FUNDAMENTAL RESEARCH OBJECTIVE: THE STUDY OF TOBACCO PRODUCTS RISXS FOR THE PURPOSE OF ALLEVIATING PERCEIVED HEALTH THE COURSE OF ACTION: DESIGN A PROGRAMME THAT TAKES US FROM OUR PRESENT PROGRAMME OF GROSS REDUCTION OF TOXIC TOBACCO SMOKE COMPONENTS TO A PROGRAM OF SELECTIVE REDUCTION OF SPECIFIC TOBACCO SMOKE COMPONENTS TO REDUCE THE SPECIFIC TOXICITY OF TOBACCO SMOKE. THIS PROGRAMME WILL BE BASED ON THE RECOMMENDATIONS OF MEDICAL AND SCIENTIFIC EXPERTS, SOME OF WHOM ARE IDENTIFIED ON PAGE 2. FUNDAMENTAL RESEARCH IS NOT, IN ITSELF, AN OBJECTIVE; IT IS A STRATEGY. IT IS A SELECTED COURSE OF ACTION WHICH AFFORDS THE MOST SUPPORT TO THE ACHIEVEMENT OF AN OBJECTIVE. C:) BATCo document for Province of British Columbia 28 October 1999 FUNDAMENTAL RESEARCH FUNDAMENTAL A. OBJECTIVE .THE ONGOING PROGRAMME OF FUNDAMENTAL RESEARCH Is WORLDWIDE IN SCOPE AND ENTAILS AN IN-DEPTH STUDY OF TOBACCO PRODUCTS FOR THE PURPOSE OF ALLEVIATING PERCEIVED HEALTH RISKS.' PAUL PARE JUNE 7, 1985 A MODEL WAS DEVELOPED TO FACILITATE EXAMINATION OF THE FACTORS PERCEIVED AS HEALTH RISKS, AND To FORMULATE AN APPROACH FOR THE REMOVAL OF THE IDENTIFIED UNDESIRABLES. EMN THE ACTIVITY WOULD BE IN THREE PHASES ELIMINATE MODIFY NEUTRALIZE THE NEXT STEP WAS TO GET AN IDEA OF THE MODIFICATIONS THAT OTHER PEOPLE THOUGHT SHOULD BE MADE TO A CIGARETTE, TO REDUCE PERCEIVED HEALTH RISKS. HERE ARE SOME EXAMPLES Q) CZ) (JI BATCo document for Province of British Columbia 28 October 1999 -2- B. SOME RELEVANT SUGGESTIONS 1 D.M. WARBURTON ET AL 2 SMOKING & ARTERIAL DISEASE M. JARVIS 3 JOURNAL OF CHRONIC DISEASE D.B. PETITTI & G.D. FRIEDMAN 4 ROYAL COLLEGE OF PHYSICIANS 5 ROYAL COLLEGE OF PHYSICIANS 6 DIETRICH HOFFMAN & ERNST L. WYNDER 7 FOURTH SCARBOROUGH CONFERENCE ON PREVENTI.VE MEDICINE 8 ASSESSMENT OF CARCINOGEN EXPOSURE IN 14AN 9 BIOLOGICAL ACTIVITY USING SIX IN VITRO SHORT-TERM TESTS BATCo document for Province of British Columbia 28 October 1999 -3- EMN C. IDENTIFY THE UNDESIRABLES THIS MODEL USES THE LIST OF THE MAJOR TOXIC AGENTS IDENTIFIED IN THE 1981 SURGEON GENERAL'S REPORT. GAS PHASE 2. IT IS SUGGESTED THAT AN ATTEMPT BE MADE TO IDENTIFY THRESHOLD VALUES SO THAT PRIORITIES CAN BE DETERMINED. 