Toxicological assessment of kretek cigarettes part 4: Mechanistic investigations, smoke chemistry and in vitro toxicity

Regulatory Toxicology and Pharmacology

Volumn 70, Issue S1, 2014, Pages S41-S53

  Roemer, E ^a   Dempsey, R ^a   Lawless Pyne, J ^b   Lukman, S ^b   Evans, A Deger ^a   Trelles Sticken, E ^c   Wittke, S ^c   Schorp, M K ^a  

^a PHILIP MORRIS PRODUCTS S A   (Switzerland)

^b PT HM Sampoerna Tbk   (Indonesia)

^c Philip Morris Research Laboratories GmbH   (Germany)

Author keywords

Clove cigarettes; Cytotoxicity; Eugenol; Kretek; Mutagenicity; Smoke chemistry

Indexed keywords

1,3 BUTADIENE; 2 METHYLANILINE; 2 NAPHTHYLAMINE; 2 NITROPROPANE; 4 BIPHENYLAMINE; ACETALDEHYDE; ACETAMIDE; ACROLEIN; ACRYLONITRILE; ALCOHOL; BENZENE; CARBON MONOXIDE; CATECHOL; CIGARETTE SMOKE; CLOVE OIL; CROTONALDEHYDE; EUGENOL; FORMALDEHYDE; HYDROQUINONE; ISOPRENE; NICOTINE; NITROGEN OXIDE; NITROSAMINE; PHENOL; PROPIONALDEHYDE; STYRENE; TAR; TOLUENE; VINYL CHLORIDE; OLEORESINS; PLANT EXTRACT; SMOKE;

AMES TEST; ANIMAL CELL; ARTICLE; CLOVE; CONTROLLED STUDY; CYTOTOXICITY; DILUTION; EMBRYO; GENOTOXICITY; IN VITRO STUDY; MOUSE; MUTAGENICITY; NONHUMAN; PARTICULATE MATTER; SALMONELLA; TOBACCO; TOXICITY TESTING; 3T3 CELL LINE; ADVERSE EFFECTS; ANALYSIS; ANIMAL; CELL SURVIVAL; DRUG EFFECTS; EUGENIA; GENETICS; MUTAGEN TESTING; SALMONELLA ENTERICA SEROVAR TYPHIMURIUM; SMOKE; TUMOR CELL LINE;

BACTERIA (MICROORGANISMS); NICOTIANA TABACUM; SYZYGIUM AROMATICUM;

ANIMALS; BALB 3T3 CELLS; CELL LINE, TUMOR; CELL SURVIVAL; CLOVE OIL; EUGENIA; EUGENOL; MICE; MUTAGENICITY TESTS; PLANT EXTRACTS; SALMONELLA TYPHIMURIUM; SMOKE; TOBACCO PRODUCTS;

EID: 84919910893     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2014.09.012     Document Type: Article

References (65)

