Coltey, et al. (13) studied the inctdcnce oi pnzLr1nor~i~1 2nd
t,ronchitis in 2.705 cllildren over the first 5 ye3rs Of life ill Jt'l3liOil 10
tll< smoking hhits ot` both parents. Tiwy found 111at :I relationsllip
b2t\LYerl p3rentnl smoking  habits and respirator), infection in
children occurred only Turin, 0 the first years of life (Table 6). Tlrey
also showed a relationship between parental cough 2nd phlqm
production and infant infection (Table 6) whiclt was found to 1~
independent of the effect of parental smoking habits. The relation-
ship between parental smokin,.
                         0 and infant infection was greater when
both parents smoked and increased with increasing number ot
cigarettes smoked per day. The relationship persisted after social
class and birth \veight had been controlled for.

  Titus. respiratory infections during the first year of life are
closely related to smoking habits independent of parental symptoms.
social class, and birth weight. Because of the dose-response relation-
ship between parental smoking and infant respiratory infection
established by Colley. et al. (13). it is reasonable to suspect tltat
ci?zrettc smoke in the atmosphere of tl1e home may be tire caL1se of
thess infections; however, other factors such as parental neglect may
               '
3150 pl3y a role.

  The shove stdies examrned the effects of involLrnt3ry smoking
on relatrvely healtliy people. A substantial proportion of the U.S.
population suffers from chronic cardiovascular and pulmonary
diseases. however. and they represent the segment of the population
most seriously jeopardized by conditions found in involuntary
smoking situations. In Chapter 1 of this report (Cardiovascular
Diseases) evidence was presented which showed that levels of CO
sometimes experienced in smoke-filled environments (50 ppm) are
capable of significantly decreasing the exercise tolerance of- persons
with angina pectoris and intermittent claudication. In addition, these
levels of CO have been shown to decrease cardiac contractility and to
raise left ventricular end-diastolic pressure (an indication of heart
fatlure) in persons with cardiovascular disease.

  Persons with chronic bronchitis anti emphysema have consider-
able excess mortality under conditions oi severe air pollutton. In
smotie-filled environments levels of CO and several other pollulants
may be 3s high or hi&her tlian OccLIr during dir pollution rmer_rerlcies.
TIK effects of short-term exposure of persons wittt chronic obstruc-

501


TABLE 6. - Pnelrmonio and bronchitis irt fire first 5 yews of rife hy parerlfs'srnakir~g /labif ad rnorrlirzg phlegm

Annual incidence of pneumonia and bronchitis per 100 children
      (Ahsolute number, in parentheses)

                          Both ex-smokers

Year of
Followup I  Both nonsmokers i    One smoker /   Both smokers I  or one c*-smoker
                                       or smoking habit I       All

changed

N     O/O      N     O/B      N     O/B      N     O/B       N      O/B

1.6      10.3     10.4     i4,a     15.3     23.0     8.2      13.2     10. I      16 1
(343)    (29)    (324)    (118)    (339)    (139)    (546)    (I?'))    (I ,652)    (42s)
8.1      8.3            15.5     x.7      9.2     65      10.7     1.4       I I.3
(322)    (36)  :;kS,    (129)    (286)    (152)    (599)    (159)    (1.572)    (476)
6.9      8. I     10.5     94      7.9      1 I .o     8.2      11.6     8.4       10.6
(305)    (37)    (353)    (107)    (242)    (154)    (661)    (173)    (1,561)    (471)
8.0      I I.1     7.5      10.8     1.6      II 6     8.2      9.1      7.9       10.3
(287)    (36)    (306)    (102)    (236)    (121)    (695)    (187)    (1.524)    (4461
6.7      14.7    5.6      9.4      3.9      10.6     6.4      7.3      5.9       9.1
(285)    (34)    (267)    (107)    (208)    (132)    (737)    (219)    (1,497)    (492)

NOTI<. - N=nr~~hrr with winter morning phlegm, O/B=one 01 both with winter morning phlegm.
Source: Colley. J.K.T.. et al. (13).


ti\e bronchopulmonnry disease (COPDI to these conditions Ila1.e not
been evaluated. Persons with COPD dre ;~lso possibly at ~ncre~rcd risk
to CO exposure because of their low alvc`olar PO* Dur: to tl~e
reduced amount of oxygen av3il3bie to compete with the CO for
hemoglobin binding sites. these persons nii$~t experience 3 carbosy-
hemoglobin to oxyhemoglobin ratio higher than those in healthy
subjects under the same conditions of CO exposure. The retention of
CO may also be prolonged due to both this increased binding ofC0
to hemoglobin under low alveolar Paz and decreased ventilator-y
capacity to excrete CO.

  in summary,  the effects of cigarette smoke on healthy
nonsmokers consists mainly of minor eye and throat irritation.
However, people with certain heart and lung diseases (angina
pectoris, COPD, allergic asthma) may suffer exacerbations of their
symptoms as a result of exposure to tobacco smoke-filled environ-
ments. These effects are dependent on the degree of individual
exposure to cigarette smoke which is determined by proximity to the
source of the tobacco smoke, the type and amount of tobacco
product smoked. conditions of room size and ventilation as well as
the amount of time the individual spends in the smoke-lilled
environment, and his physiologic condition at the time of exposure.

503


  I. Tobacco smoke can be 3 si_Wificant source of atmospheric
pollution in enclosed areas. Occasionally under conditions of he3v)
smoking and poor venttlation. the maximum limit for an &hour
work exposure to carbon monoxide (SO ppm) may be exceeded. The
upper limit for CO in ambient air (9 ppm) may be exceeded even in
cases where ventilation is adequate. For an individual located close to
a cigarette that is being smoked by someone else. the pollution
exposure may be greater than would be expected from atmospheric
measurements.

  2. Carbon monoxide, at levels occasionally found in cigarette
smoke-filled environments,  has been shown to produce slight
deterioration in some tests of psychomotor performance. especially
attentiveness and cognitive function. It is unclear whether these
levels impair complex psychomotor activities such as driving a car.
The effects produced by CO may become important when added to
factors such as fatigue and alcohol which are known to have an effect
on the ability to operate a motor vehicle.

  3. Unrestricted smoking on buses and planes is reported to be
annoying to the majority of nonsmoking passengers, even under
conditions of adequate ventilation.