3. THE DOSE MAKES THE POISON 4. RELATIVE RISK 5. MAJOR TOXIC AGENTS - THRESHOLD 6. DOSE RESPONSE CURVE 7. COMPLETE DOSE RESPONSE CURVE 8. EXAMPLES OF THRESHOLD APPLICATION VINYL CHLORIDE HEAVY METAL cz::) BATCo document for Province of British Columbia 28 October 1999 -4- EMN D. ELIMINATE THE UNDESIRABLES LEAF BIO-TECH PROCESS E. MODIFY PRODUCT DESIGN CIGARETTE F. NEUTRALIZE NUTRIENTS G. PAST BIOLOGICAL RESEARCH IN THE BAT GROUP Q1 \4 C) BATCo document for Province of British Columbia 28 October 1999 SUSCEPTIBILITY TO THE SMOKING HAZARD ROYAL COLLEGE OF PHYSICIANS I EXTERNAL INFLUENCES 2 GENETIC FACTORS CAUSES OF CANCER IF WE LOOK AT THE MAJOR FACTORS - DIET - THERE ARE SOME INTERESTING OBSERVATIONS THAT CAN BE 14ADE 1 DIETARY CARCINOGENS AND ANTICARCINOGENS, BRUCE N. AMES 2 ACCOUNTS OF CHEMICAL RESEARCH, CARCINOGENS ACCEPTABLE IN FOOD 3 CHEMICAL CARCINOGENS AND INHIBITORS OF CARCINOGENESIS IN THE HUMAN DIET 4 AMERICAN OCCUPATIONAL HEALTH CONFERENCE CARCINOGENSa ANTI-CARCINOGENS, AND CANCER CAUSATION. BRUCE N. AMES 5 REC06NITION OF THE ROLE OF DIET HAS PROMPTED THE PUBLICATION OF THE FOLLOWING DOCUMENTS 6 CANCER PREVENTION RESEARCH SUMMARY U.S. DEPT. OF NUTRITION HEALTH 3 HUMAN SERVICES 7 CANCER PREVENTION RESEARCH: CHEMOPREVENTION & DIET NATIONAL CANCER INSTITUTE 8 DIET NUTRITION AND CANCER NATIONAL RESEARCH COUNCIL 9 DIETj NUTRITIONj AND CANCER: DIRECTIONS FOR RESEARCH COMMITTEE ON DIET, NUTRITION, AND CANCER. COMMISSION ON LIFE SCIENCES, NATIONAL RESEARCH COUNCIL BATCo document for Province of British Columbia 28 October 1999 -6- THE ROYAL COLLEGE OF PHYSICIANS ALSO IDENTIFIED GENETIC FACTORS AS PART OF .SUSCEPTIBILITY TO THE SMOKING HAZARD' SIMILAR VIEWS AS EXPRESSED BY R.L. WHITE IN HUMAN GENETICS' WHILE IN AN ARTICLE .REDUCING RISK: A CHANGE OF HEART' COVERS MOLECULAR GENETICS, AND THE ENVIRONMENTAL APPROACH OF DR. LEONARD SYME. THIS LEADS US TO A CONSIDERATION OF LIFE STYLE ENVIRONMENT BATCo document for Province of British Columbia 28 October 1999 -7- LIFE STYLE ENVIRONMENT GENETIC THE DOTTED LINE SIGNIFIES THE CORRELATION BETWEEN SMOKING AND DISEASE; IT IS DOTTED RATHER THAN SOLID TO SUGGEST THAT THE CORRELATION MAY NOT BE BASED ON ANY DIRECT CAUSATION. THE SOLID LINES IN THE FIGURE SUGGEST THAT GENETIC FACTORS PLAY A LARGE PART OF THE CAUSATION OF DISEASE. 