1. Atsumi T., Iwakura I., Fujisawa S., Ueha T. Reactive oxygen species generation and photo-cytotoxicity of eugenol in solutions of various pH. Biomaterials 2001, 22:1459-1466.
2. Azizan A., Blevins R.D. Mutagenicity and antimutagenicity testing of six chemicals associated with the pungent properties of specific spices as revealed by the Ames Salmonella/microsomal assay. Arch. Environ. Contam. Toxicol. 1995, 28:248-258.
3. Baker R.R., Bishop L.J. The pyrolysis of tobacco ingredients. J. Anal. Appl. Pyrolysis. 2004, 71:223-311.
4. Baker R.R., Pereira da Silva J.R., Smith G. The effect of tobacco ingredients on smoke chemistry. Part II: casing ingredients. Food Chem. Toxicol. 2004, 42(Suppl.):S39-S52.
5. Bombick D.W., Putnam K., Doolittle D.J. Comparative cytotoxicity studies of smoke condensates from different types of cigarettes and tobaccos. Toxicol. In Vitro 1998, 12:241-249.
6. Borenfreund E., Puerner J.A. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol. Lett. 1985, 24:119-124.
7. Borenfreund E., Puerner J.A. Short-term quantitative in vitro cytotoxicity assay involving an S-9 activating system. Cancer Lett. 1987, 34:243-248.
8. Caldwell J. Perspective on the usefulness of the mouse lymphoma assay as an indicator of a genotoxic carcinogen: ten compounds which are positive in the mouse lymphoma assay but are not genotoxic carcinogens. Teratog. Carcinog. Mutagen. 1993, 13:185-190.
9. Chang H.J., Kim J.M., Lee J.C., Kim W.K., Chun H.S. Protective effect of beta-caryophyllene, a natural bicyclic sesquiterpene, against cerebral ischemic injury. J. Med. Food. 2013, 16:471-480.
10. Chang Y.C., Tai K.W., Huang F.M., Huang M.F. Cytotoxic and nongenotoxic effects of phenolic compounds in human pulp cell cultures. J. Endod. 2000, 26:440-443.
11. Chen P.X., Moldoveanu S.C. Mainstream smoke chemical analyses for 2R4F Kentucky reference cigarette. Beitr. Tabakforsch. Int. 2003, 20:448-458.
12. Chepiga T.A., Morton M.J., Murphy P.A., Avalos J.T., Bombick B.R., Doolittle D.J., Borgerding M.F., Swauger J.E. A comparison of the mainstream smoke chemistry and mutagenicity of a representative sample of the US cigarette market with two Kentucky reference cigarettes (K1R4F and K1R5F). Food Chem. Toxicol. 2000, 38:949-962.
13. Clive D., Flamm W.G., Machesko M.R., Bernheim N.J. A mutational assay system using the thymidine kinase locus in mouse lymphoma cells. Mutat. Res. 1972, 16:77-87.
14. Cole J., Muriel W.J., Bridges B.A. The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2c)] mouse lymphoma cells. Mutagenesis 1986, 1:157-167.
15. Davies, H.M., Vaught, A., 2013. The reference cigarette. Kentucky Tobacco Research & Development Center, Lexington Kentucky. Available from: (accessed February 2013). http://legacy.library.ucsf.edu/tid/rrk20i00/pdf.
16. Dorange J.L., Delaforge M., Janiaud P., Padieu P. Mutagenicity of the metabolites of the epoxide-diol pathway of safrole and its analogs. Study on Salmonella typhimurium. C R Seances Soc. Biol. Fil. 1977, 171:1041-1048.
17. EFSA, 2009. Flavouring Group Evaluation 60 (FGE.60) 1: consideration of eugenol and related hydroxyallylbenzene derivatives evaluated by JECFA (65th meeting) structurally related to ring-substituted phenolic substances evaluated by EFSA in FGE.22 (2006). EFSA J. ON-965, 1-53.
18. Fischer I.U., von Unruh G.E., Dengler H.J. The metabolism of eugenol in man. Xenobiotica 1990, 20:209-222.
19. Fujisawa S., Atsumi T., Kadoma Y., Sakagami H. Antioxidant and prooxidant action of eugenol-related compounds and their cytotoxicity. Toxicology 2002, 177:39-54.
20. Fujisawa S., Atsumi T., Satoh K., Kadoma Y., Ishihara M., Okada N., Nagasaki M., Yokoe I., Sakagami H. Radical generation, radical-scavenging activity, and cytotoxicity of eugenol-related compounds. In Vitro Mol. Toxicol. 2000, 13:269-280.
21. Guidotti T.L., Binder S., Stratton J.W., Schechter F.G., Jenkins R.A. Clove cigarettes: development of a fad and evidence for health effects. Curr. Top. Pulmonary Pharmacol. Toxicol. 1987, 2:1-23.
22. Guidotti T.L., Laing L., Prakash U.B. Clove cigarettes. The basis for concern regarding health effects. West J. Med. 1989, 151:220-228.
23. Ho Y.C., Huang F.M., Chang Y.C. Mechanisms of cytotoxicity of eugenol in human osteoblastic cells in vitro. Int. Endod. J. 2006, 39:389-393.
24. IARC, 1985. International Agency for Research on Cancer, Tobacco Smoking. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, vol. 38. Lyon, France.
