Similar types of diverse effects on drug disposition caused by
marijuana have been found in man. Vessel1 and Passananti (78) found
that oral doses (0.6 mg/kg/day) of Ag-THC for 7 days caused a slight
increase in the antipyrine tl;z. Dalton, et al. (18) examined the effects
of smoking a marijuana cigarette containing 0, 150, and 500 pg/kg
cannabidiol (a major cannabinoid constituent of Cannabis sutira) and
found that cannabidiol did not alter secobarbital disposition.

Lemberger, et al. (41) found that chronic marijuana users eliminated
Ag-THC from blood plasma with a tl/z of 23 hours compared to 57 hours
in nonusers. The apparent volume of distribution did not significantly
differ between the two groups.

Purified cannabinoid appears to inhibit the induction of the drug-
metabolizing enzyme, but the marijuana smoke is generally inhaled;
the chronic inhalation of marijuana smoke results in enzyme induction
caused by the PAHs in the smoke. The multiple components in the
smoke of a "joint" may play an additive or an inactive role in altering
drug disposition as does tobacco smoking. Therefore, the chronic use of
marijuana must be considered as a source of pharmacological drug
interaction not only because of its psychoactive actions, but also
because of its ability to stimulate or to inhibit the metabolic rate of
susceptible drugs used in man.

Summary

Despite the warning "The Surgeon General Has Determined That
Cigarette Smoking Is Dangerous To Your Health" on each pack of
cigarettes, the use of tobacco is still "enjoyed" by one out of three
adults in the United States. This extensive use of tobacco and the
frequency of altered disposition and pharmacological effects of many
drugs in smokers make it apparent that smoking of tobacco should be
considered as one of the primary sources of drug interactions in man.

The majority of the in vivo and in v&o experimental work
conducted to the present time indicates that the dominant effect of
smoking is enhanced drug disposition caused by an induction of hepatic
microsomal enzymes. The primary causal agent for this induction is
probably the PAHs which are potent enzyme inducers and which are
persistent in the tissues. Many other ingredients of tobacco smoke are
capable of inducing (nicotine, cadmium, and insecticides) or inhibiting
(carbon monoxide and hydrogen cyanide) drug-metabolizing enzymes.
Inhibition of the drug-metabolizing enzymes is apparently overridden
by the inducers in tobacco smoke, because presently there are no
reports of diminished rates of drug metabolism in man or animals
treated with tobacco smoke. Alteration of drug-transport processes can
occur, as seen by the enhanced bioavailability of glutethimide by
smokers, but this does not appear to be a common pathway. Diminished
protein binding of drugs in smokers could occur, but there is no
evidence for this at the present time. Factors such as the volume of

12-43


distribution of drugs in smokers and nonsmokers have been examined.
The variability in drug disposition for antipyrine and theophylline was
appreciable. There is evidence for genetic control of the degree of
enzyme induction from smoking which may also be a common factor in
the carcinogenicity of inhaled chemicals.

Reports of altered pharmacological or toxicological effects of drugs
in smokers can sometimes be explained by induced metabolism of the
drug (pentazocine, theophylline). On the other hand, smokers differ
from nonsmokers in their pain threshold, psychosomatic characteris-
tics, and drug consumption; the presence of substances, such as
nicotine, which cause competing or additive pharmacological effects,
may complicate the action of drugs used in treating pain or anxiety
(propoxyphene, benzodiazepine, chlorpromazine).

In addition to the identification of a wider array of drugs, enzymatic
pathways, and clinical effects which are altered by tobacco smoking,
future studies should investigate the role of smoking in affecting other
clearance processes. Even though it is known that some of the hepatic
microsomal drug-metabolizing enzymes are stimulated in smokers, the
selectivity of this induction is unpredictable and the effects of smoking
on other potential rate-limiting disposition processes, such as the effect
of smoking on protein binding of various drugs, and the contribution of
nonhepatic tissue such as kidney, lung, and intestine are largely
unexplored.

12-44


Effects on Pharmacokinetlcs and Pharmacodynamics:
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Specific Drug Interactions
Oral Contraceptives

In early 1970, Frederiksen and Ravenholt (8) presented data showing
an association between thromboembolism and smoking. Sartwell (16),
however, reported that he could find no evidence that smoking
enhanced the effect of oral contraceptives to produce increased blood
clotting. In 19'73, the Collaborative Group for the Study of Stroke in
Young Women (5) stated that cigarette smoking may potentiate the
effect of oral contraceptives on thromboembolism or cardiovascular
disease. A subsequent report by this Group (6) showed that women who
took the pill and smoked one pack of cigarettes had a ZOO percent
increased risk of a stroke. Perhaps the most important articles
published on smoking and oral contraceptives were published by Mann,
et al. (12,13). In these articles, the authors quantitated the association
between cigarette smoking and oral contraceptives. They showed that
the relative risk of myocardial infarction increased from 1.2 in women
smoking fewer than 15 cigarettes a day, to 4.1 in women smoking 15 to
24 cigarettes a day, and to 11.3 in women smoking 25 or more
cigarettes a day. Jain (9) reanalyzed the data from the United States
and Great Britain and reported that: (1) the use of oral contraceptives
in the absence of smoking is considerably safer than no fertility control
for all ages, including the group aged 40-44; (2) the use of oral
contraceptives among smokers aged 40 and over is substantially more
hazardous than no fertility control, although there is little difference
for light smokers; (3) the use of oral contraceptives among heavy
smokers in the group aged 30-39 may be more hazardous than no
fertility control; and (4) the use of oral contraceptives among heavy
smokers in the group aged 15-29 may be more hazardous than any
other method of fertility regulation. Ory (15) has stated that his
analyses show "that cigarette smoking is the most important factor in
increasing the likelihood of myocardial infarction." The effect is
independent of oral contraceptive use, but oral contraceptive use also
appears to be a risk factor. The use of oral contraceptives in the
absence of other predisposing factors appears, however, to have only a
small effect in increasing the risk of dying from myocardial infarction.

