2
0-
   1935-44     1945-54    1955-64 1965-74 1075-79
FIGURE S.-Mean annual incidence rates per 100,000 population for males of
     bronchogenic carcinoma by cell type, Olmsted County, MN, 193%
      79, by decade
SXKCE Bed c`t .II , IYXFl.
a reduced effect. Statistical methods are used with epidemiologic data to describe in-
teractions. Either an additive or a multiplicative scale may be used to measure interac-
tion statistically (Saracci 1987). For two exposures, on an additive scale, the sum of
the two independent relative risks reduced by one is compared with the relative risk ob-
served when both exposures are present. On a multiplicative scale. the comparison rela-
tive risk value is the product of the two independent relative risks. For public health
purposes, a positive departure from additivity is considered to represent synergism
(Saracci 1987). As the extent of interaction increases, the proportion ofthe excesscases
attributable to the interaction also increases (Saracci 1987).
This Section briefly reviews the current evidence on host characteristics and environ-
mental agents that may modify the risk of cigarette smoking.

Familial Factor\
The I963 Report considered and dismissed the "constitutional hypothesis" that
predilections to cigarette smoking and t,a lung cancer share a common genetic origin.
The Report did consider that i-- (renetic factors might determine susceptibility for a
minority, ofcases. Subsequent epidemiologic studies have provided empirical evidence
of possible genetic or familial determin;..nt\ of susceptibility (Tokuhata and Lilienfeld
I963a. 1963b: Samet. Humble. Pathak 13X6: Ooi et al. 19X6). For example. in a recent
case-control study in Nevv Mexico (Samet. Humble. Pathak 19X6). a parental history
of lung cancer vva\ associated with a fivefold increase in lung cancer risk, after adjust-
ment for cigarette smoking. Clinical studies of selected families have also indicated
familial aggregation (Brisman et al. 196'7: Lynch et al. 1982; Goffman et al. 1982).
Research has not yet identified the mechanisms underlying the familial aggregation
of lung cancer.  In 1973. Kellermann. Shaw, and Luyten-Kellerman (1973) reported
the promising observation that patients with lung cancer had a higher degree of in-
ducibility of aryl hydrocarbon hydroxylase than did control subjects. Because this en-
zyme converts polycyclic aromatic hydrocarbons to more active carcinogens and be-
cause enzyme concentrations are under genetic control. this observation suggested a
possible genetic determinant of lung cancer risk. However. not all subsequent studies
have been confirmatory. and the inheritance of inducibility in humans has not yet been
fully described (Mulvihill and Bale 19X-1).
Other Host Factors
Acquired host characteristics have also been examined as determinants of lung can-
cer rish including pulmonary tuberculo4s. chronic bronchitis, COPD. disorders as-
sociated with interstitial fibrosis ofthe lung. and peripheral pulmonary scars. However,
the evidence related to these disorders i5 incomplete and frequently is derived from case
series rather than from epidemiologic investigations. Recent epidemiologic evidence,
however. has indicated increased lung cancer risk for smokers with COPD compared
with unaffected mohers (Peto et al. 19X3: Samet. Humble. Pathak 1986; Skillrud. Of-
ford. Miller 19X6).
Occupational Exposures
Diverse agent\ inhaled in the workplace have been shown to cause lung cancer. In-
teraction between occupational expo\ur:s and smokin, ~7 was the focus of the 19X5
Report of the Surgeon General (US DHHS 19X5). That Report concluded that "For the
ma.jority of American workers who make. cigarette smoking represents a greater cause
of death and disability than their workplace environment." The Report also highlighted
the limitations of the evidence on interactions between smoking and occupational ex-
posure\.
Little new information ha\ become available since the 1985 Report. The evidence
remains strongest for interactions of smoking with exposure to radon decay products
and with exposure to asbestos (Saracci 1987). For both exposures. the preponderance

of the evidence indicates synergism (Doll and Peto 1985; National Research Council
198X). although the results of some individual investigations are inconsistent vvith
synergism.
Ambient Air Pollution
The 1964 Report noted that lung cancer mortality rates tended to be higher in urban
than in rural locations. Air pollution was considered a plausible explanation for these
differences. The association of lung cancer with atmospheric pollution derives biologi-
cal plausibility from the presence of carcinogens in polluted air and has some support
from epidemiologic data. However. epidemiologic investigation of ambient air pollu-
tion as a risk factor for lung cancer has been hampered by methodological problems.
including the necessity of considering cigarette smoking and the difficulty of assessing
pollution exposure (NIH 1986). Recent epidemiologic investigations have not shown
strong effects of air pollution (Samet et al. 1987: Buftler et al. 198X): and Doll and Peto
( 19X I ). in their review of the causes of cancer. estimated that only I to 2 percent of lung
cancer was related to air pollution.
Indoor Air Pollution
As the hazards posed by ambient air pollution from conventional fossil fuels have
diminished in some countries. the relevance of indoor air quality for health has become
increasingly apparent. Studies of time-activity patterns demonstrate that residents of
more developed countries, including the United States. spend on average little time out-
doors (Spenglerand Sexton 1983: Samet. Marbury. Spengler 1987). Indoor spaces may
be polluted by entry of contaminants from outdoor air and by indoor sources including
those related to human activity. such as tobacco smoking, building materials. combus-
tion devices, personal care and other household products. and other sources. A trend
of reduced building ventilation in the aftermath of the energy problems of the 1970s
may have worsened indoor air quality.
Two pollutants in indoor air have been causally linked to lung cancer: environmen-
tal tobacco smoke (ETS) (US DHHS 1986a) and radon (National Research Council
1988). The evidence on ETS and cancer was comprehensively reviewed in the 1986
Report (see Section on Involuntary Smoking in this Chapter).
Radon is an inert gas that is formed from radium during the natural decay of uranium.
The predominant source of radon in indoor air is the soil beneath structures. Radon dif-
fuses through the ground into basement and crawl spaces. and then throughout the air
in a home. or crosses cracks and other penetrations in homes on concrete slabs to enter
the indoor environment. Radon daughters are invariably present in indoor air and a
wide range of concentrations has been observed in homes (Samet et al. 198X). Some
homes have levels comparable to those measured in uranium mines, but the majority
of homes probably have levels that are currently considered acceptable.
Radon decays into short-lived particulate decay products. Two of the decay products
emit alpha particles. which are highly effective in damaging cells because of their high
energy and high mass. When these alpha emissions take place within the lung. the

epithelial lining of the tracheobronchia, tree may be damaged and lung cancer may ul-
timately result. Extensive epidemiologic data from studies of uranium and other un-
derground miners have established a causal association between exposure to radon
daughters and lung cancer (National Research Council 1988). The committee on the
Biological Effects of Ionizing Radiation (BEIR) IV concluded that the studies of miners
indicated synergism between cigarette smoking and radon decay products (National
Research Council 1988). The evidence, however, was not considered adequate to deter-
mine if the interaction was multiplicative or submultiplicative.
To date, epidemiologic investigations of domestic radon daughters as a risk factor
for lung cancer have been limited and preliminary (Samet et al. 1988). However, it is
assumed that radon decay products are carcinogenic in the indoor environment as they
are in the mining environment.  Dosimetric analyses indicate equivalent car-
cinogenicity in the domestic and mining environments (National Research Council
1988). Thus, radon must be considered one of the most important factors interacting
with cigarette smoking. All smokers are exposed to radon, some at unacceptable levels.
Quantitative estimates of the contribution of radon to lung cancer are variable. The es-
timates vary with the underlying assumptions and the risk model employed (Samet et
al. 1988).
Although cigarette smoking is by far the major cause of lung cancer, radon must also
be considered a cause of the disease. The public health burden of radon-related lung
cancer is substantially increased by the synergism between cigarette smoking and radon
exposure.
Diet
Diet has recently been considered as potentially influencing the risk of lung cancer
in smokers. Nutrients of particular interest include preformed vitamin A, carotene,
vitamin E, and vitamin C (Colditz, Stampfer, Willett 1987).
An enlarging body of experimental and epidemiologic evidence supports the
hypothesis that the risk for certain cancers varies inversely with consumption of
preformed vitamin A or beta-carotene, its precursor (Peto et al. 1981; National
Academy of Sciences 1982; Colditz, Stampfer, Willett 1987). The biological
plausibility of this hypothesis derives from the known effects of vitamin A deficiency
on the differentiation of epithelial surfaces, from in vitro and in vivo models, which
show that retinoids can suppress the deve,lopment of malignancy, and from possible an-
ticarcinogenic activity of beta-carotene. the principal dietary precursor of vitamin A
(Peto et al. 198 I: National Academy of Sciences 1982). The epidemiologic evidence
indicates a protective effect of dietary vitamin A intake from vegetable sources, but not
of preformed vitamin A, which is derived from meat and dairy sources, and vitamin
supplements. Clinical trials on vitamin .4 and lung cancer risk are in progress.
Vitamins E and C are antioxidants, which might have anticancer effects. To date,
the epidemiologic data on these vitamins are sparse and inconclusive (Colditz,
Stampfer. Willett 1987).
54

