\-B~T' BRITISH·~E~~H TOBACCO COMPANY LTD PUNOAMCNtAL RCSIAReH eeNtRE gllthllpt)l BII1IPI FROM Mr A,1, Heard, Dr R.R, Baker Mltlbank AEF RRII~~ I OATE 26th Ipr~ 1991 Renort by I· Riebe, ~lll~r~ ~e~~lh, blAa, I ~~rlsol of the ~lrh~?p~t~v~s 11 ~11S This is the formal report suhmitted from Hannover of a piece of research which was of joint interest to BAT Sauthrpton and BATCF, Hamburg, The wort was done about two ycan ago and has been su~arfsed In Status Review Notss~ ed 11I was to examine the potential of amammalian cell transformation assay to measure tobacco smoke activity · part of the 5carch for Additional Bioassays work area, The tnno~n~tloa system uses an epitheliat celt line and the end point of th assay is production of anchorage independent cell colonies, fhe smoke condensates examined were obtained from cigarettes containing either: a, I single grade surley tobacco ~21), cigarette ePdo d380, given Is condensate 88/32 in the Report, b, I single grade virginia tobacco (8152), cigarette code A255, given as condensate 88/33 In the Report, The cltotoxlc properties of the two condensates were complex and may indicate 1 growth otlrlato~ effect for some smoke condensates in the assay, Dver the dose range tested, which had been set on the basis of toxicities to prcyious smoke condensates, the observed transformation fraguenclas were In the range of variation of the solvent control value, We have no plans to do any further work on smoke condensate with this assay at present since the UK 6overnment eomnittee on Mutagenicity (1989) considers that further research 1s needed to Impmve the rcpraduefMtity and rnbustnesr al thir type of assay, Or I.R, Baker Enc, ClibPDF - v~~fastio.soni A CanparfsPn of the tranrfPrming Activities of THo Cigarette Sw~e edndansates in Fetal Syrian Hamster Lung Epithelial Cells Author: M, Riebe Institute for Bperinentat Patholapy Meditinsche Hoehschule Hannover Germany Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 T!~~t 3!~eG CO~PABISOn OF THE TB~IHSFCIBnIWC ACTIVTTIES OF TWO CIFABETIE SEK)IIE eOWDENSaTIS IQ FETAL SYBTIU( HI~SIEB LUHG EPITHELIAI CELLS In Vitro SleassaY systems ~ULVI been deve loped for assessing various aspects of the toxicitxy of subs tance s, An area, of pbt:ie'Jlar interest by regulatory bodies is their appiie~tion to determining the genotoxi c action of chemi cal s such as mutagenesis and clastogenesis, Another aspect of biological response which can be demonstrated in vitro is cell transformation, In which tbc~growth behaviour of an established all culture is altered in response to an external agent, Far several years we have bean working to develop a test system fat detecting transformation events following chemical treatment of cpilnc!lal cells in vitro, Special interest lies in animal and human eoithelial cells of the respiratory tract, The assay we have developed is based on an established cell line of fetal lung cells derived from the Syrian golden hamster (M3E3/Cj ). ~hcse cells are character ized by their ability to exhibit certain df ff erent iation patterns depending on the culture conditions supplied, A df ff erent lat ion of particular Interest for this tYPC ef regeareh is the metabolic capacity of 5 Ihe cells: ID I(v)rll E)1eJ It her heen shown that there cells have a sartinlar ability to aa!vare polyclc!le arcmatle hydrocarbons , whi ch is considered important for the proper evaluation of compounds and complex mixtures. In the cell line M3E1/C3, which is very stable in culture , the induction on in Vitro transformation can be cbs erved, Transformation events are evidenced by an altered growth behaviour of transformed cells, whi ch grow anchorage independently in a Icml·Jolid medium (soft agar) and form r~ec· dimensional colonies, In a number of preliminary experiments a response to cigarette smoke condensate has Seen demonstrated In this assay, In the presented study two cigarette smoke condensates, encoded 88/3! and 88/33 have been conpared with regard to their ability to Icd'Jet i:! vitro cell transformation in ~13iS/C3, 1 IV Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ExPtrtmental hotocol frozen stock e~lrures of the 23rd paise? at the cell line M3B/C3 from the fetal hamster lug were thawed and cultured for 3 · 4 days with growth medium BFII 1640 containing Zai fetal bovine serum (FBS), htter cnz~matle deraebent of the cells by tiyp~in trtatncnr they uere seeded It a density of 105 cells/21 ca dish with the above mentioned growth medium into tissue culture dishes coveredwith a collagen gel matrix, T~ec days later the medium was changed for a medium SUpplCrnZOd Withb number of growth factors and hormones (Ice table I) to induce an eplthellal morphology and an activlrrabolism for polycycllc aromatic hyd~ocarbans In the cells, ~bout 4 days later the cells reached the necessary degree of differentiation and metabolic activity and were then treated with the cigarette smoke condensates, Table 1: Composition of the differentiation medium and substratum for ceil line 113mlG3 Medium: BSnI f640 mi Fetal bovine serum 20,0 mi Insulin 0,6 mo Hydrocor:l sone 0,18 mg ~fs·3stradiol nmol Epidermal Growth Factor 0,002 leg Transferrin 2,50 mg Qoleratcxine O ,I mg Calciume~lorlb 5 ,16 mo Trace elements Substratum: Collagen gel Gelatine 0,003 t Thecddensatcs encodeC88/31 and88/33 vtreprepared bySAT Southanpron, ilmpedlatcll delivered to our laboratory and freshly used for the In vitro assay, For the treatment the medium U 16 he changed by removing the old medium followed by addition of fresh medium (spe table ii containing defined concentrations of the two cigarette smoke condensates dissolved in the solvent O dime~h)lsulphcx!de [DMSD1, r~e treatment pratoal II Civet inO 2 Crl Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 table t, Five different concentrations of each condensate rangiq f:lm t5 to 150 luglml IPdlum have hesn Ippiled, Al a positive reference substance benzo( a )pyrene was used in a eoneenttlticn of i luglnl, also dissolved in DMSO, Al 1 negative control cultures were treated just with the solvent In the same concentration (~~5: in the medium) which was reached In all condensate and blnze(a)peent treated cultures, too, The concentrations of cigarette smoke condensates given in table 2 have been chosen in accordance with former experiments,The lowest concpntratfon value of 25 lu9lIJ la6dima represents 4 doe whf oh accordi ng to previous studies using condensates should lead to 1 slight but measurable transformation Fate or 1 depending on the activity of the condensate, might also show no cffer.. The highest conctnrrstion' of 150 Iqlml· ~adlum represents a dose which Is presumably already in the slightly toxic range and will thus give an impression of the toxicity of the condensates as well as of their transforming activity, Table 2: Treatment protocol for trana· formation assay using M3U/C3 Fish no. CSC (lupllll B(d)P [lug/ai) 1,2,3 4,5,6 1 7,8,9 i50 (88/32) 100 (88/32) 13,14,15 75 [88/32) fb,ii,rs SO (88/32) 19,20,21 25 (88/32) 22123,24 190 (88/33) 25,26,27 100 (88/33) 28,29,30 75 (88/33) 33,32,33 50 (88/33) 34,35,36 25 (88/33) CSC I cigarette smoke condensate aca,P I 8ent,o(a)pyrene The treatment medium retained on the cultures for three days and war then removed followed by a further cultivation period of one day for the calls on the collagen gel matrix without presence of h the test condensates in the medium, I~a collagen gels were then moved by collagenase treatment t a single cell suspension was P 3 P Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 prepared by an additional tryzsin treatment and by pressing the cell suspension through nylon gaute, The cell number of each specimen was counted using a Coulter Counter, To examine the toxicity of the condensate treatments, the eolony·farmfnS efficiency (C~~ 1) of the cells was determined by seeding 200 cells of each culture into three small culture di shes , respectively, with normal growth medium (~O~I 164012(1: F3S), Colony growth on the plastic surface was evaluated seven days later when the c o lonf a s had been fixed with met hano 1 and stained, From the remaining corlqen·derived cell suspensions t x 105 cells of each treatment specimen were seeded into plastic flasks with BPhI r640/!05 F3S and cultivated for another two days, They were then trps fnited, a single cell suspension was prepared as described above and the cell number was counted using a Coulter Counter, Again, the colong·forming efficiency (CFL 2) was determined, as described for ei~ I, From the remaining cell suspensions, !0~ cells of C6Ch spc!man vere seeded into Jeml· solid soft