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4 Oriain of the cicarctte smoke. In contrast to a widesproad opinion, cigarette smoke is no a produat pS. comhustton. In the presence of oxygen and at high temporatures, com- bustion leads to degradation products which are rich in oxygen. In the cigarette, the tobacco itself does not undergo such a reaction; only the carbon in the leaf does this. Therefore, the actual combustion products in smoke are only carbon dioxide and carbon monoxide. The many hundred smoke constituents of an organic mixture originate during heating, practi- ca]1y in the absence of oxygen, and therefore may be divided into two main groups: 1. Distillation products: substances which evaporate from the tobacco to:.rard the rear of the glowing zone, and are distilled away without under- going a chomical change. To this group belong all of the substances which are found in the to5acco and in the smoke -- such as paraffins, waxes, terpenes, and many volatile acids and bGses, as well as aromatic substances, among the various classes of substances. The most important distillation product is nicotine; it is especially interesting because on account of its limited volatility (boiling point 247°C) it is alt-says distilled only in the great,er part, while the rest is pyrolyzed (see : ibure 1). 2. Pyrolysis products: substances which have originated by random combination or rccombination of molecular fragments which were formed by the destruction of difficultly volatile and non-volatile substances (above all polysaccharidcs and polyreptid.es). Corresponding to the great role plzyed by chance in these changes, the pyrolysis products embrace practically the entire irLmense assortment of substances in the lower iaolocular weight organic chemistry. 'lhat reraains aftor distillation and pyrolysis is practically pure I

LTV,".ATU!'.r (1) Wenuech A.: Z. Untereuch. Lebonemittel. 7!, 178-186 (1937). [R] ii'snuiah A.: D" Tabakrauch. Arthur (}eist Verlag, Bromen 1939. (Vergriffen, freundliobet. weieo von 1)r. :-k lCuhn, Wion, (k herhuwn.) [3] Pyriki C.: ISnr: inet. T.bakforooh. Draulen 2, 127-141 (1966). (4) Borbdy P.: Z. Priiventivmodizin, 8onderhoftr Die Toxikologio dee Tab.ks l! (198Z). (6] Keith C. H. und J. C. Derriek: Tob. 8oi. V, 64-91 (1941). (8) lVartrnan W.B., l:'.C.Cogbift und E.6.Narlow: Ansl. Chem: dl, 1706-1709 (1959). (7] NoJjmann D. und E.L.Wytulcr: J. N.t. C.noec Inst. i0, 47 (1963) (deeteoh in Beitc. suc T.b.lfor.chung 2. 61-88 (1903). f81'Bnears A.: Tob. rici. VII. 78-80 i19831. • [9] Ykkcry H. B. und 0.1V. PucAcr: J. Biol. Chem. i(, 433-541 (1929). •. [10] Laurens A.H. und T.O.NarrcJt: Ansl. Chem. ?0, 1800 (1968): . ' (11j Grob K.: Beitc. z. Teb.kforech. 97-100 (1981). (12) Orob K.: J. of t3.e Chromatog. (im Druck). (1'] Lipp O.:• Vortng Croupe Frrnls du Cers.w, P.rie, !0. Juni 1963. 14

. the method described by Grobii. The reproducibility of the measurements is naturally best in the fiberglass filter and in the absorption liquid.. On tho other hand, the determination in the butt is less exact, on the one hand because small deviations in the butt length are unavoidable, and on the other hand be- cause thc amount of nicotine present in the unloaded butt was determined on a parallel sample, and therefore is subject to the small but always present differences from cigarette to ci.garettc, as an additional source of error. In the calculation of the nicotine loss, final.ly, it must be taken into account that the error is the summation of all of the other doter:nin- a.tion5. Since the amount of nicotine absorbed in the "saliva" is strongly deppax3.ent upon the liqui.d surface and the duration of the contact, the flow rat^ of the smoke andd the vibration of the-glass tube above all have to be reproduced as exactly as possible. RP.si)lts anr) ca i.scnssion As tr,a.y be seen from Figure 1 and Table 5, there is a considerable difference bet~recn the individual types of tobacco, 1•rith respect to the amount of nicotine carri.edd over from the smoke into the "saliva.11 This difference is shot-m not only in the absolute measured quantity of nicotine, but also in the percentage based on thee nicotine contained in the smol:e comin" out of the cigarette, or upon the nicotine contained originally in the tobacco. Only about 1/10th of the total amount of nicotine in the smoke leaving the cir:irettes is taken up by the "saliva" in the case of smo',;e of lo~•r p?i (1iGht :'irri.n); on the ot.hcr hand, in the case of an all:a- line reaction of the siiol.e (Para6ni3y, Jap1r,c:c.e Burley) about 1/5th is taken up. The P'lrylandd tobrieco, traditionally very much liked in Srritzerland, takes up an intermedi.lte position: Althourh ot.h9r factors could also ~_

