TECHNICAL REPORT The Eight International Meeting on W-Nitroso Compounds Hold at Banff, Alberta, Canada 5 t.h-9th September, 1983 By: D.A. Matkin 42. CD L14 BATCo document for Province of British Columbia 19 April 1999 STH INTERNATIONAL MEETING ON 'N-NZTROSO COMPOUNDS : OCCURRENCE AND BIOLOGICAL EFFECTS" SPONSORS Agricultural Canada Alberta Heritage Foundation for Medical Research Consumer and Corporate Affairs Canada Environment Canada Health and Welfare Canada University of Alberta Edmonton CANADIAN EXECUTIVE COMMITTEE VON BORSTEL R.C., (co-chalrperson), University of Al rta, Edmonton MILLER C.T., (co-chairperson), Environment Canada LONG J.E., (co-person), Health and Welfare Canada ARCHER M., Ontario Cancer Research Institute BRUCE W.R., Ludwig Institute for Cancer Research CHAPPEL C., F.D.C. Consultants Inc. CHOI N.W., University of Manitoba SCHOLEFIELD P.G., National Cancer Institute of Canada HEN N.P., Health and Welfare Canada STICH H.F., British Columbia Cancer Research Centre WILLIAMS D., Health and Welfare Canada ORGANISING SECRETARIAT OF THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER LYON, FRANCE BARTSCH B. OINZILL I.K. CASTEGNARO M. GRANJkRD Y. KESELTINE E. CZ) CD I'D c0 BATCo document for Province of British Columbia 19 April 1999 Page no. Introduction .................................................. ... I List of Participants ............................................. 2 Conference Programe ............................................. 20 Author Index .................................................. ... 32 Notes on Papers and Posters ...................................... 36 Notes on Tobacco Session ......................................... 36 notes on Other Sessions .......................................... 41 .9 ~b C:) CD ~10 (-P4 cc BATCo document for Province of British Columbia 19 April 1999 THE EIGHTH INTERNATIONAL MEETING ON N-NITROSO COMPOUNDS TECHNICAL REPORT By: D.A. Matkin INTRODUCTION The Eighth International meeting on N-Nitroso Compounds was held at the Banff Centre, Alberta, Canada, 5th-9th September, 1983. This meeting was organised by the International Agency for Research on Cancer UARC), who are situated in Lyon, France, and are funded by the World Health Organisa- tion (WHO). There were 175 delegates, who were mostly scientists working in the general area of nitrosamines, representing many countries including the Third World. 117 papers were presented, which included 63 poster presentations. The conference was organised into seven sessions: 1. Analysis, occurrence and formation of N-mitroso compounds. 2. Biological effects - DNA repair and adducts. 3. N-Nitroso compounds in tobacco carcinogenesis. 4. Recent analytical/methodological advances in the identification of (new) N-nitraso compounds. 5. Metabolism and modifying factors. 6. Biological effects - modifiying factors, epidemiology. 7. Survey of laboratory/epidemiology investigations linking N-nitroso compounds and their precursors with human carcinogenesis. Of major impor-tance to the Tobacco Industry. was the third session on 'N-Nitroso Compounds In Tobacco Carcinogenesis". The majority of the papers given in this session were from the "Hoffmann School" in the Naylor Dana Institute, American Health Foundation, Valhalla, New York State, although there were other interesting and relevant papers (for example, R.A. Andersen on "Accumulation of Nitrite and NNN in Burley Tobacco") from other institutes. Consequently, this report will concentrate largely on the third session: however, other relevant papers given in the other sessions are also commented on. Full copies of virtually all the papers and posters given at the conference were obtained and are available on reauest from the author of this report. C) c0 r1 i BATCo document for Province of British Columbia 19 April 1999 LIST OF PARTICIPANTS Z.D. ADAMS American Health Foundation 1 Dana Road Valhalla, N.Y. USA 10595 L. AIROLDI Istituto di Ricerche Parmacologiche Mario Negri Via Eritrea 62 20157 Milano Italy R. ANDERSEN Agricultural Research Service U.S. Department of Agriculture Department Of Agronomy University of Kentucky Lexington, Kentucky USA 40546 T. ANJO Tokyo Biochemical Research Institute Takada 3-41-8 Toshima-ku, Tokyo Japan 171 X.E. APPEL Max von Pettenkofer Institute Federal Health Office Thielallee D-1000 Berlin 33 F.R.G. M.D. ARCHER Ontario Cancer Institute 500 Sherbourne Street Toronto, Ontario M4 X IK9 J. BARBOUR Food Science & Technology Department Oregon State University Corvallis, OR USA 97331 H. BARTSCH International Agency for Research an Cancer 150 cours Albert Thomas 69372 Lyon Cedex co LA BATCo document for Province of British Columbia 19 April 1999 L.S. BELICZKY T. BELLANDER Department of Occupational Medicine Block E. University Hospital 5-22185 LUND, S.eden S.V. BHIDE Carcinogenisis Division Cancer Research Institute Bombay, India 400012 P. BOGOVISKI Institute of Experimental and Clinical Medicine 42 Hiiu Street, Tallinn, Estonia USSR 200015 S. BOMBOSCH Institut fur Forstzoologie D-34 Gottingen-Weende Busgenweg 3 Germany M. BORZSONYI National institute of Hygiene Gyali ut 2-6 Budapest, Hungary 1966 X.. BRUNNEMANN American Health Foundation I Dana Road Valhalla, NY USA 10595 G. BURKLE Treiskrankenhaus 7710 Donaueschingen, Germany J.S. CAMPBELL P.O. Box 3068 Wilson, NC USA 27893 A. CASTONGUAY American Health Foundation 1 Dana Road Valhalla, NY USA 10595 J.A. CASTRO CEITOX - Zufriategui y Varela Villa Martelli (1603) Pcia. Buenos Aires - Argentina C. CAYGILL Central Public Health Laboratory Epidemiological Research Laboratory 175 Colidale Avenue, London, NW9 5HT CD U-4 00 BATCo document for Province of British Columbia 19 April 1999 4 - B. CHALLIS Chemistry Department Imperial College London, England SW7 2&Z P.A. CRA.NDRA Department Health & Social Security Toxicology Division (MED-TEP), Roo. 919 Hannibal House, Elephant & Castle London, England SEI 6TE C.I. CHAPPEL PDC Consultants Inc. 1196 Botany Hill Oakville, Ontario L6J 6J5 N.W. CHOI Manitoba Cancer Treatment and Research Found., 100 Olivia Street, Winnipeg, Manitoba R3 E OV9 Y.L. CHOW Department of Chemistry Simon Fraser University Burnaby, BC V5A IS6 S. CLARKSON Consumer & Corporate Affairs Standards, Tunney's Pasture Ottawa, Ontario KIV 7PS A. COLLI U.S. E.P.A. (TS 794) 401 M. Street SW Washington DC USA 20640 F. CHUNG American Health Foundation 1 Dana Road, Valhalla, N.Y. USA 10595 P. CORREA LSU Medical Centre 1901 Perdido Street, New Orleans, LA USA 70112 V. CRADDOCK Toxicology Unit MRC Laboratories Woodmansterne Road Carshalton, England A.F. CROISY Unite INSERM 219, INSTITUT CURIE Section de Biologie, Centre Universitaire Batiment 110-112 91405 ORSAY Cedex (FRANCE) C-- C) co Ln 13 ATCo document for Province of British Columbia 19 April 1999 B. DAWSON Pharmaceutical Chemistry Division Sir Frederick G. Banzing Bldg. Twiney's Pasture, Ottawa, Ontario KIA OL2 K.L. DOUGLASS Colgate-Palmolive Co. 909 River Road Piscataway NJ 08854 G. EISENBRAND Universitat Kaiserslautern Erwin-Schrodinger-Strasse 6750 Kaiserslautern GERMANY J.B. ELDER University of Manchester Department of Surgery, The Royal Infirmary Oxford Road, Manchester UK G. ELLEN National Institute of Public Health P.O. Box 1 3720 BA Bilthoven The Netherlands J. ESTLVE 150, cours Albert Thomas F-69008 Lyon FRANCE T. FAZIO Food & Drug Administration 200 "C" Street SW Washington, DC USA 20204 R. FERGUSON P.O. Box 26583 Richomond, Virginia USA 23261 W. FIDDLER Food Safety Laboratory 600 East Mermaid Lane Philadelphia, Pennsylvania USA 19118 U.N. FINE New England Institute for Life Sciences 125 Second Avenue Waltham, MA USA 02154 L.Y.Y. FONG Biochemistry Department University of Hong Kong Sassoon Road, Hong Kong Li4 LPJ co CN BATCo document for Province of British Columbia 19 April 1999 6 - D. FORMAN Imperial Cancer Research Fund Cancer Epidemiology & Clinical Trials Gibson Laboratories Radcliffe infirmary, Oxford, OX2 6HE N. FRANK Institut fur Toxilokologie und Chemotherapie Im Neuenheimer Feld 280 D-6900 Heidelberg I GERMANY E. FREI Institut fur Toxilokologie and Chemotherapie Im Neuenheimer Feld 280 D-6900 Heidelberg 1 GERMANY B. GOLD Eppley Institute University of Nebraska Medical Centre 42 and Dewey Avenue Omaha, Nebraska USA 68105 Y. GRANJARD International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cedex FRANCE J.1. GRAY Department of Food Science and Human Nutrition Michigan State University East Lansing, Michigan USA 48824 R. CRAY Cancer Studies Unit Radcliffe Infirmary Oxford, England OX2 6HE J. CRY Institute of Toxicology National Food Institute 19 Morkhoj Bygade DK 2860 Soborg, Denmark C.N. HALL St. George's Medical School Department of Medicine - 2 London SW17 England. M. HAMANO Tokyo Kaseigakuin University Faculty of Home Economics 22 Sanban-cho, Chiyoda-ku Tokyo 102, Japan X~. CD C) co -14 BATCo document for Province of BritiSh Columbia 19 April 1999 D.C. HAVERY Food fi Drug Administration 200 C Street SW HFF-459 Washington, DC USA 20204 S.S. HECHT American Health Foundation 1 Dana Road, Valhalla, NY USA 10595 U.G.G. HENNIG Department of Genetics University of Alberta Edmonton, Alberta TGG 2E9 E. HESELTINE International Agency for Research on Cancer 150 cour Albert Thomas 69372 Lyon Cedex 08 K. HILDRUM. Norwegian Food Research Institute Postbox 50 1432 AAs-NLH Norway M. HILL PHLS - CAMR Porton Down Salisbury Wilts England R. HINDLE Western Laboratory Laboratory Services Division Agriculture Canada 102 11 Avenue SE Calgary, Alberta T2 G OX5 J.H. HIRSCH hskimsgatan 7 S-413 19 Goteborg Sweden D. HOFFMAN Naylor Dana Institute American Health Foundation Dana Road Valhalla, NY USA 10595 T. ISHIBASHI Japan Medical Food Association Research Laboratory, 5-3-11 Maesawa, Higashi-kurume-shi Tokyo 180-03 Japan C:) C) co c0 BATCo document for Province of British Columbia 19 April 1999 H. ISHIWATA NaLional Institute of Hygienic Sciences, 18-1, Kamiyoga 1-chome Setagava-ku, Tokyo, Japan 158 P. ISSENBERG Eppley Cancer Institute University of Nebraska Medical Centre O.aha, (Nebraska) NE USA 68144 T. JJLLINSKI Oscar Mayer Foods Corporation. 