agar medium, plated upon a nutritive solid agar layer and cultivated for seven walks. Calls with normal growth regulation did not divide under these conditions and remain as single cells in the agar whereas transformed cells grow out to form throe·dimonsional round cc lonias, The number of these colonies was datermi ned us ing a ster eo microscope , The transformation rate was calculated in consideration of the eolony·~Drming efficiency (CfE 7) of the respective culture, Results With respect to a presumed dilution error the treatment concentration of 50 luglml of both condensates has been wrongly prepared, Those specimen could not be evaluated, thus leading to dolc·r~sponse relationships obtained from only four different concentrations of the test condensates, 4 11~ Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 i, T4XICltL Irom the two eolony·iordng efficiencies (e~ 1 and 2) the toxicity of the condensate treatment was estimated. The percentage values of colonies grown in GFE 1 and Ci~ 2 are given in figure i, As becomes evident from figure i condensate 88/32 lead one day after the end of condensate treatment to 1 reduced C~ in the dose groups of t5 end·ff lug~lpl medium, wberedl the two higher concentrations exhibited CTis higher than the respective solvent control value, Condensate 88133, on the other ~and, lead in all concentrations applied to higher C~Es as compared to 88/32 and also to the solvent control, The relationship of the Clit determined three days after the and of treatment was dif ferent, as is also shown in figure i, Almost all GfJ values are lower than ·thcir respective control value with the QEr of condensate 881j3 being lower than 'that of condensate 88/32, ~rc_l Colony fcrmfm~ dffdcnda of M3E31CJ ircaied nft~ t~o difiucnt dprene Imo~e coPdrPnta 1CSC) one day (eFE 1) and thm days dtu t~tnmt ~ 3 c5~o t m ODRWW etsmoseo cs~ l~tnO c~c~t Wz IcnawPnl~B~n Ile~n, IBM in figure 2 the t,lsatlonmip of C13s from e3ndenuta·traatcd cultures are given in comparison to the solvent control and the ·~ cultures treated with bento(a)pyrena, Bento(a)Wrene showed a typical pattern of Ciis as its t~T 2 was much higher than CTE i, ludinf to the assumption rSpt rsgcnetulvl processes bye taken O f N Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 E!cure 2 Colony formlq cfifdczd# of M1EflC3 tnslcd ~fth dguctte rmolre eoldewt# (ESa for thrn 8;633 o I a R II 2J a I dQ CSClOln~ eooeoe 133 6833 OI~M1·Er~uOuS~ Ilsw~n O .n·nnn I·n3~~1·U.LhLa3 place in the benzo( a )pyrenc·r:s~tld cultures, h similar phenomenon becomes evident with condensate 88/3 2, whereas the second condensate, 88/33, exniblted a pulte diiilrtnt tox!clt) pattern, in this case the toxic influence of the condensate treatment appears not to decrease with time after the end of L1Pure 3 1) Rclstlonrhfp htnwn Cn! udCWI ~CIT i: CFE II I UC~1IGEI O a a a oo a w ac~~o~na LIOn~W11st~BLVj2 ~rrub63 I erdnu~ 66133 & ·c~oy imnI eniDwr( fs 6 O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 treatment hut to increase, since C321 values were almost in the range of the solvent control and GT~ Z values were slightly lour than C~ 2, Figure 3 trier tp Cert:f5e tha celarlonJllp between the two EOlanl·ferminp efficiencies and by that to compare the toxicity of both condensates, The ratio C~ 2/CE i gives an impression of this toxicity, The solvent control values which also include a slight toxic effect were set i; in the case of bento(a)p)Tene the ratio was higher than 1 since the acute toxic effects are repaired and the carls regenerate from the treatment with increasing time after the end of treatment, Both condensates showed ratios below i which were, however, different and lead to the assumption that condensate 88/32 is slightly more toxic t~n condensate 88!33, The ratios found for condensate 88/33 night represent a grouth-stlmulat ing effect rather than a toxic one, This growth stimulaticn at first leads to a relativelyhig)! C~ 1 · an effect that disappeared in the subsequent cell generat! an which was not exposed to the stimulating claicals, Transformation: ihe results obtained in the t:a~sforsatlon assay are summarited In figure 4, Transformation is given as 'transiorrd eel!rl!0j cpleny·fon!np cf!!e!ent ails', This value hat been calculated in X of the . solvent contra 1 'Tnn~lorrm~oir nuwlakPd b t~a ~fiicnnt dpnne' aPi~e condensates (CSO In bl3BIQ bol~aP1 cwtroi310WI) iM~omPb nu no a st I .nnulL~D cs~ui Imr*IKD CS SrufrmcM nu ·;n~lr~ nl~ ~w ~O' cllY ~murg Illlcm nl!~ 2 . O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 trans format ion rate which was In the range of about fO transfon~d ceil colonies/l0f E3lony·fotning tfIicitn~ cells, Condensate 88/32 exhibited, as compared to the control, a slightly enhanced transforming activity in the lower dose groups of 25 · 75 Iqlmi ~ld!~m, mt induee2 rrans!aaa~!on rate was, however, clearly higher thn that observed with condensate 88/33,In thchighar dosegreuss ofiOO · 150 luFlal botn condensates showed almost ident Ical transforming activities, This included a drap·daun of the transformation rats a! 88/32 in the tfeatmsnt group of loO IYlml, an effect which aignt he due to the described toxicity of this condensate, 88!33, an the other hand, showed no transforming activity in the lour dose groups, The observed transformation frequencies were within the . range of variation of the solvent control value, Only a slightly enhanced transformation rate us induced in the highest dose group, It has to be stated In general that both cigarette smoke condensates tested In this assay exhibited a very low transforming capacity, This becomes more evident when the transformation frequency obtained for the positive control substance benzo(a)pyrene which Is net given in figure is cons idered, Benro~ a )pyrene was applied In 1 concentration of enly~ luglmland lodto atanJsoomarlcn f:cquenclai250t when rotated to the solvent control value as 100 r, · Since the results from the toxicity assay and the transformation assay were obtained tram the same treated call cultures both results can be directly compared, Condensate 88/32 was shown to I he the moretoxic ons whereas 88/33 night have a slight growth stimulatory effect, In the transformation experiment condensate 88/32 again was the more active ons whereas the transformation rate induced by condensate 88/33 us negleglble In the concentration range applied, This mlght,however, not be true far. concentrations higher than those applied In our asr~!, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Yat will be largely hrmiliar With the M1Sors inventin~ fea sf~es~eam ~ske slRoesden that t~ FXC b~ devised, Ne are ~aftirq a patent at the ce~L: alenre version 1 the others are r~her elcse to peiac art, Ne s~fw ~at~ ~eak is glaraed in this area at the FP~ese~t C~;c, i j;O·~C A,~, Henrd AlflFC Ist Fe~wa~, 1991 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ~I TI~WSM~BTON REPCRT u~c~rm~Ka#o#c#y# :3 Fl T 3W ROOR ( 31 OCt '~O 15:E ) xlX1YISI1~1WtSylylOlXIYtXXllrlyt~XVS~~yXxlryi r DATE STFdT r REMOTE TERMIrC~ MODE f~I2 RESULTS TOtRL DEFT, x fX~ ~LEM~FIC~~CN PRGES SODE o u 310Ct iS:tl x SMJEB982 GjSi 01'$" OK 82 x mx J w4"a Iwe, r O O N O O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ya ~:· ~Y(·~·l Draft Bioloedcal ResLat~ ~wirq reviewed ~~ al tho art in rclatian 0 the a d nlrassays fathe R~auaticn of tc~icus teet ~terials, I belie~e L ~allaJin3 ~wld rgesent r ~ p3licl on tkis I. ~~~ritot·t~rd~ in ttws cperqerce ~ at bioesJayJ 1~ denlcp oq~tiu in uyre ~~ L iwarce te tOabael FpC~Ct~. i. 4~ the m~ertatnty associatd vith aarwt: ~ vitro tests a u sFpli~b~ t" c~lsx niub~, 1 ~ ~ tlseW i I 1 ' if ~ ~911ts differ Si(p~fiCMtly~ cnrent rrns tkeY Ldicdte thet ~ d~Pieal ~w3~L anand M? bnther rcsearc~ ic ~iTal, ~. arr Folic( tbenfcar ~ ~ ~ ~ tests as are anrcntly z~imilable ~es~ Qast~icgenici~y, ~3 to screen ra hdjitiYB~ aC Si~Lp~itid~l~ FeCCCSS ~MjOS ~ PPSYd i W) ta ~ Fe~atien hp ~ ~' II BPlle~E~~ · ~ ~ (i Fresent scintific anl trdiea~ evidence, there apF~ars ~ ~ · justiricaticn + s~ckirq ~earc~ ~ re~in? values aeas~n~ed by tbe awently wailabio biwssays, a~L1 lieat·d )I~HIX 3~ Octc~er, 1990 ClibPDF - v~~fastio.soni TEi ~s~jl II· :~oljj~ ·- -· : ·,' 5·, u I $B '31· ~~ · h. ~' '' II .· \PCL " 1, ·, I ~P~9d~~ed I RtSeAReH a DEVE~PYE~T CEMTRC 8 i, -i c t 14,1~~ h~ I~~ LrDIIPaa 1O9 Irt t~Cld TIlIphunI 9lawp# 101031 11~11 s ~n:1112i3 hi 110332 '' ;· "* I· '1~A~ ,t ~! · · .· - .· · . 