EXPOSURE OF HUMANS TO CARBON MONOXIDE COMBINED WITH INGESTION
OF DIPHENHYDRAMINE HYDROCHLORIDE OR PHENACETIN
Report No. : CRC APRAC CAPM-3-68 MCOW-ENVM-CO-74-1
From the Department of Environmental Medicine, The Medical College of
Wisconsin, Milwaukee,, Wisconsin 53226
Supported by Contract CRC-APKAC, Project No. CAPM-3-68, from the
Coordinating Research Council. Inc. , and The Environmental Protection Agency
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INTRODUCTION
The toxic effects of carbon monoxide (CO) have been known for
many years. The exposure level, or resulting percent carboxyhemoglobin
saturation (COHb), which will produce the first toxic effect, however, has
(1-4)
become controversial. Whatever the initial effect, the possibility of a
synergistic effect of CO and commonly used drugs becomes of primary con-
cern when establishing air quality standards.
The purpose of this investigation was to evaluate any synergistic
effect of CO and two commonly prescribed drugs, phenacetin and diphen-
hydramine hydrochloride. Phenacetin (N-p-ethoxyphenylacetamide), an
antipyretic and analgesic, is a common constituent of many proprietary
pain relievers. Diphenhydramine hydrochloride (2-diphenylmethoxy-N, N-
dimethylethylamine, hereafter referred to as Benadryl ) is a potent
antihistaminic agent which possesses anticholinergic, antitussive, antiemetic
and sedative effects. In order to discern any potential effect at levels
of CO and drug doses commonly incurred, the COHb saturation tested was
(5)
above average for cigarette smokers, while the drug doses were those
(6)
usually prescribed. The results of this investigation are presented in this
report.
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EXPERIMENTAL PROCEDURES
Testing Procedures
During June, 1973, seven healthy male college or medical students
(Table 1) volunteered for the study. The study consisted of twelve experiments
run in a double blind mode to investigate the effects of CO alone, drug alone,
and CO plus drug, with two replicates of each. The CO exposures were
designed to rapidly raise the subjects' COHb saturation to a level of
approximately 14% and then to maintain it at that level. A chronological
listing of the exposures with the mean and standard deviation of the CO
level and the average COHb saturation reached are presented in Table 2.
The phenacetin dosage form was prepared by grinding 300 mg
tablets (Lilly) to a powder in a mortar and pestle. The powder was
thoroughly mixed and weighted into individual 000 gelatin capsules on a daily
basis. The dosage preparation was calculated to give each subject 10 mg
phenacetin/kg body weight. The 50 mg Benadryl (Parke-Davis) capsules
were hidden in the 000 gelatin capsules with corn starch. For the no drug
experiments, the gelatin capsules were filled with corn starch. As noted
in the testing protocol in Table 3, drug or placebo plus a cup of water
was given 5 minutes prior to entry into the environmental chamber.
Exposure Chamber
All CO exposures were carried out in the controlled environment
(4)
chamber located in the Department of Environmental Medicine, The
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Medical College of Wisconsin. The environmental system (Carrier)
provided accurate control of temperature (72±2°F) and relative humidity
(40 ±5% RH) within the chamber, a room measuring 20 x 20 x 8 feet. The
chamber was operated at a slight negative pressure with an air circulation
rate of 1,200 cfm. Exhaust and make-up air capacities of 1,000 cfm
provided a rapid chamber flushing capability when desired. The chamber
featured pleasant lighting, comfortable chairs, individual testing carrels
and a restroom facility. The subjects were under continuous visual
surveillance by medical personnel while in the chamber, and in addition,
their activities were visually monitored and periodically video taped
by closed circuit TV (Sony).
Exposure Chamber Atmosphere
On non-exposure days, outside ambient air was flushed through
the chamber. On exposure days, CO was continuously metered into the
chamber's environmental system from a compressed gas cylinder in
the adjacent command laboratory. Chemically pure CO with a minimum
purity of 99. 5% was used. The concentration of CO in the chamber atmosphere
was continuously recorded from an infrared spectrophotometer (Wilks
Miran I) equipped with a 20-meter path-length gas cell which was continuously
flushed with air drawn from the chamber through 1/4" diameter poly-
ethylene tubing. An MSA CO Meter and Alarm, Model 701, was also
independently flushed with chamber air to provide a second independent
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-4-
means of continuously monitoring chamber concentration. The chamber
atmosphere was also periodically monitored by a gas chromatograph (GC)
equipped with a sequential sampler (Varian Aerograph).
All three methods of monitoring CO concentration during an exposure
were calibrated from within the chamber with standards prepared in
50 liter saran bags.
Analysis of Carboxyhemoglobin Saturation
Five-mi, aliquots of venous blood were collected in Vacutainer
tubes containing edetic acid and immediately analyzed for the hemoglobin
concentration and the percent Carboxyhemoglobin saturation using a
CO-Oximeter (Instrumentation Laboratories, Inc. ).
Behavioral Tests
The Flanagan Coordination Test (Science Research Associates, Inc.,
259 East Erie Street, Chicago, Illinois) measured the subject's ability to
rapidly and accurately follow a spiral pathway with a pencil. The subject,
while sitting comfortably at a desk in the individual carrel, was allowed
40 seconds to complete each of 6 spirals. The first two were considered
practice and the last four were scored and totaled. The score was determined
by the distance covered in each spiral minus the number of times the
sides of the spiral were touched -with the pencil and had a maximum of 100.