Beral (.2) has shown that the death rate from diseases of the
circulatory system in women who used oral contraceptives was 5 times
that of controls who had never used them; the death rate in those who
had taken the pill continuously for 5 years or more was 10 times that of
controls. The author concluded that the excess annual deaths were 1
per 10,090 for oral contraceptive users who had quit smoking and 1 per
3,000 users who smoke.

In a recent article, Jick, et al. (11), comparing oral contraceptive
users with nonusers, stated that, in otherwise healthy young women,
the relative risk of a myocardial infarction is 14. While myocardial

12-51


infarction is rare in most healthy women, the risk in women older than
37 years who smoke and take oral contraceptives appears to be high.

Tietzc (IN) has updated his findings on mortality related to
pregnancy. His article shows that up to the age of 30 the risk to life
from pregnancy and childbirth among noncontraceptors is far in excess
of that experienced by users of any method. After age 30, the
mortality risk experienced by pill users who smoke rises dramatically,
but among nonsmokers the risk remains relatively low-and is lower
than the risk of death among noncontraceptors even after age 40.

In another recent study Slone, et al. (17) investigated the smoking
habits of women under the age of 50 who had survived a recent
myocardial infarction. The subjects had not been using oral eontracep-
tives, and other identifiable risk factors were excluded. A dose-
response relationship was evident; among women smoking 35 or more
cigarettes per day the rate of myocardial infarction was estimated to
be some 2%fold higher than among those who had never smoked. This
study demonstrates quite strongly that cigarette smoking is a risk
factor for myocardial infarction in young women who are otherwise
apparently healthy.

Estrogens

A recent report (10) of apparently healthy women aged 39 to 45 who
were taking noncontraceptive estrogens estimated a relative risk of 7.5
for nonfatal myoeardial infarction, when comparing estrogen users
with nonusers. All but one of the nonfatal myocardial infarction
patients were cigarettes smokers. Although this is only one report, it
appears that women aged 39 to 45 may have a substantial risk when
they both smoke and take estrogens. Further study on this subject is
needed.

Cardiovascular Drugs

There is comparatively little clinical evidence of interactions between
smoking and cardiovascular drugs. The ability of smoking to stimulate
various hepatic microsomal enzymes is a potentially important effect
and affects numerous drugs, but, thus far, few such interactions have
been recognized. A second, potentially important set of interactions
could arise from interactions with the pharmacologic effects of
nicotine.

-4s summarized in detail in The Health Consequences of Smoking(l9)
nicotine causes increased heart rate, blood pressure, cardiac output,
stroke volume, myocardial contractility, myocardia1 oxygen consump-
tion, and arrhythmia formation, most of which is explained by release
of catecholamines from both neuronal and extraneuronal sites. Apart
from potential toxicity of elevated catecholamines, some interesting
potential interactions with drugs can be postulated; these have been

12-52


studied to some extent, although not definitively. Aronow, et al. (1)
have shown increased angina in patients who smoke.

Frank1 and Soloff (7) studied the interaction of smoking and
propranolol. They reported that, in four of five normal subjects,
smoking two cigarettes led to a small increase in blood pressure
associated with increased cardiac output, increased heart rate, and
decreased peripheral resistance (cigarettes are usually found to
increase peripheral resistance). When cigarettes were smoked after
treatment with propranolol, blood pressure increased further, heart
rate and cardiac output fell, and peripheral resistance increased. These
results are compatible with the predicted effects of propranolol, viz.
beta-blockade blocks the chronotropic, inotropic, and vasodilator
effects of the catecholamines (all beta effects), but does not affect
their peripheral vasoconstrictor effects (an alpha effect), thus unmask-
ing or exaggerating this effect. Propranolol is known to increase
peripheral resistance even in the absence of nicotine, however, and it
would have been helpful to examine the contribution of propranolol
alone to increased peripheral resistance by studying a group treated
with propranolol alone, in addition to the nicotine and nicotine-
propranolol groups. The results suggest, however, that the increase in
resistance was greater than that caused by propranolol alone;
propranolol normally decreases blood pressure, despite the increase in
resistance it causes in the absence of smoking, but in this study blood
pressure rose after propranolol administration. The reported hemody-
namic changes are in a direction generally considered harmful,
especially for persons with underlying cardiac disease.

