Summary

Epidemiologic data have long linked smoking with increased risk of
cardiovascular disease, increased osteoporosis, amblyopia, and other
disorders. Recent data demonstrate that smoking during pregnancy
results in a greater risk of smaller birth weight and perinatal mortality
among pregnant women. Smoking causes changes in plasma and
leukocyte concentrations of vitamin C and impairs biochemical
functions of this vitamin. Vitamin Biz is metabolized in the detoxifica-
tion process of cyanide derived from smoking. Some heavy smokers
develop an amblyopia which is reversed by either vitamin By
supplementation or termination of smoking. Evidence is also presented
suggesting that smoking may alter the metabolism of lipids, carbohy-
drates, proteins, and other vitamins such as vitamin Be.

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Nutrient interactions: References

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(28) FREEMAN, A.G. Thiocyanate metabolism in human vitamin B-12 deficiency.
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(26) HALAWA, B., MAZUREK, W. Wplyw palenia tytoniu na poziom witaminy B-12
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serum). Wiadomosci Lekarskie 29(6): 469-472, March 15, 1976.

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phages: Comparison of phagocytic ability, glucose utilization, and ultrastruc-
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(28) HAUSER, G.A. Genussmittel in der schwangerschaft (Voluptuaries in pregnan-
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(29) HELMAN, N. Macrocytosis and cigarette smoking (Letter). Annals of Internal
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(81) ILEBEKK, A., MILLER, N.E., MJOS, O.D. Effects of nicotine and inhalation of
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(82) JAYLE, G.E., METGE, P., CHAIX, A., VOLA, J.L., TASSY, A. Exploration
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(84) KEITH, M.O., PELLETIER, O. The effect of nicotine on ascorbic acid retention
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884, December 1973.

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83(1): 108-127, January 1970.

KRISHNASWAMY, K., NADAMUNI NAIDU, A. Microsomal enzymes in
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LOH, H.S. Cigarette smoking and the pathogenesis of atherosclerosis—a
hypothesis. Irish Journal of Medical Science 142(4): 174-178, July 1973.

LUBCHENCO, L.O. The infant who is small for gestational age. Major
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MCCLEAN, H.E., DODDS, P.M., ABERNETHY, M.H., STEWART, A.W.,
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229, April 14, 1976.

MCGARRY, J.M., ANDREWS, J. Smoking in pregnancy and vitamin B-12
metabolism. British Medical Journal 2(5805): 74-77, April 8, 1972.

MITCHELL, D.A., SCHANDL, E.K. Carbon monoxide, vitamin B-6, and
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MOLLER, E., KLEIN, B. Herzinfarkt und subklinishcer diabetes (Myocardial
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1970.

ORSETTI, A., AMARA, F., COLLARD, F., MIROUZE, J. Influence du tabac sur
les hormones essentielles de la glycoregulation (The influence of tobacco on
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PELLETIER, O. Cigarette smoking and vitamin C. Nutrition Today 5(8): 12-15,
Autumn 1970.

PELLETIER, O., Vitamin C and cigarette smokers. Annals of the New York
Academy of Sciences 258: 156-168, 1975.

PELLETIER, O. Vitamin C status of cigarette smokers and nonsmokers.
American Journal of Clinical Nutrition 23(5): 520-524, May 1970.

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PETTIGREW, A.R., FELL, G.S., CHISHOLM, LA. Red cell glutathione in
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PHILLIPS, C.L, AINLEY, R.G., VAN PEBORGH, P., WATSON-WILLIAMS,
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POTTS, A.M. Tobacco amblyopia. Survey of Ophthalmology 17(5): 313-389,
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RATZMANN, K.-P., RIEMER, D., SPOERL, L., WEBER, L., WITTKOPF, E.
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Instituto de Cardiologia de Mexico 43(1): 4-17, January/February 1978.

SCHETTLER, G., MOERL, H. Risikofaktoren der atherosklerose in beziehung
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SIMS, E.A-H. Experimental obesity, dietary-induced thermogenesis, and their
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action of ascorbic acid and sulfur compounds against acetaldehyde toxicity:
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WADIA, N.H., DESAI, M.M., QUADROS, E.V., DASTUR, D.K. Role of
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WELLS, D.G., LANGMAN, M.J.S., WILSON, J. Thiocyanate metabolism in
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YEUNG, D.L. Relationships between cigarette smoking, oral contraceptives,
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Trace Constituents in Smoke

Trace elements in tobacco that are sublimated at the temperature of
smoking may interact with dietary components. These elements
include organic compounds that are not pyrolyzed at these tempera-
tures and compounds that may be formed during pyrolysis. The
interaction may result because cigarette smoke contains: (1) signifi-
cant amounts of trace components normally present in the food, e.g.,
heavy metals, pesticides, and naturally occurring carcinogens, which
may represent an important additional source of exposure to these
compounds; and (2) components that alter the metabolism of food
additives or constituents. Because of the large number of components
that may occur in cigarette smoke, only those considered significant
are discussed here.

