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Cigarette smoking and serum chemistry tests
J Chron Dis 1974, Vol. 27, pp, 293-307. Pergamon Press. Printed in Great Britain
CIGARETTE
SMOKING
AND SERUM
CHEMISTRY
TESTS*
LORINGG. DALES?, GARY D. FRIEDMAN,A. B. SIEGELAUB and CARL C. SELTZERS
Department
of Medical Methods Research, Permanente
Medical
Group,
3779Piedmont Ave., Oakland, California 94611, U.S.A. (Received 18 June, 1973)
INTRODUCTION THIS PAPERis one of a series on the characteristics of smokers and nonsmokers using data from the Kaiser-Permanente Multiphasic Examinations [l-3]. The focus of attention here is on data concerning serum concentrations of eight chemistriesalbumin, globulin, glucose, uric acid, cholesterol, creatinine, calcium and glutamic oxaloacetic transaminase (SGOT)-in 57,352 white men and women and in 9812 black men and women ages 15-79. The purpose of the study was to determine whether or not cigarette smokers and nonsmokers differed in these various serum chemistry levels. Where differences were found, analyses were made for (1) persistence of the differences after stratification of the subjects by variables considered to be potentially mediating factors, and (2) relation of the differences to amount smoked. METHODS
The data on characteristics of cigarette smokers and nonsmokers come from general health examinations performed between July 1964 and August 1968 on ambulatory persons belonging to the Northern California Kaiser-Permanente Medical Care Program. The nature of the health appraisal, termed the Multiphasic Health Checkup, is outlined elsewhere along with a basic description of the smoking classifications used [I]. Persons taking Multiphasic Health Checkups, who are mostly well persons seeking a general physical examination, fill out comprehensive health questionnaires and undertake a battery of clinical and laboratory tests. Kaiser Health Plan members represent a broad spectrum of the community. *This study was supported by the Council for Tobacco Research, U.S.A., Grant 787; the National Center for Health Services Research and Development, PHS Grant HS 00288; and the Kaiser Foundation Research Institute. tReprint requests to Dr. Dales. *Department of Nutrition, Harvard School of Public Health. C
293
294
LORING G. DALES, GARY D. FRIEDMAN,A. B. SIEGELAUBand CARL C. SELTZER
Smoking status was assessed by means of a self-administered questionnaire. For purposes of this study, two types of persons have been selected: Nonsmokers, who had never used tobacco in any form, and current, established cigarette smokers, who had been smoking for over 1 yr at the time of examination. Serum chemistry determinations were performed on samples of venous blood drawn 1 hr after ingestion of 75 g of glucose. Subjects were asked to refrain from eating, but not from smoking, for 4 hr prior to examination. The determinations were done on an 8-channel Technicon auto analyzer. The specific analytic methods employed for each serum chemistry were as follows: albumin-Haba Dye, globulin-total protein (determined by the Quantitative Biuret method) minus albumin, serum glucosepotassium ferrocyanide, uric acid-phospho tungstate and cyanide, cholesterolLieberman-Burchard reaction, creatinine-alkaline picrate, calcium-cresyl phthalein dye, and SGOT-DPN reduction. Because some of these biochemical determinations are affected by hemolysis and chylemia, the data were analyzed both including and excluding those serum specimens which were chylous or showed hemolysis. It was found that this distinction had no appreciable effect on the study results. Therefore the chemistry values from chylous and hemolyzed specimens were included in these analyses. Age-specific mean serum chemistry levels were examined for both white and black cigarette smokers and nonsmokers. The numbers of cigarette smokers and nonsmokers examined and the age group-sex-race specific mean values for each chemistry test are shown in Tables 1 (a and b). A measure of the variation for each test is given in these tables by the standard deviations for the entire age range studied. Because of the large numbers of subjects examined, tests for statistical significance tended frequently to give positive results in nonsmoker-smoker comparisons, even when the differences were slight. Therefore, significant test results are generally omitted from this presentation. As an example of the statistical significance of nonsmoker-smoker differences observed in these data, consider serum albumin among whites. Each point in the agespecific albumin level plots shown in Fig. l(a) represents a mean value for groups ranging in size from 122 to 3928 persons. The distributions of the observations from which the means are calculated were unimodal and reasonably symmetrical, with similar variances in each pair of smoker and nonsmoker groups. Therefore, using the assumption of underlying normality for the albumin distributions, t-values were computed for each of the 14 age-sex-specific contrasts of smokers and non-smokers. The sum of these independent t-values, which was 42.7, is essentially a random normal variable with mean 0 and variance slightly greater than 14 under the null hypothesis. The sum of the t-values divided by the square root of the variance can therefore be considered a standard normal deviate. It’s value is slightly more than 11. This corresponds to an exceedingly small probability (p~O.OOOOOOl) under the null hypothesis of no difference between smokers and nonsmokers. Even if the parametric assumptions are discarded and the very conservative sign test applied, with each of the age-specific serum albumin levels regarded as a single value rather than a mean for a rather large group of individuals, the null hypothesis of no difference between smokers and nonsmokers is still rejected at p c 0.02.
15,017
3.98
4.02
4.00
3.88
4049
50-59
60-69
70-79
15-79 (N) 17.452
0.52
3.98
30-39
15-79 (SD)
3.91
3.89
20-29
0.51
3.95
3.96
3.94
3.94
3.88
3.93
0.57
13,610
4.00
7801
15-79
3.84
15-19
3.92
70-79
3.93
4.07
0.56
4.06
(N)
4.17
50-59
60-69
4.13
4.24
4.28
4.22
S
15-79 (SD)
4.29
4.28
4.29
20-29
30-39
4.17
15-19
4049
NS
Age classes
Serum albumin
0.56
17,162
3.08
3.01
3.00
3.03
3.09
3.19
0.55
14,782
2.96
2.92
2.93
2.92
2.97
3.08
3.09
0.56
3.17
13,341
0.57
3.08
3.04
2.91
2.88
2.87
2.89
2.98
S
48.8
18,447
201.9
196.8
188.1
177.7
172.9
161.0
154.3
46.3
8270
191.1
188.0
182.9
177.2
167.8
159.8
150.5
NS
S
49.6
15,9s5
205.0
201.7
194.0
183.1
174.4
160.8
151.4
49.4
14,460
193.5
191.1
187.9
182.6
173.9
161.0
144.9
Serum glucose
1.20
17,508
5.07
5.02
4.77
4.35
4.17
4.13
4.27
5.97
I.13
14,983
5.13
4.93
4.76
4.34
4.16
4.11
4.11
women
I .28
13,529
White
1.31
7790
6.19
5.77
5.78
5.96 5.93
5.67 5.76
5.83 5.93
5.67
5.74
men
5.68
White
S
256.6
255.0
244.6
222. I
209.5
201.2
189.3
40.6
7697
232.3
231.1
229. I
225.7
214.0
197.0
179.3
NS
44.0
S
41.7
14,259
253.9
252.0
245.2
226.1
211.4
201.7
190.0
39.9
13,256
227.0
231.9
233.5
231.2
220.7
202.2
179.8
Serum cholesterol
I.22
1.11
I.12
1.10
1.10
I .08
I .04
NS
0.25
17,584
0.98
0.95
0.92
0.90
0.88
0.87
0.87
0.27
1.16
1.10
I .08
I .08
1.07
1.07
1.02
S
0.26
15,134
0.98
0.94
0.91
0.89
0.87
0.86
0.87
0.27
13,700
Serum creatinine
0.47
17,870
9.78
9.81
9.82
9.71
9.74
9.79
9.92
0.49
7960
9.72
9.73
9.77
9.81
9.90
10.00
10.07
NS
S
0.47
15,372
9.76
9.80
9.80
9.71
9.72
9.79
9.85
0.48
13,854
9.72
9.77
9.79
9.82
9.91
9.99
10.03
Serum calcium
ANDCIGARETTE SMOKERS(S)
7860
NONSMOKERS (NS)
16,895
WHITE
5.65
NS
Serum uric acid
smunf CHEMISTRY CONCENTRATIONS FOR
7661
3.11
2.99
2.88
2.87
2.92
2.96
3.03
NS
Serum globulin
TABLE la. MEAN
9.5
17,694
19.1
19.0
18.6
17.1
16.8
16.9
17.4
13.3
7933
20.3
21.0
21.6
22.5
22.0
20.9
20.4
NS
20. I
21.6
21.0
21.8
22.1
20.8
21.6
S
10.7
15,285
20.9
18.3
18.9
17.5
16.7
16.6
16.7
13.7
13,817
SCOT
0.52
3.83
3.71
3.79
3.83
3.84
15-79 (SD)
15-19
20-29
30-39
40-49
SO-59
3048
0.48
70-79
15-79 (N)
IS-79 (SD)
0.57
2982
(3.39)
3.39
3.54
3.52
3.55
3.61
3.55
0.55
1042
(3.62)
3.48
3.41
3.31
3.39
3.32
3.35
NS
S
0.55
2656
(3.60)
3.07
3.41
3.34
3.43
3.50
3.46
0.58
2426
(3.43)
3.34
3.36
3.26
3.19
3.27
3.30
Serum globulin
43.3
3201
(170.4)
170.7
166.2
158.0
147.7
142.2
134.2
44.7
1112
(193.2)
168.6
172.3
154.5
148.1
135.2
129.9
NS
S
43.0
2849
(171.8)
172.1
168.9
156.2
151.5
143.2
132.5
43.4
2597
(172.7)
164.6
167.0
162.1
155.8
142.4
126.1
Serum glucose
3.75
3.79
1.26
3052
(5.25)
5.09
4.85
4.37
4.07
1.42
2469
1.22
2709
(4.71)
5.28
4.95
4.41
4.10
3.87
3.73
Black women
1.39
1066
5.89 (5.55)
6.31
5.81
5.69
5.54
5.39
5.32
Black men
S
(5.75)
6.01
5.73
5.62
5.52
5.43
NS
Serum uric acid
44.5
2992
(258.5)
257.3
244.9
228.6
211.6
199.3
186.4
41.9
1040
(228.6)
227.5
233.5
229.1
216.6
202.7
180.5
NS S
40.2
2650
(267.1)
257.6
240.9
225.1
210.5
201.5
182.9
41.3
4997
(246.5)
230.1
226.6
225.3
213.9
197.8
180.2
Serum cholesterol
MEANSERUMCHEMISTRYCONCENTRATIONSFORBLACKNONSMOKEIU
*Mean values in parentheses are for groups of less than 20 persons.
