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

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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)
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20 C.~LUSEINOVA. V. 3.4 - Benrpyrcne determ~nz~t~on in the smoky xtrnosph~re of
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    ,,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.
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    (`0 ~~,nc~ntr.~l~w ,n otlice rooms. Inrerru~wnatri Arch~v iur Arbrlltmedizin
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26  Ft.-IRKt<. H. -P.. BLEICtll:RT. A. Zurn Problem des P3ssivrwchens (The problem of
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27  HARKE. H.-P.. LIEDL. W., DENKER, D. The problem of' passive smoking. II.
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28  IIARKE. H. -P.. PETERS. H. The problem of passive smoking 111. The influence of
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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
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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.
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  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.
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     December I97 I. 85 pp.
49  U.S. PL'ULIC HEALTH SERVICE. The Halth Conwqurncrs or Smnkine. A Report of
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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

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