910 Mayer Avenue, P.O. Box 7188 Madison, Wisconsin USA 53707 C. JANZOWSKI Lebensmittelchemie & Umwelttoxikologie rachbereich Chemie, Universitat Kaiserslautern Erwin-Schrodinger-Strasse 6750 Kaiserslautern FRG S. Kim K.I.T. Rm 56-310 77 Massachusetts Avenue Cam ridge MA USA 01239 B.L. KABACOFF 945 Zerega Avenue Bronx, NY USA 10473 T. KAWABATA Department of Biomedical Research on Food National Institute of Health 2-10-35 Kamiosaki, Shinagawa-ku Tokyo 141 Japan L. KEEFER National Cancer Institute NIH Bldg. 37, Rm. 1E22 Bethesda, MD USA 20205 P. TLEIHUES Pathologisches Institut Universitat Freiburg 78 Freiburg West Germany R.G. laxiN Inatitut f. Toxikologie und Chemotherapie Deutsches Krebsforschungszentrum I= Neuenheimer Feld 280 6900 Heidelberg. c::) C) co 110 BATCo document for Province of British Columbia 19 April 1999 B. KLDS Austria Tabakwerke AG Hasnerstrase 124& A-1160 Wien AUSTR.IA Y. KONISHI Oncological Pathology Cancer Centre, Nara Medical College 840 Shijyocho, Kashihara Nara 634, Japan M.B. KROBEGER-KOEPKE LBI-BRP NCI-FCRF P.O. Box B Prederick, MD USA 21701 S.R. KOEPKE LBI-BRP NCI-FCRI P.O. Box B Frederick, MD USA 21701 N. XOPPANG National Veterinary Institute Postboks 8156 Dep. Oslo, I NORWAY S.J. KUBACIU 4328 N. Henderson Road 1 Arlington, Virginia USA 22203 B. LANGSTROM C/o. Stationsgatan 3 S-781 30 Borlange SWEDEN M. LANS UCL 7369, Avenue E. Mounier B - 1200 BRUSSELS L.W. LeVAN Hazleton Raltech Inc. 3301 Kinsman Blvd. P.O. Box 7545 Madison Wisconsin USA 53707 W. LIJINSKY NCI - Frederick Cancer Research Facility LBI - Basic Research Program Box B Frederick, MD, USA 21701 G.P.A. LIPP Martin Brinkmann AG Forschung und Entwicklung Postfach 10 79 05 2800 Bremen/West Germany -9 ~b C) CD BATCo document for Province of British Columbia 19 April 1999 10 - R.N. LOEPPXY 123 Chemistry Department of Chemistry University of Missouri Columbia MO USA 65211 J. L40NG Health Protection Branch National Health & Welfare Tunneys Pasture Ottawa, ON KIA OL2 J.W. LOWN Department of Chemistry University of Alberta Edmonton, AB T6 G 2G2 S. LU Cancer Institute Chinese Academy of Medical Sciences Beijing People's Republic of China D. MACKENZIE 28 Hinchley Wood Grove Brampton, Ontario L6 V 3M3 P.N. MAGEE Temple University School of Medicine Philadelphia, Pennsylvania USA 19140 T. MAKI Tokyo-Metropolitan Research Laboratory of Public Health 3-24-1, Hyakkunin-cho, Shinjuku-ku Tokyo, Japan. A.K. MANDAGERE 334 - C Food Science Bldg. MSU. Fast Lansing, MI, USA 48824 M.M. MANGINO Department of Pathology Northwestern University Medical School 303 E. Chicago A~enue Chicago, Illinois USA 60611 D. MATKIN Group Research & Development Centre British-American Tobacco Co., Regents Park Road, Southampton, UK. England. (J-4 BATCo document for Province of British Columbia 19 April 1999 R.D. MERTA Department of Genetics University of Alberta Edmonton, Alberta T6 G 2E9 R. MEHTA Department of Medical Biophysics University of Toronto Ontario Cancer Institut. 500 Sherbourne street, Toronto, Ontario M4X 1T,9 B. KELBOURNE C.J. 141CHEJDA Chemical Carcinogenesis Program NCI-FCRF P.O. Box B Frederick, 14D USA 21701 A.B. MILLER NCIC Epidemiology Unit mcmurrich Bldg. 3rd Floor 12 Queen's Park Crest W University of Toronto Toronto, Ontario MSS IAB C. KILLER Chief, Assessment Branch Toxic Chemicals Management Centre Place Vincent Massey, Hull, PQ VA 108 S. MIRVISH Eppley Institute University of Nebraska Medical Centre Omaha, NE USA 68105 M. MOCHIZUK-1 Tokyo Biochemical Research Institute Takada 3-41-8 Toshima-ku, Tokyo Japan 171 R. MONTESANO International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cedex 08 France BATCo document for Province of British Columbia 19 April 1999 - 12 - Y. MORI Laboratory of Radiochemistry Gifu College of Pharmacy 6-1, Kitahora-higash! 5-chome Gifu 502, Japan X. MORIMOTO Division Medical Chemistry National Institute of Hygienic Sciences X--4yoga, 1-18-1, Setagaya-ku Tokyo, Japan 158 J.B. MORRISON American Health Foundation I Dana Road, Valhalla, NY USA 10595 E. MUSKAT Staatl. Chem. Unters. Amt Marburger Str. 54 6300 Giessen West Germany D.J. MCWEENY Food Science Laboratory Ministry of Agriculture Fisheries and Food Queen Street, Norwich, NRZ 4SX, England M NAGAO Biochemistry Division National Cancer Centre Research Institute 1-1 Tsukiji 5-chome, Chuo-ku Tokyo 104 Japan D.L. NAGEL Eppley Institute for Research in Cancer University of Nebraska Medical Centre Omaha, NE USA 68105 M. NATAKUPA Kanaga.a Prefectural Public Health Laboratory 52 Nakaocho Asahi-Ku, Yokohama 241 Japan G.B. NEURATH Rexentwiete 32 D-2000 Hamburg 56 P.R. Germany R. OESHIMA International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cedex France -92~- CD C) BATCo document for Province of British Columbia 19 April 1999 - 13 - M. OKADA Tokyo Biochemical Research Institute Takada 3-41-8 Toshima-ku, Tokyo Japan 171 I. O'NEILL International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cedex 08 France A. PEAKE Western Laboratory Laboratory Services Division Agriculture Canada 102 11 Avenue SE Calgary, Alberta T2 G OX5 A.E. PEGG Department of Physiology The Milton S. Hershey Medical Centre Pennsylvania State University Box 850, Hershey, PA USA 17033 B. PIGNATELLI International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cedex, France J. POLLOCK Pollock International Ltd., Ladbroke Close, Woodley, Reading England RGS 4DA J. POWELL Box 3392 Maybelline No. Little Rack Arkansa 22117 USA S. PRESTON-MARTIN USC School of Medicine Family a Preventive Medicine 2025 Zonal Avenue P14B B 301 Los Angeles, CA USA 90033 R. PREUSSMANN German Cancer Research Centre Institut of Toxicology IM Nevenheimer Feld 280 D-6900 Heidelberg Germany 4-- CD ~10 L.,4 L-4 1.0 _t~b BATCo document for Province of British Columbia 19 April 1999 14 - S. PUJU Department of Nutrition and Food Hygiene Peking Medical College, Peking People's Republic of China M.F. RAJEWSKY Institute of Cell Biology University of Essen Hufelandstrasse 55 4300 Essen 1 Federal Republic of Germany C. RAPPE Department of Organic Chemistry University of Umea S-901 87 UMEA Sweden P.I. REED 144 Harley Street, London, England. WIN IAH E.J. REIST SRI International Bio-Organic Chemistry Laboratory 10008 333 Ravenswood Avenue Menlo Park, CA USA 94025 R. ROPER Institut fur Organische Chemie und Biochemie der Universitat Hamburg Martin-Luther King Platz 6 2000 Hamburg 13 A. RODGMAN Director, Fundamental R&D Bowman Gray Technical Centre R.L. Reynolds Tobacco copany Winston-Salem, NC 27102 I.E. ROSENBERG Clairol Incorporated 2 Blachley Road, Stamford, CT. USA 06922 M.L. ROSENTHAL Robeco Chemicals Inc. 99 Park Avenue New York, NY USA 10016 E.B. SANSONE NCI. FCRF Program Resources, Inc. Box B Frederick, KD USA 21701 CD %-0 U4 13 ATCo document for Province of British Columbia 19 April 1999 - is - B. SAUL Ontario Cancer Institute 500 Sherbourne Street 7 th Floor Toronto, Ontario M5 A 3T2 J.E. SAAVEDRA Chemical Carcinogenesis Program NCI-Frederick Cancer Research Facility Box B Frederick, MD USA 21701 R.A. SCANLAN Food Science and Technology Oregon State University Corvallis, OR USA 97331 D. SCHMAERL German Cancer Research Centre Institute of Toxicology and Chemotherapy 6900 Heidelberg FRG P.G. SCHOLEFIELD National Cancer Institute of Canada Suite 1001 130 Bloor Street W Toronto, Ontario M5 S 2V7 M. SCHREINER 28 Hinchley Wood Grove Brampton, Ontario L6 V 3K3 F. SCHWEINSBERG Hygiene-Institut d. Universitat Silcherstr 7 7400 Tubingen I M. SEN Food Research Division Health Protection Branch Sir F Banting Research Centre Ott..