Smoking Cessation
Cessation of cigarette smoking results in a gradual decrease in lung cancer risk.
Several of the prospective and retrospective epidemiologic studies have demonstrated
a reduction in lung cancer risk over time following smoking cessation. One example
is provided from the U.S. Veterans study (Kahn 1966) (Figure 9).
Other recent studies have continued to confirm the benefit of smoking cessation for
lung cancer risk (Lubin et al. 19X4b: Alderson. Lee, Wang 19X5: Pathak et al. 19X6;
Higgins. Mahan. Wynder 19Xx). Forexample. Lubin and colleagues ( 1984b) described
the pattern of reduction in risk following smoking cessation in a case<ontrol study that
Ratio
20+    Nonsmoker
Number of Years Stopped Smoking
FIGURE 9.-Lung cancer mortality ratio for male former smokers
SOLRCE, L .S. Vererm\ tK.ihn IYhhl.
involved 7. IX I lung cancer patients and I 1,006 controls.  For men and women in this
study who had smoked for less than 20 years and had not smoked for IO years, the risks
of lung cancer were approximately the same as those of lifelong nonsmokers. On the
basis of the study of British physicians, Peto and Doll (1984) have suggested that the
effect of cigarette smoking cessation is to fix the age-specific risk of lung cancer at the
rate achieved at the time of cessation, based on the smoking history up to that time. Ac-
cording to this analysis, the former smoker's relative risk of lung cancer declines as the
background rate for lung cancer rises with age.
Therefore, smoking cessation is clearly beneficial in reducing the risk of lung cancer
compared with continued smoking; but cessation may not reduce the risk to the levels
of a lifetime nonsmoker even after many years of cessation. (See Table 2. Chapter 3.)

Laryngeal, Oral. and Esophageal Cancer
The I964 Surgeon General's Report concluded that cigarette smoking was causally
related to laryngeal cancer in men and that pipe smoking was causally related to lip
cancer (US PHS 1964). Subsequent reports reviewed the accumulating epidemiologic
evidence that established that cancers of the larynx. oral cavity, and esophagus are
caused by smoking in both men and women. The mortality ratios for these cancers are
similar for smoker\ whether they smoke cigars. pipes. or cigarettes. A strong dose-
response relationship exists. and the risk decreases with cessation, compared with con-
tinued smoking. Recent studies have confirmed these findings (Blot et al. 1988; El-
wood et al. 1984: Schottenfeld 19X4). (See Chapter 3.)
Alcohol consumption is also a ris!< factor for oral. pharyngeaf, laryngeal. and
esophageal cancer. The combination of alcohol and smoking produces a synergistic
increase in risk. In one study (Schottenfeld 19X4). for all upper airway cancers com-
bined, the risk was X.6 for those smoking 30 or more cigarettes per day in combination
with 20 oz of alcohol consumed per week.
Bladder and Kidney Cancer
A relationship between smoking and bladder cancer was noted in the 1964 Surgeon
General's Report. The 1979 Report concluded that cigarette smoking acts inde-
pendently and probably acts synergistically with other risk factors to increase the risk
of bladder cancer. The 19X2 Surgeon General's Report concluded that cigarette smok-
ing is a contributory factor for both bladder and kidney cancer. Cigarette smoking i\
estimated to account for 30 to 40 percent of bladder cancer (US DHHS 1982).
Recent studie\ have confirmed earlie*findings. For bladder cancer. in both men and
women. cigarette smoher\ have a relative risk of 2 to 3. A dose-response relationship
has been demonstrated. and the risk of bladder cancer decreases following smoking ces-
sation (McLaughlin et al. 1984: Hartge et al. 1987; Zahm, Hartge. Hoover 1987).
There is a positive association between smoking and kidney cancer. with relative
risks ranging from I to more than 5. The, increased risk of kidney cancer due to cigarette
smoking is found for both males and females, and there is a dose-response relation-
ship. as measured by the number of cigarettes smoked per day.
Pancreatic Cancer
The first Surgeon General's Report did not examine the relationship between smok-
ing and cancer of the pancreas. Several ,ubsequent reports of the Surgeon General have
noted that cigarette smoking is a contributory factor for pancreatic cancer.
The major prospective epidemiologic, studies have consistently shown an increased
risk of pancreatic cancer among both male and female cigarette smokers. The mortality
ratio for cigarette smokers compared WI th nonsmokers is generally in the range of 2 to
56

Laryngeal, Oral, and Esophageal Cancer
The 1964 Surgeon General's Report concluded that cigarette smoking was causally
related to laryngeal cancer in men and that pipe smoking was causally related to lip
cancer (US PHS 1964). Subsequent reports reviewed the accumulating epidemiologic
evidence that established that cancers of the larynx. oral cavity. and esophagus are
caused by smoking in both men and women. The mortality ratios for these cancers are
similar for smokers whether they smoke cigars. pipes. or cigarettes. A strong dose-
response relationship.exists. and the risk decreases with cessation, compared with con-
tinued smoking. Recent studies have confirmed these findings (Blot et al. 1988; El-
wood et al. 1984; Schottenfeld 1984). (See Chapter 3.)
Alcohol consumption is also a risk factor for oral, pharyngeal, laryngeal, and
esophageal cancer. The combination of alcohol and smoking produces a synergistic
increase in risk. In one study (Schottent'eld 1984). for all upper airway cancers com-
bined. the risk was 8.6 for those smoking 30 or more cigarettes per day in combination
with 20 oz of alcohol consumed per week.
Bladder and Kidney Cancer
A relationship between smoking and bladder cancer was noted in the 1964 Surgeon
General's Report. The 1979 Report concluded that cigarette smoking acts inde-
pendently and probably acts synergistically with other risk factors to increase the risk
of bladder cancer. The I982 Surgeon General's Report concluded that cigarette smok-
ing is a contributory factor for both bladder and kidney cancer. Cigarette smoking is
estimated to account for 30 to 40 percent of bladder cancer (US DHHS 1982).
Recent studies have confirmed earlier findings. For bladder cancer, in both men and
women. cigarette smohers have a relative risk of 2 to 3. A dose-response relationship
has been demonstrated. and the risk of bladdercancerdecreases following smoking ces-
sation (McLaughlin et al. 1984; Hartge et al. 1987; Zahm. Hartge. Hoover 1987).
There is a positive association between smoking and kidney cancer. with relative
risks ranging from I to more than 5. The increased risk of kidney cancer due to cigarette
smohing is found for both males and females. and there is a dose-response relation-
ship. as measured by the number of cigarettes smoked per day.
Pancreatic Cancer
The first Surgeon General's Report did not examine the relationship between smok-
ing and cancer of the pancreas. Several s'dbsequent reports of the Surgeon General have
noted that cigarette smoking is a contributory factor for pancreatic cancer.
The major prospective epidemiologic studies have consistently shown an increased
risk of pancreatic cancer among both male and female cigarette smokers. The mortality
ratio for cigarette smokers compared with nonsmokers is generally in the range of 2 to