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I~ Teblo I li~u Be tc~i~ity rudia rcqui~ci~ ia pmtieide :r: ~Jldla~ ~bs apr IOXWty e~t~orl# m all RICchronic,Ehmnic ~ndmagslidtytrJtiag.EMhutioa d (c~tPlc~ieity tod Idvnre Irploduetirr dfeCLI me kssks ;;j~L;e~-2~C~I ~~ocludcd undH chronic ~ating.AnlmJmet~boji~m ~nd Yad ptnrlfition hdin n towld in e ~cci~l Intia~ edrbDbit'I cllegs~~ E~ar~aldirihJbrlt~tkn~ (i~L*h·lurrilhlkCI~. ;;;~~;i:::dUh~llp~:·Y:li~·(:i ii ~e~todcst~~$II:~1Slii 1·, 1 ~ tnitul 1sp 1I1 the uiscy mhudw of I pnticide I.G: ;':L;il·;·.· I; produah danmininl itllcu~l ~caYly Tbs W"'d I 'Way~d~ ~ . · .klud$ .I Kllle tonicity tahhg h SDday d~rro~lb~hda~lon Rlt etc nclblish tonicity~ebdv~ la othw chria~ by ~·$~4WrliswOloliuly Hen '· · defining t~r lnsdisn IrU dose (101 end LClo)~ t~ hmC~.: I ·:'· · to p!olih iaill inhmulion on L madr of Lolic '~LjO0CO~C~~.Ct~::':'. ·:~I~~ RI( md nixol ~; :;F~mmnr~no~I;~~~ kl ad dpj ''~: tct~o, ~l·Tr~;;o~nMy..;S~\i~~.I:!·I;!·i~ end n~M ·ii · (, identity pmribi~ ryPlqillie in(nlcLi~, ~d 011a frcm t~K (IlhUCUEedlOde(alllljtthCl~ip~3)rwd t~o~tu~llietl :i~ · to rdu~~r d#ip lor lub:hronic lull md Ih~ hard nming altemlRI dll 1PP~Y On IL ~ rmt~tion ,d~i~~:~i'Vi~bs ~'r~l" I palieidr product ~b~; jn ~omplc, If the pdrideIr i~"~·C~O~O~D~n oknlHon ··~·~::Hri~~ghiyq~LjDs6~A~e IO1(Clr(OUE(0191 1D~oin at C50 mgihg) thr~gnlwPrdi,P~EI M1!i. M3~P~~IVtlte Pafign mwr k (m the hbel. ;litlp~e~~l~ s·~~·~ jo Lllonlol) mirmb, ~uJU~ d end nbbitr, us :,~Mllabdwn ,~::r~.~.~r~: ; erpwd D r riryk icu pi ihr tul rub~~ner Ta~ie dial rclult:ng Inle IngfiD;Pn, i0hdlloh ~nd Yn end nr CHM[~CII RRUUI 1919 I O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ~ ' "7 BIIT 60'73# UK TEL No.O;Oj 796;, 0111119~ ~--- ··-·· :::~::,~.~.~i~:~:.:;i·~;~l: : ::~ ~: Department of Health Report on Health and Social Subjects 35 C~uiddine~ for the Tesf~ of~71tlt~sR4LIBRARY C~mic~sfor IO JUL 1989 i· G Mutagenidty I, I 0. SOcltH~a~rb Committee on Mutegenlci~j of Chemicals in food, Consumer Products and the Errimnment ~· I ·'j 'C lofA~on lier Majesty's Stationery Office 11'C" :·~n?l*lnrlle~l~·F'·I· U i;llOIU Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 B~i X~o'ras ~u. TEI Hp,073~ 7q?5:7 OY~11189 li:5i F.D~ "' "'~'~' ' 1.313 ~~ muuJe qpci/ic (peKI (ond dosli~~n, piubl~ ~ ThC screens for anyoundr poaaill muragcnir point mutations, some of which can be small deletions, II an be applied ~o mi would be nccclr~a only if mud' jnv germ FEIIryblbnb.C9PPYsp~~B*il. reUI. eeeause of the large numbers ofanimaIs needed, ILla~ijrd8ldonly 1 nnd 10 low Ulhir plsssl ~~ul in csrrpi6nJ circumstances, wbm a full rir~·bmcli~ analysis is nret~ury~ cases where humans were lil(ely to hi I,~J,a The RIOLIK I~il~bl~ ~n~ora60n u nil may be applied to d or to moderate levels for prolonp attain food ddiriv#, or whrrtnru~' yrm rcllt, 1t is msl((~rliv( fpl mill parlmrioti~ ~lg, but has been ad the nU~ace liionLJ bl in vi to dnhr low levels oIefTect is ~pamaloEoll stem cells, Because it is iahour, Lenx;Fe and mluirn large numbers olanimais its use is justified only then 3 full rilli·benrli~ analysis is reguired, 1,34.9 tlrsp~rm m~pholo~ Psoy, 31111 amy has, In addition, ban io~ aiCllrd a 3 mul~pnicily a, but the results in some circuntstanceJ have been due to direct toxleily Or Ll/nutri(iOD rather that to mula~midty, or from 1 combination of both, Svmrnarl ~7,31 An outline recommended testing strategy is given in figun I,1, '1.id 'Thir strategy must nor be regarded a an innuibie stepserluence of ~t· /·: C ins to he rigidly TPllod in all wn, A nexible approach should be adopted, with each compound being ootuIdered on I eue~b~ca~e basis, talcing into account: (1) the chrmieal structure of the compound [inlormation on the rc~i\ily of the substance a its metabolites and the Cold ebemieal class (31, ~o~d~a~ufT), an be very usefuIll C3 information on absorption, metabolism and di\tribution: (iii) the misting howledge Dlilr mutagenic propenirsl and (iv) its intended use and the resulting npolure to mat, IJI Tnllr, Stage I covers the type of tests that should be Earrled out for a new dlLmials and products, II for my raon nupifion arises about any chemical already in wide use, it should d~o be mb~Kled to thae testing p~ redu!a, Where 1 chemical is not proposed for human ingestion, and when it ~ · h named dot is ure will be lin~iJ, tad Ihedcl~e elhumn upcmle small ~·- : ·'' olcontsinable, L is acceptable to limit investigation to two tests, one to detect pt mutation in bacteria, and the second 10 detect dutoptnif effects in mammalian cells, Y(here it h urpected bat human urpolrn, although a low dose levels, will be sustained and ubiquitous fa, food additives, pesticides, a~nnif preparations or domestic ehemieals), the third rat Is dro aeenrjr~~ · 7,31 the need to carry our these studies to 1 bit pwllW and to hlfil rigorous protocols, should be Emphuircd, B~ dzF of the study should be dfqurlr 111 obtain significant results, The emphasis is on a limited number of in vitro studies carried out to 1 very high standard, 739 The Lie 3 studies cover in vive imalnujonr of mJtblgmic potential in lonl9e cdb, it is not jlu(irwble to use such studies for general screening purpuw~, since the three k vitro studies in Stage I should detect essentially all I ; o r: .~I~·' O O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 BAT SO'TON U~ TEl No.070j 7adjj! I,, '·F' ~ I . n~. ~·; · .· ·· ~ ~·~~··· ·~-· ~Ulal: ~PWLd~PlOllllsllY~y*h.~4~YIIMU~(IY~nlYI ~~ubl~ns, In Y)vo nm STAGE 3 srAGr 1 ~nili~ kllViq CI Bleurial mr#y for Cm ,hlr,sP If rkk IULI4Wnl f# Cm csl JK(I k ola nquU ii ~ bl reEF whw mU""" iu~a~ la b~ of pmpemk induda~ hurmn IxpcsurlwoJd ~o rpocrod to pl~n~uc0~wh wod ~nllclpl~ bs *lorsiv~ odv a~M4 md, U till br 6rwpmcily in dilkull Io Iv0id, wNn JI IhnO inn n mln~&n ooiir for aampls rnupuw mJyJr C ~~ 0~ d ~b m·L noe#uuv Id Teet for peM nwu~n in a~c~cair, rnmnulkn d Ilw uumpla he 1SltEY TK~I· u#y) In Mvo tcru 9rAOrl ton 106 lol Bon~ Maim tart fa Compounds pa~i~e in one or moro tsm ehlamosoms dwnege C in Smgt I, (repha emlYJr Or Ind rjuouckul t#tl ~ eompoclndt where high, or modsnto, prdo~ed kve~ of hUMn aXpMur(M ~ku, if ebove n~01o~, uld my mtlcipd b ~w teet po~~i~J mt tmtioi to Ixunr whothnr muFlpnidt~ or Niden# of ONA dlrraga #n k rimmmOud in olhu aya Ou~nJu~ Illld[H fril ruong log Ruw, PL cl ibrudon In vian ol their long dureJDn, eolu end un of Cgl rumkn of Jnu~. ,ew~~lolSCJnnZ Ilms~~~~a~w~AA~ur~lr n~Jnakdrrkwhn~~nc~uoar tnn~k~urr*rmmulnu c~a~n MI IMW #pD#I~~WuA C~lihrClrk~Cu~dCrr C' ii a C··' -·C · j·· O I, 1·I .·r 1; . o I N o .I , o Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 BET SO'IOH ilK TEl No.070j 78dj32 041111bS F.O~ ~I r.j*.~; L* LIBRARY 2537W-1 ~1 JAN 187 nl..m"~;7~,~~Y R.~D~ SOUMAMPtCIII eUIDEtINES ON THE USE OF IIIUTAGENferl"l TESTS Ix Mt TOXICOLD;IUI EY~UOIMI g 1HWIULI :· r; A Report of the DNH 1 W/OOE Environmental Contamlunt~ C1 I' j Mviiory tdMe M yy~mnll Pubtlshed by ktnorlty of the Hinister of National Health and Yeltare and the Mlnfstet of the Environment attwa, canada 198~ 1IV Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 iii Np.~71)~ 7803j! O~.ll~d~ 11:55 F.07 BFlT SO'TON UI i' a: ' ,~*I e~·~·~.-CC'--e~ ~- ·59- ability or the latter ryrtem to detect a, many authentic in uiua putaglnr and i~r~lnogmr ar ~llibl8 tdrartr pf ~Jian liver brt.added to Ihe~ test cultures. 0bviwily, rub a lyrtan fer *tpbplip ~atiatiPn is only 4 first appmxjr~~~n to the complex metabolic processes that occur In v(up~ II ~ioo arrays In rodents better reflect the delicate balance between patrmays for activation and inactivation of chemicals in human beinp, leenhelerr, in uilr somatic tell assays also have Wlrieneier; in particular, they are currently available for only I very limited nunmer of C.tir~uer~ if the cnal~al bar its effect primarily In one tissue, oarureaentr made on another tissue may be misleading, In order to owrto~ some of the proalenr arrociaiea with EEll·frH liver ht~penltl, sonr Invcltig~lan have utllllea intact viable cells from the liver or other relevant organs Of rodents a a source of elogenour metabolism In in uitro tests. There is, a yet, i M rinple rolution to the dliwna Ihll in uiuo tlltl lr( dlIl'1bie becauri they utfile intact activation and inactivation pathuap, but are less than perfect because the tar tissue may net be apnp there affected by the particular d~mt being tared. hence, a combination of in Pie and in Cvicn arcyr provid~i a.n ILillldOly ~lll(ly lm 01 ~rrmpri~lag in vi~J or in vltw asray~ alone, 5.3.1 The Hlnism Battery: Tests at 10C i To beasrigned to IOC I, the lowest initial 10C, the Dloeular structure of Dr material must be wtn that neither olutagenicity nor earclnogenicity seams Illely on thtni(ai graundl ~lons and tnl txpleu8 Ixpiun levels In )h io ·N