Equivalence of a New Tobacco Product: Responses to Frequently Asked Questions Draft Guidance, 4pp. Notice by the FDA in the Federal Register on 5 March 2015. Silver Spring, MD, USA: Food and Drug Administration. Available at: https://www.federalregister.gov/articles/2015/03/05/2015-05023/demonstrating-the-substantial-equivalenceof-a-new-tobacco-product-responses-to-frequentlyasked (Accessed 26.03.15).
25. Choiniere, C.J. (2015). Modified Risk Tobacco Product Applications Guidance [Webinar presentation], 35pp. Silver Spring, MD, USA: FDA Centre for Tobacco Products. Available at: http://www.fda.gov/downloads/TobaccoProducts/NewsEvents/UCM324241.pdf (Accessed 22.07.15).
26. Anon. (2015). Exemption from Substantial Equiv - Alence. Silver Spring, MD: USA: FDA. Available at: http://www.fda.gov/TobaccoProducts/Labeling/TobaccoProductReviewEvaluation/NewTobaccoProductReviewandEvaluation/ExemptionfromSubstantialEquivalence/default.htm (Accessed 22. 07.15).
27. Schauzu, M. (2000). The concept of substantial equivalence in safety assessment of foods derived from genetically modified organisms. AgBiotech Net Vol. 2 April, ABN 044.
28. Ho, M.W. & Steinbrecher, R. (1998). Fatal flaws in food safety assessment: Critique of the joint FAO/WHO biotechnology and food safety report. Environmental & Nutritional Interactions 2, 51-84.
29. Clissold, D.B. (2015). Proposed Legislation Would Link the "Grandfather" Date in the Tobacco Control Act to FDA's Deeming Regulations. Available at: http://www.fdalawblog.net/fda-law-blog-hyman-phelps/2015/04/proposed-legislation-would-link-thegrandfather-date-in-the-tobacco-control-act-tofdas-deeming-regu.html (Accessed 22.07.15).
30. Zeller, M. (2014). Progress and Challenges: The State of Tobacco Use and Regulation in the U.S. Silver Spring, MD, USA: FDA. Available at: http://www.fda.gov/NewsEvents/Testimony/ucm397399.htm (Accessed 22.07.15).
31. Phillips, C.V. (2014). FDA Signals that Nothing Is Ever "Substantially Equivalent". Available at: http://antithrlies.com/2014/08/31/fda-signals-thatnothing-is-ever-substantially-equivalent/(Acc - essed 22.07.15).
32. Ashley, D.L. & Holman, M. (2012). Reports on Substantial Equivalence (905(j)(1)(A)(i) Reports): An Update [Webinar presentation], 40pp. SilverSpring, MD, USA: FDA Centre for Tobacco Products. Available at: http://www.fda.gov/downloads/TobaccoProducts/ResourcesforYou/Retail/UCM316450.pdf (Accessed 22.07.15).
33. Anon. (2014). Scientific Literature on the Com - parative Risks to Health Presented by Cigarettes and Smokeless Tobacco Products, 119pp. Silver Spring, MD, USA: FDA. Available at: http://www.regulations.gov/contentStreamer?documentId=FDA-2011-P-0573-0005&attachmentNumber=2&disposition=attachment&contentType=pdf (Accessed 22.07.15).
34. Stier, J. (2014). Calling for a Different Approach to Tobacco and Nicotine Regulation. Brussels, Belgium: EurActiv Health & Consumers Section. Available at: http://www.euractiv.com/sections/health-consumers/calling-different-approachtobacco-nicotine-regulation-307926 (Accessed 02.09. 15).
35. Anon. (2015). April 9-10, 2015 TPSAC Meeting Slide Presentations. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/ucm443148.htm (Accessed 22.07.15).
36. Anon. (2012). Scientific Standards for Studies on Modified Risk Tobacco Products, 370pp. Report by the Committee on Scientific Standards for Studies on Modified Risk Tobacco Products, Board on Population Health and Public Health Practice, Institute of Medicine of the National Academies of Sciences. Washington, DC, USA: National Acad - emies Press.
37. Donny, E.C., Taylor, T.G., LeSage, M.G., Levin, M., Buffalari, D.M., Joel, D. & Sved, A.F. (2012). Impact of tobacco regulation on animal research: New perspectives and opportunities. Nicotine & Tobacco Research 14, 1319-1338.
38. Anon. (2015). OECD Guidelines for the Testing of Chemicals. Paris, France: Organisation for Econ - omic Co-operation and Development. Available at: http://www.oecd.org/env/ehs/testing/oecdguidelinesforthetestingofchemicals.htm (Accessed 26.03.15).
39. Coggins, C.R. (2007). An updated review of inhalation studies with cigarette smoke in laboratory animals. International Journal of Toxicology 26, 331-338.
40. Dorato, M.A. & Wolff, R.K. (1991). Inhalation exposure technology, dosimetry, and regulatory issues. Toxicologic Pathology 19, 373-383.
41. Gad, S.C. (2014). Safety assessment of therapeutic agents administered by the respiratory routes. In Inhalation Toxicology (ed. H. Salem & S.A. Katz), 3rd edn, pp. 537-580. Baton Rouge, FL, USA: CRC Press.
42. Pauluhn, J. & Mohr, U. (2000). Inhalation studies in laboratory animals - current concepts and alternatives. Toxicologic Pathology 28, 734-753.
43. Morrow, P.E. & Mermelstein, R. (1988). Chronic Inhalation Toxicity Studies: Protocols and Pitfalls. In ILSI Monograph: Inhalation Toxicology (ed. U. Mohr, D. Dungworth, G. Kimmerle, J. Lewkowski, R. McClellan & W. Stober), pp. 103-117. New York, NY, USA: Springer-Verlag, Inc.
44. Coecke, S., Ahr, H., Blaauboer, B.J., Bremer, S., Casati, S., Castell, J., Combes, R., Corvi, R., Crespi, C.L., Cunningham, M.L., Elaut, G., Eletti, B., Freidig, A., Gennari, A., Ghersiegea, J-F., Guillouzo, A., Hartung, T., Hoet, P., Ingelman- Sundberg, M., Munn, S., Janssens, W., Ladstetter, B., Leahy, D., Long, A., Meneguz, A., Mon shouwer, M., Morath, S., Nagelkerke, F., Pelkonen, O., Ponti, J., Prieto, P., Richert, L., Sabbioni, E., Schaack, B., Steiling, S., Testai, E., Vericat, J-A. & Worth, A. (2006). Metabolism: A bottleneck in in vitro toxicological test development. The Report and Recommendations of ECVAM Workshop 54. ATLA 34, 49-84.
45. Sacks, P.G., Zhao, Z.L., Kosinska, W., Fleisher, K.E., Gordon, T. & Guttenplan, J.B. (2011). Concentration dependent effects of tobacco particulates from different types of cigarettes on expression of drug metabolizing proteins, and benzo(a)pyrene metabolism in primary normal human oral epithelial cells. Food & Chemical Toxicology 49, 2348-2355.
46. Rotunno, M., Yu, K., Lubin, J.H., Consonni, D., Pesatori, A.C., Goldstein, A.M., Goldin, L.R., Wacholder, S., Welch, R., Burdette, L., Chanock, S.J., Bertazzi, P.A., Tucker, M.A., Caporaso, N.E., Chatterjee, N., Bergen, A.W. & Landi, M.T. (2009). Phase I metabolic genes and risk of lung cancer: Multiple polymorphisms and mRNA expression. PLoS One 4, e5652.
47. Harris, J.E. (1996). Cigarette smoke is more than a triad of tar, nicotine, and carbon monoxide. In The FTC Cigarette Test Method for Determining Tar, Nicotine, and Carbon Monoxide Yields of U.S. Cigarettes. Smoking and Tobacco Control Monograph No. 7, Chapter 5, pp. 59-75. Bethesda, MD, USA: National Cancer Institute.