3. A detailed review of the epidemiology of pancreatic cancer was written by Gordis
and Gold ( 1984).
For those in the MRFIT Study who smoked 30 or more cigarettes a day, the mortality
ratio for pancreatic cancer was 2.3 compared with nonsmokers. Other recent studies
(Mack et al. 1986: Whittemore et al. 1985) report that cigarette smoking is strongly and
consistently related to pancreatic cancer. Most epidemiologic studies show a dose-
response relationship between cigarette smoking and pancreatic cancer for both men
and women and a gradual decline in the ri\k of developing pancreatic cancer follow-
ing smoking cessation (US DHHS 1982; Mack et al. 1986).
Autopsy studies report hyperplastic changes in the pancreatic duct cells and atypical
changes in their nuclei among cigarette smokers compared with nonsmokers. The
pancreas is probably exposed to tobacco carcinogen5 or carcinogenic metabolites
present in bile or blood (US DHHS 1982).
Stomach Cancer
The 1964 Surgeon General's Report reviewed smoking and stomach cancer and. on
the basis of the limited evidence available at that time. concluded that there was no
relationship between smoking and stomach cancer. Evidence from prospective and
retrospective studies available more recently has shown a small but consistent increase
in mortality ratios, averaging approximately I.5 for smokers compared with non-
smokers.  Dose-response relationships have been demonstrated for the number of
cigarettes smoked per day. The 1982 Surgeon General's Report concluded that cancer
of the stomach is associated wsith cigarette smoking.
Cervical Cancer
Cancer of the uterine cervix was not reviewed in the I964 Surgeon General's Report.
The 1982 Report of the Surgeon General reviewed the studies published up to that time
and concluded that further research was necessary to define whether there was an as-
sociation between cigarette smoking and cervical cancer.
There are several risk factors for cervical cancer including early and frequent coitus.
multiple sexual partners. pregnancy at an early age. and the presence of sexually trans-
mitted diseases. Some of these risk factors may also be associated with smoking.
Winkelstein and coworkers (1984) reviewed 12 studies dealing with smoking and
cervical cancer, and in most studies there was a positive relationship that could not be
explained by other risk factors. Two studies published in 1985 c&firmed these find-
ings (Clarke et al. 1985; Greenberg et al. 1985).
Baron and coworkers ( 1986) reported on a case<ontrol study of I, I74 patients w,ith
cervical cancer. Cigarette smoking was associated with a statistically significant in-
crease in risk for cervical cancer. LaVecchia and associates ( 1986) in Italy studied the
relationship between cigarette smoking and the risk of cervical neoplasia in a case--Con-
trol study of 183 women with intraepithelial neoplasia. Cigarette smoking was as-
sociated with an increased risk of intraepithelial neoplasia and invasive cancer. This
association could not be totally explained by potential confounding factors. In a case-

control study of 480 patients with cervical cancer, there was a 50-percent excess risk
of cancer among cigarette smokers (Brinton et al. 1986). This excess risk persisted
after adjustment for sexual practices associated with smoking such as age at first inter-
course and number of sexual partners. There was a twofold excess risk of cervical can-
cer for women who smoked more than 40 cigarettes per day. The dose-response
relationship persisted after adjusting for several variables. There was no increased risk
of cervical cancer among former smok.ers.
The finding of nicotine and cotinine: in the cervical secretions of cigarette smokers
(Sasson et al. 1985) and of mutagenic mucus in the cervix of smokers (Holly et al. 1986)
complements the epidemiologic findings.
In summary, more than 15 epidemiologic studies have consistently shown an in-
creased risk for cervical carcinoma in cigarette smokers compared with nonsmokers.
Supportive clinical studies provide a plausible biological basis for the relationship. The
available data confirm an association between cigarette smoking and carcinoma of the
uterine cervix.
Endometrial Cancer
Several studies have reported that endometrial cancer is less frequent among women
who smoke cigarettes than among nonsmokers (Baron et al. 1986). Cigarette smoking
exerts an antiestrogenic effect that may explain this inverse association. The public
health significance of this association is limited because of the overall adverse impact
of cigarette smoking on morbidity and mortality.
Coronary Heart Disease
The 1964 Surgeon General's Report (US PHS 1964) noted that male cigarette
smokers have higher death rates from CHD than nonsmokers. Subsequent reports con-
cluded that cigarette smoking can caus,e death from CHD and that smoking is one of
the major independent risk factors for heart attack, manifested as fatal and nonfatal
myocardial infarction and sudden cardiac death. Smoking also increases the risk of
heart attack recurrence among survivors of a myocardial infarction (US DHEW 1979).
The 1980 Report (US DHHS 1980) noted the increased risk of CHD among women
who smoke. It also described the synergistic interaction between smoking and oral con-
traceptive use that substantially increases CHD risk. The 1983 Report (US DHHS
1983) stated that cigarette smoking is a major cause of CHD and noted the decreased
risk of CHD among former smokers compared with current smokers.
Epidemiology
The findings from several pr0spectib.e studies involving more than 20 million per-
son-years of observation in North America, Northern Europe, and Japan have been
remarkably similar: cigarette smokers are at increased risk for fatal and nonfatal
myocardial infarction and for sudden death. Overall, smokers have a 70 percent greater
58

CHD death rare. a two- to fourfold greater incidence of CHD, and a two- to fourfold
greater risk for sudden death than nonsmokers (US DHHS 1983).
Although women experience lower CHD rates than men, cigarette smoking is a major
determinant of CHD in women. In a recent prospective study of 1 19,404 female nur-
ses, smoking accounted for approximately one-half of the coronary events (Willett et
al. 1987). Cigarette smoking produces a greater relative CHD risk in men and women
under SO years of age than in those over 50 years of age (Clover. Kuber et al. 1982;
Rosenberg. Miller et al. 1983).
Dose-response relationships between cigarette smoking and CHD mortality have
been demonstrated for several measures of exposure to cigarettes, including the num-
ber of cigarettes smoked per day, the depth of inhalation, the age at which smoking
began. and the number of years of smoking (US DHHS 1983). Smoking cigarettes with
reduced yields of tar and nicotine has not been found to reduce CHD risk (Kaufman et
al. 1983).
Coronary Heart Disease Risk Factors
The risk of experiencing a heart attack is multifactorial (US DHHS 1983). The
presence of one or more of the major CHD risk factors, cigarette smoking, hyper-
cholesterolemia, and hypertension, identifies individuals at high or very high risk.
These risk factors interact synergistically to greatly increase CHD risk (Figure IO). The
risk of CHD associated with cigarette smoking is comparable to that associated with
the other major CHD risk factors.
The risk of CHD is greatly increased among diabetic men and women who smoke
cigarettes (Suarez and Barrett-Connor 1984; Stamler. Wentworth. Neaton 1986), and
the sex differences in CHD are substantially reduced among diabetics. Among the
MRFIT screenees free of a history of heart attack, there were 5,245 diabetics and
350.977 nondiabetic men aged 35 to 57 years at the time of enrollment (Suarez and
Barrett-Connor 1984). The CHD death rate was much higher among diabetics than
among nondiabetics. Smokers had higher CHD death rates than nonsmokers among
both diabetics and nondiabetics. Six-year CHD mortality was 4.0/1.000 for non-
smokers who were nondiabetic and 23.2/1,000 for diabetics who smoked at least 36
cigarettes per day.
Hyperlipoproteinemia is a primary cause of premature coronary atherosclerosis and
heart attacks. Cigarette smoking substantially increases the risk of CHD among in-
dividuals with genetic familial hyperlipidemias. Williams and coworkers (Williams et
al. 1986; Hopkins, Williams, Hunt 1984) studied four large Utah pedigrees with familial
hypercholesterolemia. They noted a substantially increased risk of CHD within the
high-risk pedigrees in relation to cigarette smoking.
Miettinen and Gylling (1988) have recently completed a long-term followup of 96
patients with familial hypercholesterolemia.  Cigarette smoking was a significant
predictor of coronary mortality after adjustment for disease history. sex, and various
metabolic parameters.
59