lo Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 BilT JU'T$~ u% iEl Mo.l7jJ i:''ji~2 j ·60· low, becordinply, chemicals It L06 I nsdre 01 lee: tertlnp, The pinilaal test batten should consist of one test for gene nutation and on test for chrolwsomal aberrations, because of the possibility that 1 substance wy cause preferentially one or the olhe effect, The battery or tests ntomoatd ay the ecnsPittee for iOC 1cMslstr Of two typer of tests, with and without a paa~lian activation systln [5·9), gene lutattens in sitro and (I~MDIMIII effects In panaallan cells in uit~~ The loraer test would npmlllr he elthet the Splmo~llalsdeallan nlcrotonl arsayl or an appmprlate yeast or lmrrmllaa all assay, Brar, the tert ior rhmwlcn~J i: C; tllKlr ~us Le done unda cMdidonl that guad(a upMun oi thpre teiis 0 j: the agent, an in vive pla~ll~n ooe~aa. assay Is thmn~i~al drgt upUil be an acceptable part of this testing only if it could be shown that the i: Becsurr of re higher cost of in viva agent rechcd Ihe bone marrow, e IlliYI, it if II11I1 tlli P, II.i:iy ~iB urlnp a~lia rlil in i~·cultun w3uld he ad. This proposal is suppnrted 4 Me rrtcmarndadon of an international int~rla~morl study or r~rclnogen~ and non.tartinogml that the tug in vitro tests ISt efficiently Fompien~ndnp each other In the detection of 1 highly selected group of earclnogenr an the $ho~atlal rpaealian nlcrosome hay I~ncl test) Ed a test for Ch101MIsOnll aberrations (Rrhay et 3,, 1985). me consequences of testing are illustrated in Fig, 5·1. If both tests are negative, then the agent is placet in the lowest level of concern (10C UJ, dr long II exposure levels nlaln low, Should additional uses for the cheal(al be proposed, or new Infolaatlon hKolne Ivalllble rhal chm9et the e~tisto of 'O j i ..,.......,-·---·-- ···· ·-I I IU ~~~---~---- ·~ %I Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ·C·C ~ BLP14P sas gr Hr n G~M(D ~h #on~~r 1988 a ~u~oM of wovn PAODU~ L Bb~B rpln Ibl~ h~ b n I I Cw, h uJ~np b ~4Y ~I d q alpdrP k bl 3~ d b dpl J Iqq ~ Y~ ~r ~~ C ~Y dY ~ k ~ d~ O~WP d~l b b r~gld I~lflwnl yr h pob ~lcpnrt I~ ~ ~I~ ~~ IT ~I ~ dop~ndl~ oa ~ abjedala d ~ Indhidr~ p66. L #~ LY 'II r bpt I yY ~ r t dlla,d AW mg b 1~~ tom LI 1Bde I,~n d, r~ #Ils ~ ~Cbr ~~ m~+n~4 t ~I~ Ipp~ L ~pp~Y. i UYn Io~ - P~131 I~pl t ~ mnl o~nb nd h ~rd Iruf~etu~, : I Ch~nhl m$C olPinlh~ nd YMloam ImRr blYr~on R. b Ysnr QO W Pq ~ b k dr I ~~9mloxiti~. IV h~gsm~tt. V ht~s~ion ~Y~, 1 ~ C~ htsnd~d Ihl r L1 p~L ~nrl b ~~~C~ ~n In' ~w u~d ~t Ibnrrt pPbC ~ha~d tl a~h~ ~1 p~durr deswd Ipgop~l~ LILr Yb~~du~r ···g~a!d!~~lll~ld dus&. Unbn mlr of 1~ ompntn8 clll L nl mauhdP~ dlhl ~ pdud 8u~ ~ revi~w n~ ~l~b cuP~ CJ d ~o~g, Ae~nO h~ ilm$ or ~ ~~md ~us ~ Y+~ ol ur h nl alumlr 91dl ~I ( ~~ nucrl ol q p3d In~ on nl chml~ d n, m~l rbY ~ detomlnld by ~lag out Idaald P~ysis on mohtha nd ~Ywtdlm ~~b~ CPIPOIRII b ~ inalyssd ~Y bl drm I ~ng bo Init d ~ 10 I~ ClibPDF - v~~fastio.soni B~T 60'10~ UK iEl No.O7il3 :1033: gj,11189 12:01 F,IO 'exIended oLer nnxae' I~t In addltlcn n~olne, panollto m~~ and Snaa~a palycyollc alPlde ~dRa~l should he tdphd Any ~thr analysie will d~ on ns speciflO construolfon of hi prod~d ~I 81 A battery Ip~d 1 in ~ toxloolOgy 11110 ha been widely advocated by a number Of legislative bodor h ~es~ hvc sp may be considered r hi pat igphd 1O ·q out Adnbt; i, BaeIerIaI m~s~lf · AmnJ ~; 2 ehamoaome ba~lon in ntantnlla dC~ A I,dsl of suPPon aeeaye may be Eanaldered at by points in the psojest; /· L R6P~ Ipdle gene locus mg · mammalan alb. i i.. I BYsdP~~d~oC·131··L. 5~ Single strand bL · mammalian air Al teats fn follow documented recognd protocols, r. )· 'Tiar IV k I n~rl progreaalOO km in ~ (onc~~dt, the use of in vlvO alJ b bsing dmqb Idwold YLI I sObstenee may be pnP~s h ~ I cpuld be imFortant to hnll~ I lueh a ~~ is tnalIsnd In the whnle afmaI. f· t bn alr~~ b~Pallla~q4rCI8dll'~ chwmosom~ ~ndon, 1 As a ~Yona asaay: 2 Unlehddld OHA lnnsd ~ hepeb~ following in vivo orporan. Th~ al cdu~r n~r v BE hhdgon tOxlcolOgy of smoke r ~ ·::hN~B~ 01 L( legislation and ~Pmmsdd by company eonldlm~, b general, regulatory auVlorlHes ~dn exposures of up to 80 days although ekperlence suggeete that shorter p,ldl b '~3 Is be suitable. ~,~I m(l ct obl,n~cl as listed bl hi lSCSH, OECD and EM should be followed as PppRpd~a ~~sr~on snould he given to the use of both mt and hamster, partlcuY~1 ohrnnio sIudIea ate entb~gsd. ClibPDF - v~~fastio.soni a~f.rjO)aOH UK TEL H~,1!76l?s,~;:·iai 09,11135 11:01 P.11 I· i As Ddoie, dtflailed acceptable protocols (~!lljl re OWdjptJ· AIROlj9h a Study may not be registered for Good laboratory Prdce IGLP), thr yllaiily ass~l~le~ associated with GLP mist be adllored to, i j Sdverl key iosses should be amsaered when evalua~ing the loxiolty of 3 new ·produet. 1. 'Nilh regard lo a speca~e component it may be appropriate to er~lulte its toxicity h isolation as well as a part of the c~Yene. 2 In all Gases care must be taken in extapclating any acquired inbimdlion i, Corn one product to another, It should not be assumed that any product des~n, if satisfactory fw a pani~ula~ blend, rie be rlfa2srl lor /I ~p~ si 1 blend that may be considered. Each case most be evaluated on ifs own ~C; mea. i:. 3, 11 is clear that each project may well have dinerenr objeeEve3 whid; ~lpy be clearly stated and used as a guide, This is pa~cvl~ impoitwl Fhen ii 4. comes to toxicity teslicq ar,ll will influance the paint of campison ~al is ts c i be used, For elampis, Is the'coni~oi' group going to he a rtJnodrd reference eiearenecr a substance known to poduco 3 Il~ativ~ Rsi;3aj? In any Faffcular way, On what basis any eompariscr, ; !o be mdde sh~uV b~ determined for me various p~cj~cts under review; it .Ili~d, that they Ins; ir; nolbe t~s same, J, The appiicalior! of additional tesb suld well be necesaq: ( (~ Tal~iPgel.ii$; (bj Pharmawb~·m;lbo re~·ar!':' impn,micnnatill)a: .!· folian ., inhahtion. ;i (c) Sellsdisatior! ' photora (d) Long term .arc;·?~· I 1! the s~naire Lhemlshy ;s dl3ma[if3~ji ~":` ·( Id6live or other design dlange. IY4 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 C, 7G IBkT; BRITlSW ~EBIC~IN TOBACCO COMPANY LTD FUNO~MEN~L ReSBAReH eeNTAE Illl~~luil~ll Jlul~~~~l sOOLIE snIllla P~elr EO~·UI uEOr·l Lel·~lll RRB/pr TEE MQIIILE Dr J,S. Wlgand, BbW, USA Or P,d, Dunn, In, Cdnada Or E. Balcb, BATeF, Gemwny Or C.J.P, de Siquein, Soula Crur, Bratll FpOM: Or R,R, Baker DATE: 16.11,90 NO OF PIGES IESSAGE: Ihe 1991 F~C Work progransne follows, Mhleh incorporates suggestions etc. made at the RPG Meeting, This will be presented to the TSRT kctfsg in late November and r vill send the Pregra# to you In book form at the end of the lnonth, It has now been hcidcd that the leaf ageing review will be undertaken entirely by Sours Cru2 SO this projeet does not appear In the FPC Prograa, Be Spcelll kllltleal Brojcets area has been Ilde more speelfle to !nalytf cal work aimed at r~kf ng ~upcrlorl~, Some of the topics in the slnoke folmatlonltransfer and physical parameterlsmoke quality work areas In dependent on Input from BaCF and 81W as discussed at the RPG Meeting, If you have any specific eoratl on this Programne cauld you ptease let ~ know leebictcly. With best wisher, Yours slneerely, R,R, Baker cc~ LL Llrd A Mnmen ni br I A T lndullnn Cpl O L~ OIP IO kl is,' Walantr ilauK. I M~L*L london ·II ZL IrPrd I london k 131~1 N ClibPDF - v~~fastio.soni : !;'o··1 ~r~l 1Y9G Note fnr Eh~~ B,D, I~QPlev iv 'Ihe attac~ed rate is self-043~aM~n~t, ard yol may recall that I as)ced for your view as to ~Pcher n~Uler wpk on ~se dwiees is justified, m $ viaJ this wepje s~n~ld orly ha I~nas~d it Qiven by a ~a~ceti~ i~n~tfon, I am sure w would be iranrit~ a ast ~nJ~Arhim Cld,000 to cseate sin~e ~m~np3s of such devices but d~elqment costs to ccmercialisatfcn w3uld be at least f100,000, C~,·ci~""' ~Wlse 31st CetPber, 1990 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 I BT/ BRITISH·AMERICAE~I TOBACCO COMPANY LTD FUNDAMENTAL FEIEAFeH eENTRti Sou~hsmgton Englaad FROM TO P,O, Case Mr A,L, Heard R,R, Baker DATE 11.09,90 PDelRRBlpr Davf#5 that nbn rldcstrc~ saoLe A pnp consisting of P,O, Case, O,J, Oittrieh, J,A, Luke, R.6, Hook, e,j. Proctor and R,1, Prowse has considered devices that reduce sidestrea~ snsh e~nissions from norrmal dgarettes, Three general approaches have been considered: i, Room devices which nduce ETS levels These an stand alone rwm filters, pncipitaton, ozonlsers etc., available cenc~i~ily, and each show varying degrees of success especially for particulate phase laterial (up to Sos nductioos obtained), Thesean the only realistic devices which can redua total ETS which