Tobacco Documents Online

0. .as In- ~is Iat ?r- ea1 Nct mal 11 'the hne , ing. art- No. 4' CHAPTER 7 Al llergy ting ttcet

C~onten#s Introduction .......................................... Antigenic Properties ............. ............ ............ Skin Testing ........................................... Additional Immunological Effects ....................... Effect on the Immune Response .............. ........... Irritant and Pharrnacol'ogic Effects ...................... Clinical Allergy ........................................ Summary .............................. References .............................................. Page 103 . 104 105, 107 108'. 109 . 1110 1 111 ' 11112 rmu

INTRODUCTION As early as 1886 reference was made to an entity called "tobacco asthma" (64)., Subsequently, controversy has arisen over whether tobacco srnoking, causes clinical allergy (61) and whether such tobacco alliergy is associated with the major smoking-related dis- eases (25, 69). In 1957; Silvette, et al. (64) reviewed more than 100 papers con- cerned with "'the immunological aspects of tobacco and smoking." They concluded that inadequate animal studies had been performed in this area. Referring to.clinical studies, they observed: "'. . . virtu- ally all reported clinical investigation has been limited to d'etermi- nations of cutaneous sensitivity to tobacco extt'racts ; and it must be regretfully admitted't'hat much of this published work is equivocal, uncritical, and inadequately controlled."' Such criticism~ is also applicable to many: studies published'! since then. Epidemiologic studies designed to determine the prevalence of tobacco allergy have not been carried out; hence, it is difficult to evaluate the magnitude of the problem. Allergy may be defined as a specifi'c, alteration in response medi- ated by an antigen-antibody reaction. When a hereditary suscepti- bility to allergic illness is present, the term atopy is used. For ex- ample, hay fever and asthma are atopic diseases. Thereil& no single test or observation whi~ch can be used to de- termine whether ai substance may be responsible for allergic dis- ease ;, however,, f ulfillment of' the following criteria constitutes evi~- dence for such a relati,onship : 1. Demonstration that the substance is antigenic, Le:, capable of stimulating,the production of antibody and then reacting withi the antibody. 2.. Demonstrationthat, upon exposure to the substance,, signs and symmptoms simulating an allergic reaction are elieited whichh disappear upon its removall 3. D!emonstration that the immunologic event is related to the clinical event. Recent advances in the understanding of'irnmunological reactions as well as in the methodology of'immunology are now being applied 1os

to problems of clinical allergy. For example, Ishizaka (37), using radioimmunoelectrophoresis, recently reported that the so-called "allergic antibody" (reagin, skin-sensitizing antibody (SSA), atopic antibody) belongs to~ a new class of immunoglobulins, IgE. Although the skin test remains a simple and definitive method of demonstrating reagins in the allergic patient, there are many vari- ables involved in this technique which must be carefully weighed when interpreting; test results. In the area of tobacco skin testing, such variables include: diffierences in antigenic content of the test extract, diifferences in, route of administration, and heterogeneity of test groups. ANTIGENIC PROPERTIES Tobacco leaf contains a complex mixture of chemical components inchzding : celluloses, starches, proteins, sugars, alkaloids, pectic substances, hydrocarbons, phenols, fatty acids, isoprenoids, sterols, and inorganic minerals (69). Theoretically, relatively few of'these substances should be antigenic. Tobacco~extracts of different compo- sition result from dlifferences in tobacco types and species, process- ing of tobacco, and preparation of the extract. Harkavy (26) has shown in some patients a differential skin reactivity to extracts from different types of tobacco. Cbltoiu, et al. (9) reported that 13 different antigens capable of inducing; precipitins in rabbits have been isolated1from tobacco pollen. Chu, et al. (7) prepared aqueous extracts of five commercial tobacco products which stimulated anti body formationi in rabbits. Ti he antigens contained in the extracts included both proteins and polysaccharides and had molecular weights ranging from, 20;000 to 60,000: Silvette, et al. (64) reviewed several papers dealing with the immunology of nicotine and concluded that nicotine was nonanti- genic. Harkavy (25),, who performed some of the earliest studies on the antigenicity of nicotine, could not exclude the possibility that nicotine may act as a hapten. A hapten is a compound which, a1- thoughnot antigenic by itself, reacts with antibody andl conveys antigenic speeificity when combined with another compound.. With pyrolysis many of the tobacco constituents undergo reac- tions involving, oxidation, dehydrogenation, cracking,, rearrange- ment„ and condensation (69). Many new comrpounds are formed. Pipes (51) demonstrated, through exhaustion of passive transfer reactivity ini skin sites, that allergy to, tobacco smoke in man, is dis- tinct from that of allergy to tobacco leaf: Tobacco smoke exhausted reactivity in sites injected with tobacco smoke sensitized serurn; reactivity was reduced but not exhausted with tobacco extract. The converse was true with passive transfer sites of tobacco-sensitizedi serum; tobacco extracts abolished allergic reactivity whereas to- r04

bacco smoke extract produced a diminutioni but not totall exl.iaustion:. He concluded that it would be useful to test human suba ects for both tobacco leaf and tobacco smoke sensitivity. Kreis„ et al. (3'9)': have. speculated that tobacco leaf antigenieity may be lost with pyrolxsis.. CaItoiia, et ah (9), recently emphasized the importance of remov- ing all irritants from~ test extracts. Dn a clinical setting, allergy too tobacco additives such as menthol ha& also been suspected (47). SKIN TESTING 7e ti, es at al- iys ~c- ~e- edL Fer iis- tedi rm;; 'he ;ed to- Intracutaneous injection of test antigen is a widely usedi method of skin testing. Patch tests have also beem used in cases of suspected contact dermatitis. Roseni (54)', has observed that skin testing does not accurately duplicate the xnost common route of exposure to tobacco, i.e., tobacco smoke inhalation.. For those involvedl in the production of tobacco prodhzcts, inhalat'ioni of tobacco dust or direct contact with tobacco may play important roles in sensitization (9);. The extensive literature on cutaneous sensitivity to tobacco ex- tracts includes comparisons of the.prevalence of' positive skin reac- tions in different groups, such as "not7mal"nonsmoking adults(17,. 68), "'normalP''smokers (17, 33)~, allergic patients (59, 76), children (41, 50), tobacco workers (6„9), and patients with~ specific diseases, e.g., thromboangiitis obliterans (28, 73). Harkavy reportedl on, tobacco skin reactions in several different groups of patients (34). Many of the apparently discordant results in some of these, reports can be traced to failure to compare similar populations or to control for differences in the test antigen or in the method of testing. Sulzberger (66) studied the different types of skin reactions pro- duced by intracutaneous inj eetion of' denicotinized tobacco extract.. Three types of positive skin responses were observed: eczematous reactions ; immediate wheal-and-flare reactions ;; and late reactions, probably of the tuberculin type. The: wheal-anMare response has beeni by far the predominant type (42). This immediate wheal-and-fiare response! is a specific immune re- action (6k) largely mediated by IgD: Patterson (48): recently pro- posed a simplified model explaining the mechanism of action of the skin, sensitizing antibody (SSA). "Subsequent to stimulation of the: animall by antigen, SSA are produced by cells of the lymphoid sys- tem possibly located in the alimentary and respiratory tract. ... The SSA so produced are secret'ed! in such a way that they reach the cir- culatiion, where: circulating, cells, predominantly basophilic leuka cytes; are sensitized', by attachment of the SSA to the cell'surfaee: In addition, the SSA also: leave the, vascular compartment and sen- sitize rnediator-releasing cells in tissues. The tissue cells are pri- marily mast celIs ... The immediate-type allergic reaction occurs 105 ~,,

when antigen is introduced into the individu~ali sensitized by SSA,either by transfer of antigenic molecules, through the respiratory or alimentary mucosal surface or by injection into the skin or vascular system.. The antigens reach the antibody on the surface of the mast cellls and initiate the intracellular events that result in mediator re- lease from the cells." The actions of these mediators include smooth muscle contraction, vasodilation„and increased capillary permeabil- ity which can produce such clinical pictures as hay fever, asthma, and generalizedl anaphylaxis:. Until recently, direct skin testing and the passive transfer test (Prausnitz-Kustner reaction): were the on]y methods of studying IgE mediated responses. In the passive transfer test, serum from, an allergic patientis injected into the skin of' a normal! subject. After a suitable interval the antigen is injected into the prepared site and adjacent normal skin. In a positive response, cutaneous reactivity is transferred to the.normal subject at the! injection~ site. The absence, of' a positive response in nearby normal skin excludes nonspecific irritationi as a cause of the response and shows that the normal subject is not himself allergic to the antigen. Harkavy and W'itebsky (34), found andl selectively absorbed' tobacco reagins in patients showing multiple sensitivities. This, se- lective absorption documented the immunologic mechanism of then skin reaction., Passive transfer of the SSA was also reported by P'eshkin, and Landay(50~) and by Lirna and Rocha (41):. Lowelli (.4'3:) stated, "The individual possessing skin-sensitizing antibody to the tobacco extract may be regarded as unequ2vocally allergic to the extract...... Despite the inability of Sulzberger and Feit (87),' to: demonstrate tobacco reagins in their skin test positive patients; several investigators have found them (26, 50, 75). Harkavy (23) biopsied urtiicarial wheals after intradermal injec- tion of tobacco extract and foundl a local eosinophilia. He felt that this helped confirmithe allergic mechanism of the positive skin test. He also biopsied the site of' a delayedi skin reaction to tobacco and foundlan eczemat'ous type of response.. The delayed type hypersensitivity reactioni is manifested by in,- duration and erythema developing,within 2:4 to 48 hours after injec- tion of antigen. The absence of' response ini the first 6 to 8 hours after exposure to antigeni helps exclude an Arthus reaction, which is also a slowly evolviing allergic response. Serum antibodies are nott involved in the initiation of delayed type hypersensitivit'y; rather, the initial step is thought to involve interactioniof antigen and spec- ialized lymphocytes(1'0, 11)~. Contact dermatitis~ is thought, to be very nearly a pure type, dlelayed' hypersensitivity reaction (10, 11) ., The foregoing discussion has hig)ilighted the: studies concerning cutaneous sensitivity to tobacco extracts. Despite the complexities andl contradictions, numerous workers agree that tobacco extract 106

(leaf or smoke) is antigenic and' can sensitize (2, 7, 9, 18; 26; 43; 60; 52, 64,, 66, 76) . Silvette, et al. (64) concluded!, "It is, indeed', beyond question that allergy to tobacco extracts, presumably atopic in na- ture, is an established fact. ..." Lowell (43) observed that, in most instances, skin reactivity to an, extract of tobacco actually means the presence of'allergy in some degree to something in the extract. Arrneni and Cohen (2), Harkavy and Perlman (31)I, and Popescu, et al. (52)1 observed! that tobacco extract is weakly antigenic. Armen and' Cohen (2) were abl'e to sensitize rabbits to tobacco proteins only after absorbing the pro- tein to alurninum hydroxide, which served' as' an adjuvant. Even though a positive skin test to tobacco extract may be due to a specific allergic reactions the interpretation of such a positive test in a given patient or group of patients poses problems, since sen- sitivity to a battery of antigens has been demonstrated' in indiuid uals who are entirely free from allergic symptoms upon exposuree to the antigens. Rosen (54) statedl that this lack of correlation be- tween positive skin tests and clinical symptoms is great'er, for to- bacco thani for other antigens such as pollens,, dusts, and feathers. He and others have emphasized that the skin test has value only when correlated with clinical evidence. Analysis of'skin test studies in nonsmokers (64) shows that ap- proximately 15 percent of such "'healt'hy"' individuals give positive reactions to tobacco extracts. Some studies of smokers reporting a 30 percent or more prevalence of skin sensitivity to tobacco ex- tract (33;, 43) have considered patients withi multiple sensitivities, including that to tobacco. Atopic individuals have been noted, to have a greater prevalence of skin sensitivity to, tobacco than, non- atopics (64) ; hence, in some studies an excess of' atopic patients may account for al substantial part of' the elevated prevalence of tobacco skin sensitivity reported for smokers: Several workers have sought to use the skin test as a screening device for indicating, an unusual susceptibility to the adverse effects of tobacco. DeCrinis, et al. ('13)1, Font'ana (17), and, Redisch (53) have reported that patients with positiiae skin tests to tobacco ex- tracts were more likely to have an adverse vascular response to tobacco as indicated by a fall in peripheral skin temperature on smoking. More recent studies have shown that a decrease in skin temperature with smoking is al reproducible response to nicotine found in "normal" " individuals and does not appear to be confined to a specific group of smokers (1, 56, 70). ADDITIONAL IMMUNOLOGICAL EFFECTS. Additional evidence is available toisupport the view that tobacco indhces immunologic changes in, man and animals. Armen and G'1

Cohen (2); C'hu,, etal. (;7)~, Harkavy and P'erlknan (31)~,and Zuss-man (76) induced precipitin formation in animals sensitized to tobacco extract. Kreis, et al. (39) studiedlprecipitation reactions in, 657 hospitalized patients, many of whom were suffering from tu- berculosis or lung cancer. A precipitation reaction between the pa- tients''sera andlal commercial tobacco extract was found in 62.5 per= cent of the patients. Chu, et al. (7), using the same antigens as those ernployed to stimulate precipitin fmrmationi in rabbits, found serum antibodies in 40percent of a group of smokers which precipi- tatedl specificially with, the tobacco antigens. Only 7 percent of a group,of nonsmokers demonstrated, these ant'ibodies. Savel (59) studied! eight nonsmoking, allergic individuals who; developed immediate upper respiratory discomfortafter being; ex- posed to cigarette smoke. As measured by: the uptake of tritia,tedd thymidine, the lymphocytes of these individuals were stimulated by cigarette smoke;, while "normal" lymphocytes were depressed. The authorstated, t'hatthet correlat'ion, of this test with specific forms of clinical allergy: remains uncertain. Some investigators have observed abnormal laboratory test re- sults in smokers as compared to nonsmokers, which may indicate an allergic response in the former group. Schoen and Pizer (60)~ de- scribed a smoking woman, who demonstrated a striking blood eosino- philia while smoking cigarettes. U'pon cessation of smoking, the eosinophil count returned promptly to normal levels. Resumption of smoking was associated with a return of the eosinophilia. Heiskells et al. (36), found al significant increase in, C-reactive protein and an abnormal seroflocculant for ethyl cholledienate in smokers as com- pared to nonsmokers. Plasma; histaminase levels were reportedl by Kameswaran, et all (38): to:be elevated in smokers. Experimental animal sensitization to tobacco: was reported by Friedlander, et al. (19) in male rat's: Harkavy (29) confirmed these results in male rats and also obtained positive S'chultz-Dale reac- tions in the sensitized animals ; however, female rats failedl to dem- onstrate this sensitizat'iom. Harkavy (24) reported cardiac histo- logical abnormalities in three rabbits sensitizedl with denicotinizedl tobacco extracts. The abnormalities found ini the three rabbits, re- spectively, included: intimal proliferation, focal fragmentation of the, internal elastic membrane, and' loss of smooth muscle fibers in the media of a branch of a coronary artery; focall intimal prolifera- tion and fibrinoid alterations, in the media of a small coronary ves- sel ; and a: focus of rnyocardiall fibrosis and' necrosis. EFFECT ONI TH'K IMMUNE RESPONSE The effect of tobacco oni the immune response has received some attention. Early studies in rabbits suggested that tobacco smoke re- , U8