  4. Childien of parents who smoke are more likely to have
bronchitis and pneumonia durin, 0 the first year of life, and this is
probably at least partly due to their being exposed to cigarette
smoke in the atmosphere.

  5. Levels of carbon monoxide commonly found in cigarette
smoke-filled environments have been shown to decrease the exercise
tolerance of patients with angina pectoris.

504


RILlLIOGRAPHY

.A\lERICAN COSFERESCE OF COVERSMENT ISDC&TRIAL IiYGENlSTS.
   TLVS" rhrelhold hmlt values for chem!cal subsuncec 111 workroom 311 adopted
  b:/ the AmerlcJn conference of ~o%rrnmenr industrlzl hypen~str for 1973. J0urn9
  or- Occupar~onal .\ledlcme 16(l): 3949. January 1974.

ANDERSON. E. W.. ANDELhlAN. R. J.. STRAUCfI. J. hf.. FORTUIN. N. J.. KNEL-
  SON. I. H. Effect of low-level carbon monolidr exposure on onset and duratron
  of angns pcctorls. A study of ten patients wlrh ixhernlc heart dlseate. Annals of
  Internd \ledicme 79(l): 46-50. July 1973.

ANDERSON. G.. DALHAMN. T. The risks to health of passive smoking. L3kxtid-
  niqen 70: 2833-2836. August 15. 1973.

ARONOW. w. s.. CASSIDY. 1.. VANGROW. J. S.. hlARCH, tl.. KERN, J.C..
  GOLDSMITH, 1. R.. KHEMKA. hf.. PACANO. 1.. VA\VfER. hi. Effect of
  cigrette smohing and breathing carbon monoxide on cardiovnsculzr hemo-
  dynamics in angrnal patients. Circulation SO(2): 340-347. August 1974.

AROSOW. W. S.. ISBELL. hl. W. Carbon monoxide effect on exercise-induced angina
  pectoris. Annals of tnternal hfedlcine 79(3): 392-395. September 1973.

BESDER. W.. GOTHERT, M. MALORNY, C. Effect of low carbon monoxide
  concentrartlons on psychological functions. Staub Reinhaltung der Luft 32(4):
  5460. April 1972.

BRIDGE. D. P.. CORN, Xl. Contribution to the assessment of exposure of nonsmokers
  to air poilutmn from cigarette and cigar smoke in occupied spaces. Environmental
  Research S:l92-209. 1972.

BRC.VNE>lANN. K. D.. HOFFMANN. D. Chemical studies on tobxco smoke. XXIV.
  A quantitauve method for carbon monoxide and carbon dloxlde in cigarette and
  cigar smoke. Jourrwl of Cbromatographic Science 12(2): 70-75, February 1974.

CAMERON. P.. KOSTIN. J. S.. ZAKS. J. %l., WOLFE. 1. H., TIGHE, G., OSELETT.
  B.. STOCKER, R.. WINTON. I. The health of smokers' and nonsmokers' chddien.
  Journal of Al:ergy 43(6): 336-341. June 1969.

CASIERON. P.. ROBERTSON, D. Effect of home environment tobacco smoke on
  famdy health. Journal of Applied Psychology 57(2): 142-147. 1973.

CASO. J. P.. CXTALIN, J.. BADRE, R.. DUMAS, C., VIALA. A.. GUILLEMlE, R.
  Determination de la nlcotme par chromatographie en phase gazeuse. II
  Applications Ann&s Pharmaccutiques Francaises 28(1 I): 633-640. 1970.

COLLEY. J. R. T. Respiratory symptoms in children and parental smoking and phlegm
  production. British !&dtcal Journal 2: 201.204, April 27, 1974.

COLLEY. J. R. T.. IIOLLAND. W. W. CORKHILL, R. T. Influence of passive smoking
  and parental phlegm on pneumonia and bronchitis in early chddhood. Lancet
  2(7888): 1031-1034, November 2, 1974.

CORN. hf. Characteristics of tobacco sidestream smoke and factors Influencing its
  CoDcentiatlOn and distrtbution in occupied spaces. Scandinavian Journal of
  Respiratory Diseases (Supplementurn 91): 21.36, 1974.

D.-\wA\lN. T.. EDFORS. Sl.. RYLANDER. R. hfouth absorption of vprious
  compounds in c@rette smoke. ArchIves of Environmental Hed:h I6(6):
  831-835. June 1968.

I

2

3



4

5



6





. 7

8





9





10



11




12



13





14

IS

505


18 t-.SVIKOS\It.NTAL PROTECTION ACESCY. Natiorul prlmxy and wconddr)
    ambvznt sir quality sczmd3rds. Federal Regstcr 36(X--Part 113:8186-8201. Aprd
      30.1971.

19 I ODOR. G G.. \\`IKSTKE. C. Effect of tow CO concrnrnlions on rcvx~~ncc to
     monotony and  on prychomotor c~paaly. Staub Keinhaltung der Luft
     32(4).46-54. Aprd 1972.

20 C.~LUSEINOVA. V. 3.4 - Benrpyrcne determ~nz~t~on in the smoky xtrnosph~re of
    SOWI mcetnne rooms and rcsuurz~nts. A conrrlbution to the problems ot to-called
    ~JTXI\I` Tmohtn:. Scoplxma t 1 :465-168. 1964.

21  GODIS. G.. \\RlGlIT. C.. SIlLPttARD. R. J. ItrbJn e\po%ure 10 carbon mono\tde.
     ,\rchives of Environmenf31 tlcalth 25(j)-3OS-313. November 1972.

22  (;ROLL-KS';\PP. E.. WACSLR. 11. tlAL!CK. II.. ItAtDER. .\I Efftxtr of tow carbon
    ,,w,no\~d~ conccntr~t~on~ on w$~nce xnd computer-x~aly~d brun potentnls.
    S~:,ub Rcmtutfun~ der Lul-t 32(-1).6468. Aprd 1972.

2-t  Ii-\RKl-:. tt. -P. The pri,t&m of ~J\"Y' \mokine. I. The ir~tlurnue of smokin< on rhe
    (`0 ~~,nc~ntr.~l~w ,n otlice rooms. Inrerru~wnatri Arch~v iur Arbrlltmedizin
     3313): 199.2r16. 1974.