consists of aged sidestrean and exhaled mainstream smoke, 2. Devices fitted to the cigarette Prototype saa~pla an enclosed: ceraaiclgllfr cigarette holderrltuber; fibreglass sleeves, These give substantial reductions in visible sidestna~n, brought about by changes in air flow patterns into the cigarette burning tone, 3,nodlfied cisarette construction Strictly speaking this al ternative Is not in the original brief. prototypes have been Pde conrllting of a ce·dxiat design with a fast burning Inner core and I non·permelle outer wrapper, Substantial reductions in visible lidestrea~a Ire obtained, Cont,,,, Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 _ __ ·_ ·2· fhe devices outlined in (2) address the brief directly · they can be used on any conventional cigarette. The ~ndveed sideltrea~ yields an obtained at the expense of increased puff mnnber and mainstrekm deliveries, and I~ne tendency for the cigarette to seif·extingulsh. In order to off set the increased mainstream deliveries a prototype special attachment to fPm 1 ventilated mouth piece b been made, An envisaged developnent would then be 1 type of cigantte holder consisting of t~ mouth piece attached to the sleave, ~e devices also would appear to offer ways to reduce cigarette ignition potential, current Status A report on the devices is being mitten, Further development Is needed to make these prototype idea into more realistic con~mertiat possibilities, No further kork will be done until a fin directive has been given IIcl"~· Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 .u'· ... ~31 ic"a;i $I~F.~;:·2: i FRC WORK PROGRAMME Meetings on the Ilth t lul September 1490 Present: Mr. AL Heard (Millbank) MI. ML Reyndds (8&W) Dr, 8R, Massay yen) Dr. El(wseh (BATCF) Dr, RR, Baker (FRCJ Dr, R~A. Creilin (FRC) in pad Mr. JA. Luke (FRC) in pan Or. D~P, Rbbins6n (FRCJ in pad Fcnowing the recommendations of the markefng diectPrs' mednq held in Montreal in August 1990 La above group met to discuss the implicalions to the FRC Wo~ Programme· Ruse specificwork areas were considered: icbaccolSmdia Chem$, Uaterisls Science and ~anced Pladuct Research. TabaceolSmoke Chernistrl II ~J agreed Ihi ~e main lunc5oo ol La TobacmiSmoke WoOc Area sholq be directed towards: a) Smoking quality superiori~ Bi Unden~nd~ hnvto makeiau dOLwyJrOdUdSah real~arts and~a6s~2~o. c) ENuring Vlai Group ComFanias can mdinue to ope~e in their p~cular business envi~nments. d) Supartof otheragreedFRC pmiecls, The cunenlTobacco and Smoke Chemis~y Work Area should thus be changed so that a does not primad[y serve the potential requbements arising Imm a cdnsideraticn of regulataqissues. Instead, this should become the reserve mission for this Work Area, is, a I~9~1 which is capable of rapid adion when specific legislat~e matters - requiring clearly definable ana~lical or pmject work · become focussed C: I i I; PDF -!::!!::!!::!.f3 StlC.i: 0111 f;3 ~ ·. \ -·. . Outside of such situalcns, the main mission in Tobacco and Smoke Chemisby H171 be ta~eted towards the needs of the product A number of specific project needs ham this area were identified which will need to be sharpened up and developed in the next k weeks into a proposed Work Programme. The theme running through much of the ide~fied work is to tie into chemosensory eonsaera~a~y to see the sensory effects and attempt to relate these to chemical changes in tobacco and smoke, Spedfically, a Work Programme mil be put together which addresses somelaa of the loliow'ng questionslissues tin no parficular oner): What is the effect of sheet thickness on smoke inila60n and what cfiemiealy, is changing? Wnat is it in sheet which is deleten'ous to smoke quali~ ~is-~vis the sta~ng lamina? What is the chemical basis of sensory'effects', particularly aftertaste, mouth coating and dlynessl What · in smoke chemistry terms · underpins Philip Morris smoke taste balance, particularly the balance of strength: scratchiness? What are the ~ela~ve importances of physical and chemical product attnbutes in die~ting sensory consequence? How can products with law tar:nicotine ratio be modified in smoke compctaion terms to restore sensory appeal and sah'sfactionl Where does the border lie in lowering tar fat acceptable Ficotine) in sensory distortion terms and what, chemically, happens? ham the existing programme, ii is iewgnised that the Components of Tobacco and Smoke Database should be completed and a is accepted that Fate of Addib~es work will only he a legislative necessity in the business of gaining approval fornew adles and processes. Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 .. ···-r· .·*·--· · .I-·C··CI··.C-'·III·I·* 'LI" ~···CC'··· Materials Science It was agreed that the objedjves of this Work Area should be aimed at condudng fundamental research into novel materials aimed atthe evoidjon ct components for future cigarette praduds which will: in order to achieve greater or aj improve their general smoki~ performance preferential consumer apeptahil~, bj all~v~ oppo~n8eo $ ~xlending te rmge oi prodd Eer Ihd Can be of~ed in the market place, cj rignii~an~ymnhmu~tounde~"dimlpmluyreMsorda~ans~pshlolms of minor constituents, A nupberof amendmentswere made $ be exis89 p9'ammein orderlo bring ninlo be with these objedives, Work on tobacco modification will be directed towarde looking at effects an consumer acceptabiiit~ in adLn to concentraSng an minorwmpcnenls. ihisl increase effort ailodon in this area, which will also consider the effects of the reeontitution proeea itself on smoking quality. Workon sidoEtteam~3dvc~~nwiil ~eorientated$ determilng the mechanism of saes~9amreduetion andwl include effedrr of cigarette eo~uction in addition to paperm0dir~a~an. Work on Ultra~M weight S~uetures wiil Eonlinue to be directed towards themost efficient use oiiobacco in obtainhg reguind deCe~s Tne research aspects of Project GREENDOTwl mntime using a variety of methods to achieve the objectives of low tarlmedium nicotine. Conrided~nwiilhegiventowo~kon rel~ct~,e~ba~PnanCac~ed ~a~bonloPomng a literature review. Advanced Ptaduct Res~4 Recognisingthatlheconeeptof an altemafive produdisno bngecrequiedthewbjects ' ' within this Work Area were considered in relationship to thirreievance to mnventhnai and btar(medium niedne products. It was agreed Via thee wrj pmbaMy rope for combining the current work an smoke elution into a more general project area on compound release, unoke formation and combus~n. The cumentwark an Vlermal studies is very muet~teckdtowards an aitwnalie product, and i~l not co~e as such although aspBets of a could be used in Vie compound release and cigarette ignaion potential areas. Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 rS~ ~tl b La 4~ 1~O' p~d~l ~ ~ I rk~aCld L~ Ban L ·Inoa be b~ml ~dl I~Cld h hC #d kr Hllvr, ~ a qld Lt Rb h Llbran IhOlY Odll) b~l d LI II(I ·01d d ~bno d Po pa~~ hnCld ~~ p~~p d RC ~ YI ~hAl~lb drod in Yrch 1991. b d be ~a B Y ~RI bl) DlrllR ~I b) b~dY bb ~Cd p~ebt RCYL~L, asdl~a,b, mr,~ b ab~Y~~ Rs~ YnqaPhbP h I~ O~~r br hmr ~nal~oa ClibPDF - v~~fastio.soni ~~qL,e b~~' · BRITIGH·AMEB~N TOBACCO COM~NP LTD Inohloh~ bA~T Idsrdl Gmup ~IVSC ~ )J~st, ~O PO h ill L~~ HwK t fi~illb~ Loedea S'JFIP jE Bl~r: o~·m an Ma:~4 Y~OIG r, J, Wiganl, WII:~bnl~b arW I~search ard I~velqant IculsJills EQlb~elcl, i need te diso~J yacc lettrr in depth with 1, Baker ~ Lolsavet preswt, ~~r~SFCb~fe~L1~BdlY ~b Elx~e~ netirq, h~~ points: i' '~''P~Jt63~ -tbel bave ~ c~han;Ed si8iligntly ~i least three yeats, ycn eq5;lsk rmli~yJ te k pi y plalitl ~FPwrat. 7. ~ 1~ ~plics alrcet ns intprat i FetsltL1 nplatoly tna ~ " tdqhsd ca~venatia~ ~ f rat t& ~. Lqi~Jlati~ ard ~ cl ~' resprs~illtia 1 clearly ag~ad 3, ~ L material ;ed inpdlclRJ e, ~iLt Irk~xll~inl~ IC respxsibilitia, · ~ Hcopise ~~ i asldm tra c~alixd c~c~dfratien ei these ~t~c~ ~ the Qapl ( ~~ Ii~hPninl b L ~ ~ ~ucrk rn slddnJ pralf~ in ralaticn b I~4ulateoy tqdO in r FXC pppirr, ~1~ tO ILhiE~ OXpnsus cf all ec~x~itxltjrq caqwnir, EJ F I aera, Carsl, i" irsta~, seelc5 I hsasj aF~s~ en I~s~latorl laara, n f t , this ream that next al~ aelirg ie iapstant + ·, ~iqctully it will aable tie to pricritke. Ii co~loeti~y · atl ~ · Fdcdfw tie p nqmp ~ atwt ~CSO~LS Ipe~Y~ · ycl irdiedte t )J~ytieal) plite enily, I aiprocinte L offat I I plttfrq inte helpirq Mablish a ewd Fn~e~qranr at ~. With kitd roa~a~, Ya~n sirccrcly a I 1,L, Ifeard ]·~di~~ X1~71 OI·:~YI~RI i O ,O ClibPDF - v~~fastio.soni ii",13 X~G1990~61 XI ~ [~jExportJ Limiled j, IgUlen a DIVIU~III CIlTlI # . 