180
170
160
150
140
130 I
8   120
;   110
it   100
if   90
2   60
   70
   60
   50 j
40
30
20
10 1
  23
I
None    SM only    c or Ii     SMBC
103
-
-
92
-
TiT-
-
RISK FACTOR STATUS AT ENTRY *
Pathophysiological Mechanisms
.Autopsy \tudie\ indicate that cigarette smoking has a significant positive association
with uthero\clero\is (US DHHS IYX3). Studies have noted the strongest relationship
of cigarette smoking vv ith aortic atherosclerosis. but smohers also show increased
coronary atherosclerosis compared with nonsmokers (US DHHS IYX3). Smokers un-
dergoins coronary an?iography ha\ie more coronary artery disease than nonsmoker\
(Peur\on 19x31. Cigarette smokers ~"70 continue to smoke following transluminal
coronary angioplasty may be more likely to require repeat angioplasty than nonsmokers
(Galan et al. IYXX)
Cigarette smoking exerts both acute and chronic adv*erse coronary effects (US DHHS
1983: Holbrooh et al. 1984). It contributes to acute ischemic and occlusive events
through several possible mechanisms: an imbalance between myocardial oxygen sup-
ply and demand. coronary artery spasm. a hypercoagulable state. increased platelet ad-
hesivenes\ and aggregation. and a decreased ventricular fibrillation threshold (US

DHHS 1983: Martin et al. 1984; Fitzgerald, Oates. Nowak 19X8). Cigarette smoking
also contributes to the development of coronary atherosclerosis. Possible mechanisms
for this chronic effect include: repetitive endothelial injury. a decreased high-density
lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol ratio. abnormalities in the
synthesis of thromboxane A2 and prostacyclin. and increased neutrophil elastase ac-
tivity (Holbrook. in press: Nowak et al. 1987: Weitz et al. IYX7).
Clinical Correlations
Cigarette smoking has an advjerse effect on individuals with symptomatic or
asymptomatic CHD. Compared with nonsmokers. smokers having a positivle exercise
test (Rautaharju et al. 1986: Gordon et al. IYX6) or a history of coronary bypass surgery
(Vlietatraet al.lY86:Kempet al. 1986) face a worse prognosis. Smokers who have an-
gina pectoris have a higher risk of death than nonsmokers (Hubert. Holford. Kannel
I%?) and have a poorer long-term prognosis after a myocardial infarction (Ronnevik.
Gundersen. Abrahamsen 19x5: Kuller et al. 1983). Continuing to smoke increases the
likelihood of recurrent acute myocardial infarction and sudden death (Hallstrom. Cobb.
Ray 1986). Smoking may alsocause silent ischemic disturbances in patients w,ith stable
angina pectoris (Deanfield et al. 1986).
Cigarette smoking interferes with the efficacy of medication used to treat CHD such
as propranolol. atenolol. and nifedipine (Deanfield et al. 1983).
Smoking Cessation
Prospective epidemiologic studies have documented a substantial reduction in CHD
death rates following smoking cessation (US DHHS 1983). While some studies have
shown a benefit within 2 years after quitting. other studies have suggested that the
former smoker's CHD risk gradually decreases over a period of several years (Cook et
al. 1986). For heavier smokers, the residual CHD risk is proportional to the total
lifetime exposure to cigarettes.
Cerebrovascular Disease (Stroke)
In the United States stroke is the third leading cause of death. It is also a major cause
of morbidity. with more than 400.000 Americans suffering nonfatal strokes each year
(Harrison's Principles of Internal Medicine 1987).
There are two major types of cerebrovascular disease: ( I ) cerebral infarction due to
occlusion of a vessel by an embolus or thrombosis, and (2) cerebral hemorrhage. in-
cluding subarachnoid and parenchymal. The terms cerebrovascular accident and stroke
are nonspecific and usually refer to clinical syndromes.
A stroke may be caused by disease of the extra- or intracranial blood vessels. Em-
bolization from the heart or extracranial arteries is also an important cause of stroke.
The stroke can result from hemorrhage from a blood vessel or from occlusion of an
artery because of atherosclerosis. thrombosis, or embolization. In the Framingham
study, atherothrombotic brain infarction accounted for the majority of ctrokes (Wolf.

Dawber et al. 197X). Improved diagnostic methods have provided a better categoriza-
tion of the causes of stroke. Epidemiologic studies have shown that hypertension is the
most important risk factor for stroke (US DHHS 1983).
The 1964 Report of the Surgeon General stated that the large epidemiologic studies
of Hammond and Horn (1958) and Dorn ( 1958) had found a moderate increase in the
mortality rate from cerebrovascular dsease in cigarette smokers compared with non-
smokers.
The I97 I Report (US DHEW I97 I l reviewed six major prospective epidemiologic
studies. Cigarette smokers in these studies experienced increased stroke mortality com-
pared with nonsmokers. The 1980 Report (US DHHS 1980) noted that women who
smoke have an increased risk of subarachnoid hemorrhage. The 1983 Report (US
DHHS 1983) reviewed the data associating cigarette smoking with stroke and found an
increased risk for stroke among smokers that was most evident in younger age groups.
It also noted that women cigarette smokers experience an increased risk for subarach-
noid hemorrhage and that the concurrent use of both cigarettes and oral contraceptives
greatly increased this risk.
Since the release of the 1983 Surgeon General's Report the relationship between
cigarette smoking and stroke has been clarified in several large studies involving men
and women.
The risk of stroke was evaluated in a prospective study of 8,006 Japanese-American
men living in Hawaii (Abbott et al. 1986). After I2 years of followup. cigarette smokers
had two to three times the risk of thromboembolic or hemorrhagic stroke compared
with nonsmokers. The increased risk was independent of other risk factors such as hy-
pertension and CHD. Those smckers who stopped smoking during the course of the
study experienced more than a 50-percent reduction in the risk of stroke compared with
continuing smokers.
The impact of cigarette smoking on stroke incidence was assessed prospectively in
the Framingham Study of 4,255 men and women (Wolf et al. 1988). This cohort was
followed for 26 years. and the diagnoses were confirmed by clinical examination.
Cigarette smoking made a significant. independent contribution to the risk of stroke.
The risk increased as the number of cigarettes smoked increased. Smoking cessation
resulted in a significant decrease in stroke risk so that 5 years after stopping smoking
the risk was at the level of nonsmokers.
The relationship between cigarette srnoking and the risk of stroke was evaluated in
a prospective study of I 18.539 middle-aged women who were followed for 8 years
(Colditz, Bonita. Stampfer 1988). Compared with nonsmoking women. those who
smoked I to I4 cigarettes per day had a relative risk of fatal and nonfatal stroke of 2.2.
Those who smoked 25 or more cigarettes per day had a relative risk of fatal and non-
fatal stroke of 3.7. In this latter group of women, the relative risk of subarachnoid
hemorrhage was 9.8. The contribution of cigarette smoking to increased stroke risk
was independent of other risk factors. Smoking cessation resulted in a prompt decrease
in stroke risk; the relative risk of stroke in women who had stopped smoking for 2 years
was I .4. compared with women who had never smoked. The authors of this study also
reviewed eight prospective cohort studies and seven case-control studies involving
62