&, ON, KIA OL2 R. SETLOW Biology Department Brookhaven National Lab Upton, NY' USA 11973 C) C:) C, BATCo document for Province of British Columbia 19 April 1999 - 16 - D. SHUXER MRC Toxicology Unit Medical Research Council Laboratories Woodmansterne Road, Carshalton Surrey, England SM5 4EF M. SIMENOFF Jefferson Medical College 1025 Walnut Street, Room 1018 Philadelphia, PA USA 19107 G.M. SINGER LBI-BRP NCI-FCRF Box B Frederick, 14D USA 21701 S.S. SINGER LBI-BRP NCI-FCRF Box B Frederick, MD USA 21701 P. SONG Department of Nutrition and Food Hygiene Peking Medical College Peking, People's Republic of China B. SPIEGELHALDER Deutsches Kzebstorschungszentrum Institut fur Toxikologie und Chemotherapie 1 m Neuenheimer Feld 280 D-6900 Heidelberg I GERMANY S. SRIANUJATA Research Centre Ramathlbodi Hospital Rama 6 Road Bangkok, 10400 Thailand R.F. STICH Environmental Carcinogenesis Unit BC Cancer Research Centre 601 West 10th Avenue Vancouver BC T. SUGIMURA National Cancer Centre Research Institute 1-1 Tsukiji 5-chome Chuo-ku Tolyo 104 Japan C) C=) BATCo document for Province of British Columbia 19 April 1999 - 17 - E. SUZUKI Tokyo Biochemical Research Institute Takada 3-41-8 Toshima-ku, Tokyo Japan 171 X. SUZUKI Institute of Physical and Chemical Research Animal Physiology Laboratory Wako-shi, Saitama, 351 Japan P. SWANN Courtauld Institute of Biochemistry Middlesex Hospital Medical School Mortimer Street, London WPI 5PN England S.R. TANNENBAUM K.I.T. Room 56-309 77 Massachusetts Avenue Cam ridge, MA USA 02139 H. TJALVE Department of Biochemistry University of Uppsala Box 573 S-751 23 Uppsala, S.eden L. TOMATIS International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon FRANCE 1. TOMITA Shizouka College of Pharmaceutical Sciences H TAXENAKA 2-2-1 Oshida Shizuka 422 Japan L.G. TORSTENSSON K. TSUDA Biochemistry Division National Cancer Centre Research Institute 1-1 Tsukiji 5-chome, chuo-ku Tokyo 104 Japan G.B. URE CD CO BATCo document for Province of British Columbia 19 April 1999 R. VAINIO International Agency for Research on Cancer 150 cours Albert Thomas 69372 Lyon Cadex 08 France L.M. VAN BROEXHOVEN Centre for Agrobiological Research Box 14 6700 AN Wageningen NETHERLANDS R.C. VON BORSTEL Department of Genetics University of Alberta Edmonton, Alberta, T6 G 2E9 D. WAGNER M.I.T. Room 56-320 77 Massachusetts Avenue Cambridge, MA USA 02139 X. WAKABAYASHI High-Risk Study Division National Cancer Centre Research Institute 1-1 Tsukiji 5-chome, Chuo-ku Tokyo 104 Japan G.L. WALTERS 2 Corunna Drive Horsham West Sussex, RH13 SHG UK. N.H. WARFIELD Philip Morris USA Research Centre Box 26583 Richmond VA USA 23261 S. WATSON G. WENKE American Health Foundation 1 Dana Road, Valhalla, MY USA 10595 c::) Cz:) BATCo document for Province of BritiSh Columbia 19 April 1999 19 - M. WIESSLER Institut fur Toxikologie und Chemotherapie Im Neuenheiner Feld 280 D-6900 H.id.lberg 1 D.T. WILLIAMS Environmental Health Centre Realth & Welfare Canada Turmey's Pasture Ottawa, Ontario KIA OL2 D. WINN Environmental Epidemiology Branch National Cancer Institute Landow Building RM 3C15 Bethesda, Maryland USA 20205 J.S. WISHNOX X.I.T. Room 56-313 77 Massachusetts Avenue Cam ridge MA USA 02139 T. YAMADA National Institute of Hygienic Sciences 18-1 Kamiyoga Setagaya-ku, Tokyo Japan 158 M. YAMAMOTO National Institute of Hygienic Sciences 18-1 Kamiyoga Setagaya-ku, Tokyo Japan 158 C.S. YANG Department of Biochemistry New Jersey Medical School, Newark, NJ USA 07103 C:) C) C:) BATCo document for Province of British Columbia 19 April 1999 - 20 - STH INTERNATIONAL MEETING ON "N-NITROSO COMPOUNDS : OCCURRENCE AND BIOLOGICAL EFFECTS" BANFF, CANADA, 4-9 SEPTEMBER 1983 SUNDAY 4 SEPTEMBER: Registration MONDAY 5 SEPTEMBER: 09.00 Welcoming addresses; L.E. McLEOD, President, Alberta Hertiage Foundation for medical Research Opening address: L. TOMATIS, Director IARC Keynote address: T. SUGIMORA MORNING SESSION: Analysis, Occurrence and Formation of N-Nitroso Compounds (Chairman: P. BOGOVSKI and L. KEEFER) 09.40 Occurrence and exposure to N-nitroso compounds and precursors (0-1) R. PREUSSMANN 10.10 Nitrosation of peptides (0-2) B.C. CHALLIS, A.M. Hopkins & J.R. Milligan 10.25 A chemical model of nitrosamide carcinogenesis : the nitrosation of amide linkages and facile transformation of nitrosamides (0-3) Y.L. CHOW, S.S. Dhaliwa & J. Polo 10.40 The nitrosating agent in mice exposed to nitrogen dioxide (0-4) S.S. KIRVISH, J.P. Sams & P. Issenberg 10.50 COFFEE 11.15 Catalysis and inhibition of N-nitrosation reactions (0-5) M. ARCHER 11.45 Dietary phenolics and betel nut extracts as modifiers of N-nitrosation in rat and man (0-6) H.F. STICH, B.P. Dunn, B. Pignatelli, H. Oh9hima & R. Bartsch 12.00 Modulation of endogenous synthesis of N-nitrosoproline by dietary factors (0-7) D.A. WAGNER, D.E.G. Shuker, C. Bilmazes, M. Obiedzinski, V.R. Young & S.R. Tannenbaum 12.15 Nitrosoproline in urine from patients and healthy volunteers after administration of large amounts of nitrate (0-8) G. ELLEN & P.L. Schuller 12.30 Analysis for and intestinal metabolism of precursor nitroso-compounds in normal subjects and patients -ith chronic renal failure. (0-9) M. SIMENHOFF, S. Dunn L P. Lele 12.45 LUNCH This programme is correct for manuscripts and abstracts received by 5 August 1983 C) 110 BATCo document for Province of BritiSh Columbia 19 April 1999 - 21 - MONDAY 5 SEPTEM33ER (continued) Afternoon poster session: Analysis, occurrence and formation of N-nitroso compounds (Chairmen : B. CHAT-1-IS and S. TANMEBAUM) 14.00 - 16.00 Poster display discussion 16.00 - 17.00 Plenary discussion 15.30 - TEA POSTERS: (P-1) Dest-ructon of carcinogenic and mutagenic N-nitrosaides in laboratory wastes G. LUNN, E.B. Sansone, A.W. Andrews, 14. Castegnaro, J. Michelon, I.Brouet & L.K. Keefer. (P-2) Rapid formation of NDMA from the alkaloid gramine: a natural ly-occurring tertiary amine precursor of NDKA in barley malt M.M. KANGINO & R.A. Scanlan (P-3) Formation of nitrosa.ines in non-ionic and anionic emulsions in the presence and absence of inhibitors B.L. KABACOFF, M.L. Douglass, I.E. Rosenberg, L.W. Levan, J.K. Punwar & R. Lechnir (P-4) Determination of N-nitrosobis(2-hydroxypropl)amine (BHP) in environ- mental samples P. ISSENBERC, E.E. Conrad, J.W. Nielson, D.A. Klein & S.E. Miller (P-5) Further factors influencing !I-nitrosamine formation in bacon J.1. CRAY, D.J. Skrypec, A.K. Mandagere, A.M. Booren & A.M. Pearson (P-6) Formation of N-nitroso compounds in cured meat products produced in full Commercial scale with different nitrite and ascorbate levels J. GRY, N.J. Damm Rasmussen & E. Pedersen (P-7) Volattle N-nitrosamines in baby bottle rubber nipples and pacifiers: analysis, occurrence and migration N.P. SEN, S. Seaman, S. Clarson, F. Garrod & P. Lalonde (P-8) N-Nitrosodimethylamine in soil: formation, stability and passage Lnto plants B. KOWALSKI, T. Juszkiewicz & W. Myskow (P-9) Quantitative measurements of the extrapolation rate of volatile 1-nitrosamines in inhalation experiments with anaesthetized SD-rats R.G. KLEIN, & P. Schmezer (P-10) Ester mediated nitrosamine formation from nitrite and secondary or tertiary amines R.N. LOEPPKY, W. Tomasik & T.G. Millard (P-11) Photolysis of N-nitrosamines in neutral media C.J. .41CHEJDA & T.M. Rydstrom CD CZ) (P-12) The decompositions of hydroxyalkylnitrosoureas and nitrosooxazolidones in aqueous buffer S.S. SINCER U4 X:.. C) r1 j BATCo document for Province of BritiSh Columbia 19 April 1999 MONDAY 5 SEPTEKBER AFTERNOON (Continued) (P-13) Amadori - and N-mitroso-Amadori compounds and their pyrolysis products. Chemical, analytical and biological aspects H. ROPER, S. Roper, X. Heyns & B. Meyer (P-14) Conjugates of ji-nitroso methyl-t-burylamine: attempted analysis in the urine. M. WIESSLER, G. Rossnagel & B. Rugewitz-Blackholm (P-15) Mutagenicity of various Japanese foodstuffs treated with nitrite (11). Direct-acting autagens produced fro. N-containing compounds in foodstuffs. 