! f z e tarded the, production of agglutinins in rabbits immunized against typhoid (14). A variety of observations indicate that ingestion of antigenic materiall by the macrophage rnay be an essential step in the immune response (3). Btu,ni (5) found that cigarette smoke suppressed phagocytosis in rabbits. Green and Carolin (20)i performed in nitro studies in rabbit alveolar macrophages and observed that cigarette smoke inhibited the capacity of these cells to inactivate bacteriaL Harris; et al. (35), reported no differences in the phagocytic ability of macrophages taken from human, smokers and nonsmokers, but he also concluded that his data neither contradicted nor supported Green's work. Cohen and Cline (&'), while noting,that macrophages from smokers had normal phagocytic capacity, demonstrated sub- optimal macrophage function in an environment of low O',, tension, a state found' more frequently in smokers than nonsmokers. Max- well, et al. (45), using guinea pigs, found that smoke exerted no effect on phagocytosis;, nevertheless,, smoke seemed to: impair the phagocytes'' ability to inact'ivate bacteria. Nicotine has been shown by Meyer,, et al. (46) to exert ai depressant effect on sheep pulmo- nary alveolar macrophage respiration and ATPase activity. Re- cently, Yeager (74)i reported that water soluble constituents of cigarette smoke depress protein-synthesis in rabbit alveolar macro- phages in vitro,Lewis, et al. (40) found that cigarette smoking had a suppressive act'ion, on, secretory IgA production in normal subj ects but not in subjects with chronic respiratory disorders. Vos-Brat and Rumke (71)i recently reportedi that IgG serum concentratiions and, the :~e- sponse of lymphocytes to phytohemagglutinin w~eresignificantlylower in smokers thani nonsmokers. A number of' investigators have reported increased rates of res- piratory iillnesses among cigarette smokers (70). Finklea,, et a1L (16')' studied antibody response in 289 volunteers after the 1968' Hong Kong,inliuenza epidemic. They reportedla significant decrease among cigarette smokers in the persistence of hernagg)'utinatibni in- liibition antibody after natural infection or vaccination with A_., anta'igens.Theypostulated that thisantibody defiicit among cigarette smokers might be related to increased illness during influenza out- breaks: IRRITANT' AND~ PHARIVIACOLOGIC EFFECTS As Lowell (43) has emphasized, the pharmacolbgic., irritant, andd allergic effects of tobacco~ are difficult to distingu2sh. Acrolein and acetaldbhyde are potent irritants foundl in tobacco smoke, which, as demonstrated in animali studies, are capable of releasing chemical mediators such as histamine (58)!. The inhalation of tobacco smoke . io,

causes bronchial' constriction, mucus hypersecretion,, and ciliary stasis (57)n in man, all of'which can contribute to a clinical picture indistinguishable from an allergic reaction. Several authors (4.4, 61, 63) share Sherman's (62) view that "... tobacco smoke is an im- portant secondary factor in precipitating, allergic symptoms through its action as a nonspecific irritant." Speer (65)' recently compared the subjective responses of twa groups of nonsmokers to tobacco srnoke exposure., One group of 191 patients suffered' from documented allergies:, In one-sixth of these patients a positive skin test to tobacco extract was found; but only a few patients were seen~ with objective symptoms which could be traced to tobacco smoke. The other group of 250 patients had no historyof'allergy, and was studied!by q,u~estionnaire only. Eye irrita- tion, nasal symptoms, headache, and cough were common in both groups. Speer concluded that these effects of tobacco smoke were irritative rather than allergic in origin. The data presented ini this study demonstrate that tobacco smoke can contribute to the, dis- comfort of many individuals ; they do not rule out a possible con- tribution from allergic reactions. Harkavy (30)eited experimental data distinguishing allergiiec effects f'romm pharmacologic effects of smoking such, as increasedd heart rate and decreased skin temperature:, Additional studies are needed' to separate the pharmacologic, ir- rit'ant, and' allergic effect's of tobacco srnoke: CLIIrTICAL ALLERGY It is important to understand what role tobacco and tobacco smoke may play in clinical allergy because many individuals are exposed'. to them in varying concentrations throughout the year. A variety of'conditions have been ascribed to allergic rnanifesta- tions toward tobacco leaf or smoke including : asthma, rhiniti's, urticaria, angioneurotie edema (giant hives), contact dermat'iti's, migraine headache, gast''rointestinali sy~:xnptoms„ and various cardia vascular disturbances (64) ; however, some case reports are lacking in documentation (4, 49). A small group of patients having, cutane- ous sensitivity to tobacco and showing complete disappearance of symptoms when free from exposure to tobacco were reported by Rosen and Levy (55). Included in this group were cases of asthma and urticaria. Studies of atopic indivi'duals have revealed a, group of nonsmoking patients with cutaneous sensitivity to tobacco who develbped clinical syrnptoms upon exposure to tobacco smoke (56; 76)~. In none of these.studies (54, 59, 76), have detailed immunologic investigations, attempting to link clini'cal and immunologic events, been performed. Lowell (43) reviewed case reports of contact dermatitis to to- rM

bacco among tobacco workers and noted: that because of ".. . the smalll proportiom of exposed individuals who develop such lesions, and the: tendency for it to clear completely when contact with tobacco is avoide& and to return on reexposure, an allergic cause in, certainn instances wouId appear to be highly probable:"' Recently, case re- ports have appeared identifying tobacco smoke and tobacco smoke, residue as causes of contact derrnatitis (6, 12, 72) . Harkavy's (28) early reports of a greater number of reactors to: tobacco extract among patients with thromboangiitis obliterans. (TA% than among, controls drew attention to the cardiovascular system as a possible "susceptible"'organ for allergic reactions (15).. Harkavy continues to be a strong, proponent of the role of tobaccoo allergy in a wide range of cardiovascular abnormalities, including, coronary artery disease (21, 22, 25, 27, 31, 32). This view ono tobacco allergy as one of'the etiological factors in coronary heart disease. (CHD) has not received much attention. Silivette, et aI. (64) reviewed reports(28„ 33, 66, 68, 73)~ on t'heprevalence: of skini sensitivity in patients with TAO as compared to controls and cited possible reasons for a higher prevalence of' posi- tive skin, tests to tobacco in these patients. In general",, th~eevidencerelating, TAO, to, tobacco allergy is incon- clusive. t SUMMARY 1. Tobacco leaf,, tobacco pollen, and tobacco smoke are antigenicc ini man and animals. 2. (a) Skin sensitizing antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipit'at'ing antibodies specific for tobacco antigens have also been found ini both smokers and nonsmokers. (b) A delayed t'ype of hypersensitivity: to tobacco has been demonstratedl in man.. (c) Tobacco may exert an adverse effect on protective mecha- nisms of the imrn.une system in man and animals: 3. (a) Tobacco smoke can contribute to the discomfort of many iind'ividuals:, Itexerts, corn~plexpharmacol'ogic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) E'xposure t'o tobacco smoke may produce exacerbation of allergic symptoms in nonsmokers who are suffering from allergies of diverse causes. 4.Little is known about the pathogenesis of tobacco allergy and its possibie relationship to other smoking-related diseases. irr

ALLERGY REFERENCES' (1)~ ALLISON, R; D., ROTH, G. M. Central and peripheral vascular effects during, cigarette smokings Archives of Environmental Health 19'(2) :. 189-198, August 1969: (2) ARMEN, R. N., COHEN, S. The effect of' forced' inhalation of tobacco smoke on the elect'rocardiogram of' normal and tobacco-sensitized rab- bits. Diseases of the Chest 35(6) : 663-676, June 1959, (3) AUSTEN, K. F. Disorders due to hypersensitivity and alteredl immune response. IN: Wintrobe, M. M., Thorn, G: W., Adams, R. D.,, Bennett; I. L,„Jr., Braunwald„E., Isselbacher;,K. J!.,,Petzrsdbrf;,R. G: (Editors): Harrison?'s Principles of Internal Medicine. Sixth Edition. New York,McGraw-Hi1l Book Company, 1970. pl 342. (l`), BLUE, J:, A. Cigarette; asthma and tobacco allergy. Annals of Allergy 28 ( (3) 110-115 t lYla. r c h 1970. (S) BxUNi, A. Influenza delliavvelenamentoda fumo di tabacco sulla fago- citosi. (Effect, of tobacco smoke paisoning, on~ phagocytosis.) Speri mentale 85: 523-543, 1931. (6) CHANIAL, G., JOSEPH, J., CouIN„ L,, DuctAux, C. Les dermites chez les travailleurs du tabac (a propas de 9 observations). (Dermatitis in tobacco workers. Nine observations.) Bulletinide la Sbciete Franqaise de Dermatologie et de Syphiligraphie 77 (2) : 281-283, July 1970: (7) CHL, Y. M.,, PARLE'rr, R. C., WRIGHT, G. L.,, JR. A preliminary investi-, gation, of some immunologic aspects of tobacco use. American Review of' Respiratiory Disease 102(1) : 118-123, Jialy 1970. (8) COHEN, A. B., CLrNE, M. J. The human alveolar macrophage:~ Isolatibny cultivation in vitroj and studries of' morpholagic and functional char- acteristics. The Jaurnal' of Clinical Investigation 50(7) : 1390-1398, July 1971. (9) COLTOIU, A., MAITEESCU, D., LEBE, V. Consideratii priwind, sensibilizarea la tlatun: (~Cbnsideratians concerning sensitization tb tpbacco.) Viata Medicala 16 (1) :: 29-37, January 1969: (I1'0) COOMBS, R. R. A. The basic types of'allergic reactivity producing disease. Triangle 9 (2) : 43-46; 1969. (11) CoolvlBS,, R. R: A.,, GELL, P: G, H. Classification of allergic reactions re- sponsible for clinical hypersensitivity andl disease. Chapter 20. IN:: Gel14 P.G:H., Coombs, RI.R.A. (Editors). Clinical Aspects of Immu- nalogy: Second Edition. Philadelphia, F: A. Davis Company, 196&& pp. 575-596: (22))i CORMIA, F. E., DEGARA,; P. F. Vesiculobullbus dermatitis from tobacco smoke. Journal of the American Medical Association 193 (5) : 391-392', August 2, 1965. (1:7)' DECRINIS, K., REDLSCH, W., FONTANA, V., LEWIS, A.,, SULZBERGER; M. B., STEELEy J. M. Vascular responses to smoking tobacco compared with responses to skin testing of tobacco extracts. Annals of Internal. . Medicine 52 (5)', : 1'035-1041, May: 1960. ((14) DONZELLI, F. Influenza sulle agglutinine dell'avvelenamentlo~ da~ fumoo di, tabacco. (Effect of tobacco smoke poisoning on agglutinins.) Gior- nale di Batteriologia e Immunolbgja Tli: 1012-101$, 1933. (15) FERSTL, A. Die bedeutung der tabakrauchallergie bei erkrankungen des Gafasssystems. (~The importance of allergy tio tobacco in diseases of the vascular system:) Weiner Zeitschrift fur Innere IWtedizin und Ihre Grenzgebiete 43!: :455-458 , 1962. (i1s)~. FINKLEA, J. F., HASSELBLAD, V_RIGGAN, W. B., hlELsoN,,Rl. C~.,, HAM~- ntER„ D. I., I+TEwILL„ V. A. Cigarette smoking and, hemagg)utination 1' 112,

inhibition response to influenza after natural disease and immuniza- tion. American Review of Respiratory Disease,104 (3) : 368-376, Sep- t'ember 1971.. (17) FqNmANA, V'. J. Tobacco hypersensitivity. Annals of the New York. Academy of' Sciences 90(11)I: 138-141, September 27;, 1960. (18) FoNTANA, V.,J:, REnISCFI, W., NEMIR,, R., L., S1WIIITH, M. K., DECRINIS, K., SunzBERGER; M. B. Studies in tobacco hypersensitivity. III. Reac- tions to skin tests and peripheral vascular response& Journal of Allergy 30'(3) : 241-249, May-.Iiune 1959. (19), FRIEDLANDER, M., SILBERT, Si, LASKEY, N. Toe lesions following tabaccoo injections in rats. Proceedings of the Society for Experimental Biology andl Medicine 34:,156'-1157, 1936. (20) GREEN,, G. M:,, CAROLIN, D. The depressant effect of cigarette smoke on, the in vitro antibacterial activity of' alveolar macrophages. New England Journal of Medicine 276: 422-427, February 23„ 11967. (21') HARKAVY, J. Cardiac manifestations due to hypersensitivity. Annals of. Allergy 28(6) :~ 242-251, June 1970; (22) HARKAVY, J. Cardiovascular manifestatfions due to hypersensitivity: New York State Journal of Medicine 69(21)~:, 2757-2765~ November 1, 1969.. (23) HARKAVY,, J. Hypersensitiveness to tobacco and biopsy studies of skini reactions in vaseular disease. Journal of Allergy 9:475-488, 1938'.. (24) HARKAVY,, J. Tobacco allergy. Chapter 13. IN: Vascular Allergy: andl its Systemic Manifestations. Washington, Butterworths, 1963, pp. 101-11i6 i (25) HARKAVY, J. Tobacco allergy in cardiovasculam disease:~ A review. Annals of' Allergy 26:(8) : 447-4'59, August 11968. (126:) HARxnvY,, J!. Tobacco~ allergy in vascular diseases. Review of Allergy and Applied Immunology 11: 189-212, March 1957. (27') HARKAvy„ J. Tobacco sensitiveness in, angina pectoris and coronary artery disease: Proceedings'of the Society for Experimental Biology andl Medicine 30: 683-684, 1933'., (28) HARKAVY, JI. Tobacco sensitiveness. in tlhromboangiitis~ obliterans„ mi- gratiing, phlebitis and, coronary artery disease. Bulletin of the New York Academy of Medicine 9:~ 318-322, 1933. (29) HARKAVY, J. Tobaeeo sensitization in rats. Journal of Allergy, 9: 275- 277, 1938. (30) HARKAVY,, J'. Tobacco: skin reactions and their clinical significance. The Journal of Investigatiive Dermatology 2: 257-279, 1939.. (31) HARKAvY,, J., PERLMAN, E. Tobacco allergy in coronary artery disease. Annals of the New York Academy of' Sciences 90 (1) ~: 327-332; Sep- tember 27, 1960. (3'2) HARKAVY,, Jl, PERLMAN, E. Tobacco allergy in coronary artery disease. New York State Journal of Medicine 64(11) r, 1287-1296, June 1, 1964: (33) HARKAVx,, J., ROMANOFF,, A. Skin reactions to tobacco~ and other aller= gens in normal men and women smokers. Journal ofI Allergy 6: 62r 70, 1934'. (34), HARKAVY,, J., WiTEBSKr, E. Studies of' speeificity in multiple hyper- sensitiveness by quantitative titration and absorption of' reagins. Journal of Allergy 6: 437-447, 1935. (35) HARRIS, J. 0'.,, SweNSON, E. W.,, JoHNSON, JL E. III. Human alveolar macrophages: Compari'son of' phagocytic ability, glucose utilization, and ultrastructure in smokers and nonsmokers. The Jburnal of Clini- cal Investigation 49': 2086-2096„ 1970~: 11'3 4~ J W

(36) HEISKELL, C. L., MILLER, J. N., ALDRICH,,H. J., CARPENTER;, C, M. Smok- ing and serolbgic abnormalities. Journal of the American Medlcal. Association 151(,8) : 674-fi77„ August 25, 1962.(3'7) IsR2.zAKA, K. The identification and significance of Gamma E, Hospital Practice : 70-81, , September 1969. (98) KAMESWARAN, L., KANAKAIWIBAL,, K., VIJAYASEKARA'N, V. Studies onn plasma histaminase levels in normal and allergic individuals., Indian Journal of Physiology and PhaTmacolbgy 12(4): 159-165, October 1968. (39) KREIs, B, PELTIER, A., FOURNAUD, S., DUPI;N GIROD, S+ Reaction db precipitation entre certains serums humains et des extraits solubles dle tabac. (Precipitation reaetionI between certain human sera, andd soluble tobacco extracts.) Annales de Medecine Interne: 121(4) : 437- 440, April 1970. (40)~ LEwIS, D. M., LAPP, N. LER., BURRELL, R., Quantitation of' secretory i:mmunoglobulin A in chronic pulmonary disease. American Review of' Respiratory Disease 101(YI) : 5'5-61, January 1970. (1,1) LIMA, A. 0:,, RoCHA, G. Cutaneous reactions to tobacco:antigen in aller- gic and nonallergic childrem Annals af' Allergy 7(4) : 528'-531, July- August 1949. (42) LovNSBURY, J. B,,, OuGxTERSON,, A. W. Specificity of: tobacco antigen. Yale Journal of Biology andi Medicine 7(4) : 305-316, March 1935. (43) LOWELL, F. C. t?'.llergy: IN,: Wynder, E. (Editor)~. The Biologic Effects of l Tobacco. Boston, Little,, Brown,, and Company, 11955. pp. 1i51-170.. (44) 11IAURER, M. L,, SPAIN, W. C. The allergic response to tbbacco: Journal of! the American Geriatric Society 2: 278-283, 1954. (i1,5) MAXWELL, K. Vfd'.,, MARCUS; S., RENZETrI`, A. C!, Ja, Effect of tobacco smoke: on the phagocytic and cytopeptic activity af'guinea pig alveolar macrophages. American Review of Respiratory Disease 96'(1)1: 156, 1967: (4;6) MEYER, D„ H., CROSS, C. E., IBICaHI1aI, A. B:, MUSTAFA, M. G., Nicotine effects on alveolar macrophage respiration and adenosine triphos- phatase activity. Archives of Environmental Health, 22 (3) : 362-365, March 1971. (47) PAPA, C. Mi., SHELLEY, W~. B. Menthot hypersensitivity. Diagnostic basophil response in a, patient with chronic urticaria,, flushing, and hCadaches.. Journal of the Ameriean, Medical Association 189'(7) : 546-548; August 17, 1964. (48) PATTERSON, R. Skin-sensitizing antibodies. Advances in Internal Medi- cine 16 : 351-371, 1970.. (49) Pavr-IK, L, CERMAKOVA, Z. Casna kozni rea.kee na tabakovy: extrakt uu chorob dychadel. (Early skin reaction against tobacco extract in res- piratory system disease. ), Rozhledy v Tuberkulose av Nernocech Plienich124 (9')', : 629-635, 1964. (50)~ PESHKIN, M. M., LANDAY, L. H. CutaneousI reactions totobacco antigenn in allergic and nonallergic children with the:direct andI indirect (local passive transfer) methode of testing. Journal ofI Allergy10: 241-245, 1939. (51) PIPES,, D. M. Allergy to tobacco smoke. Annals of Allergy 28 (3)~ : 277- 282', July-August 1945. ( 52) POPESCU, I. G., PAUNs R~_M'oLNER, C., OLARU, C.,GHEORGxQU, T., IOTA, Cl G:, Contributii la studfnl aiergiei, la tatun. (Contributions to the study of'tobacco allergy:)i Revue Roumaine de Medecine Interna 1(5) : 427=436, 1964. 11i4