women, and concluded that most of these studies had shown a positive association be-
tween cigarette smoking and stroke (Table 3).
In the ongoing study of approximately I .2 million persons (CPS-II), cigarette smokers
under the age of 65 years experienced increased risks of death from stroke. For men
and women (current smokers), the relative risks of death from stroke were 3.7 and 4.9,
respectively. The relative risks for those over age 65 years were 1.9 and 1.5 for men
and women, respectively (Chapter 3).
Cigarette smoking was associated with decreased cerebral blood flow in a recent
clinical study involving 192 normal volunteers (Rogers, Meyer et al. 1983). In a sub-
sequent study of 268 normal volunteers, abstention from cigarette smoking improved
cerebral perfusion (Rogers, Meyer et al. 1985).
As already noted in this Chapter, cigarette smoking increases the risk for CHD, and
consequently for congestive heart failure, both of which increase the risk for stroke.
Data from the Medical Research Council study on the treatment of mild hypertension
illustrate the impact of cigarette smoking on the efficacy of drug therapy and stroke in-
cidence (Medical Research Council Working Party 1985). Nonsmokers receiving
propranolol to control hypertension experienced a reduction in stroke incidence, while
cigarette smokers did not.
Wolf and coworkers (1988) recently reviewed the association between
cigarette smoking and stroke and concluded that it is causal. These investigators noted
that the causal connection is supported by all of the traditional epidemiologic criteria;
these include an increased risk for stroke among smokers compared with nonsmokers
that is independent of other risk factors, a dose-response relationship, and a decrease
in stroke risk with smoking cessation (Abbott et al. 1986; Wolf et al. 1988; Colditz,
Bonita, Stampfer 1988). The aforementioned recent clinical studies also confirm that
cigarette smoking increases the risk for stroke. Thus, current evidence indicates that
cigarette smoking is a cause of stroke and that smoking cessation reduces the risk for
stroke.
Atherosclerotic Peripheral Vascular Disease
Lower extremity arterial vascular disease causes substantial mortality and morbidity;
the complications may include intermittent claudication, tissue ischemia and gangrene,
and ultimately, loss of the limb.
The 1964 Surgeon General's Report commented that little is known about the
relationship of smoking to peripheral arteriosclerosis.  Subsequent reports have
described the evidence establishing that cigarette smoking is a cause of and the most
powerful risk factor for atherosclerotic peripheral vascular disease and that smoking
cessation is the most important intervention in the management of this problem (US
DHEW 1971,1979; US DHHS 1983).
Cigarette smoking is directly related to the extent of atherosclerotic disease involv-
ing large and small arteries in the lower extremity (Criqui et al. 1985). Cigarette smok-
ing also causes peripheral vasoconstriction. Epidemiologic and clinical studies have
clearly demonstrated that cigarette smokers have a higher prevalence than nonsmokers
hi

TABLE 3.-Summary of studies of cigarette smoking and stroke in women
                           No.
First author  Cohort size Type of stroke   of cases   Relative risk        Comments
Colditz
Salonen
Tanaka
Sacco
Vessey
Doll
Layde
Petitti
Wolf
Prosper tive cohort studies
I 18.539  All          274    2.2 (95% a, 1.5-3.3)   1-14 cigarettes/day
                     2.7 (95% CI, 1.9-3.7)   15-24 cigarettes/day
                      3.7 (95% CI, 2.7-5.1)  225 cigarettes/day
4,334  Infarction           I .4 (90% a. 0.4-5.0)
      Other    :li   0.8 (90% Cl, 0.3-2.2)
1.68 I  Hemorrhage     30    2.1 (NS)           Included 780 men
     Infarction      81    I .O (NS)
2,42 I  Subarachnoid    22    1.6             Relative risk was 2.9
    hemorrhage                  for heavy smokers
17,000  Subarachnoid    I3    3.0
    hemorrhage
    Nonhemorrhagic  33    I.4
6,194  Cerebral throm-   68    0.5 for 15-24 ciga-    Risk tended to
      bosis           rettes/day         decrease with amount
                                     smoked
46,000  Subarachnoid    20
    hemorrhage
16.759 Subarachnoid I I
    hemorrhage
     Other        23
2.42 I   All         238
           Smokers had higher
              risk of fatal
              subarachnoid
           hemorrhage
5.7 (90% a, 1.8-17.8)
4.8 (90% CI. 2.3-9.8)
I .6 (p<O.O25)
Case-control studies
Taha
Bell
Collaborative study
Abu-Zeid
Bomta
Bomta
Herman
Subarachnold 124
hemorrhage
Subarachnoid    134
hemorrhage
Hemorrhage I92
Thrombo\ts     140
Hemorrhage    137
Thrombosis    410
Subarachnoid 70
hemorrhage
Not subdrach- 53
noid hemorrhage
Stroke        25
2.6 for aneurysm      Based on 68 female
               cases
3.7(907c Cl, 2.3-5.9)
           Smoking doubled risk
              No increased risk
1.4 (NS)           Included men
2.4 (p<o.OOI)
4.7 (95% CI, 2.9-7.6)   Dose-response
           relationship not
           significant
2.6 (95% Cl. 1.64.6)
I.2 (95% CI, 0.7-2.3)   Included 78 men
NOTE: Cl. confidence mterval: NS. not r~gmficant.
SOURCE Colditr. Bonita, Stampt'er f 1988).
64

Jf both symptomatic and asymptomatic lower extremity arterial disease (US DHHS
1983).
In the Lipid Research Clinic prevalence study (Pomrehn et al. 1986). -&X percent of
individuals with claudication were current cigarette smokers compared with 30 percent
of the controls. Smoking was twice as frequent among individuals developing leg pain,
compared with those not developing leg pain. during the exercise test.  In the
Framingham Study, the risk of developing intermittent claudication was directly and
strongly related to cigarette smoking (Kannel and Shurtleff I Y73).
Diabetes mellitus and cigarette smoking are the key risk factors for lower extremity
arterial disease and subsequent amputation. Peripheral neuropathy and lower extremity
arterial disease and infection predispose individuals with diabetes to gangrene and am-
putation (Herman, Teutsch. Geiss 1987). Diabetics have a sixteenfold increased risk
of lower extremity amputation compared with nondiabetics; about SO percent of the
lower extremity amputations in the United State> are performed on diabetics. Ap-
proximately 3 1,000 American diabetics undergo such surgery each year. The disease
tends to be more progressive and occurs at younger ages in diabetic smokers than in
nonsmokers.
In a study in Sweden, practically all diabetic patients under the age of60 years with
gangrene were cigarette smokers (Lithner 1983). The prevalence of lower extremity
arterial disease was evaluated for diabetic subjects. One-third of the smokers had
evidence of peripheral vascular disease compared with only I6 percent of the non-
smokers. Diabetics who stopped smoking for at least 3 years had a 30 percent lower
prevalence of lower extremity arterial disease than those who continued to smoke.
Epidemiologic studies in a Rochester, MN, population (Zimmerman et al. 1981)
demonstrated that for 1,073 residents over the age of 30 who were diagnosed with
diabetes mellitus between 1945 and 1969. about 8 percent of men and 7 percent of
women had clinical evidence of peripheral vascular disease at the time that diabetes
was diagnosed. The annual incidence of lower extremity arterial disease among the
diabetics was 21/1,OOO for men and 17.6/l ,000 for women; about 20 percent had
gangrene and 36 percent had intermittent claudication. Among diabetics with lower
extremity arterial disease, 77 percent of men and 43 percent of women had been
cigarette smokers compared with 55 percent of normal control men and 36 percent of
normal control women.
Effective treatment of diabetes mellitus and smoking cessation are the two most im-
portant interventions to prevent the development of atherosclerotic peripheral vascular
disease.
Atherosclerotic Aortic Aneurysm
The I964 Report of the Surgeon General commented on the increased mortality rates
fOJ aortic aneurysm in cigarette smokers compared with nonsmokers. The 1969 Report
concluded that there is a close association between cigarette smoking and death caused
by aortic aneurysm. The 1983 Report summarized the epidemiologic data and noted
that the mortality rate forabdominal aortic aneurysm was 2 to 8 times greater in cigarette
smokers than in nonsmokers. A\ already noted, pathology studie\ have shown a rig-
65