2s  HARKE. ii. -P.. IrAARS. A. t-RAHXl. B.. PETtRS. H.. SCtILUTZ. C. Zum Problem
    dec P.~xx~vr.~ucbcn\ (7 he problem of passive smoking.) lnlerna~ronales Archiv fur
     Arbclt,rnrdizin 79-333-339. 1972.

26  Ft.-IRKt<. H. -P.. BLEICtll:RT. A. Zurn Problem des P3ssivrwchens (The problem of
   pacsi\e \Inoking.) In~~:rrut~on~les Archiv fur Arbeitsmedtzln 29:31 2-322. 1972.

27  HARKE. H.-P.. LIEDL. W., DENKER, D. The problem of' passive smoking. II.
    Invrxriea:lons of CO level in the automobile after cigarette smoking. Inler-
    nalmn;le~ Archiv fur Arbeitsmedirin 33(3):207-220, 1974.

28  IIARKE. H. -P.. PETERS. H. The problem of passive smoking 111. The influence of
   smoklne on the CO concentration in driving automobiles. Internalionales Archiv
    fur Arhrltsmedirln 33(3):221-229, 1974.

29 IIARLAP. S.. DAVIES. A. hf. Infant a4mitsions to hospital and matern& smoking.
    L3ncer 1(7857):529-532. hlarch 30, 1974.

30  HARMSEN. t4.. EFFENBERGER. E. Tobacco smoke in transportation vehicles. living
   and working rooms. Archw fur Hygiene and Baklenolo:ic 14I(5):383400, 1957.

31 HOEGC. U. R. The slgniticance of cigarette smoking in confined >pacec. Thesis.
   Unlverslty of Cmcinnati. Diwsion of Graduate SItidle-.. D~parlment of EnCiron-
     mental Health. 1972 137 pp.

32  HOEGG, U. R. Cigsrelte smoke rn closed spaces. Entironrr~~nt~l Ilc.~l[t~ Pcnpecfivet
    2:1 I 7-128. October 1972.

506


3s

36

37

38

39

10

41



42



43



44

45

46

41

JOH\SOS. \I R. tlALL. J \V. NEDLOCK. J n'.. GRCUBS. II. J WI\ t I.1 1) 11
  7hc ,bsrnhu:~on ot products bctu-<en ,".~,",tr<z~m .i"d \dc~trc~m \r"ol.c-. Torxco
  175121):-13-16. October 12. 1973.

LAWTHER. P. J.. CO!.l\lINS. B. T. Cigarette smoklnF 2nd cxpoxure to cz~rbo"
  monoxide. Ann& of the I\`ew York Audemy of Science\ 17J:I 35.117. Octuhrr
  5.19iO.

LUQCEI-IE. A. J.. LANDISS. C. W., MERKI. D. J. Some Imrnedutc ellects oi a
sm~krns UI~~XXI~IKIII WI chlldre" of clementxy school ZI:~. nle Jour".d oi
  School Hsslth 40(10):533-536. December 1970.

\lcFARL;\SD. R. A. A study of the etfecrs of low lcvclc of carbon mono\~dr q`on
humans pxformmz dr~wng tssks at Ihr Hxrwrd School of Publtc IleJllh 1373
  Auromotl\e AU Follut~on Resexch Sgmpo?ium. Wa%hinston. D C . \ljrch 7 9.
   1973.

\fcFARLASD. R. A. Low level exposure to carbon monoxide :md drlxlne pcrfor-
  m~ncc. ArchIves oi Environment31 Health 27(6):355-359. Dsccmber 1973.

R.\Y. .A. 51.. ROCKWELL. T. H. An e&ploratory $tudy of 3uturnobde d:kv~nz
performance under the innuence of low levels of c~rbo\yhen~o~lob~n. A"n,ds 01
  the hew York Academy of Sciences 174:396-108, October 5. 1970.

RIISSELL. \I. A. H., COLE. P. V., BRO\W. E. Absorption by "on-v"okrrx ofc~rbon
  monoxide irom loom air polluted by tobacco smoke. bncet 1(7503):576-579,
  March 17, 1973.

RYLXSDER, R. (EdItor). Environnrcntnl tobacco smoke effeclr on the non->m~k~r.
  Scand~na\un Journal of Respuatory Diseases (Supplcmrn~u"~ 91 ): I-90. 197-t.

SCH!.tELTZ. I.. HOFFMANN, I)., WYNDER. E. L. The intluence oi tohzcca <make on
  Indoor atmospheres. 1. An ovewew. Prcvent~ve Xledicme4:66-82. 1975.

SCHL'LTE. J. H. Effects of mild carbon monoTide into\wztion. Archivrs of
  Envlronmenul Health 7(5):30-36, November 1963.

SEIFF. H. E. Carbon monoxide ;1c 3" indicator of cigrettecaused pollutmn levels in
  inrerclty buses. U.S. Department of Transportntion, Federal HI$wxy Adminztm
  lion. Burwu of lrlotor Carrier Safety, April 1973, I1 pp.

SRCH, \I. LXxr due Eedeutunp des Kohlenoxyds heim Zi:~rcttcnrauchenim Fersonen-
  kr3ftuagenmnern. Deutsche Zeitsrhrift fur grrichtltchc \lcdirin 60:80-89. 1967.

STEWART. R D.. BARE~TA, E. D, PLATTE. L. R.. STtWART. E. B.. KALB-
  TLEISCH. I. H.. VAN YSERLOO. B.. RI\l\l. A. A. C~rho\)~hcmo$ob~n levels in
   Amencan blood donors.  Journal of the Amertcan hledlcal Xssoclation
  2?9(9): 1187-l 195. Aucust 26, 1974.

STEU'4RT. R. D.. SEWTON, F. E.. HOSKO. J. J.. PETERSON. J. E. Eiiect 01 carbon
  monoxide on tlmr perceptlo". Archives of EnwronmentdI tltJlth 27t3)-155-160.
  September 1973.

507


48 U.S. DEPARTMENT OF TRANSPORTATION. ItDtR:!L X\`I:\TIOS \D\lt\lS.
    TRATIOS. U.S. DEPARTMENT OF HtALTIi. EDLXIATIOS. ASD \IP.Ll--\Rt
     NATIONAL INSTI TmE FOR OCCUPATIOSAL SAILTY AXLI Ht Al.TfI.
     Healrh ~specfs of smoking in trxnrport a~rcr~l~. Rockv~llr. .\lJ AD-i34c)97.
     December I97 I. 85 pp.