~al Eal ion an ier de IEs ,nd 17- pry lew ~er- Dcts'. ~70. inal' ltco qlar ~56, I I Eine kios- 365; >stic ~and' 7) kiedi- I kt u r'es+ ~cech tig¢n local -245, ,277- IOTA, ~ the (5)1: (53')' REDISCH, W: Tobacco allergy and vascular responses. IN: James, G., Rosenthal, T. (Editors),. Tobacco and Health. Springfield, C: C. Thomas,, 1962'. pp. 352--359: (54) RosErrs F. L. Studies in tobacco allergy. Journal of the Medical Society of New Jersey 51(3) : 109-114, March 1954. (55) 1 ROSEN, F. L., LEVY,,A. Btonchial asthma, due to allergy to tobacco:smoke in an, infant. A case report. Journal ofl the American Medical Asso- ciation 1144 (8) : ~ 620-621, October 21, 1950: (56) ROTH, G. M., ScHICx, R!. M. The effects of smoking, on the peripheral circulation. Diseases of the Chest 37 (2) : 203-210, February 1960. (57), ROYAL CULL'EGE OF PHYSICIANS. Smoking, and Health Now. Londbn,. Pitman Medical and Scientific Publishing Company, Ltd., 1971. 148 pp. (58) SAINDELLE,, A., RUFF, F., FLAVIAN, N.,, PARROT, J.-L~ Liberation d'his- tamine par des aldehydes a courte chaine: (Liberation of histamine by: short-chain aldehydes.) Cbmptes Rendus Hebdomadaires des Seances : de l''Academie des! Sciences Paris. Series D 266 ( 2)i : 139-1!41, January 8, 1968. (59) SAVEL, H. Clinical hypersensitivity to cigarette smoke.Archives of En- vironmental Health 2Y (2) : 146-148, August 1970. (60)1 SCHOEN, I., Piz'ERy M. Eosinophilia apparently related to cigarette smok- ing: New England Journal of'Medicine 270(25)1:, 1344-1347, June 18, 1964. (6Z ) SaEI:DON,, J. M., LovELL, R'. G., MATHEWS, K. P. (Editbrs). House dust and miscellaneous allergens. IN': A Manual of Clinical Allergy. Sec- ond Edition. Philadelphia, W. B, Saunders Co:, 1967. pp. 437-455.. (62) SHERMAN, W. B, (~Editor). Agents causing atopic diseases. IN: Hyper- sensitivity. Mechanisms and Management. Philadelphia, W. B:, Saun- d'ers Company, 1968; p. 130. (63) SHURE, Nl, HARRIS, M. C: Distribution of commonplace inhalant aller- gens: Chapter 4, IN: Harris, M., C, Shure, N:(Editors). Sensitivity. Chest Di'seases. Philadelphia, F. A. Davis Company, 1964. pp. 62-97:. (64) SIwETTE, H., LARSON, P. S., H!AAG; H. B. Immunological aspects of tobacco and smoking. Ameriean~ Journal of the Medical Sciences 234(5) :, 561-589, November 1957., (65) SPEER, F. Tobacco and the nonsmoker. A study of subjective symptoms. Archives of Environmental Health 16(3) : 443-446, March 1968. (66) SULZBER.GER; M'. B. Studies in tobacco hypersensitivity., I.. A comparison betlween reactions to nicotine and to denicotinized tobacco extract. Journal of Immunology 24(1) : 85-91, L933'. (67). SULZBEItGEx, M., B',,, FEIT, E. Studies in tobacco hypersensiti'vity. II. Thromboangiitis obliterans with positive urtScarial skin reactions and negative reagin findings. Journal of' Immunology 24'(5) : 425-432, 1933. (68)' TRASOFF, A., BLUMSTEIN, G., MARKS, M. The immunologic aspect of' tobacco in thromboangiitis obliterans and coronary artery disease. Journal of Allergy 7: 250-253, 1936. (69) U.S. PUBLIC HEAi.Tx SExvICE., Smoking and Health. Report of'the A& visory Committee to the Surgeon General of the Public Health Service. Washingtony U.S. Department of Health, Education, and Welfare, Public Health Service Publication No, 1103, 1964. 387 pp. (70): U.S! PUBLI'C' HEtuLTH SERVZCn. The Health Consequences, of' Sinoking:, A Report of the Surgeon General: 1971. Washington, U.S. Depart- ment ofI Health, Education, and Welfare, DHEW Publicationi No. (HSM) 71-7513, 1971. 458 pp. 115

(71) Vos•BsAT; C., RuMKE;, P: Inxmunoglobulim concentrations, PH!A reac- tions of lymphocytes in vitro, and certain antibody titers of healthy smokers. Jaarboek Karkeronderzoek Kankerbestruding 19: 49-53, 1969. (72) VfIEasY; P.E'., WOOD, B.T: Allergic contact dermatitis from tobacco smoke residues, Journal of the American Medical' Association 208(10): 1905-1906, June 9, 1969. (78) WESTCOTT; F. H., WRIGHT, I. S. Tobacco allergy and' thromboangiitiss obliterans. Journal of Allergy 9: 555-564, 1938. (74) YEAGER, H., Js, Alveolar cells: Depressant effect of cigarette,smoke on protein synthesis. IN: Proceedings of the Society for Experimental Biology and Medicine 131: 247-250, December 26, 1968., ('75) ZussMAxts B; K Atopic symptoms caused by tobacco hypersensitivity. Southern Medical Journal 61(11)1r 1175-1179, November 1968. (76) ZusSM'Arr; B; M. Tobacco sensitivity in the allergic patient. Annals of' Allergy 28(8) : 371-377; August 19701 116

CHAPTE 8 Publ ic Exposure to Air Pollut'io!n From Tobacco Smoke 4•

Contents The Extent to which the Components of Cigarette Smoke Contaminate the Atmosphere and are Absorbedl by the The Effects of Low Levels of Carbon Monoxide on Human Health .................................................. Allergic and Irritative Reactions to Cigarette Smoke Among Nonsmokers ....................................... The Known Harmful Effects of the Passive InMalation of ry Cigarette Smoke in Animals ........................... References .............................................. LIST OF TABLES Table! 1.-Percent of COHb during and following exposure to 50 p.p:m. of C0 .................................... Tab1e 2'.-Effects of carbon monoxide ................... . Page. 1211 125 128 129 130 131 124 127 . 1,19

:. ~

PUBLIC EXPOSURE TO AIR' POLLUTION FROlVI. TOBACCO SMOKE. The purpose of this chapter is to summarize the present state of evidonce concerning the effects of exposure to an atmosphere con- taining either tobacco smoke or its constituents. Since the identifi- cation of cigarette smoking as a, serious health hazamd to1 the smoker was based on clinical and epidemioIogiical' observations that non- smokers have much Iower mortality and morbidity rates from a number of' conditions, it is obvious that cigarette smoking is nor- rna11y! a greater hazard to the smoker than is the typical levei of ex- posure to air pollutant's produced by the smoking,of cigarettes which many nonsmokers experience. This would be consistent with~ the voluminous data which show a dose-response relationship between the Ievel of exposure to smoke and the magnitude of its effect. The researchi so far reported on the nature and effects of exposure to smoke-pollutants in the atmosphere has not been as extensi've and well~controlled' as that done on, the health effects of smoking on, the smoker himself. Knowledge on this subject can be separated into four major areas of concern : T. The extent to which the components of cigarette smoke con- taminate the atmosphere and are absorbed by the nonsmoker., 2. Tlie effects of low levels of carbon monoxide on human health~. 3. AlIergic,, adverse, and irritative reactions to: cigarette smoke among nonsmokers. 4. The known harmful effects of the passive inhalation of ciga- rette smoke in animals. THE EXTENT TO' WHICH THE COlbIPO'NENTS OF CIGARETTE SMOKE CONTAMINATE THE ATMO'SPHERE. AND ARE ABSORBED BY THEI NONSMOiKER. Theoreticall modolg of this contamination have been constructed~. Owens and Rossano (44) have noted that most popular cigarettes release into t'he' atmosphere.approximat'ely 70 rngf of dry particulate matter (about 60 mg, in the sidestream and slightly over 20 mg. in the mainstream, about one-half of the latter being absorbed by the smoker and one-half expelled' into the ambient air) and 28 rng. car-

boni monoxide per cigarette. This material adds to the cleaning problem of the air of any encliosedl space and contributes to residual odbrs. In a recent study of particulate matter filtration, in domestic premises (35), the authors observed that the smoking of one cigar completely overcame the effect of an electrostatic filtration device for one hour. Atmospheric pollutants caused by smoking are derived from two major sources: mainstream and sidestreaxn smoke. 1Vlainstream, smoke emerges from! the tobacco product through the mouthpiece during puffing, whereas sidestream smoke comes from the burning cone and from the mouthpiece during puff intermissions (60). The tobacco: srnoke released iinto the atmosphere consists of all the side- st'ream smoke as well as that part of the mainstream smoke whichh has been either held in the smoker's mouth or taken into his lungs and then expelled. The actual amount of material, to whichi individ- uals are exposed ini the presence of smokers depends upon the amount of smoke produced,, the depth of inhalat'ion, on the part of the smoker, the ventilation availabl'e for the rernoval or dispersion of the smoke, andithe proximity of the individual to the smoker. The length of time of exposure to those pollutants is ext'remely; impor- tant ini determining, how much is absorbed into the, body. The pat- tern of smoking influences the amount produced by altering the content of the exhaled' smoke. As shown by Dalhamn, et al. (10; 11),, mouth absorption removes approximately 60 percent of the water-sol'uble volatile components (e:g,, acetaldehyde), 20 percent of the nonwater-soluble volatile components (e:g., isoprene), 16 percent of the particulate matter, andi only three percent of the car- bon monoxidle., Thus, the smoker who does not inhale "filters"' a portipni of the smoke components in his mouthi before expelling them into the ambient air. On the other hand~ the lungs retain from 86' to 99 percent of the volatile and particulate substances and approxi- mately 54 percent of the carbon monoxide inhaled. Hence, the inhal- ing smoker "filters" the mainstream smoke rather effectively before expelling it into the ambientair. A factor which has apparently: not been, investigated is the difference in the srnokers" "filtration"' of' mainstream smoke when the smoke is exhaled through the nose instead of the mouth. Thus, the nonsmoker breathes smoke-containing air composed of sidestream smoke and mainstream smoke exhaled by smokers. The inhaling smoker receives nearly the full, amount of mainstream smoke as well as a portibn of sidestream srnoke and smoke exhaled by himself and other smokers. The smoker who does not inhale re-, ceives those compounds which are absorbed from the mainstreasn smoke in his mouth, as well as absorbing the sidestream smoke and the smoke exhaled by himself and other smokers contained', in the air he breathes. 122

Since pipe and cigar smokers inhale less commonly than db ciga- rette smokers, their contribution to the substances in the air breathed in exposure to smoke pollutants consists of a composite of sidestream smoke and relatively unfiltered mainstream smoke which has been held in the mouth and then expelled. The actual effluents in the mainstream andl sidestream cigarette smoke have been considered by Pascasio; et a1. (45) and Scassellati Sforzolini and colleagues (50, 51). T'hese authors stated that "tar" and nicotine,levels.in sidestream smoke may be significantly higher than those of mainstream smoke and may be~ harmful to the non- smoker. Actual volume measurements were not reported, however.. Actual measurements of'the contamination due to cigarette smok- ing,have been carried out by a number of research groups. A recent, welt-controlled study by Harke (24) involvedl the smoking of' 42 cigarettes in, 16 to 18 minutes using German blendi cilgarettes of 8!5, mm. length, 18 mm. filter, and smoked to a 25 mmL butt length, in a room, with ai volume of 57 cubic meters (approximately the equivalent of a room with a 10!-foot ceiling and dimeusions of 12~by 14 feet).'phe author observed that in the absence of ventilation the atmosphere contained up, to 50, p.p.m. carbon monoxide and .57 mg./mL3 nicotine. With substantial ventilation, these levels fell sig- nificantly ('to approximately 10 p,p.m. carbon monoxide and .10'. mg./m~' nicotine)i. He also found that cigar smoke (9 cigars of Clear Sumatra tobacco smoked in 30 to 35' minutes) produced similar amounts of' contamination while pipe smoke (3' grams of Navy type medium cut tobacco smoked as; eight pipefuls in 35 to 40 minutes): produced much less. Other authors have made similar measure- ments., Galuskinova ('2Q) found that 3,4-benzpyrene levels in, a smoky restaurant were from 2.82 to 14.4 mg./100 rn.' as compared to outside atmospheric levels of 0.28 to: 0.46 mg./100 m.',, althoughi burning of food particles may have contributed to the presence of. 3',4-benzpyrene in this setting. Kotin and Falk (33) have show:n thatsidestream cigarette smoke condensate may contain more than three times as much benzo ( a) pyrene as mainstream smoke.Si-ch (55) observed that the smoking, of 10, cigarettes to, a 5 mm. butt lengthi in an enclosed car of 2.09 mL 3 volume produced carbon monox- iide leveisup to 90 p.p.mL Lawther and!Cornmans (34) 1, working with a ventilated chaxnber, found levels of up to 20 p,p.m. of carbon mo- noxide after seven cigarettes were smoked in one hour; however, peaks of up to 90 p,p:m. were recorded at the seat next to the smoker.. Cbburny et al. (9)', recorded levels of'20 p.p.m. of carbon monoxide in a small conference room aft'er, 10, cigarettes were "burned." Harmsen and Effenberger (25) reported up to 80, p:p;m. of carbonn monoxide:in an enclosed 98m.3 iroom (approximately the equivalent of a room withi a 10-foot ceiling and dimensions of 18 by 20 feet)' in which 62' cigarettes had been smoked in two hours. 123

TABLE' 1.-Percent o f COHb during a,nd' f ollowing exposure to 50 p~~.P:M. of C0. Time during exposure Mean Range Number of subjects Preexposure 0.7 0.4L-1.5 11 30 minutes 1.3 1.3 3 1 hour 2.1 1.9-2.7 11 3'hours 3.8 3:6-4.2 10 6 hours 5.1 4.9-5.5 5' 8 hours 5.9 5'.4-6.2I 5 12 hours 7.01 6.5-7.9! 3 15 17i hours 7.6 7.2'-8.2' 3 22 hours 8.5 8.1-8.7 3 24 hours 7.9 7.6'-82 3' Time without exposure after 1 hour of exposure 30 minutes 1.8 1.8 3 1 hour 1.7 1.6-1.8 3, 2'hours 1.5 1.4-1.5 3 5 hours 1.11 1.0-1.1 2 Time without exposure after 3 hours of exposure 30 minutes 3,7 3.4-3.9 3 1 hour 3.3'. 2.7-3.8' 3 2 hours 2'.7 2.3-3.0 3 Time witlhout exposure after 8 hours of exposure 30 minutes M 511-5'.9 3 1 hour 5,1 4.8-5.4 3 1 si'4 hours 4.0 - - 11 hours 1.5 1.4-1.7 3 Time without exposure after 24 hours of exposure 30 minutes 7.5 7.2'-7.8 3 1 hour 6.7 6.4-7.1 3'. 2 hours 5.8 5.6-6,2 3'. Soa[tcs% Stewart„ etl all.. (56~) i. Another set of contaminants probably present in a tobacco smoke- polluted atmosphere are the oxides of' nitrogen. These; specificially NO' and NO2,, have : been shown to be present in tobacco smoke a1- thoughthe type most 11ke1y to be present in the atmosphere is NO~2. No measurements have been reported of the amount of N02 in smoke-filled rooms: The importance of obtaining,and evaluating'.this information is stressed by; the resul'ts' of' Freeman and Haydon and! 124