48. Combes, R.D., Gaunt, I. & Balls, M. (2004). A scientific and animal welfare assessment of the OECD Health Effects Test Guidelines for the safety testing of chemicals under the European Union REACH system. ATLA 32, 163-208.
49. Balls, M. & Combes, R.D. (2006). The OECD Health Effects Test Guidelines: A challenge to the sincerity of commitment to the Three Rs. ATLA 34, 105-108.
50. Arts, J.H., Muijser, H., Jonker, D., van de Sandt, J.J., Bos, P.M. & Feron, V.J. (2008). Inhalation toxicity studies: OECD guidelines in relation to REACH and scientific developments. Experi - mental & Toxicologic Pathology 60, 125-133.
51. Anon. (2009). Guidance Document on Acute Inhal - Ation Toxicity Testing. Series on Testing and Assessment Number 39, 71pp. Paris, France: Organisation for Economic Co-operation and Development.
52. Anon. (2009). Guidance on Dose Level Selection for Regulatory General Toxicology Studies for Pharm - Aceuticals, 36pp. Tamworth and London, UK: Laboratory Animal Science Association and National Centre for the 3Rs.
53. Grant, R.L., Kadlubar, B.J., Erraguntla, N.K. & Honeycutt, M. (2007). Evaluation of acute inhalation toxicity for chemicals with limited toxicity information. Regulatory Toxicology & Pharmacology 47, 261-273.
54. Arts, J.H.E., de Jong, W.H., van Triel, J.J, Schijf, M.A, de Klerk, A., van Loveren, H. & Kuper, C.K. (2008). The respiratory local lymph node assay as a tool to study respiratory sensitizers. Toxicological Sciences 106, 423-434.
55. Illing, P. (2001). Toxicity and Risk, 154pp. Abingdon, UK: Taylor & Francis.
56. Combes, R., Balls, M., Illing, P., Bhogal, N., Dale, J., Duvé, G., Feron, V., Grindon, C., Gülden, M., Loizou, G., Priston, R. & Westmoreland, C. (2006). Possibilities for a new approach to chemicals risk assessment. The Report of a FRAME Workshop. ATLA 34, 621-649.
57. Travis, K.Z., Pate, I. & Welsh, Z.K. (2005). The role of the benchmark dose in a regulatory context. Regulatory Toxicology & Pharmacology 43, 280-291.
58. Vermeire, T.G., Baars, A.J., Bessems, J.G.M., Blaauboer, B.J., Slob, W. & Muller, J.J.A. (2007). Toxicity testing for human health risk assessment. In Risk Assessment of Chemicals: An Introduction (ed. C.J. Van Leeuwen & T.G. Vermeire), 2nd edn, pp. 227-280. Dordrecht, The Netherlands: Springer.
59. Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, 238pp. London, UK: Methuen.
60. Anon. (undated). The Molecular Basis of Addiction and Depression. New York, NY, USA: Mount Sinai School of Medicine. Available at: http://neuroscience.mssm.edu/nestler/MolecularBasisofAddiction&Depression.html (Accessed 26.03.15).
61. Fowler, C.D., Lu, Q., Johnson, P.M., Marks, M.J. & Kenny, P.J. (2011). Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature, London 471, 597-601.
62. Rahman, S., López-Hernández, G.Y., Corrigall, W.A. & Papke, R.L. (2008). Neuronal nicotinic receptors as brain targets for pharmacotherapy of drug addiction. CNS & Neurological Disorders: Drug Targets 7, 422-441.
63. Panlilio, L.V. & Goldberg, S.R. (2007). Self-administration of drugs in animals and humans as a model and an investigative tool. Addiction 102, 1863-1870.
64. Edwards, S. & Koob, G.F. (2012). Experimental psychiatric illness and drug abuse models: From human to animal, an overview. Methods in Molecular Biology 829, 31-48.
65. Henningfield, J.E., Shiffman, S., Ferguson, S.G. & Gritz, E.R. (2009). Tobacco dependence and withdrawal: Science base, challenges and oppor - Tunities for pharmacotherapy. Pharmacology & Therapeutics 123, 1-16.
66. Bérubé, K., Aufderheide, M., Breheny, D., Clothier, R., Combes, R., Duffin, R., Forbes, B., Gaça, M., Gray, A., Hall, I., Kelly, M., Lethem, M., Liebsch, M., Merolla, L., Morin, J.P., Seagrave, J., Swartz, M.A., Tetley, T.D. & Umachandran, M. (2009). In vitro models of inhalation toxicity and disease. The Report of a FRAME workshop. ATLA 37, 89-141.
67. Scott, D.A. & Wang, X.L. (2005). Molecular mechanisms of tobacco-induced diseases - current and future directions. In Molecular Mechanisms of Tobacco-induced Diseases (ed. X.L. Wang & D.A. Scott), pp. 403-415. Hauppauge, NY, USA: Nova Publishers, Inc.
68. Johnson, M.D., Schilz, J., Djordjevic, M.V., Rice, J.R. & Shields, P.G. (2009). Evaluation of in vitro assays for assessing the toxicity of cigarette smoke and smokeless tobacco. Cancer Epidemiology, Biomarkers & Prevention 18, 3263-3304.
69. Thorne, D. & Adamson, J. (2013). A review of in vitro cigarette smoke exposure systems. Experi - men tal & Toxicologic Pathology 65, 1183-1193.
70. Andreoli, C., Gigante, D. & Nunziata, A. (2003). A review of in vitro methods to assess the biological activity of tobacco smoke with the aim of reducing the toxicity of smoke. Toxicology in Vitro 17, 587-594.
71. Manuppello, J.R. & Sullivan, K.M. (2015). Toxicity assessment of tobacco products in vitro. ATLA 43, 39-67.
72. Nichols, J.E., Niles, J.A, Vega, S.P. & Cortiella, J. (2013). Novel in vitro respiratory models to study lung development, physiology, pathology and toxicology. Stem Cell Research & Therapy 4, Suppl. 1, S7.
73. Costa, D.L. (2008). Alternative test methods in inhalation toxicology: Challenges and opportunities. Experimental & Toxicologic Pathology 60, 105-109.
74. Bernhard, D. & Wick, G. (2005). In vitro methods for the analysis of cigarette smoke effects. In Molecular Mechanisms of Tobacco-induced Diseases (ed. X.L. Wang & D.A. Scott), pp. 29-54. Hauppauge, NY, USA: Nova Publishers, Inc.
75. Gray, A.C., Mcleod, J.D. & Clothier, R.H. (2007). A review of in vitro modelling approaches to the identification and modulation of squamous metaplasia in the human tracheobronchial epithelium. ATLA 35, 493-504.
76. Swindle, E.J. & Davies, D.E. (2011). Artificial airways for the study of respiratory disease. Expert Review of Respiratory Medicine 5, 757-765.
77. Huang, S., Wiszniewski, L., Derouette, J-P. & Constant, S. (2009). In vitro organ culture models of asthma. Drug Discovery Today: Disease Models 6, 137-144.
78. Blume, C. & Davies, D.E. (2013). In vitro and ex vivo models of human asthma. European Journal of Pharmaceutics & Biopharmaceutics 84, 394- 400.
79. Adamson, J., Haswell, L.E., Phillips, G. & Gaça, M.D. (2011). In vitro models of chronic obstructive pulmonary disease (COPD). In Bronchitis (ed. I.M. Ãn-Loeches), pp. 41-66. Rijeka, Croatia: InTech.
80. Anon. (2013). Developing a Platform of In Vitro Models of Asthmatic and Healthy Lung: An Alternative to the Use of Animals in Asthma Research. London, UK: NC3Rs. Available at: https://www.nc3rs.org.uk/developing-platformvitro-models-asthmatic-and-healthy-lungalternative-use-animals-asthma-research (Accessed 02.09.15).