1. TOMITA, N. Kinae, Y. Nakamura, H. Takenaka, H. H. Xanamori, H. Rashizume & T. Yokoyama (P-16) The pres-ce of 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carbo xylic acids and tyramine as precursors of mutagens in soy sauce after nitrite treatment. S. WAKA.BAYASHI, M. Nagao, M. Ochiai, M. Tsuda, Z. Yamaim-i , H. Saito & T. Suqimura (P-17) Analysis and occurrence of total N-nitroso compounds in Japanese diet T. Yawabata, M. Matsui, T. Ishibashi & M. Hamano (P-18) Oxidation of ammonia and hydroxylamine to nitrate in the rat R.L. SAUL, & M.C. Archer. (P-19) Formation and metabolic losses of nitrate in humans and rats D.A. WAGNER (P-20) Absorption, secretion and excretion of dimethylamine in rats H. ISHIWATA, R. Iwata & A. Tanimura (P-21) N-Nitrosamine formation by intestinal bacteria Z SUZUKI & T. Ptitsuoka (P-22) The blocking effects of Chinese Actinidia sinensis juice on nitrosamine formation: the blocking effects in vitro and in vivo P. SONG, Z. Lin, L. Yin Zang, D. Lan & S.R. Tannenbaum (P-23) Nitrosating properties of bis-methylthio diron tetranitroysl (Roussin's Red methyl ester), a nitroso compound isolated from pickled vegetables consumed in Northern China A. CROISY, H. Ohshima & H. Bartsch (P-24) N-nitrosoproline excretion in urine, faces and m.Llk from cows, related 'Eo the composition of the feed. L.W. Van Broekhoven, J.A.R. Davis & J.H. Guerink (P-25) Studies on excretion routes of endogenously-formed N-nitrosoproline P. BOGOVSrI, J. Kann & M. Rooma (P-26) On the endogenous formation of N-nitrosoproline upon cigarette smoke inhalation. X.D. BRUNNEKANN, J.C. Scott, N.J. Raley D. Hoffmann X~- CD C) 1.0 \0 LA BATCo document for Province of BritiSh Columbia 19 April 1999 - 23 - MONDAY 5 SEPTEMBER - Afternoon - (Continued) (P-27) Nitrosation of piperazine in man T. BELLANDER, B.G. Os"rdahl and L. Hagmar (P-28) A sensitive new method for the detection of N-nitrosomorpholine formation in vivo J.B. MORRISON & S.S. Hecht (P-29) In-vivo formation of NDKA in humans after amidopyrine intake B. SPIEGELHALDER & R. PREUSSMANN (P-30) Nitrosation of amines by amyl and butyl nitrites in human plasma J.S. WISHNOK, V. Ng. & S.R. Tannenbaum CD (ZD BATCo document for Province of British Columbia 19 April 1999 - 24 - TUESDAY 6 SEPTEMBER Morning sessions: Biological effects - DNA repair and adducts (Chairmen: A. PEGG and M. BORZSONYI 08.30 Enzymology of repair of DNA adducts produced by N-nitroso compounds (0-10) R.B. SETLOW 09.00 Repair and replication of DNA containing 06-methylquanine in foetal and adult animal tissues in relation to their susceptibilities to cancer induction by N-nitroso-N-alkyl-areas (0-11) V.M. CRADDOCK 09.15 Properties of 06-alkylguanine - DNA repair system of ma-lian cells (0-12) A.E. PEGG 09.30 DNA methylation by N-nitrosomethylbenzylamine in target and non-target tissues of laboratory rodents. Comparison with carcinogenicity (0-13) 0. WIESTLER, A. Uozumi & P. Kleihues 09.45 Tissue and species specificity of the metabolism of N-nitrosomethyl- benzylamine (0-14) R. MEHTA, G.E. Labuc & M. Archer 10.00 COFFEE 10.15 Use of antibodies for the detection of DNA adducts produced by !I-nitroso compounds and application of the technique to monitor human exposure (0-15) M.F. RAJEWSKY 10.45 Methylation of protein and nucleic acids in vivo: use of trideutero- methylating agents or precursors. (0-16) D.E.G. SHUKER, E. Bailey G P.B. Farmer 11.00 Characterization of alkanedinitrogen species implicated in the carcino- genic, mutagenic and anticancer activities of N-nItroso compounds (0-17) J.W. LOWN, R.R. Koganty G S.M.S. Chauhan 11.15 Contrasting responses of rats and Syrian hamsters to orally administered N-nitroso compounds (0-18) LIJINSKY 11.30 Discussion 12.00 LUNCH C) I'D .10 C) BATCo document for Province of British Columbia 19 April 1999 - 25 - TUESDAY 6 SEPTEMBER (Continued) AFTERNOON SYMPOSIUM : N-Nitroso compounds in tobacco carcinogenesis (Chairmen: R. PREUSSMANN and L. TOMATIS) 13.30 Formation and analysis of N-nitrosamines in tobacco products and their endogenous formatior~_in tobacco consumers (0-19) D. HOFFKANN, K.D. Brunnemann, J.D. Adams & S.S. Hecht 14.00 Tobacco and risk of cancer: importance of kinds of tobacco (0-20) J. ESTEVE and A. Tuyns 14.20 Post-harvest treatment and the accumulation of nitrite and N-nitroso- nornicotine in burley tobacco (0.21) R.A. ANDERSEN & M.J. Kasperbauer 14.35 Carcinogenicity and metabolic activation of tobacco specific nitrosa- mines: current status and future prospects (0.22) S.S. HECHT, A. Castonguay, F.L. Chung & D. Hoffmann 15.05 The role of methylation in carcinogenesis and mutagenesis by the tobacco specific nitrosamine 4-(methylnitrosamine)-I-(3-pyridyl)-l- butanone (NNK) (0.23) A. CASTONGUAY, A. Darnule & S.S. Hecht 15.20 Increased endogenous nitrosation in smokers (0-24) X.F. LADD, H.L. Newmark & M.C. Archer 15.35 TEA 15.50 Epidemiological and experimental studies on tobacco-related oral cancer in India (0-25) S.V. BHIDE, A.S. Shar, J. Nair & D. Nagarajrao 16.10 On the formation of N-nitrosa.ines during betel quid chewing (0-26) G. WENKE, K.D. Brunn~e~ann a D. Hoffmann 16.25 The effect of long-term application of snuff and Herpes simplex virus type I on rat oral -osa (0-27) J-K HIRSCH, S.L. Johansson, H. Thilander & A. Vahlne 16.40 Tobacco chewing and snuff dipping: an association with human cancer (0-28) D.M. WINN 17.00 Final Discussion .C~b CD CZ) %-0 1 ~0 LA .I-,. C) CYN BATCo document for Province of British Columbia 19 April 1999 - 26 - TUESDAY 6 SEPTEMBER (Continued) EVENING WORKSHOP: Recent analytical/methodo logical advances in the identifica- tion of (new) N-nitroso compounds (Chairmen: T. KAWABATA and R.A. SCANLAN) 19.30 Pitfalls to avoid in determining N-nitroso compounds as a group (0-29) C.L. WALTERS, P.L.R. Smith & P.I. Reed 19.50 N-Nitrosamine analysis in foods: N-nitrosamino acids by HPLC/TZA and total N-nitroso-amines content by chemical denitro3atibn/TEA (0-30) R.C. HASSEY, P.E. Key, D.J. McWeeny & M.E. Knowles 20.05 on-line combination of HPLC-total N-nitroso determination apparatus for the determination of N-nitrosamides and other N-nitroso compounds, and some recent data on t7he levels of N-nitrosopro'line in foods and beverages (0-31) N.P. SEN & S. Seaman 20.20 Determination of nonvolatile N-nitrosamines in foods. (0-32) S. KUBACKI, D.C. Ha~ery & T. Fazio 20.35 Production of N-nitrosoiminodialkanoic acids by nitrite in gastric juice (0-33) J.R. OUTRA14 & J.R.A. Pollock 20.50 BREAK 21.00 Description of a new TEA technique for the sensitive and selectIve analysis of N-nitrosamides (0-34) D.H. FINE & F.P. Rounbehler 21.15 Presence In human urine of a new sulfur-containing 11-rtitrosamino acid; N-nitrosothiazolidine 4-carboxylic acid and N-nitroso 2-methyl- thiazo;lidine 4-carboxylic acid (0-35) H. OHSHIMA, I.K. O'Neill, M. Friesen, B. Pignatelli & H. Bartsch 21.30 Study on analysis of N-nitrosamines in human urine by GC-TEA (0-36) K. TSUDA, T. Kakizoe, T. Hirayama & T. Sugimura 21.45 Discussion CD C) %~o .10 L,4 X.11 C) -14 BATCo document for Province of British Columbia 19 April 1999 - 27 - THURSDAY 8 SEPTEMBER MORNING SESSION: Metabolism and modifying factors (Chairmen: N. SEN and M. ARCHER) 06.30 Comparative metabolism of N-nitrosamines in relation to their organ and species specificity (0-37) M. OKADA 09.00 Alpha-hydroxylation of nitrogen-15 labelled N-nitrosamines by isolated hepatocytes (0.38) S.R. KOEPKF-, M.B. Troeger-Koepke, Y. Tandeur, J.G. Farrelly, M. Ste-ar-- & C.J. Michejda 09.15 Alternative bioactivation routes for beta-hydroxynitrosamines: bioche- mical and chemical model studies (0-39) R.N. LOEPPKY, W. Tomasik, D.A. Kovacs, R. Outram & K.H. Byington 09.30 Metabolism of nitrosamines by cytochrome P-450 isozymes (0-40) C.S. YANG, Y.Y. Tu, J. Hong & C. Patten 09.45 Distribution and metabolism of N-nitrosobis(2-hydroxypropyl)amine in rats. (0-41) Y. MORI, T. Takahashi, H. Yamazaki, K. Toyoshi, T. Obara, T. Makino, D. Nakae, S. Takahashi & Y. Xonishi 10.00 Urinary metabolites of a series of alicyclic nitrosamines (0-42) G.M. SINGER & W. MacIntosh 10.15 COFFEE 10.30 The effect of ethanol on nitrosam.1ne metabolism and distribution (0-43) P. SWANN 11.00 Inhibition of target tissue activation of N'nitrosonornicotine and N- nitrosopyrrolidine by dietary components (0.44) F.L. CHUNG, A. Juchatz, J. Vitarius & S.S. Hecht. 11.15 Influence of disulfiram on the metabolism of nitroso-diethylamine (0-45) N. FRANK, D. Hadjiolov & M. Wiessler 11.30 Effect of disulfiram on N-nitroso-N-methylbenzylamine metabolism (biochemical aspects) (0-46) F. SCHWEINSBERG, I Weissenberg, B. Bruckner, E. Schweinsberg, V. Burkle. H. Wittenberg H.J. Reinecke 11.45 Discussion 12.15 LUNCH -9 t.. C) CD 110 CD c0 BATCo document for Province of British Columbia 19 April 1999 - 28 - THURSDAY 8 SEPTEMBER (Continued) AFTERNOON POSTER SESSION Biological effects - modifying factors, epidemiology (Chairmen: W. KIJINSKY, P. FLE1HUES, k.B. MILLFR) 14.00 - 16.00 Poster display discussion 16.00 - 17.00 Plenary discussion 15.30 - TEA POSTERS: (P-31) Investigations on nitrite treated meat P. OLSEN, J. Gry, I. Knudsen, 0. Meyer & E. Poulsen (P-32) Experimental model for evaluating animal exposure to endogenous N-nitrosodi-n-butylamine by measuring its urinary metabolites N-butyl- 'g-(4-hydroxybutyl)nitrosamine and N-butyl-N-(3-carboxy-propyl)"Eitro- samine L. AIROLDI, C. Spagone, A. Macri r. R. Fanelli (P-33) Biochemical and biological properties of prospective N-nitrodialkylamine metabolites and their derivatives. E. FREI, B.L. Pool, W. Plesch & M. Wiessler (P-34) Metabolism of N-nitrosodialkylamines E. SUZUKI, M. Rochizuki, N. Sekiguchi L M. Okada (P-35) Metabolism and activation of 1,1.