Subsequently, Coffman (4) examined a closely related question,
measuring blood pressure and vascular resistance in the foot in 13
smoking volunteers before and after propranolol. He found that while
nicotine or smoking increased blood pressure and foot resistance over
baseline, the addition of propranolol did not seem to exaggerate these
effects, as the author felt would have been expected if propranolol
unmasked an alpha-adrenergic effect of smoking. This analysis may be
incorrect. An unusual finding of this study, similar to that of Frank1
and Soloff, is that propranolol increased both foot resistance (expected)
and blood pressure (not expected). Propranolol, despite increasing
peripheral resistance, is normally a hypotensive agent, presumably
because the vasoconstriction it causes is offset by decreased cardiac
output. The rise in pressure seen here suggests that the increased
catecholamines provoked by smoking were still present when propran-
0101 was given (it was always given after the first smoking period) and
that alpha-effects were in fact unmasked by propranolol-inhibition of
beta-mediated vasodilation. This explanation is strengthened by the
observation that the pre-smoking baseline blood pressure and foot
resistance were higher for the second (propranolol) phase of the study,
suggesting persistent cigarette effect.

12-53


The Frank1 and Soloff and the Coffman studies are thus not
necessarily incompatible, but their small size and lack of concurrent
controls render them inconclusive.

In a more recent study, Carruthers (3) examined the effects of
smoking low and high nicotine cigarettes on 12 normal volunteer
smokers given oxprenolol (a beta-blocker) and placebo on a crossover
basis before smoking. Oxprenolol prevented the smoking-induced rise
in heart rate and systolic and diastolic pressure seen in placebo-treated
subjects. There was no suggestion that it exaggerated this effect.
While this study certainly does not demonstrate unmasking of alpha-
stimulation, the blood pressure after high-nicotine smoking in oxpreno-
lol-treated patients was equal to the blood pressure before oxprenolol
or smoking in these patients. The nicotine thus obliterated the
hypotensive effect of oxprenolol.

The possibility that smoking reverses or blocks, even in part, the
antihypertensive effect of beta-blockers, a major antihypertensive
class, is obviously a suitable subject for study and a matter for concern.
We are not aware of any hypertension clinical trial that has analyzed
smoking as a covariant. It should also be noted that a "cardioseleetive"
beta-blocker, which would not block the beta-mediated peripheral
vasodilating effects of catecholamines, might behave differently from
propranolol.

Zuskin, et al. (21) studied the interaction on airways of beta-blockade
and smoking. They found that, in nonsmokers and light smokers,
cigarettes cause decreases in flow rates on maximum or partial
expiratory flow-volume curves, evidence of slight obstruction of small
airways, and that propranolol alone has no effect on these rates.
Propranolol did not add to these effects in light smokers or
nonsmokers, but potentiated the constricting effect of smoking in
regular smokers, who had little response to smoking alone. This was
interpreted as suggesting that beta-adrenergic stimuli protect smokers
against vasoconstriction, and that this protection can be removed by
beta-blockade. The interaction at this point appears to be of marginal
importance, but deserves further study, especially in persons with
impaired pulmonary function. Here too, it is likely that cardioselective
beta-blockers would behave differently from nonselective ones.

Furosemide

Vapaatalo, et al. (20) have reported a reduced diuretic effect of
furosemide in smokers, probably related to nicotine-stimulated in-
creased secretion of ADH. This interaction is of negligible clinical
significance.

Negative Findings
The ability of cigarette smoke to alter drug metabolism has led to
concern that it might alter anticoagulant metabolism and, therefore,

1244


anticoagulant dosage requirements. While many drugs affect warfarin
metabolism, Mitchell (14) reported that maintenance doses of warfarin
were not different in nonsmokers, light smokers, or heavy smokers.

12-55


Specific Drug Interactions: References

(f) ARONOW, W.S., KAPLAN, M.A., JACOB, D. Tobacco: A precipitating factor in
  angina pectoris. Annals of Internal Medicine 69(3): 529-536, September 1968.
(2) BERAL. V. Mortality among oral contraceptive users. Lancet 2: `727-731,
  October 81977.

(3) CARRUTHERS, M. Modification of the noradrenaline related effects of
  smoking by beta-blockade. Psychological Medicine, 6: 2.51~256,1976.
(4) COFFMAN, J.D. Effect of propranolol on blood pressure and skin blood flow
  during cigarette smoking. Journal of Clinical Pharmacology 9: 3944,
  January/February 1969.

(5) COLLABORATIVE GROUP FOR THE STUDY OF STROKE IN YOUNG
  WOMEN. Oral contraception and increased risk of cerebral ischemia or
  thrombosis. New England Journal of Medicine 288(17): 8'71-878, April 26,1973.
(6) COLLABORATIVE GROUP FOR THE STUDY OF STROKE IN YOUNG
  WOMEN. Oral contraceptives and stroke in young women: Associated risk
  factors. Journal of the American Medical Association 231(7): `718722, February
   17,1975.