81. Pucheu-Haston, C.M., Copeland, L.B., Vallanat, B., Boykin, E. & Ward, M.D.W. (2010). Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential. Toxicology & Applied Pharmacology 244, 144-155.
82. Anon. (2014). FDA NCTR Annual Report FY 2013 - FY 2014, 149pp. Jefferson, AR, USA: National Center for Toxicological Research.
83. Huang, S., Wiszniewski, L., Constant, S. & Roggen, E. (2013). Potential of in vitro reconstituted 3D human airway epithelia (MucilAir™) to assess respiratory sensitizers. Toxicology in Vitro 27, 1151-1156.
84. Combes, R.D. (2004). The use of human cells in biomedical research and testing. ATLA 32, Suppl. 1A, 43-49.
85. Anderson, R., O'Hare, M., Balls, M., Brady, M., Brahams, D., Burt, A., Chesne, C., Combes, R., Dennison, A., Garthoff, B., Hawksworth, G., Kalter, E., Lechat, A., Mayer, D., Rogiers, V., Sladowski, D., Southee, J., Trafford, J., van der Valk, J. & van Zeller, A-M. (1998). The availability of human tissues for research. The Report and Recommendations of ECVAM Workshop 32. ATLA 26, 763-777.
86. Kuehn, D., Majeed, S., Guedj, E., Dulize, R., Baumer, K., Iskandar, A., Boue, S., Martin, F., Kostadinova, R., Mathis, C., Ivanov, N.V., Frentzel, S., Hoeng, J. & Peitsch, M.C. (2015). Impact assessment of repeated exposure of organotypic 3D bronchial and nasal tissue culture models to whole cigarette smoke. Journal of Visualized Experiments 96, e52325.
87. Talikka, M., Kostadinova, R., Xiang, Y., Mathis, C., Sewer, A., Majeed, S., Kuehn, D., Frentzel, S., Merg, C., Geertz, M., Martin, F., Ivanov, N.V., Peitsch, M.C. & Hoeng, J. (2014). The response of human nasal and bronchial organotypic tissue cultures to repeated whole cigarette smoke exposure. International Journal of Toxicology 33, 506-517.
88. Majeed, S., Frentzel, S., Wagner, S., Kuehn, D., Leroy, P., Guy, P., Knorr, A., Hoeng, J. & Peitsch, M.C. (2014). Characterization of the Vitrocell® 24/48 in vitro aerosol exposure system using mainstream cigarette smoke. Chemistry Central Journal 8, 62.
89. Schlage, W.K., Iskandar, A.R., Kostadinova, R., Xiang, Y., Sewer, A., Majeed, S., Kuehn, D., Frentzel, S., Talikka, M., Geertz, M., Mathis, C., Ivanov, N., Hoeng, J. & Peitsch, M.C. (2014). In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures. Toxicology Mechanisms & Methods 24, 470-487.
90. Bardet, G., Achard, S., Loret, T., Desauziers, V., Momas, I. & Seta, N. (2014). A model of human nasal epithelial cells adapted for direct and repeated exposure to airborne pollutants. Toxicology Letters 229, 144-149.
91. Switalla, S., Knebel, J., Ritter, D., Dasenbrock, C., Krug, N., Braun, A. & Sewald, K. (2013). Determination of genotoxicity by the Comet assay applied to murine precision-cut lung slices. Toxicology in Vitro 27, 798-803.
92. Combes, R.D. (2012). Cell transformation assays: Are we barking up the wrong tree? ATLA 40, 115-130.
93. Combes, R., Balls, M., Curren, R., Fischbach, M., Fusenig, N., Kirkland, D., Lasne, C., Landolph, J., LeBoeuf, R., Marquardt, H., McCormick, J., Müller, L., Rivedal, E., Sabbioni, E., Tanaka, N., Vasseur, P. & Yamasaki, H. (1999). Cell transformation assays as predictors of human carcinogenicity. The Report and Recommendations of ECVAM Workshop 39. ATLA 27, 745-767.
94. Aufderheide, M. & Mohr, U. (2004). A modified CULTEX system for the direct exposure of bacteria to inhalable substances. Experimental & Toxicologic Pathology 55, 451-454.
95. Wolz, L., Krause, G., Scherer, G., Aufderheide, M. & Mohr, U. (2002). In vitro genotoxicity assay of sidestream smoke using a human bronchial epithelial cell line. Food & Chemical Toxicology 40, 845-850.
96. Stewart, A., Wong, K., Cachat, J., Gaikwad, S., Kyzar, E., Wu, N., Hart, P., Piet, V., Utterback, E., Elegante, M., Tien, D. & Kalueff, A.V. (2011). Zebrafish models to study drug abuse-related phenotypes. Reviews in the Neurosciences 22, 95-105.
97. Panlilio, L.V. & Goldberg, S.R. (2007). Self-administration of drugs in animals and humans as a model and an investigative tool. Addiction 102, 1863-1870.
98. Combes, R.D. & Shah, A.B. (2015). A review of the roles, and contributions to the Three Rs (Refine - ment, Reduction and Replacement) of animal and non-animal models used in vision research and the treatment of vision disorders. [Manuscript in preparation.].
99. Grebenstein, P., Burroughs, D., Zhang, Y. & Lesage, M.G. (2013). Sex differences in nicotine self-administration in rats during progressive unit dose reduction: Implications for nicotine regulation policy. Pharmacology, Biochemistry & Behavior 114-115, 70-81.
100. D'Souza, M.S. & Markou, A. (2011). Neuronal mechanisms underlying development of nicotine dependence: Implications for novel smoking-cessation treatments. Addiction Science & Clinical Practice 6, 4-16.
101. Proctor, C.J., Shepperd, C.J., Cunningham, A., Newland, N., Sommarstrom, J. & Williamson, J. (2013). Challenges in using occasional confinement designs in clinical studies of potential modified risk tobacco products. Poster POS3-125, pp. 205. Society for Research on Nicotine and Tobacco International Meeting, 13-16 March 2013, Boston, MA, USA. Available at: https://srnt.org/conferences/SRNT-2013-Abstracts-I-Modified.pdf (Accessed 26.03.15).
102. Rees, V.W., Kreslake, J.M., O'Connor, R.J., Cummings, K.M., Parascandola, M., Hatsukami, D., Shields, P.G. & Connolly, G.N. (2009). Methods used in internal industry clinical trials to assess tobacco risk reduction. Cancer Epidemiology Biomarkers & Prevention 18, 3196-3208.
103. Theophilus, E.H., Coggins, C.R., Chen, P., Schmidt, E. & Borgerding, M.F. (2015). Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: A oneweek clinical confinement study. Regulatory Toxicology & Pharmacology 71, 225-234.
104. Thibault, C., Hassan, S. & Miles, M. (2005). Using in vitro models for expression profiling studies on ethanol and drugs of abuse. Addiction Biology 10, 53-62.
105. Talikka, M., Sierro, N., Ivanov, N.V., Chaudhary, N., Peck, M.J., Hoen, J., Coggins, C.R.E. & Peitsch, M.C. (2012). Genomic impact of cigarette smoke, with application to three smoking-related diseases. Critical Reviews in Toxicology 42, 877-889.
106. Phillips, J., Kluss, B., Richter, A. & Massey, E. (2005). Exposure of bronchial epithelial cells to whole cigarette smoke: Assessment of cellular responses. ATLA 33, 239-248.
107. Breheny, D., Cunningham, F., Kilford, J., Payne, R., Dillon, D. & Meredith, C. (2014). Application of a modified gaseous exposure system to the in vitro toxicological assessment of tobacco smoke toxicants. Environmental & Molecular Mutagenesis 55, 662-672.