0.47
2698
4.14
(3.99)
3.92
(3.76)
60-69
3.86
3.87
3.78
3.71
3.88
0.53
2467
1065
15-79 (N)
3.94
4.02
3.80
3.98
SO-59
(3.94)
4.11
40-49
4.13
3.85
4.11
30-39
4.11
(3.77)*
4.15
20-29
4.08
70-79
4.05
15-19
S
60-69
NS
Age classes
albumin
serum
TABLE lb.
0.38
3058
(0.96)
1.02
0.97
0.94
0.91
0.90
0.88
0.23
1060
(1.21)
1.24
1.21
1.18
1.16
1.15
1.11
NS
S
0.28
2719
(0.93)
1.02
0.93
0.94
0.90
0.89
0.88
0.26
2466
(1.22)
1.22
1.16
1.14
1.12
1.14
1.03
Serum creatinine
(S)
0.24
3107
(9.99)
9.85
9.89
9.79
9.78
9.80
9.91
0.24
1074
(9.91)
9.85
9.85
9.90
9.92
10.07
10.11
NS
S
0.25
2761
(10.20)
9.79
9.91
9.84
9.77
9.80
9.98
0.22
2512
(9.78)
9.84
9.84
9.92
9.95
10.04
10.16
Serum calcium
(NS) AND CIGAREITESMOKEW
8.9
3091
(19.0)
19.1
19.8
18.8
17.7
17.2
17.1
14.2
1080
(18.0)
21.0
22.7
24.5
23.4
21.1
20.0
NS
23.6
23.6
23.3
23.7
23.2
20.7
S
12.7
2750
(19.4)
19.9
21.5
18.8
18.9
17.3
18.7
15.1
2498
(17.3)
SGOT
Cigarette Smoking and Serum Chemistry Tests (0)
Serum olbumm
(d)
Serum
297
uric ocld
Whate women
i
White
4 0
s
E”
5a
;
IO
30
50
70
IO
30
50
70
50.
E 45.-
(b) 9
women
Serum
32
globulin
White
men
.--,
40
Whate women
I,, IO
ie)
30
Wh!te
(g 1 Serum
men
IO
I
30
White
men
women
White
women
calcium
9 6.k p8 30
70
creatnne
White
IO
50
I
Age, yr
Age, yr Serum
(
Serum cholesterol White
If)
1
..
,
-
50
I
/
I
70
IO
30
women
50
70
4 h I Serum SGOT
230
I ;.,
White
White
women
Non-smokers
!
IO
men
30
1
I
/
I
50
70
IO
30
FIG. 1. Mean serum chemistry levels among white nonsmokers (interrupted line) and cigarette smokers (solid line) grouped by sex and age.
I
50
70
xp-
1 50
I 70
298
LGRING
G.
DALES,
GARY D. FRIEDMAN,A. B. SIEGELAUBand CARL C. SELTZER
Associations noted between smoking status and serum chemistry levels were examined further by stratifying subjects according to potential underlying variables that could possibly explain the relationships. The stratifications were performed on the largest race and age-specific subgroups, white men and women ages 40-49 yr. The associations were also examined for relationship to quantity of cigarettes smoked, with smokers subdivided into those consuming less than a pack and a pack or more daily. Results of the analyses are presented and discussed for each serum chemistry in turn. RESULTS
Serum albumin Smokers’ mean serum albumin levels were significantly lower than those of nonsmokers for both sexes in whites, with the difference being more pronounced among men (Table la, Fig. la). The direction of the difference was consistent over virtually the entire age span of the subjects studied. The differences were less consistent for blacks (Table lb). Among black men ages 40-69, the mean serum albumin levels of smokers were lower than those of nonsmokers, but among black women ages 40-69, lower levels were seen for nonsmokers. The absolute sizes of the mean differences were quite small, averaging less than 0.1 g/100 ml. Several possible explanations for the smoking status-serum albumin association were considered. Because albumin levels are frequently depressed in decompensated Laennec’s cirrhosis and because alcohol usage has been noted to be more common in smokers [3], a higher prevalence of alcohol-induced liver damage in the smokers could possibly explain their lower serum albumin concentrations. Accordingly, the white subjects (ages 40-49) were stratified by level of alcohol consumption as reported on the medical questionnaire completed at the checkup (Table 2). In each column of Table 2 it can be seen that mean serum albumin concentration did not consistently decrease with increased alcohol consumption. In each row of the table it is apparent that the lower serum albumin concentrations for smokers persisted at all alcohol-consumption levels. TABLE 2.
MEAN SERUMALBUMINLEVELS ACCORDING
AMONG NONSMOKERS AND CIGARETTE TO ALCOHOLCONSLJMPTIONHISTORY
White men ages 40-49 Mean serum albumin level (g %) Alcohol consumption history Nondrinkers 12 Drinks daily 23 Drinks daily Total
Cigarette smokers
Mean difference*
4.23 (394)-t 4.28 (1083) 4.42 (121)
4.06 (260) 4.14 (2150) 4.11 (863)
-0.17 -0.14 -0.31 -
4.28 (1598)
4.12 (3273)
-0.16 -
Nonsmokers
SMOKERS
GROUPED
White women ages 4049 Mean serum albumin level (g %)
Cigarette smokers
Mean difference*
3.97 (1234) 3.98 (2160) 3.94 (123)
3.94 (409) 3.94 (2441) 3.90 (440)
-0.03 -0.04
3.97 (3517)
3.93 (3290)
-0.04 -
Nonsmokers
*Smokers’ mean minus nonsmokers’ mean. tNumbers in parentheses indicate sample size in each category.
-co4 -
Cigarette Smoking and Serum Chemistry Tests
299
Cigarette smokers and nonsmokers were also subdivided according to presence or absence of liver disease history. In both categories the smokers again had lower mean serum albumin levels than did nonsmokers. Because the smokers in the study more frequently reported a history of severe diarrhea, which can be accompanied by decreased serum albumin concentration, the white smokers and nonsmokers were grouped by diarrhea history. The result once more was persistence of the smoker-nonsmoker differences in serum albumin levels. Similarly, grouping subjects by presence or absence of proteinuria did not alter the relationship between cigarette smoking and albumin concentration. Men ages 20-29
Men ages 40-49
Men ages 60 and over
4.30
4 IO
390 ae m 1.332 872 1,536*
1,714886 2,609
I.183 512 925
.c E
Women 20-29
2 0
E zl k v)
oges
Women 40-49
oqes
Women oqes 60 ond over
430
410
3.9c
2.648I.771 1.800
FIG.
2.
3,2981.4972,245
3,750 578 550
Mean serum albumin levels according to quantity of cigarettes smoked, among white men and women in three age groups.
The relation of serum albumin level to quantity of cigarettes smoked among white men and women in three lo-yr age groups is shown in Fig. 2. In general, the pattern is one of decreasing serum albumin level with increasing amount smoked; that is, a consistent dose-response relationship exists. A search of the medical literature uncovered no experimental or observational studies on humans relating tobacco consumption to serum albumin concentration.
300
LORING G. DALES, GARY D. FRIEDMAN, A. B. SIEGELAUB and CARLC. SELTZER
There have been animal studies demonstrating a variable effect of nicotine in lowering total serum protein concentration, but the nicotine dose involved was far higher than that which might be encountered through smoking cigarettes [4]. Serum globulin
In white males below age 40, mean serum globulin levels were lower in cigarette smokers than in nonsmokers, but above age 40 mean serum globulin levels tended to be higher in the smokers (Table la, Fig. lb). Among white women and blacks of both sexes, smokers consistently had lower globulin concentrations (Table la and b). Among smokers, no consistent relationship was found between serum globulin level and amount smoked. There appear to be no other observational or experimental studies on smoking and serum globulin in the medical literature. Serum glucose
In both white men and women, cigarette smokers had higher mean 1-hr post-sugaringestion serum glucose levels than nonsmokers (Table la, Fig. Ic). For blacks, a slight trend toward higher glucose levels among smokers was noted. However, the pattern was not consistent (Table lb). The expected positive relationship between age and mean serum glucose levels was seen. Less expected were the striking differences between whites and blacks in serum glucose levels. On the average, the values for whites were 15-25 mg/lOO ml higher than those for blacks. To determine if part or all of the serum glucose differences in whites could be accounted for by systematic differences in carbohydrate consumption shortly before examination, cigarette smokers and nonsmokers were stratified according to length of time since last food at the time of glucose ingestion for the 1-hr serum glucose measurement. When this was done, the association between smoking status and serum glucose levels persisted with almost no reduction in magnitude. Approximately three per cent of the subjects failed to consume part or all of the glucose solution given but still had blood drawn 1 hr later. Eliminating these persons from the tabulations had the expected effect of raising mean serum glucose levels, by as much as 5-6 mg/lOO ml in the older age groups. Nonetheless, the relationship between smoking status and glucose level remained virtually unchanged when the comparisons were restricted to subjects who took the full glucose load. To check out the possibility that differential nonsmoker - smoker usage of thiazide diuretics might be involved in the association, the comparisons were repeated excluding persons on such medication. When this was done the observed relationship between smoking status and serum glucose was not altered. Because alcohol ingestion is known to be accompanied by at least a transient hyperglycemia [5], serum glucose values were examined with white cigarette smokers and nonsmokers (ages 40-49) grouped by quantity of alcohol consumed (Table 3). Among nondrinkers of both sexes (top row of the table) the relationship between smoking status and serum glucose concentration virtually disappeared, while among drinkers, the same association persisted to varying degrees. In addition, a striking positive relationship existed between alcohol consumption and serum glucose concentration (except at the highest level of daily alcohol intake) with the relationship being more pronounced for smokers than for nonsmokers. When similar tabulations were made for whites ages 50-59, the results were the same.