-dimethylhydrazine and methy1hydrazine two products of nitrosodimethylamine reductive biotransformation H. GODOY, M.I. Diaz Gomez & J.A Castro. (P-36) On the pharmacokinetics of tobacco-specific N-nitrosamines J.D. ADAMS, E.J. LaVoie, M. O'Donnel & D. Hoffmann (P-37) Fate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-l-butanone (NNK) in pregnant and young mice. H. TJALVE, A. Castonguay & S.S. Hecht (P-38) Comparative metabolism of beta-oxidi.ed nitrosa.ines D. NAGEL, A. Scott Helgeson, R. Le-is & T.A. La.son (P-39) Metabolic inactivation of N-nitrosamines by cytochrome P-450 in vitro an in vivo X.E. APPL & C.S. Ruhl (P-40) Effects of fluorination on in vitro metabolsim and biological activity of dialkylnitrosa-ines C. JANZOWSKI, J. Gottfried, R. Preussmann & G. Eisenbrand (P-41) Effect of ascorbic acid and some reducing agents an the N-nitroso- piperidine metabolism by liver microsome M. NhKhMURA, Y. Horiguchi & T. Kawabata (P-42) Evidence for the penetration of the nuclear envelope by N-nitrosomethyl CD CZ) 110 110 LAI 2 ~-. CD 1 ~0 BATCo document for Province of British Columbia 19 April 1999 - 29 - THURSDAY 8 SEPTEMBER - Afternoon - (Continued) (P-43) Interaction of bis- and mono-N-nitrosoureas with rat liver chromatin in vitro X. MORIMOTO & T. Yamaha (P-44) MutagenIcity of alpha-hydroxy N-nitrosamines in V79 Chinese hamster cells M. MOCKIZUKI, M. Osabe, T. Anjo, X. Takeda, E. Suzuki & X. Okada (P-45) Genetic activity in yeast assays of reputed nonmutagenic, carcinogenic N-nitroso compounds and methapyriline hydrochloride R.D. MERTA & R.C. Von Borstel (P-46) Induction by N-methyl-N'-nitro-N-nitrosocjuanidine of mutation, error proof repair and error-prone repair in Escherichia coli fluctuation assays E.R. NESTHANN, T.R. Harrington, D.J. Ko-k>el & A.A. Potter (P-47) Investigations on the mutagenicity of N-nitrosothiazolidine using the Ames Salmonella test W. FIDDLER, A.J. Miller, J.W. Pensabene & R.C. Doerr CP48) Genetic and biochemical factors affecting the induction of bacterlophage lambda by N-nitroso compounds R.K. ELESF7UTRU, S.K. Gonda & S.C. Moore (P-49) The role of the respiratory system in metabolism of nitrosamines after simultaneous application with disulfiram V. BURKLE, H. Wittenberg, F. Sch.einsberg, 1. Weissenberg, E. Sch.einsberg & B.. Bruckner (P-50) N-Nitrasodimethylamine- induced fore stomach tumors In male Sprague-Dawley rats fed a zinc-deficient diet. L.L.Y. FONG, W.L. N9 & P.M. Newberne (P-51) Involvment of thiols in MNNG - induced gastric cancer; biochemical and autoradiographic studies P. Xleihues 6 0. Wiestler (P-52) Action of N-methyl-N'-nitro-N- nitrosoguanidine on the target cells of the rat7stomach mucosa A.I. BY`KORZZ & Y.D. Ivashschenko (P-53) Pancreatic carcinogenic nitrosamines in Syrina hamsters P.M. POUR & T. LAWSON (P-54) Biological analysis of the hepatocarcinogenic process: Comparison of the effects of two nitrosmines and two promoters M. ROBERFROID, V. Preat, J. de Gerlache, K. Lans & H. Taper CD \0 CD BATCo document for Province of British Columbia 19 April 1999 - 30 - THURSDAY 8 SEPTEMBER - Afternoon - (Continued) (P-55) Carcinogenicity of N-mitrosodiethylanLine in snakes (python reticulatus, baidae) D. SCHM.AHL & H.R. Scherf (P-56) Dose and time relationships for nitrosamine carcinogenesis among inbred Colworth rats: the large BIBRA/UK government study R. GRAY, R. Peto, P. Brantom a P. Grasso (P-57) Geographic and social class variation withing the UK in levels of secretion of salivary nitrates and nitites - a preliminary report D. FORMAN, S. Al-Dabbagh & R. Doll (P-58) Biological monitoring in the metal working industry B. SPIEGELRA.LDER, H. Hartung & R. Preussmann (P-59) Nitrate and nitrite in saliva and urine of habitants in the area with low and high incidence of Cholangio-carcinoma in Thailand S. SRIANUJATA, L. Tangbanleukal, A. Valyasevi a S. Bunyaratavej (P-60) Nitrosamines in smoked meat and their relation to diabetes T. HELGASON S.W.B. Ewen, B. Jaffray, J.M. Stowers, J.E. Outram & J.R.A. Pollock (P-61) The relevance of gastric achlorhydria to human carcinogenesis C. CAYGILL, J. Craven, R. Hall, M. Hill & C. Miller (P-62) N-Nitroso compounds and human intracranial tumors S. PRESTON-KARTIN r. B.E. Henderson (P-63) Epidemiological assessment of risk to humans from exposure to nitrosa- mines A.B. MILLER J12. C) BATCo document for Province of BritiSh Columbia 19 April 1999 - 31 - FRIDAY 9 SEPTEMBER 14 ORNING SYMPOSIUM: Survey of laboratory/epideziology investications linking N-nitroso comoounds and their precurosrs with human carcino- genesis (Chairmen: P. CORREA and A.B. MILLER) 08.30 Anticancer nitrosoureas : investigations on ai,tineoplastic and neoplastic activities (0-47) G. EISENBRAND 08.50 Occupational exposure to nitrosamines: air measurements and biological monitoring. B. SPIEGELHALDER 09.05 Recent studies on nitrosamine and esophageal cancer (0-49) S.H. LU, H. Bartsch & H. Ohshima 09.35 In vivo nitrosation precancerous lesions and cancers of the gastro- intestinal tract: on-going studies and preliminary results (0-50) H. BARTSCH, H. Ohshima, N. Munoz, M. Crespi, V. Cassale, V. Ramazotti, A. Lehtnen, M. Inberg, A. Kitio, R. Lambert, Y. Minaire, J. Forichon, H. Tulinius G C.L. Walters 09.55 Ascorbic acid treatement in achlorhydric subjects - effect on gastric juice nitrite and N-nitroso compound formation (0-51) P.I. REED, P.L.R.'961th, 1C. Summers, C.L. Walters, B.A. Bartholomew, X.J. Hill, S. Vennit, F.R. House, D. Hornig & J.P. Bonjour 10.15 The Influence of H2 blocking drugs on endogenous nitrosation in humans as monitored by N-nitrosoproline secretion in the urine (0-52) J.B. ELDER, K. Burdett, P.L.R. Smith, P.I. Reed & C.L. Walters 10.30 COFFEE 10.4S Nitrite, nitrate and nitrosamines in gastric juice in patients with gastric cancer or duodenal ulcer and nitrite stability In their gastric juice. (0-53) J. UIBU & N Kalashnikova 11.00 Formation of nitrite in gastric juice of patients with various gastric disorders after Ingestion of a standard dose of nitrate a possible risk factor in gastric carcinogenesis (0-54) G. EISENBRAND, B. Adam, M. Peter , P. Malfertheiner P. Schlag 11.15 Discussion 11.30 Summary and closing remarks P.N. MAGEE AFTERNOON 14.00 Editorial Meeting (Chairpersons only) CD C) L14 X~b r1 J 13 ATCo document for Province of British Columbia 19 April 1999 - 32 - AUTHOR INDEX ADAMS J.D. ADA14 B. AIROLDI L. AITIO A. AL-DABBAGH S. ANDERSEN R.A. AKDREWS A.W. ANJO T. APPEL X.E. ARCHER M. BAILEY E. BARTHOLOMEW B.A. BARTSCH H. BELLANDER T. BHIDE S. BILMAZES C. BOGOVSKI P. BONJOUR J. BOOREN A.M. BRANTOM P. BROEKHOVEN L.W. van BRUCKNER B. BRUNNEKANN K.D. BUNYARATAVEJ S. BURDETT K. BURKLE V. BYINGTON K.H. BYYOREZ A.I. CASSALE V. CASTEGNARO M CASTONGUAY A. CASTRO J.A. CAYGILL C. CHALLIS B.C. CHANHAN S.M.S. CHOW Y.L. CHUNG F.L. CLARKSON R. CONRAD E.E. CRADDOCK V.K. CRAVEN J. CRESPI M. CROISY A. 0-19, P-36 0-54 P-32 0-50 P-57 0-21 P-1 P-44 P-39 0-5, 0-14, 0-24 P-18 0-16 0-51 0-6, 0-35, 0-49, 0-50, P-23 P-27 0-25 0-7 P-25 0-51 P-5 P-56 P-24 0-46, P-49 0-26, P-26 P-59 o-52 P-49 0-39 P-52 o-50 P-1 0-22, 0-23, P-37 P-35 P-61 0-2 0-17 0-3 0-22, 0-" P-7 P-4 0-11 P-61 0-50 P-23 DARNULE A. DAVIS J.A.R. DE GERLACHE J. DRALIWA S.S. DOERR R.C. DOLL R. DOUGLAS K.L. DUNN B.P. DUNN. S.R. EISENBRAND G. ELDER J.B. ELESPURU R.K. ELLEN G. ESTEVE J. EWEN S.W.B. FANELLI R. FARMER P.B. FARRELLY J.G. FAZIO T. FIDDLER W. FINE D.H. FONG L.Y.Y. FORICHON J. FORK" D. FRANK N. FREI E. FRIESEN K. GARNHAM J.C. GARROD F. GEURINK J.H. GODOY H. GOLD B. GOMEZ M.I.D. GONDA S.K. GOTTFREID J. GRASSO P. GRAY J.1. GRAY R. GRY J. RADJIOLOV D. ILAGMAR L. HALEY N.J. HALL R. HAMMANO H. HARRINGTON T.R. HARTUNG M. HASHIZUKE H. HAVERY D.C. HECHT S.S. D-23 P-24 P-54 0-3 P-47 P-57 P-3 0-6 0-9. 0-47, 0-54, P-40 0-52 P-48 0-8 0-20 P--60 P-32 0-16 0-38 0-32 P-47 0-34 P-50 0-50 P-57 0-45 P-33 0-35 0-51 P-7 P-24 P-35 P-42 P-35 P-48 P-40 P-56 P-5 P-56 P-6, P-31 0-45 P-27 P-26 P-61 P-17 P-46 P-58 P-15 0-32 0-22, 0-23, 0-44, P-28, P-37 CD -10 I'D 13 ATCo document for Province of British Columbia 19 April 1999 - 33 - AUTHOR INDEX H ELG ESON A. P-38 LABUC G.E. 0-14 HELGASON T. P-60 LADD K.F. 0-24 HENDERSON P-62 LALONDE P. P-7 HEYNS K. P-13 LAMBERT R. 0-50 HILL M.J. 0-51 LAIN D. P-22 HILL H. P-61 LANS V.