49  U.S. PL'ULIC HEALTH SERVICE. The Halth Conwqurncrs or Smnkine. A Report of
    the Surgeon Grner~. 1972. U.S. Department oi flralth. Education. and \\`eIf3re.
    Washington, DHEW Publication No. (HS\I) 726516. 1972. 158 pp.

50  WRIGHT. G.. RANDELL. P.. SHEPHERD. R. J. Carbon monoxide 2nd drwine skulls.
     Archives of Environmental Heallh 27(6): 349-354. December 1973.

508


Chapter 0
      Allergy

Source: 1972 Report, Chapter 7. pages 99 116

509


Contents

                                       PUQC3
Introduction  .......................................    513
Antigenic Properties  ................................   514
Skin Testing  ......................................   515
Additional Immunological Effects  ....................   517
Effect on the Immune Response  ......................   518
Irritant and Pharmacologic Effects  ...................   519
Clinical Allergy  ....................................   520
Summary .-...-.................: .................   521

References  ........................................    522

511


ISTRODUCTION

As early as 1886 reference was made to an entity called "tobacco
asthma" (64). Subsequently, controversy has arisen over whether
tobacco smoking causes clinical allergy (61) and whether such
tobacco allergy 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 determi-
nations of cutaneous sensitivity to tobacco extracts; and it must be
regretfully admitted that much of this published work is equivocal,
uncritical, and inadequately controlled."
Such criticisni 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 specific 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.
There is no single test or observation which can be used to de-
termine whether a substance may be responsible for allergic dis-
ease ; however, fulfillment of the following criteria constitutes evi-
dence for such a relationship :

1. Demonstration that the substance is antigenic, i.e., capable of
stimulating the production of antibody and then reacting with
the antibody-

2. Demonstration that, upon exposure to the substance, signs and
symptoms simulating an allergic reaction are elicited which
disappear upon its removal.

3. Demonstration that the immunologic event is related to the
  clinical event.

Recent advances in the understanding of immunological reactions
as well as in the methodology of immunology are now being applied

513


to problems of clinical allergy. For example, Ishizaka (37), using
radioimmunoelectrophoresis, recently reported that the so-called
"alIergic 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: differences in antigenic content of the test
extract, differences in route of administration, and heterogeneity
of test groups.

ANTIGENIC PROPERTIES

Tobacco leaf contains a complex mixture of chemical components
including: 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 differences 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. Coltoiu, et al. (9) reported that 13
different antigens capable of inducing precipitins in rabbits have
been isolated from tobacco pollen. Chu, et al. (7) prepared aqueous
extracts of five commercial tobacco products which stimulated anti-
body formation in rabbits. The antigens contained in the extracts
included both proteins and polysaccharidea 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-
genie. 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,aL
though not antigenic by itself, reacts with antibody and conveys
antigenic specificity 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 compounds are formed-
Pipes (51) demonstrated, through exhaustion of passive transfer
reactivity in 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'serum;
reactivity was reduced but not exhausted with tobacco extract. The
converse was true with passive transfer sites of tobacco-sensitized
serum ; tobacco extracts abolished allergic reactivity whereas to-

514


bacco smoke extract produced a diminution but not total exhaustion.
He concluded that it would be useful to test human subjects for both
tobacco leaf and tobacco smoke sensitivity. Kreis, et al. (39) have
speculated that tobacco leaf antigenicity may be lost with pyrolysis.
Coltoiu, et al. (9) recently emphasized the importance of remov-
ing all irritants from test extracts. In a clinical setting, allergy to
tobacco additives such as menthol has also been suspected (47).

SKIN TESTING

Intracutaneous injection of test antigen is a widely used method
of skin testing. Patch tests have also been used in cases of suspected
contact dermatitis.

RQsen (54) has observed that skin testing does not accurately
duplicate the most common route of exposure to tobacco, i.e., tobacco
smoke inhalation. For those involved in the production of tobacco
products, inhalation 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 "normal" nonsmoking adults (17,
68). "normal" 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 reported on
tobacco skin reactions in several different groups of patients (30).
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 injection 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-and-flare response has
been by far the predominant type (42).

This immediate wheal-and-flare response is a specific immunere-
action (64) largely mediated by IgE. Patterson (48) recently pro-
posed a simplified model explaining the mechanism of action of the
akin sensitizing antibody (SSA). "Subsequent to stimulation of the
ammal by antigen, SSA are produced by cells of the lymphoid sys-
tem possibly located in the alimentary andrespiratory tract. . . . The
SSA SO produced are secreted in such a way that they reach the cir-
culation, where circulating cells, predominantly basophilic leuko-
V'~J.% are sensitized by attachment of the SSA to the cell surface.
In addition, the SSA also leave the vascular compartment and sen-
sitize mediator-releasing eelis in tissues. The tissue cells are pri-
marily mast cells . . . The immediate-type allergic reaction occurs

515


when antigen iz introduced into the individual sensitized by SSA,
either by transfer of antigenic molecules through the respiratory or
alimentary mucosal surface or by injection into the skin or vascular
ayatem. The antigens reach the antibody on the surface of the mast
cells 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 cIinica1 pictures as hay fever, asthma,
and generalized anaphylaxiz.

Until recently, direct skin testing and the passive transfer test
(Prausnitz-Kiistner reaction) were the only methods of studying
IgE mediated responses. In the passive transfer test, serum from
an allergic patient is injected into the skin of a normal subject.
After a suitable interval the antigen is injected into the prepared
aite 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 irritation as a cause of the response and shows that the
normal subject is not himself allergic to the antigen.

Harkavy and Witebsky (34) found and selectively absorbed
tobacco reagins in patients showing multiple sensitivities. This se-
lective absorption documented the immunologic mechanism of the
skin reaction. Passive transfer of the SSA was also reported by
Peshkin and Landay (50) and by Lima and Rocha (42). Lowell
(4.9) stated, "The individual possessing skin-sensitizing antibody
to the tobacco extract may be regarded as unequivocally allergic to
the extract.. . ." Despite the inability of Sulzberger and Feit (67)
to demonstrate tobacco reagins in their skin test positive patients,
several investigators have found them (26, 50, 75).