Cigarette Smoking and Serum Chemistry Tests TABLE
3.
MEAN
Alcohol consumption history Nondrinkers 212 Drinks daily 3-5 Drinks daily 6-8 Drinks daily 29 Drinks daily Total
SERUM
301
GLUCOSE LEVELS AMONG NONSMQKERS ACCORDINGTOALCOHOLCONSUMPTION
AND CIGARETTE HISTORY
White men ages 40-49 Mean serum glucose level (mg%)
White women ages 4049 Mean serum glucose level (mgT<)
Nonsmokers
Cigarette smokers
Mean difference*
174.3 (408)t 178.2 (1154) 182.5 (10% 181.1 (16) 155.0 (11)
173.5 (276) 181.7 (2279) 184.7 (644) 201.2 (189) 186.7 (87)
-0.8
177.4 (1694)
182.8 (3475)
5.4
2.2 20-l 31.7 -
GROUPED
Cigarette smokers
Mean ditTcrence* --I.5
G
175.3 (434) 183.6 (2569) 192.8 (401) 201.4 (42) 184.2 (19)
178.1 (3698)
183.9 (3465)
5.8
Nonsmokers
3.5
SMOKERS
176.8 (1299) 178.2 (2272) 188.4 (114) 196.9 (13)
5.4 4.4 4.5
-
*Smokers’ mean minus nonsmokers’ mean. ‘rNumbers in parentheses indicate sample six in each category.
Since the cigarette smokers tended to have less heavy body builds and to have less subcutaneous fat than the nonsmokers, as indicated by mean ponderal index and triceps skinfold values, the higher serum glucose levels found for smokers could not be explained by obesity differences. Generally, serum glucose levels correlated positively with quantity of cigarettes smoked, though there were inconsistencies in the younger subjects (Fig. 3). The literature on smoking and blood glucose is fairly extensive. Nicotine administration elevates blood sugar in experimental animals, an effect which is abolished by adrenalectomy [6]. It is hypothesized that nicotine achieves this effect by stimulating release of epinephrine from the adrenal medulla and other peripheral depots, which in turn activates hepatic glycogenolysis. Reports on the effect of cigarette smoking on blood sugar in humans in the experimental setting arc conflicting: Some investigators say fasting blood sugar is raised by smoking [7, 81; others say there is no change [9, lo]. No experimental study could be found relating smoking to I-hr post-glucoseingestion blood sugar. With regard to observational studies, Blackburn reported that, among men, smokers had significantly higher (p~O.01) fasting blood sugars than did nonsmokers [ll]. Higgins found higher 1-hr post-glucose-loading blood glucose in smokers of both sexes, though the differences were not statistically significant [12]. Glausen noted that one month after quitting smoking, ex-cigarette smokers showed a reduction in 30 min postprandial blood sugar [13], but the number of subjects involved was rather small and the observations were not fully controlled. Information gathered in the present study suggests that at least part of the positive association between cigarette smoking habits and blood sugar level which has been noted in observational settings may be explained by the relationship of alcohol consumption habits to both smoking habits and serum glucose.
LORING G.DALES, GARYD.FRIEDMAN,A.B.
302
Men oges 60 and over
Men oges 40-49
Men ages 20 -29
I
s
SIEGELAUB~~~ CARL C. SELTZER
150
?
1.403 937 1,619*
Women 20-29
1,819935 2,770
Women 40-49
ages
I.251 536 981
oges
ages ond over
Women 60
r 3~205 1,8671.93’2 FIG. 3.
3,953 614 %I5
4.137 I.591 2,361
Mean
serum glucose levels according to quantity of cigarettes smoked, among white men and women in three age groups. (See footnote to FIG. 2 for key.)
Uric acid
Among white men, the cigarette smokers showed distinctly lower serum uric acid levels, while the differences for white women were minimal (Table la, Fig. 1d). Among the black men, the mean serum uric acid levels of smokers were also lower than those of nonsmokers (Table lb). On the other hand, in black women, the serum uric acid levels tended to be slightly higher in the cigarette smokers. Since the differences were most substantial in white men, further analyses were limited to this group. TABLE 4.
MEAN SERUM URIC ACID LEVELS AMONG ACCORDING
Triceps skinfold thickness Light: I 9.9 mm Medium: 10.0-13.9 mm Heavy : 2 14.0 mm Total
TO TRICEPS
NONSMOKERS SKINFOLD
AND CIGARETTE SMOKERS GROUPED
THICKNESS
White men ages 40-49 Mean uric acid levels (mg%) Cigarette Mean Nonsmokers smokers difference* 5.80 (34O)t 6.02 (386) 5.97 (542) ..- ._~___~_~ 5.94 (1268)
_.
5.68 (766) 5.78 (850) 5.88 (1035)
-0.12 -0.24 -0.09 -
5.79 (2651)
-0.15 -
*Smokers’ mean minus nonsmokers’ mean. TNumbers in parentheses indicate sample size in each category.
Cigarette Smoking and Serum Chemistry Tests
Menages 20-
29
303
Men ages 60 ond over
Men ages 40-49
509
FIG. 4.
91:
Mean serum uric acid levels according to quantity of cigarettes smoked, among white men in three age groups. (See footnote to FIG. 2 for key.)
Because of the observations that nonsmokers tend to be heavier than smokers and that obese people tend to have higher serum uric acid concentrations [12], mean uric acid values were studied at different levels of body weight. When smokers and nonsmokers were grouped according to triceps skinfold thickness, there was a slight tendency toward reduction of the difference in uric acid levels, but in general the relationship persisted (Table 4). The same was true when the smokers and nonsmokers were stratified according to a second measure of relative weight, ponderal index. Among smokers, uric acid level was inversely correlated with quantity of cigarettes smoked in two of the three IO-yr age groups studied (Fig. 4). The literature on smoking and uric acid concentration contains conflicting information. An experimental study published in the international literature has apparently shown that persons smoking several cigarettes can experience an acute, transient rise in serum uric acid [14]. Two observational studies on men reported no correlation between smoking habits and uric acid level [15, 161. A third, performed as a casecontrol study, comparing hyperuricemic to normal men, found a positive correlation [17]. The results of a fourth [l2] were similar to those of the present study: male smokers had lower uric acid levels, but among women the difference was small. Serum cholesterol
Except for subjects in the oldest subgroup, white male smokers studied tended to have higher serum cholesterol levels than nonsmokers (Table la, Fig. le). The same general trend was true for women, although to a lesser extent. Among black men and women the direction of the difference was reversed, with non-smokers having the higher serum cholesterol values (Table lb). When white male smokers were grouped by quantity of cigarettes smoked (Fig. 5), there was a stepwise rise in serum cholesterol values with increasing amount smoked for the two younger age groups studied but not for the oldest, where no smoker - nonsmoker difference had been seen anyway. Experimentally, long-term nicotine administration to animals (at dose levels above those encountered in cigarette smoking) leads to a substantial rise in serum cholesterol [I 81. It has been postulated that catecholamines released through nicotine stimulation act on adrenergic beta receptors of adipose tissue cells to increase lipid mobilization, resulting in a rise in serum cholesterol [19]. When serum cholesterol levels have been followed in humans smoking cigarettes in the experimental situation, the results have been contradictory [20, 211. Observational studies reporting at least slightly higher
304
LORING G. DALES, GARY D. FRIEDMAN, A. B. S~EGELAU~and CARL C. SELTZER
serum cholesterol values in male smokers than in nonsmokers are about equally balanced by studies reporting no difference [22-241. The data presented here can be added to those of other observational studies showing a tendency toward higher serum cholesterol levels in smokers among white men.
s
I
Menages
Men ages 60 and over
Men ages 40-49
20-29
E”230 I-
1,313 845 FIG. 5.
1,489X
1,703 867
2,540
6
498
901
Mean serum cholesterol levels according to quantity of cigarettes smoked, among white men in three age groups. (See footnote to FIG. 2 for key.)
Serum creatinine Mean serum creatinine concentrations for smokers of both sexes and races were generally lower than those of nonsmokers, though the differences were not large (Tables 1 (a and b), Fig. If). To explore the possibility that systematic differences in hydration might be involved in the relationship, smokers and nonsmokers were stratified according to coffee consumption habits, alcohol consumption habits, and presence or absence of nocturia. In all cases the association between smoking status and creatinine level persisted. On the other hand, when creatinine concentrations were studied in relation to amount smoked in three different lo-yr age groups, consistent patterns were rarely seen. One other study of serum creatinine levels in cigarette smokers and nonsmokers reported no difference [16]. Serum calcium Mean serum calcium concentrations of white and black smokers did not differ appreciably from those of nonsmokers (Tables 1 (a and b), Fig. lg). SGOT While there was a tendency among blacks for mean serum transaminase (SGOT) levels of smokers to be slightly higher than those of nonsmokers, no consistent differences were noted for whites (Tables 1 (a and b), Fig. lh). GENERAL
COMMENT
With the exceptions of serum calcium and SGOT, the smokers’ mean values for the serum chemistries examined tended to differ from those of nonsmokers. When such differences between smokers and nonsmokers were found, the magnitude of the divergence was frequently, though not always, greater for men than for women.