25. International Organization for Standardization (ISO) International Standard ISO 3308, Routine Analytical Cigarette Smoking Machine - Definitions and Standard Conditions 2000, ISO, Geneva, Switzerland. 4th ed.
26. ISO, 1991. International Standard ISO 4387, Determination of total and nicotine-free dry particulate matter using routine analytical smoking machine. International Organization for Standardization, Geneva, Switzerland.
27. ISO International Standard ISO 3402, Tobacco and Tobacco Products - Atmosphere for Conditioning and Testing 1999, International Organization for Standardization, Geneva, Switzerland.
28. ISO International Standard ISO 10315, Cigarettes - Determination of Nicotine in Smoke Condensate - Gas Chromatographic Method 2000, International Organization for Standardization, Geneva, Switzerland. 2nd ed.
29. ISO International Standard ISO 8454, Cigarettes - Determination of Carbon Monoxide in the Vapour Phase of Cigarette Smoke - NDIR Method 2007, International Organization for Standardization, Geneva, Switzerland. 3rd ed.
30. Kadoma Y., Kumada W., Asai Y., Sugita Y., Yokoe I., Fujisawa S. Radical-scavenging activity of the reaction products of isoeugenol with thiol, thiophenol, mercaptothiazoline or mercaptomethylimidazole using the induction period method. Molecules 2007, 12:1836-1844.
31. Lorge E., Lambert C., Gervais V., Becourt-Lhote N., Delongeas J.L., Claude N. Genetic toxicity assessment: employing the best science for human safety evaluation. Part II: performances of the in vitro micronucleus test compared to the mouse lymphoma assay and the in vitro chromosome aberration assay. Toxicol. Sci. 2007, 96:214-217.
32. Maralhas A., Monteiro A., Martins C., Kranendonk M., Laires A., Rueff J., Rodrigues A.S. Genotoxicity and endoreduplication inducing activity of the food flavouring eugenol. Mutagenesis 2006, 21:199-204.
33. Maron D.M., Ames B.N. Revised methods for the Salmonella mutagenicity test. Mutat. Res. 1983, 113:173-215.
34. Minet E.F., Daniela G., Meredith C., Massey E.D. A comparative in vitro kinetic study of [14C]-eugenol and [14C]-methyleugenol activation and detoxification in human, mouse, and rat liver and lung fractions. Xenobiotica 2012, 42:429-441.
35. OECD OECD Guideline 471, Bacterial reverse mutation test 1997, Organization for Economic Cooperation and Development, Paris, France.
36. OECD OECD Guideline 476, In Vitro Mammalian Cell Gene Mutation Test 1997, Organization for Economic Cooperation and Development, Pais, France.
37. Parry J.M., Parry E., Phrakonkham P., Corvi R. Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis 2010, 25:531-538.
38. Piadé, J.-J., Roemer, E., Dempsey, R., Hornig, G., Deger Evans, A., Völkel, H., Schramke, H., Trelles-Sticken, E., Wittke, S., Weber, S., Schorp, M.K., 2014a. Toxicological assessment of kretek cigarettes. Part 2: kreteks and American-blend cigarettes, smoke chemistry and in vitro toxicity. Regul. Toxicol. Pharmacol. 70, S15-S25.
39. Piadé J.-J., Roemer E., Dempsey R., Weiler H., Meurrens K., Vanscheeuwijck P., Schorp M.K. Toxicological assessment of kretek cigarettes. Part 3: kreteks and American-blend cigarettes, inhalation toxicity. Regul. Toxicol. Pharmacol 2014, 70:S26-S40.
40. Polzin G.M., Stanfill S.B., Brown C.R., Ashley D.L., Watson C.H. Determination of eugenol, anethole, and coumarin in the mainstream cigarette smoke of Indonesian clove cigarettes. Food Chem. Toxicol. 2007, 45:1948-1953.
41. Prashar A., Locke I.C., Evans C.S. Cytotoxicity of clove (Syzygium aromaticum) oil and its major components to human skin cells. Cell Prolif. 2006, 39:241-248.
42. Reeve L., Baldrick P., Hewings S., Skinner M. A battery of genotoxicity studies with an allergy vaccine adjuvanted with monophosphoryl lipid A (MPL(R)) for the treatment of grass pollen allergy. J. Appl. Toxicol. 2012, 32:608-616.
43. Renne R.A., Yoshimura H., Yoshino K., Lulham G., Minamisawa S., Tribukait A., Dietz D.D., Lee K.M., Westerberg R.B. Effects of flavoring and casing ingredients on the toxicity of mainstream cigarette smoke in rats. Inhal. Toxicol. 2006, 18:685-706.
44. Roemer, E., Dempsey, R., Hirter, J., Deger Evans, A., Weber, S., Ode, A., Wittke, S., Schorp, M.K., 2014a. Toxicological assessment of kretek cigarettes. Part 6: The impact of ingredients added to kretek cigarettes on the smoke chemistry and in vitro toxicity. Regul. Toxicol. Pharmacol. 70, S66-S80.