- P-54 HINES L. P-42 LAVOIE E.J. P-36 HIRAYAMA T. 0-36 LAWSON T.A. P-38, P-53 HIRSCH J.M. 0-27 LECHNIR R. P-3 HOFFMANN D 0-19, 0-22, 0-26, LEHTONENN A. 0-50 P-26, P-36 LELE P. 0-9 HONG J. 0-40 LEVAN L.W. P-3 HORNIG D. 0-51 LEWIS R. P-38 HOUSE F.R. 0-51 LIJINSKY W. 0-18 LIN Z. P-22 INBERG M. 0-50 LEOPPKY R.N. 0-39, P-10 ISHIBASHI T. P-17 LOWN J.W. 0-17 ISHIWATA H. P-20 LU S.H. 0-49 ISSENBERG P. 0-4, P-4 LUNN G. P-1 IVASHCHENKO U.D. P-52 IWATA R. P-20 MACINTOCH W. 0-42 MACRI A. P-32 MAGEE P.N. 0-56 JAFFRY B. P-60 MAGINO M.H. P-2 JANZOWSKI C. P-40 MAKINO T. 0-41 JOHANSSON S.L. 0-27 McWEENEY J.W. 0-30 JUCHATZ A. 0-44 MALFERTHEINE P. 0-54 JUSZKIEWICZ T. P-8 MANDAGERE A.K. P-5 MASSEY R.C. 0-30 KhBACOFF B.L. P-3 MATSUI M. P-17 XAKIZOE T. 0-36 MEHTA R. 0-14, P-45 KALASHNIKOVA N. 0-53 MEYER B. P-13 KANAMORI H. P-15 MEYER 0. P-31 KANN J. P-25 MICHEJOA C.J. 0-38, P-11 KASPERBAUER M.J. 0-21 MICHELON J. P-1 KAWA,BATA T. P-17, P-41 MILLARD T.G. P-10 KEEFER L.K. P-1 MILLER A.B. 0-55. P-63 KEY P.E. 0-30 MILLER A.J. P-47 KINAE N. P-15 MILLER C. P-61 KLEIHUES P. 0-13, P-51 MILLER S.E. P-4 KLEIN D.A. P-4 MINAIRE Y. 0-50 KNOWLES M.E. 0-30 MIRVISH S.S. 0-4 KNUDSEN I. P-31 MITSUOKA T. P-21 KOEPKE S.R. 0-38 MOCHIZUKI M. P-34, P-44 KOGANTY R.R. 0-17 MOORE S.G. P-48 KONISHI Y. 0-41 MORI Y. 0-41 KOVACS D. 0-39 MORIMOTO K. P-43 KOWALSKI B. P-8 MORRISON J.B. P-28 KOWBEL D.J. P-46 MUNOZ N. 0-50 KROEGER-KOEPKE 0-38 KYSKOW W. P-8 KUBhCKI S. 0-32 C:) C) U4 BATCo document for Province of British Columbia 19 April 1999 - 34 - AUTHOR INDEX NAGARAJRAO D. NAGAO M. NAGEL D. NAIR J. NAY_kMURA M. NAKAMURA Y. NAXNI D. NESTMANN E.R. NEWBERNE P.M. NEWMARK H.L. NG W.L. HG V. NIELSON J.W. OBARA T. OBIEDZINSKI M. OCHIAI M. 0 DONNELL M. OHSHIMA H. OKADA M. OLSEN P. 0 NEILL I.K. OSA.BE M. OSTERDAHL B.G. OUTRAM J.R. PATTEN C. PEARSON A.M. PEDERSEN E. PEGG A.E. PENSABENE J.W. PETER M. PETO R. PIGNATELLI B. PIESCH W. POLLOCK J.R.A. POLO J. POOL B.L. POTTER A.A. POULSEN E. POUR P. PREAT V. PRESTON-MARTIN S. PREUSSMANN R. PUNWAR J.K. RAJEWSKI M.F. RAMAZOTTI V. RASMUSSEN N.J.D. RECH B. REED P.I. REINECKE H.J. 0-25 P-16 E-38 0-25 P-41 P-15 0-41 P-46 P-50 0-24 P-50 P-30 P-4 0-41 0-7 P-16 P-36 0-16, 0-35, 0-49 0-50, P-23 0-37, P-34, P-44 P-31 0-35 P-44 P-27 0-33, 0-39, P-60 0-40 P-5 P-6 0-12 P-47 0-54 P-56 0-6, 0-35 P-33 0-33, P-60 0-3 P-33, P-46 P-31 P-53 P-54 P-62 0-1, P-29, P-40, P-58 P-3 0-15 0-50 P-6 P-9 0-29, 0-51, 0-52 0-46 ROBERFROID M. ROOMA M. ROPER H. ROPER S. ROSENBERG I.E. ROSSNAGEL G. ROUNBEHLER D.P. RUGEWITZ- BLACKOLM B. RUHL C.S. RYDSTROM T.M. SAITO H. SAMS J.P. SANSONE E.B. SAUL R.L. SCANLAN R.A. SCHERF H.R. SCHLAG P. SCHMAHL D. SCHMEZER P. SCHULLER P.L. SCHWEINSBERG E. SCHWEINSBERG F. SCOTT J.C. SEAMAN S. SEKIGUCHI N. SEN N.P. SETLOW R.B. SHAH A.S. SHUKER D.E.G. SIMENHOFF M.L. SINGER G.M. SINGER S.S. SKRYPEC I.D.J. SMITH P.L.R. SONG P. SPAGONE C. SPIEGELHALDER B. SRIANUJATA S. STEWART M. STICH H.F. STOWERS J.M. SUGIMURA T. SUMMERS K. SUZUKI K. SUZUKI E. SWANN P. TAKAHASHI S. TAKAHASHI T. TAKEDA K. TAKENAKA H. TANGBANLEUYAL L. TANIMURA A. P-54 P-25 P-13 P-13 P-3 P-14 0-34 P-14 P-39 P-11 P-16 0-4 P-1 P-18 P-2 P-55 0-54 P-55 P-9 0-8 0-46, P-49 0-46, P-49 P-26 0-31, P-7 P-34 0-31, P-7 0-10 0-25 0-7, 0-16 0-9 0-42 P-12 P-5 0-29, 0-51, 0-52 P-22 P-32 0-48, P-29, P-58 P-59 D-38 0-6 P-60 0-36, P-16 0-51 P-21 P-34, P-44 0-43 0-41 0-41 P-44 -9b. P-15 C) P-59 C) P-20 %10 Ln BATCo document for Province of British Columbia 19 April 1999 - 35 - AUTHOR INDEX TANNENBAUM S.R. 0-7, P-22,P-30 TAPER H. P-54 TAUTS 0. P-25 THILANDER H. 0-27 TJALVE H. P-37 TOMASIK W. 0-39, P-10 TOMITA 1. P-15 TONDEUR Y. 0-38 TOYOSHI K. 0-41 TSUDA m. 0-36, P-16 To Y.Y. 0-40 TULINIUS H. 0-50 TUYNS A. 0-20 UIBU J. 0-53 UOZUKI A. 0-13 VAHINE A. 0-27 VALYASEVI A. P-59 VENITT S. 0-51 VIELHUBER S.F. P-3 VITARIUS J. 0-44 VON BORSTEL R.C. P-45 WAGNER D.A. 0-7, P-19 WAKABAYASHI S. P-16 WALTERS C.L. 0-29, 0-50, 0-51, 0-52 WEISSENBERG 1. 0-46, P-49 WENKE G. 0-26 WIESSLER M. 0-45, P-14, P-33 WIESTLER 0. 0-13, P-51 WINN D.M. 0-28 WISHNOK J.S. P-30 WITTENBERG H. 0-46, P-49 YAMAHA T. P-43 YAMAIZUMI Z. P-16 YAMAZAKI H. 0-41 YANG C.H. 0-40 YINZANG L. P-22 YOKOYAMA T. P-15 YOUNG V.R. 0-7 BATCo document for Province of British Columbia 19 April 1999 - 36 - NOTES ON PAPERS AND POSTERS - TOBACCO SESSION Paper No. 19 Formation and Analysis of N-Nitrosamines in Tobacco Products and their Endocenous Formation in Tobacco Consumers Given by D. Hoffmann, Naylor Dana Institute, American Health Foundation, Valhalla, New York. This was a general review and contained little new information. Boffmann was asked whether he thought tobacco-specific nitrosamines could be formed endogenously in smokers' lungs from nicotine. The reply from Hoffmann was that it was likelyl Paper No. 20 Tobacco and Risk of Cancer: 1mvDrtance of Kinds of Tobacco This was an important review by J. Esteve from IARC, Lyon, France. There was, however, a language problem. The major conclusion of this paper was that there is little convincing epidemiological evidence that air-cured tobacco should be more or less carcinogenic than flue-cured tobacco. There is some indication that the risk difference, if any, might be greater for bladder cancer. Should there be an effect on laryngeal and oesophageal cancer this would, in any case, be of little importance as compared with the effect of alcohol and other parameters of smoking affecting risk. Paper No. 21 Post-harvest Treatment and the Accumulation of Nitrite and N-Nitrasonor- nicotine in Burley Tobacco By R.A. Andersen of the United States Department of Agriculture, Depart- ment of Agronomy, University of Kentucky, USA. Concentrations (dry weight basis) of nitrate, nitrite and NI-mitrosonor- nicotine (NUN) in Burley tobacco were determined durimg successive processing stages of experimental homogenised- leaf cured MC) material, after conventional air curing and during prolonged storage ("aging") of HLC and air-cured tobaccos. During homogenised leaf curing, 6 p-q/g nitrite-N and < 10 Vg/g NNN were found in tobacco frozen immediately after aerobic incubation of homogenates, at 40*C for 0, 4, 8, 20 and 25 h. Up to 550 H/9 nitrite-N and 850 g/g NMI occurred in tobacco incubated similarly for 20 h and then allowed to stand I h without aeration. Samples of two genetic Burley lines of high and low alkaloid content were similarly incubated, allowed to stand I h, dried and "aged" for up to one year in partially anaerobic environments. NNN contents were postively correlated with "at harvest" alkaloid content and UNN increased at each subsequent stage of processing, reaching a maximum of 1800 g/g in the high-alkaloid line after one year of "aging". Small increases of NNN (I to 50 ~Lg/g) " ' C) . occurred in tobaccos that were air-cured and then aged (Z) 110 1.0 BATCo document for Province of BritiSh Columbia 19 April 1999 - 37 - Paper No. 22 Carcinogenicity and metabolic Activation of Tobacco Specific Nitrosamines: Current Status and Future Prospects This paper was given by S.S. Hecht of the Naylor Dana Institute, American Health Foundation, Valhalla, New York. NNK is a very strong carcinogen, much more so than either NNN, NAtB or NAB. In the Syrian Golden Hamster, NN`K is as active as nitrosomorpho line. The conclusion of this paper was that tobacco-specific nitrosamines are a key class of compounds, especially NNX. Paper No. 23 Kinetics of DNA Methylation by the Tobacco-Soecific Carcinogen 4-(Me,thylnitrosamLno)-I-(3-pyridyl)-l-Butanone in the F344 Rat By A. Castonguay of the Naylor Dana InstItute. 4-(Methvlnitrosamino)-I-(3-pyridyl)-l-butanone (NNK) was Injected i.v. (0.41 mmol/kg) to F344 rats. DNA from target organs (lung, liver) and a non-target organ (kidney) was extracted, hydrolysed and analysed for mathylated guanines and assayed by cation exchange HPLC-fluorimetry. Levels of 06 -methy lqua nine, a promutagenic lesion, and 7-methylquanine were 3 to 8 times higher in the liver than in the lung. Neither base could be detected in the kidneys. The extent of methylation of hepatic DNA by NNY, as 35 times lower than that observed with an equimolar dose of NDMA by Swann et al (1983). The levels of the two methylated guanines in liver and lung DNA increased between 4 hrs and 24 hrs following NNK injection. NNX is rapidly metabo- lised in F344 rats to 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butan-l-oI (NNAL). The relatively slow methylation of hepatic DNA after NNK injection could be due to a slow release of methylating species from the major circulating metabolite NNAL. This low but sustained level of OrO-metl.yl- guanine induced by NNK could, in part, explain its carcinogenic potency. Paper No. 24 Increased Endogenous Nitrosation In Smokers This was an interesting, well presented paper, given by M.C. Archer of the University of Toronto. In short, the conclusions were that NOX is not involved in n1trosation of &mines in the respiratory tract and that, folioing ingestion of nitrate and proline, smokers produce significantly greater amounts of nitroso- proline. The later result suggests that endogenous synthesis of carcino- genic N-nitroso compounds may be greater in smokers than in non-smokers. Additionally, Archer has shown, in agreement with other workers, that smokers have 3-4 times higher levels of salivary thiocyanate than non- smokers. Thiocyanate is well known to cat-alyse nitrosation reactions under moderately acidic conditions (Boyland -et al., "The Catalysis of Nitrosation by Thiacyanate from Saliva, Fd- Cosmet. Toxicol., 9, 639-643). CZ) C:) 110 I'D c0 BATCo document for Province of British Columbia 19 April 1999 - 38 - Paper No. 25 Epidemiological and Excerlmental Studies on Tobacco-Related