108. Bardet, G., Achard, S., Loret, T., Desauziers, V., Momas, I. & Seta, N. (2014). A model of human nasal epithelial cells adapted for direct andrepeated exposure to airborne pollutants. Toxicology Letters 229, 144-149.
109. Adamson, J., Thorne, D., Errington, G., Fields, W., Li, X., Payne, R., Krebs, T., Dalrymple, A., Fowler, K., Dillon, D., Xie, F. & Meredith, C. (2014). An inter-machine comparison of tobacco smoke particle deposition in vitro from six independent smoke exposure systems. Toxicology in Vitro 28, 1320-1328.
110. Lenz, A-G., Stoeger, T., Cei, D., Schmidmeir, M., Pfister, N., Burgstaller, G., Lentner, B., Eickel - berg, O., Meiners, S. & Schmid, O. (2014). Efficient bioactive delivery of aerosolized drugs to human pulmonary epithelial cells cultured at air-liquid interface conditions. American Journal of Respiratory Cell & Molecular Biology 51, 526-535.
111. Thorne, D., Kilford, J., Payne, R., Haswell, L., Dalrymple, A., Meredith, C. & Dillon, D. (2014). Development of a BALB/c 3T3 neutral red uptake cytotoxicity test using a mainstream cigarette smoke exposure system. BMC Research Notes 7, 367.
112. Adamson, J., Thorne, D., Dalrymple, A., Dillon, D. & Meredith, C. (2013). Assessment of cigarette smoke particle deposition within the Vitrocell W exposure module using quartz crystal microbalances. Chemistry Central Journal 7, 50.
113. Combes, R.D. (2013). Progress in the development, validation and regulatory acceptance of in vitro methods for toxicity testing. In Elsevier Reference Module in Chemistry, Molecular Sciences and Chemical Engineering (ed. J. Reedijk), pp. 1-25. Waltham, MA, USA: Elsevier.
114. Anon. (2004). The Rationale and Strategy for Conducting In Vitro Toxicology Testing of Tobacco Smoke, 20pp. CORESTA In Vitro Toxicology Task Force. Paris, France: Co-operation Centre for Scientific Research Relative to Tobacco www.coresta.org/Reports/IVT-TF-Rationale-IVT-Testing-Tob.-Smoke-Report-Jun04.pdf (Acc - essed 26.03.15).
115. Simms, L. (undated). The CORESTA Recom mended In Vitro Test Battery alongside the NRC Vision for Toxicity Testing in 21st Century. [Presentation at CORESTA meeting, 12-16 October 2014, Quebec City.] Bristol, UK: Imperial Tobacco. Available at: http://www.imperialtobaccoscience.com/files/pdf/smoketoxicology/the-CORESTA-Recommended-In-Vitro-Test-Battery-Alongside-the-NRC-Vision-for-Toxicity-Testing-in-21st-Century.pdf (Acc - essed 22.07.15).
116. Crooks, I., Scott, K., Dalrymple, A., Dillon, D. & Meredith, C. (2015). The combination of two novel tobacco blends and filter technologies to reduce the in vitro genotoxicity and cytotoxicity of prototype cigarettes. Regulatory Toxicology & Pharmacology 71, 507-514.
117. Combes, R., Scott, K., Dillon, D., Meredith, C., Mcadam, K. & Proctor, C. (2012). The effect of a novel tobacco process on the in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter. Toxicology in Vitro 26, 1022-1029.
118. Combes, R., Scott, K., Crooks, I., Dillon, D., Meredith, C., McAdam, K. & Proctor, C. (2013). The in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter with reduced toxicant yields. Toxicology in Vitro 27, 1533-1541.
119. Coggins, C.R., Ballantyne, M., Curvall, M. & Rutqvist, L.E. (2012). The in vitro toxicology of Swedish snus. Critical Reviews in Toxicology 42, 304-313.
120. McAdam, K.G., Gregg, E.O., Liu, C., Dittrich, D.J., Duke, M.G. & Proctor, C.J. (2011). The use of a novel tobacco-substitute sheet and smoke dilution to reduce toxicant yields in cigarette smoke. Food & Chemical Toxicology 49, 1684-1696.
121. Cervellati, F., Muresan, X.M., Sticozzi, C., Gam - bari, R., Montagner, G., Forman, H.J., Torricelli, C., Maioli, E. & Valacchi, G. (2014). Comparative effects between electronic and cigarette smoke in human keratinocytes and epithelial lung cells. Toxicology in Vitro 28, 999-1005.
122. Scott, K., Saul, J., Crooks, I., Camacho, O.M., Dillon, D. & Meredith, C. (2013). The resolving power of in vitro genotoxicity assays for cigarette smoke particulate matter. Toxicology in Vitro 27, 1312-1319.
123. Halle, W. (2003). The Registry of Cytotoxicity: Toxicity testing in cell cultures to predict acute toxicity (LD50) and to reduce testing in animals. ATLA 31, 89-198.
124. Tan, C.E., Kyriss, T. & Glantz, S.A. (2013). Tobacco company efforts to influence the Food and Drug Administration-commissioned Institute of Medicine report clearing the smoke: An analysis of documents released through litigation. PLoS Medicine 10, e1001450.
125. Anon. (2014). Guidance on the Operation of the Animals (Scientific Procedures) Act 1986, 164pp. London, UK: Home Office.
126. Anon. (2014). Directive 2014/40/EU of the Euro - pean Parliament and of the Council of 3 April 2014 on the approximation of the laws, regulations and administrative provisions of the Member States concerning the manufacture, presentation and sale of tobacco and related products and repealing Directive 2001/37/EC. Official Journal of the European Union L127, 29.04.14, 1-38.
127. Bates, C., Fagerström, K., Jarvis, M.J., Kunze, M., McNeill, A. & Ramström, L. (2013). European Union policy on smokeless tobacco: A statement in favour of evidence based regulation for public health. Tobacco Control 12, 360-367.
128. Balls, M. & Combes, R. (2005). Validation via weight-of-evidence approaches. ALTEX 22, Special Issue 2, 288-291.
129. Grindon, C., Combes, R., Cronin, M.T., Roberts, D.W. & Garrod, J.F. (2008). Integrated testing strategies for use with respect to the requirements of the EU REACH legislation. ATLA 36, Suppl. 1, 7-27.
130. Combes, R.D. & Balls, M. (2011). Integrated testing strategies for toxicity employing new and existing technologies. ATLA 39, 213-225.
131. Combes, R.D. (2012). In silico methods for toxicity prediction. Advances in Experimental Medicine & Biology 745, 96-116.
132. Combes, R.D. (2011). Challenges for computational structure-activity modelling for predicting chemical toxicity: Future improvements? Expert Opinion on Drug Metabolism & Toxicology 7, 1129-1140.
133. Simms, L. (2012). Quantitative Risk Assessment vs. the Whole Story? Presented at 66th Tobacco Science Research Conference, Concord, NC, USA. (10 September, 2012). Available at: http://www.imperialtobaccoscience.com/files/pdf/smoketoxicology/quantitative-risk-assessment-vs-whole-story.pdf (Accessed 22.07.15).
134. Cunningham, F.H., Fiebelkorn, S., Johnson, M. & Meredith, C. (2011). A novel application of the Margin of Exposure approach: Segregation of tobacco smoke toxicants. Food & Chemical Toxicology 49, 2921-2933.
135. Hatsukami, D.K., Benowitz, N.L., Donny, E., Henningfield, J. & Zeller, M. (2013). Nicotine reduction: Strategic research plan. Nicotine & Tobacco Research 15, 1003-1013.
136. Czogala, J., Goniewicz, M.L., Fidelus, B., Zielinska-Danch, W., Travers, M.J. & Sobczak, A. (2014). Secondhand exposure to vapors from electronic cigarettes. Nicotine & Tobacco Research 16, 655-662.