45. Roemer, E., Dempsey, R., Schorp, M.K., 2014b. Toxicological assessment of kretek cigarettes. Part 1: Background, assessment approach, and summary of findings. Regul. Toxicol. Pharmacol. 70, S2-S14.
46. Roemer E., Ottmueller T.H., Zenzen V., Wittke S., Radtke F., Blanco I., Carchman R.A. Cytotoxicity, mutagenicity, and tumorigenicity of mainstream smoke from three reference cigarettes machine-smoked to the same yields of total particulate matter per cigarette. Food Chem. Toxicol. 2009, 47:1810-1818.
47. Roemer E., Schramke C., 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 cigarette 3R4F and 2R4F. Beitr Tabakforsch Int. 2012, 25:316-335.
48. Roemer E., Stabbert R., Rustemeier K., Veltel D.J., Meisgen T.J., Reininghaus W., Carchman R.A., Gaworski C.L., Podraza K.F. Chemical composition, cytotoxicity and mutagenicity of smoke from US commercial and reference cigarettes smoked under two sets of machine smoking conditions. Toxicology 2004, 195:31-52.
49. Roemer E., Tewes F.J., Meisgen T.J., Veltel D.J., Carmines E.L. Evaluation of the potential effects of ingredients added to cigarettes. Part 3: in vitro genotoxicity and cytotoxicity. Food Chem. Toxicol. 2002, 40:105-111.
50. Rustemeier K., Stabbert R., Haussmann H.J., Roemer E., Carmines E.L. Evaluation of the potential effects of ingredients added to cigarettes. Part 2: chemical composition of mainstream smoke. Food Chem. Toxicol. 2002, 40:93-104.
51. Sallsten G., Gustafson P., Johansson L., Johannesson S., Molnar P., Strandberg B., Tullin C., Barregard L. Experimental wood smoke exposure in humans. Inhal. Toxicol. 2006, 18:855-864.
52. Schnitzler P., Wiesenhofer K., Reichling J. Comparative study on the cytotoxicity of different Myrtaceae essential oils on cultured vero and RC-37 cells. Pharmazie 2008, 63:830-835.
53. Schramke H., Meisgen T.J., Tewes F.J., Gomm W., Roemer E. The mouse lymphoma thymidine kinase assay for the assessment and comparison of the mutagenic activity of cigarette mainstream smoke particulate phase. Toxicology 2006, 227:193-210.
54. Schramke H., Roemer E., Dempsey R., Hirter J., Meurrens K., Berges A., Weiler H., Vanscheeuwijck P., Schorp M.K. Toxicological assessment of kretek cigarettes. Part 7: The impact of ingredients added to kretek cigarettes on inhalation toxicity. Regul Toxicol Pharmacol 2014, 70:S81-S89.
55. Sekizawa J., Shibamoto T. Genotoxicity of safrole-related chemicals in microbial test systems. Mutat. Res. 1982, 101:127-140.
56. Siani A.C., Souza M.C., Henriques M.G., Ramos M.F. Anti-inflammatory activity of essential oils from Syzygium cumini and Psidium guajava. Pharm. Biol. 2013, 51:881-887.
57. Sofuni T., Honma M., Hayashi M., Shimada H., Tanaka N., Wakuri S., Awogi T., Yamamoto K.I., Nishi Y., Nakadate M. Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay using the microwell method: interim report of an international collaborative study. Mutagenesis 1996, 11:349-355.
58. Stea S., Savarino L., Ciapetti G., Cenni E., Trotta F., Morozzi G., Pizzoferrato A. Mutagenic potential of root canal sealers: evaluation through Ames testing. J. Biomed. Mater. Res. 1994, 28:319-328.
59. Sukumaran K., Kuttan R. Inhibition of tobacco-induced mutagenesis by eugenol and plant extracts. Mutat. Res. 1995, 343:25-30.
60. Tewes F.J., Meisgen T.J., Veltel D.J., Roemer E., Patskan G. Toxicological evaluation of an electrically heated cigarette. Part 3: genotoxicity and cytotoxicity of mainstream smoke. J. Appl. Toxicol. 2003, 23:341-348.
61. Tisserand R., Young R. Essential Oil Safety 2014, Churchill Livingstone Elsevier, London, UK.
62. To L.P., Hunt T.P., Andersen M.E. Mutagenicity of trans-anethole, estragole, eugenol, and safrole in the Ames Salmonella typhimurium assay. Bull. Environ. Contam. Toxicol. 1982, 28:647-654.
63. US-CPSC, 1993. US Consumer Product Safety Commission: Toxicity Testing Plan for Low Ignition-Potential Cigarettes, vol. 3. Washington DC.
64. US-DHHS, 2004. The health consequences of tobacco use: A report of the surgeon general. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Washington DC, USA.
65. US-DHHS (Ed.), 2010. How tobacco smoke causes disease: The biology and behavioral basis for smoking-attributable disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Rockville MD, USA.