2 THAT GENETIC FACTORS PLAY A LARGE PART OF THE CAUSATION OF SMOKING1 IT IS SUGGESTED THAT THESE FACTORS ARE LIKELY TO OVERLAP 3 GENETIC FACTORS ARE VERY INFLUENTIAL IN DETERMINING INDIVIDUAL DIFFERENCES IN PERSONALITY, AND THAT THESE DIFFERENCES IN TURN ARE RELATED TO 4 SMOKING 5 DISEASE 6 STRESS IS RELATED TO SMOKING AND 7 DISEASE C~) c0 BATCo document for Province of British Columbia 28 October 1999 -9- REVIEW OF PAST BIOLOGICAL-RESEARCH ASSOCIATION OF SMOKING WITH CHRONIC DISEASES CANCER MECHANISMS BEGINNING TO BE UNDERSTOOD BIOASSAYS AVAILABLE A) MOUSE SKIN PAINTING B) INHALATION TESTS C) SHORT-TERM TESTS 2. CARDIOVASCULAR DISEASES MECHANISMS POORLY UNDERSTOOD NO SUITABLE ANIMAL MODEL 3. CHRONIC OBSTRUCTIVE LUNG DISEASES MECHANISMS POORLY UNDERSTOOD NO SUITABLE LABORATORY MODEL C=) (-.n BATCo document for Province of British Columbia 28 October 1999 -10- CANCER - POSSIBLE MECHANISMS 1. EXISTENCE OF A RELATIONSHIP BETWEEN CARCINOGENESIS AND MUTAGENESIS 2. THE MUTATION THEORY OF CANCER CANCER RESULTS FROM MUTATION OF SOMATIC CELL 3. MUTATED SOMATIC CELLS OUTGROW SURROUNDING CELLS 4. LONG PERIOD BETWEEN MUTATIONAL EVENT AND DEVELOPMENT OF CANCER 5. TWO-STAGE THEORY A) INITIATION B) PROMOTION CZ) BATCo document for Province of British Columbia 28 October 1999 CM itt LLJ LLJ Ln CN tn LIJ zr LLJ Cn LLI C/) CD I-e C) LLJ V) C/7 C-,> Cn C-) LLJ = Lki Cn Cn -cc C4 Lj LLJ LLI - V) CD C) LL.j Zn :Z r LLI 0- U-~ LLJ C!!:: LLj V) C) LD I-- C1. Lo -cc LJ ev, -i C= LLJ LLI L.J C) L-) C/3 1 = 0- M. LLJ 2!: = LLJ LLJ V) __j :x - LLJ -- a. U- C/) C) I-- cc LLJ -cc CIO Cn C/I LLJ - LLJ .4c (-j --r ::. 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PAPER POROSITY 0 < 2. HIGHER PUFF VOLUME 2. GRANULATED TOBACCO 2, SILICA GEL FILTER 3 INCREASED FLOW RATE 3. FILTERS 3. INCREASING TOBACCO MOISTURE FROM 0 . A) ACETATE 12% To 20%. 4. INCREASED CUTS PER B) POLYETHYLENE GLYCOL 4 DARK TOBACCO - GERMAN I NCII c) CHARCOAL . 5 BURLEY TOBACCO AND D) CHARCOAL (PELLET TYPE) 5. SUN-CURED - INDIAN 0 , STEM E) CELLULOSE ACETATE 6. CIGAR LEAF 0 F 6. VIRGINIA STEM 11. ADDITIVES 7. GRAMULATED IN CIGAR 3 9 7. RECONSTITUTED SHEET A) MALIC ACID 8. RECONSTITUTED SHEET 2) A) GERLACH B) 2% DIETHYLENE GLYCOL A) ARENCO c0 B) PCL c) 1% GALLIC ACID-N- B) BORGWALDT 0 0 SRT PROPYL ESTER c) AMF 0 cr D) SCHWEITZER 9. ADDITIVES 0 8. ADDITIVES A) POTASSIUM MALATE c0 A) POTASSIUM NITRATE B) POTASSIUM HYDROGEN MALATE w w B) COPPER NITRATE 0 COPPER POTASSIUM MALATE 0 POTASSIUM NITRITE D) POTASSIUM CARBONATE (NO STEAM) D) SODIUM NITRATE E) AMMONIUM SULPHAMATE E) POTASSIUM CARBONATE 0 0 (PLUS STEAM) S 1.) 01 .. , ;%,.-I - 0- CD I'v, CM LLJ LLJ cz: w C3 LLJ CD CD -j (-) L-.) C1. W LJ L-) CD Z: CL -::c CC C-) CD -j = = L.)