Cigarette Smoking and Serum Chemistry Tests
305
For serum albumin, glucose, cholesterol, and uric acid the diff’erences noted between smokers and nonsmokers among whites were not evident, or were much less evident, in blacks. Because black cigarette smokers have been reported to use smaller quantities of cigarettes than whites [l], these four chemistries were also studied with black cigarette smokers stratified by amount smoked. In general, for all four chemistries the findings were that even when the heavy smokers among the blacks were singled out for examination, the associations with smoking status were not impressive. Thus, racial discrepancies exist which make interpretation of the relationships difficult. The possibility that the non-smoker-smoker differences observed here in a group of self-selected subjects might not be true in general was examined by studying serum chemistries in a small, representative sample of Health Plan members who had been invited in for Multiphasic Health Checkups (for a different purpose). The findings in this sample did not differ appreciably from those just described for the larger group. For three of the serum chemistries-albumin, uric acid, and cholesterol-the associations with smoking status in whites persisted when examined for the effect of potential intervening variables and/or showed consistent relationships with amount smoked. These findings do not prove that cigarette smoking directly caused the changes in the serum chemistry concentrations, however. Perhaps some intervening variable not examined could still account for part or all of the relationships, as was the case for alcohol consumption habits in the association between smoking and serum glucose. Moreover, it was pointed out in the sections on uric acid and choiesterol that the relationships have not been consistently observed by other investigators. Finally, Yerushalmy has reported on an instance where a cigarette smokers’ trait (higher frequency of low birth weight infants) at first suspected to be a result of smoking actually appeared to be a characteristic of smokers even before they began to smoke [25]. This possibility has not been ruled out for the associations described here. The fact that serum concentrations of four serum chemistries-albumin, globulin, uric acid, and creatinine-tended to be lower in the cigarette smokers studied raised the possibility of a hemodilution effect of smoking. Animal studies have indicated that nicotine can cause a decrease in water diuresis, presumably by means of stimulating posterior pituitary hormone release [26]. Experimental studies on humans suggest that cigarette smoking has a transient antidiuretic effect in hydrated subjects [27-291. However, the failure to observe lower serum concentrations for four other chemistries-glucose, cholesterol, calcium and SGOT-or lower hemoglobin concentrations and white cell counts among the smokers studied [2] appears to rule out a hemodilution hypothesis, That there are differences between groups of cigarette smokers and non-smokers in a number of serum chemistry levels is clear, but the meanings of these associations are not easy to assess. On the one hand, it is possible that cigarette smoking may have some direct or indirect physiologic effect on serum chemistry concentrations. On the other hand, cigarette smokers are a self-selected group (or groups) known to differ from nonsmokers in many ways which are not thought to result from the act of smoking itself [30-331. For several of the chemistries, discrepancies in the smoker-non-smoker differences among various age-sex-race subgroups add to the difficulty of interpreting the findings. The relationships between cigarette smoking habits and the serum chemistry levels described here still need clarification.
306
LORING G. DALES, GARY D. FRIEDMAN, A. B. SIEGELAUBand CARL C. SELTZER
SUMMARY
Eight serum chemistry levels were studied in over 65,000 cigarette smokers and nonsmokers. On the average, creatinine and albumin levels were lower in the smokers of both sexes, while the opposite was true for I-hr post-challenge serum glucose. Globulin levels were consistently lower in the women smokers only. Uric acid concentrations were lower in the men who smoked. Cholesterol levels were higher in the white men who smoked but not in the black male smokers. Calcium and SGOT levels of smokers were quite similar to those of nonsmokers. Alcohol consumption played a role in smoker-nonsmoker differences in serum glucose concentration. However, for other chemistries no additional factors were identified that could explain the relationships to cigarette smoking. Thus they may be either directly affected by smoking or related to undefined underlying differences between smokers and nonsmokers. Acknow[edgemmrs-Drs. Robert Feldman and Derek Crawford, Chiefs of the Automated Multitest Laboratories in Oakland and San Francisco, respectively, supervised data collection in these facilities. In addition, Dr. Feldman assisted in the interpretation of the serum glucose findings. Dr. Hans Ury provided consultation on the employment of statistical inference tests. Mrs. Arlette Gaulene performed the computer-programming. REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Friedman GD, Seltzer CC, Siegelaub AB, Feldman R, Collen MF: Smoking among white, black, and yellow men and women. Amer J Epidem 96: 23-35, 1972 Friedman GD, Siegelaub AB, Seltzer CC, Feldman R, Collen MF: Smoking habits and the leukocyte count. Arch Environ Health (Chicago) 26: 137-143, 1973 Seltzer, CC, Friedman, GD, and Siegelaub AB: Smoking and drug consumption in white, black and oriental men and women. Amer J Public Health 64: 466-473, 1974 Aizawa K, Komoriyama K, Ohno S: Influence of nicotine on serum protein and the amount of circulating blood and extracellular fluid. Showa Dg Zasshi 20: 195-203, 1960 Goodman LS, Gilman A (eds): The Pharmacologic Basis of Therapeutics. 4th ed. London, Macmillan, 1970, p 140 Milton AS: The effect of nicotine on blood glucose levels and plasma nonesterified fatty acid levels in the intact and adrenolectomized cat. Brit J PharmacoI26: 256-263, 1966 Murchison LE, Fyfe T: Effects of cigarette smoking on serum lipids, blood glucose, and platelet adhesiveness. Lancet 2: 182-184, 1966 Szanto S: Smokers’ hyperglycemia. J Irish Med Ass 58: 22-24, 1966 Kashemsant U, Smulyan H, Eich KH: Changes in blood catecholamines with smoking. Circulation 32 Suppl 11: 19, 1965 Kingsbury KJ, Jarrett RJ: Effects of adrenaline and of smoking in patients with peripheral atherosclerotic vascular disease. Lancet 2: 22-23, 1967 Blackburn H, Brozek J, Taylor HL, Keys A: Comparison of cardiovascular and related characteristics in habitual smokers and nonsmokers. Ann N Y Acad Sci 90: 277-289, 1960 Higgins MW, Kjelsberg M : Characteristics of smokers and non-smokers in Tecumseh, Michigan. II. The distribution of selected physical measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers Amer J Epidem 86: 60-77, 1967 Glausen SC, Glausen EM, Riedenberg MM, et al: Metabolic changes associated with the cessation of cigarette smoking. Arch Environ Health (Chicago) 20: 377-381, 1970 Hogler F: Zur frage der nihotinshadigung. Wien Med Wschr 93: 309-312, 1943 Oberman A, Lane NE, Mitchell RE, Graybill A: The Thousand Aviator Study: Distribution and Intercorrelations of Selected Variables. (U.S. Naval Aerosp Med Inst Monog No. 12), Pensacola, Fla, 1965 Andrus LH, Miller DC, Stallones RA, ef a/.: Epidemiological study of coronary disease risk factors-l. study design and characteristics of individual study subjects. Amer J Epidem 87: 73-86,
17.
1968
Lanese RR, Gresham GE, Keller MD: Behavioral and physiological characteristics uricemia. JAMA 207: 1878-1882, 1969
in hyper-
Cigarette Smoking and Serum Chemistry Tests 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
33.