911*~*1· 1~0~1 ~M B~B~ Baker L~ A~L, lleerd PLD llillbank PTF PPBICa IWE lJth Lglt USE S~CPB~ coMlIENTS on DP. J, n~~ lETTEn o0 9TB AuGIlsT OX B~ RESEARcH mDs 1Y Iattar i *V helpful In outlinln( 18t ad ~~~ The three hrood ldl given I Page 1 fail into the a~ of four dWCP Sections: i. Chemosenscry work w~ i. r~baccoll~l CL+~ Section (Y v(ith r ~, of emphasl of ~ inthat Section). 3. Advanoed Product It;earch and Meterials Science I~a/d~, Cbenistry B~~ main prahlem with ~ ,,h arte is the rurent daminah hy the interests of the ~r~ I1 prae~ce ~ I do aore I~ P~Q h ~ ~ ~ which do not hate sudc a 1~~1 regnlatpry Y. ~~ MitebellC arigioel ·ppstion r in fact 8 have 1 nl~~ wcrldng in a tobaomlsnolre bi~ a nhich could be turmed to rogolatcry authority de ~~ a~d~ The rJrrent prciects are in ~ programme be(lluse no one ·~d 4 sltemativel YI or bYI our tcchniai mectinli Ayril~ I accept that I IY1 ~ BWiDUI thought to the ·ggestkl ~ ~ ~ a i poved to that it i a ateud 6nl aa rather then ultimately lanaged by TQI~ i bl YI t should he directly linked to the ehoaa group r aptsd~ ACP Th, bP work is vital to Bllb and until hIareh wee funded by BI\TOo rather then CAC, ~pB bl of the P~ of the ICP i directed et oe interests it a Ibrays be done P~~$ for BATCo needs, O ClibPDF - v~~fastio.soni IITB ~l~~r~u Mr. A.L. Heard 13th August 1990 To move the AGP function to the ETC would necessitate TCM, GS and others to divide their time between ETC and FRC, Could the ACP worts, which uses a total of 2.1 man years direct effort plus nadvanced" analytical support as necessary, be funded directly by the BATCo contribution to the FRC! Materials Science Clearly B~W are not interested in the nother noxae" part of the work although in the past we have done a large amount of work for them on nitrosamines, The nother noxae" work is strongly supported by ITL, BATCF and Souza Cruz, I actually tried to get the nother noxae" work de·emphasised at the Research Review last March · with little successl However, when you read the details in the current Work Programme it is apparent that this work also relates to sensory as well as nother noxae" aspects. It is, in fact, more realistic to regard the work as tobacco beatment and the assessment of the effect on taste and flavour and "other noxae" aspects, R.R. BAKER Manager · Fundamental Research Centre Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 r""-? `~!4~~C BPOWN~~VILUAMSON ls,,~1990 TOBACCDCORWBATION ~k55 J~fiREYIWK~D.~hO Vb~n~id~~ h~bDmlqw#II August 9, 1990 Mr. A, L, Heard British-American Tobacco Company, Ltd, P,O, Bor 482 Westminster House ? Millbank London, S,W,1P 3JE E~GLA~JD Dear Alan: we understand the mission of the BATCO Fundamental Research Centre (FRC) as providing scientific building blacks to serve the business needs of the Operating Companies, Brown 6 Williamson's needs from the FRC are in three broad areas: i, Superior smoking quality, Understanding the relation- ship between smoke chemistry and consumer response, 2, Product chemistry, Understanding the relationship between tobacco chemistry and smoke chemistry needed to provide preferred smoke chemistry, 3, Product innovation, Understanding and developing the chemistry, physics and materials required to develop products with clear and demonstrable consumer benefits and having relevant points of difference, These broad strategic objectives have been endorsed by the B&W Executive Committee and are the basis for our continued support in funding the Fundamental Research Program, Earl Kohnhorst and i clearly enunciated these needs at the Match 1990 Research Review in Southampton, just before the ~rwmrm~s~E~pa. Dnw#o, la~NP~E~m~u~(sml Sot~ EI~I#wP~ C: I i I; PDF -!::!!::!!::!.f3 StlC.i: 0111 P~ Mr, A, L, Beard Page Two August 9, 1990 formation of the FRC was announced, We also pointed cut that as a U,S, Company, Brown h Williamson must be fully responsible for the materials and ingredients used in its Domestic and International products and for good manufac- turing practices, It cannot delegate this to the FRC, This was further reiterated by Lance Reynolds at the May SRG Meeting in Montreal, While the FRC currently provides this service to a number of BATCO Companies, in the longer term it may be more appropriate for this function to be housed in the BATCO Technology Centre (BTC), As you know, Richard Baker and his start have worked with our scientists to flesh out and refine the FRC Program over the last four months, Following the Suly visits of David Rcbinscn and Peter Befan, we now believe the Ad- vanced Product Research and Chemosensory Programs to have good definitions. WI! do have concern, however, that there map be insufficient analytical capability in the latter group, This brings me to the Analytical Chemistry Section, We See their main purpose as serving the business need of under- standing the relationship between tobacco chemistry and smoke chemistry needed to provide preferred smoke chemistry, Their 6,4 years of effort is, however, devoted entirely to presumed regulatory authority needs, This may be due to the section being administratively managed by the "Scientific Issues" group, If this is so, then one approach to the analytical shortfall in the Product Chemistry and Sensory group is to move the Analytical Chemistry Section over to them, This would have the major benefit of pulling together the resources we see as neces- sary to masting two of our key business needs, Out final comments cover the Materials Science Section which, together with Advanced Product Research, must pro- vide the building blocks for product innovation, Roughly one-third, 4~9 man years, of this group's effort is devoted to minor constituents of smoke "which are of current or potential interest to Regulatory Authorities", It is uW 8~YN ~ ~YIIlU~SRY~VLP. W 8a JSOBO,LISUISI~L m ~o~JI, doll ~k·~ C: I i I; PDF -!::!!::!!::!.f3 StlC.i: Dill TO~E~M COVO~I~n~l~Nm~l"nYPl~n~C~~ B~V It, A, L, Llrd PIOL Three Augnet 9, 1999 diffiwlt to see how thil vork rfll pro~idl clolr ii dslnstrlbls eonaar bsnsfits, mrt~s~rb, It mnst co~ r pete for anll~ic~l resources. ~s grojnets os totll aidestream rlbction end altrP-light weight ~~tnctatsa are, however, meh note to the point end we endorse ~ell Best regards, Binc~tab, J, SI /dla cc: It, P, J, Ptlteherd Mr, r~ g, 8sndetut, Sr, Mt, 1, I, Iohnhoret I P i WUWISPII· I I 10UIMUL ·I. I~ I ClibPDF - v~~fastio.soni rl:. m I P, P,1, ~XIRI ~ 1~ L 1) ~II SOE~T~AIIPTON, ~NGI~NDI m: n, I.~. um, ~ ~TI~L, P~tBker bll#P1\ r ~hl, )l~r~ iLd Itt~eh~d co~wPt~ )qd b Il~dm b~~r m ~I ~LtlrMI Ici~ocl" ~ Dtearl 1, rt i~ ~iif~e ibr r b rl~l~ ~ db ~ iudb~~ d ~~ Indivib~ )rojld~ ~ ~1~~ Irmlx~n~ ~ithout ~ idu oi ~I liio~ ~ke~Uo, 1, I #la 1~ ~ nitnratl ~~ ~a~nt~ ~, k P~ ~'~ ~~ to ~ ~td 11~ ~ill i) Lt~tlu ~ ~11 at 1~1l ~ ~g aQ ~ 1~ ~i~ ~ CCIWntl J L ~ m ~t~~ oi ~kP~kl II)~ tlbnuy ld0 q~dl~ ~.tobrco ~Jklng rt~WI~ II) L luppcr? b~ crll~i~ la ~t L ~ Dod'l )~d b ~ tr~~ ~ (Rtftld 'h~aL1 ior ~Fo~et fmontiw~' 'sd i~ll ~ ~~ r~~iti~~ k ~i~ ol~ ~houla b~ L ~ I d'"~' ~~ ~t r~gud~, Ya~n lineu~41 cc: LIZ, Id (tllll~uJI) P,J, Lop /N ·O ClibPDF - v~~fastio.soni PT~ HEI(O Ly 21, 1990 lurn~s ma eRaolr eMPQHTJ on na 199e noRX ~RWI~ Otnerel Cbmr~nt~: luch of the wor~ In this srsa is very rrplat~torp, uith I strong .onphuil on ways oi applying nonl pronallpp tachnoi,ogy to prPdUCt~, Although I as a iQ advoeltl a~ IrgLinp nn ldaas ed Wmok~ to not nnfaiiy thought out ncPda, mny oi the pm~set~ sound Ilka tachnolog! In auch of n r Igplleat!on, ~h, ~hbsL ahollid of ePuns ha on Erraful eonalbaratfon ol what chanpw in tba pmduet an sdvantagtoua and how thay em ha In~l~wntB por w~pls, swersl ptdjects have redUCsd rod reight or density as an objwti~~~ Although than art pormtial advantagn to night ~stfon, without a pPc~st dwtlopnunt drlvtn naad, tlcknologlell Pu!atfoe on eakhg a light wtight red will II~~ t~afn leborotorl e~ufo~ltiwl Swcffic Ecnzwnt~l RI~Etfan of other noxee: & hive bnn the strangest suppartsr of this Iln in the rest end still feel it should he pursued in the future. I~etion of 00 hi esrbon filba L un)olown to rm (swcupt at vary iou ~~(eahua~), is thata ny work tkst supports this wnceptl Tolel IIs n~dPctian: Evn though ITI dots not codd~r ddwtrw r~Qletlan to to I high priority at pnHnr, producta which do st nOpoad aidastnse with eipie3 ehan~v to otbar amoWng ohtrantariatina m o! poantl kndlt, Is would liics effort to he fonoentreted an oodifiostion of tests chsrsotsristios and seduction of on deliveriss, dna these art perhsls the ooet inportellt obj#tlou 0 the introdsotion of FJch prcducte, Rs for altelmstfws to n00 PsPer, ue do not und~nt~nd the retionele blhind onzp trdatrsnt oi paper, nor do ua sat aalch opportunity ~pr the lac oi lnarOenie sheets, ,h MavzsteEa io ic Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ·1· Ilfr~ L~t r1~8t Itat~l: If!otf Ihld b~ caecPt~~d or pm~t~ ~i~ L~ proport~n~ ai toheeo (1011), ~~ ClltLn II. ulllr Ct Ip~t~n i~ ~,/1~1 ~~ ~uppart hnllla: ~I i~ ~ ~~~ ~~~ie alla~on d tKhno~l~ m~ibrd wh~~t r nl~d A~lp~dl C~I~I la ~ple:l ol ~L r~ ~ ~n bl ~lon · ii rt b I, blD c~~~~l~ bf ~r oi ~ e~ti~~, ~ pmfal ~~ bl~a ~i~l ~~t ptoduct ~~i~~ ~ i~d trwa~: ~iiort ~hald L l~~~td pa ~ p~ct vi~ b01~ tobra, ~~ it !