FINAL Report on Carcinogens Background Document for Environmental Tobacco Smoke December 2 - 3, 1998 Meeting of the NTP Board of Scientific Counselors Report on Carcinogens Subcommittee Prepared for the: U.S. Department of Health and Human Services Public Health Services National Toxicology Program Research Triangle Park, North Carolina 27709 Prepared by: Technology Planning and Management Corporation Canterbury Hall, Suite 310 4815 Emperor Boulevard Durham, NC 27703 Contract Number NOI-ES-85421 RoC Background Document for Environmental Tobacco Smoke Table of Contents Summary Statement..................................................................................................................v 1 Physical and Chemical Properties ......................................................................................1 1.1 Chemical Identification...........................................................................................1 2 Human Exposure.................................................................................................................9 2.1 Biomarkers of Exposure..........................................................................................9 2.1.1 Nicotine and Cotinine...............................................................................9 2.1.2 Carbon Monoxide and Carboxyhemoglobin ...........................................10 2.1.3 Thioethers ..............................................................................................10 2.1.4 Thiocyanate............................................................................................10 2.1.5 Tobacco-Specific N-Nitrosamines..........................................................10 2.2 Environmental Exposure.......................................................................................11 2.3 Occupational Exposure .........................................................................................17 2.3.1 Restaurants.............................................................................................17 2.3.2 Bars .......................................................................................................17 2.3.3 Airplanes................................................................................................17 2.4 Regulations...........................................................................................................21 3 Human Studies ..................................................................................................................23 3.1 IARC report of 1986 (Appendix 3A).....................................................................23 3.2 U.S. EPA report of 1992 (Appendix 3B)...............................................................24 3.3 California EPA report of 1997 (Appendix 3C) ......................................................24 3.4 Current Epidemiology Studies ..............................................................................25 3.4.1 Total Cancers:.............................................................................................25 3.4.2 Lung Cancer: ..............................................................................................25 3.4.3 Bladder Cancer: ..........................................................................................27 3.4.4 Breast Cancer:.............................................................................................27 3.4.5 Cervical Cancer:..........................................................................................27 3.4.6 Nasal Sinus Cancer: ....................................................................................27 3.4.7 Childhood Cancers:.....................................................................................28 3.4.7.1 All cancers combined: .................................................................................. 28 3.4.7.2 Childhood brain cancer: ............................................................................... 28 3.4.7.2 Childhood lymphomas/leukemias: .............................................................. 29 3.5 Discussion ............................................................................................................40 4 Studies of Cancer in Experimental Animals ....................................................................43 4.1 Summary of Earlier Experiments ..........................................................................43 4.1.1 Exposure of laboratory animals to tobacco smoke by inhalation .............43 4.1.2 Tobacco smoke condensate ....................................................................43 4.2 Experiments Conducted Since the Last Review.....................................................43 4.2.1 Exposure of laboratory animals to tobacco smoke by the inhalation route ...............................................................................................................43 i RoC Background Document for Environmental Tobacco Smoke 4.2.2 Interactions of cigarette smoke with known carcinogens ........................49 5 Genotoxicity.......................................................................................................................52 5.1 Prokaryotic Systems .............................................................................................52 5.1.1 Induction of Mutation in Salmonella typhimurium .................................52 5.2 Mammalian Systems.............................................................................................53 5.2.1 Sister Chromatid Exchange ...................................................................53 5.2.2 DNA Adducts ........................................................................................53 6 Mechanistic and Relevant Studies ....................................................................................55 6.1 Administration of tobacco-smoke condensate .......................................................55 6.2 Carcinogenicity of tobacco-specific carcinogens...................................................57 6.3 Metabolism of tobacco-specific nitrosamines........................................................57 7 References..........................................................................................................................60 Appendix 1 ..............................................................................................................................76 Appendix 2 ..............................................................................................................................90 Appendix 3A - IARC (1986)…………………………………………………..bound separately Appendix 3B - U.S. EPA (1992)..……………………………………………..bound separately Appendix 3C - California EPA (1997)………………………………………..bound separately ii RoC Background Document for Environmental Tobacco Smoke List of Tables Table 1-1. Typical cigarette SS and MS chemical components and yields ...................................1 Table 1-2. Selected chemical carcinogens and toxicants identified in tobacco smoke...................4 Table 2-1. TSNA in indoor air...................................................................................................11 Table 2-2. Environmental exposure to ETS ...............................................................................13 Table 2-3. Occupational exposure to ETS..................................................................................18 Table 2-4 Regulations ...............................................................................................................21 Table 3-1. Human Studies of ETS exposure and cancer, published since IARC (1986) *...........30 Table 4-1. Sidestream smoke characteristics to which A/J mice were exposed 6 hours a day, 5 days a week for 6 months..........................................................................................................43 Table 4-2. Incidence and multiplicity of lung tumors in A/J mice exposed to sidestream smoke for up to six months ..................................................................................................................44 Table 4-3. Average chamber concentrations to which A/J mice were exposed for 6 hours a day, 5 days a week for up to 6 months .................................................................................................44 Table 4-4. Average chamber concentrations to which A/J mice were exposed for 6 hours a day, 5 days a week for up to 5 months .................................................................................................45 Table 4-5. Lung tumor incidences in mice exposed to sidestream smoke for up to five months .46 Table 4-6. Lung tumor incidences in A/J mice exposed to sidestream tobacco smoke and fed BHT..........................................................................................................................................46 Table 4-7. Labeling indices in the Alveolar zone of A/J mice exposed to tobacco smoke then administered BrdU....................................................................................................................47 Table 4-8. Average chamber concentrations to which A/J mice were exposed for 6 hours a day, 5 days a week for up to 5 months .................................................................................................48 Table 4-9. Lung tumors in strain A/J mice exposed to tobacco smoke for up to five months......48 Table 4-10. Average chamber concentrations to which A/J mice were exposed for 6 hours