Trace Metals

Nadkarni (12) has reported that toxic elements in tobacco smoke
include cadmium, lead, arsenic, and selenium. Cadmium from
cigarettes represents a very substantial additional burden for smokers
when compared with that normally present in the diet and other non-
industrial sources. For a person smoking two to three packs of
cigarettes a day, the estimated respiratory cadmium intake ranges
from 4 to 6 yg. The retention of cadmium via this route is high; it has
been estimated that of the 4-6 yg of the cadmium in the inhaled smoke,
up to 2.82 yg would be absorbed. This represents a very significant
exposure when compared with the proportion of cadmium retained
from other sources, e.g., of the 50 yg/day cadmium ingested in food,
retention may be of the order of only 3.0 yg. The significantly greater
retention of cadmium by smokers is clearly reflected in greater levels
of tissue cadmium in smokers compared to nonsmokers. Smokers
accumulate more cadmium in the kidney cortex, liver, pancreas and
other tissues than nonsmokers (13). For a person smoking one pack of
cigarettes a day for 50 years, Elinder, et al. (5) estimated an increase in
body burden of cadmium of about 8 mg. In another study, Johnson, et
al. (9) estimated the body burden of cadmium in nonsmokers to be 10.3
mg compared to 14.9 mg for smokers.

Studies on the contribution of smoking to the body burden of other
metals are limited. Cigarette smokers have been shown to have higher
lead concentrations in the liver, pancreas, and kidney tissues, and
slightly higher levels of lead in muscle and fat than nonsmokers (6).
Johnson, et al. (9) have reported that zinc and mercury concentrations
were significantly higher in the pancreas and fat tissues of smokers,
but lower in the kidney tissue than in the case of nonsmokers.

210Polonium, which is present in the leaves of tobacco and volatizes at
the temperature at which cigarettes burn, is deposited in smoke
particles and enters the lung with the particles. The 2Po concentration

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in cigarettes varies from 0.15 to 0.63 p Ci/g. Approximately 20 percent
of the 2°Po content of a cigarette enters the lungs with the smoke
stream, with one cigarette yielding about 0.08 p Ci of #°Po to the body.
This is almost as much 2°Po as a person inhales from the atmosphere in
24 hours (14).

There is no information to indicate that the increased body burden of
these toxic elements results in toxic effects related to increased
exposure to the elements. It is possible that subclinical effects may
occur, although these effects cannot be demonstrated by the presently
available methodology.

Nitrosamines

Tobacco smoke not only represents a source of exposure to nitrosable
amines which can undergo nitrosation, but it is also a major source of
exposure to preformed N-nitrosonornicotine (NNN), which is present
in processed tobacco. Its concentration ranges from 0.3-90 ppm in
smoking tobacco, chewing tobacco, and snuff. Hilfrich, et al. (8) have
estimated exposure to NNN from tobacco smoke at 140-250
ng/cigarette. Fine (6) has estimated the exposure to nitrosamines from
tobacco smoke, primarily NNN, to be 4.1 pg/day (from 20 cigarettes)
compared to 6 yg/day (nitropyrollidine and other nitrosamines) from
food. NNN induces tumors of the esophagus, pharynx, and the nasal
cavity in rats, and it is possible that the increased incidence of cancer in
tobacco smokers and chewers may be related to the carcinogenicity of
this compound (5). In addition, it is not known if the possible
carcinogenic action of this compound may be additive or may
potentiate the effect of nitrosamines occasionally found in the diet.

Schmeltz, et al. (15) have detected N-nitrosodiethanolamine in cured
tobacco at concentrations ranging from 0.1 to 173 ng/g. They postulate
that it is derived from the use of diethanolamine, a solubilizing agent
for the plant growth regulator, maleic hydrazide. Schmeltz and
Hoffmann (16) have reviewed the occurrence of nitrogen-containing
compounds in tobacco and tobacco smoke. Included in the list of
compounds reported are numerous aliphatic amines, notably secondary
and tertiary amines, as well as aromatic amines, which have the
potential of being converted to nitrosamines in the presence of nitrite
or nitrogen oxide. Because saliva normally contains low levels of nitrite
(18), there is a potential for nitrosation of the amines to occur in vivo.
In addition, nitrite in certain processed foods may represent a source of
nitrite for nitrosation of these amines. The synthesis of nitrosamines
may be further catalyzed by the presence of thiocyanate in saliva.
Because thiocyanate levels are greatly increased in the saliva, as well
as in the stomach content, of smokers compared to that of nonsmokers,
the potential for in »ivo nitrosation is greatly increased in smokers (5).
However, other dietary components, e.g. ascorbic acid (1) or a-

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tocopherol (10), may reduce the potential for nitrosation, primarily by
reacting with the free nitrite.

Nicotine is a major constituent of tobacco smoke, but Lijinsky and
Singer (11) report that it is only very slowly nitrosated in aqueous
solutions and thus does not provide a significant source for amines that
may be nitrosated in the stomach.

Pesticide Residues

Atallah and Dorough (2) have reported on studies with cigarettes
impregnated with “C-labelled pesticides (carbaryl, carbofuran, lepto-
phos, DDT, and mirex) and have provided information on both the
stability of these pesticides under smoking conditions as well as the
amount transferred to mainstream smoke. Mirex was reported to be
the most stable compound (70 percent of “C in mainstream was
unchanged mirex). Carbofuran was almost as stable as mirex. From 40
to 45 percent of the 4C in mainstream smoke from carbaryl and DDT
was in the form of the parent compound. Leptophos was the least
stable, with only 21 percent of the 4C in the mainstream smoke present
as the parent compound. Rats which inhaled the “C-labelled smoke
derived from the treated cigarettes did not show patterns or tissue
distribution of inhaled “C-labelled pesticides which could be considered
characteristic for a particular type of pesticide. In contrast, Atallah
and Dorough (2) cited a report by Guthrie (7) which states that
carbamates and organophosphate pesticides were almost completely
degraded during the smoking process.

More information is needed on the nature and ultimate fate of
insecticide residues inhaled in tobacco smoke, Based on the information
reviewed, it is not possible to assess the health significance of pesticide
residues in tobacco.