~ Yt~l I! v~ eoPla mt r~ l#~P~~cll trt~ ~ Il~tmu ~rom~nt IBld b~ ~ ·It ~~C PPl~ld~, LI it I~ L ~rlld ~~ 61 ·)·I~ oi anti lm ~V littl~ Ltla~ L ~ ·I·tQlca) ~h tut~~, I~eaaddloal II L r~ ~tl q fo IU Ilul ~ I r~~d p~3, r ~Cai~lly pn, ~~ ~1·ltaa I~ all~ II II ·d ~ Illtl~ a ~ p 11~ concrltl ca~r propo~d~, I ~lllt bit U r ~I te ~ ~ ~~e~ !~ II ~tLtoa'l rl O~·,' Ihll ~ ~ Jiaa II~ ~il~ I 'rllh·ll~~' c~ pajrtl e~ rlll oi J Lit · Rib ~ugpcrt~ L I11 611 eqre iotPrl pr~lld r~ p~ra vitb a 'ri8·l~lt' ·d p~id~ ~~~t D~I11~ foz projl~:~ u~ C rC luppo~, cc: f,J, ~n II~I L1III Clltal 1!1~ ClibPDF - v~~fastio.soni Note for Hr, B,D, Btamleg I have deferred a dedeion on arranging this yesr'l lleaearch Policy Group pHflpg (80ade Of PP) until ve had had last weclr'e Ieeting clarifiing our mcchaPism for aPeuting stroragle directfon for 860, You will aae fra ehs weoqmying note that wa now have a fralneworlr, and f now propo1e tht this ~etiog ahwld th p~~Ee in wcclr of lse Occobar in Caraang (glIGp have agreed to hole a ~cat~ne over ehns dags in Bctlln), Hoat of q the paaiei3anta will travel onto Greece for the COBESTB Sf~polian, which is the igortane fout(~aat avant of this odentiile bog. `a ·j In view of the inpcnding holiday #olop, it iJ lwportant thar i cordi~ thiJ plan without deLp Do;e ~hil ban fOPr Ipaaaael "'"j 6"~1* A,L Heard dLB/SC 18eh Hay, 1990 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Hate fot Htl B,D, Bto~PI~ r ~~ ~n~~D. F1E~~1990 I belie~E rLe the Bortd riait to I~D Ihoald b unPgLd for batrg 1991 1J~En both reaaarch ptogtn~c~ end rcfurbisln~ ere ea~pre~e, We eleo Pould need to consider whether the Board vents to see its 8i~eo, Trchnologf @otre end ~t~ Ictioitiu, or the PPndementel BeJeatch C~ntn tot both), QY/d~ a.l, an~d ~alse 18eh ~yl 1990 Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Xotl Lolr. l.D. Bramlev Heetlnp to Dist~uss ~ndamental Research Strategy 15th116th May, 1990 · Hamburg A meeting had bean arranged with participation by Hessrs, Bramley, Ritchard and Berter to agree mechanisms far ensuring that RrndaPPental Research p~095~DRS reflect business strategies of the company. In the event Mr. Bramley was unable to be present and the meeting was briefer than originally planned hut a o~mbtr of decisions wan reached, ~. PriWlard believed that the correct approach was for management to set the strategic re~lwments of the Group and for tbs scientists subsrflantly to relate these to science and derive appropriate research programses, Be acknowledged however that this process should not be entirely one way because maaagep~nt Feeds to be aware of technical. break-throughs that may emerge uns~dedly in research. Because of the long term nature of fundamental research WP felt that getting this process correct was most in~rtant. In addition to establishing strategies for Pmdemsntal Research, there is a need to establish unified paliq on, for instance, GGRRSTA issues which ate of Group intetsot. In order to achieve a consensus between the reguirements of the individaal CRI:c~papies on all thess matters, it was agreed that the Chairmen' of these companies should meet (haoing held discussions with their Bead of RhD), to establish a unified set of strategies for subsepuent proposal to the TSRT, where any conflict of interests between participating con~anies should be resolved. The agreed strategic guidelines should than be passed to Group W) Cc-ordinator who would call a meeting of the Beads of WI, including the Bead of the Fundamental Research Centre, to initiate the process of producing an R~D programme. This would then be presented to the next TSILT with budgetarp re~ire~aats, ~, Berter endorsed this process for the Funda~ntal Research activities and stressed and that we should keep a clear distinction between the fundamental activities and the development activities undertaken in the ~ndivi~al 8&D esntres, In the latter case it is also important that T~D is briefed on the strategic needs of its individual ct~pany end the role of the Research Co·crdinrtor hen is to ensure that there are no conflicts of interest or radsndancy in projects undertaken in the different cantros, It was suggested that a rather larger RbD conference in which scientists of all levels from the individual companies participated, and in which major areas of development work wars shared, might be considered. ~ Rt the TSRT meeting on 18th May it was agreed that the Marketing Directors rather than the Chairmen would participate in this meeting. Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 The neetfng pt the saadb at R&D to agee the R~ndaMntal Ile~aard~ pralrap~u should he timed such that budgets can he agretd before the pear end and thus should be in the last cF~ttsr. The general IW wnference cwld take pbrs at any tfme, Tt was agreed that tha first meeting of the Chairmen of tbs CAC's should take place ahead of the neat TSRT scheduled for the Ilth September and that the subsequent Beads of Research masting should take plaeo between that TStlT and the next, scheduled for the 30th Nooe~sr, While the rasponsibilitp for bdding the fndi~fdaal QairnleP will lie with their dead or BhO, it wee ~arfswtsd that the ~unddn~tal Reesareh botre pmduees a statue tsport on its existing projects as additional briefing material. a~lkl ,JtzalPI c.c. ~pssrs, R.J, Prftchard II. Barter ~tlse 18.5,90 E~ Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 mit nr SIAnluim Srrcl Xlmln~l, ~p. HC b pwlDs~l~l ta aol ~soo cv, ~luariill, RP, H1e 1[6 ObkClbbhlirp' trC\ fHlx bU·173 rtwa~eo~r~x~3sMlt t~CPI nen~wt~ ···.··········1···11····~II················~···*1·11··~·111·~······I·~······~·· TO ~q~aAlr~n~L-I~a ~~I %~qlS~L~L~dP~·~L~b~ C ...mmle!~unMlrr II SH1XO IJ Lm PAOB~ W~M ~rJ CDWI IW~gl WYT~b: 385118931413 GET, ~llJ II L D TlltebDIER HO, m atNo b~asuo ronomnull ~·Jitsl~'nl~ BUm KH), .O ;O Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 Imperial TP~acw limiledllimit~e :HIO, NI' S(·,\:15illl' Sltllc[ Ilonm~~l. P~P. IIX 18? P 13. Ik 15121CP Slanlsal. P.U 113('%1~ 1L]rZ T;b'~ id·6UO:3 hay ii, 1990, br, R, R, Bllur, i B1A1TI (U,lc, I Ulpdrt), R, L O, Centre, RegantJ Pack Road, ~prct~Mlaton, 109 log, Oaar R~ctard, thank you for your hospttality during our visit, we sncloae Ifl's canunents on the revised version of the chenwaensory orogrMme and on the tobacoo end bkl eh6~n~ltry progrsnme las described In your FAX of 03,01,90), Al you can see from the contents, then 15 guarded support for the chamounsoy program, however, then Is no support wftnln Itl for the tobacco and bb Chwistry progrumw, In roga~ to your raouest for a list or additives for which evidence of their ii occurrence In tobacco and their fats during unoking are required, we have no subml se 1 on, kind regsrda, Andrew_Portar T4 $ith Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 c~wb~agwv I~r ~ EeOIIIIl I MPQ#ll ~Ad~E tb~ OOmoOntI ~~ by Ill aonornlrl rh a~glrl ~~~nlarl rIIIIleh p~rl (IO dt~ehd) haI Ilryll ~n ddrrJ In fb nrlld prolrr Ot ~prtl ttl nr~~ tllIrI IrI Icvlr~ elntl (a of uhlsh um brpglY ID II ~hl dllcrl~la~ ~ $dqrd rHd 11 fill ~onl ~ ~~~d: \ ~Plln(n~~d~ob~l~~ nn, ~r~~1~1~4 thtt thll rlnl th~ th nrl~J oroIrO II only In tlltld lak It InpIet, Ir~t~~on nd I~l~lltll 1Rd fhlt On In dIPth ~II Y1]1 11 proad ~llo~n~lc~n~l Ilt~nt~r, nvta In IIth Ifll Ind dl~eul~lonl ul~ rtlm~l eonsultlnts, i) yl~~pdlr~ga~ cnntIot ktvOn tin dh~nc~llloa Inup rd e~e COmolnt(lJ to snlprl rhlt w ~r~ fully Inload of rIIvItI and ~(n, to Iny nlvly pllWlld dln~l~t In ~ pmlru, 3) elp~r~tt~l9111 for th rIrlbrI ItudlII loold b DbtIfnId fro 111 pbr?l~P~lnB OC opmlla, ITL 1I vll~~ to lupply ~~1~, lor work In tnI In~l of Ir~tltlOR id eUlblf If~~ldl, 4) in arrsl~tlng uKlkI c~llln ulth Il~~srCI DrooltIII, ~tlow~Rc~ luOt bo oIdO br IotuIl ~m ~a~l Iltltc, If 11 to thIt huoOn ooutll 1ln1~ eIn r~~ dl~ncrtb 11 ~ sls~l~lo of chlngIns lllOkl shrllt~l 5) It lhwld bl lIoogntlId tn~ r~putdlP of ~laa~ CUII IIIII dtl91 oOr nOvo ~ll~d~ 1Cdll(be It IhI ncc~od Ir cJrdll ~IF In tb CO~IX) Or bth, Co~ld~rlble clutlon Ihould k oIId In int~~pntln( th ~lh~l of lueh IntINInrlonI' If It 11 fIlt nlu~3~Y to rptoy trrl 1) I~unPI~~ L1 11I ph~ltbl0(lll