-15 - Type of tobacco Ratio of pyridino and pyridino dorivatives to nicotine Virgin Rhodceicn ................... .... , 1,1 :1 Virgin USA ........... ............... 0,26:1 Maryland USA ....... . ....... . . : . . . . 4.. 0,48: 1 Paraguay ................ .:.......... 0,08 : 1 Burley Japan ........................ 0,10:1 According to this, the nicotine cannot only be absorbed more easily from s:nokA which reacts alkaline, but the absorbod rniaturo, in addition, is in genAral loss contaminated with pyridine and pyridine derivatives. Associated with this circumstance is also the fact that the alkaline smoke contains a larger fraction of the tobacco nicotine, since on the one hand less nicoti.ne is held back in the tpbacco butt, and on thp other hand the loss from hnatin- arx•3 the side stream is rather smaller. Our determination that on the one hand a higher fraction of the to- :A=QUU nicoLine is lost at lov:er p?i values, and on the other hand the fraction absorbed in the tobacco butt is likewise o eater than at hic;ier pa, may be explaincd in the folloi•ring way: In tobacco +.-rith an acid reaction, the nicotine is more stronolJ held t.)ack b°cause of its lower vapor pressure; it therefor.e gocs over into the c smoke only at higher temperature. On +.he one hand this causes an increased enrichnent in the tobacco butt and on the other hand the higher temperature necessary for the transfer into the smoke also ~ives assistance to an in- creased decomposition by heat. In this manner, a hi ;her proportion of the pyridinc fraction would T,e favored in the smoke. The situation is con- sidera.bly simpler w:ien there in an artificial constant filter material in place of the tobacco butt (Lipp13). .. We thank iterr A. Cossy for carryin~ out the nicotine± d.c~ters~inltion:.

smoke the problom is generally of less si;,mificance, in our case wo were afraid of greater disturbances. As a consequence of the much higher vola- tility of pyridine, the proportion of this in,the mixture absorbed by the "saliva" would have to increase significantly. For this reason, we have investigated Frith the gas chromatograph the composition of the photo- metrically determined fraction (the so-called °total alkaloids"). Capi1- lary columns were used uith a "coating liquld" which we synthesized, whieh is discussed separately (Grob12 ). Figure 6 shows a corresponding gas chromatogram. to ... 8. ~ ' a . •7 • . . A . _f Ilp' .1 ISO' /85' M.IA. Fig. 6. Gas cflromatograni or the hises Absorbedd in Vlc ''s;iliva" frorh the smoke from Japanese ?w.•ley. Coluin: 50 m10.5 m7 stationlry p:iase• • polycthyloneimine; carrier C?.s: nitrogen; detector: flzTno ionization. .;.d.ontificd co:r,nonents: ].. pyri- .iine, 2. 2-:.,ettiiylpyridine, 3. 2,6-Jimethyl.pyri:iine, !F. 2-'°thyl- pyrid=ze , 5. 3-methylpyridine, 5. 3-ethylpYr i{7.ine , 7. 2,4-d i- Methylpyridine, P,. 2,3-dimothylpyridino, 9. 3-cyanopyridinP, 10. nicotine. P'one of the tobaccos investig-ated produced, in the fractions absorbed by the "sali.va", amotLhts of acconP^.nying alkaloids which were definitely nieasurc-%ble. Tha raVo of pyridine to its simple derivatives (methyl, rlimethyl, and ethyl pyri3ine and others) showed no graat variation. On the other hand, thc: ratio of the total pyridine fractIon to the amount of nico- tine was q»itn diffcrent, as may be seen from the ."ollowing surtu,iary.