137. Dillon, D., Combes, R. & Zeiger, E. (1998). The effectiveness of Salmonella strains TA100, TA102 and TA104 for detecting mutagenicity of some aldehydes and peroxides. Mutagenesis 13, 19-26.
138. Williams, M., Villarreal, A., Bozhilov, K., Lin, S. & Talbot, P. (2013). Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol. PLoS One 8, e57987.
139. Tang, M.S., Wang, H.T., Hu, Y., Chen, W.S., Akao, M., Feng, Z. & Hu, W. (2011). Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Molecular Nutrition & Food Research 55, 1291-1300.
140. Cheng, T. (2014). Chemical evaluation of electronic cigarettes. Tobacco Control 23, Suppl. ii, 11-17.
141. Hecht, S.S. (1998). Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chemical Research in Toxicology 11, 559-603.
142. Brown, B.G., Borschke, A.J. & Doolittle, D.J. (2003). An analysis of the role of tobacco-specific nitrosamines in the carcinogenicity of tobacco smoke. Nonlinearity in Biology, Toxicology, Medicine 1, 179-198.
143. Nair, J., Ohshima, H., Nair, U.J. & Bartsch, H. (1996). Endogenous formation of nitrosamines and oxidative DNA-damaging agents in tobacco users. Critical Reviews in Toxicology 26, 149-161.
144. Camacho, O.M., Eldridge, A., Proctor, C.J. & McAdam, K. (2015). Empirical characterisation of ranges of mainstream smoke toxicant yields from contemporary cigarette products using quantile regression methodology. Regulatory Toxicology & Pharmacology 72, 458-472.
145. Benowitz, N.L. (1996). Biomarkers of cigarette smoking. In The FTC Cigarette Test Method for Determining Tar, Nicotine, and Carbon Monoxide Yields of U.S. Cigarettes. Smoking and Tobacco Control Monograph No. 7 Chapter 7, pp. 93-111. Bethesda, MD, USA: National Cancer Institute.
146. Combes, R.D. (1991). Use of clinical samples for biomonitoring of genotoxic exposure to pharmaceuticals. In Clinical Measurement in Drug Evaluation (ed. W. Nimmo), pp. 173-191. London, UK: Wolfe Medical Publications Limited.
147. Younesi, E., Ansari, S., Guendel, M., Ahmadi, S., Coggins, C., Hoeng, J., Hofmann-Apitius, M. & Peitsch, M.C. (2014). CSEO - The Cigarette Smoke Exposure Ontology. Journal of Biomedical Semantics 5, 31.
148. Mauderly, J.L., Gigliotti, A.P., Barr, E.B., Bechtold, W.E., Belinsky, S.A., Hahn, F.F., Hobbs, C.A., March, T.H., Seilkop, S.K. & Finch, G.L. (2004). Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats. Toxicological Sciences 81, 280-292.
149. Gordon, T. & Bosland, M. (2009). Straindependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke. Cancer Letters 275, 213-220.
150. Doll, R. & Peto, R. (1976). Mortality in relation to smoking: 20 years observations on male British doctors. British Medical Journal 2, 1525-1536.
151. Proctor, R.N. (2012). The history of the discovery of the cigarette-lung cancer link: Evidentiary traditions, corporate denial, global toll. Tobacco Control 21, 87-91.
152. Coggins, C.R. (2007). An updated review of inhalation studies with cigarette smoke in laboratory animals. International Journal of Toxicology 26, 331-338.
153. Hecht, S.S. (2012). Lung carcinogenesis by tobacco smoke. International Journal of Cancer 131, 2724-2732.
154. Combes, R.D. (2005). Assessing risk to humans from chemical exposure by using non-animal test data. Toxicology in Vitro 19, 921-924.
155. Stevens, J.L. & Baker, T.K. (2009). The future of drug safety testing: Expanding the view and narrowing the focus. Drug Discovery Today 14, 162-167.
156. Stevens, J.L. (2006). Future of toxicology - mechanisms of toxicity and drug safety: Where do we go from here? Chemical Research in Toxicology 19, 1393-1401.
157. McKim, J.M. (2010). Building a tiered approach to in vitro predictive toxicity screening: A focus on assays with in vivo relevance. Combinatorial Chemistry & High Throughput Screening 13, 188- 206.
158. McKimm, J. (2012). Development and application of in vitro models for screening drugs and environmental chemicals that predict toxicity in animals and humans, 49pp. Kalamazoo, MI, USA: Cyprotex. Available at: http://www.epa.gov/ncct/download-files/chemical-prioritization/EPA%20Presentation%202012.pdf (Accessed 26.03.15).
159. Anon. (2003). Uncertainty Factors: Their Use in Human Health Risk Assessment by the UK Government, 73pp. Leicester, UK: The Interdepart - mental Group on Health Risks from Chemicals, MRC Institute for Environment and Health.
160. Anon. (2001). Guidance Document on Using In Vitro Data to Estimate In Vivo Starting Doses for Acute Toxicity, 102pp. Based on Recommendations from an International Workshop Organised by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and the National Toxicology Program (NTP) Inter - Agency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) National Institute of Environmental Health Sciences National Institutes of Health US Public Health Service Department of Health and Human Services. Triangle Park, NC, USA: NIEHS. Avail - Able at: http://www.epa.gov/hpv/pubs/general/nih2001b.pdf (Accessed 26.03.15).
161. Bhattacharya, S., Zhang, Q., Carmichael, P.L., Boekelheide, K. & Andersen, M.E. (2011). Toxicity testing in the 21 century: Defining new risk 286 Comment assessment approaches based on perturbation of intracellular toxicity pathways. PLoS One 6, e20887.
162. Keller, D.A., Juberg, D.R., Catlin, N., Farland, W.H., Hess, F.G., Wolf, D.C. & Doerrer, N.G. (2012). Identification and characterization of adverse effects in 21st century toxicology. Toxicological Sciences 126, 291-297.
163. Krewski, D., Acosta, D. Jr, Andersen, M., Anderson, H., Bailar, J.C., Boekelheide, K., Brent, R., Charnley, G., Cheung, V.G., Green, S. Jr, Kelsey, K.T., Kerkvliet, N.I., Li, A.A., McCray, L., Meyer, O., Patterson, R.D., Pennie, W., Scala, R.A., Solomon, G.M., Stephens, M., Yager, J. & Zeise, L. (2010). Toxicity testing in the 21st century: A vision and a strategy. Journal of Toxicology & Environ - mental Health 13, 51-138.
164. Combes, R.D., Dandrea, J. & Balls, M. (2003). FRAME and the Royal Commission on Environmental Pollution: Common recommendations for assessing risks posed by chemicals under the EU REACH system. ATLA 31, 529-535.
165. Bhogal, N., Combes, R. & Balls, M. (2008). Preclinical drug development planning. In Preclinical Development Handbook (ed. S.C. Gad), pp. 1-64. Hoboken, NJ, USA: John Wiley & Sons, Inc.
166. Kirkland, D., Pfuhler, S., Tweats, D., Aardema, M., Corvi, R., Darroudi, F., Elhajouji, A., Glatt, H., Hastwell, P., Hayashi, M., Kasper, P., Kirchner, S., Lynch, A., Marzin, D., Maurici, D., Meunier, J.R., Muller, L., Nohynek, G., Parry, J., Parry, E., Thybaud, V., Tice, R., van Benthem, J., Vanparys, P. & White, P. (2007). How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop. Mutation Research 628, 31-55.