nificant association between cigarette srnoking and atherosclerosis that is most striking
in the aorta (US DHHS 1983).
Chronic Obstructive Pulmonary Disease
In the 1950s increasing morbidity and mortality from chronic respiratory conditions
prompted clinical and epidemiologic investigations of the etiology of chronic
bronchitis, emphysema, and related disorders. A variety of terms have subsequently
been applied to permanent airflow obstruction in cigarette smokers. In the 1984 Sur-
geon General's Report, chronic obstructive lung disease (COLD) referred to chronic
mucus hypersecretion, airways abnormalities, and emphysema. In this Report, the
term COPD is used for the permanent airflow obstruction that develops in cigarette
smokers. Thirty years ago, the most widely advanced hypothesis on the etiology of
COPD linked progressive lung damage to recurrent respiratory infection and atmos-
pheric pollution (Stuart-Harris 1954). However, epidemiologic investigations, largely
carried out in the United Kingdom. quickly indicated the predominant role of cigarette
smoking in causing COPD (Stuart-Harris 1968a.b).
By 1964. the evidence was sufficiently compelling to support the conclusion by the
Advisory Committee to the Surgeon General that "Cigarette smoking is the most im-
portant of the causes of chronic bronchitis in the United States, and increases the risk
of dying from chronic bronchitis and emphysema" (US PHS 1964). The Report stopped
short of classifying the relationship between cigarette smoking and emphysema as
causal. however.  The Report also noted the increased prevalence of respiratory
symptoms and the reduction of lung function in smokers. The epidemiologic data cited
in support of these conclusions were drawn from seven prospective studies of mortality
in relation to cigarette smoking and about a dozen surveys of respiratory morbidity;
only one prospective study on lung function had been reported at that time.
In the 25 years that have elapsed since the release of the 1964 Surgeon General's
Report. the findings of numerous laboratory. clinical, and epidemiologic studies have
continued to reaffirm the predominant role of cigarette smoking in causing COPD and
have extended understanding of the pathogenesis. pathophysiology, and natural history
of this disorder. As the evidence has accumulated, the conclusions of the Surgeon
General's Reports on cigarette smoking and COPD have been strengthened. The 1967
Surgeon General's Report labeled cigarette smoking as the most important of the causes
of COPD (US PHS 1968). In the I97 I and 1979 Reports. the conclusions of the 1964
and 1967 Reports were strengthened (US DHEW 1979). Increased morbidity and mor-
tality from chronic bronchitis and emphysema were documented in cigarette smokers
compared with nonsmokers. Additionally, autopsy evidence confirmed that the lungs
of smokers were widely damaged, and the evolving protease-antiprotease hypothesis
provided a framework for understanding mechanisms through which cigarette smoke
causes emphysema.
The 1984 Surgeon General's Report focusedon COLD (US DHHS 1984). The over-
all conclusion of the Report was: "Cigarette smoking is the major cause of chronic
obstructive lung disease in the United States fOJ both men and women. The contribu-
tion of cigarette smoking to chronic obstructive lung disease morbidity and mortality
66

far outweighs all other factors." In contrast to the sparse evidence in the 1964 Report,
the 1984 Report reviewed numerou\ cross-sectional and longitudinal studies of mor-
bidity and mortality. The longitudinal studies described the evolution of the cigarette-
related decline in lung function that leads to impairment sufficient to result in a clini-
cal diagnosis of COPD.
This Section provides an overview of the evidence on COPD that has accumulated
since the 1964 Report in the areas of pathogenesic, pathophysiology. and natural his-
tory of COPD and the role of cigarette smoking.
Pathogenesis
The 1964 Report described the deposition of cigarette-smoke particles and gases in
the lungs and the effects of cigarette smoke on lung defense\ but did not address the
mechanisms by which cigarette smoking causes COPD (US PHS 1964). Much of the
subsequent investigation of the mechanism of lung injury by cigarette smoke was
sparked by the observation that homorygous deficiency of alphat-antitrypsin. the major
protease inhibitor. is associated with familial panlobular emphysema (Laurel1 and
Eriksson 1963; Eriksson 1964). This observation led to the hypothesis. generally
referred to as the protease-antiprotease hypothesis. that the development of emphysema
results from an imbalance between proteolytic enzymes and their inhibitors (Janoff
1985: Niewoehner 1988). Cigarette smoking is postulated to produce unchecked
proteolytic activity by increasing proteolytic enzyme activity in the lung while decreas-
ing antiprotease activity.
Experimental and clinical observations have been consistent with the protease-an-
tiprotease hypothesis (US DHHS 1984). Observations that smokers, compared with
nonsmokers. have an increased number of neutrophils in peripheral blood (Yeung and
dy Buncio 1984). in bronchoalveolar lavage fluid. and in lung biopsy specimens
(Hunninghake and Crystal 1983) provide indirect evidence for an increased elastase
burden in smokers' lungs. since neutrophils are the primary source of elastase (Janoff
1985). Furthermore. elastase levels are elevated in bronchial lavage fluid immediate-
ly after smoking cigarettes (Fera et al. 1986). Cigarette smoking has also been shown
to decrease the levels and activity of antiproteases. an effect attributed to oxidants in
cigarette smoke and the pulmonary macrophages of smokers (Janoff 1985: US DHHS
1984). Animal models confirm that unchecked proteolytic activity can cause em-
physema (US DHHS 1984).
The lungs of patients with COPD generally display both emphysema and abnor-
malities of the small airways. Mechanisms by which cigarette smoke damages small
airways have not been so extensively investigated as the factors determining the
development of emphysema.
Pathoph&ology
The lungs of smokers with COPD generally have both thickening and narrowing of
airways and emphysema, although the extent of these two processes is variable (US
DHHS 1984). Both the airways changes and emphysema produce airflow obstruction.
67

The I Y6-l Report noted that smohcr\` I ung\ displayed air\bay> change\ and emphysema:
however. the pathoph> Gological correlates of the\e changes Mere not explored.
Suhquent in\c`stifution\. correl;tinf structural changes with function, have
described the relationship between mohing-caused changes in lung structure and
airtloti obstruction. Emphy~ttma and small-airway injury contribute to the phyciologi-
cal impairment found in COPD: in individual\ with symptomatic airflow obstruction.
either type of in,iuq ma> be predominant. but both are probably important (US DHHS
IYXS). While the I%4 Report de\crihed effect\ of cigarette smoking on the airways.
the importance of the small airMay\ as a \ite of airflow obstruction was not recognized
until the late IYhOs (Hofg. Machlem. Thurlbech IY6Xj. More recent investigations
have confirmed that measures of mall-airway injury are correlated with the degree of
airflow obstruction (US DHHS I YX4: Hale et al. I YX-I: Nagai. West. Thurlbeck I YXS).
Autopsy studies have shown that chan:;es in the small airways develop in the lungs of
young smohers and antedate the development of symptomatic airflow obstruction
(Niewoehner. Kleinerman. Rice lY71)
The importance of emphysema in pro'.iucing chronic aifflow obstruction has also been
amply documented %ince the IYh3 Report. Emphysema reduces the driving pressure
for evpiratory tltru and contribute3 to i,lcrea\ed airways resistance by reducing tether-
ing of small airMay\. In patient\ with symptomatic airflow obstruction. the extent of
anatomic emphysema is correlated with the severity of airflow obstruction, as are
small-airway abnormalities (US DHHS 1984; Hale et al. 1984; Nagai, West, Thurlbeck
IYX5). Thux. the \mohlng-cau\etl lung changes in the air\vay\ and parenchyma have
both been unquivocalt~ linhed to airt`l~)w oh<truction.
Natural History of COPD and the Role of Cigarette Smoking
NearI> all the epidemiologic e\,idenr,e reviewed in the lY64 Report M;I~ cross-sec-
tional in nature. These data estahli\hed that cigarette smohing increased respirator)
symptom\ and reduced the level of ventilator\ function. but they did not provide in-
Gght into the temporal evolution of COPD. Sub\equent cro\s-sectional studies have
provided more complete quantitative description\ of the effects of cigarette smoking
on lung function. and ncn longitudinal studies have partially dehcribcd the evolution
of lung function change\ in mohcrs and the factory determining the rate ofchange over
time.
The numcrou\ cro\\-\ection;ll \tudie+, published \incz the IY6-l Surgeon General's
Report have shop n that cigarette mokin, (7 is a strong determinant of the level of ven-
tilator! function. LI hich is most often asressed b! the measurement of the I -set forced
expiratory volume (FEV, ). The level of FEVt declines ;I> the amount of smoking in-
crea\e\ CL'S DHHS IYXJ). Multiple re:;re\sion techniques have been applied to data
from se\,erat different population\ to de\cribe the quantitati\,e relationship between the
amount smohed and lot\ of ventilator\ function. These anal>\es indicate that ven-
tilator! function decline\ in ;I lineart;t\hion u ith cumulative consumption ofcigarettes.
usualI> e\;pre\\ed ;I\ pa&>ears (Burrows et al. lY77: Docker) et al. IYXX). For ex-
ample. bused on anal) s~s of data from X. I Y I men and women from six U.S. cities. Dock-
er\ and other\ ( 1 YXX) reported that male kImohers of a\ erage height lose 7.J mL of FEV I
6X