In addition to the active principals contained in pesticides, other
subtances such as surfactants or solubilizing agents of inert carriers
may, if transferred to tobacco smoke, interact with compounds in the
diet or undergo conversion to potentially hazardous substances in the
tobacco leaf itself, e.g., nitrosation of diethanolamine which is used as a
solubilizing agent for maleic hydrazide. Very little is known regarding
these potential interactions and the effects, if any, in humans.

There is also little information on the fate of N-containing
agricultural chemicals after their application to tobacco. Maleic
hydrazide is present in cured tobacco (20-80 ppm) and a small portion
(4-10 percent) is transferred unchanged to mainstream smoke.

Metabolic Effects

Constituents of tobacco smoke may inhibit or induce enzyme activity in
human tissues and alter the rate of metabolism of food additives or
food constituents.

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Nicotine has been shown to cause significant reduction in rats’
intestinal alkaline phosphatase activity. The significance of the
reduced activity of this marker enzyme of intestinal mucosa is not
known, but it may be indicative of a reduced metabolic activity of the
mucosal cells. Shankar (17) has postulated that this may be one of the
factors causing sensitivities of mucosal cells to acid destruction.

A large number of polynuclear aromatic hydrocarbon (PNAs) have
been identified in tobacco smoke. Wynder and Hoffmann (19) have
reported that the concentration of PNA in the smoke of one cigarette
ranges from 0.6-70.0 ng. In addition to their well-known effects as
initiating carcinogens, PNAs are well-known inducers of mixed
function oxidases. The effect of PNAs on the proliferation of
microsomal enzymes and on subsequent increases in cytochrome P-450
has already been discussed in detail. However, it is of interest to note
that cigarettes contain substances that may depress the activity of
microsomal enzymes at one site and increase them at another site, e.g.,
cigarette smoke depresses pulmonary ary! hydrocarbon hydroxylase
(AHH) activity in guinea pigs but increases liver AHH activity (3). The
depression of pulmonary AHH activity may be due to the presence of
carbon monoxide or cyanide in tobacco smoke combining directly with
the cytochromes and rendering them unavailable for their role in the
enzymatic action.

It is not known if these metabolic changes can affect the metabolism
of food chemicals or food constituents, or if the level of changes that
can occur are significant in relation to the inhibition or increase of
microsomal activity by normal dietary constituents or contaminants in
the diet. Another area of concern relates to the possible effect of
enzyme inducers of the developing fetus. Enzyme inducers that cross
the placental barrier may effect changes in the enzyme patterns of the
developing fetus. Such changes or biochemical imprints may persist
throughout life and could possibly result in altered patterns of
metabolism of food additives and contaminants. It is not known to
what extent, if any, constituents of tobacco smoke may cause these
changes. However, a major problem in evaluating any possible effect
due to the constituents of tobacco smoke is the lack of knowledge of
the quantitative aspect of the relative amounts and activities of the
components in tobacco smoke compared with those active substances
normally present in the diet or present as contaminants (e.g.,
environmental contaminants, PCBs, DDT) of the diet, and the possible
interactions between such compounds.

Summary

Although cigarette smoking will result in an additional body burden of
Cd and Pb, there is little evidence that this will result in known
adverse effects. The effects of nitrosamines and inhibitors and
activators of enzymes in tobacco smoke have not been established.

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Trace Constituents in Smoke: References

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ARCHER, M.C., TANNENBAUM, S.R., FAN, T.-Y., WEISMAN, M. Reaction of
nitrite with ascorbate and its relation to nitrosamine formation. Journal of the
National Cancer Institute, 54(5): 1203-1205, May 1975.

ATALLAH, Y.H., DOROUGH, H.W. Insecticide residues in cigarette smoke.
Transfer and fate in rats. Journal of Agriculture and Food Chemistry, 23(1):
64-71, 1975.

BILIMORIA, M.H., JOHNSON, J., HOGG, J.C., WITSCHI, H.P. Pulmonary ary!
hydrocarbon hydroxylase: Tobacco smoke-exposed guinea pigs. Toxicology and
Applied Pharmacology 41: 433-440, 1977.

BOYLAND, E., WALKER, S.A. Effect of thiocyanate on the nitrosation of
amines. Nature, 248: 601-602, April 12, 1974.

ELINDER, C.G., KJELLSTROM, T., FRIBERG, L., LIND, B., LINNMAN, L.
Cadmium in kidney cortex, liver, and pancreas from Swedish autopsies.
Archives of Environmental Health 31(6): 292-302, November/December 1976.

FINE, D.H. An assessment of human exposure to N-nitroso compounds.
Presented at the Fifth meeting on Analysis and Formation of N-nitroso
Compounds, International Agency for Research on Cancer, Durham, N.H.,
August 22-24, 1977, 15 pp.

GUTHRIE, F-E. The nature and significance of pesticide residues on tobacco
and in tobacco smoke. Beitrage zur Tabakforschung 4(6): 229-246, November
1968.

HILFRICH, J., HECHT, S.S., HOFFMANN, D. A study of tobacco carcinogene-
sis. XV. Effects of N’-nitrosonornicotine and N’-nitrosoanabasine in Syrian
golden hamsters. Cancer Letters 2: 169-175, 1977.

JOHNSON, D.E., PREVOST, RJ., TILLERY, J.B., THOMAS, R.E. The
Distribution of Cadmium and Other Metals in Human Tissue. San Antonio,
Southwest Research Institute, September 1977, 231 pp.