(7) FRANKL, W.S., SOLOFF, L.A. The hemodynamic effects of propranolol
  hydrochloride after smoking. American Journal of the Medical Sciences 254:
  623-628, November 1967.

(8) FREDERIKSEN, H., RAVENHOLT, R.T. Thromboembolism, oral contracep
   tives, and cigarettes. Public Health Reports 85(3): 197-295, March 1970.
(9) JAIN, A.K. Mortality risk associated with the use of oral contraceptives. Studies
   in Family Planning 8(3): 59-54, March 1977.
(10) JICK, H., DINAN, B., ROTHMAN, K.J. Noncontraceptive estrogens and
   nonfatal myocardial infarction. Journal of the American Medical Association
   239(14): 1467-1468, April 3,1978.
(If) JICK, H., DINAN, B., ROTHMAN, K.J. Oral contraceptives and nonfatal
   myocardial infarction. Journal of the American Medical Association 239(14):
   1463-1496, April 3,1978.

(12) MANN, J.I., INMAN, W.H.W. Oral contraceptives and death from myocardial
   infarction. British Medical Journal 2: 245248, May 3,1975.
(13) MANN, J.I., VESSEY, M.P., THOROGOOD, M., DOLL R. Myocardial infarction
   in young women with special reference to oral contraceptive practice. British
   Medical Journal 2: 241245, May 3,1975.

(14) MITCHELL, A.A. Smoking and warfarin dosage. New England Journal of
   Medicine 287(22): 1X3-1154, November 30,1972.
(15) ORY, H.W. Association between oral-contraceptives and myocardial infarction -
   A review. Journal of the American Medical Association 237(24): 26192622,
   June 13,1977.

(26) SARTWELL, P.E. Oral contraceptives and thromboembolism: A further report.
   American Journal of Epidemiology 94(3): 192201, September 1971.
(17) SLONE, D., SHAPIRO, S., ROSENBERG, L., KAUFMAN, D.W., HARTZ, S.C.,
   ROSSI, AC., STOLLEY, P:D., MIETTINEN, O.S. Relation of cigarette
   smoking to myocardial infarction in young women. New England Journal of
   Medicine 298(23): 1273-1276, June 8,1978.
-(18) TIETZE, C. New estimates of mortality associated with fertility control. Family
   Planning Perspectives 9(2): 74-76, March/April 1977.
(19) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
   Reference Edition: 1976. Department of Health, Education, and Welfare,
   Public Health Service, Center for Disease Control, HEW Publication No.
   .(CDC) 788357,1976,657 pp.
(20) VAPAATALO, HI., NELJVONEN, P.J., TISSARI, A., MANSNER, R., PAASO-
   NEN, M.K. Effect of cigarette smoking on diuresis induced by furosemide.
   Annals of Clinical Research 3: 159162,197l.

i2-56


(21) ZUSKIN,E., MITCHELL,C.A.,BOUHUYS, A. Interaction between effects of
  beta blockade and cigarette smoke on airways. Journal of Applied Physiology
   36(4): 449-452, April 1974.

12-57


Biologicals
Viral Vaccines

Most viral vaccines, such as poliovirus, measles virus, mumps virus, and
rubella virus, are primarily administered to children. Some viral
vaccines, such as influenza, are administered to persons of all ages in
the general population during pandemic periods. During other periods,
those persons at high risk, such as the elderly or persons with chronic
upper respiratory and other debilitating diseases, are vaccinated. Other
vaccines are given to groups of people at high risk; for example,
adenovirus vaccine to military recruits or yellow fever vaccine to those
individuals travelling in areas of endemic infection.

Very little attention has been paid to whether or not smoking
influences the response of individuals to vaccination. Several studies
have found increased incidences of respiratory illness in smokers (21).
On the other hand, Monto and Ross (IS), in a study of the relationship
between the frequency of acute respiratory infections, smoking, and
chronic pulmonary disease, found an increase in infections in subjects
with chronic lung disease which was independent of the smoking
factor.

Studies in Huwtans

Finklea, et al. (2), in a study involving 239 volunteers, reported a
significant decrease in the persistence of hemagglutination inhibition
antibody among cigarette smokers after natural infection or vaccina-
tion with influenza AZ antigens. Although this investigation suggests a
rapid decrease in antibodies to influenza vaccination in the group that
smoked when compared to the nonsmoking group, the results obtained
in this study have to be criticized for two reasons: the 239 volunteers
were subdivided into very small groups making the assessment of
statistical significance difficult and the data were not presented in a
manner which allowed a judgment regarding the validity of the
presumption that the response of the two populations, nonsmokers and
smokers, was functioning under the same multinomial distribution
upon which the investigators based their statistical analyses.