on average for each pack-year and that women lo\e 3.4 mL per pack-year. Although
the decline in mean level of FEV I appears hmall. the distributions of lung function level
in smokers and in nonsmokers are different: the distribution for smokers is skewed
toward lower levels co that a much greater proportion of smokers than nonsmokers have
levels below the usual limit of normal (Figure I 1) (US DHHS 19X4: Burrows et al.
1977: Dockery et al. 19X8).
30 -                      0 Pn-TRS
x 2o *                     N=3303
IO-                     lOA=.
  0+                                  I
  -3.0   -2.0   -1.0   0.0    1.0    2.0    3.0
.y ;ij~~:zs?"`"
  -3.0   -2.0  -1.0 3'. .
                 0.0 1.0 2.0
~1409PK-TRS
Ik638
-3.0   -2.0   -1.0    0.0    1.0    2.0    3.0
SE] ,& ~~~fP,~~"'
  -3.0   -2.0   -1.0    0.0  1.0 2.0 70
30 7          fy3,"  PK-YRF
20 .
S
10.            I;lA..8*1
  04
  -3.0   -2.0   -1.0   0.0    1.0 2.0 3.0
30 -
s 2O .                r   E+,`,K-`"5
  10.                      lOR1.966
  07
  -3.0   -2.0   -1.0   0.0   1.0 2.0 3.0
HElGhT ROJUSTEO FEYI RESIDUF4L iLITERS
FIGURE Il.-Percent distribution of predicted values of forced expiratory
      volume in I-set (FEV I) in subjects with varying pack- years of smok-
      ing.
NOTE Trmgle Indlcotz\ 111e3311. IQR I\ mtrrquart~le rany
SOLRCE:  Dochery et ~1. I IWX,
The longitudinal studies published Gnce the 1964 Report have partially described the
natural history of lung function changes in COPD (Fletcher et al. 1976: US DHHS
1984). Ventilatory function. ;1s measured by FEVt. for example. increases during
69

childhood and reaches a peak level during early adulthood (Figure 12). From the peak
level, ventilatory function declines with increasing age. In cigarette smokers who
develop symptomatic airflow obstruction, a similar loss of function takes place, but at
a more rapid rate than in nonsmokers and in smokers who do not develop disease. A
physician is likely to diagnose COPD when continued excessive loss of ventilatory
function results in sufficient impairment to cause dyspnea and limitation of activity.
I          I         I         I          I        t
25         35         45         55         65         75
FIGURE 12.-Decline of FEVI at normal rate (solid line) and at an accelerated
       rate (dashed line)
The factors influencing rate of lung function decline in cigarette smokers have not
yet been fully characterized. The rate of decline tends to increase with the amount
smoked, and former smokers generally revert IO the rate of loss of nonsmokers. In fact,
the excessive decline observed in some smokers may represent a common physiologi-
cal consequence of different pathophysiological mechanisms. Habib and coworkers
(1987) carefully characterized 13 subjects from a longitudinal study in Tucson with a
mean annual decline in FEV I greater than 60 mL per year. Clinically, these subjects
were not unique and none had alphat-antttrypsin deficiency. Physiological assessment
70

suggested that some were developing emphysema, whereas others appeared to have
disease of the large and/or small airways.
The studies of longitudinal change in lung function have spanned only segments of
the full natural history of COPD. and many questions remain unanswered. It is unclear,
for example, whether the excessive decline takes place at a constant rate in continuous
smokers, as suggested by much of the epidemiologic evidence. or whether the exces-
sive decline occurs intermittently after some triggering event. The factors determining
the susceptibility of individuals to cigarette smoking are also unclear. Current
hypotheses emphasize determinants of protease-antiprotease imbalance, level of non-
specific airways reactivity, and severe respiratory illness during early childhood.
Since the release of the 1964 Surgeon General's Report. abundant evidence has in-
dicated the overwhelming importance of cigarette smoking in causing COPD: in fact,
COPD would be an uncommon condition in the United States without cigarette smok-
ing. Unfortunately, death rates due to COPD have paralleled those for lung cancer and
have increased progressively over the last 25 years (National Center for Health Statis-
tics 1986). The trends are consistent with cohort changes in smoking; in this regard,
while age-specific rates for males have been increasing at older ages, a recent decline
in COPD mortality has been observed at younger ages (US DHHS 1984). While im-
portant scientific questions remain unanswered concerning the pathogenesis of COPD,
the available evidence provides sufficient rationale for preventing COPD through
smoking prevention and cessation.
Pregnancy and Infant Health
Several endpoints have been studied to evaluate the adverse effects of smoking on
pregnancy, including (1) infant birthweight: (2) fetal and infant mortality; (3) congeni-
tal malformations; (4) fertility; and (5) long-term effects on the child.
The 1964 Report indicated an association between smoking and low-birthweight
babies (US PHS 1964) but it did not consider the evidence sufficient to establish a
causal relationship.
The 1969 Report (US PHS 1969) confirmed the association between maternal smok-
ing and low-birthweight babies. an increased incidence of prematurity, spontaneous
abortions, stillbirths, and neonatal deaths. The 1971 Report (US DHEW 1971) con-
cluded that maternal smoking during pregnancy exerts a retarding influence on fetal
growth. The 1973 Report (US DHEW 1973) noted that cigarette smoking is a prob-
able cause of increased late fetal mortality and infant mortality. The 1977-78 Report
(US DHEW 1978) noted a dose-response relationship between smoking and abruptio
placentae, placenta previa. bleeding during pregnancy. and prolonged premature rup-
ture of membranes, as well as the association of smoking during pregnancy with im-
paired physical and intellectual development of the offspring. The 1979 Report (US
DHEW 1979) linked smoking with sudden infant death syndrome. The 1980 Report
(US DHHS 1980) noted that up to 14 percent of preterm deliveries in the United States
may be attributed to maternal smoking. It also surveyed studies of men and women
suggesting that cigarette smoking may impair fertility.
71

In 19X5. the Center for Health Promotion and Education of the Centers for Disease
Control. Atlanta. GA. defined the fetal tobacco syndrome as follows. (I) The mother
smoked 5 or more cigarettes a day throughout the pregnancy. (2) The mother had no
evidence of hypertension during pregnancy, specifically no preeclampsia and
documentation of normal blood pressure at least once after the first trimester. (3) The
nevvborn has symmetrical growth retardation at term, 37 weeks, defined as birthweight
less than 3.500 g. and a ponderal index (weight in grams divided by length) greater than
2.32. (4) There is no obvious cause of intrauterine growth retardation. that is, congeni-
tal malformation or infection (Nieburg et al. 1985).
Infant Rirthweight
A clear dose-response relationship exists between the number of cigarettes smoked
during pregnancy and the birthweight deficit (US DHHS 1980; Committee to Study the
Prevention of Low Birthweight 1985). Compared with nonsmokers, light and heavy
smokers have a S4- and l30-percent increase. respectively, in the prevalence of new-
borns weighing less than 2,500 g. A review of five studies including I I3.000 births in
the United States. Canada, and Wales found that from 2 I to 39 percent of the incidence
of low birthweight w*as attributed to maternal cigarette smoking (Committee to Study
the Prevention of Low Birthweight 1985). Also, cigarette smoking seems to be a more
significant determinant of birthweight than the mother's prepregnancy height, weight,
parity, payment status. or history of previous pregnancy outcome. or the infant`s sex.
The reduction in birthweight associated with maternal tobacco use seems to be a direct
effect of smoking on fetal growth.
Mothers who smoke also have increased rates of premature delivery. The newborns
are also smaller at every gestational age. The infants display symmetrical fetal growth
retardation with deficits in measurements of crown-heel length, chest and head circum-
ferences. and birthweight.
A recent study in Boston (Lieberman et al. 1985) attempted to evaluate the reasons for
differences in rates of prematurity between blacks and whites. Of the 1,365 black
women. 34.7 percent were cigarette smokers compared with only 23.4 percent of the
white w'omen. Cigarette smoking and low hematocrit levels were two of the most im-
portant risk factors accounting for the differences in prematurity rates between blacks
and wjhites.
Finally. a number of careful studie\ have found that the effect of cigarette smoking
on birthueight is not mediated through decreased maternal appetite or weight gain (US
DHHS 19X0).
The most widely accepted hypothesis relating maternal smoking and the effects on
the fetus and newborn is intrauterine hypoxia (Rush and Cassano 1983). The hypoxia
could occur as a result of factors associated with smoking. such as increased levels of
carbon monoxide (CO) in the blood. reduction of blood flow. or inhibition of respiratory
enzymes. There is strong experimental evidence that maternal smoking causes fetal
hyposia.
72