their colleagues (17, 18, 19, 27, 28) and of Blair, et al. (5) who ob- served bronchial and' pulmonary parenchymal lesions in~ rodents continuously exposed to low levels of'NOiz. Other experimenters have measuredcarboxyhemoglobin (COHb)' levels in nonsmokers exposedl to cigarette smoke pollutants. Srch (55), observed t'hat'the COHb~levelintwononsmokers, rose from 2' to 5 percent (that of smokers from 5to 10' percent) when seated in the cigarette-smoke contaminated car mentionedl above (exposure to 90 p.p.m.). Harke (2'.4)i reported that wheni seven, nonsmokers were exposed for approximately 90 minutes to a"smoked'°' room containing 30 p.p.m. of'CO there was a rise in COHb from a mean of 0.9 percent to 2.01 percent. In 111 smokers subjected to the same conditions, C.OHb rose from a mean of' 3.3' percent to 7.5 percent. With improved ventilation of the experimental room, the COHb levell decreased' significant'ly.. The CO exposures and COHb levels reported above closely approx- imate the results obtained following, experimental chamber expo- sure of' humans to various levels of CO. The uptake of CO by the person depends on, arnong, other parameters : CO concentrration, previous COHb level, the level of activity, andl the person's state of health. Equilibrium between CO' concentratilon in the lung and in the bloo& requires over 12' hours exposure. However; as may be noted in table 1, reproduced from Stewart, et al. (~56) and derived from measures of COHb in young sedentary males who were not smoking, over half of the equilibriumi COHb level is reachedl within three to four hours of the onset of exposure. The equ2librium, value associatedlwith 100' p:p.m, is approximately 1!4 to 15 percent COHb. Exposure to 100 p.p.m. in, the nonsmoker can lead to 3.0 percent of COHb within 60 minutes and 6.0 percent in two hours (16). Of equall significance is that COHb has a half-life of at least three to four hours in the body. As shown in table 1, the COHb level fell only to 2.7 percent in the two, hours following cessation of' exposure to 50 p.p.m. from the end exposure level of 3! 7 percent. Thi's lengthy half- life extends the period of effect of exposure to CO and provides for a buildup of COHb concentration from fresh exposures. ke- ally ali- ,02.. in ;his and THE EFFECTS OF LOW LEVELS OF CARBON MONOXIDE ON HUMAN HEALTH The data on the effect of low levels of carbon monoxide on humann psychological and physiological function have been summarized inn two recent publications (8, 58). There is presently much discussion as to the physiologic and psychophysiologic effects of exposure tollevels of CO approximating, 50 to 1001 p.p.m. Beard andl Grandstaff (4), observed that exposure to 50 p.p:mL of CO1 for from 27 to 90 minutes altered auditory dis- iss

crimination, visual acuity, and the ability to distinguish relative brightness. McFarland ('.4Q) observed that COHb levels of 4 to 5 percent caused visuail threshold impairment. Ray and Rockwell (48), reporting on a study of the driving, ability of three suba ects under varying, CO exposure, observed that the presence of 10 per- cent COHb was associated with increased response time for tai1~ light discrimination and increased variance in distance estimation. Schulte (152) observed that increased errors in, cognitive and choice dliscriminat'ion tests were manifest at levels of COHb as low as 3 percent. Chevalier, et al. (7), have also observed that levels of' 4 percent COHb in nonsmokers are associated with an, increase in oxygen debt formationi with exercise similar to that seen in smokers. On the other hand, other investigators utilizing complex psychomotor tasks in men and monkeys have observed no decrement in functi~onupon exposures to CO1 at, 50 to 2'50~ p.p.m. (2;,8,, 23, 41, 56). Animals exposed to low levels of CO ( 50 to 100 p.p.m.) continu- ously for weeks have shown varying degrees of cardiac and cerebrall damage similar to that produced by hypoxia (21,,k7; 57). Fina11y, the possible effects of exposure to 50-100 p.p.m, CO on, patients with coronary heart disease ( CHD ) were investigated by Ayres, et al. (1) who observed a decrease in arterial and mixed venous oxygen tensions with COHb saturations of 5 percent. Certain patients with CHiD' developedi altered laetate and pyruvate metabo- lism, with COHbleveUs of 5 to 10 percent suggesting myocardial hypoxia. The evidence concerning the effect of low levels of carbon monox- ide has recently been reviewed and eval!uatedl by the National Air Quality Criteria Committee of the National Air Po1lution Control' Administration (58). The following is taken from the published conclusions of the Advisory Committee (also see table 2) : "Experimental exposure of' nonsmokers to 5'8' mg/m3 (50 ppm) for 90 minutes has been associated with impairment in time-interval discrimination.... This exposure will prod'uce: an increase of' about 2 percent COiHb in the blood. This same increase in blood CO'Hb wi11' occur with continuous exposure to 1'2 to 17 7 mg/m3 (10 to 15 ppm) 1 for 8 or, more hours,... "Ekperimental exposure to CO concentrations sufficient to produce bloodl COI+Ib levels of about 5, percent (a level pro- ducible by exposure to, about 35 mg/m' for 8 or more hours)' has provided ini some instances evidence of impaired perform- ance on certain other psychomotor tests, and an impairment in visual discrimination.. . . "Experimental exposure to CO' concentrations sufficient to, produce blood COHb levels above 5, percent (a level producible. 126

Tasa.,E 2'.-Eff ects'af carbon monoxide. Environmental conditions Effect. Comment 58' mg./m~3' (50 p,p.m.) Impairment of time- Blood COHb levels not for 90 minutes interval discrimination available, butl antici- in inon-smokers. pated to be about 2.5 percent. Similar blood COHb levels expected from exposure to10to17mg./m.3 (10 to 15 p.p.m.) for 8'or more hours. 115 mg./m.3' (100 p:p:m.) intermit- tently through a facial mask. High concentrations of C 0' were admin- istered for 30 to 120 seconds, andl then 10 minutes was allowed for washout of' alveolar CO before blood COHb wass measured. Impairment in perform- ance of some psycho- motor tests at a COHb level of 5 percent. Exposure sufficient to pro- duce blood COHb levels above 5 percent has been shown to place a physio- logic stress on patients with heart disease. Similar results may have been observed at' lower C00 Hb levels, but'blood measurements were not accurate., Data, rely on COHb levels produced rapidly after short exposure to highh levels of CO'.; this is not', necessarily: comparabiee to exposure over a longer time period or under equilibrium conditions. Soaecn:. Adapted feom.U.SS Public.Healthi Serviee., AicQualitxCriteria~forCArbon.ffionoxide: Washington, D:C., U.S. Department.of Health,.Education, and. Welfare (58)',. by exposure to 35 rng/rn3 or' more for 8' or more hours) hass provided evidence of physiologic stress in patients with heart disease. . . ." 50 ~n ce ne'. ,ree to ro- s) rn- ,in to )le The lovels of carbon monoxide found to be present in "smoked"' rooms (20 to 80 p.p.m.) are similar to the levels (30 to 50 p:p.ln.) which the Advisory: Committee has conchadled are associated with adverse health effects :', ``An exposure of 8' or more hours to a carbon monoxide con~- centration of 12'to 17 mg/m3 (1!0 to 15, pprn) will prodhce a blood carboxyhemoglobin level of' 2:0 to 2.5: percent in non, smokers.. This level of blood carboxyhemoglobin has been asso- ci~ated with adverse health effects! as man~ifest'edby ilmpai'red time interval discrimination. Evidence also indicates that an exposure of 8 or more hours to a C0'. concentrationi of 35 mg/m31 (30 ppm) willl produce blood carboxyhemoglobin levels of about 5 percent in nonsmokers: Adverse health effects as mam ifested by impa2redperformance on certain other psychomotor 1127 c G

test's have been associated with this blood carboxyhemoglo- bin level~, andl above this level there is evidcnce of physiologic stress in patients with heart disease."' These llevels of C0 are also similar to that set, as the time- weightedl occupationall Threshold Limit Value of 50 p.p.m. for a 40-hour week (five 8-hour days) ) which has been in effect in the United States for the past several years (Z3). A further reduction in this limit to 25 p.p.m. is, now under consideration. These levels of' CO' exceed those recently set by the Environmentai Protection Agency as the national primary and secondary ambient air quality standards for C0! (14Y. These standards are: (a) 10 milligrams per cubic meter, (9' p.p,m.) -maximum 8- hours concentration not to be exceeded more than, once per year. (.b) 40 milligrams per cubic meter (3'5 p:p.m.)-maxirnum 1-hour concentration not to be exceeded! more than once per year.. ALLERGIC AND! IRRITATIVE REACTIONS TO CIGARETTE SMOKE AMONG NONSMOKERS (A more detail'edl discussion of this subject is presented in the. Allergy chapter of this report,. ). Several investigators have reported' on the discomfort and symp- toms experienced by both allergic andi nonallergic individuals upon exposure to tobacco smoke. Johansson and Ronge (31,, 32) in 1965 and', 1966 have observed that the acute irrit'at'ion experienced by nonsmokers in the presence of tobacco smoke is maximal in warm, dry air and that nonsmokers experience more nasal irritation than ocular irritation as compared with smokers exposed to similar am.ounts, of'smoke in the atmosphere. Speer (54) studied the reac- tions of 441 nonsmokers divided into two groups, one composed of individuals with a history of allergic reactions and the other of in- dividuals without such a history. The a111ergic group underwent skin t'est'ing for the presence of sensitivity to tobacco extract while, the "nonallergic" group was determined solely by questionnaire con- cerning subjective allergic responses. Approximately 70 percent of both groups experienced eye irritation while other symptoms dif- fered in their frequency from group to group (nasal symptoms: allergic 67 percent, "nonallergic" 29 percent; headache: allergic 46 percent, "nonallergic" 31 percent;, cough : allergic 46 percent, "non- allergic"'' 25', percent; and wheezing,: allergic 22 percent, "'nonaller- gic'''' 4 percent). Thus, a significant proportion of nonsmoking, in- dividuals report discomfort and respiratory: symptoms, on exposure to, tobacco smoke. -Z

. t I n1 ie Other authors have attempted to separate out those patients who! may have specific allergies to smoke., Zussman ( 61) found that in a random series of 200~ atopic patients 16 percent were clinically sen- sitive to tobacco smoke, and that a majority of these were aided by desensiitization therapy. In an earlier study, Pipes (46) observed' that 1i3' percent of 229 patients with respiratory allergy showed posi- tive skin tests to tobacco smoke. Savel (49) has recently reported on eight nonsmokers observedlto be clinically hypersensitive to tobacco smoke. After in vitro incubation of their lymphocytes with cigarette smoke, increased incorporation of tritiat'edthyrrridine was recorded; similar exposure of the lymphocytes of those not sensitive resulted, in depression of tritiated thymidine uptake.. Luquette, et al. (39)' have recently report'ed~ on the immediate ef- fects of exposure to cigarette smoke in: school-age children. They observed that heart rate and blood pressure rose with such ex- posure, although questions remain about the adequacy of their con- trols and the manner in which the experimental situation may have excited the subjects. Finally, Cameron, et al. (6) observed' that acute respiratory illnesses were more frequent among, children from homes& in~ which the parents smoked than among children of non- smoking; parents. The meaning of these results is uncertain since smoking by the children was not consideredi and the level of ex- posure to cigarette smoke in their homes was not measured. Shy,et , al. (53) in a study of second grade Chattanooga school children failed to demonstrate a relationship between parental smoking habits and the respiratory illness rates of their children. THE KNOWN HARMFUL EFFECTS OF THE PASSIVE. INHALATION OF CIGARETTE SMOKE IN ANTIVIAL& A number of investigators have studied the effects of the passive inhalation of'high concentrations of' cigarette smoke on the pulmo- nary parenchyma and tracheobronchial'tree of'animals. The resultss of these investigations are listed in detail in the recent report to Congress, "The Health Consequences, of' Smoking," (59) in table 9 of the Rronchopulmonary chapter,, and table 16 of the Cancer chapter. The pathologic changes observed in the respiratory tract of the ani~mal& included parenchymal d'isrupt'ion, bronchitis,, tracheobron- chial epithelial dysplasia and': rnetaplasia, and pulmonary adenoma- tous tumor formation. Leuchtenberger, et al. (36) exposed 151 mice to the smoke of from 25 to 1,526' cigarettes over a period of 1 to 23' months and observed that 20' percent of the animals develope& severe bronchitis& with atypism. Working with 30 control rabbits exposed to up to 20 cigarettes per day: for two to~five.years, Holland, et al. (30) observed increased focal and generalized' hyperplasia of 129'

the bronchial' epithelium and generalized emphysema in the ex- posed rabbits. Hernandez, et al. (29) observed significantly more pulmonary parenchymal disruption in, adult greyhound dogs ex- posed to cigarette smoke 10, times per week for approximately one year than in nonexposed' controll animals. Lorenz, et al. (38) observed no increase in, respiratory tract tu~- mor formation above that seen in controls in, 97 Strain A mice ex- posed to cigarette smoke for up to,693 hours, Essenberg (15), how- ever, exposed Strain A mice to cigarette smoke for 12 hours a day for up to, one year and observed significantly more papillary adono- carcinomas in the exposed than in the cont'rol group. An increased percentage of' hybrid mice were found by Muhlbock (42) to have alveolar carcinomas among, the experimental group exposed to smoke for two hours a day for up to 684 days when compared with a nonexposed group. Similarly, Guerin (22')' observed that 5.1 per- cent of rats exposedl to cigarette smoke for 45 minutes a day for two to six months showed pulmonary tumors compared to 2.4 per- cent of the controll mice., Leuchtenberger, et al. (37), working with 40& female CF, mice„ observed only a slight increase in the presence of pulmonary adeno. matous tumors among those exposed to cigarette smoke compared wit'h those in the control group The authors commented that the presence of' tumors showed an age relationship: independent of smoking, exposure:, Otto (43) found that 11 percent of a group of albino mice exposed to 12, cigarettes a day for up to 24 months showed pulmonary adenomas as compared with five percent of the controll non-exposed group. Dontenwill and Wiebecke: (12)d found. that increasing the exposure of golden hamsters to up to four ciga- rettes a day for up to: two years was associated with an increasing percentage:of animals showing, desquamative metaplasia and bron- chial papillary metaplasia. Harris and Negroni (26): exposed 200 C57BfL mice to~ cigarette smoke for 20, minutes a day: every other day for life and found eight adenocarcinomas as compared~ to, none in the control' group.Because the damage observed in these experimentswas, seen after prolonged exposure to high concentrations of cigarette smoke, and because the comparability of animali exposure to smoke with that of human exposure in smoke-filled rooms is unknown, it is presentllyintpossible to be certain from animal experiment'ationi about the ex- tentof the damage that may occur during, long-term, intermittent exposure to lower concentrations. SUMMARY 1. An atmosphere contaminated with tobacco smoke can con~- tribut'e t'o the discomfort of many individuals. 130'

BX- )re ex- jne tu- ex- iw- lay po- ged ave I to rith Ier- for >er- ice, !no- ~red' the E of p of iths the und ;iga- Sihg ron- ;200 ther aone kfter andl at of' mtly e ex- ttent con- 2'. The level of carbon monoxide attained in experiment's, using rooms filled! witli tobacco smoke has' been shown to equal, and att times to exceed, the legal' limits for maximum air pollution per- mitted for ambient air quality in several localities and can also ex- ceed the occupational Threshold Limit Value for a normal work period presentlyih effect for the United States as a whole. The pres- ence of such levels indicates that the effect of exposure to carbon monoxide may on occasion, depending uponi the length of exposure,, be sufficient to be harmful to the health of'an exposed person. Thiss would be particularly: significant for people who are already suffer- ing from chronic bronchopulmonary disease and coronary heart d'isease., 3. Other components of tobacco smoke, such as particulate mat- ter and the oxides of' nitrogen, have been show,n, in various concen- trations to adversely affect animal pul4nonary and cardiac struct'ure, andl function. The extent of the contributions of'these substances to illness ini humans exposed to the concentrations present ini an atmo- sphere contaminatedi with tobacco smoke is not presently known. PUBLIC EXP'OSURE' TO AIR POLLUTION FROM TOB:ACCO' SMOKE REFERENCES (1) AYRES, & M., GIANNELLI, S., JR., MUELLER, H. Myocardial and systemic responses to carboxyhemoglobin: Annals of' the N'ew York Academy of'Scienees 174(1): 268-293; October 5, 1970.. (2) BACK, K. C. Effects of' carbon rnonoxide on the performance of monkeys.. IIN r, Proceedings of the 5th Annual Conference on Atmospheric Con- tamination in Confined Spaces, September 16-18, 1969. Aerospace Medical! Research Laboratory,, Aerospace Medical Division, December 1969., pp. 41-51. (3) BACK, K. C., DolvtIxGUEZ, A. M. Psychopharmacology of carbon mon- oxide under ambient and altit'ude conditions. IN:~ Proceedings of'the 4th Annual Conference on Atmospheric Contamination in Confined Spaces,, September 10-12, 1968. Aerospace Medical Research Labora- tories,, Aerospace Medical Division~, December 1968: pp. 81-92. (4) Be:Altn; R:, R.,, C'.RANDSCAFF;, N. Carbon monoxide exposure and cerebral function. Annals of the New York, Academy of' Sciences 174 (1) : 385- 395, O'ctlober 5, 1970: (5) BLAIR, W. HHENRY, 1WI., C., EHRLICH, R. Chronic toxicity of' nitrogen, dioxide., IiL Effect on histopathology, of' lung tissue.. Archives of' En- vironmental Health 18 (2') : 186-192, February 1969. (6) CA,MERON, P., KOSTIN, J~ S., ZAKS, J. M.,,WOLFE, J. H., TIGHE, G., OSEL- ETT;, B,, STOCKER;, R., wiNTON; J. The health of' smokers' an& non- smokers' children. Journal of Allergy 43(6) : 336-341, June 1969: (7) CHEVALIER, R. B,, KRUMxoLZ, R.,A., Ross,,J. C. Reaction of nonsmokers to carbon monoxide inhalatiorr., Cardiopulmonary responses at rest and during, exercise.Journal of the Ameriean Medical Association 198(10) : 1061-1064, December 5, 1966.. (8)' COSURN,,R, F., (Editor):.,Bioiogicai Effects of Carbon Monoxide. Annals of the New York Academy of Sciences 174 (Article 1), Oetober 5, 1970. 430 pp. 111