167. Balls, M., Amcoff, P., Bremer, S., Casati, S., Coecke, S., Clothier, R., Combes, R., Corvi, R., Curren, R., Eskes, C., Fentem, J., Gribaldo, L., Halder, M., Hartung, T., Hoffmann, S., Schechtman, L., Scott, L., Spielmann, H., Stokes, W., Tice, R., Wagner, D. & Zuang, V. (2006). The principles of weight of evidence validation of test methods and testing strategies. The Report and Recommendations of ECVAM Workshop 58. ATLA 34, 603-620.
168. Balls, M., Blaauboer, B.J., Bruner, L., Combes, R.D., Ekwall, B., Fentem, J.H., Fielder, R., Guillouzo, A., Lewis, R., Lovell, D., Reinhardt, C., Repetto, G., Sladowski, D., Spielmann, H. & Zucco, F. (1995). Practical aspects of the validation of toxicity test procedures. ATLA 23, 129-147.
169. Curren, R.D., Southee, J.A., Spielmann, H., Liebsch, M., Fentem, J.H. & Balls, M. (1995). The role of prevalidation in the development, validation and acceptance of alternative methods. ATLA 23, 211-217.
170. Kinsner-Ovaskainen, A., Maxwell, G., Kreysa, J., Barroso, J., Adriaens, E., Alépée, N., Berg, N., Bremer, S., Coecke, S., Comenges, J.Z., Corvi, R., Casati, S., Dal Negro, G., Marrec-Fairley, M., Griesinger, C., Halder, M., Heisler, E., Hirmann, D., Kleensang, A., Kopp-Schneider, A., Lapenna, S., Munn, S., Prieto, P., Schechtman, L., Schultz, T., Vidal, J.M., Worth, A. & Zuang, V. (2012). Report of the EPAA-ECVAM workshop on the validation of Integrated Testing Strategies (ITS). ATLA 40, 175-181.
171. Anon. (2011). FDA Statement on the Institute of Medicine Report: Scientific Standards for Studies on Modified Risk Tobacco Products, 1p. Silver Spring, MD, USA: Food and Drug Administration. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm283628.htm (Accessed 26.03.15).
172. Anon. (2015). E-cigarettes: A New Foundation for Evidence-based Policy and Practice, 6pp. London, UK: Public Health England. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment-data/file/454517/Ecigarettes-a-firm-foundation-for-evidence-based-policy-and-practice.pdf (Accessed 02.10.15).
173. McNeill, A., Brose, L.S., Calder, R., Hitchman, S.C., Hajek, P. & McRobbie, H. (2015). E-cigarettes: An Evidence Update. A Report Commissioned by Public Health England, 113pp. London, UK: Public Health England. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment-data/file/457102/Ecigarettes-an-evidence-update-A-report-commissioned-by-Public-Health-England-FINAL.pdf (Accessed 02.10.15).
174. Britton, J. & Bogdanovica, I. (2014). Electronic Cigarettes. A Report Commissioned by Public Health England, 30pp. London, UK: Public Health Eng - land. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment-data/file/311887/Ecigarettes-report.pdf (Accessed 02.10. 15).
175. Hajek, P., Etter, J-F., Benowitz, N., Eissenberg, T. & McRobbie, H. (2014). Electronic cigarettes: Review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction 109, 1801-1810.
176. Farsalinos, K.E. & Polosa, R. (2014). Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: A systematic review. Therapeutic Advances in Drug Safety 5, 67-86.
177. Nutt, D.J., Phillips, L.D., Balfour, D., Curran, H.V., Dockrell, J.M., Foulds, J., Fagerstrom, K., Letlape, K., Milton, A., Polosa, R., Ramsey, J. & Sweanor, D. (2014). Estimating the harms of nicotine-containing products using the MCDA approach. European Addiction Research 20, 218-225.
178. Willoughby, J.A. (2014). Predicting respiratory toxicity using a human 3D airway (EpiAirway) model combined with multiple parametric analysis. Applied in Vitro Toxicology 1, 21-31.
179. Pucheu-Haston, C.M., Copeland, L.B., Vallanat, B., Boykin, E. & Ward, M.D. (2010). Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential. Toxicology & Applied Pharmacology 244, 144-155.
180. Kimber, I. & Dearman, R.J. (2002). Chemical respiratory allergy: Role of IgE antibody and relevance of route of exposure. Toxicology 181-182, 311-315.
181. Roggen, E., Aufderheide, M., Cetin, Y., Dearman, R.J., Gibbs, S., Hermanns, I., Kimber, I., Regal, J.F., Rovida, C., Warheit, D.B., Uhlig, S. & Casati, S. (2008). The development of novel approaches to the identification of chemical and protein respiratory allergens. Progress made from the Conclusions and Recommendations of ECVAM Workshop 60. ATLA 36, 591-598.
182. Isola, D., Kimber, I., Sarlo, K., Lalko, J. & Sipes, I.G. (2008). Chemical respiratory allergy and occupational asthma: What are the key areas of uncertainty? Journal of Applied Toxicology 28, 249-253.
183. Boverhof, D.R., Billington, R., Gollapudi, B.B., Hotchkiss, J.A., Krieger, S.M., Poole, A., Wiescinski, C.M. & Woolhiser, M.R. (2008). Respiratory sensitization and allergy: Current research approaches and needs. Toxicology & Applied Pharmacology 226, 1-13.
184. Rovida, C., Martin, S.F., Vivier, M., Weltzien, H.U. & Roggen, E. (2013). Advanced tests for skin and respiratory sensitization assessment. ALTEX 30, 231-252.
185. Holsapple, M.P., Jones, D., Kawabata, T.T., Kimber, I., Sarlo, K., Selgrade, M-J.K., Shah, J. & Woolhiserk, M.R. (2006). Assessing the potential to induce respiratory hypersensitivity. Toxicol ogical Sciences 91, 4-13.
186. Murugan, A., Prys-Picard, C. & Calhoun, W.J. (2009). Biomarkers in asthma. Current Opinion in Pulmonary Medicine 15, 12-18.
187. Huang, S., Wiszniewski, L., Derouette, J-P. & Constant, S. (2009). In vitro organ culture models of asthma. Drug Discovery Today: Disease Models 6, 137-144.
188. Blume, C. & Davies, D.E. (2013). In vitro and ex vivo models of human asthma. European Journal of Pharmaceutics & Biopharmaceutics 84, 394-400.
189. Anon. (undated). Developing a Platform of In Vitro Models of Asthmatic and Healthy Lung: An Alternative to the Use of Animals in Asthma Research. London, UK: NC3Rs. Available at: https://www.nc3rs.org.uk/developing-platform-vitromodels-asthmatic-and-healthy-lung-alternativeuse-animals-asthma-research (Accessed 27.03.15).
190. Wynn, T.A. (2011). Integrating mechanisms of pulmonary fibrosis. Journal of Experimental Medicine 208, 1339-1350.
191. Rock, J.R., Barkauskas, C.E., Cronce, M.J., Xue, Y., Harris, J.R., Liang, J., Noble, P.W. & Hogan, B.L.M. (2011). Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proceedings of the National Academy of Sciences of the USA 108, E1475-E1483.
192. Todd, N.W., Luzina, I.G. & Atamas, S.P. (2012). Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis & Tissue Repair 5, 11.
193. Anon. (undated). Fibrosis. Albuquerque, NM, USA: Lovelace Research Institute. Available at: http://www.lrri.org/exploring-fibrosis.aspx (Accessed 27. 03.15).
194. Molina-Molina, M., Pereda, J. & Xaubet, A. (2007). Experimental models for the study of pulmonary fibrosis: Current usefulness and future promise. Archivos de Bronconeumologia 43, 501-507.
195. Adamson, J., Haswell, L.E., Phillips, G. & Gaça, M.D. (2011). In vitro models of chronic obstructive pulmonary disease (COPD). In Bronchitis (ed. I.M. Ãn-Loeches), pp. 41-66. Rijeka, Croatia: InTech.