The only other report in the literature on smoking, vaccines, and the
immune response is a study by MacKenzie, et al. (12). These
investigators studied the effects of cigarette smoking on the response
to vaccination against influenza. Their results indicate that a higher
number of cigarette smokers than nonsmokers sero-converted after
vaccination with live attenuated influenza vaccine as measured by the
hemagglutination inhibition test. There was no difference in response
between smokers and nonsmokers to killed subunit vaccine. However,
when the investigators studied the longevity of the immune response
over a period of 50 weeks, they found that the smokers vaccinated with
killed subunit vaccine had a significant depression (t = 2.35, 111 D.F.,

12-58


P 5 0.05) in antibody titer. No significant difference was found
between titers of smokers and nonsmokers who received the live
attenuated vaccine. Again, although there are indications that smoking
influences the immune response, this study has limitations: because of
the small number of subjects in each group, significance of differences
is difficult to assess; inconsistencies were found in the immune
response of subjects to live vaccine versus killed vaccine; and, in the
strictest sense, there was a control group for the live influenza vaccines
that received injections of saline, but there was no placebo or control
group for the subjects administered the killed subunit vaccine by intra-
nasal spray. The one control group was used as the control for both
experimentally vaccinated groups.

Animal Modd System

Thomas, et al. (19) reported testing the effects of fresh cigarette smoke
on the immune response of mice. They found that the antibody
response to sheep red blood cells was inhibited, depending on the
concentration of the cigarette smoke solution.

MacKenzie (11) developed a model system in mice to study the
influence of smoking on influenza virus. He reported that short
exposures to cigarette smoke enhanced the response of mice to
vaccination while prolonged exposure depressed the humoral response
as measured by the hemagglutination inhibition test.

Bacterial Products

There are no reports of studies on the influence of and response to
bacterial vaccines or bacterial products in humans who smoke.
Campbell and Hilsenroth (I) investigated the response of mice
immunized with tetanus toxoid after the mice had been exposed to
nitrogen dioxide (a byproduct of cigarette smoke) or ozone. The mice
were then challenged'with tetanus toxin. The results indicated that
there was more mortality and morbidity in the animals exposed to the
two gases when compared to the controls.

Carcinoembryonic Antigen Test

Cold and Freedman (4) reported finding tumor-specific antigens in
adenocarcinomata of the human colon. These antigens are not found in
normal adult colonic tissues. When rabbits are immunized with these
antigens, tumor-specific antibodies can be demonstrated by different
immunologic methods, such as agar gel diffusion, immunoelectrophore-
sis, passive cutaneous anaphylaxis, and the hemagglutination inhibi-
tion test. Cold and Freedman (5) characterized the antigens and found
that, for the most part, they could be detected in cancerous tissues of
the human digestive organs. The origin of these organs in fetal life is
the endodermally derived epithelium. The antigens were detected in

12-59


human fetal gut, liver, and pancreas tissues obtained between 2 and 6
months of gestation. Normal adult colon and the other adult tissues
tested, as well as fetal gut, liver, and pancreas in the third trimester,
were devoid of these antigens. Gold and Freedman termed these
antigenic components of the human digestive system, carcinoembryon-
ic antigen (CEA), and suggested that CEA represented cellular
components found in the normal developing (embryonic) digestive
system epithelium. These components are repressed after the sixth
month of embryonic life but reappear in colon malignancy by
derepression of differentiation as the adult colon cells metastasized.
Krupey, et al. (9) characterized CEA as a protein-polysaccharide
complex. It is a glycoprotein of high molecular weight (200,000)
normally found as a constituent of the glycocalyx of embryonic
endodermal epithelium and is also present in extracts of colon
carcinoma cells. Thomson, et al. (20) developed a radioimmunoassay to
detect CEA circulating in the blood of patients. This test permits the
detection of nanogram (ng) amounts of CEA. To obtain more specific
antiserum and thereby reduce false positive results in the radioimmu-
noassay, Krupey, et al. (10) developed a procedure to purify CEA used
to immunize the rabbits. Originally the CEA test was only sensitive
enough to detect concentrations of 2.5 ng/ml but by this improved
procedure 1.0-2.0 ng/ml could be detected.

Gold (3) reported on a study of 212 sera. Seventy percent (30143) of
the patients with non metastatic cancer had hemagglutination
inhibition titers > 1:80 to CEA.

Moore, et al. (16) and Rule, et al. (18) reported finding elevated CEA
levels in patients with inflammatory bowel disease. Holyoke, et al. (8)
reviewed the literature on CEA and cancers of the gastrointestinal
tract and reported that evidence was accumulating that the detection
of elevated CEA levels could be used as a tool in prognosis of colon
carcinoma after surgical removal of the tumor. However, the use of
CEA as a diagnostic tool was doubtful because of the finding of
elevated levels of CEA in disease states, such as Crohn's disease and
other chronic inflammatory bowel diseases. Meeker, et al. (14) reported
finding 90 percent (66/73) of patients with gastrointestinal tract
cancer with CEA levels above 2.5 ng/ml. In a joint study of the
National Cancer Institute of Canada and the American Cancer Society
(17), the sera of 503 patients were examined for CEA titers to
determine whether or not the results of the test were reproducible in
different laboratories and whether or not patients with colon tumors
could be distinguished from patients with other malignancies. The
results indicated that the CEA test was reproducible in different
laboratories and that determination of CEA titers was an important
aid in the diagnosis of colon cancer.