KAMM, J.J., DASHMAN, T., NEWMARK, H., MERGENS, W.J. Inhibition of
amine-nitrite hepatotoxicity by a-tocopherol. Toxicology and Applied Pharma-
cology 41: 575-583, September 1977.

LIJINSKY, W., SINGER, G.M. Formation of nitrosamines from tertiary amines
and nitrous acid. In: Bogovski, P. and Walker, EA. (Editors). N-Nitroso
Compounds in the Environment. Proceedings of a Working Conference held at
the International Agency for Research on Cancer, Lyon, France, October 17-
20, 1973. Lyon, International Agency for Research on Cancer, 1975, pp. 111-
114.

NADKARNI, R.A. Some considerations of metal content of tobacco products.
Chemistry and Industry 17: 693-696, September 7, 1974.

OFFICE OF TOXIC SUBSTANCES. Multimedia Levels—Cadmium. Environ-
mental Protection Agency, Office of Toxic Substances, September 1977, pp. 5-
1-5-21, 6-1-6-14.

PARFENOV, Y.D. Polonium-210 in the environment and in the human
organism. Atomic Energy Review 12(1): 75-148, 1974.

SCHMELTZ, I., ABIDI, S., HOFFMANN, D. Tumorigenic agents in unburned
processed tobacco; N-Nitrosodiethanolamine and 1,1-Dimethylhydrazine.
Cancer Letters 2: 125-131, 1977.

SCHMELTZ, I., HOFFMANN, D., Nitrogen-containing compounds in tobacco
and tobacco smoke. Chemical Reviews 77(3): 295-311, June 1977.

SHANKAR, R. Effect of chronic nicotine administration on the intestinal
mucosal alkaline phosphatase in rats. Indian Journal of Experimental Biology
18: 360-362, July 1975.

TANNENBAUM, S.R., WEISMAN, M., FETT, D. The effect of nitrate intake
on nitrite formation in human saliva. Food and Cosmetics Toxicology (Oxford)
14: 549-552, 1976.

12—77
(19) WYNDER, E.L.,, HOFFMANN, D. Tobacco and tobacco smoke. Seminars in
Oncology 3(1): 5-15, March 1976.

12—78
Smoker and Nonsmoker Responses to Diagnostic Tests

Numerous epidemiological studies have indicated that cigarette
smokers have increased mortality ratios for lung cancer, coronary
heart disease, and nonmalignant respiratory disease. That the relation-
ship is causal, and not purely statistical, was determined through —
examination of evidence on the biochemical, cytological, pathological,
and pathophysiological effects of cigarette smoking (22). As more
prospective screening studies involving clinical laboratory analyses
have been done on apparently healthy subjects (5, 6, 8, 12), more
differences at the biochemical level have become apparent between
smokers and nonsmokers. As discussed in the 1976 The Health
Consequences of Smoking (22), some of the differences in analytical
values of clinical/diagnostic tests may be due to the fact that the
nicotine in cigarette smoke causes increased levels of serum catechol-
amines, which in turn lead to increased levels of serum free fatty acids.
Other effects, particularly those involving the erythrocyte, are
probably the results of the relatively high levels of carbon monoxide in
cigarette smoke. ,

The major portion of the experimental results and data to be
presented here was obtained by testing individuals who were
apparently normal and healthy and not suffering from any of the
smoking-related diseases listed above or from other diseases. The
evidence indicates that smoking causes significant changes in the
“normal” values in various biochemical and clinical tests that may be
done routinely in the clinical laboratory. In addition, values obtained in
certain less routine analyses, such as platelet aggregation and
carcinoembryonic antigen tests, may depend upon the smoking status
of the individual subject. Although conflicting results have been
obtained in some of the experimental reports, it is apparent that the
smoking status of an individual should be reported along with
parameters such as age and sex.

Leukocytes

Results from a large number of studies have shown that smokers have
higher numbers of white blood cells than nonsmokers (3, 4, 5, 12, 13, 16,
17, 20).

In a study on 108 males aged 20 to 39, Okuno (17) found that the
leukocyte count was significantly higher in smokers than in nonsmok-
ers. Okuno (17) stated that, since his subjects were healthy and
completely free of symptoms, smoking alone appeared to be the cause
of the increased leukocyte counts. Similar results in leukocyte counts
were found by Sagone, et al. (20) ina study of 27 healthy white men
between the ages of 20 and 32. The 9 men in this study who smoked one
or more packs of cigarettes per day had higher white cell counts than
the 18 nonsmokers (20).

12—79
Friedman, et al. (8), in a study involving 86,488 ambulatory patients
undergoing multiphasic examinations, related the leukocyte count to
(1) quantity smoked, (2) inhalation, and (3) smoking duration.
Cigarette smokers showed the highest leukocyte counts and nonsmok-
ers showed the lowest. Differences in the mean leukocyte count were
shown by Friedman, et al. (8) to be present in all ages from 15 to 79, in
both sexes, and in all three races tested (yellow, black and white). Data
from Friedman, et al. (8) showing the leukocyte patterns discussed
above are presented in Table 9. These authors suggest that the
increased leukocyte counts in smokers might be due to nicotine-induced
release of catecholamines or to an irritant effect of smoke on the
respiratory tree with resultant inflammation. They state that the age,
sex, racial composition, and smoking habits of the reference population
should be taken into account in arriving at “normal” values for the
leukocyte count.