Z. PFAVENTrr1-M. 9. 14-25 (1964) e . NICOTINE ABSOP.F'TION FROM CIGAItETTE SMOKE (Delivered in abridged form.at the "Seventeenth Tobacco Chemists' Research Conferenco- I.ontreal, September, 1963) by A. J. Artho and K. Grob Addrisses: Dr. A. J. Artho, F. J. Burrus & Company, Boncourt Dr. K. Grob, Organic Chemical Institute of the University, Zurich . Summary Tho quantity of nicotine ("total alkaloids") absorbed from cigarctto smoko by an arti.. ficial "saliva" was found to vary,consid- orably botwoon different tobacco types. Thie indicates that neither tho amount of nicotine originally presont in the tobacco, nor the amount present in tho condonsod "t.otal particulate matter" of the smoke, can be taken as a reliablo measure of the physiological strength of difforent ciga- rottos. rree nicotine is eaeuy absorbea by a buffored liquid such as the saliva. With highor pH valuo of the smoke, the vapor •, pressure of nicotine (at 37 ° C) is also higher, thus more free nicotine is availablo in tho vapor phase, and more is absorbed by , the "saliva". The surface area contacting the smoke (depth of inhalation) and tho duration of the contact must also be taken in consid- oration. Furthormoro, since a considerable , portion of the nicotino can be rotainod in , the butt as the smoke passes through it, and revaporiaod as the burning zone advan- ooa, the importance of the ~butt length i. ' readily understood.. . Thp posi ttnn of ni ccti.nA nrnonn the :%^!AkA cc,nstit.u~nt:In spite of increased rec.earch efforts, nicotine, out of the hur-drods of known substances in cigarette smoke, remains at present the only one which could be studied as an individu.ll and well-dofined substancfi rrith smoko producns in definite physiological effects. For other effects which

P human there are unfortunately still no Fnoific causative agents knorm. Indeed, exact relationships between sourcos and effect have been discussed again and again; however, the hypotheses always remain poorly supported. And also, for these hypotheses certain i:rours of substances must always be kept in view, never a single substance such as nicotine. To be sure, tobacco contains several alkaloids. However, in terms of quantity, other than nicotine they play no noteworthy role in the smoke of practically all varioties of tobacco. hF rQlationshi.p between threA nicotine nuant.itIc_s_: in the tobacco. in the smoke, and in the body of the smoker. It is much more important to have the most exact information possible concorning the nature and the mothod by which nicotine is transferred from the tobacco into the human body. For df:cades, the nicotine content of a tobacco has been considered as a reliable basis for the evaluation of its ..t,. . ~..~....z...1 . rr.,..~,. ~.rsas a~,. .,....i`.,1 ,r ....r3 r..~~........~~....d s:.,3L- .,1 .~..e t..~.~--'o_.....~ .~~ ._- -... .. ~~. -~ _~ r;.,...~ . .~....~r..,,_. we began to rely upon the nicotine content of the smoke -- an essential ad- vance, since the two values are connected in no simple manner. However, 1,2 Wenusch has shown as early as 1937 that even on tho basis of the smoke nicotine content, the alkaloid effect of a tobacco can be grossly misunder- stood! Later, Pyriki has also confirmed this thesis in several papers (for example, reference 3). Figure 1 shows that in this case we are not at all dealing with sub- tletiPs. Cigarnttos made from various crude tobaccos were smoked in a small tube, the inner wall of which was rinsed by p buffered liquid, which thus served as a model of the oral cavity (for details, see the discussion method). Amon~ the numbered examples used, the first two tobaccos produced an acid smoke, the last two produced basic smoke, while the X.aryland variety ~