(9) CbBURN, R. F:, FORSTER, R. E., KANE, P., B. Considerations of'the physi- ological variables that determine the blood carboxyhemoglobin con- centration in man. Journal of Cli:nicai Investigation 44 (11) : 1899- 1910, November 1965: (10) DALHAMN, T., EDFORS, 1VT.-L,, RYLANDER, R. Mouth absorption of'vari- ous compounds ini cigarette smoke. Archives of Environmental Health: 16(6) :,831-835; June 1968. (11') DALHAIMN,, T., EDFORS,, M.-L,, RYLANDER, R. Retention, of cigarette smoke components in human lungs! ArchivesofEnviranmental Health 17 ( 5), : 746-748, November 19&8l, (12) DONTENWILL, W., WIEBECKEy B. Tracheal and pulmonary alt;erations following the inhalation of cigarette smoke by the goldeni hamster., IN:~ Severiy L. (;Editor)., Lung: Tumors in Animals. Perugia, Italy, Division of' Cancer Research, University of Perugia, June 1966., pp., 519-526'. (13) DuBoiS, A. B, Establishmentl of "threshold" CO exposure levels. Annals of the New York Academy of Sciences 174 (1) 1r 425-428, October 5, 1970. (14) ENYIRONMENTstL PEIOTEC'rLONi AGENCY: National' primary andi secondary ambient air quality standards. Federal Register 36 ($4) : 8186-8201,. April 30; 1971., (15) EssENBERrry J. M. Cigarette smoke and the incidence of' primary neo- plasm of' the lung in the albino mouse: Science 1116: 561-562, No- vember 21, 1952. (16) FORBES, W'. H. Carboni monoxide uptake via the lungs. Annals of'the New York Academy of'Sci:ences 1Z4!(1) : 72-75, October 5, 1970., (17) FREEM'A N, G., CRANE, S': C., STEPHENS; R. J., FURIQSI, N. J. Pathogenesis of the nitrogen dioxide-induced lesion in the ratl lungc, A review and presentation of' new observations. American Review of Respiratory Diseases 98'(i3!):: 429-443, September 1968'. (18) FREEMAN, G., H'AYDOrr; G. B'. Emphysema, after low-level exposure to NO.,. Archives of'Environmental Health,8(1) : 125'-128, January 1964. (13) FREEMAN, G., S'rEPHENS,, R. Ji., CRANE, S., C., FURSosi, N. J. Lesion, of the lung in rats continuously exposed to two parts per million of nitrogeni dioxide. Archives of Environmental Health 17,(2) : 181-192,, August 1968! (20) GALUSKINOVA, V. 3,4LBenzpyrene determination in the smoky atmos- phere of social meeting rooms and restaurants. A contribution to the problem of the noxiousness ofl so-called passive smoking. Neoplasma 11( 5') : 465 -468; 1964. (21) GOLDSMITH, JL R.,, LANDAw, S! A. Carbon monoxide and human health:. Science 162'(3860) : 1352=1359„ December 20, 1968., (22): GUERiN„M. Tumeurs pulmonaires et cancer buccal chez le rat soumis a I'inhalation de fumee de cigarette.(Pulinonary tumors and oral can- cers in rats subj iected to inhalatlion of cigarette smoke: ) i Bulletin de 1'Association Francaise pour 1PEtude du Cancer:46(2) : 295-309,,1959. (23') HiANxs, T. G. Human performance of'a a psyehomotor test as a, function of exposure to carbon monoxide.. Annals of the New York Academy of Sciences 174(1) , : 421-424, October 5, 1970. (24) HIaRxE, H.-P. Zum Problem des "Passir-Rauchens:" (The problem of "passive smoking,") Miinchener Medizinische Wochenschrift:L12'(51,) :. 2328'-2334, 1970: (25)' HARMSEN, H., EFFENBERGER, E. Tabakrauch in V'erkchrsmitteln„ Wohn- und Arbeitsraumen. (Tobacco smoke in transportation vehicles„living 132

>, f f 1 f and working rooms.) Archiv fur Hygiene und Bakteriologie 147(5) : 383-400,1957. (26): HARRIS, R: J. C., NEGRONis G. Production of'lung carcinomas in C57BL mice exposed to a cigarette smoke and air mixture. British Medical Journal 41(5580'): 637-641, December16~, 1I967!. (27) HAYDONS G;, B., DAYIDSON!„ J. T., LILLINGTON, G. A.,, WASSERMAN, K. Nit'!rogen dioxide-induced emphysema in rabbits: American Review of Respiratory Diseases 95 (5) : 797-805, Miay 11967. (28) HAYDON, G. B, FxEEMAN„G.,,F1;rRiosi, N. J. Covertl pathogenesis of N02 induced emphysema in the rat. Archives of' Environmental Health 11(6) : 776-783, December 1965., (29) HERNANDEZ, J. A.,, ANDERSON, A. E,,, JR., HOLMES, W'. L.,, FORAKER, A. G. Pulmonary parenchymal defects in dogs following, prolongedd cigarette smoke exposure., American Review of Respirat'ory Diseases 93'(il) : 78-83, January 1966. (30) HOLLAND, R. H., KoZLOwsKI!„ E. J., BaoKER; L. The effect of cigarette smoke on the respiratory system of the rabbit. A final report. Cancer 16 (5')i :' 612-615, May 1963. (3'1) JoHA'NSSON„C. R., RbNGE,, H. Klimatinverkan pa lnkt och irritationsef- fekt, av tobaksrok. Pteliminart meddelande. (Climatic influence on smell andl irritation effects from tobacco smoke. Preliminary report.) Nordisk Hygienisk Tidskrift 47: 33-39, 1966, (32) JOHANSSON, C1 R,, RONGE, H. Akuta irritationseffekter av tobaksrok I rumsluft. (Acute irritation effects of' tobacco smoke in the room atmosphere.) Nordisk Hygienisk Tidskrift 46: 45-50~ 1965.. (33)! KOTIN, P., FALK, H. L. The role and action, of environmental agents in the pathogenesis of lung cancer. IiIL Cigarette smoke., Cancer 13(2) : 250-262, March-April 1960: (34) LAWTHER, P. J;, COMM'INs„ B. T. Cigarette smoking and exposure to carboni monoxide. Annals of the New York Academy of Sciences 174(1):~P35-147, October 5, 1970: (35) LEFCOEy N. MI.,IrrCULET; I. I. Particulates, in domestic premises. I. Ambient levels and central air filtration. Archives of Environmental Health 22 (2) : 230-238„ February 1971. (36): LEUCHTENBERGER,, C., LEUCHTENBERGER; R., ZEBRUN, W.,, SHIAFFER, P. A, correlated histological~ cytological,, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette srnake.. II.. Varying responses of major bronchi to cigarette smoke, absence of bronchogenic carcinoma after prolbnged exposure,, and disappear- ance of bronchialllesions after cessation of exposure. Cancer 13(4):: 7211-732; July-Augustl 1960. (37) LEUCHTENBERGER,, R., LEUCHTENBERGER, C,, ZEBRUN, W., SHAFFER:, P. A correlated, histological, cytological, andd cytochemicall study of the tracheobronchial tree andl lungs of mice exposed to cigarette smoke. III. Unaltered incidence of' grossly visible adenomatous lung tumors in female CF, mice after prolonged exposure to cigarette smoke.. Cancer 13'(5)1: 956-958, September-October 1960: (38) LORENZ,, E., STEWART, H. L_ DANIEL, J. H., NELSON, C. V. The effects of breathing tobacco smoke on Strain A mice. Cancer Research 3(2) :. 123„ 194'3: (39) LUQuETTE, A., J., LANDISs,, C. W., MERKi; D. J., Some immediate eff'ects of a smoking environment om children of elementary sehool, age. Journal, of School Health 40 ('10') : 533-536, December 197!0: 1331 . i bA

(40) McFnIZLA,ND, R:, A. The effeets of exposure tb small quantities of carbon monoxide on vision. Annals of the New York Academy of' Sciences 174 (1) : 301-312, October 5, 1970. (41) MI'K,iPLKA,, P.,, 0'DONNELL, R:, HEINIG,, P., THEODORE, J. The effect of carbon monoxide on human performance. Annals of the New York Academy of Sciences 174(1) 1: 409-420; October 5, 1970. (42) MuxLBOCK, 0. Carcinogene VWerking, van Sigarettenrook bij Muizen. (Carcinogenic aetioni of' cigarette smoke in mice.) Nederlands Tijd sehrift voor Geneeskunde 99(31) : 2276-2278, July 30; 1955: (;/,:S') OTTO, H. Experimentelle Untersuchungen ani Mausen mit passiver Zigarettenrauchbeatlmung., (Experimental investigations on micee through passive inhalation of cigarette smoke.): Frankfurter Zeit- schrift fiir Pat'hologie 73!: 10-23;, 1963. (44) OwENS;, D. F., RoseANp, A. T. Design, procedures to controll cigarettee smoke and other air pollutants. Paper presented at ASH!RAEI Semi- annual Meeting; Chicago, January 27-30;, 1969. 110: pp. (45) PASCN.SIO, F.,,SCASSELLA'TI', SFOR.ZOLINI, G., SAVINQ, A., CONTI, R. Catrame e nicotina nella porzione aspiratla e nella porzione ambientale del fumo di vari tipi' di sigarette. (Tar and, nicotine content both in inhaled smoke and in smoke dispersedlin room-air by various cigarette brands.): Annali della, Sanita Pubblica 27'(5) : 971-978, September-October 1966. (!,6) PTPES„ D. M.A1lergy to tobacco smoke. Annals of Allergy 28(3) : 277- 282, July-August 1945. (47) PREZIO81, T. J., LINDENBERG,, R, LEVY, D., CHRISTENSON, M. An experi- mental investigation in animals of'~ the funetionali and morphologic effects of'single and repeat'edl exposures to high andilow concentrations of' carbon monoxide: Annals ofl the New York Academy of Sciences 174'(1) : 369-384, October 5„ 197Q. (48) RiAY,, A. M., ROCKWELL, T. H. An exploratory study of automobile driv, ing performance under the influence of' low levels of carboxyhema globin. Annals of the New York Academy of Sciences 174(1) : 396- 408, October 5; 1970: (49) S'AVEL, H., Clinical hypersensitivity to cigarette smoke. Arcfiives of En- vironmental Health 21(2) :~ 146-1i4'8; August 1970 (50) SCASSELLATI SFORZOLINI, G.,, SALDI, G. UlteriOri ricerche Sugli, idro- carburi policiclici del fumo di sigaretta. Conf'rontb tra il fumo aspirata e quello raccolto nell aria ambiente. (Further research on the poly- cyclic hydrocarbons of cigarette smoke. Comparison of' smoke inhaled'i and that taken from the ambient atmosphere.) Bollett'ino de11a Societa Italiana di Biolbgia, Sperimentale 37 :~ 769-771, 1961. (i51) SCASSELLATI SEOItZOLINI, G., SAVINO, A. Valutazione di un indice rapido- di contaminazione ambientale da furno di sigaretta, in relazione alla composizione della fase gassosa del fumo. (Evaluation of a rapid in- dex of environmental pollution by cigarette smoke in relation t'o the composition of' the gas phase of, the smoke. ) Rivista Italiana D'Igiene 28'(1-2) : 43-55, January-April 1968. (i52) SCHULTE, J., H. Effects of mild carbon monoxide intoxication. Archives of Environmental Health 7(5): 524-530, November, 1963. (',53)SHY, C. M~,, CREASON, J., P., PEARLMAN,M.E;,McCcAIN; K. E.,, BENSON, F. B'.,, YOUNG, ML Mi. The Chattanooga schooLchilldren study: Effects of' community exposure to nitrogen dioxide. IIL Incidence of'' acute respiratory illness: Jburnal of the Air Pbllution Controli Associationi 20 ( 9))1: 582-588, September 1970. 134

(54) SPEER„ F. Tobacco andl the nonsmoker. A study of subjective symptoms. Archives of Environmental Hiealth 16(3) : 443-4'46;, March 1968. (55) 5RCH,,M'. Uber die Bedeutung des Kohlenoxyds beim Zigarettenrauchenn im Personenkraft-wageninneren. (The: significance of' carbon mon- oxide in eigarette smoke in passenger car interiors.) Deutsche Zeit- sehrift fur die Gesamte Gerichtliche Medizin 60 (3) : 80-89, 1967. (56), STEWART, R. D.,, PETERSONS J. E.,, BARETTA, E. D., BACHAND, R. T.,, Hosxo, M. J., HERRivtANN,, A. A. Experimental' human exposure t'a~ carbon monoxide. Archives of Ehvi'ronmentai Health 21(2) :: 154-164„ August 1970: (57) STUPFEL, M.,, BOULEY, G. Physiological and' biochemicali effects on rats and mice exposed to small concentrations of'carbon monoxide for long periods. Annals of' the New York Academy of' Sciences 174(1) : 342'- 368; October 5, 1970. ('S8)) U.S! PUSLtC HEAi.T~H ShRViCE., Air Quality Criteria for Carbon Mon- oxide. ~'Vashington, U.S. Depart'ment,of Health„Education, and WelL fare, Public Health Service, National Air Pollution Control Admin- istration Publication No. AP-62, March 1970! (59) U.S., PUBLIC HEALTH SERVicE: The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington„U:S. Department of Health, Education,,andi Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (60) WYNDER, E. L.,, HoFFMANN, D. Tbbacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press; 1967. 730 pp. (61) ZUSSmAN,, B. M. Tobacco sensitlivity in the allergic patient. Annals of Allergy 28 (8): 371-377, August 1970. k p a e e 6 B e n 135'.

CHAPTER 9 Harrmfal Constituents of Cigarette Sm,oice I

Contents, The Dose Relationship~ . Page 141 References ........................................... 146 LIST OF TABLES Table 1.-Compounds in, cigarette smoke judged most likely to contribute to the health hazards, of smoking ........... 143! Tablle 2.-Cbrnpounds in cigarette smoke judged as probable contributors to the health hazards of srnoking; ........... 144 Table 3.-Cbrrmpounds in cigarette smoke judked as suspectedd contributors to the health hazard's of'smoking . . . . . . . . . . 145