Several studies have demonstrated that smoking cessation prior to or during pregnan-
cy can partly reverse the reduction in the child's birthweight (Rush and Cassano 1983;
Hebel, Fox. Sexton 198X). In a large study using the 1970 British Birth Cohort (Lieber-
man et al. 1987). an inverse relationship between measures of social class and the
prevalence of smoking w/as demonstrated that was similar to that seen in the United
States. In all social class groups. babies of the nonsmokers weighed more than those
whose mothers had smoked during pregnancy. and the women who had stopped smok-
ing either before or during pregnancy had babie\ with higher birthweight than women
who continued to smoke throughout pregnancy.
Fetal and Perinatal Mortality
Kleinman and colleagues (19X8) from the National Center for Health Statistics used
Missouri birth records from 1979-83 (Table 3) tn study the relationship betvveen
cigarette smoking in mothers and infant mortality. Among the 133.429 primiparas, the
infant mortality rates (adjusted for age. parity. education. and marital status) were (per
I.000 subjects) IS.1 for white nonsmokers. 1X.X for whites who smoked less than I
pack of cigarettes per day. and 23.3 for whites who smoked more than I pack of ciga-
rettes per day. For black nonsmoking women. the infant mortality rate (per 1,000
women) was 26.0: for blacks who smoked less than I pack per day. 32.4: and for blacks
who smoked greater than I pack per day. 39.9. Mortality was increased during the fetal.
neonatal, and postneonatal periods. It was estimated that if all pregnant women stopped
smoking. the number of fetal and infant deaths vvould be reduced by approximately IO
percent. In the United States this would result in about 4,000 fewer infant deaths each
year. A study conducted by the Office on Smoking and Health attributed approximate-
ly 2.500 infant deaths to maternal smoking in 1984 (CDC 1987).
Stein and associates (1981) have studied the causes of spontaneous abortion in three
New York City hospitals. They compared women with spontaneous abortion to con-
trols (women who carried their pregnancy to 2X weeks or more). Within the spon-
taneous abortion groups. they then compared those with evidence of chromosomal ab-
normalities and those with apparently normal chromosomes. The odds of a spontaneous
abortion increased by 46 percent for the first IO cigarettes smoked per day and by 6 I
percent for the first 20 cigarettes smoked. Smoking was not associated with the spon-
taneous abortion of chromosomally abnormal conceptions. but only with those in which
the chromosomes were normal. These results were not confounded by such factors as
maternal age or race.
Congenital Malformations
Evidence that exposure to tobacco and cigarette smoking could be related to congeni-
tal malformations is less clear. About 3 percent of all live birth5 have major congeni-
tal malformations (Behrman and Vaughn 1987). Maternal smoking has not been
demonstrated to be a major risk factor for the induction of congenital malformations,
although elevated risks have been reported in some studies. Kelsey and coworkers
(1978) reported an increased risk of 1.6 for congenital malformations among the
73

TABLE 4.-Infant mortality rates and odds ratios (95% confidence intervals), by maternal race, among 134,429 primiparas,
     based on multiple logistic regression, Missouri, 1979-83
   Crude rates            Adjusted rates
  (per I .ooo)            (per I .ooo)
Whites      Blacks        Whites        Blacks
    Adjusted odds ratios
Whites                 Blacks
Marital status
Married
Unmarried
Education (years)
<I2
12
>I2
Age (years)
<I8
18-19
2G-24
25-29
3&34
235
Smoking
0
~1 pack/day
>I pack/day
14.5        25.4          15.9         29.5           I .OO                  I .oo
24.0        2X.6          2 I .o         27.2         1.33(1.1X-1.50)         0.92 (0.73-I. 16)
22.9        13.2          !9.X         33. I                 1.36(1.16-1.59)
IS.2        25.9          16.7         28.8                 l.l4(1.02-1.28)
12.8        21.5          14.6         25.3                   1.00
24.0        33.7          18.X         32.2                 I .24 ( I .06-l .45)
IX.2        26.0         16.3         27.9                 1.08 (0.95-I .22)
14.2        23.4          15.2         26.0                   1.00
13.2        27. I          16.1         27.6                 I.06 (0.94-I .20)
16.1        19.9          I X.6         31.9                 1.23(1.01-1.50)
25.4       69.3         31.1         52.9                 2.09 (I .49-2.93)
13.9        25.3          15.1         26.0
19.1        33.7          18.8         32.4
24.3       41.5         23.3         39.9
1.00
1.25(1.13-1.39)
I .56 ( I .37-I .77)
SOURCE: Kleinman et al. (1988)

offspring of women smoking more than 1 pack of cigarettes per day compared with
women reporting no smoking during pregnancy. Similarly, Himmelberger, Brown, and
Cohen (1978) reported a 2.3-fold higher risk of congenital abnormalities for smoking
mothers than for nonsmokers.
One study has also reported an increased frequency of congenital malformations
based on the smoking habits of the father (Schardein 1985). The trends with paternal
smoking were independent of maternal smoking level, maternal and paternal age. and
social class.
The relatively low incidence of congenital malformations, the different types of mal-
formations, and the various possible biological mechanisms have made the study of the
relationship between environmental factors and congenital malformations extremely
difficult. New techniques to monitor pregnancy outcomes may enhance our under-
standing of the interrelationship between cigarette smoking, other environmental fac-
tors, and congenital malformations.
Fertility
A recent study has substantiated previous reports that suggested that women who
smoke may have reduced fertility (Baird and Wilcox 1985). Data on smoking history
and number of noncontraceptive cycles until conception were collected from 678 preg-
nant women. Of nonsmokers, 38 percent conceived in their first cycle compared with
28 percent of smokers. Smokers were 3.4 times more likely than nonsmokers to have
taken greater than 1 year to conceive. After adjustment for other risk factors, it was es-
timated that the fertility of smokers was 72 percent of that of nonsmokers. Heavy
smokers experienced lower fertility than light smokers. Fertility was not affected by
the husbands' smoking.
The effects of cigarette smoking on sperm quality in men (Ablin 1986) were also
evaluated in relation to density, motility, and morphological abnormalities in 238 age-
related smokers and 135 nonsmokers. Spermatozoa from smokers possessed sig-
nificantly decreased density and motility compared with those from nonsmokers. Mor-
phological abnormalities of the sperm were also noted more frequently among smokers
than among nonsmokers (Ablin 1986).
Long-Term Effects on the Child
Relatively few studies have evaluated the long-term consequences of smoking during
pregnancy on the child. One of the larger recent studies looked at neurological hand-
icaps among children up to 14 years of age whose mothers had smoked during preg-
nancy and among control children born in northern Finland in 1966 (Rantakallio and
Koiranen 1987). Seventy-eight children of smokers and 62 controls had mental retar-
dation (IQs less than 85), cerebral palsy, or epilepsy. The incidence of mental retarda-
tion alone was 15.9/1.000 among the children of the mothers who smoked and 13.9
among the controls. For any combination of mental Letardation, cerebral palsy, and
epilepsy, the rates were 42.8/l ,000 for children of smoking mothers and 34/l ,000 for
the controls, a relative risk of 1.27 with confidence limits of 0.90 to 1.79.