-10- L A further difficulty results from the fact that the sucking in and expulsion of the smoke which occurs in naturstl smoking is very difficult to counterfeit mocha.nically. In the custorr,aty mechanical smoking equip- ment, a quantity of smol:e which corresponds to the dead volume of the absorption apparatus always remains in contact with the absorbing medium for the duration of the puff interval. Hot•rever, since in the present experiment the duration of the contact existing bet•reen tho smoke and the "saliva" is directly of decisive significance, we have done away with the intermitting of the smoke puff, and have smoked instead in a"eontinuous puff'' in A. flota of 80 ml/minute. The size of the glass tube was so chosen that at thP given flo!•7 rate the smoke •.ias in contact with the liquid svr- face for 2 secoM^. This type of snol-in- also hinders among other thin--s an cxcessive "ar-in-" of the smoke after the exit from the end of the cigarette (I:eith and Derrick5). As may be concluded from the light yellow color of the absorption liquid, the~.re i.s no notet•rorthy precipitation of the smoke particles in the tube, so that the quantity of alkaloid present in the liquid can be regarded. as pract~cally exclusively absorbed from the gas prase. r All ciglrettes rTgre snoked. to a butt lendtl: of 23 mm. Then the butt, the artificial "saliva" and the fiberglass filter were acidified with HCI, and the "total alkaloids" t•rere determined as nicotine:, spectrophotomFtri.- ca.lly, after stean disti111tion (Lai:rpne and Harre1110). The nicoti.ne ori.-in-i.17.y contained in the smoked tobacco ura.s determined on a cor:;ara.con serfes of ciC:rpttes. The Amount of nicctine; held back in the t•obacco butt •••as obt~ined from the difference beti•lePn the r+.nount determi.ned in t:Ie 0 zmokMl butt and thr- or;-in!?l• ar..eiint rrn.ent in the unsmoked butt. ThA p'i values of the smoke for the indivzdual types of tol--occo vere detormin-1 by V 0 N ~ ~ ~ t o* 0

! 1 VIBRATOR to We smoking machine ~ ~IBSs tube t•-ith 0.6 nS off buffer solution Fig. 3. Schematic repre:.c.ntation of the experimental arranre- mcnt for smokine. I s ri J. h. !'i.F!i•* o." the ~x~rim~r+.al rpparatts duping :moki.n,;. At talE Inrt, iS V,n c1.-1r^.•Ftc; ln th!o c!•ntor nf i!in r7.ct.nre a tlic VC•11ss tt>>)n t41A.r11 di.hn into t'in v1tcr ~t,d in r•ov,,d l-,y thn vibrator; on thn ri;,llt ;s tyc t'~r0,rid"o fi.]t.nr arIrl flnc :.ucticn connoction to tlin :melan„ mrlchir.o.

6 in the gas form disappears from the smoke because of absorption on a suit- able surface, the loss is immediately replaced by evaporation from the particles, And thus the disturbed distribution equilibriury is reestablished. This leads to a surprisingly rapid transport of nicotine from the particle phase to the interfaces of the surroundings, without the particles having to contact these interfaces directly. This transport mochanism was first established experimentally using phenols as examples (Hoffman and Wynder7; Spears8). The behavior of the nicotino.in smoke is decisively influenced by its characteristics as a base. In basic surroundinos, nicotine is present in the form of a neutral molecule, tinich could be found in the gas phase. In acid surroundings it is protonated, and has the forin of positive ions which could exist only in the liquid. or solid phase. As the neutral point (pII = 7), the nim;erical ratio of molecules to ions is about 1;4 (Vickery and Puchcr9). A decrease in the pH value signii'ies an increase in the num- ber of ions, and therefore a decrease in the volatility. As is apparent from Figur.e 1, the distribution of the nicotine may now be explained in the follo•-.in~~ l•:ay: Pyrolycis or di:,+.i114tinn: more nicotine is pyrolyzed from acid tobac- co, because it is less volatile. Therefore, it stays behind lon~er as the glowing zono advances, and is exposed to higher temperatures. Some nicotine is also always volatilized with the side stream, between the sr:o;:c puffs. - Abn,crp1 aon in the ar^). ewit_y: the sm~.^.ll surface of the oral c~vity can ho'..d bicl: onl.y a vlnishi.n;ly small portion of the smoke dro-~let.s. On the other hand, the saliva is an effecti.vo solvent,for the ni.cotinr: in the r; ~ S ~~,L ~.`^.. The saliv:, ;nay then withdraw n icotino from the r•~rticle }~hasA