307
Kershbaum A, Bellet S: Cigarette smoking and blood lipids. JAMA 187: 32-36, 1964 Kershbaum A, Jiminez J, Bellet S, Zanuttine D: Modification of nicotine-induced hyperlipidemia by anti-adrenergic agents. Circulation 30: 18, 1964 Short JJ, Johnson JJA: A direct comparison of the reaction of the human system to tobacco smoke and adrenalin. J Lab Clin Med 24: 590-593, 1938-39 Page IH, Lewis LA, Moinudin M: Effects of cigarette smoking on serum cholesterol and lipoprotein concentrations. JAMA 171: 1500-1502, 1959 Larson PS, Haag HB, Silvette H: Tobacco Experimental and Clinical Studies. Baltimore, Williams & Wilkins, pp 332-334, 1961 Larson PS, Silvette H: Tobacco: Experimental and Clinical Studies. Supplement 1. Baltimore, Williams & Wilkins, pp 174-176, 1968 Larson PS, Silvette H: Tobacco: Experimental and Clinical Studies. Supplement Il. Baltimore, Williams & Wilkins, pp 150-152, 1971 Yerushalmy J: Infants with low birth weight born before their mothers started to smoke cigarettes. Amer J Obstet Gynecol 111: 277-294, 1972 Grewal RS, Lee MC, Allmark MG: Release of posterior pituitary hormones in rats by nicotine and lobeline. Fed Proc 19: 167, 1960 Hokfelt B: The effect of smoking on the production of adrenocortical hormone. Acta Med Stand Suppl 369: 123-124, 1961 Yamamoto I: Thiamine as a nicotine antagonist. Jap J Pbarmacol 13: 240-252, 1963 Levine RR, Pelikan EW, Kensler CJ: The ellect of cigarette smoking on the excretion of phenol red. Fed Proc 20: 414, 1961 Hammond EC, Garfinkel L: Smoking habits of men and women. J Nat Cancer Inst 27: 419-442, 1961 Yerushalmy J: Statistical considerations and evaluation of epidemiologic evidence. In Tobacco and Health. James G. Rosenthal T (Edsl. Sorinafield Ill: Thomas. I). 208. 1962 Higgins MW, Kjelsberg M, Metzner ‘I-I:’ Characteristics of smokers ‘and nonsmokers in Tecumseh, Michigan. 1. the distribution of smoking habits in persons and families and their relationship to social characteristics. Amer J Epidem 86: 45-59, 1967 Lilienfeld AM: Emotional and other selected characteristics of cigarette smokers as related to epidemiological studies of lung cancer and other diseases. J Nat Cancer Inst 22: 259-282, 1959
CIGARETTE
SMOKING
AND SERUM
CHEMISTRY
TESTS*
LORINGG. DALES?, GARY D. FRIEDMAN,A. B. SIEGELAUB and CARL C. SELTZERS
Department
of Medical Methods Research, Permanente
Medical
Group,
3779Piedmont Ave., Oakland, California 94611, U.S.A. (Received 18 June, 1973)
INTRODUCTION THIS PAPERis one of a series on the characteristics of smokers and nonsmokers using data from the Kaiser-Permanente Multiphasic Examinations [l-3]. The focus of attention here is on data concerning serum concentrations of eight chemistriesalbumin, globulin, glucose, uric acid, cholesterol, creatinine, calcium and glutamic oxaloacetic transaminase (SGOT)-in 57,352 white men and women and in 9812 black men and women ages 15-79. The purpose of the study was to determine whether or not cigarette smokers and nonsmokers differed in these various serum chemistry levels. Where differences were found, analyses were made for (1) persistence of the differences after stratification of the subjects by variables considered to be potentially mediating factors, and (2) relation of the differences to amount smoked. METHODS
The data on characteristics of cigarette smokers and nonsmokers come from general health examinations performed between July 1964 and August 1968 on ambulatory persons belonging to the Northern California Kaiser-Permanente Medical Care Program. The nature of the health appraisal, termed the Multiphasic Health Checkup, is outlined elsewhere along with a basic description of the smoking classifications used [I]. Persons taking Multiphasic Health Checkups, who are mostly well persons seeking a general physical examination, fill out comprehensive health questionnaires and undertake a battery of clinical and laboratory tests. Kaiser Health Plan members represent a broad spectrum of the community. *This study was supported by the Council for Tobacco Research, U.S.A., Grant 787; the National Center for Health Services Research and Development, PHS Grant HS 00288; and the Kaiser Foundation Research Institute. tReprint requests to Dr. Dales. *Department of Nutrition, Harvard School of Public Health. C
293
294
LORING G. DALES, GARY D. FRIEDMAN,A. B. SIEGELAUBand CARL C. SELTZER
Smoking status was assessed by means of a self-administered questionnaire. For purposes of this study, two types of persons have been selected: Nonsmokers, who had never used tobacco in any form, and current, established cigarette smokers, who had been smoking for over 1 yr at the time of examination. Serum chemistry determinations were performed on samples of venous blood drawn 1 hr after ingestion of 75 g of glucose. Subjects were asked to refrain from eating, but not from smoking, for 4 hr prior to examination. The determinations were done on an 8-channel Technicon auto analyzer. The specific analytic methods employed for each serum chemistry were as follows: albumin-Haba Dye, globulin-total protein (determined by the Quantitative Biuret method) minus albumin, serum glucosepotassium ferrocyanide, uric acid-phospho tungstate and cyanide, cholesterolLieberman-Burchard reaction, creatinine-alkaline picrate, calcium-cresyl phthalein dye, and SGOT-DPN reduction. Because some of these biochemical determinations are affected by hemolysis and chylemia, the data were analyzed both including and excluding those serum specimens which were chylous or showed hemolysis. It was found that this distinction had no appreciable effect on the study results. Therefore the chemistry values from chylous and hemolyzed specimens were included in these analyses. Age-specific mean serum chemistry levels were examined for both white and black cigarette smokers and nonsmokers. The numbers of cigarette smokers and nonsmokers examined and the age group-sex-race specific mean values for each chemistry test are shown in Tables 1 (a and b). A measure of the variation for each test is given in these tables by the standard deviations for the entire age range studied. Because of the large numbers of subjects examined, tests for statistical significance tended frequently to give positive results in nonsmoker-smoker comparisons, even when the differences were slight. Therefore, significant test results are generally omitted from this presentation. As an example of the statistical significance of nonsmoker-smoker differences observed in these data, consider serum albumin among whites. Each point in the agespecific albumin level plots shown in Fig. l(a) represents a mean value for groups ranging in size from 122 to 3928 persons. The distributions of the observations from which the means are calculated were unimodal and reasonably symmetrical, with similar variances in each pair of smoker and nonsmoker groups. Therefore, using the assumption of underlying normality for the albumin distributions, t-values were computed for each of the 14 age-sex-specific contrasts of smokers and non-smokers. The sum of these independent t-values, which was 42.7, is essentially a random normal variable with mean 0 and variance slightly greater than 14 under the null hypothesis. The sum of the t-values divided by the square root of the variance can therefore be considered a standard normal deviate. It’s value is slightly more than 11. This corresponds to an exceedingly small probability (p~O.OOOOOOl) under the null hypothesis of no difference between smokers and nonsmokers. Even if the parametric assumptions are discarded and the very conservative sign test applied, with each of the age-specific serum albumin levels regarded as a single value rather than a mean for a rather large group of individuals, the null hypothesis of no difference between smokers and nonsmokers is still rejected at p c 0.02.
15,017
3.98
4.02
4.00
3.88
4049
50-59
60-69
70-79
15-79 (N) 17.452
0.52
3.98
30-39
15-79 (SD)
3.91
3.89
20-29
0.51
3.95
3.96
3.94
3.94
3.88
3.93
0.57
13,610
4.00
7801
15-79
3.84
15-19
3.92
70-79
3.93
4.07
0.56
4.06
(N)
4.17
50-59
60-69
4.13
4.24
4.28
4.22
S
15-79 (SD)
4.29
4.28
4.29
20-29
30-39
4.17
15-19
4049
NS
Age classes
Serum albumin
0.56
17,162
3.08
3.01
3.00
3.03
3.09
3.19
0.55
14,782
2.96
2.92
2.93
2.92
2.97
3.08
3.09
0.56
3.17
13,341
0.57
3.08
3.04
2.91
2.88
2.87
2.89
2.98
S
48.8
18,447
201.9
196.8
188.1
177.7
172.9
161.0
154.3
46.3
8270
191.1
188.0
182.9
177.2
167.8
159.8
150.5
NS
S
49.6
15,9s5
205.0
201.7
194.0
183.1
174.4
160.8
151.4
49.4
14,460
193.5
191.1
187.9
182.6
173.9
161.0
144.9
Serum glucose
1.20
17,508
5.07
5.02
4.77
4.35
4.17
4.13
4.27
5.97
I.13
14,983
5.13
4.93
4.76
4.34
4.16
4.11
4.11
women
I .28
13,529
White
1.31
7790
6.19
5.77
5.78
5.96 5.93
5.67 5.76
5.83 5.93
5.67
5.74
men
5.68
White
S
256.6
255.0
244.6
222. I
209.5
201.2
189.3
40.6
7697
232.3
231.1
229. I
225.7
214.0
197.0
179.3
NS
44.0
S
41.7
14,259
253.9
252.0
245.2
226.1
211.4
201.7
190.0
39.9
13,256
227.0
231.9
233.5
231.2
220.7
202.2
179.8
Serum cholesterol
I.22
1.11
I.12
1.10
1.10
I .08
I .04
NS
0.25
17,584
0.98
0.95
0.92
0.90
0.88
0.87
0.87
0.27
1.16
1.10
I .08
I .08
1.07
1.07
1.02
S
0.26
15,134
0.98
0.94
0.91
0.89
0.87
0.86
0.87
0.27
13,700
Serum creatinine
0.47
17,870
9.78
9.81
9.82
9.71
9.74
9.79
9.92
0.49
7960
9.72
9.73
9.77
9.81
9.90
10.00
10.07
NS
S
0.47
15,372
9.76
9.80
9.80
9.71
9.72
9.79
9.85
0.48
13,854
9.72
9.77
9.79
9.82
9.91
9.99
10.03
Serum calcium
ANDCIGARETTE SMOKERS(S)
7860
NONSMOKERS (NS)
16,895
WHITE
5.65
NS
Serum uric acid
smunf CHEMISTRY CONCENTRATIONS FOR
7661
3.11
2.99
2.88
2.87
2.92
2.96
3.03
NS
Serum globulin
TABLE la. MEAN
9.5
17,694
19.1
19.0
18.6
17.1
16.8
16.9
17.4
13.3
7933
20.3
21.0
21.6
22.5
22.0
20.9
20.4
NS
20. I
21.6
21.0
21.8
22.1
20.8
21.6
S
10.7
15,285
20.9
18.3
18.9
17.5
16.7
16.6
16.7
13.7
13,817
SCOT
0.52
3.83
3.71
3.79
3.83
3.84
15-79 (SD)
15-19
20-29
30-39
40-49
SO-59
3048
0.48
70-79
15-79 (N)
IS-79 (SD)
0.57
2982
(3.39)
3.39
3.54
3.52
3.55
3.61
3.55
0.55
1042
(3.62)
3.48
3.41
3.31
3.39
3.32
3.35
NS
S
0.55
2656
(3.60)
3.07
3.41
3.34
3.43
3.50
3.46
0.58
2426
(3.43)
3.34
3.36
3.26
3.19
3.27
3.30
Serum globulin
43.3
3201
(170.4)
170.7
166.2
158.0
147.7
142.2
134.2
44.7
1112
(193.2)
168.6
172.3
154.5
148.1
135.2
129.9
NS
S
43.0
2849
(171.8)
172.1
168.9
156.2
151.5
143.2
132.5
43.4
2597
(172.7)
164.6
167.0
162.1
155.8
142.4
126.1
Serum glucose
3.75
3.79
1.26
3052
(5.25)
5.09
4.85
4.37
4.07
1.42
2469
1.22
2709
(4.71)
5.28
4.95
4.41
4.10
3.87
3.73
Black women
1.39
1066
5.89 (5.55)
6.31
5.81
5.69
5.54
5.39
5.32
Black men
S
(5.75)
6.01
5.73
5.62
5.52
5.43
NS
Serum uric acid
44.5
2992
(258.5)
257.3
244.9
228.6
211.6
199.3
186.4
41.9
1040
(228.6)
227.5
233.5
229.1
216.6
202.7
180.5
NS S
40.2
2650
(267.1)
257.6
240.9
225.1
210.5
201.5
182.9
41.3
4997
(246.5)
230.1
226.6
225.3
213.9
197.8
180.2
Serum cholesterol
MEANSERUMCHEMISTRYCONCENTRATIONSFORBLACKNONSMOKEIU
*Mean values in parentheses are for groups of less than 20 persons.