Harkavy (29) biopsied urticarial wheals after intradermal injec-
tion of tobacco extract and found a local eosinophilia. He feIt that
this heIped confirm the allergic mechanism of the positive skin test.
He also biopzied the site of a delayed skin reaction to tobacco and
found an eczematous type of rezponse.

The delayed type hypersensitivity reaction is manifested by ip-.
duration and erythema developing within 24 to 48 hours after injec-
tion of antigen. The absence of response in the first 6 to 8 hours
after exposure to antigen helps exclude ariArthus reaction, which ie
alzo a slowly evolving allergic response. Serum antibodies are not
involved in the initiation of delayed type hypersensitivity; rather,
the initial etep iz thought to involve interaction of antigen and spec-
ialized lymphocytes (10, 21). Contact dermatitis is thought to be
very nearly a pure type, delayed hypersensitivity reaction (10, II).

The foregoing dizcuzzion haz highlighted the studies concerning
C~~MMXM senzitivity to tobacco extracts. Despite the complexities
and contradictiona, numerouz workerz agree that tobacco extract

516


(leaf or smoke) is antigenic and can sensitize (2, 7,9,fs, e6,4s, 50,
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 (4s) 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. Armen and Cohen (2)) Harkavy
and Perlman (SZ) , and Popescu, et al. (52) observed that tobacco
extract is weakly antigenic. Armen and Cohen (2) were able to
sensitize rabbits to tobacco proteins only after absorbing the pro-
tein to aluminum hydroxide, which served as an adjuvant.
Even though a positive skin test to tobacco extract may be due to
a specific allergic reaction, 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 individ-
uals who are entirely free from allergic symptoms upon exposure
to the antigens. Rosen (54) stated that this lack of correlation be-
tween positive skin tests and clinical symptoms is greater for to-
bacco than 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 "healthy" 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, 4.9) have considered patients with multiple sensitivities,
inchrding that to tobacco. Atopic individuaIs 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 a 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. (I.?), Fontana (17), and Redisch (53)
have reported that patients with positive skin tests to tobaccoex-
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 a 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 to support the view that tobacco
induces immunologic changes in man and animals, Armen and

517


Cohen (2) , Chu. et al. (7)) Harkavy and Perlman (.?I ), and Zuss-
man (76) induced precipitin formation in animals sensitized to
tobacco extract. Kreis, et al. (39) studied precipitation reactions in
651 hospitalized patients, many of whom were suffering from tu-
berculosis or lung cancer. A precipitation reaction between the pa-
tients' sera and a commercial tobacco extract was found in 62.6 per-
cent of the patients. Chu, et al. (7)) using the same antigens as
those employed to stimulate precipitin formation in rabbits, found
serum antibodies in 40 percent of a group of smokers which precipi-
tated specificially with the tobacco antigens. Only 7 percent of a
group of nonsmokers demonstrated these antibodies.
Save1 (59) studied eight nonsmoking, allergic individuals who
developed immediate upper respiratory discomfort after being ex-
posed to cigarette smoke. As measured by the uptake of tritiated
thymidine, the lymphocytes of these individuals were stimulated by
cigarette smoke, while "normal" lymphocytes were depressed. The
author stated that the correlation of this test with specific forms of
clinical allergy remain9 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-
phiiia while smoking cigarettes. Upon cessation of smoking, the
eosinophil count returned promptly to normal levels. Resumption of
smoking was associated with a return of the eosinophilia. Heiskell,
et al. (36) found a significant increase in C-reactive protein and an
abnormal seroflocculant for ethyl choledienate in smokers as com-
pared to nonsmokers. Plasma histaminase Ievels were reported by
Kameswaran, et al. (~8) to be elevated in smokers.

Experimental animal sensitization to tobacco was reported by
Friedlander, et al. (19) in male rats. Harkavy (29) confirmed these
results in male rats and also obtained positive Schultz-Dale reac-
tions in the sensitized animals ; however, female rats failed to dem-
onstrate this sensitization. Harkavy (24) reported cardiac histo-
logical abnormalities in three rabbits sensitized with denicotiniz+%l
tobacco extracts. The abnormalities found in the three rabbits, re-
spectively, &luded: 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; focal intimal prolifera-
tion and fibrinoid alterations in the media of a small coronary ve9-
se1 ; and a focus of myocardial fibrosis and necrosis.

      EFFECT ON THE IMMUNE RESPONSE
The effect of tobacco on the immune response has received some
attention. Early studies in rabbits suggested that tobacco smoke re-

518


tarded the production of agglutinins in rabbits immunized against
typhoid (14).

A variety of observations indicate that ingestion of antigenic
material by the macrophage may be an essential step in the immune
response (3). Bruni (5) found that cigarette smoke suppressed
phagocytosis in rabbits. Green and Carolin (20) performed in vh-0
studies in rabbit alveolar macrophages and observed that cigarette
smoke inhibited the capacity of these cells to inactivate bacteria.
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 (8)) while noting that macrophages
from smokers had normal phagocytic capacity, demonstrated sub-
optima1 macrophage function in an environment of low 0, 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 inactivate bacteria. Nicotine has been shown
by Meyer, et al. (46) to exert a depressant effect on sheep pulmo-
nary alveolar macrophage respiration and ATPase activity. Re-
cently, Yeager (74) 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
action on secretory IgA production in normal subjects but not in
subjects with chronic respiratory disorders. Vos-Brat and Rumke
(71) recently reported that IgG serum concentrations and the re-
sponse of lymphocytes to phytohemagglutinin were significantly
lower in smokers than nonsmokers.

A number of investigators have reported increased rates of res-
piratory illnesses among cigarette smokers (70). Finklea, et al.
(16) studied antibody response in 289 volunteers after the 1968
Hong Kong influenza epidemic. They reported a significant decrease
among cigarette smokers in the persistence of hemagglutination in-
hibition antibody after natural infection or vaccination with A2
antigens. They postulated that this antibody deficit among cigarette
smokers might be related to increased illness during influenza out-
breaks.