12-60


The results of a large double-blind study by Cold, et al. (6), which
involved 597 individuals, showed that over 95 percent (33187) of
patients with malignant colon tumors had CEA levels over 2.5 ng/ml.

Hansen, et al. (?`) have reported on a collaborative study involving
some 35,000 plasma samples from more than 10,006 patients. In this
study 97 percent (865/892) of the healthy nonsmokers had CEA levels
below 2.6 ng/ml and 3 percent (251892) had CEA levels of 2.6 to 5.0
ng/ml, while 15 percent (931620) of smokers had levels of 2.6 to 5.0
ng/ml. In the same study, 833 subjects at high risk (uranium miners)
were examined: 19 percent (911484) had CEA levels above 2.5 ng/ml
while 3.9 percent (191434) had CEA levels over 5.0 ng/ml. In an
attempt to further correlate elevated CEA levels, these investigators
extended their studies to look at the sputum cytology of 581 uranium
miners of whom 456 were smokers with a history of smoking (289) or
former smokers (167). Uranium miners were considered to be a high
risk population for the development of pulmonary cancer. Eighteen
percent (521289) of the subjects had CEA levels above 2.5 ng/ml. The
sputum cytological examination revealed nine of these 52 individuals
had carcinoma in situ and three had carcinoma, while the remaining 28
individuals had mild to marked atypic sputum reports. These results
confirmed the previous findings of elevated CEA levels in patients
with pulmonary cancers. These investigators were the first to report
elevated CEA levels in people who were chronic, heavy smokers.

Meeker, et al. (14) reported finding CEA levels greater than 25
ng/ml in 11 percent (191176) of individuals classified as healthy
subjects. These investigators examined a number of factors such as
sex, age, and so forth, to determine those which might influence CEA
levels. The only factor found to influence CEA levels was smoking.
When CEA levels of those who did not smoke and those who smoked
were compared; a highly significant difference (k = 905) was found.
The mean level of 1.5 _+ 0.96 ng/ml was found in the nonsmokers
whereas the smokers had a mean level of 2.1 +: 1.2 ng/ml.

McCartney and Hoffer (13) mentioned that chronic cigarette
smoking was associated with elevated CEA levels in the absence of
other specific diseases, but they did not elaborate further on the
subject.

Summary

There is suggestive evidence that antibody titers to natural infection
or vaccination with influenza virus in cigarette smokers decrease more
rapidly than the titers of nonsmokers. To confirm these findings,
studies need to be done with larger groups of individuals.

Carcinoembryonic antigen levels found in many smokers are
elevated to the levels observed in patients with proven carcinoma of
the colon. The significance of these elevated levels is not clear at this

12-61


time. However, when the CEA test is used as an adjunct in diagnosis,
this fact needs to be considered when interpreting the results obtained.

12-62


Blologicals: References

(I) CAMPBELL, K.I., HILSENROTH, R.H. Impaired resistance to toxin in toxoid-
  immunized mice exposed to ozone or nitrogen dioxide. Clinical Toxicology 9(6):
  943-954, December 1976.

(f) FINKLEA, J.F., HASSELBLAD, V., RIGGAN, W.B., NELSON, W.C., HAM-
  MER, D.I., NEWILL, V.A. Cigarette smoking and hemagglutination inhibition
  response to infIuensa after natural disease and immunization. American
  Review of Respiratory Disease 164(3): 368376, September 1971.
(3) GOLD, P. Circulating antibodies against carcinoembryonic antigens of the
  human digestive system. Cancer 29(10): 1663-166'7, October 1967.
(4) GOLD, P., FREEDMAN, S.O. D emonstration of tumor-specific antigens in
  human colonic carcinomata by immunological tolerance and absorption
  techniques. Journal of Experimental Medicine l21(3): 439462, March 1, 1965.
(5) GOLD P., FREEDMAN, S.O. Specific carcinoembryonic antigens of the human
  digestive system. Journal of Experimental Medicine 122(3): 467481, Septem-
  ber 1,1965.

(6) GOLD, P., WILSON, T., ROMERO, R, SHUSTER, J., FREEDMAN, S.O.
  Immunology and colonic cancer: Further evaluation of the radioimmunoassay
  for carcinoembryonic antigen of the human digestive system as an adjunct in
  cancer diagnosis. Diseases of the Colon and Rectum 16(5): 358365, Septem-
   ber/October 1973.
(7) HANSEN, H.J., SNYDER, JJ., MILLER, E.,VANDEVOORDE, J.P.,MILLER,
  O.N., HINES, L.R., BURNS, J.J. Carcinoembryonic antigen (CEA) assay. A
  laboratory adjunct in the diagnosis and management of cancer. Human
  Pathology 5(2): 139-147, March 1974.
(8) HOLYOKE, E.D., CHU, TM., MURPHY, G.P. Carcinoembryonic antigen (CEA)
  and gastrointestinal malignancy. Review of Surgery 39(5): 395-311, Septem-
   ber/October 1973.