0.47
2698
4.14
(3.99)
3.92
(3.76)
60-69
3.86
3.87
3.78
3.71
3.88
0.53
2467
1065
15-79 (N)
3.94
4.02
3.80
3.98
SO-59
(3.94)
4.11
40-49
4.13
3.85
4.11
30-39
4.11
(3.77)*
4.15
20-29
4.08
70-79
4.05
15-19
S
60-69
NS
Age classes
albumin
serum
TABLE lb.
0.38
3058
(0.96)
1.02
0.97
0.94
0.91
0.90
0.88
0.23
1060
(1.21)
1.24
1.21
1.18
1.16
1.15
1.11
NS
S
0.28
2719
(0.93)
1.02
0.93
0.94
0.90
0.89
0.88
0.26
2466
(1.22)
1.22
1.16
1.14
1.12
1.14
1.03
Serum creatinine
(S)
0.24
3107
(9.99)
9.85
9.89
9.79
9.78
9.80
9.91
0.24
1074
(9.91)
9.85
9.85
9.90
9.92
10.07
10.11
NS
S
0.25
2761
(10.20)
9.79
9.91
9.84
9.77
9.80
9.98
0.22
2512
(9.78)
9.84
9.84
9.92
9.95
10.04
10.16
Serum calcium
(NS) AND CIGAREITESMOKEW
8.9
3091
(19.0)
19.1
19.8
18.8
17.7
17.2
17.1
14.2
1080
(18.0)
21.0
22.7
24.5
23.4
21.1
20.0
NS
23.6
23.6
23.3
23.7
23.2
20.7
S
12.7
2750
(19.4)
19.9
21.5
18.8
18.9
17.3
18.7
15.1
2498
(17.3)
SGOT
Cigarette Smoking and Serum Chemistry Tests (0)
Serum olbumm
(d)
Serum
297
uric ocld
Whate women
i
White
4 0
s
E”
5a
;
IO
30
50
70
IO
30
50
70
50.
E 45.-
(b) 9
women
Serum
32
globulin
White
men
.--,
40
Whate women
I,, IO
ie)
30
Wh!te
(g 1 Serum
men
IO
I
30
White
men
women
White
women
calcium
9 6.k p8 30
70
creatnne
White
IO
50
I
Age, yr
Age, yr Serum
(
Serum cholesterol White
If)
1
..
,
-
50
I
/
I
70
IO
30
women
50
70
4 h I Serum SGOT
230
I ;.,
White
White
women
Non-smokers
!
IO
men
30
1
I
/
I
50
70
IO
30
FIG. 1. Mean serum chemistry levels among white nonsmokers (interrupted line) and cigarette smokers (solid line) grouped by sex and age.
I
50
70
xp-
1 50
I 70
298
LGRING
G.
DALES,
GARY D. FRIEDMAN,A. B. SIEGELAUBand CARL C. SELTZER
Associations noted between smoking status and serum chemistry levels were examined further by stratifying subjects according to potential underlying variables that could possibly explain the relationships. The stratifications were performed on the largest race and age-specific subgroups, white men and women ages 40-49 yr. The associations were also examined for relationship to quantity of cigarettes smoked, with smokers subdivided into those consuming less than a pack and a pack or more daily. Results of the analyses are presented and discussed for each serum chemistry in turn. RESULTS
Serum albumin Smokers’ mean serum albumin levels were significantly lower than those of nonsmokers for both sexes in whites, with the difference being more pronounced among men (Table la, Fig. la). The direction of the difference was consistent over virtually the entire age span of the subjects studied. The differences were less consistent for blacks (Table lb). Among black men ages 40-69, the mean serum albumin levels of smokers were lower than those of nonsmokers, but among black women ages 40-69, lower levels were seen for nonsmokers. The absolute sizes of the mean differences were quite small, averaging less than 0.1 g/100 ml. Several possible explanations for the smoking status-serum albumin association were considered. Because albumin levels are frequently depressed in decompensated Laennec’s cirrhosis and because alcohol usage has been noted to be more common in smokers [3], a higher prevalence of alcohol-induced liver damage in the smokers could possibly explain their lower serum albumin concentrations. Accordingly, the white subjects (ages 40-49) were stratified by level of alcohol consumption as reported on the medical questionnaire completed at the checkup (Table 2). In each column of Table 2 it can be seen that mean serum albumin concentration did not consistently decrease with increased alcohol consumption. In each row of the table it is apparent that the lower serum albumin concentrations for smokers persisted at all alcohol-consumption levels. TABLE 2.
MEAN SERUMALBUMINLEVELS ACCORDING
AMONG NONSMOKERS AND CIGARETTE TO ALCOHOLCONSLJMPTIONHISTORY
White men ages 40-49 Mean serum albumin level (g %) Alcohol consumption history Nondrinkers 12 Drinks daily 23 Drinks daily Total
Cigarette smokers
Mean difference*
4.23 (394)-t 4.28 (1083) 4.42 (121)
4.06 (260) 4.14 (2150) 4.11 (863)
-0.17 -0.14 -0.31 -
4.28 (1598)
4.12 (3273)
-0.16 -
Nonsmokers
SMOKERS
GROUPED
White women ages 4049 Mean serum albumin level (g %)
Cigarette smokers
Mean difference*
3.97 (1234) 3.98 (2160) 3.94 (123)
3.94 (409) 3.94 (2441) 3.90 (440)
-0.03 -0.04
3.97 (3517)
3.93 (3290)
-0.04 -
Nonsmokers
*Smokers’ mean minus nonsmokers’ mean. tNumbers in parentheses indicate sample size in each category.
-co4 -
Cigarette Smoking and Serum Chemistry Tests
299
Cigarette smokers and nonsmokers were also subdivided according to presence or absence of liver disease history. In both categories the smokers again had lower mean serum albumin levels than did nonsmokers. Because the smokers in the study more frequently reported a history of severe diarrhea, which can be accompanied by decreased serum albumin concentration, the white smokers and nonsmokers were grouped by diarrhea history. The result once more was persistence of the smoker-nonsmoker differences in serum albumin levels. Similarly, grouping subjects by presence or absence of proteinuria did not alter the relationship between cigarette smoking and albumin concentration. Men ages 20-29
Men ages 40-49
Men ages 60 and over
4.30
4 IO
390 ae m 1.332 872 1,536*
1,714886 2,609
I.183 512 925
.c E
Women 20-29
2 0
E zl k v)
oges
Women 40-49
oqes
Women oqes 60 ond over
430
410
3.9c
2.648I.771 1.800
FIG.
2.
3,2981.4972,245
3,750 578 550
Mean serum albumin levels according to quantity of cigarettes smoked, among white men and women in three age groups.
The relation of serum albumin level to quantity of cigarettes smoked among white men and women in three lo-yr age groups is shown in Fig. 2. In general, the pattern is one of decreasing serum albumin level with increasing amount smoked; that is, a consistent dose-response relationship exists. A search of the medical literature uncovered no experimental or observational studies on humans relating tobacco consumption to serum albumin concentration.
300
LORING G. DALES, GARY D. FRIEDMAN, A. B. SIEGELAUB and CARLC. SELTZER
There have been animal studies demonstrating a variable effect of nicotine in lowering total serum protein concentration, but the nicotine dose involved was far higher than that which might be encountered through smoking cigarettes [4]. Serum globulin
In white males below age 40, mean serum globulin levels were lower in cigarette smokers than in nonsmokers, but above age 40 mean serum globulin levels tended to be higher in the smokers (Table la, Fig. lb). Among white women and blacks of both sexes, smokers consistently had lower globulin concentrations (Table la and b). Among smokers, no consistent relationship was found between serum globulin level and amount smoked. There appear to be no other observational or experimental studies on smoking and serum globulin in the medical literature. Serum glucose
In both white men and women, cigarette smokers had higher mean 1-hr post-sugaringestion serum glucose levels than nonsmokers (Table la, Fig. Ic). For blacks, a slight trend toward higher glucose levels among smokers was noted. However, the pattern was not consistent (Table lb). The expected positive relationship between age and mean serum glucose levels was seen. Less expected were the striking differences between whites and blacks in serum glucose levels. On the average, the values for whites were 15-25 mg/lOO ml higher than those for blacks. To determine if part or all of the serum glucose differences in whites could be accounted for by systematic differences in carbohydrate consumption shortly before examination, cigarette smokers and nonsmokers were stratified according to length of time since last food at the time of glucose ingestion for the 1-hr serum glucose measurement. When this was done, the association between smoking status and serum glucose levels persisted with almost no reduction in magnitude. Approximately three per cent of the subjects failed to consume part or all of the glucose solution given but still had blood drawn 1 hr later. Eliminating these persons from the tabulations had the expected effect of raising mean serum glucose levels, by as much as 5-6 mg/lOO ml in the older age groups. Nonetheless, the relationship between smoking status and glucose level remained virtually unchanged when the comparisons were restricted to subjects who took the full glucose load. To check out the possibility that differential nonsmoker - smoker usage of thiazide diuretics might be involved in the association, the comparisons were repeated excluding persons on such medication. When this was done the observed relationship between smoking status and serum glucose was not altered. Because alcohol ingestion is known to be accompanied by at least a transient hyperglycemia [5], serum glucose values were examined with white cigarette smokers and nonsmokers (ages 40-49) grouped by quantity of alcohol consumed (Table 3). Among nondrinkers of both sexes (top row of the table) the relationship between smoking status and serum glucose concentration virtually disappeared, while among drinkers, the same association persisted to varying degrees. In addition, a striking positive relationship existed between alcohol consumption and serum glucose concentration (except at the highest level of daily alcohol intake) with the relationship being more pronounced for smokers than for nonsmokers. When similar tabulations were made for whites ages 50-59, the results were the same.