IRRITANT AND PHARMACOLOGIC EFFECTS

As Lowell (43) has emphasized, the pharmacologic, irritant, and
allergic effects of tobacco are difficult to distinguish. Acrolein and
acetaldehyde are potent irritants found in tobacco smoke, which, as
demonstrated in animal studies, are capable of releasing chemical
mediators such as histamine (58). The inhalation of tobacco smoke

519


causes bronchial constriction, mucus hypersecretion, and ciliary
stasis (57) in man, all of which can contribute to a clinical picture
indistinguishable from an allergic reaction. Several authors (44,61,
65) 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 two
groups of nonsmokers to tobacco smoke 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
history of allergy and was studied by questionnaire 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 in 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 (80) cited experimental data distinguishing allergic
effects from pharmacoIogic effects of smoking such as increased
heart rate and decreased skin temperature.
Additional studies are needed to separate the pharmacologic, ir-
ritant, and allergic effects of tobacco smoke.

CLINICAL ALLERGY

It is important to understand what roIe 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 manifesta-
tions toward tobacco leaf or smoke including: asthma, rhinitis,
urticaria, angioneurotic edema (giant hives), contact dermatitis,
migraine headache, gastrointestinal symptoms, and various cardio-
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 individuals have revealed a group of nonsmoking
Patients with cutaneous sensitivity to tobacco who developed clinica
symptoms upon exposure to tobacco smoke (59, 76). In none of
these studies (54,59, 76) have detailed immunologic investigations,
attempting to link clinical and immunologic events, been performed.
Lowell (43) reviewed case reports of contact dermatitis to to-

520


bacco among tobacco workers and noted that because of I`.. . the small
proportion of exposed individuals who develop such lesions, and the
tendency for it to cIear compIetely when contact with tobacco is
avoided and to return on reexposure, an allergic cause in certain
instances would appear to be highly probable." Recently, case re-
ports have appeared identifying tobacco smoke and tobacco smoke
residue as causes of contact dermatitis (6,12, 72).

Harkavy's (28) early reports of a greater number of reactors to
tobacco extract among patients with thromboangiitis obliterans
(TAO) than among controls drew attentiqn to the cardiovascular
system as a possible "susceptible" organ for allergic reactions (15).
Harkavy continues to be a strong proponent of the role of tobacco
allergy in a wide range of cardiovascular abnormalities, including
coronary artery disease (21, 22, 25, 27, 31, 32). This view on
tobacco allergy as one of the etiological factors in coronary heart
disease (CHD) has not received much attention.
Silvette, et al. (64) reviewed reports (28, 33, 66, 68, 7.3) on the
prevalence of skin 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, the evidence relating T-40 to tobacco allerg)l is incon-
clusive.

SUMMARY

1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic
  in 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.
   Precipitating antibodies specific for tobacco antigens
    have also been found in both smokers and nonsmokers.
(b) A delayed type of hypersensitivity to tobacco has been
    demonstrated in man.
(c) Tobacco may exert an adverse effect on protective mecha-
    nisms of the immune system in man and animals.

3.  (a) Tobacco smoke can contribute to the discomfort of many
   individuals. It exerts complex pharmacologic, irritative,
   and allergic effects, the clinical manifestations of which
   may be indistinguishable from one another.
(b) Exposure to tobacco smoke may produce e-xacerbation 01
   allergic symptoms in nonsmokers who are suffering from
    allergies of diverse causes.

4. Little is known about the pathogenesis of tobacco allergy and
its possible relationship to other smoking-related diseases.

521


ALLERGYREFERENCES

(1) ALLI%X, R. D., ROTH, G. NI. Central and peripheral vascular effects
   during cigarette smoking. Archives of Environmental Health 19(2) :
   189-198, August 1969.

(2) ARXEN. R. N.. COHEN, S. The effect of forced inhalation of tobacco
   smoke on the electrocardiogram 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 altered immune
   response. IN: Wintrobe, M. M., Thorn, G. W., Adams, R. D., Bennett,
   I. L., Jr., Braunwald, E.. Isselbacher, K. J., Petersdorf, R. G. (Editors).
   Harrison's Principles of Internal Medicine. Sixth Edition. New York,
   McGraw-Hill Book Company, 1970. p. 342.
(4) BLUE, J. A. Cigarette asthma and tobacco allergy. Annals of Allergy
   28(3) : 110-115. March 19'70.

(5) BRUNI. A. Influenza dell'awelenamento da fumo di tabacco sulla fngo-
    citosi. (Effect.of tobacco smoke poisoning on phagocytosis.) Speri-
   mentale 85: 523543, 1931.

(6) CH~IAL, G., JOSEPH, J., COLIN. L., Ducuux, C. Les dermites chez les
   travailleurs du tabac (B propos de 9 observations). (Dermatitis in
   tobacco workers. Nine observations.) Bulletin de la Societi? Francaise
   de Dermatologie et de Syphiligraphie 77 (2) : 281-283, July 1970.
(7) CHU, Y. b'f.,PARLETT. R. C., WRIGHT, G. L.. JR A preliminary investi-
   gation of some immunologic aspects of tobacco use. American Review
   of Respiratory Disease 102(l) : 118-123. July 1970.
(8) COHEN, A. B., CLINE. hi. J. The human alveolar macrophage: Isolation,
   cultivation in vitro, and studies of morphologic and functional char-
   acteristics. The Journal of Clinical Investigation KO(7) : 1399-1398,
   July 1971.

(9) COLTOIU, A., bIATEESCU, D., LEEE. V. Consideratii privind sensibilizarea
   la tatun. (Considerations concerning sensitization to tobacco.) Vista
   hIedicala 16(l) : 2937, January 1969.
(IO) COOMBS, R. R. A. The basic types of allergic reactivity producing disease.
   Triangle 9(2) : 43-46, 1969.

(11) COOMBS, R. R. A., GFZLL, P. G. H. Classification of allergic reactions re-
   sponsible for clinical hypersensitivity and disease. Chapter 20. IN:
   Gell, P.G.H., Coombs, R.R.A. (Editors). Clinical Aspects of Immu-
   nology. Second Edition. Philadelphia, F. A. Davis Company, 1968. pp-
     675596.

(12) CORMIA. F. E., DEGAIU, P. F. Vesiculobullous dermatitis from tobscco
    smoke. Journal of the American Medical Association 193(6) : 391-392,
    August 2, 1965.

(13) DECRINIS, K, REDISCH, W., FONTANA, V., Lgwrs, A., SUL.ZBERCE& M.
   B., STEELE, J. M. Vascular responses to smoking tobacco compared
   with responses to skin testing of tobacco extracts. Annals of Internal
   Medicine 62(6) : 1035-1041, May 1960.