196. Gray, A.C., McLeod, J.D. & Clothier, R.H. (2007). A review of in vitro modelling approaches to the identification and modulation of squamous metaplasia in the human tracheobronchial epithelium. ATLA 35, 493-504.
197. Dillon, M. (2008). A role for squamous metaplasia in COPD airway obstruction. Thorax 63, 258.
198. Araya, J., Cambier, S., Markovics, J.A., Wolters, P., Jablons, D., Hill, A., Finkbeiner, W., Jones, K., Broaddus, V.C., Sheppard, D., Barzcak, A., Xiao, Y., Erke, D. & Nishimura, S.L. (2007). Squamous meta plasia amplifies pathologic epithelial-mesen - chymal interactions in COPD patients. Journal of Clinical Investigation 117, 3551-3562.
199. Vanhée, D., Gosset, P., Boitelle, A., Wallaert, B. & Tonnel, A.B. (1995). Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis. European Respiratory Journal 8, 834-842.
200. Kamp, D.W. (2012). Pneumoconiosis. In American College of Chest Physicians Pulmonary Medicine Board Review, 26th edn, Chapter 18. Available at: http://dx.doi.org/10.1378/pulm.26.0 (Accessed 26.03. 15).
201. Gulumian, M., Borm, P.J., Vallyathan, V., Castra - nova, V., Donaldson, K., Nelson, G. & Murray, J. (2006). Mechanistically identified suitable biomarkers of exposure, effect, and susceptibility for silicosis and coal-worker's pneumoconiosis: A comprehensive review. Journal of Toxicology & Environmental Health Part B: Critical Reviews 9, 357-395.
202. Griffith, J.W. & Riling, S.A. (1996). A primate bronchoscopy model of pneumoconiosis: Description of the model and initial anthracite and quartz dustinduced lesions. Applied Occupational & Environ - mental Hygiene 11, 996-1007.
203. Hayden, P.J., Jackson, G.R., Bolmarcich, J.L., Stolper, G., Spiller, E. & Klausner, M. (2007). Cytokine-induced Goblet Cell Hyperplasia in the (EpiAirway-FT) In Vitro Full-thickness Human Airway Model. Poster B33, American Thoracic Society Annual Meeting, San Francisco, CA, USA, 22 May 2007. Ashland, MA, USA: MatTek Corpor - Ation. Available at: http://www.mattek.com/446-cytokine-induced-goblet-cell-hyperplasia-in-the-epiairwayft-in-vitro-full-thickness-human-airwaymodel(Accessed 27.03.15).
204. Haswell, L.E., Hewitt, K., Thorne, D., Richter, A. & Gaça, M.D. (2010). Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: A potential model of goblet cell hyperplasia. Toxicology in Vitro 24, 981-987.
205. Bolmarcich, J., Wilbert, S., Wright, C., Jackson, G.R., Kenney, T., Baker, B. & Hayden, P.J. (2011). Mechanisms of Goblet Cell Hyperplasia Induced by Simulated Viral Exposure or TH2 Cytokines in the EpiAirway-FT™ In Vitro Human Airway Model. Presented at the American Thoracic Society Meet - ing, Denver, CO, USA, 13-18 May 2011. Available at: http://mattek.com/technical-references/TR-663 (Accessed 27.03.15).
206. Rogers, D.F. (1994). Airway goblet cells: Responsive and adaptable front-line defenders. European Respiratory Journal 7, 1690-1706.
207. Huang, S., Wiszniewski, L., Constant, S. & Roggen, E. (2013). Potential of in vitro reconstituted 3D human airway epithelia (MucilAir™) to assess respiratory sensitizers. Toxicology in Vitro 27, 1151- 1156.
208. Combes, R.D. (2013). Progress in the development, validation and regulatory acceptance of in vitro methods for toxicity testing. In Elsevier Reference Module in Chemistry, Molecular Sciences and Chemical Engineering (ed. J. Reedijk), pp. 1-25. Waltham, MA, USA: Elsevier.
209. Kim, J.E., Koo, K.H., Kim, Y.H., Sohn, J. & Park, 288 Comment Y.G. (2008). Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Experimental & Molecular Medicine 40, 709-720.
210. Mas, C., Huang, S., Wiszniewski, L. & Constant, S. (2014). In Vitro Human Airway Tissue Model for Lung Cancer Research. Abstract A3455, American Thoracic Society 2014 International Conference, San Diego, CA, USA, 16-21 May 2014.
211. Switalla, S., Knebel, J., Ritter, D., Dasenbrock, C., Krug, N., Braun, A. & Sewald, K. (2013). Determination of genotoxicity by the Comet assay applied to murine precision-cut lung slices. Toxicology in Vitro 27, 798-803.
212. Phillips, J., Kluss, B., Richter, A. & Massey, E.D. (2005). Exposure of bronchial epithelial cells to whole cigarette smoke: Assessment of cellular responses. ATLA 33, 239-248.
213. Combes, R.D. (2000). The use of structure-activity relationships and markers of cell toxicity to detect non-genotoxic carcinogens. Toxicology in Vitro 14, 387-399.
214. Hernández, L.G. (2009). Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutation Research/Reviews in Mutation Research 682, 94-109.
215. Lee, S.L., Yum, Y.N., Kim, S.C., Kim, Y., Lim, J., Lee, W.J., Koo, K.H., Kim, J.H., Kim, J.E., Lee, W.S., Sohn, S., Park, S.N., Park, J.H., Lee, J. & Kwon, S.W. (2006). Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis. Scientific Reports 3, 2783.
216. Combes, R., Balls, M., Curren, R., Fischbach, M., Fusenig, N., Kirkland, D., Lasne, C., Landolph, J., LeBoeuf, R., Marquardt, H., McCormick, J., Müller, L., Rivedal, E., Sabbioni, E., Tanaka, N., Vasseur, P. & Yamasaki, H. (1999). Cell transformation assays as predictors of human carcinogenicity. The Report and Recommendations of ECVAM Workshop 39. ATLA 27, 745-767.
217. Combes, R.D. (2012). Cell transformation assays: Are we barking up the wrong tree? ATLA 40, 115-130.
218. Schlage, W.K., Iskandar, A.R., Kostadinova, R., Xiang, Y., Sewer, A., Majeed, M., Kuehn, D., Frentzel, S., Talikka, M., Geertz, M., Mathis, C., Ivanov, N., Hoeng, J. & Peitsch, M.C. (2014). In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures. Toxicology Mechanisms & Methods 24, 470-487.
219. Misra, M., Leverette, R.D., Cooper, B.T., Bennett, M.B. & Brown, S.E. (2014). Comparative in vitro toxicity profile of electronic and tobacco cigarettes, smokeless tobacco and nicotine replacement therapy products: E-liquids, extracts and collected aerosols. International Journal of Environmental Research & Public Health 11, 11, 325-11, 347.
220. Desai, U., Chougule, M., Okaro, C. & Sin, M. (2010). AlgiMatrix® 3D Cell Culture System as an In Vitro Tumor Model for H460 Non-small Cell Lung Cancer Cell Line. Poster Abstract No. 3234, American Association for Cancer Research 101st Annual Meeting, Washington, DC, USA, 17-21 April 2010. Available at: http://tools.lifetechnologies.com/content/sfs/posters/AACR-algimatrix-3D-2010-Abstac-%20no-3234.pdf (Accessed 27.03.15).
221. Mishra, D.K., Sakamoto, J.H., Thrall, M.J., Baird, B.N., Blackmon, S.H., Ferrari, M., Kurie, J.M. & Kim, M.P. (2012). Human lung cancer cells grown in an ex vivo 3D lung model produce matrix metalloproteinases not produced in 2D Culture. PLoS One 7, e45308.