HARMFUL, COI*1STITUENTS' OF CIGARETTE S1VlOKE*' Cigarette smoke contains a large number and a wirle variety of compounds which may result in complex and multiple pathophysio- logical effects on various tissues andi organi systems. Although the constituents of cigarette smoke are usually divided for eonvenience; into the two categories of particulate and gas phases, ** many of them, exist in a distribution equilibrium,, that is,, they are present partially in the gas phase and partially in the particulate phase:Thi& reviewconcerns itselfwithjudgxnents concerning the harmful constituents of cigarette smoke whether these are found primarily in the gas phase or in the particulate phase: Constituents of' cigarette smoke may enter the body by a variety of routes, Theoretically, the route of entry and subsequent absorp- tion could affect the degree to: which various organs are subjected to specific cigarette smoke constituents: Some constituents, par- ticularly the water solhble components of the gas phase, may be absorbedi by the nasal and oropharyngeal mucous membranes, or may be dissolved in the salival and swall,owed~ thus allowing, for pos- sible gastric or intestinal absorption. Other constituents are ab- sorbed along the tracheobronchial'tree, and the distance which they reach before being, absorbed! or deposited depends, on such factors as, the depth of inhalation and the particle size: The absorption of gases, in the tracheobronchial tree appears to, be in part dependent on the adsorption of gases to particulate matt'er: Another factor affecting; the route: and degree of absorption is the adequacy: of pul'monary' clearance'by which constituents deposited ord'nssolvediin: the mucous sheath, are delivered to the pharynx and then usually swallowed. Of the hundreds of compounds identifiedlin cigarette smoke, some occur ini the smoke in concentrations which may be considered suf- ficient to present hazards to health. Other compounds appear in * This reportat;tempts to summarize.the.areas of..generallconsensus reached' in..a.special one- dayy conference of expertss inthisfield which met indune.. 1970i.. This iss notl to imply that therewas~unanimousagreemenYon all.statements contained herein. A.list of: participantss in.the meet- ing: appears: im the: Acknowledgments. *' Itshouldbet notied, thatt there.e ia, at present, no available instrumentation ~ permittingg the separation and individual colleetiom of the partieulate and gas phases whiah, duplicates the precisephysicoohemical conditionsprevailingins cigarettee smoke as~~ it iss iinhaled.. AA widely ac-cepted arbitrary distinetionbetween the two, phasess is as foll6wss If 500 percent or more of' a given constituent is retainedl on a Cambridge filter (CM-113 ) during standardized machine: smok- ing'of a cigarette,.then the compound is, considered to helongto thee particulate phase; if'an,theother hand' more than 50: percent~ of the compound passea throughthe: Cambridge filter: under these:conditions, then theconstitoent is~consideredto:belong;to:thegas:phase.. 141

borderline, concentrations. Still others, although potentially: harm- ful, are' probably not present in sufficient concentrations to con- tribute to the hazard;, andl some may be hazardous only when they interact with other subst'ances in the smoke. Substances and classes of substances ini cigarette smoke' which have been judged to contribute to the hazard of cigarette smoking, have, been classified into three priority groups. Those compounds which are judged most likely to contribute to the health hazards of smoking are listed'i in table 1. Additional subst'ances which probably contribute to, the, health, hazards of smoking are listed in table 2. Those compounds which are suspected contributors to the, health hazards of smoking in the concentrations in which they are present in tobacco smoke are listed in table 3. Many other constituents of tobacco smoke are considered toi be toxic und'er some conditions but probably do not present a, health hazard in the concentrations in which they are generally found in cigarette smoke; these are not listed'. This listing is not presented as final,, and may be subject to modification as more informat'ionbecomes available.* In 11966, the Public Health Service preparedl a technical report oni "tar"' andlnicot'ine. (60).Tobacco "tar" is the.name given to the ag- gregate of particulate matter in cigarette smoke after subt'racti'ng nicotine and moisture. In that report it was stated : "'It is clear that the overall risk associated with cigarette smoking increases as the average number of cigarettes con- sumed per day increases. In the studies which have reported other measures of exposure such as pack-years, degree of in- halation, and' maximurn level of cigarette consurnption, the same type of relationship: holds.''' Individuals may differ in their inherent susceptibility to diseases ini which cigarette smoking plays a role and differ in their exposure to other factors which may increase the likelihood of these!diseases: Within these groups of varying risk, the degree of exposure to ciga- rette smoke appears to be the most critical factor for the develbp- ment of'smoking related disease. Therefore,, the general statement that the lower the dosage the iower the risk is the most useful guide available. It was also stated that : "'It is possible for a cigarette to be altered in such a way that its `tar' and nico'tine'cont'ent is reduced but certain other harmful effects, for example the effect of the gaseous phase, may be increased. Although this is a theoreticall possibility, 'Subsequent tothe aonferencean~ which thisreportwasbased, severalstndiea were published reporting the presence of: N nitrosamines in cigarette smoke. Since these substances are accepted ascaroinagensin experimentali animals, theyrepresentl anotherportianof: the~ "tar" which probably contribu,,es to the total health hazard (18, 24). 14'2,

t e S e ~- i- itt le .y. e ~ there is no evidence that this has occurred to any serious degree." The consensus is that there is inadequate evidence to supportaa change in that view at the present time. In addition, it was con:cluded,that "the preponderance of scientificc evidence strongly suggests that the lower the `tar" and nicotine con- tent of cigarette smoke;: the less harmful would be the effect."' Sev- erall studie& reported since: t'hat:timteh~aveadded! strong, support t~oth!is positiion.. The present review is an attempt to identify those constituents of the "tar" as well as those constituents considered part of the gas phase which are most likely to contribute to the health hazards from: cigarette smoking.: TABLE 1i.-Com:pou:n:ds in cigarette smoke judged'mo:;t lik:ely: ta con- . tribute to the health, hazards of smoking. PrBmaryphase Concentration.inclassific.ationcigarette smoke G-gas Chmpound' micrograms/cigarette P=particulate: References Carbon Monoxide 5,240-21,400 G (1, Y0„23,!26,,29, 34, 35, 37,,42; 46, 49, 61,63) Nicotine 200-2,400 P (9) i'"'Dar"' 3,000-33,000: P' (9) 1"Tar:" is defined as:the: total particulatemattercollectedibya: Cambridge filter (CM-11.3); after subtracting moisture and nicotinee and includes the: class of' compounds knownn as polycyclic aromaticc hydracarbons. (PAH). PAH: aree generally accepted.d as beingrespans:ibleg for a sub-stantial portion of the carcinogenic activity, of thetotal. "tar." Although "tar" from different cigarettes variess in its carcinogenicc potential, as measured by the bioassayme,thodsin current use, itremainsthet most practical single. "indicator^of' total carcinogenic: potential. Speciall mention shauldi..be.made ofBeta1`Iaphthy.laminewhichis, aknownhuman: urinarybladdercar-cinogen~farwhich there.isnoknown safe level,of.exposure andiwhichhas.been.reportedpresentin.tobacc!o amokein verylowconcentrations: (16, 28, 3'0.). (0.022: µgm./cigarette), It is recognized' that the:substances in cigarette.srnoke may: inter- act so that the combined pathological effects of several' substances& may be quite different from the sum of their effects produced ini isolation. An example of this type of interaction might be the car- cinogenic eff!ects of tobacco "tar" as a: result of the combined action of cancer initiating, cancer promoting, and, cancer accelerating agents in producing, the total effect. Such interactions theoretically could take place among substances within the gas phase, or sub- stances within the particulate phase;: or between constituents of the gas phase and constituents of'the particulate phase. In the absence of data which identify the interactions of cigarette smoke compo- nents;: judgments concerning the act'ion, or identification of harmful substances in cigarette smoke have; of necessity,, been rnade pri- 143

TABLE 2,-Compounds in cigarette smoke judged as probable con- triiiutors' to the health hazards o f s-moking: Compound Primaryphase. Concenttatfion in classification cigarette smoke. G-gas microgramslciBaretteP-particulat'e References. Acralein 45-140 G' (12;,20,,21,27„36; 43,45) . C'resol (all isomers) 68-97' P (20;,4'0). Hydrocyanic Acid 100-400 G (26,, 38, 43, 45; 4'6;, 49,53) Nitric Oxide 0-600 G (1, 3, 15, 40, 42„44',. 57)' Nitrogen Dioxide 0-10 G (1, 40, 44, 57). Phenol 9-202I P' (7„ 19;, 20, 32, 50; 52)) marily on the basis:of the action of the individual substances. Never- theless, experimental evaluation of modified cigarette smoke should'i be designed to take into account the possibility of such interaction. Untill there is a better understanding of the relative: importance of the interaction of'the constituent's' of cigarette smoke in the de- velopment of the diseases associated with cigarette smoking; it widll be difTicult to assess the significance of the reduction or elimination of one or several of the constituents named in this report. H'owever, it is reasonable to take the position that unless there is positive' in formation to the contrary, cigarettes in which overall "tar"' andl nicotine levels have:been reduced present to the smoker lower con- centrations of the harmful substances in the particulate phase. If, at the same time; significant reductions are made in those gas phasee constituentls which also contribute to the hazards of' smmking, the. resulting product should be less hazardous to health.* The consensus is that a progressive and simultaneous reduetionn of all substances considered likely to be involved in; the health haz- ards of' smoking' should' be encouraged as the most promising' step: available at the present time towards the'development of a less haz- ardous cig'arette:. Primary emphasis shouldl be given to~ the reduc- tioni of the three substances or classes of substances named in the first table, and as a second priority to, the reduction of those! sub- stances or classes of substances ini the second table before reducing •'An alternative.point.of'view heldbysomeisthatsmokingbehavior.is.aresponseto.theneed to reach aa certain nicotine level and that loweringtheamount'g ofnicotinef availablee from a cigarette may result in an increase in the number af~ cigarettes smoked, the depth of inhalttion, or thee number ofl puffss in order too maintain an accustomed level. Such ann increase in amokingg might result in an,increased inhal§tion of other hazardous substances in the smoke, thereby potentiallynegatingthey effectl of! reducingg the amount available in each~ cigarette.. I t 144

TABLE 3.-Compounds in cigarette smoke judged' as suspected con tributors to the health hazards of' smoking. Primary phaseCtancentratian.inclAssification. Compound cigarette smoke micrograms/cigarette G-gass P-particulateReferences Acetaldehyde 180-1,440 G (4, 21,27, 36, 43, 45, 48', 49, 53, 59) Acetone 88=650 G (112, 21, 27,,36, 43; 45, 48, 49„ 53) Acetonitrile 14ID-200 , G (12, 43). Acrylonitrile 10-15 G (12, 43) Ammonia. 60-330 G (2, 22, 40„41, 43,. 64) Benzene 12-100 G (11, 12, 25, 43, 45„ 49, 53): 2,3-Butadione 43-200 G (43;, 46, 49, 53) Butylamine 3' P (31, 40; 41) t CarbonDioxide, 23,100-78,300 G (1, 10, 15, 23„ 26; 29, 34; 35, 42; 46, 49, 63) Crotononitrile 4 G (43) Dimethylamine 10-11 P' (31,40,41) D DT 0-0:77 P ('1'7, 39, 54), Endrin 0:06 P (14) Ethylamine 1I0-11 G (22, 31, 40, 41) Fbrmaldehyde 20~41 G, (4, 36,43,4'8, 53), Filrfural 45-110 P (4, 13, 36) Hydrogen Sulphide 12-35' G (11% 43„51'„58) Hydroquinone 83 P (6„7Y Methacrolein 9-11i G (12,43) . MiethyI Alcohol 90-300. G (12, 21'„43, 46, 49), M th l i 20-22 G 31 40 41 (22 y am ne e ! , ) , „ Nickel compounds 0=0.58 P (5, 8, 47, 55„ 56) Pyridine 25-218 P (40; 62) 1CQ:, is; includedlbeeause of.the:hazard: it.mayrepresent to:those withCO_, retention, such as those with advanced COPD.. those named in the third table:, In, addition to the epidemiolog,ical and pathologicald'ata gained from human st'ud'ies,, it isirnportant to develop better bibassaysystems to evaluate cigarettes modified by these general guidelines. 145 . W

It should again be emphasized that, in, addition to the variation in chernicall properties of the cigarette being smoked,, procedures within the control of the individual smoker such as how many ciga- rettes he smokes, how far down he smokes the cigarette,, and how frequently andl deeply he inhales are critical factors in determining how' lnuch, of'the harmful substances which can be produced''i by the burning cigarette is given the opportunity to iiljure him. R'EFERENCES ON hIAR11"IFUL CONSTITUENTS (1) BoKHOVENS C:, NTESSEN,, H. F. Amounts of! oxides of nitrogen and carbon monoxide in cigarette smoke, with and without inhalation. Nature 192(4801) : 458-459, November 4, 19611. (2) BRADFORD, J., A., HARLOW, E. S., HARLAN,, W'. R'., HANMERy H.,R. Nature of' cigarette smoke. Voiatile bases and' acids. Industriall and Engi- neering Chemistry 29:(1) :, 45-50, January 1937. (:3) BROADnvs; G. M. YORK, J. E,, JR:, MOSELEY, J. M. Factors affecting the levels of nitrate nitrogen in cured tobacco loaves. Tobacco Science 9: 149-157, 1965: (4) BuYSKE, D: A., OWEN, L. H'.,,VrdILDER, P.,,HOBBS, M. E: Chromatography of the 2,4-dinitrophenylhydrazones of some aldehydes and ketones in tobacco smoke. Analytical Chemistry 28 (0) : 910-91i3,, May 1956.. (5) COGBILL, E. C.,, H'oBBS, M. E'. Transfer of metallic constituents of' ciga- rettes to the mainrstream smoke. Tobacco 144!: 24-29, May: 10, 1957. (6) CoMM1NS, B. T.,,LINDSEY; A. JL Some phenolic constlituents of cigarette smoke. Britishi Journal of Cancer 10 (3)! :, 504-506,, September 1956: (17) CoMMINS, B. T.,,L1NDSEY„ A. J. The determination of phenols by chror matogxaphy and spectrophotometry of' their metihyli ethers: IV.. The determination of phenols in cigarette smoke. Analytica Chimica Acta 15 (16) : 557-558, December 1956. (8) DAY, J. M., Bn'rEMAN,, IL:, C:, COGBILL, E. C. Determination of trace amounts of nickel in tobacco by: neutron activation, and analysis. (abrtract) Paper presented at the 145tih, American Cancer Society. Meeting, New York, N.Y'.,,1963. (19)i FEDERAL TRADE COMMISSION. Tar and nicotine content of cigar.ettles.. Washington, U.S. Department of Health, Educationti, and Welfare,, DHEW Publication No. (,HSM) 72-7510, Augustl 1971. (10) FISxEL,, J. B., HASKINS,, J. F. Composition of' cigarette smoke„ the gaseous phase. Industrial and Engineering, Chemistry 41(7): 1374- 1376, 1949c (11) GROB, K. Gas chromatography of cigarette smoke: Part' III: Separation of the overlap region of gas andl particulate phase, by capillary, col~ umns. Journal of Gas Chromatography 3(2') :~ 52-56„ February, 1965. (12) GROB, K. Zur Gaschromatographie des Cigarettenrauehes. 2' Teil. Ver- feinerte Trennung mit Hilfe von Kapillarkolonnen. (Gas chromatog- raphy of' cigarette smoke: P'art, 2. Improved separatlion with the aid' of capillary columns.) Beitrage zur Tabakforschung 1(9) : 315-323, December 1962. (13) GROB,, K. Zur Gewinnung, und Behandltng; frischer Gasphase aus Ciga- rettenrauch. (Preparatlion and treatlment of'fresh gas phase of'ciga- rette smoke.) Beitrkge zur Tabakforschung 3'(14)ie 243'-250, October 1965. 146

1 in res 9a- OW ing the -bon ture ture ngi- : the ;e 9: tphy ;s in :iga- 7:, ^ette , 6. ,hro- The Acta ,race liysis. ciety: ettes. If are, i, the 1374- -ation y col- 1965. Ver- :atog- ,e aid ;-323, Ciga- ciga- tober (14) GtTHRIE;, F. E, BOwERY, T. G: Pesticide residues on tobacco. Residue Review 19: 31-56, 1967.. (,15)1 HAAGEN-SMIT; A. J., BRUNELLF.T,, M. F., HARA„J. Nitrogen oXide contentl of smokes from different types of tobacco. A.M.A. Archives of Indus- trial Health 20!(5) : 399--4'00, November 1959. (16) HOFFMANN, D., MnsuDA, Y'.,, WYNDER, E. L. Alpha-naphthyTamine and beta naphthydamine in cigarette smoke. Nature 221'(5177): 254-256,. January 18, 1969. (i17')! HOFFMANN, D., RATHIfAM'P,, G., WYNDER, E. L. Chemical studies on tobacco smoke. IX. Quantitative: analysis of chlorinated hydrocarbon, insecticides: Beitrage zur Tabakforschung, 5'(3)1: 140-148,, December 1969! (i18) HOFFMArrN, D., VAIS, J. Analysis of'volatile N-nitrosamines in unaged mainstream smoke of cigarettes:. Paper presented at the 25th Tobacco Chemists' Research Conference: Louisville, Ky., October 6-8, 1'971. (19): HaeFMANN, D:, WYNDER, E. L. Die Filtration von Phenolen aus Ciga- rettenrauch. (The filtration of phenols from cigarette smoke.) Beit- rage zur Tabakforschung, 2(2) : 51~-66, June 1963~ (20)~ HOFFMANN, D., WYNDER, E., L: Die quantitative Bestimmung von Phenolen im TabakrauchL (The quantitative determination of'phenols in tobacco smoke.) Beitrage zur Tabakforschung, 1i(3) :~ 101-106, August 1961. (21) IRRY;, R. M.,, JR., HiARLOw, E. S. Cigarette smoke. Ii. Determinatiion of certaini vapor constituents. Tobacco 148'(;16) : 2-6, April 17,, 1959: (22) IzAwA, M., KoaASI1I; ~~'. Fractiionation of' cigarette smoke components and some low boiling, points-nitrogenous compounds (I)~.. Bulletin of' the Agricultural and Chemical Society: of Japan, 21(6) : 357-363, 1957.. (23)~ JARRELL„JL E.,,de la BURDE, R. A st'udyof'the major gaseous constituents in, the mainstream smoke of' a cigarette. Tobacco Science 9: 5-11, January 8„1965., (24) JOHNSON, D. E.,, RHOADES, J. W. N-nitrosamines in smoke condensate, from several varieties of tlobacco: Paper presentled! at the Second!World Conference on Smoking, and'' Health. Londons England,, September 20- 24, 197,1. 11 pp. (25) JOHNSTONE, R'., A. W., QUAN, P. M., CARRUTHERS'; W. Composition of cigarette smoke: Some low-boiling, components. Nature 195 (4948) : 1267-1269„ September 29, 1962: (26) KEITH,, C. H.,, TESH, P. G. Measurement of!. the total smoke issuing fromm a burning cigar.ette. Tobacco 160(15),: 2&'-29; April 9, 1965. (27) LAURENE, A. HL, LYERLY„ L. A., YOUNG, G. W. Direct vapor chromato- graphic determination af' acetaldehyde,, acrolein, and acetone in ciga- rette smoke. Tobacco 159 (22), :~ 34-37, November 27, 1'964., (28) MASUDA, Y.,, HoFFMANNy, D: Quantitative determination of' 1-naphthy- lamine and, 2rnaphthylamine in cigarette smoke. AnalyticaU Chem istry 4!11(4) : 650-652,, April 1969.. (29) MILLER,, J. E; Determination of the camponentis of pipe tobacco: andl cigar smoke by means of a new smoking machine. IN: Proceedings of the Third World Tobacco Scientific Congress, Salisbury; Southern Rhodesia, F~ebruary 18-26,,1963, pp. 584L595. (30): MILLER, R. L.,, STEDMAN, R. L. Essential absence of'beta-naphtlhylamine in cigarette smoke condensate: Tobacco 1i65'(18) : 32, August 25; 1967. (,31) MOKHNACHEV; I. Gl, KANEVCH',EVA, IC S. Kolichestlvennyy: sostav arninovv tabachnogo dyma~ (J. Qualitative composition of' tobacco smoke amines.)~ Izvestiia Vysshikh Uehebnykh Zavedenih Pischevaia Tek- nologiia, (56)~: 62-63, 1967. 1I4'7'