Corre, et al. (5), in a study of 4,264 men, showed that the number of
leukocytes is increased in smokers as compared to nonsmokers.
Investigation of a subgroup revealed that the increase was in
granulocytes, lymphocytes, and monocytes. The authors found no real
change in the differential leukocyte count, thus excluding the
hypothesis of involvement of an infectious process. As shown in Table
10, their data indicated that the average number of leukocytes is
greater in smokers who inhale than in those who do not, regardless of
the amount smoked. They also stated that the leukocyte count is higher
in light smokers who inhale than in heavy smokers who do not inhale.

Parulkar, et al. (18), in an examination of 130 healthy Indian males
aged 16 to 60 of different social and economic status, found a direct
relationship between smoking and an increase in the lymphocyte count.
They suggested the presence of a chronic inflammatory process, such
as bronchitis, based on data in which the lymphocyte count was higher
in smokers than in nonsmokers, with little change in other types of
cells. The data also showed an increase in lymphocyte count with
increasing numbers of cigarettes smoked per day. Parulkar, et al. (18)
noted the difference between results of their work and that of Corre,
et al. (5). —

Helman and Rubenstein (12) examined 1,000 patients randomly
selected from the clinic population. By chart review, the authors
excluded the following: overt or chronic debilitating illness, known
chronic respiratory disease, hepatic disease, hematologic disorders,
hematinic therapy, history of splenectomy, gastric surgery, and small
intestinal surgery. Following complete blood counts, the authors
eliminated women with hemoglobin outside the limits of 11.0 to 17.0
gm per 100 ml and men with hemoglobin outside the limits of 13.0 to
19.0 gm per 100 ml. They also eliminated those with gross erythrocytic
abnormalities. They stated that, when both sexes and all ages were
grouped, it was clear that the heavier the smoking, the higher the

12—80
TABLE 9.—Mean leukocyte count in 1,000s (WBC) according to
race, sex, and smoking category

 

 

Study group
White Black Yellow
Smoking Men Women Men Women Men Women
category
Nonsmokers
No. 8246 =: 18,438 1,108 3,199 709 1,308
Mean WBC/cu mm 72 14 63 68 70 73
SD 16 17 15 18 16 LT
% > 11,000 19 0 0.5 23 2.1 23
Cigar or pipe
(noncigarette)
No. 1573 wee 214 Lee 42
Mean WBC/cu mm 72 wee 62 Lae 67
SD 16 wee 15 tee 13
% > 11,000 22 Lee 09 Lee 0.0
Ex-cigarette—-none
No. 6,065 5,379 503 487 143 136
Mean WBC/cu mm 13 1 67 72 10 15
SD LT al LT 18 15 18
% > 11,000. 3.0 49 22 39 21 22
Ex-cigarettecigar
or pipe
No. 1,776 fae 184 2 59
Mean WBC/cu mm 16 Lee 67 Lae 74
SD 7 tee 19 an 20
% > 11,000 42 Lee 16 Lae 3.4
Current established
cigarette smokers
No. 14,416 15,972 2,590 2,847 651 44
Mean WBC/cu mm 84 84 72 16 78 719
SD 20 20 19 21 18 18
% > 11,000 10.0 10.0 39 64 58 5.0

 

SOURCE: Friedman, G.D. (8).

white cell count. The authors (12) concluded that the cause of smoking-
associated leukocytosis is unknown.

Billimoria, et al. (4) examined 187 volunteers aged 30 to 60 years
divided into heavy and light smokers and nonsmokers. In the male
heavy smokers, they found, a significant increase in the leukocyte
count, with the differential count indicating rises in neutrophils and
lymphocytes. The changes were not significant in the female heavy
smoking group.

In an extensive study of erythrocytosis, Sagone and Balcerzak (19)
noted an increased leukocyte count among the parameters they
examined.

12—81
TABLE 10.—Number of leukocytes per cu mm in smokers as a
function of quantity smoked and of inhalation
(number of subjects in parentheses)

 

Quantity .
Inhalation status se
smoked No inhalation Inhalation Significance (p)
(g./day)
19 5801 (539) 6321 (208) 0.001
10-19 6130 (546) 69380 (563) 0.001
20-29 6263 (397) 7287 (610) 0.001
30 + 6276 (121) 7397 (199) 0.001
Significance (p) 0.05 0.001

 

SOURCE: Corre, F. (5).

Noble and Penny (26) examined leukocyte function and other
hematological measurements in a group of 27 healthy white males 20
to 30 years of age. Total leukocyte counts were significantly higher in
smokers and temporarily abstaining smokers as compared to the
nonsmoking group. Although leukocyte chemotaxis was depressed in
the smoking subjects, smoking was not observed to affect the whole
blood bactericidal and phagocytic tests with either Staphylococcus
aureus or Klebsiella pneumoniae. Anderson, et al. (2) observed higher
readings in the nitroblue-tetrazolium test among smokers than in
nonsmokers and concluded that smoking may give rise to false positive
results in this test.

Erythrocytes and Intraerythrocytic Parameters

Okuno (17) observed that smokers showed increases in hemoglobin,
hematocrit, and mean corpuscular volume when compared to nonsmok-
ers. Similar differences were obtained (17) between heavy smokers and
light smokers.