Cigarette Smoking and Serum Chemistry Tests TABLE
3.
MEAN
Alcohol consumption history Nondrinkers 212 Drinks daily 3-5 Drinks daily 6-8 Drinks daily 29 Drinks daily Total
SERUM
301
GLUCOSE LEVELS AMONG NONSMQKERS ACCORDINGTOALCOHOLCONSUMPTION
AND CIGARETTE HISTORY
White men ages 40-49 Mean serum glucose level (mg%)
White women ages 4049 Mean serum glucose level (mgT<)
Nonsmokers
Cigarette smokers
Mean difference*
174.3 (408)t 178.2 (1154) 182.5 (10% 181.1 (16) 155.0 (11)
173.5 (276) 181.7 (2279) 184.7 (644) 201.2 (189) 186.7 (87)
-0.8
177.4 (1694)
182.8 (3475)
5.4
2.2 20-l 31.7 -
GROUPED
Cigarette smokers
Mean ditTcrence* --I.5
G
175.3 (434) 183.6 (2569) 192.8 (401) 201.4 (42) 184.2 (19)
178.1 (3698)
183.9 (3465)
5.8
Nonsmokers
3.5
SMOKERS
176.8 (1299) 178.2 (2272) 188.4 (114) 196.9 (13)
5.4 4.4 4.5
-
*Smokers’ mean minus nonsmokers’ mean. ‘rNumbers in parentheses indicate sample six in each category.
Since the cigarette smokers tended to have less heavy body builds and to have less subcutaneous fat than the nonsmokers, as indicated by mean ponderal index and triceps skinfold values, the higher serum glucose levels found for smokers could not be explained by obesity differences. Generally, serum glucose levels correlated positively with quantity of cigarettes smoked, though there were inconsistencies in the younger subjects (Fig. 3). The literature on smoking and blood glucose is fairly extensive. Nicotine administration elevates blood sugar in experimental animals, an effect which is abolished by adrenalectomy [6]. It is hypothesized that nicotine achieves this effect by stimulating release of epinephrine from the adrenal medulla and other peripheral depots, which in turn activates hepatic glycogenolysis. Reports on the effect of cigarette smoking on blood sugar in humans in the experimental setting arc conflicting: Some investigators say fasting blood sugar is raised by smoking [7, 81; others say there is no change [9, lo]. No experimental study could be found relating smoking to I-hr post-glucoseingestion blood sugar. With regard to observational studies, Blackburn reported that, among men, smokers had significantly higher (p~O.01) fasting blood sugars than did nonsmokers [ll]. Higgins found higher 1-hr post-glucose-loading blood glucose in smokers of both sexes, though the differences were not statistically significant [12]. Glausen noted that one month after quitting smoking, ex-cigarette smokers showed a reduction in 30 min postprandial blood sugar [13], but the number of subjects involved was rather small and the observations were not fully controlled. Information gathered in the present study suggests that at least part of the positive association between cigarette smoking habits and blood sugar level which has been noted in observational settings may be explained by the relationship of alcohol consumption habits to both smoking habits and serum glucose.
LORING G.DALES, GARYD.FRIEDMAN,A.B.
302
Men oges 60 and over
Men oges 40-49
Men ages 20 -29
I
s
SIEGELAUB~~~ CARL C. SELTZER
150
?
1.403 937 1,619*
Women 20-29
1,819935 2,770
Women 40-49
ages
I.251 536 981
oges
ages ond over
Women 60
r 3~205 1,8671.93’2 FIG. 3.
3,953 614 %I5
4.137 I.591 2,361
Mean
serum glucose levels according to quantity of cigarettes smoked, among white men and women in three age groups. (See footnote to FIG. 2 for key.)
Uric acid
Among white men, the cigarette smokers showed distinctly lower serum uric acid levels, while the differences for white women were minimal (Table la, Fig. 1d). Among the black men, the mean serum uric acid levels of smokers were also lower than those of nonsmokers (Table lb). On the other hand, in black women, the serum uric acid levels tended to be slightly higher in the cigarette smokers. Since the differences were most substantial in white men, further analyses were limited to this group. TABLE 4.
MEAN SERUM URIC ACID LEVELS AMONG ACCORDING
Triceps skinfold thickness Light: I 9.9 mm Medium: 10.0-13.9 mm Heavy : 2 14.0 mm Total
TO TRICEPS
NONSMOKERS SKINFOLD
AND CIGARETTE SMOKERS GROUPED
THICKNESS
White men ages 40-49 Mean uric acid levels (mg%) Cigarette Mean Nonsmokers smokers difference* 5.80 (34O)t 6.02 (386) 5.97 (542) ..- ._~___~_~ 5.94 (1268)
_.
5.68 (766) 5.78 (850) 5.88 (1035)
-0.12 -0.24 -0.09 -
5.79 (2651)
-0.15 -
*Smokers’ mean minus nonsmokers’ mean. TNumbers in parentheses indicate sample size in each category.
Cigarette Smoking and Serum Chemistry Tests
Menages 20-
29
303
Men ages 60 ond over
Men ages 40-49
509
FIG. 4.
91:
Mean serum uric acid levels according to quantity of cigarettes smoked, among white men in three age groups. (See footnote to FIG. 2 for key.)
Because of the observations that nonsmokers tend to be heavier than smokers and that obese people tend to have higher serum uric acid concentrations [12], mean uric acid values were studied at different levels of body weight. When smokers and nonsmokers were grouped according to triceps skinfold thickness, there was a slight tendency toward reduction of the difference in uric acid levels, but in general the relationship persisted (Table 4). The same was true when the smokers and nonsmokers were stratified according to a second measure of relative weight, ponderal index. Among smokers, uric acid level was inversely correlated with quantity of cigarettes smoked in two of the three IO-yr age groups studied (Fig. 4). The literature on smoking and uric acid concentration contains conflicting information. An experimental study published in the international literature has apparently shown that persons smoking several cigarettes can experience an acute, transient rise in serum uric acid [14]. Two observational studies on men reported no correlation between smoking habits and uric acid level [15, 161. A third, performed as a casecontrol study, comparing hyperuricemic to normal men, found a positive correlation [17]. The results of a fourth [l2] were similar to those of the present study: male smokers had lower uric acid levels, but among women the difference was small. Serum cholesterol
Except for subjects in the oldest subgroup, white male smokers studied tended to have higher serum cholesterol levels than nonsmokers (Table la, Fig. le). The same general trend was true for women, although to a lesser extent. Among black men and women the direction of the difference was reversed, with non-smokers having the higher serum cholesterol values (Table lb). When white male smokers were grouped by quantity of cigarettes smoked (Fig. 5), there was a stepwise rise in serum cholesterol values with increasing amount smoked for the two younger age groups studied but not for the oldest, where no smoker - nonsmoker difference had been seen anyway. Experimentally, long-term nicotine administration to animals (at dose levels above those encountered in cigarette smoking) leads to a substantial rise in serum cholesterol [I 81. It has been postulated that catecholamines released through nicotine stimulation act on adrenergic beta receptors of adipose tissue cells to increase lipid mobilization, resulting in a rise in serum cholesterol [19]. When serum cholesterol levels have been followed in humans smoking cigarettes in the experimental situation, the results have been contradictory [20, 211. Observational studies reporting at least slightly higher
304
LORING G. DALES, GARY D. FRIEDMAN, A. B. S~EGELAU~and CARL C. SELTZER
serum cholesterol values in male smokers than in nonsmokers are about equally balanced by studies reporting no difference [22-241. The data presented here can be added to those of other observational studies showing a tendency toward higher serum cholesterol levels in smokers among white men.
s
I
Menages
Men ages 60 and over
Men ages 40-49
20-29
E”230 I-
1,313 845 FIG. 5.
1,489X
1,703 867
2,540
6
498
901
Mean serum cholesterol levels according to quantity of cigarettes smoked, among white men in three age groups. (See footnote to FIG. 2 for key.)
Serum creatinine Mean serum creatinine concentrations for smokers of both sexes and races were generally lower than those of nonsmokers, though the differences were not large (Tables 1 (a and b), Fig. If). To explore the possibility that systematic differences in hydration might be involved in the relationship, smokers and nonsmokers were stratified according to coffee consumption habits, alcohol consumption habits, and presence or absence of nocturia. In all cases the association between smoking status and creatinine level persisted. On the other hand, when creatinine concentrations were studied in relation to amount smoked in three different lo-yr age groups, consistent patterns were rarely seen. One other study of serum creatinine levels in cigarette smokers and nonsmokers reported no difference [16]. Serum calcium Mean serum calcium concentrations of white and black smokers did not differ appreciably from those of nonsmokers (Tables 1 (a and b), Fig. lg). SGOT While there was a tendency among blacks for mean serum transaminase (SGOT) levels of smokers to be slightly higher than those of nonsmokers, no consistent differences were noted for whites (Tables 1 (a and b), Fig. lh). GENERAL
COMMENT
With the exceptions of serum calcium and SGOT, the smokers’ mean values for the serum chemistries examined tended to differ from those of nonsmokers. When such differences between smokers and nonsmokers were found, the magnitude of the divergence was frequently, though not always, greater for men than for women.