(14) DONXLLI, F. Influenza sulle aggiutinine dell'awelenamento da fumo
   di tabacco. (Effect of tobacco smoke poisoning on agglutinins.) Gior-
   nale di Batteriologia e Immunologia 11: 1012-1018, 1933.
(15) FERSIL, A. Die bedeutung der tabakrauchallergie bei erkrankungen
   des Gaftisssystems. (The importance of allergy to tobacco in diseases
   of the vascular system) Weiner Zeitschrift fiir Innere Medizin und
   Ihre Grenzgebiete 43: 455-458, 1962.

(16) FIN- J. F., HASSELBLAD, V., RIGCAN, W. B., NELSON, W. C., HAM-
   MEX, D. I., NEWILL, V. A. Cigarette smoking and hemagglutination

i22


inhibition response to influenza after natural disease and immunize-
tion. American Review of Respiratory Disease 104 (3) : 368-376. Sep-
tember 1971.

(17) FONTAYA, V. J. Tobacco hypersensitivity. Annals of the New York
   Academy of Sciences 90(l) : 138-141, September 27, 1960.
(18) FONTMA. V. J., REDISC~, W.. NEMILR. R. L., SMITH. M. K.. D~Cmsrs.
   K., S~L~BER~E~ hi. B. Studies in tobacco hypersensitivity. III. Reac-
   tions to skin tests and peripheral vascular responses. Journal of
   Allergy 30(3) : 241-249, May-June 1959.
(19) FRIEDLANDER, N.. SILBERT, S., LXXEY. N. Toe lesions following tobacco
   injections in rats Proceedings of the Society for Experimental Biology
    and Medicine 34: 156157, 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. 1967.
(21) HARWW, J. Cardiac manifestations due to hypersensitivity. Annals of
    Allergy 28(6) : 242-251, June 1970.
(ze) HARJU~Y, J1 Cardiovascular manifestations due to hypersensitivity.
    New York State Journal of Medicine 69(21) : 2757-2765, November
    1, 1969.

(~3) HAXKAW, J. Hypersensitiveness to tobacco and biopsy studies of skin
   reactions in vascular disease. Journal of Allergy 9:47b88, 1938.
(2~) HARKAW, J. Tobacco allergy. Chapter 13. IN: Vascular Allergy and
   its Systemic Manifestations. Washington, Buttenvorths, 1963. pp.
     101-116.

(2.5) HARKAYY, J. Tobacco albergy in cardiovascular disease: A review.
   Annals of Allergy 26(8) : 447-459, August 1968.
(26) HARWW, J. Tobacco allergy in vascular diseases. Review of Allergy
   and Applied Immunology 11: 189-212. March 1957.
(~7) HARKA~Y, J. Tobacco sensitiveness in angina pectoris and coronary
   artery disease. Proceedings of the Society for Experimental Biology
    and Medicine 30: 683-684, 1933.

(28) HARKAYY, J. Tobacco sensitiveness in thromboangiitis obliterans, mi-
   grating phlebitis and coronary artery disease. Bulletin of the New
   York Academy of Medicine 9: 318-322, 1933.
(29) HAXKAW, J. Tobacco sensitization in rats. Journal of Allergy 9: 275-
   277,1938.

(JO) HARKAW, J. Tobacco skin reactions and their clinical significance. The
   Journal of Investigative Dermatclogy 2: 257-279, 1939.
(31) HARKAW, J., PERLMAN, E. Tobacco allergy in coronary artery disease.
   Annals of the New York Academy of Sciences 90(l) : 327-332, Sep-
   tember 27, 1960.

(32) HARKAW. J.. &KLMAN. E. Tobacco allergy in coronary artery disease.
   New York State Journal of hIedicine 64 (11) : 1287-1296, June 1, 1964.
(JJ) HARKAW. J., ROMANOFF, A. Skin reactions to tobacco and other aller-
   gens in normal men and women smokers. Journal of Allergy 6: 62-
    70, 1934.

(34) HARKAW. J., WITEBSKY, E. Studies of specificity in multiple hyper-
   sensitiveness by quantitative titration and absorption of reagins.
   Journal of Allergy 6: 437-44'7, 1935.

(35) HARRIS, J. O., SWENBON, E. W., JOHNSON, J. E. III. Human alveolar
   macrophages: Comparison of phagocytic ability, glucose utilization,
    and ultrastructure in smokers and nonsmokers. The Journal of Clini-
   cal Investigation 49: 2086-2096, 1970.

523


(ST) HEIS~~E~L, c. L., NILLEX, J. N.. ALDRICH. a. J., CARPENTRY C. M. Smok-
  ing and serologic abnormalities. Journal of the American Medicai
   Association 181(8) : 6'7-77. August 25, 1962.
(17) ISHLWCA, K. The identification and significance of Gamma K. Hospital
   Practice: `/ml, September 1969.

(~8) KAMESWARAN, L., K,WAKAMW., IL.. VIJAYASEKARAN, V. Studies on
  plasma histaminase levels in normal and allergic individuals. Indian
   Journal of Physiology and Pharmacology 12(4) : X9-166, October
     1968.

(39) KREB, B., PELTER, A., FOWWAUD. S., DUPIN-GIROD. S. Reaction de
  precipitation entre certains serums humains et des extraits solubles
   de tabae (Precipitation reaction between certain human sera and
   soluble tobacco extracts.) Annales de Medecine Inteme 121(4) : 437-
    440, April 1970.

(40) ms, D. hf., LAPP, N. LER., B-L, R. Quantitation of secretory
   immunoglobulin A in chronic pulmonary disease. American Review
   of Respiratory Disease lOl( 1) : 65-61, January 1970.
(U) LIP A. 0.. R~CHA, G. Cutaneous reactions to tobacco antigen in aller-
   gic and nonallergic children. Annals of Allergy `f(4) : 628-631, July-
   August 1949.