In a study of the effects of smoking on tissue oxygen, Sagone, et al.
(20) demonstrated that smokers had higher values for carboxyhemo-
globin, hematocrit, hemoglobin, red cell count, and red cell mass. Red
cell 2,3-diphosphoglycerate was not changed in smokers while ATP and
Pso were significantly lower. The authors suggested that, in cases
where a decreased oxygen-hemoglobin affinity has been observed, the
hypoxia due to exposure to low levels of carbon monoxide is different
from hypoxia due to other causes. It was concluded that adaptation to
carbon monoxide in cigarettes is reflected by an increased red cell mass
and hemoglobin. In a study by Isager and Hagerup (14), a positive
correlation between cigarette smoking and hematocrit was found in a
group composed of 394 men and 339 women.. Hematocrit values above
normal were shown to be more common in cigarette smokers than in
nonsmokers, with the differences statistically significant in the male

12—82
group. Cigarette consumption and lung function were negatively
correlated in both sexes, but there was no evidence of any correlation
between lung function and hematological variables (14). As Sagone, et
al. (20) have done, these authors (14) suggest that the increase in
packed cell volume and hemoglobin in cigarette smokers may be caused
by elevated blood levels of carbon monoxide.

Helman and Rubenstein (12) related blood parameters to sex, age,
and smoking habits. Although Helman and Rubenstein felt that the
difference was not clinically significant, they showed that, under age
50, men who smoke have slightly higher hemoglobin levels than
nonsmokers. After age 50, the hemoglobin of nonsmokers increases
while that of smokers decreases. After age 60, the nonsmoker has a
higher hemoglobin level than the smoker. Women smokers were shown
(12) to have clearly higher levels of hemoglobin than nonsmoking
women. These authors (12) found higher erythrocyte counts in
nonsmoking men than in smoking men, but in women the RBC was
independent of smoking. Smokers, both men and women, had higher
hematocrit values than nonsmokers. It was found (12) that mean
corpuscular volume and mean corpuscular hemoglobin are higher in
smokers than in nonsmokers in both sexes and increase with age.
Further, nonsmoking men were shown to have a slightly higher mean
corpuscular hemoglobin concentration than men smokers and women.
The authors (12) suggest that carbon monoxide and cyanide in
cigarette smoke may be responsible for the increased hemoglobin and
hematocrit in smokers with no increase in red cell count.

Heavy smoking was suggested as a reversible cause of polycythemia
by Sagone and Baleerzak (19). They evaluated five smokers who were
found to have very high values for hemoglobin, hematocrit, and
erythrocyte mass as compared to nonsmokers. They reported that the
patients did not have lung disease, shunt physiology, hemoglobin with
increased oxygen affinity, erythropoietin-producing tumor, renal
disease, or polycythemia rubra vera. In the period of 3 to 3 1/2 months
after two of the subjects stopped smoking, it was observed that they
both showed large decreases in erythrocyte mass and hematocrit
values. The erythrocytosis found by these authors (19) appeared to be
an adaptation to carboxyhemoglobin and a decreased oxygen-carrying
capacity.

Cholesterol, Triglycerides, Lipoproteins

The effects of smoking on serum lipid levels are discussed in The
Health Consequences of Smoking (22) with respect to coronary heart
disease and immediate or acute effects of cigarette smoking. Inconsis-
tencies in results described there are still prevalent. Howell (13) found
no significant variation in either serum cholesterol or beta lipoprotein
levels between heavy smokers, nonsmokers, and ex-smokers. On the
other hand, Billimoria, et al. (4) found that male heavy smokers showed

12—83
increases in most indices associated with lipids. Compared with male
nonsmokers, the male heavy smokers had a higher fasting serum
turbidity and higher levels of cholesterol, serum phopholipids and
triglycerides. The esterified fatty acid index of beta and pre-beta
lipoprotein was also higher in male heavy smokers. Changes in
cholesterol levels, the beta-esterified fatty acid index, phospholipids,
and serum fasting turbidity were not observed in female heavy
smokers in this study.

Other Chemistry Tests

Dales, et al. (6) studied levels of eight serum components in more than
65,000 cigarette smokers and nonsmokers. Creatinine and albumin
levels were lower in smokers in both sexes, while the opposite was true
for 1-hour post-challenge serum glucose. Globulin levels were consis-
tently lower in women smokers, while uric acid levels were lower in
male smokers. Cholesterol levels were higher in white men who
smoked, but not in black male smokers. Calcium and serum glutamic
oxalacetic transaminase (SGOT) levels of smokers were similar to
those of nonsmokers. While alcohol consumption played a role in
smoker-nonsmoker differences in serum glucose concentration, no
additional factors were identified that could explain relationships to
smoking for the other chemistries studied.

Glauser, et al. (9) examined seven subjects during a period in which
they were smoking and 1 month after cessation of smoking. Statistical-
ly significant decreases were observed in protein-bound iodine level,
30-minute postprandial blood glucose level, and serum calcium level.

Clotting Factors

In a controlled, double-blind study, Levine (15) showed that the
smoking of a single cigarette increased the platelet’s response to a
standard aggregating stimulus (Figure 7). The platelet effect appeared
to be independent of the rise in plasma-free fatty acid which followed
cigarette smoking. It was suggested that potentiation of platelet
aggregation might help explain the increased incidence of arterial
thrombi in cigarette smokers.

Hawkins (11) examined the relationship between smoking, platelet
function, and thrombosis in a group of healthy young men divided into
nonsmokers, light smokers, and heavy smokers. It was observed that
platelets from smoking subjects seemed to be more active when
aggregated with ADP than those from nonsmokers. When samples
from each group were compared, a lower concentration of ADP was
required in the two smoking groups to induce permanent platelet
aggregates. The coagulation time of whole blood of smokers during a
nonsmoking period was significantly shorter than that of nonsmokers.
In the heavy smoking group there was an increase in maximum tensile

12—84
“Ty

50 PN
>
PN
be
aS

30

MY MI
ISN

MAXIMUM PERCENT AGGREGATION

20

ba

L 4 1

 

PRE POST PRE POST PRE POST
SHAM LETTUCE STANDARD
SMOKING LEAF SMOKING TOBACCO SMOKING

FIGURE 7.—Maximum platelet aggregation in response to a fixed
dose of ADP. Paired experiments before and after sham smoking,

non-nicotine cigarette smoking, and standard cigarette smoking
SOURCE: Levine, P.H. (75).

strength of the clot, when compared with the clot strength of
nonsmokers.