(9) KRUPEY, J., GOLD, P., FREEDMAN, S.O. Physicochemical studies of the
   carcinoembryonic antigens of the human digestive system. Journal of
   Experimental Medicine l28(3): 387398, September 1,1968.
(10) KRUPEY, J., WILSON, T., FREEDMAN, S.O., GOLD, P. The preparation of
   purified carcinoembryonic antigen of the human digestive system from large
   quantities of tumor tissue. Immunochemistry 9(4): 617-622, April 1972.
(II) MACKENZIE, J.S. The effect of cigarette smoke on infIuensa virus infection: A
   murine model system. Life Sciences 19(3): 499-412, August 1,1976.
(12) MACKENZIE, J.S., MACKENZIE, I.H., HOLT, P.G. The effect of cigarette
  smoking on susceptibility to epidemic influenza and on serological responses to
  live attenuated and killed subunit influenza vaccines. Journal of Hygiene
   (Cambridge) 77(3): 469-417, December 1977.

(IS) MCCARTNEY, W.H., HOFFER, P.B. The value of carcinoembryonic antigen
   (CEA) as an adjunct to the radiological colon examination in the diagnosis of
   malignancy. Radiology llo(2): 325-328, February 1974.
(14) MEEKER, W.R., JR., KASHMIRI, R, HUNTER, L., CLAPP, W., GRIFFEN,
   W.O., JR. Clinical evaluation of carcinoembryonic antigen teat. Archives of
  Surgery 197(2): 266274, August 1973.

(15) MONTO, A.S., ROSS, H.W. The Tecumseh study of respiratory illness. X.
   Relation of acute infections to smoking, lung function and chronic symptoms.
   American Journal of Epidemiology 197(l): 57-64, January 1978.
(16) MOORE, T.L., KANTROWITZ, P.A., ZAMCHECK, N. Carcinoembryonic
  antigen (CEA) in inflammatory bowel disease. Journal of the American
   Medical Association m(8): 944947, November 29,1972.

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(17) NATIONAL CANCER INSTITUTE OF CANADA/AMERICAN CANCER
   SOCIETY. A collaborative study of a test for carcinoembryonic antigen (CEA)
   in the sera of patients with carcinoma of the colon and rectum. A joint
   National Cancer Institute of Canada/American Cancer Society investigation.
   Canadian Medical Association Journal 107(l): 2533, July 8,1972.
(18) RULE, A.H., STRAUS, E., VANDEVOORDE, J., JANOWITZ, H.D. Tumor-
   associated (CEA-reacting) antigen in patients with inflammatory bowel
   disease. New England Journal of Medicine 297(l): 24-26, July 6,1972.
(19) THOMAS, W.R., HOLT, P.G., KEAST, D. Antibody production in mice
   chronically exposed to fresh cigarette smoke. Experientia 3O(l.2): 1469-1470,
   December 15,1974.

(20) THOMSON, D.M.P., KRUPEY, J., FREEDMAN, SO., GOLD, P. The radioim-
   munoaasay of circulating carcinoembryonic antigen of the human digestive
   system. Proceedings of the National Academy of Sciences, U.S.A. 64(l): 161-
   167, September 1969.

(61) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
   Reference Edition: 1976. U.S. Department of Health, Education, and Welfare,
   Public Health Service, Center for Disease Control, HEW Publication No.
   (CDC) 79-9257,1976,657 pp.

12-64


Nutrients Interactions

Epidemiology data have long linked smoking with increased risks of
cardiovascular disease, increased osteoporosis, amblyopia, and other
disorders (5, 9, 14, 18, 24, 29, 43, 53, 56, 68). As early as 1939 (6X),
scientists demonstrated that smoking causes changes in levels of
nutrients, which may help to explain the impact smoking has on health.
Since the complete "cause and effect" relationships of these nutritional
changes have not been clearly identified, only those of nutrients for
which the effect is more clearly understood will be considered in this
section.

Macronutrients
Lipi&

Because smoking has been established epidemiologically as a major
factor in cardiovascular disease, the interaction between smoking and
lipid metabolism has been extensively investigated. Several studies
demonstrate that blood cholesterol levels are higher in smokers than in
nonsmokers (52, 55, 72). In carefully controlled studies, however,
Elwood, et al. (20) reported that the differences are not statistically
significant. An explanation for these observations, proposed by several
investigators, is that they are associated with vitamin C metabolism
(35, 38,62, 63). These researchers claim that vitamin C has a role in the
transport of cholesterol to the liver where catabolism and excretion
take place. Smoking has heen shown to increase plasma triglyceride
levels (5%`,55,58) and differences between smokers and nonsmokers are
highly significant. Yeung (72) has reported that smoking together with
oral contraceptives results in even higher plasma triglyceride levels.

Carbohydrates

Several investigators have demonstrated that alterations in carbohy-
drate metabolism are frequently associated with smoking (24, 27, 37,
52,55, 61). Orsetti, et al. (44) supported epidemiological observations in
a clinical nutrition study in which both smokers and nonsmokers were
required to smoke two cigarettes in a 10 minute period. Of the 18
subjects studied, 10 showed a significant rise in somatotropic hormone
for 20 minutes post smoking. Plasma catecholamine levels increased
for five of six subjects tested.