= w W - C3 C> -CC CL. U- = LLJ C:) CD "i C/) C-~ LU k-) I-- (M C:) LAJ LLJ LLI LLJ L-) -CC = - = = -j 'Se -cc C:) - = CM " ; cl~ p'; Ll~ r_: 06 ) C 0 LIJ Ljj tn -4 CD LLj V) Ln 4 z LLJ LLJ LJ < L.) LL- w U- LLJ L L, C:) = C) LLJ = = -J = LL. C) CM LL. -j LLJ C:) LLJ= - LL- LL. I.- = CD F- C=) LL. LL- -j = (-) = L-) - - - = - LLJ (Z U- -C ca ' Cz rl~ Z:~ 00 Cn U; r~, F- LLJ LLJ LLJ CD -j L-L) C/5 ILJ LLJ >- CD (-~ -j :x LL- LLJ ::c ::c N4 = LD Cn LL. CD C) = LLJ L-) C:) LL- I-- LLJ L.) _j V) =: = CC L.Lj CD 0- CC -CC -j LO cc Q- = 2::= = C/) LL- LU L-) L.) >- LD = ~!~e k.V CL. C/) 2'- W LAJ LU w LLJ - I-- F- :M ca- LLI Uj a. VI) LLJ (= = - - >< LLJ = __j V) 4c CA U ~he ,-j C,4 fe% --3, Ln L.0 p" 00 471 CD -.1 C-_ C_- BATCo document for Province of British Columbia 28 October 1999 -14- A COMPARISON OF THE JANUS SERIES IN CARCINOGENICITY AND MUTAGENICITY TESTS CIGARETTES B9 SERIES ETHANOL EXTRACTION ETHANIOL EXTRACT RETURNED PCL-PLUS GERLACH ADDITIVE r--rRLACH SHEET GERLACH SHEET FROM ETHANOL EXTRACTED TOBACCO B11 SERIES PCL SRT B15 SERIES INCREASED PAPER POROSITY T-!J,rREASED PRESSURE DROP FILTER TIP VENTILATION ELECTROSTATIC PERFORATION PAPER ADDITIVE EFFECT ON CARCINOGENICITY VIUTAGEENICITY - 0 - + 0 - 0 - + + 0 cz~~ BATCo document for Province of British Columbia 28 October 1999 -15- A COMPARISON OF BIOLOGICAL ACTIVITIES OF CONDENSATE IN THE CARCINOGENICITY AND MUTAGENICITY TESTS CONCLUSIONS DRAVIN FROM TESTS FOR WHICH THERE WAS AGREEMENT DISAGREEMENT L'OVER CIRCUIMIFERE."'CE. PAPER POROSITY FILTER VENTILATION VIRGINIA TOBACCO HIGHER PUFF VOLUME BURLEY TOBACCO EXPANDED STEM WIDTH OF TOBACCO CUT (0) CASINGS HIGHER TOBACCO MOISTURE DARK TOBACCO (+) EXPANDED TOBACCO GERLfi,CH SHEET PCL SHEET CYTREL (-) SCHWEITZER SHEET fl-) VIRGINIA STEM (-) COCOA ADDITION (0) C:> C) 13 ATCo document for Province of British Columbia 28 October 1999 -16- FUTURE STUDIES I. EXPLORE THE SHORT TERM TESTS, INCLUDING TESTS FOR "PROMOTION" ACTIVITY OF TOBACCO SMOKE. 2. STUDY PROTECTIVE MECHANISMS IN ANIMAL MODELS. 3. USE OF AMES TEST TO STUDY: A) TOBACCO TYPE-S, PARTICULARLY DIFFERENT BURLEYS. B) SMOKE FRACTIONATION. 