Billimoria, et al. (4) observed no changes in fibrinogen levels or
platelet adhesiveness. However this group of workers did find
euglobulin lysis times significantly longer for both male and female
heavy smokers. It was also determined that Stypven clotting times of
heavy smokers were significantly shortened in both males and females.

Dintenfass (7) examined a group of blood viscosity factors in 125
healthy male Caucasian smokers and nonsmokers of 45 to 55 years of
age. Hematocrit values, fibrinogen levels, plasma viscosity, blood
viscosity, and red cell aggregation were elevated in the smokers.

12—85
Table 11.—CEA titers in selected groups of 2107 healthy

 

 

subjects*
0.0-2.5 2.6-5.0 5.1-10.0 > 10.0
Mumier mg/ml mg/ml mg/ml mg/ml
Nonsmokers 892 865 5 2 0
Presently smoking 620 502 93 19 6
Former smokers 235 219 12 2 2
Pregnant females 369 316 11 3 0

 

*Individuals with no known disease.
SOURCE: Hansen, H.J. (10).

Carcinoembryonic Antigen

In a study by Stevens and MacKay (21), sera from 955 unselected
persons aged 60 years and older, obtained as part of a population
survey, were tested for carcinoembryonic antigen (CEA). Among the
903 current smokers, ex-smokers, and nonsmokers who had no
detectable cancer, a positive test (5 ng/ml or greater) was found in 13.6
percent of the 110 smokers but in only 1.8 percent of the 433
nonsmokers. Similar results were obtained by Alexander, et al. (1) who
determined CEA levels in 276 healthy volunteers, of whom 154 were
smokers and 122 were nonsmokers. They found mean CEA levels to be
significantly higher in smokers than in nonsmokers, and a significantly
higher percentage of smokers had elevated CEA levels. The results (21)
also indicated that CEA levels of smokers declined to those of
nonsmokers in about three months after cessation of smoking.

Hansen, et al. (10) in a collaborative study evaluating the clinical
usefulness of the CEA assay in more than 10,000 patients and healthy
subjects, suggested that the patient’s smoking history must be taken
into consideration when interpreting the CEA titer. As shown in Table
11, these investigators (10) found that 25 of 620 healthy subjects who
were smokers had CEA titers above the value used to separate normals
from abnormals.

Summary and Conclusions

1. Cigarette smoking is associated with an increase in leukocytes
which appears to be dependent on the amount of smoke inhaled.

2. Cigarette smoking may cause increases in red cell mass,
hemoglobin, carboxyhemoglobin, hematocrit, and mean corpuscular
volume.

3. Cigarette smoking appears to have an effect on serum levels of
creatinine, albumin, globulin, and uric acid.

4. Cigarette smoking appears to increase platelet aggregation,
plasma viscosity, blood viscosity, and tensile strength of the clot along
with a decrease in coagulation time.

12—86
5. Cigarette smoking appears to increase the serum carcinoembryon-
ic antigen level in otherwise healthy individuals.

6. The majority of the blood components elevated due to cigarette
smoking appear to revert to approximately normal levels after

cessation of smoking.
7. The smoking status of an individual should be included in reports
of clinical/diagnostic tests performed on that individual.

12—87
Smoker and Nonsmoker Responses to Diagnostic Tests:
References

(1) ALEXANDER, J.C., JR., SILVERMAN, N.A., CHRETIEN, P.B. Effect of age
and cigarette smoking on carcinoembryonic antigen levels. Journal of the
American Medical Association 235(18): 1975-1979, May 3, 1976.

(2) ANDERSON, R., RABSON, A.R., SHER, R., KOORNHOF, H.J. The N.B.T. test
in cigarette smokers. American Journal of Clinical Pathology 61(6): 879, June
1974,

(3) BANKS, D.C. Smoking and leucocyte-counts. Lancet 2(7728): 815, October 9,
1971.

(4) BILLIMORIA, J.D., POZNER, H., METSELAAR, B., BEST, F.W., JAMES,
D.C.O. Effect of cigarette smoking on lipids, lipoproteins, blood coagulation,
fibrinolysis and cellular components of human blood. Atherosclerosis 21(1): 61-
16, January/February 1975.

(5) CORRE, F., LELLOUCH, J., SCHWARTZ, D. Smoking and leucocyte-counts.
Lancet 2(7725): 632-634, September 18, 1971. ;

(6) DALES, L.G., FRIEDMAN, G.D., SIEGELAUB, A.B., SELTZER, C.C. Ciga-
rette smoking and serum chemistry tests. Journal of Chronic Diseases 27(6):
293-307, August 1974.

(7) DINTENFASS, L. Elevation of blood viscosity, aggregation of red cells,
haematocrit values and fibrinogen levels in cigarette smokers. Medical Journal
of Australia 1(20): 617-620 May 17, 1975.

(8) FRIEDMAN, G.D., SIEGELAUB, A.B., SELTZER, C.C., FELDMAN, R.,
COLLEN, M.F. Smoking habits and the leukocyte count. Archives of
Environmental Health 26(3): 137-143, March 19738.