Proteins

Albanese, et al. (3) in a study involving 7 nonsmokers and 10 smokers,
reported a significant difference in protein utilization. Nonsmokers
were more efficient in retaining nitrogen than were smokers. The
authors concluded that the apparent difference in protein metabolism
was associated with impairment of tryptophan utilization. As discussed
later, an impairment in protein metabolism may also be partially

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responsible for low birthweight found in infants born to smoking
mothers. Crosby, et al. (16) have shown that smoking mothers had
lower leukocyte RNA synthesis and lower plasma levels of 14 amino
acids than did non-smoking mothers,

Micronutrients

Vitumin C

Strauss and Scheer (65) reported that the urinary excretion of vitamin
C was lower in heavy smokers than it was for nonsmokers. Several
investigators later showed that smoking causes changes in the vitamin
C levels found in plasma and leukocytes (9, IO, 20, 25, 30, 33, 40, 45, 46,
47, 43, 60, 72, 73). The reasons for these observed changes have not
heen completely established. Keith and Pelletier (34) have demon-
strated a decrease in vitamin C absorption when high levels of nicotine
were administered to laboratory animals. Dewhurst and Kitchen (19)
and Sprince, et al. (64) have postulated that there is increased
oxidation of vitamin C from compounds, such as acetaldehyde, which
are derived from smoking. Other scientists postulate that increased
secretion of adrenaline and adrenal steroids stimulated by nicotine
causes increased utilization of vitamin C. Vitamin C is known to be
essential for the metabolism of tyrosine which, in turn, is a precursor
of adrenalin and noradrenalin. The importance of vitamin C in the
formation of collagen, the synthesis of neurotransmitters, and in many
other biochemical functions has stimulated several hypotheses for the
pathogenesis of degenerative diseases for which smoking is known to
be a risk factor (6,35,38, 62,63).

Vitamin BM

The observation that tobacco amblyopia and nutrition-induced amblyo-
pia respond to hydroxycobalamin, a form of vitamin BE, led to the
discovery that smoking lowers both blood and tissue levels of vitamin
Blz(2, 11, 15, 22, 32, 36, 49, 50, 51). The loss of vitamin B~is attributed
to the use of this vitamin in the detoxication of cyanide derived from
inhaled tobacco smoke (23,26,28, 70, 72). Predictably, vegetarians have
been shown to have lower vitamin BE levels than nonvegetarians, and
vegetarians who smoke have the lowest levels of this vitamin (17, 69).
Sohrauzer and Lee (57) have postulated that carbon monoxide in
tobacco smoke reacts with Co + + + in vitamin BE to form Co+ + (57).
The occurrence of amblyopia is believed to be associated with
individuals having a genetic or acquired error of cyanide or vitamin BIZ
metabolism in that cyanide is not converted to thiocyanate, but
remains as cyanocobalamin (13, 27, 54, 71). Agamanolis, et al. (1) have
suggested that the occurrence of amblyopia is an early symptom of
vitamin BIZ deficiency and that pernicious anemia and other symptoms
occur at a much later stage.

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Vitamin Be

El-Zoghby, et al. (21) have reported the possible existence of a
smoking-induced vitamin I% deficiency, as indicated by the finding that
tryptophan metabolites follow different excretion patterns in smokers
and nonsmokers. Supplementation with vitamin Bs restores the
excretion of some metabolites for smokers to the levels found in
nonsmokers; however, other metabolites remain at abnormal levels
despite the additional vitamin Bg. A report by Mitchell and Schandl
(42) suggests a possible mechanism for vitamin B6 loss which involves a
reaction between vitamin Bs and carbon monoxide.

Minerals

Some observations have been made that bone mineral losses associated
with postmenopause are accelerated with smoking. In two studies
involving 72 and 80 women, osteoporosis in nonobese smokers was
significantly higher than for nonobese nonsmokers (8). Obese women
showed no similar effect between smoking and nonsmoking. The
increased loss of bone mineral may be a secondary effect induced by
other nutritional conditions such as low vitamin C levels.

obesity

Although many individuals have reported significant weight gains
when smoking was terminated, there appears to be no scientific
evidence to support the existence of a thermogenesis effect. In a
carefully controlled study, Sims (61) observed no change in resting
metabolic rate, thermic response to exercise or meals, and no change in
serum T-8 or T-4. Subjects participating in this study revealed,
however, that their appetite ratings were lower during periods of
smoking.

Smoking in Pregnancy

Fetal malnutrition associated with smoking mothers has been observed
both in the United States and in Great Britain. Besults of these studies
demonstrate that babies born to smoking mothers are smaller and have
a greater risk of perinatal mortality when compared to babies of
nonsmoking mothers (4, 7, 16, 28, 39, 59). The exact causes of these
observations have not been established. It is likely that a combination
of nutritional factors, such as lower levels of amino acids, vitamins BE
and C, and glucose and fatty acids in maternal blood, contribute to the
causes of these observations (12,41). In addition, it has been postulated
that higher levels of carbon monoxide, nicotine, and cyanides result in
decreased oxygen for the fetus.

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