0 ANTIMUTAGENS, D) ROLE OF NICOTINE. E) DESIGN AND TEST "LOW ACTIVITY" CIGARETTES, 4. USE OF AMES TEST TO MONITOR: A) RECONSTITUTED TOBACCOS. B) ADDITIVES - FLAVOURINGS, CASINGS, ETC. 0 NEW MARKEET ENTRIES. CJ1 ON BATCo document for Province of British Columbia 28 October 1999 -17- THE WAY FORWARD - RECOMMENDATIONS FOR FUTURE RESEARCH ASSOCIATION OF SMOKING WITH CHRONIC DISEASE CANCER 2. CARDIOVASCULAR DISEASE - MECHANISMS POORLY UNDERSTOOD 3. CHRONIC OBSTRUCTIVE LUNG DISEASE (BRONCHITIS, EMPHYSEMA) MECHANISMS POORLY UNDERSTOOD 4. HYPERTENSION - MECHANISMS POORLY UNDERSTOOD - LINK WITH SMOKING BEING SERIOUSLY DEBATED cz:) ---4 BATCo document for Province of British Columbia 28 October 1999 TOBACCO AND HEALTH RESEARCH APPROACHES TO RENDERING CIGARETTES LESS HARMFUL SMOKE CHEMISTRY - REDUCTION OF TOXIC COMPONENTS 2. SHORT TERM AND LONG TERM BIOASSAYS 3. EPIDEMIOLOGICAL STUDIES 4. MECHANISMS OF DISEASE PRODUCTION Q) c0 BATCo document for Province of British Columbia 28 October 1999 -19- APPROACH 1. SMOKE CHEMISTRY REDUCTION OF TOXIC COMPONENTS 1. TAR REDUCTION - FILTRATION 2. TAR MODIFICATION - COMBUSTION 3. IDENTIFIED SMOKE COMPONENTS ASSOCIATED WITH DISEASE, ELIMINATED BY A) SPECIFIC FILTRATION B) REMOVING PRECURSORS 4. IDENTIFICATION OF SMOKE COMPONENTS WITH 14ULTIPLE PATHOLOGIC EFFECTS EG. FREE RADICALS BATCo document for Province of British Columbia 28 October 1999 -20- APPROACH 2. SHORT TERM AND LONG TERM BIOASSAYS 1. CORRELATION OF CARCINOGENESIS - NUTAGENESIS LONG TERM, SHORT TERN TESTS I.E. MOUSE SKIN PAINTING - AMES TESTS 2. IDENTIFY SMOKE FRACTIONS ASSOCIATED WITH BIOLOGICAL ACTIVITY; IDENTIFY SPECIFIC COMPONENTS IN THOSE FRACTIONS. 3. EXPERIMENTAL ANIMAL MODELS LOOKING FOR POSSIBLE SYNERGY WITH OTHER FACTORS BATCo document for Province of British Columbia 28 October 1999 APPROACH 3. EPIDEMIOLOGIAL STUDIES STUDIES SHOWING STRONG LINKS BETWEEN SMOKING AND DISEASE 2. EVIDENCE OF DOSE RESPONSE TOTAL INTAKE OF SMOKE REDUCTION CORRELATED WITH REDUCED INCIDENCE BATCo document for Province of British Columbia 28 October 1999 -22- APPROACH 4. MECHANISMS OF DISEASE PRODUCTION PRODUCTION MECHANISMS 2. SMOKING AND IMMUNE MECHANISMS 3. IDENTIFICATION OF SUSCEPTIBLE INDIVIDUALS 4. GENETIC APPROACH N.) BATCo document for Province of British Columbia 28 October 1999 -23- IMPACT ON LONG TERM BUSINESS REQUIREMENTS MARKET SHARE PRODUCT DIFFERENTIATION ON BASIS OF 14UTAGENIC (CARCINOGENS?) ACTIVITY 2. MICROBIOLOGICAL QUALITY 3. PRODUCT MODIFICATION BASED ON TOXICOLOGICAL KNOWLEDGE 4. NEW MARKET ENTRIES BASED ON NEW SCIENTIFIC CRITERIA INDUSTRY PARTICIPATION INTO REGULATORY LAWS C=) (Z--) BATCo document for Province of British Columbia 28 October 1999