(~32) MOKHNACHEV, h G., LATAYEVA, D! N. Kolichestvennoe opredeleniye letuchikh fenolbv tabachnogo dyma. (Quantitative determination of volatile phenols of tobacco smoke.) Izvestiia: Vysshikh Uchebnykh Zavedeniii Pischevaia Teknologiia (57) : 47-49, 1967. (33) MoKHNACHEV;, I. G., PISKLOV, V. P. Gazovyye uglevodorody tabachnogo dyma. (II., Research into the gaseous hydrocarbon ofl tobacco smoke.) Izvestiia Vysshikh Uchebnykh Zavedenii. Pischevaia Teknologiia (56): 64-67, 1967. (31,) MoKHNACHEV„ I: G., PISKLOV, V. P. Issledovanie gazovoy fazy tabach- nogo dymaL (Study of' the gas phase of tobacco smake.) Tabak 4:~ 31-34, 1966. (35)' MOKHNACHEV, I. G., POPOVA, L. P., DULAN4 L, A., SIROTENKO;, A. A,.,, KAME'NSTCH',IKOVA,, S. V., KOVTUNOV„V. S.,, LATAYEVA, D'. N., PISKLOV„ V. P., SERDJUK„ L. G. The gas phase of smoke and the influence aff the neutral part of tobacco resin on its composition. INI: Proceedings of the Fourth International Tobacco Scientific Congress. At''hens; Greece, September 19-26, 1966: pp. 1040-1061.. (36) MOLD, JL D., McRAE„ M. T. The determinatinni of some lbw molecular weightlaldehydes and ketones in cigarette smoke as the 2,4Ldinitro- pheny?]hydrazones. Tobacco Science 1: 40-46, 1957: (Z~7) MvmPqwER, R. C:, LEWIS; JL S., TbuEY, G. P. Determination of'carbon monoxide in cigarette smoke by gas chromatography. Tobacco Science 6: 142=145, 1962. (08) NALL, J. F. Complexed cyanide in collected cigarette smoke. Abstracts of 20th Tobacco Chemi'sts'' Research Conferenee,, November 1-3, 1966, Winston-Salem, N. C., 1966: pp. 26-27. (39) NESEMANNS E., SCHRODER;, R., SEEHOFERy F. Methqdenzur quantitativen Bestimmung von Insektiziden iin Tabak und Tabakrauch. I., Mittei- lung: Zur Bestimmung von Organo-Chlor-Insektiziden. (Metlhods far the ouantlitative determination of insecticides in tobacco and, tobacco smoke. I. Report: Determination of' chlorinated hydrocarbon insecti- cides.) Beitrage zur Tabakforschung, 4(41) : 182-188, May 1968. (i40) NE.URATIH, G. Stickstoffverbindungen des Tabakrauches. (Nit'rogen com- pound's in tobacco smoke.) Beitrdge zur Tabakforschung 5'(i3!):: 1115- 133„ December 1969. (41 ) NEURA'THS G., DUNGER, ML,, GEwE, J., LUTTiICH, W., W'ICHERN; H. Un- tersuchung der FlUchtigen Basen des Tabakrauches. (Volatile bases of' tobacco smoke.) Beitrage zur Tabakforschung 3'(i9) : 563r569, December 1966., (4'2) NEWSOME, J. R., KEITH, C. H. Variation, of the gas phase composition within a; burning cigarette. Tobacco Science 9: 65-69;, Aprill 16, 1965. (l;3) NEWSOME, J. R.,, NIORMAN, V., KEITH, C. H. Vapor phase analysis of tobacco smoke. Tobacco Science 9: 102-110, July 23, 1965. (44) NORMAN, V., KEITH, C., H. Nitrogen oxides in tobacco smoke. Nature 205(4974) : 915-916,, February 27; 1965: (.4:5) NORMAN, V., NEwsan-IE;, J. R., KEITH, C. H. Smoking machines f'or the analysi's of the vapor phase of cigarette smoke. Tobacco, Science 12I: 216-221, 1968. (1/,6) OSBORNE, J. S., ADAMEK, S., HoeBS,, M. E. Some components of' gas phase of'cigarette smoke. Anallytical Chemistry 28i(i2)1: 211-215, Feb- ruary, 11956. (4x') PaILER„ M., KUHN,, H. Kurzer Bericht uber das Vorkommen: von Nicket im Zigarettenrauch. (Short report on the occurrence of nickel inn cigarette smoke,)~ Fachliche Mitteilungen der-0sterreichisohen Taba- kregie (4!) : 61-63, 1963! 1' 4 8

e e (48)~ PAILER,,IVI., KUHN, H., GtturrBERGER, D, tber Quantitative Unterschiedee im Auftreten von niedermolekularen Carbonylverbindungen imi Rauchh von Zigaretten verschiedener Tabakmischung undl verschiedenen. Feuchtigkeitsgehaltes. (iQuantitative differences in the occurrence of'f low-molecular carbonyl compounds in the smoke of cigarettes having, different tobacco mixtures and different moisture contents.) Fach- liche Mitteilungen der Osterreichischen Tabakregie 3: 33-39, March 1962. (49) PHiLi~PPE,R. J., Hasss;, Mi. E. Some componentsof' the gas, phase! of' cigarette smoke. Analytical Chemistry 28 (12) : 2002-2005, December 1956. (50): RAvRURN, C. H., HARLAN, W., R,,, HANMER, H. R. Determination of volatile phenols in cigarette smoke., Analytical Chemistry 25'(9) : 1419, Sept'ember 1953. (51) SCHOLLER, R. Uber deni G:ehalt des gasformigen und des festflussigen. Anteils des Tabakrauches an Cyanwasserstoff. (i11he content of hydro- gen cyanide in the gaseous and stable liquid portions of tobacco smoke.), Fachliche Mitteilungen der Osterreichischen Tabakregie 1:. 7-10, 1938. (52) SPEARS, A. W. Quantitative determination of phenol in cigarette smoke. Analytical Chemistry 35(3)) : 320-322, March 1963. (53) SQEARS„ A. W.,, RouTH, W. E. A combined approach to the quantitative analysi's of the volatile components of' cigarette, smoke. Paper, pre- sented at the 18t!h Tabacco: Chemists Research Conference, Raleigh„ N. C., 1964, (51,J STEDrvrA,N„R. L. The chernical'composition of tobacco andltobacco smoke. Chemical Reviews 68 (2) : 1153-207„ April 1968. (55) SUNDERMANy, F. W., SU^IDERM'AN, F: W., JR. Nickel poisoning. XI. Im- plication of:nickel as a pulmonary carcinogen in tobacco smoke. Ameri- can Journal of Clinical Pathology 35(3): 203-209; March 1961. (56), SZADKOWSKI, D., S"CHULTZE; Ill,,, SCHALLER;, K,-H,,, LEHNERT, G:, Zur okologischen Bedeutung des Schwermetallgehalts voni Zigaretten. B'lei ; Cadmium- und Nickelanalysen des Tabaks sowie der Ga:s-und Partikellphase: (Oncological significance of' heavy metal content of' eigaretltes. Lead-, cadmium-, and' nickel analyses of tobacco as well as of'the gas- and particulate phase.) Archiv fur Hygiene undl Bak- teriologie 153 (1) : ~ 1-8; February 1969. (57) TADA, 0~ Determination of' nitrogeni oxides in the air. Report of'~ the Institute of' Science and Labor (Japan) No. 60: 7-26,, Qctober 1962. (58) TOTH, J. Uber Schwefelwasserstoff im Rauch des ungarischen Tabaks., (Hydrogen sulfide in the smoke of Hungarian tobacco.) Chemiker- Zeitung 37: 897-898, 1913. (59), TouEY, G,. P:, Gaseous phase of' cigarette smoke. Isolation and analysis for totali aldehydes., Analytical Chemistry 27: 11788-1790, 1955. (60) U.S, SENATE, 90TH CONGRESS, 1ST SESSION. Public Health Service tech- nicall report', on "tar" and nicotine. Hearings before the Consumer Subcommittee of the Committee on Commerce. August 23-25, 1967: pp. 7-8; (61) WALTZ, P'., I-'dAUSERMANN; M. Betrachtungen iiberr die Veranderung des Gesamtwasser, Pyridin, Nikotin, Phenol, Btenzcatechiny, Scopoletin und Kohlenoxid im Cigarettlenrauchi ini Abhangi:gkeit von, der Zugnu- mmer und vom: Rauchfilter. (Considerations on, the variat'ionsi in, t'o* bacco smoke of cigarettes. The yield, of'crude condensate, total water, pyridine, nicotine,, phenol, pyrocatechol, scopoletin, and' carbon mon- 149

oxide in cigarette smoke depending on the puff number and smoke filter.) Beitrage zur Tabakforschung 3'(13) : 169-202„August 1'965'. (i62), WALTZ, P.,, FIAUSERMANN,, M., MOSER,, F. Zur Bestimmung des PyridinS im Rauch von Cigaretten im Rahmen der Bestimmung der Gesamt'r alkolaide: (On the determination of' pyridines in cigarette smoke in, the scope of'tihe determination of smoke alkaloids.) Beitlrage zur Tab- akforschung 2(6): 283-293„ October 19641 (63) WATANABE,, M.,, KOBASHI, Y. Tabako kemuri seibun no bunsekiho, ni, kansuru' kenkyu. L Gasukuromatogurafi' ni yoru tabako kemurichu no itsusanka tanso oyobi~ tansan gasu no teiryo, (Analytical methodss of! chemical components in tobacco smoke. IL Determination of oarbonn monoxide and carbon dioxide in cigarette smoke by gas chromato- graphy.) Nippon Senbai Kosha Chuo Kenkyushu Kenkyu Hokoku IVo, 107: 177-180, 1965. . ('6,4)~ FF~ILLIAM~S„ J. F., PiutvT~,, G: E., Ammonia in mainstream, and si,destrearn cigarette smoke. Abstracts of 21st Tabacco Chemists' R'esearch Con- ference, Durham, I+T.C., October 19'-20; 19fi7. p. 14! 150

INIDEX. Abortion effect of'matemal'smoking, 5 ;84,85' frequency, and cigarette consumption, 85 Acetaldehyde as suspected contributor to health haz- ards of smoking; 14'5, Acetone as suspected' contributor to health hazards of smoking, 145 Acetonitrilee as suspected contributor to health haz- ards of smoking, 145 Acrolein, as irritant in tobacco smoke, 101 as probable contributor to health haz- ards of smo king;,144 AcrylbnitLile as suspected contributor to health: haz- ards of smoking,145 Adolescentss see 3tudents; high school Air pollution;, carbon, monoxide from cigarette smoke„ 7,121-123i,125 ef'fect; on nonsmokers, 121-125 tobacco smoke as a factor, 7,121-124 Air qualityy standards for carbon monoxide; 128 Alcohol! consumption effect, on mortality rates from esopha- geal neoplasms in:1'apanese males, 71 smoking, and, in, esophageal neoplasmi etiology, 4,68 ,70;71' A'lle rgy effectt on cardiovascular abnormalities, 111' tobacco and', 7,103-111 tobacco smo ke irritants and„ 11'0 Alphar-antitrypsin deficiency in emphysema etiology, 4'4: smoking and, 44! Altitude„ effect'on arterial oxygentension„22 Amblyopia, tobacco cyanides and; 6 diet,and„6 smoking and, 6 Ammoniaa as suspected contributon to health haz- ards of smoking, 145 Angina pectoris smoking and; in twin studies, 1'8 Antigen, antibody reac:tioni allergy and, 103-1A77 smokers vs: nonsmokers, 7,105,111 tobacco, and„7,104-107 Aortic aneurysm, nonsyphilitic: mortality rates;, smokers vs. nonsmokers, 2 Aromatic hydrocarbons, polycyclic effect on tobacco icarcinogenicity,,66 Arterialldiseases carboxyhemoglobin levels and; 26 smokers vs, nonsmokers; 26 smoking and, 25,26: Arteriosclerosis autopsy studies and, 19,20 cigar smoking and, 19' experimentally induced in dogs,, 19,20 pipe smoking and, 19 smokers vs. nonsmokers,,19,22,23',27' smoking classifrcation,and,,19 Asbestos pulmonary fibrosis and, 44! Asthma smoking,and,,37 Atherosclerosis see A,rteriosclerosis Autopsy studies arrteriosclerosis and,,19,20 coronary hearrt,disease and, 19',20 Benz(a)anthracene carcinogenicity; as component of ciga« rette smoke,, 66 Benzenee as suspected' conttibutor to health haz- ards of smoking; 14'5I Benzo(a)pyrenee as air pollutant from cigarette smoke, 123 carcinogenic,effects d'uring,pregnancy in rats, 89 cocarcinogenic effect, on respiratory tract in rabbits„67 hydroxylation by the placenta, 89' in smoke streams, 123' Betel nut chewing in Bombay, India, 69

in head and neck neoplasm etiology, 69 smoking and,b9 Binth weight~ effeet of maternal smoking, 5,83-87 Bladder neoplasms relative risk in females by amount smoked„73 relative risk in males:by amount smoked! 72,73 smoking and~ 68,72-74 smoking characteristics in etiology, of, 5 Body height; effect ofl maternal smoking, 88 Bionchial abnormalitiess in smokers vs: nonsmokers,,4'5 Bronchial histological changes smoking and, 4'5! Bronchitis incidence in, British males by cigarette consumption, 62 occupational diseases and, 42: prevalence in smokers in Glenwood Springs„Colorado„39 prevalence in smokers vs: nonsmokers im Yugoslavias 40 smoking in etiology of, 37, Bronchopulmonary disease, chronic ob- structive alphat-antitrypsin deficiency and, 3,44 epidemiology in Tecumseh, Michigan, 39,40 morbidity,, smokers vs: nonsmokers in. Berlin, New H!ampshire; 39' mortality, smokers vs. nonsmokers, 38,39 mortality rates for ex-smokers, and& smokers vs: nonsmokers, 3 mortality rates for pipe/cigar smokers vs. cigarette smokers, 3 occupational hazards and, 4244 smoking in,etiology of, 3,37 2,3-Butadione, as suspected contributor to health haz- ards of'smoking, 145 Butylamine as suspected contributor to~ health haz- ard5, of smoking; 14'5' Cancer see Neoplasms and specific listings, e:g,,. Lung neoplasms C:ubon idia ttide as, suspected contributor to health haz= ar& of smoking, 145 Carbon monoxide as air pollutant from, cigarette smoke„ 7,121-123s125effiect on blood, carboxyhemo&bim levels, 2'1-23',127 effect.on cardiovascular system,,22 effect an nonsmokers, 126 effect on psychomotior~ performance, 126 effect on,vision„126 as most likely contributor to health hazards of smoking; 8,143 psycholbgical and physiological effects, 125-128 Carboxyhemoglobin levels blbodicholesterol and, 23 during and following exposure to earbonn monoxide, 124,125 i,n nonsmokers exposed to cigaret!tee smoke, 125 occlusive peripheral vascular disease and, 26 smokers vs. nonsmokers, 21F23'. Carcinogenesis experimental, 65-67 initiating, agents in cigarette smoke, 66. Carcinogens effect on oral mucosa in laboratory ani- mals, 70 Cerebrovascular disease mortality rates, smokers vs. nonsmokers, 2 smoking,and,,24,x5' Cessation of smoking effect on COPD morbidity and mortal- ity, 41,42' effect on respiratory symptoms, 41,42 lung neoplasm development and, 62 myocardial infarct and, 17,18 as:preventive measure in C1dD; 1!7„18 as therapy in arterial diseases, 26' CHD see Coronary heart, disease Children effect of parental smoking, 129 passive smoking and, 129 respiratory, illness and, 129, Cholesterol in tobacco, 24' in tobacco smoke, 24 Chronic bronchitis seeBtonchitis Chronic bronchopulmonary disease see Bronchopulmonary disease, chronic obstructive 152'