222. Nichols, J.E., Niles, J.A., Vega, S.P. & Cortiella, J. (2013). Novel in vitro respiratory models to study lung development, physiology, pathology and toxicology. Stem Cell Research & Therapy 4, Suppl. 1, S7.
223. Ekert, J.E., Johnson, K., Strake, B., Pardinas, J., Jarantow, S., Perkinson, R. & Colter, D.C. (2014). Three-dimensional lung tumor microenvironment modulates therapeutic compound responsiveness in vitro-implication for drug devel opment. PLoS One 17, e92248.
224. Qadir, N., Tilley, A.E., Staudt, M.R., Fuller, J., De, B.P. & Crystal, R.G. (2012). Smoking-induced Upregulation of Microseminoprotein Beta Gene Expression in the Human Airway. Abstract D60: Health Effects of Smoking, American Thoracic Society International Conference. Available at: http://www.atsjournals.org/doi/abs/10.1164/ajrccmconference. 2012.185.1-MeetingAbstracts.A6052 (Accessed 27.03.15).
225. Mumbarkar, P.P., Raste, A.S. & Ghadge, M.S. (2006). Significance of tumor markers in lung cancer. Indian Journal of Clinical Biochemistry 21, 173-176.
226. Sanyal, S. (2010). In Vitro Models for Studying Angio genesis, 50pp. Franklin Lakes, NJ, USA: Becton, Dickinson and Company (BD). Available at: www.bdbiosciences.com/documents/webinar-2010-05-angiogenesis.pdf (Accessed 27.03.15).
227. Vailhé, L.B., Vittet, D. & Feige, J-J. (2001). In vitro models of vasculogenesis and angiogenesis. Laboratory Investigation 81, 439-452.
228. Anon. (2014). Method Review by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), 8pp. Triangle Park, NC, USA: ICCVAM. Available at: http://www.piscltd.org.uk/wp-content/uploads/2014/10/33-ICCVAM-methods-FINAL.pdf (Accessed 01.04.15).
229. Anon. (undated). JaCVAM Statements. Available at: http://www.jacvam.jp/en-effort/effort02.html (Accessed 01.04.15).
230. Anon. (2015). OECD Guidelines for the Testing of Chemicals. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/env/ehs/testing/oecdguidelinesforthetestingofchemicals.htm (Accessed 26.03. 15).
231. Anon. (2013). EURL ECVAM Recommendation on the 3T3 Neutral Red Uptake Cytotoxicity Assay for Acute Oral Toxicity Testing, 46pp. Ispra, Italy: EURL ECVAM. Available at: https://eurl-ecvam.jrc.ec.europa.eu/eurl-ecvam-recommendations/files-3t3/ReqNo-JRC79556-lbna25946enn.pdf (Accessed 01.04.15).
232. Anon. (undated). List of all ESAC Statements on Alternative Methods. Ispra, Italy: EURL ECVAM. Available at: https://eurl-ecvam.jrc.ec.europa.eu/about-ecvam/scientific-advice-stakeholdersnetworks/ecvam-scientific-advisory-committeeesac/statements-opinions (Accessed 01.04.15).
233. Anon. (2012). EURL ECVAM Recommendation Concerning the Cell Transformation Assays (CTA). Available at: https://eurl-ecvam.jrc.ec.europa.eu/eurl-ecvam-recommendations/cta-recommendation (Accessed 01.04.15).
234. Anon. (2006). OECD Environment, Health and Safety Publications Series on Testing and Assessment No. 31: Detailed Review Paper on Cell Transformation Assays for Detection of Chemical Carcinogens, 170pp. Paris, France: Organisation for Economic Cooperation and Development. Available at: http://www.oecd.org/env/ehs/testing/37863750.pdf (Accessed 01.04.15).
235. Anon. (2013). Draft Test Guideline. In Vitro Carcinogenicity: Bhas 42 Cell Transformation Assay, 21pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/env/ehs/testing/Bhas-42-CTA-TG-HRI-Draft-Rev-7.pdf (Accessed 01.04. 15).
236. Anon. (2013). EURL ECVAM Recommendation on the Cell Transformation Assay Based on the Bhas 42 Cell Line, 34pp. Ispra, Italy: EURL ECVAM. Available at: https://eurl-ecvam.jrc.ec.europa.eu/eurl-ecvam-recommendations/files-bhas/EURL-ECVAM-Recommendation-Bhas-CTA-2013.pdf(Accessed 01.04.15).
237. Anon. (2014). OECD Guideline for the Testing of Chemicals: Proposal for Updating Guideline 476: In Vitro Mammalian Cell Gene Mutation Tests using the Hprt and xprt genes, 17pp. Paris, France: Organisation for Economic Co-operation and Dev - elopment. Available at: http://www.oecd.org/env/ehs/testing/Revised%20TG476.pdf (Accessed 01.04.15).
238. Anon. (2014). OECD Guideline for the Testing of Chemicals: New Test Guideline; In Vitro Mammalian Cell Gene Mutation Assays Using the Thymidine Kinase Gene, 30pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/chemicalsafety/testing/17July-2014-TK.pdf (Acc - essed 01.04.15).
239. Anon. (2012). OECD Guideline for the Testing of Chemicals: In Vitro Mammalian Micronucleus Test, TG 487, 26pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.pasteur-lille.fr/mutagenese/userfiles/files/guidelines%20OCDE/GL487-140926-GB.pdf (Accessed 01.04.15).
240. Anon. (2011). Guidance for Industry: S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use, 35pp. Silver Spring, MD, USA: US Food and Drug Administration. Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm074931.pdf (Accessed 01.04.15).
241. Anon. (2014). OECD Guideline for the Testing of Chemicals: In Vitro Mammalian Chromosomal Aberration Test, TG 473, 10pp. Paris, France: Organisation for Economic Co-operation and Dev - elopment. Available at: http://www.pasteur-lille.fr/mutagenese/userfiles/files/guidelines%20OCDE/GL473-140926-GB.pdf (Accessed 01.04.15).
242. Anon. (2013). OECD Guideline for the Testing of Chemicals: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method, 21pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg439-2013-508.pdf (Accessed 01.04.15).
243. Anon. (2014). OECD Guidelines for the Testing of Chemicals, Draft Revised Guideline 439: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method, 17pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/chemicalsafety/testing/drafttg439-skin-corrosion-july14.pdf (Accessed 01.04. 15).
244. Anon. (2010). OECD Background Document No. 137: Explanatory Background Document to the OECD Test Guideline on In Vitro Skin Irritation Testing, 219pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono%282010%2936&doclanguage=en (Accessed 01.04.15).
245. Spielmann, H. (2009). AltTox Forum Topic: In vitro skin irritation: Acceptance as EU test method B.46 into COM regulation. Available at: http://forums.alttox.org/index.php?topic=249.0 (Accessed 01.04. 15).
246. Anon. (2014). OECD Guidelines for the Testing of Chemicals: Draft Proposal for a New Test Guideline: In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method, 21pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/chemicalsafety/testing/Draft-Keratinosens-TG-16May-final.pdf (Accessed 01.04. 15).
247. Anon. (2014). OECD Guidelines for the Testing of Chemicals: Draft Proposal for a New Test Guideline: In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA), 18pp. Paris, France: Organisation for Economic Co-operation and Development. Available at: http://www.oecd.org/chemicalsafety/testing/Draft-DPRA-TG-final-15May2014.pdf (Accessed 01.04.15).
248. Anon. (2014). EURL ECVAM Recommendation on the KeratinoSens™ Assay for Skin Sensitisation Testing, 42pp. Ispra, Italy: EURL ECVAM . Available at: https://eurl-ecvam.jrc.ec.europa.eu/eurl-ecvamrecommendations/file-kerati/JRC-SPR-Keratinosens-Rec-17-02-2014.pdf (Accessed 01.04. 15).