Oral Cancer in India This paper was given by S.V. Bhide of the Carcinogenesis Division of the Cancer Research Institute, Bombay, India. The only tobacco paper given by a delegate fro. the Third World. This was a review and contained little new information, but was well presented and interesting. many epidemiological studies carried out in India have shown the associa- tion of tobacco chewing with oral cancer. Dr. Bhide suggested that detection of tobacco-specific nitrosam.:Lnes in ~Lg quantities in chewing tobacco further strengthened the cause and effect relationship between tobacco chewing and oral cancer. Her analytical figures were in good agreement with the figures from the Hoffmann school. Paper No. 26 A Study of Betel Quid Carcinogenesis - 11. On the Formation of N-Nitros- amines During Betel Quid This paper was given by G. Wenke of the Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York. The work was done in collaboration with S.V. Bhide, Carcinogenesis Division, Cancer Research Institute, Bombay, India. Although this paper was not about tobacco, there were soe interesting parallels. The major alkaloid in betel quid is arecoline (1). In model studies it has been shown that it nitrosated to N- nitrosoquvaco line (II), 3-(methylnitro- samino)propionitrile (III), 3-(-ethylnitrosamino)propionaldehyde (IV) and two unknown nitrosamines (Scheme). C02CH3 3 C02CH3 CH 3 CEO CH N (N 3 N N ZZ:Zb N 4z::: 0 UI) (III) (IV) Scheme Compound (111) is a strong carcinogen in rats. .9 b. CD CD BATCo document for Province of British Columbia 19 April 1999 - 39 - Paper No. 27 Effect of Lona Term Application of Snuff and Herpes Simplex Virus I an Rat Oral Mucosa This paper as given by J.H. Hirsch, representing the Departments of Oral Surgery, Pathology and Virology, University of GF)tebarg, Sweden. Rats exposed to snuff or to Herpes Simplex Virus (1) and snuff had a higher incidence of tumours or tumcur-like conditions than control rats. Paper No. 28 Tobacco Chewing and Snuff Dipping: An Association with Human Cancer Dr. D.W. Winn presented this most interesting but anti-tobcco paper. Dr. Winn is a research scientist at the National Cancer Institute, Bethesda, Maryland, USA. A number of slides showing snuff dipping by children in the USA were shown. Apparently, more young teenagers are now indulging in this practice and Dr. Winn expressed her concern about this. At times, this paper was given in a most emotional vein. Dr. Winn made the statement that the evidence for the use of snuff as a cause of cancer of the oral cavity, especially of the buccal mucosa and gums, is convincing. No evidence was offered for the involvement of tobacco-specific nitrosamines, but the implication was there. NOTE: The Tobacco Session finished approximately 30 minutes late and the Chair- man, R. Preussmann, suggested that, due to the time, no final discussion should be held. This was quite puzzling as all other sessions had in- variably finished late as most presentations over-ran. One can only assu.e that it had been previously agre-nd to curtail discussions on the Tobacco Session. I felt that the nHoffmann School" was behind this in collaboration with IARC. POSTER PRESENTATIONS CONCERNED WITH TOBACCO AND CIGARETTE SMOKE Poster No. 26 On the Endogenous Formation of N-nitrosoproline upon Cigarette Smoke Inhalation This poster was given by Klaus Brunnemann of the Naylor Dana Institute, American Health Foundation, Valhalla, New York. The results indicated that inhaled cigarette mainstream smoke has the potential for endogenous N-nitrosation of proline. Brunnemann assumed that this potential extends also to other N-nitrosatable amines including i nicotine. The observation of effective inhibition of N-nitrosation by C) N) CD BATCo document for Province of BritiSh Columbia 19 April 1999 - 40 - dietary supplements of ascorbic acid is supportive of this concept and offers some degree of hope for prevention. Brunnemann posed several questions: (1) Does endogenous N-nitrosation of amines upon smoke inhalation occur primarily in the stomach, the oral cavity, the lung and/or in the blood? (2) Can formation of N-nitrosoproline be increased by administering dietary proline in several subdoses? (3) Are the oxides of nitrogen in cigarette smoke directly responsible for endogenous nitrosation, or are there other nitrosating agents formed? This will form the basis for Brunnemann's future work. Poster No. 36 On the Pharmacokinetics of Tobacco-Scecific N-Nitrosamines This interesting poster was given by J.D. Adams, Naylor Dana Institute, American Health Foundation, Valhalla, New York. [Note: Dr. Adams has previously conducted some research into filters for nitrosamines. It was found (with his limited study) that cellulose acetate is the better filter. We spoke briefly about this. Apparently, no further filter work is planned at the Naylor Dana Institute.) Methods had been developed to determine the biological half-life of NNN and NUK in Syrian Golden Hamsters and Fischer Rats. The major metabolite of NNK (1) is NNAL (2), which as estimated by a modified GC-TEA set-up. 0 0 H N=O 11 N=O I ey C-(CH2)3 N"" CH3 C-(CH2) 3-N,, ik~' 11) ~J 1 CH3 N H (2) Biological half-lives of NNN, NNK and NNAL. NNN NNK NNAL Hamster 0.77 hr 0.25 hr 1.78 hr Rat 5.78 hr 1.78 hr 3.56 hr Quite clearly, these findings illustrate a species difference in the pharmacokinetics associated with the distribution and elimination of tobacco- speci fi c nitrosamines. CD C) \0 1 ~0 (14 -rh. N.) BATCo document for Province of BritiSh Columbia 19 April 1999 - 41 - Poster No. 37 Fate of the Tobacco-Specific Carcinogen 4(Methvlnitrosamino)-l- (3-pyridyl)-l-Butanone in Pregnant and Newborn C57BI Mice This poster was given by Hans Tjllve of the Department of Toxicology, Uppsala University, Sweden. The work was done in collaboration with the Naylor Dana Institute, Valhalla, New York. It was shown, using whole body autoradiography, that NNX and/or its metabolites can diffuse through the placenta and reach the foetal-tissues in C57BI mice. Within 4 hours of introduction of NNK, a considerable proportion of NNY, metabolites present in the foetal tissues are excreted into the amniotic fluid. The author suggested that his results provide evidence that NNK could exert genotoxic effects transplacentally and in newborn mice. OTHER PAPERS AND POSTERS OF RELEVANCE AND INTEREST The first session, on the Analysis, Occurrence and Formation of N-Nitroso Compounds, proved to be very enjoyable and served as a good introduction to the nitrosamine area. Some interesting chemical papers were also presented, notably that of Challis and Chow. Paper No. I Analysis, Occurrence and Formation of N-Nitroso Compounds By R. Preussmann of the Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Federal Republic of Germany. (Note: Dr. Preussmann has been working on nitrosamines for a considerable perioa of time and, with other workers, is partially responsible for the importance that this subject assumes today.] This was a review paper and contained nothing new, but served as a good introduction into the field of nitrosamines. There were a number of "off- the-cuff" statements made by Preussmann which should be recorded. He stated that tobacco-specific nitrosamines contribute to the highest exogenous exposure of nitrosamines to van and that snuff dipping now provides direct evidence for the involvement of tobacco-specific nitros- &mines in oral cavity cancer. He also stated that, in his view, more inlor.ation should be obtained concerning the role of tobacco-specific nitrosamines in smoke with human cancers. This was very much an anti- smoking/tobacco paper. Paper No. 2 Nitrosation of Peptides This very interesting chemical paper was given by B.C. Challis of Imperial (Z) College, London. CD .10 NJ BATCo document for Province of British Columbia 19 April 1999 - 42 - The synthesis of N-(N-acetylprolyl)N-nitrozoglycine, the first authentic N-nitrosopeptide, wa; described. In acidic media, denitrosation and ~Ydrolysis of this compound occur concurrently whereas, in neutral and alkaline solutions, only hydrolysis occurs (Scheme). 