(9) GLAUSER, S.C., GLAUSER, E.M., REIDENBERG, M.M., RUSY, BF.,
TALLARIDA, RJ. Metabolic changes associated with the cessation of
cigarette smoking. Archives of Environmental Health 20(3): 377-381, March
1970. ,

(10) HANSEN, H.J., SNYDER, J.J., MILLER, E., VANDEVOORDE, J.P., MILLER,
O.N., HINES, L.R., BURNS, J.J. Carcinoembryonic antigen (CHA) assay: A
laboratory adjunct in the diagnosis and management of cancer. Human
Pathology 5(2): 189-147, March 1974.

(11) HAWKINS, R.I. Smoking, platelets and thrombosis. Nature 236(5348): 450-452,
April 28, 1972.

(12) HELMAN, N., RUBENSTEIN, LS. The effects of age, sex, and smoking on
erythrocytes and leukocytes. American Journal of Clinical Pathology 63(1): 35-
44, January 1975.

(18) HOWELL, R.W. Smoking habits and laboratory tests. Lancet 2(7664): 152, July
18, 1970.

(14) ISAGER, H., HAGERUP, L. Relationship between cigarette smoking and high
packed cell volume and haemoglobin levels. Scandinavian Journal] of Haema-
tology 8(4): 241-244, 1971.

(15) LEVINE, P.H. An acute effect of cigarette smoking on platelet function. A
possible link between smoking and arterial thrombosis. Circulation 48(8): 619-
623, September 1973.

(16) NOBLE, R.C., PENNY, B.B. Comparison of leukocyte count and function in
smoking and nonsmoking young men. Infection and Immunity 12(3): 550-555,
September 1975.

(17) OKUNO, T. Smoking and blood changes. Journal of the American Medical
Association 225(11): 1887-1388, September 10, 1973.

(18) PARULKAR, V.G., BALSUBRAMANIAM, P., BARUA, MJ., BHATT, J.V.
Smoking and differential leucocyte (W.B.C.) count. Journal of Postgraduate
Medicine 21(2): 75-77, April 1975.

12—88
(19) SAGONE, A.L., JR, BALCERZAK, S.P. Smoking as a cause of erythrocytosis.
Annals of Internal Medicine 82(4): 512-515, April 1975.

(20) SAGONE, A.L., JR., LAWRENCE, T., BALCERZAK, S.P. Effect of smoking on
tissue oxygen supply. Blood 41(6): 845-851, June 1973.

(21) STEVENS, D.P., MACKAY, LR. Increased carcinoembryonic antigen in heavy
cigarette smokers. Lancet 2(7840): 1288-1239, December 1, 1973.

(22) 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, DHEW Publication No.
(CDC) 78-8357, 1976, 657 pp.

12—89
interactions with Radiation

In studies of humans, radiation exposures to the lungs of uranium
miners who smoked cigarettes produced much more lung cancer than
did similar exposures to nonsmoking miners (3). It is not known
whether lung cancer induction by other forms of ionizing and
nonionizing radiation is similarly conditioned by smoking nor whether
other cancer sites are involved (5). Archer, et al. (2) also noted some
evidence of decreased pulmonary function and excess mortality from
chronic respiratory disease among uranium miners who smoked
cigarettes compared with nonsmoking miners. However, the authors
indicated that other substances in the mining environment, such as
silica dust and diesel exhaust, may play a role in the onset of these
conditions (1).

Experimental studies have shown some synergistic effects between
ionizing radiation exposure and chemical carcinogens such as those
contained in cigarette smoke (6). Results from a study of dogs at
Battelle Northwest, sponsored by the Department of Energy, indicate
that the effects of exposures to smoking and radiation are similar to
those in uranium miners (4). It is suggested that when epidemiological
studies of bladder and laryngeal cancer are undertaken, the possible
synergistic effects of smoking and exposure to radiation be considered
by appropriate study design and analysis of data.

12—90
Interactions with Radiation: References

(2) ARCHER, V.E., BRINTON, H.P., WAGONER, J.K. Pulmonary function of
uranium miners. Health Physics 10(12): 1188-1194, 1964.

(2) ARCHER, V.E., GILLAM, J.D., WAGONER, J.K. Respiratory disease mortality
among uranium miners. Annals of the New York Academy of Sciences 271:
280-298, May 28, 1976.

(9) ARCHER, V.E., WAGONER, J.K., LUNDIN, F.E., JR. Uranium mining and
cigarette smoking effects on man. Journal of Occupational Medicine 15(8): 204-
211, March 1973.

(4) FILIPY, R.E., STUART, B.O., PALMER, R.F., RAGAN, H.A., HACKETT, P.L.
The effects of inhaled uranium mine air contaminants in beagle dogs. In:
Karbe, E., Park, J. F. (Editors). Experimental Lung Cancer. Carcinogenesis
and Bioassays. Berlin, Springer-Verlag, 1974, pp. 403-410.

(5) LUNDIN, F.E., JR. An exposure-time-response model for lung cancer mortality
in uranium miners—effects of radiation exposure, age, and cigarette smoking.
Presented at the Second Conference on Quantitative Aspects of Environmen-
tal Epidemiology, sponsored by the SIAM Institute for Mathematics and
Society, June 26-30, 1978, 22 pp.

(6) MCGANDY, R.B., KENNEDY, AR, TERZAGHI, M., LITTLE, J.B. Experi-
mental respiratory carcinegenesis: Interaction between alpha radiation and
benzo(a)pyrene in the hamster. In: Karbe, E., Park, J.F. (Editors). Experimen-
tal Lung Cancer. Carcinogenesis and Bioassays. Berlin, Springer-Verlag, 1974,
pp. 485-491.

12—91