(.&) LOUNSBURY, J. B., OUGHTEFSON. A. W. Specificity of tobacco antigen.
   Yale Journal of Biology and Medicine `7(4) : 306316, March 1935.
(43) Lo-. F. C. Allergy. IN: Wynder, E. (Editor). The Biologic Effects
   of Tobacto. Boston, Little, Brown, and Company, 1966. pp. 161-170.
(44) MAUKEII, M. L., SPAIN, W. C. The allergic response to tobacco. Journal
   of the American Geriatric Society 2: 278-283, 1954.
(45) MAXWELL, K. W., MARCUS, S., RENZFITI, A. C., JR. Effect of tobacco
   smoke on the phagocytic and cytopeptic activity of guinea pig alveolar
   macrophages. American Review of Respiratory Disease 96(l) : 156,
     1967.

(46) MEYEX, D. H., CROSS, C. E., IBRAHIM, A. B., MIJSTAFA, M. G. Nicotine
   effects on alveolar macrophage respiration and adenosine triphos-
   phataae activity. Archives of Environmental Health 22(3) : 362-366,
    March 1971.

(47) PAPA+ C. M., SHELL=, W. B. Menthol hypersensitivity. Diagnostic
   hasophil response in a patient with chronic urticaria, flushing, and
   headaches. Journal of the American Medical Association 189(7) :
   646-648, August 17.1964.
(48) PATTFXRO N, R. Skin-sensitizing antibodies. Advances in Internal Medi-
   cine 16: 361371, 1970.

(4P) PAYI.IK, I., CERMAKOVA, Z. Casna komi reakce na tabakovy extra&u
   chorob dychadel. (Early skin reaction against tobacco extract in res-
   piratory system disease.) Rozhledy v Tuberkulose av Nemocech
   Plknich 24(9) : 629-635, 1964.

(50) I'fZEKlX, M. M, IANDAY, L. H. Cutaneous reactions to tobacco antigen
   in allergic and nonallergic children with the direct and indirect (local
   passive transfer) methods of testing. Journal of Allergy 10: 241-246,
     1939.

(61) m. D. hi. Allergy to tobacco smoke. Annals of Allergy 28(3) : 277-
   282, July-August 1946.

(at) pO=X'J. 1. G., PAUN, R., MOLNEB. C., O~ARU, c., GH~RCEIU, T,, IOTA.
   C. G. Contributii la studio1 alergiei la tatun. (Contributions to the

stndy of tobacco allergy.) Revue Roumaine de Medecine Intema l(6) :
427-436, 1964.

524


(63) R~Ix~, W- Tobxco allergy and vascular responses. IN: James, G.,
    Rosenthal. T. (Editors). Tobacco and Health. Springfield, C. C.
    Thomas, 1962. pp. 352359.
(5-h) ROSEN, F. L. Studies in tobacco allergy. Journal of the Bfedical Society
    of New Jersey 61(3) : 109-114, March 1964.
(55) ROSEN. F. L., LZVY, A. Bronchial asthma due to allergy to tobacco smoke
    in an infant. A case report. Journal of the American Medical Asso-
    ciation 144(8) : 620-621, October 21.1960.
(55) ROTE, G. M., SCHICK, R. M. The effects of smoking on the peripheral
    circulation. Diseases of the Chest 37(Z) : 203210, February 1960.
(57) ROYAL COLLEXE OF PHYSICIA??S. Smoking and Health Now. London,
    Pitman Medical and Scientific Publishing Company, Ltd., 1971.148 pp.
(58) SNNDELLE, A.. RUFF, F., Fuvuu. N.. PARUM. J.-L. Liberation d'his-
    tarnine par des aldGhydes B courte chaine. (Liberation of histamine
    by short-chain aldehydes.) Comptes Rendus Hebdomadaires des
    Seances de I'Academie des Sciences Paris. Series D 266(Z) : 139-141,
    January 8, 1968.
(59) SAYEL, H. Clinical hypersensitivity to cigarette smoke. Archives of En-
    vironmental Health 21(2) : 146148, August 1970.
(50) SCHOEN, I.. PIZFX, M. Eosinophilia apparently related to cigarette smok
    ing. New England Journal of Medicine 270(25) : 1344-1347, June 18,
     1964.
(61) SHEUXIN. J. M., LOWXL. R. G., BfATrxws, K. P. (Editors). House dust
    and miscellaneous allergens. IN: A Bfanual of Clinical Allergy. Sec-
    ond Edition. Philadelphia, W. B. Saunders Co., 1967. pp. 437-456.
(62) SIIEXMAN, W. B. (Editor). Agents causing atopic diseases. IN: Hyper-
    sensitivity. BIechanisms and Management. Philadelphia, W. B. Saun-
    ders Company, 1968. p. 130.
(65) SHUFZ, N., HARRIS, M C. Distribution of commonplace inhalant aller-
    gens. Chapter 4. IN: Harris, M. C., Shure, N. (Editors). Sensitivity
    Chest Diseases. Philadelphia, F. A. Davis Company, 1964. pp. 62-97.
(64) Sx~vxnx, H., LAMON, P. S., HAAG, H. B. Immunological aspects of
    tobacco and smoking. American Journal of the Medical Sciences
    234 (6) : 661-689, November 1957.
(65) SPEZK, F. Tobacco and the nonsmoker. A study of subjective symptoms.
    Archives of Environmental Health 16(3): 443-446, March 1968.
(88) S~LZSERI.XIZ, M. B. Studies in tobacco hypersensitivity. I. A comparison
    between reactions to nicotine and to denicotinized tobacco extract.
    Journal of Immunology 24(l) : S&91, 1933.
(87) SKJL~~ER.~E~, M. B., FEIT, E. Studies in tobacco hypersensitivity. II-
   Thromboangiitis obliterans with positive urticarial skin reactions and
   negative reagin findings. Journal of Immunology 24(b): 425-432,
     1933.
(68) `I-IUSOFF, A., BLUMSl'EIN, G., B~ARKs, M. The immunologic aspect Of
   tobacco in thromboangiitis obliterans and coronary artery disease.
    Journal of Allergy 7: 260-253`1936.
(85) U.S. PUBLIC HE~L~TH SERVICE. Smoking and Health. Report of the Ad-
   visory Committee to the Surgeon General of the Public Health Service.
   Washington, U.S. Department of Health, Education, and Welfare,
   Public Health Service Publication NO. 1103, 1964. 387 PP.
(70) U.S. R,TILIC HEALTE SERVKX The Health Consequences of Smoking-
   A &port of the Surgeon General: 1971. Washington, U.S. Depart-
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7613. 1971. 468 PP-

                                       525