0 11 C'~ 2-2H N N=O 0';; C "CH 3 -NO _Z 0 11 C _CH 2-1 C02H 0 CH3 0 11 "-OH 0'~O~ CH3 + HO-N=N-CH 2 cc2 H - N2 0 H30" C,+,'CH2C02H ' / \ ' < N H N _--O C 0 CH3 Scheme IV Products Challis suggested that, because of the high intake of protein (peptides) in man, similar compounds may be formed in the gastric tract. The inference was that nitroso, peptides could act as trans - nitrozation species to form other nitrosamines by reaction with amines. CD CD I'D I'D U-4 Jt- BATCo document for Province of British Columbia 19 April 1999 - 43 Pacer No. 3 A Chemical Model of Nitrosamine Carcinooenesis: The Nitrosation Pattern of Amide Linkages and Facile Transfonmtion of Nitrosa=nes This paper was given by Professor Y.L. Chow of the Chemistry Department, Simon rraser University, Burnaby, British Columbia, Canada. It as a great shame that this paper was presented in such an appalling manner. The author gave a somewhat confusing, rambling talk and his slides were unintelligible. In contrast, the written paper (copy obtained) was quite clear and interesting to read. N.itrite ions interact with N-methylacetamide and N-acetylglycine readily in aqueous solution (buffered to PH) to give transient nitrosauLides, N-nitroso-N-mathylacetamide and N-nitroso-N-acetylglycine, which could be detected but not isolated. He offered evidence to support the partici- pation of the carboxylate group in the nitrosation of N-acetylglycine (Scheme). N H-,N 0 CH / I IC =0 CH 0 3 1114 0 H,, 2,\ kc/ 0 0'k- / +HNO N C 2 CH3 0 0 CH3 Scheme Whether this mechanism could operate in vivo was the subject of much argument during question time. Dr. Challis was particularly vehement in his attack on Professor Chow's chemistry. Paper No. 4 The Witrosating Agent in Mice Exposed to Nitrogen Dioxide This paper was given by S. Mirvish of the Eppley Institute, University of Nebraska Medical Centre, Omaha, USA. This was a very poorly presented paper and only concerned skin exposure, not inhalation. The author suggested that free radical mechanisms may be operating. Not a particularly original thought. c, C:) CD 110 NJ BATCO document for Province of BritiSh C01UMbia 19 April 199!9 - 44 - Paper No. 5 Catalysis and inhibition of N-Nitrosation Reactions This was an excellent revie. by M.C. Archer of the Department of Medical Biophysics, University of Toronto. He covered an enormous amount of worst in a very clear and concise manner, including the work by Pignatell! and Walker at IARC. Catalysts Thiocyanate Surfactants (that form micellar aggregates) Carbonyl compounds (in particular, aldehyde) Thiols Nitrosophenols Polyhydroxyphenols Inhibitors Ascorbic acid Phenols Chlorogenic acid Pyrrole Inorganic compounds (that mop up nitrous acid) Simple alcohols Some carbohydrates Halide ions Thiourea and Thiols It is no. well established that microorganisms can facilitate nitrosation reactions by (a) Reducing nitrate to nitrite; (b) Lowering the pH; (c) Producing substances or enzymes that directly catalyse nitrosation reactions. A most interesting part of this paper, that was not reported at the conference because of the lack of time, was the catalytic effect of aldehydes and dichloromethane (Scheme). R2 NH I R'CHO OH - R2 N+ - CH R' le-Cl R 2 NH + CF 2C-*24R2NCH 2C' R 2 NNO + RI CHO < Scheme ONO (nitrite) R2 ~ CH2 ( r-.., I N- 0 0 -Ch. C) CD I'D 1.0 BATCo document for Province of BritiSh Columbia 19 April 1999 - 45 - A similar mechanism for aldehyde involvement was proposed by Dr. Challis when D.h. Matk_4n visited imperial College shortly after the conference. The possible involvement of dichloromethane in 'the catalysis of nitros- amine formation is very interesting as this is a major component of the so!vent.system used to extract and estimate nitrosamines in tobacco. Wh n th methodology -as developed in GR&DC for the measurement of nitros- &mines in tobacco, it was discovered that artifact formation (additional amounts of NAtB) -as a serious problem. This was eventually solved by the use Of CH2CI2/MeOR mixture. It was thought at the time that the methanol acted as a H~ scavenger (CH2 cl2 is decomposed by light to HC1), inhibiting the production of hitrosating species from nitrite on the tobacco. Another possibility now is that methanol inhibits the reaction of secondary amines with dichloromethane. Poster No. 5 Further Factors Influencing N-Nitrosamine Formation in Bacon This poster was given by J.I. Gray of the Department of Food Science and Human Nutrition, Michigan State University. Although this poster as of little relevance, I had an interesting conversation with Ian Gray. Apparently his group has recently completed some other work on the catalytic effect of rutin in nitrosamine formation. D r r. 'ray promised to forward this information to me later this year. Poster No. 11 Photolysis of N-Nitrosamines in Neutral Media Dr. C.J. Michejda presented an interesting poster on a most relevant topic. Photolysis is used as a method for destroying small quantities of nitrosamine residues after experimentation. It is known that nitrosamines are phatc-stable in the absence of acid. This work shows that cleavage of the N-N bond is a very facile process. In the absence of radical scavengers, however, the reformation of the nitrosamines is very rapid - hence little or no phatolysis. When scaven- gers are present the phatolysis proceeds with high efficiency to give non-nitrosamine products. In the presence of oxygen, nitramines are formed when they themselves are further transformed. These results have some importance with regard to the destruction of nitrosamine wastes. Paper No. 29 Pitfalls to Avoid in Determining N-Nitroso Compounds as a Group Presently in GRLDC individual nitrosamines are measured and not total nitrosamine levels. However, there may be a need to do this in the foreseeable future. Therefore, this excellent review by C.L. Walters, of the Leatherhead Food Research Association, Surrey, was quite timely. X:.. CD C) U-4 X:. r1 J 0 \ 13 ATCO document for Province of BritiSh Columbia 19 April 1999 - 46 - Summary of methods that can be used: (1) Irradiation with light at 360nm converts n1trosamines to nitrite (Sander, 1967). RI'll 36onm N - N - 0 ) NO 2 Nitrite produced can then be estimated by conventional methods. (2) Treatment with hydrogen bromide. R HBr N - NO R R1-1 NH + NO Br RZ i H 0 NO2 Nitrosyl bromide formed is hydrolysed to nitrite, which is measured as above. (3) Thermal Energy Analyser. N - N - 0 N . + NO Rz Nitric oxide liberated is measured by chem.11unLinescence method. Method (3) Is most widely used at present. Paper No. 30 N-'Nitrosamine Analysis in Foods: N-Nitrosamine Acids by HPLC/".MA and Total N-NitrosanLines Content by Chemical Denitrosation/TEA This was a fairly comprehensive review by Dr. R.C. Massey on methods developed, at the Ministry of Agriculture, Fisheries and Food, Food Science Laboratory, Norwich, for the measurement of nitrosamines in food. One of the co-authors of this paper is D.J. McWeeny, with whom contact was made with regard to his work an polyphenol catalysis. CD BATCo document for Province of British Columbia 19 April 1999 47 Paper No. 43 The Effect of Ethanol on Nitrosamine Metabolism and Distribution As a moderate drinker, I found this paper, by P.F. Swann of the Courtauld institute of Biochemistry, Middlesex, fascinating. It has been found that relatively small quantities of ethanol alter the distribution and metabolism of small oral doses of DMNA and DENA in rats. Swann offered evidence to show that, in the case of DMNA, this is the result of prevention of first pass clearance of the nitrosamine a s it passes in the blood draining the gut through the liver before entering the general circulation. Put simply, the presence of alcohol has the effect of reducing the potential for alkylation (via nitrosamine metb.- lites) of tissues and hence cancer formation. This is good news for drinkersi Paper No. 44 Inhibition of Tarcet Tissue Ac-tivation of N-Nitrosonornicotine and N-Nitrosaphyrrolidine This paper was given by r.-L. Chung of the Naylor Dana Institute. Twenty-one dietary and related chemicals were evaluated for their poten- tial inhibitory activities against the tumorigenic effects of 14PYR and NNN. These compounds included Phenols Cinnamic acids Cou.arins Isothiocyanates Indoles Isothiocyanates were found to have the most potent inhibitory activity for nitrosamines in acute studies, but was less active in chronic studies. This difference may be explained by the pharmacokinetic properties of these compounds. It was found that phenols, cinnamic acids, cou~arins and indoles -ere primarily inducers of NPYR metabolism. In summary, isothio- cyanate appears the most promising agent for protection against the carcinogenic effects of nitrosamines. Pacer No. 48 Occupational Exposure to Nitrosamines: Air Measurements and Biological Monitoring By B. Spigelhalder of the German Cancer Research Center, Heidelberg, West Germany. This was quite an interesting paper but did not include any reference to t:.. cigarette smoke (mainstream or sidestream) and was concerned mostly with CD the measurement (monitoring) of nitrosamines in industrial manufacturing (-,4 Nj CO BATCo document for Province of British Columbia 19 April 1999 - 48 - areas. Spigelhalder strongly advocated the establishment of representa- tIve data bases on individual exposure levels in combination with prospective epi demio logical studies. Under these conditions it might be possible to identify risk areas and to introduce preventive measures. CD C:) N) .10 BATCo document for Province of British Columbia 19 April 1999