rrCtl~ L ehmollnso~ progrr ePuld not ~ fully IddnlIId ~lon IB~dlolol, nd d~cu~~l~~ with, on~ulfmtl~ HnwIvIr wt would Itkl to nvllw 1) ~~lte~ in Ip~~ndlx 2, wnlen 11Jtl th, IntIrIIfl eonl~b~d Iy kb Flr~s wn prllcnltd, elIrflftd ~ut noI dl~cuss~~ II tn, eonllfne~ WI 115~' t~"lorl fh~~ thly will not II IreludId in IhI nrosrIo, rR ~ny IvInt ro dd not sopplt thuo, ClibPDF - v~~fastio.soni IT1 has ku using WA ~ld~s~r IdhJ~v~( sinEl Igttl Ynll~ wa uould ha Conwmld ii its usa #~ whoun to b prabllmatfe, w,would nlad to nava a usable worry·frs~ alt~m~tlvc~ It is undlrstaod fnat sons n~soreh 1~ undtng to ~lnd nyl of yting ~t~reh on Mpn Ipssd Mksn usfng a Kaya~lcn agllte~tor, but tn( Iktus o~ tkll work 1~ ~u~known, eoncarns ovar gosslbl~ dloxtn rontslrutfon rs clsrly of grown tntn~t, nod U18 eontncr work It Hlnll shauld help ddlm tho nrtnnt of VIsI Eonenll In rngord to tho tflt of taple anaslquatldnl nCsd durtng tnu melting of Sa ~wll t9so [plwn In tb Appndlx), It SI~RII to us that ncne of thul doe irFm rto 31mJ dolos(tnol Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 onaPoEModIIY s~n~rll CEIIonto OCjdln II loudoCto Y tha uldl ~& Ir aCj~tl~ Ca Caa fodld for tbll ylan but II Iblod '11~1I of thowork hi ~II d,ltnlflv~ or hoo gfvon rll~ to dfstln~ oroduot ~Rl11~'l nhat nor kohnology or knorlldOI 116 that 01nl ar Ixrt~rtan ~d w e# oolro pro)n~~ In tbl~ ~r~~t · wnv oonoontrato on tl I P~u~~ ~1~ bac at boon Irellls~lll torIotod dI thl IlrlB(I Lllu ~lftll a hovIns o doF l~~d la rbl arklt plwl ovor ths nu(t I yoanl It ulld Co an uooful to uno klphor t~r Iorll p~uct~l Slnoko-lnlokor Ilt~r~ctlon~ CrI ~pldlle to p~fcPl~r oarkot trPI1 thl I~~~~mf ol vhd 1o 'good' ~ot ~ orodoot 1o altls pnjudled bl its oorkot shonl Tblrl II thl f~rlt~l Imblr of nraellllg ttlo ankoro' Ilpnslll dl~e~~ll~ of o Crood Inoa oxoorIonoo rltC L rory pr~tlw Cut lIoltod ~ls~l onllvwl ooloIClo, · fhn 1~~ d~b~t~ no to fh looortonoo of th Hnf ootf fn d~~lnldg t~ eC~~~n~o~ orooorttoo of th elglr~ft,~ (o,DI) "l~lt llDko chrl~~~.~~~lll ournntly not aolytlatlr (DIOI) "eon~ld,ntlo rttt to Ilv,A to foot c~llt~ t~chnlqu~~,,ll Whit Soon tochnIooos In ktnp orooosodl War do you fra aoko ~f~~ Illnlflelfl) cmgln( c~tfl·t i Whot uno loornt IrP n, tid'~ ~II~ arC on tbl Ill,sls on al, of ~ltlrlag ~nvlna~t ~dftlonlt Wow foold n d~~b#~ bo of plo II ~ll~~~lnl th r~ldlonlblp Cotaon slllrlftl pl~lr~ oad rbj~stlvl pmpl~l~~l · War c~n you ~eor~rbt~ "In~f fly, Ilnlfng" In I lelmtlHe ~~yl nit m'bl~t nltholl of I~~lrnf 01 rcsla('l uhlt das thlo whlr dnJ *koy lootoro to 1~ tlrlnodlun nleottn~ oroduots' I1n1 10 .O ,O ClibPDF - v~~fastio.soni rn~onaflon Rlvlu InfanntlPn revtav Ihould k earrild out t~O~P oraoaalra a rork DrOpro, Stnokl Analvl~ Lcush at mlu of Main, 'tot enr~sf~ fflehniquu' - sla (afllv Knnwnt, bontorv Evaluation 1 \~ . Irllcr eampaCon ot Intlmal rd tdlrosl pa$~ IHIIE 1 DELtl) gave aomoarabla nllts, ObJtcllv~lSu~cCtfvl d~f~bal~ DoaJ fHI #u mon magpln91 Role or n~otto a smoke pH cnCod Earlier work found that Cdrrolat~Pn ~stw#n Ixtnctd~le ntcotts and ~R~oaet uaa not v~lld for products (lO 1 tar, rt ~I wll known that ~S nkofln~ 13 prindpllly In thl p6ttlcutab pnsvl PlrllEl~ Ilrl hu alrnady Wan lodksd at · why Ihdu]d It ha ralavMt to GREUIWtlNOVA1 1 Irrltltlon - Pnvloul work on IldlhydlJ and ~r~~atlon (aaokhurat Its,) vu not conelullvl, · j why not IWnJs baale quld~cnlllrbl Eg, why daoa Irrttft~On Incnas~ as pcklng danlltr dwnJd Why dooa Itr Inenus Irrltdlon? ate, why dp)o IPW(r mafllun Inenau Irrl#tlM? Saliva C~Mlfltn Brll~r work by Lvllyn a EoRICar on ~rttrldll and hunan mouth absorptlen Should ha nvfud ctratully, Extanl Ilt~ratun an ~ost~erlt~n9 thl mouth and ula of Irrlfmto suct~ as eapvteln should ha rsvlmd, Tni~ iJ non Itke tunduncnal n#lrch on SuljeGtlv( rss0ons, nfhv than ch#aesonoory raaaareh, Irmravmtnb ol Subl~et~vl )mw~ttr of Ovnthlfe S~1 rllPYr I"Yl.d~ m mil ra ~lsm. ~m ~u~ lul ~ Imr /e Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 r~ilc~eo s ~ sr~~ In oImrs-n #w~s P~ruwr ITI 1lal that thl pnoosod pnltr bn vtrtuslly no nllrael to ttl nlldl, IlfMr an olsnnod IddItlvIs (md hlnoo thllr tnnlllr) or on S·tllROtJ, 10r fh lollulng r~~#llt- Ihc Inat ~o~t~ pi IT1 clllr,Ctl brmdl eoa~la no tl~ ~Yltlvi~l t TII dMMIII IhZ n do II In Innrovd IIr II bY ii Ilt Id/or th, aoroon ~utnorltyl 1, th,n sn ooI nllontlon~ fbd u IoroIsoUY bl ~11~1 In thl luturo, sucR sIIntsstsanhsnaooont (Yrolltrrtl), Ir~t~tlr nduttlon or ~lb~rtl 1Sr#rr, but n 1I11 tbst thr ~n most 11Lllt tnvPhl 31~11s lhloh In Ilndl on thl qpAd hrc~ 11 sri unIL1a to jldlfl rosssrah on ~1~ on bl ~rll at q(SllltlOO thlt rhl ooY bep Ip~d to our wrk. 1 II rI ull In lddtttvl LI I asrttoular bnndl tf hi to b dllelo~~d to our (ov~nwnf, IdrtlHld bl tbd btmd lnd by cane~ntrltlcn, ~hl~ In oonjumtfon with t~l aurnnt Id llrItno nogatIvo conlwaar nle~on to ddltlv~J In pIanl, ~11~ Votr ull onl al loot roJort, 5, thoro 11 eurrlntly no Qovornmnt nputrnnt for Infonotfon nOl~lnl diftlvl trInsIIr, bnYal at oroducts or toxicology. C " In gmlrtl If 1 cont~lnmt 1s found In a product (d~tdd by snoko toofo ~tc~, or rl~~lll! or by brona), b~n Ulo oall dlo~ noodod should I to find fL sourco ond tlkl stooo to Ill~ln~tl tbo aoJsILIttty ol rurthor oonultnItton r Ilr I e~~lblr L shMlld not rtlk thl npu~ttPI d at trsdIlsrks by t~ll( to Ild hou ouch Il~ct~~~l~ In 1 productl Prdld oontbnInotIon II on Issuo tl~f 1b ~ddr~s~d bl bortng an Ili~dlv~ oroduot IntllrltY P)lel fhragk snod I~nl(mllllDlnlllon ~~ IlanuIscturtnO Indler In tbs eall ol plltleldll (~nglcld~~, n~rbfdd~~, It~), than 1~ cl~~lnly 1 nlld fno flnl to ttr far nathads ol vlstyols [II unbvsflsble or fn~dau~t~ for Ilellle tobacco purpol~~) ond for tilting of l~v~ls, tn thl se~ctll oooo ct tlOCI, thl pol of dl~loe~rCrtll In tn~ fllld wol n~vlr apotovod In elnsds. In eonIds hnllylll lor Iprtcuitursl ohonIoolI Is dent Ulrou9h tho ~vcmtnt ~utha~ti~l In r101~ to rllllfr~l~ tar uu lor crop In gonorIl, ThlFI In no gutd~tnllon tolorsneo Itrlls of such c~ielll In to~ceo lor ull In elnld~, In plMn1 Iuoh Infon~lon ~I Irn Wllt Ooroon or UIS~ gufd~tln~~, It Is pocllb)l thst lov,ls In looortld tolesl could I ol consornl ClibPDF - v~~fastio.soni ~tsgr so'ie# UK ':TEl No.r)lO: 7803j2 i~~a:~so I1:is v.o: 'j ARln IOth May 1990 SteBGT ~J~ FOR I AIL, B~RD sec yarmIJe 1,. you will recall at the Vancouver RPG peating the SRG were specifically asked to look for ptojscts related ~' : · n~cotine, particularly ~n relation to the ... increasing number of statements that smoking is an addictive behaviour, Re a result various approaches :~~ · '' ~were made.on this Issue a~d two specific proposals · rue lade bu IIDIDllOt Bf~l~l O.Y, YhllO ~i i. ' Canadtan'mlleaguee felt that Dr, Verner (nott Fight be worth supporting, r~·'· ' ~' ·· ; ·· · ' ~·~·· · ·.. 2, To allow for thesd new projeetel and to last axletlnq contractual re~fremento~ the SIIG budget was agreed by the RPC to be E86,000, pr company (four contributors) obviously with an increase to allow for ~· the ineoreatbtion oi lustalf~a to BMCo. i. ~F era I~sbll .ara$ ~alr. cornlpondaPct left by Sharon, Brown i #illiamson, just before the' last 6XG mecting~ announced their ioteotioa of limiting their contribution in 1990 to around E711000. i, When our colleagues from canada heard this, they 3; . indicated that they might not be prepared to i:, wh~bub t11(,001 either, and indeed went further and suggested that the whole basis of SRG funding should be changed, perhaps to a sharing arrangement similar to ths~laaearehcosa in general, ThL would, of course, increase the contribution falling on Brown L Williamson, 5, vacillation in the middle of the year is clearly no way to run any business, and apart from the possible embarrassment of soliciting contracts for which no funds are availabler the SRG Feeds to know at the beginning of the year how much m211cy it will Lye to spend , If; 'O iO Clit; PDF -!::!!::!!::!.f3 StlC.i: 0111 ~ 90701 U(` -i LlkA7m 100332 ~15~1 ~:50 PJ3 .2- I~PPlq tp thL ~ljcct d orlVIIller l(nottl the Cldila hslilve Ylt tLn ~, 1 cdOO far Igprti4 bin on ~cotil~t~l~td reldlrCh d OherOd and r ~td ufth L prf~p~lr to i proj8ct ~~tffi~dl ·garonl~ ast·tll I 1·!* ~ L Ilh ebl ior 2990, rccoP~ d qs Prolect i~a pafs~~or Cop d one t: trr t~(E ~tt' II I aid be It~C1IP1 caY II( lor (oJ olfl~ to rssoltr( Lit utter oel ud ir 111I eith,r ~t~eolia TQRT rctil or rbsn II Mttieiltl~ ht L OnY doent r kl '*t"dllbr·--· · r~illS t~i~ vald ~~fns ~ HssOler ~Dlb v~l r think it rooM ~l~o be approOriate to c~tlbli~h the ri·iel,~ ,, ~i~ ~ 1941 hPdJ(t i. ull Lo be aqre(d r I do d'·t ~' lltDLti00 to QEEPT IC~~ C· j j.C 10 1' lo ClibPDF - v~~fastio.soni