Cigarette Smoking and Serum Chemistry Tests
305
For serum albumin, glucose, cholesterol, and uric acid the diff’erences noted between smokers and nonsmokers among whites were not evident, or were much less evident, in blacks. Because black cigarette smokers have been reported to use smaller quantities of cigarettes than whites [l], these four chemistries were also studied with black cigarette smokers stratified by amount smoked. In general, for all four chemistries the findings were that even when the heavy smokers among the blacks were singled out for examination, the associations with smoking status were not impressive. Thus, racial discrepancies exist which make interpretation of the relationships difficult. The possibility that the non-smoker-smoker differences observed here in a group of self-selected subjects might not be true in general was examined by studying serum chemistries in a small, representative sample of Health Plan members who had been invited in for Multiphasic Health Checkups (for a different purpose). The findings in this sample did not differ appreciably from those just described for the larger group. For three of the serum chemistries-albumin, uric acid, and cholesterol-the associations with smoking status in whites persisted when examined for the effect of potential intervening variables and/or showed consistent relationships with amount smoked. These findings do not prove that cigarette smoking directly caused the changes in the serum chemistry concentrations, however. Perhaps some intervening variable not examined could still account for part or all of the relationships, as was the case for alcohol consumption habits in the association between smoking and serum glucose. Moreover, it was pointed out in the sections on uric acid and choiesterol that the relationships have not been consistently observed by other investigators. Finally, Yerushalmy has reported on an instance where a cigarette smokers’ trait (higher frequency of low birth weight infants) at first suspected to be a result of smoking actually appeared to be a characteristic of smokers even before they began to smoke [25]. This possibility has not been ruled out for the associations described here. The fact that serum concentrations of four serum chemistries-albumin, globulin, uric acid, and creatinine-tended to be lower in the cigarette smokers studied raised the possibility of a hemodilution effect of smoking. Animal studies have indicated that nicotine can cause a decrease in water diuresis, presumably by means of stimulating posterior pituitary hormone release [26]. Experimental studies on humans suggest that cigarette smoking has a transient antidiuretic effect in hydrated subjects [27-291. However, the failure to observe lower serum concentrations for four other chemistries-glucose, cholesterol, calcium and SGOT-or lower hemoglobin concentrations and white cell counts among the smokers studied [2] appears to rule out a hemodilution hypothesis, That there are differences between groups of cigarette smokers and non-smokers in a number of serum chemistry levels is clear, but the meanings of these associations are not easy to assess. On the one hand, it is possible that cigarette smoking may have some direct or indirect physiologic effect on serum chemistry concentrations. On the other hand, cigarette smokers are a self-selected group (or groups) known to differ from nonsmokers in many ways which are not thought to result from the act of smoking itself [30-331. For several of the chemistries, discrepancies in the smoker-non-smoker differences among various age-sex-race subgroups add to the difficulty of interpreting the findings. The relationships between cigarette smoking habits and the serum chemistry levels described here still need clarification.
306
LORING G. DALES, GARY D. FRIEDMAN, A. B. SIEGELAUBand CARL C. SELTZER
SUMMARY
Eight serum chemistry levels were studied in over 65,000 cigarette smokers and nonsmokers. On the average, creatinine and albumin levels were lower in the smokers of both sexes, while the opposite was true for I-hr post-challenge serum glucose. Globulin levels were consistently lower in the women smokers only. Uric acid concentrations were lower in the men who smoked. Cholesterol levels were higher in the white men who smoked but not in the black male smokers. Calcium and SGOT levels of smokers were quite similar to those of nonsmokers. Alcohol consumption played a role in smoker-nonsmoker differences in serum glucose concentration. However, for other chemistries no additional factors were identified that could explain the relationships to cigarette smoking. Thus they may be either directly affected by smoking or related to undefined underlying differences between smokers and nonsmokers. Acknow[edgemmrs-Drs. Robert Feldman and Derek Crawford, Chiefs of the Automated Multitest Laboratories in Oakland and San Francisco, respectively, supervised data collection in these facilities. In addition, Dr. Feldman assisted in the interpretation of the serum glucose findings. Dr. Hans Ury provided consultation on the employment of statistical inference tests. Mrs. Arlette Gaulene performed the computer-programming. REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Friedman GD, Seltzer CC, Siegelaub AB, Feldman R, Collen MF: Smoking among white, black, and yellow men and women. Amer J Epidem 96: 23-35, 1972 Friedman GD, Siegelaub AB, Seltzer CC, Feldman R, Collen MF: Smoking habits and the leukocyte count. Arch Environ Health (Chicago) 26: 137-143, 1973 Seltzer, CC, Friedman, GD, and Siegelaub AB: Smoking and drug consumption in white, black and oriental men and women. Amer J Public Health 64: 466-473, 1974 Aizawa K, Komoriyama K, Ohno S: Influence of nicotine on serum protein and the amount of circulating blood and extracellular fluid. Showa Dg Zasshi 20: 195-203, 1960 Goodman LS, Gilman A (eds): The Pharmacologic Basis of Therapeutics. 4th ed. London, Macmillan, 1970, p 140 Milton AS: The effect of nicotine on blood glucose levels and plasma nonesterified fatty acid levels in the intact and adrenolectomized cat. Brit J PharmacoI26: 256-263, 1966 Murchison LE, Fyfe T: Effects of cigarette smoking on serum lipids, blood glucose, and platelet adhesiveness. Lancet 2: 182-184, 1966 Szanto S: Smokers’ hyperglycemia. J Irish Med Ass 58: 22-24, 1966 Kashemsant U, Smulyan H, Eich KH: Changes in blood catecholamines with smoking. Circulation 32 Suppl 11: 19, 1965 Kingsbury KJ, Jarrett RJ: Effects of adrenaline and of smoking in patients with peripheral atherosclerotic vascular disease. Lancet 2: 22-23, 1967 Blackburn H, Brozek J, Taylor HL, Keys A: Comparison of cardiovascular and related characteristics in habitual smokers and nonsmokers. Ann N Y Acad Sci 90: 277-289, 1960 Higgins MW, Kjelsberg M : Characteristics of smokers and non-smokers in Tecumseh, Michigan. II. The distribution of selected physical measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers Amer J Epidem 86: 60-77, 1967 Glausen SC, Glausen EM, Riedenberg MM, et al: Metabolic changes associated with the cessation of cigarette smoking. Arch Environ Health (Chicago) 20: 377-381, 1970 Hogler F: Zur frage der nihotinshadigung. Wien Med Wschr 93: 309-312, 1943 Oberman A, Lane NE, Mitchell RE, Graybill A: The Thousand Aviator Study: Distribution and Intercorrelations of Selected Variables. (U.S. Naval Aerosp Med Inst Monog No. 12), Pensacola, Fla, 1965 Andrus LH, Miller DC, Stallones RA, ef a/.: Epidemiological study of coronary disease risk factors-l. study design and characteristics of individual study subjects. Amer J Epidem 87: 73-86,
17.
1968
Lanese RR, Gresham GE, Keller MD: Behavioral and physiological characteristics uricemia. JAMA 207: 1878-1882, 1969
in hyper-
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33.
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Kershbaum A, Bellet S: Cigarette smoking and blood lipids. JAMA 187: 32-36, 1964 Kershbaum A, Jiminez J, Bellet S, Zanuttine D: Modification of nicotine-induced hyperlipidemia by anti-adrenergic agents. Circulation 30: 18, 1964 Short JJ, Johnson JJA: A direct comparison of the reaction of the human system to tobacco smoke and adrenalin. J Lab Clin Med 24: 590-593, 1938-39 Page IH, Lewis LA, Moinudin M: Effects of cigarette smoking on serum cholesterol and lipoprotein concentrations. JAMA 171: 1500-1502, 1959 Larson PS, Haag HB, Silvette H: Tobacco Experimental and Clinical Studies. Baltimore, Williams & Wilkins, pp 332-334, 1961 Larson PS, Silvette H: Tobacco: Experimental and Clinical Studies. Supplement 1. Baltimore, Williams & Wilkins, pp 174-176, 1968 Larson PS, Silvette H: Tobacco: Experimental and Clinical Studies. Supplement Il. Baltimore, Williams & Wilkins, pp 150-152, 1971 Yerushalmy J: Infants with low birth weight born before their mothers started to smoke cigarettes. Amer J Obstet Gynecol 111: 277-294, 1972 Grewal RS, Lee MC, Allmark MG: Release of posterior pituitary hormones in rats by nicotine and lobeline. Fed Proc 19: 167, 1960 Hokfelt B: The effect of smoking on the production of adrenocortical hormone. Acta Med Stand Suppl 369: 123-124, 1961 Yamamoto I: Thiamine as a nicotine antagonist. Jap J Pbarmacol 13: 240-252, 1963 Levine RR, Pelikan EW, Kensler CJ: The ellect of cigarette smoking on the excretion of phenol red. Fed Proc 20: 414, 1961 Hammond EC, Garfinkel L: Smoking habits of men and women. J Nat Cancer Inst 27: 419-442, 1961 Yerushalmy J: Statistical considerations and evaluation of epidemiologic evidence. In Tobacco and Health. James G. Rosenthal T (Edsl. Sorinafield Ill: Thomas. I). 208. 1962 Higgins MW, Kjelsberg M, Metzner ‘I-I:’ Characteristics of smokers ‘and nonsmokers in Tecumseh, Michigan. 1. the distribution of smoking habits in persons and families and their relationship to social characteristics. Amer J Epidem 86: 45-59, 1967 Lilienfeld AM: Emotional and other selected characteristics of cigarette smokers as related to epidemiological studies of lung cancer and other diseases. J Nat Cancer Inst 22: 259-282, 1959