Chrysene carcinogenicity, as component of ciga- rette smoke, 66 Cigarette consumption effect on mortality from lung cancer in Poland, 61,62 Cigarettes tar and nicotine content, 142,143 Cigarette smoking see Smoking Cigar~ smokers carboxyhemoglbbin levels in„21-23 myocardial arteriole wall thickness in, 19 relative risk in esophageal, neoplasm development,,68 relative: risk in laryngeal' neoplasm de- velopmeni, 67' Coaliminers pneumoconiosis and~,42-44 Cbngenital malformations maternal smoking and, 87 COPD see Bioncfiopulmonary disease, chronic obstructive Coronary heart disease autopsy studies,, 19,200 carboxyhemoglobin levels andi, 27 cross-sectional study in Bergen,, Norway, 16 epidemiological'stu dies„ 14-16' heredity as a factor, 18 incidence among Minnesota men by age and smoking habi't„ 14-16 interaction of smoking and other risk factors, 16,58 mortality rates and' per capita cigarette consumption in several countries, 1,6 mortality rates in longshoremen, 14 retrospective studies in Goteborg, Sweden, 16 retrospective studies in Prague, Czecho- slovakia, 1I6 smoking;im etiology of, 1,2,13,14, twin studies:,,18 Cor Pulmonale see Pulmonary heart disease Cough smokers vs„nonsmokers,,4!0 , Cresol as probable contributor to health haz- ards of smoking, 144 Crotononitrile as suspected contributor to health haz- ards of smoking, 1'45'. Cyanidess tobacco amblyopia and, 6 DDT as suspectedl eonttibutor to health haz- ards of smoking, 65',145 Dermatitis among tobacco workers, 111 Dibenz(a,c)anthracene carcinogenicity, as component oE' eigae rette smoke, 66 7H-D5benz (e,g)carbozole carcinogenicity, as component of' ciga- rette smoke, 66',67 carcinogenic effect on respiratory tract in hamsters, 66s67 Diet tobacco arnblyopia and~ 6 Dimethylamine as suspected' contributor to health haz- ards of smoking,,1'45 7,12'Dimethylbenz(a)anthracene, effect on oral mucosa in,hamsters, 70 Edentuiismi smoking and, 6 Emphysema alphat-antitrypsin deficiency and, 44 experimentally induced in smoking dogs; 46; smoking in etiology ofl, 37 Endrin as suspected' contributor to~ health haz- ards of smoking, 145 Epidemiological studies bronchopulmonary diseases and smok- ing, 38,41 coronary disease and smoking„ 14-16 esophageall neoplasms and smoking, 70,71 laryngeal neoplasms and smoking, 68 lung;neoplasms and smoking, 60+65' maternal smoking and outcome of preg- nancy, 83~-87' oral neoplasms and smoking, 68-70 pancreatic neoplasms and smoking, 74' urinary bladder neoplasms and smoking, 72-74 Esophageal neoplasms alcohol consumption andi smoking in etiology ofs 4,5,71 mortality rates in Japanese males by smoking and drinking characteristics, 71 153

smoking;in etiology of, 4,70;7L Esophagus ef fect! o f smo kin g, , 9 8 Ethylamine as suspected contributor to health haz- ards of smoking, 1'45 Experimental studies nicotine andicigarette smoke„21 Ex-smokers mortality rates from lung cancer, 5 Fetus effect of maternal smoking, 5,83-89 Filtrationn smoke, effect,' on bronclio-constrictorr response in smokers; 45 Formaldehyde as suspected contributor to; health haz- ards of smoking, 145 Furfural as suspected contributor to health haz- ardsof'smoking, 145 Gas phase„cigarette smoke effect on mucous flow rates in cats, 47, harmful constituents in, 143 Gastric secretions effectof'nicotine, 97' Gastrointestinal disorders smoking and, 5,6,97,98 Genetic factors in alphat-antitrypsin deficiency, 44 smoking and~ 44 Gingivitis smoking and, 6 Heart disease see Coronary heart,disease Heredity alphat-andtrypsin deficiency and, 44 coronary heart disease and„18! smoking and, 18i Hydrocyanic acid as probable contributor to~ health haz- ards of smoking, 144 Hydrogen sulphide as suspected contributor to health haz- ards of smoking, 145: Hydtoquinone as suspected contributor to health haz- ards of smoking,,145 Hypercholesterolemi a as a, risk factor, for coronary heart, dis- ease, 16,17 154 H'ypertension i as a risk factor for coronary heart! dis, ease, 1'6,17' Hypoxemia smoking and; 22: Hypoxia effect of nicotine;, 21 experimentally induced inirats,, 21 Infant mortality effect of maternal srnoking; 83•87 low birth weight and, 86 Influenza incidence fromiantibody deficit in smok- ers, 109 Intermittent claudication smokers vs. nonsmokers, 22,26 lntra-oral smoking see Reverse smoking Ischemic heart disease morbidity ratio: from~„ in New Delhi, India4 16. Laryngeal neoplasms epidemiological, studies,, 68 relative risk, among cigarette,, pipe: and, cigar smokers; 67 smoking in etiol'ogy of, 4,67,68 Leukoplakia~ oral neoplasm development in smokers and~„68,69 smoking in etiology of, 68,69 Lip neoplasms pipe smoking as cause of, 4 Lung cancer see Lung neoplasms llung,function effecvof smoking, 37,38 in smokers vsi nonsmokers, 40. Lung neoplasms epidemiological studies, 60-65 etiology and epidemiology, 59,60 incidence in British males by amount smoked„62 incidence in Czechoslovakian~ males by amountsmoked; 611 incidence iw Jewish, vs. non-Jewish women, 63,64 incidence imuranium miners,,64,65 mortality ratios in Japanese males by amount smoked, 61 mortality ratios in Japanese women, 63' prospective study in Japanese adults, 4,60;61 I M M N [ti 6 M Rf! Iv h M M!

prospective study in~ Czechoslovakian males, 61 relationship to chronic bronchitis and smoking;,62 relative risk in ex-smokers by length of cessation and, previous duration, of habit;,62-64' smoking as cause, 4,,5,59;60 Macrophages;, alveolar effect; of tobacco smoke, 47,48 in sputum specimensoEsmokers vs. non- smokers,, 48 Maternal-fetal exchange effect of nicotine, 88! Maternal smoking see Smoking, maternal, Methacrolein as suspected contributor to health haz- ards of smoking, 145 Methyl alcoholl as suspected contributor to health haz- ards of smoking, 145 6-Methylanthranthrene carcinogenicity,, as componenY of ciga- rette smoke,,66 Morbidity fromichronic bronchopulmonary disease,, 39-41 Mortality from chronic bronchopuimonary disease, 38,39 Mortality ratess esophageal neoplasms in Japanese males by smoking and' drinking character- isrtics„7'1, lung neopiasms, in Japanese women, 63 pancreatic neopl9sms in United' States, 74 Mortality ratios lung neoplasms in Japanese: males by amount smoked, 61 incidence in men in Goteborg, Sweden, by tobacco consumption,, 15 incidence rates by smoking classifi- cation, 1'5' smokers vs. nonsmokers in Goteborg, Swedens 16 Neonatal death maternal, smoking and, 83-87- Neopiasms see also Specific types of neoplasms, e.g. lung, neopiasms smoking and„4,5;59=75 N~ickeL compoundss as suspected contributors to health, haz- ards of smoking, 14'5' Nicotine antigenic properties, 104 effect on apexcardiogram,, 211 effect on birth weight, in rats, 88' effect: on bronchoconstrictor, response in laboratory animals, 46 effect on fetus in laboratory animals, 88 effect on gastric secretions, 97- effect on gastrointestinal secretions in dogs, 6 effect on, immune response in man, 109' effect on lipid metabolism, in rabbits, 21 effect on peripheral, circulatory system, 25,26 effects during, pregnancy in laboratory animals, 88 experimental studies, 21 hypoxia and, 21 as most likely, contributor to health hazards: of smoking, 8,143 Nittic :oxide as probable contributor to health haz- ards of smoking„ 14'4' Nitrogen ~ dioxide int. Mouth ineoplasms see Oral neoplasms effect on pultnonary tissue in rats, 4'6,47' by ish Myocardial: arteriole walls effect of filtered cigarettes in dogs, 20 thickness in, smokers vs. nonsmokers,. 2,19 in emphysema etiology„46' as probable contributor to health haz- ards of smoking,, 144 Nitrogen oxides ~ thiekne.cs, in, smoking,and' nonsmoking, as air pollutants in cigarette smoke;. by dogs, 2',20 ~ 124,125 63 Myocardial infarctt epidemiological study in, Goteborg;, Non-nicotine cigarettes effect on apexcardiogram, 211 tts, Sweden, 14,15 Nonsmokers incidence among Minnesota meniby age and smoking habit, 14,15 allergic and irritative reactions to eiga, rette smoke„ 128',129' 155

allergic symptoms in, from tobacco smoke exposure, 110;111 carboxyhemoglobim levels in, 125 passive smoking and, 121-125' Obesity as a risk factor for coronary heart dis- ease, 16 Occupational diseases bronchitis, 42 chronic: obstructive pulmonary disease,, 3,42-44 pneumoconiosis, 42-44 pulmonary fibrosis, 44 smoking and, 3',42!44 Occupational hazards smoking and„ 3,4,42-44 Oral contraceptives smoking;and; 26' thrombophlebitis and, 26 Oral diseases, non.neoplastlc smoking and„6 Oral hygiene smoking,and, 6 Oral mucosa effect of' carcinogens in laboratory ani, mals, 7Q~ effect,of cigarette smoke, 6,69' effect of reverse smoking; 69' effect of tobacco/,bidi smoking, and chewing,, 69 Oral neoplasms pipe smoking;as cause; 67 relative risk in tobacco smokers and chewers, 70 smoking; in etioTogy of;, 4,67-70 Oxygen tension smokers vs: nonsmokers, 22 Pancreatic neoplasms mortality rates in United States, 74' mortality ratios in Japanese male and female smokers, 74 smoking and, 5,68,74 Particulate phase, cigarette smoke caccinogenic : accelerators in, 5',65' effect on pulmonary and cardiac struc- ture and function„7,8' harmful constituents ins 143 Passive smoking effect on children, 129, effect on respiratory tract in laboratory animals, 129,130 in neoplasm indlrction in laboratory animal „ 1130 156: Perinatal studies maternal smoking and, 83-88 Periodontal diseases smokingand„6 Peripheral vascular diseases carboxyhemoglobin levels and, 26 smoking, and4 2;252'6 Phagocytosis effect of cigarette smoke in rabbits„ 1'09 effect of tobacco smoke, 47-48 Phenol as probable contributor to health haz- ards of smoking, 144 Physical inactivity as risk factor in coronary heart disease; 16,1'7' Pipe smokers carboxyhemoglobin levels in, 21 myocardial arteriole wall thickness in,. 19 oral, neopl'asms and, 67 relative risk in esophageal neoplasm development 68 relative risk in laryngeal neoplasm development„ 67' Pneumoconiosis prevalence in coal miners, 421141 smokers vs. nonsmokers, 42-4'4! Post-operative pulmonary complicationss snokers,vs: nonsmokers, 38 Preeclampsia smoking and, 84 Pregnancy effect of maternal smoking, 5,83'-87, Prematurity effect of maternal smoking, 5,83-87 Pulmonary clearance effect of smoking, 3',47' Pulmonary fibrosis in asbestos textile workers„44 smoking and', 44 Pulmonary heart disease COPD and„24 smoking as,cause; 24',27' Pulmonary macrophages effect of smoking, 3,4,47-48 morphologic differences im smokers vs. nonsmokers, 4,47-48 Pyridine as: suspected contributor to health haz- ards of smoking, 145 Radiation exposure smoking and„ in uranium miners, 64,65 1 f F F R S S S S

Di,tS, haz- case;, 5s in; plasm plasm iations .87, -87' Aers vs. alth haz- rs, 64,65 Respiratory disorders,, acute: noninflu- enzal in smokers vs. nonsmokers, 48 Respiratory functlon tests effect of smoking„45 Respiratory infections smoking and, 3,38 Respiratory symptoms pipe/cigar smokers and cigarette smokers vs. nonsmokers, 3;40: Reverse smoking effect on oral mucosa, 6:,69,70 nicotinic stomatitis and„6,69,70: Risk factors in, coronary heart d'isease„ 16-18 Skin effecti of tobacco extracts, 105407 tobacco antigens and, 7,104,1051 Skin testing, for reactions to tobacco, 105-107 Smoke, cigarette carcinogenicity, 65,66: cocarcinogenic effect on respiratory ttactt in rabbits, 67 ef'fect, on apexcardiogram„ 211 effect on breathing in guinea pigs, 46 effect on lung surface tensioni in dogs, 48': effect on nasociliary mucosa in don- keys, 47' effect on phagocytosis in, rabbits, 109 experimentaf studies in laboratory ani- mals, 2 L harmful constituents of, 8,141-146 Smoke, tobacco as air pollutant, 7,121,122 allergic and irritative components, effect on nonsmokers, 7,1218;129 antigenic properties; 104 effect on macrophages, 47 irritants in, 109;1'10 Smokers vs.,nonsmokers arteriosclerosis and, 19 carboxyhemoglobin levels, 21-23 cerebrovascular diseases and, 25 oral diseases and, 6' respiratory symptoms, 40 thickness of myocardial arteriole walls, 119, Smoke stteams benzo(a)pyrene contents 123: effect on nonsmokers, 1'22,1I23 tar and nicotine content,, 123' Smoking bladder neoplasms and, 68,72-74 effect on cardiovascular system, 6,13,14 effect on esophageal sphincter, 97,98 effect on gastrointestinal secretions in, dogs, 6 effect on, leukocytes in guinea pigs, 46; effect on lungs in dogs, 46 effect on mortality rates from, esopha- geal neoplasm in Japanese males, 711 effect on~ neoplasm recurrence at site of primary, 69 effect on, oxygen tension in arteriali bloods 45 effect on pentagastrin-stimulatedI gastric secretion; 97 effecti on peripheraleirculatorysysrtem, 25,26 effect on pulmonary clearance„47' heartburn and, 97,98 peptic ulcers and, 6,97,98 tobacco amblyopia and, 6 Smoking, bidi in neoplasm etiology in Bombay, India, 69 Smoking, maternal carcinogenic effects on fetus, 88 effect on abortions, 5,84,$5 effect on, birth weight, 5,83-87' effect on body height of children, 88' effect on fetal growth, rate, 5;83-87 effect on neonatal mortality rates, 84-87 effect on, neoplasm development in off- spring, 87,,$8 effect on placental metabolizing activ ity„ 89 effects during,pregnancy, 5;83-87' teratogenic effects, 87 unwanted pregnancy and, 84 Smoking, parental effect on children, 129: Snuffl effect on oral mucosa in hamsters, 70 Squamous cell carcinoma smoking, in etiology of, 69 Stomatitis nicotina reverse smoking and, 6,69,70 Strokee smoking and, 24,25 Students, high school effect of smoking, 40,411 pulmonary function of smokers vs. non- smokers, 3 157

respiratory symptoms' in, 40;41I Surfactantsg effect of! tobacco smoke, 48 Tar'content •' as harmful component of cigarette smoke, 142',143' Tars, tobacco carcinogenicity, 65,66 definition, 143' Thromboangiitis obliterans tobacco alltrgy ands, 111 Thrombophlebitis oral' contraceptives and, 26 smoking and, 26 Thrombosis effect of'smoking, 23' Tobacco cholesterol content',, 24 effect on immune responses, 6,1.'07-1091 pharmacologic;, irritative, and allergic ef- fects,, 7,1'09!-1111 Tobacco antigens in smokers vs. nonsmokers, 107 Tobacco chewing oral neoplasms ands, 69 Tobacco extracts antigenic properties, 104,105 effect on skin,,105-107 irritants in, 104,105 thromboangiitis obliterans and„ 111 Tobacco leaf. antigenic properties„ 1104,105 Tobacco pollen antigenic properties, 104 Tuberculosiss smoking and~ 41 Twins smoking and coronary heart, disease: in, 18 Ulcer,, duodenal smoking and, 6,97,98 ' Ulcer, peptic increased prevalence in, male smokers, 97 smoking and,,5',6;97;9'8 smoking as cause in dogs,,, 97,98 Urinary bladder neoplasms see' Bladder neoplasms Vascular disease; peripheral carboxyhemoglobin levels and, 26 nihotine and,, 25 smokers vs. nonsmokers, 26 smoking as a risk factors 2,25;26 V ision effect of carboni monoxide;, 126 * U.S. GOVERNMENT PRINTING OFFICE: 1i972'0-445•1'91 158' Q: ~ ~ ~

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