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The random number inspection test measured the speed with
which a subject could detect the number "3" in rows of random numbers on
an 8-1/2 x 11 inch page. The subject was asked to inspect each row of
numbers beginning at the top of the page and mark as many 3's as possible
in two minutes. The subject's score was the total number of 3's struck
with a maximum score of 203 which was never achieved. Ten different
pages of random numbers were used sequentially to prevent memorization
of test answers.
The arithmetic test, which measured the subject's ability to work
with numbers, was divided into two parts. The first part, lasting five
minutes, consisted of simple addition and subtraction problems while
the second part, lasting three minutes, consisted of multiplication and
division. The maximum score available, if all answers were correct,
was 125; however, no subject completed the test in the allotted time. In
order to prevent memorization of answers, ten different tests generated
from random number tables were used sequentially.
The Marquette Time Test, previously described in detail, con-
sisted of a series of nine tone stimuli followed by a series of nine light
stimuli. Each series contained stimuli of approximately 1.0, 1.5, ... 5.0 sec.
s
duration presented in random order. At termination of each stimulus, the
subject depressed a push button switch for that interval of time he
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estimated to be equal in duration to that of the original auditory or light
stimulus. This provided a measure of his ability to estimate the duration
of the stimulus; the interval between stimulus termination and onset of
the response was a measure of reaction time.
The ten and thirty second time estimation tests consisted of
each subject depressing the push button described above for an interval
equal to that desired (10 or 30 seconds). This was repeated an additional
two times for each test.
Neurological Tests
Within five minutes of entry into the environmental chamber and
within 10 minutes prior to exit each subject performed a modified Romberg
and heel-to-toe equilibrium test which was video taped for later inspection
if necessary. The test consisted of standing upon each leg singly with
arms at the side for a minimum of three seconds, and then walking a straight
line heel-to-toe for approximately five feet. This was first done with the
eyes open and then repeated with the eyes closed.
Electroencephalograms (EEG) and visual evoked response (VER)
measurements were made on two subjects prior to and three times during
each experiment. A modified 10-20 international electrode arrangement
was used for the EEG recordings. One electrode was placed 2 to 2. 5 cm.
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above the inion and the VER was recorded from, this electrode with the
left ear as reference. The details of the recording arrangements have
(7)
been published previously.
The EEC and VER were both analyzed by visual examination. In
addition, the amplitude of the 3rd, 4th and 5th waves of the VER complex
were measured.
Clinical Testing
Each subject was given a comprehensive medical examination
prior to and after the last exposure day of the study. These examinations
included a complete history and physical examination with the following
laboratory studies: complete blood count, SMA-12 survey panel of
clinical chemistries, a 12 lead electrocardiogram (EKG), and an electro-
encephalogram. Prior to each exposure, a brief physical examination
was performed on each subject. At this time each subject was also
questioned regarding subjective symptoms. This included questions
regarding the presence of headache, eye or throat irritation, dizziness,
nausea, chest pain and abdominal pain. A similar list was then taken by the
subject into the chamber and each hour the subject reviewed the list
for any symptoms. During the time that they were in the environmental
chamber, each subject's EKG (lead II) was continuously monitored by "
telemetry, and recorded at hourly intervals.
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Data Analysis
The data analysis of the behavioral test scores used an analysis
of variance for two factors with replication. The within treatments mean
square was used as the estimate of uncontrolled variability in calculating
F ratios.
RESULTS: CO AND PHENACETIN
Behavioral Tests
Tables 4-14 present the mean scores for each test for each
experiment, and Tables 15-25 present the analyses of variance (AOV)
of these data. The AOV for the coordination test (Table 24) shows
—pfeenaeetin-had an effect, but, neither the CO effect nor the interaction
was significant. From the mean scores in Table 17, the effect was an
increase or improvement in test performance. The AOV for the arithmetic
test (Table 26) shows the interaction of CO and phenacetin to be significant
and Table 15 shows, from the mean scores, that again the effect was
improvement of test performance.
Clinical Tests
The health of all subjects remained excellent throughout the study.
The only effect which correlated with the exposures was in the subjective
response Iist0 Table 26 is a summary of the abnormal subjective responses.
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When CO was administered solely, headaches occurred after 1 or 2 hours.
When phenacetin was administered solely, headaches developed within
1/2 hour and ameliorated within 1/2 hour. When both CO and phenacetin
were administered, headaches developed throughout the exposure beginning
within 1/2 hour.
Neurological Tests
There was no discernible difference between the subjects' ability
to perform the modified Romberg test or the heel-to-toe test when under
the influence of CO and/or phenacetin at this exposure and dose level.
Presented in Figures 1-4 are a portion of the EEG recordings
of subject 154 on four different days. Three hours of CO exposure
(Figure 7) and phenacetin ingestion only (Figure 8) did not alter the EEG
from baseline conditions. However, when CO exposure was coupled with
phenacetin ingestion, the amplitude of the EEG was increased from baseline
during both replicates (Figures 9 and 10).
There were no effects of any treatment combination in either
replicate on the VER wave amplitude, latency, or configuration in either
subject. The absence of amplitude alterations is illustrated in Figures 11 and 12.
CO AND BENADRYlF
Behavioral Tests
Tables 27-37 present the mean scores for each test for each
experiment, and Tables 38-48 present the.analyses of variance (AOV)
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of these data. The AOV for the 10-second estimations (Table 38) shows
Benadryl had an effect, but, neither the CO effect nor the interaction
was significant. From the mean scores in Table 27, the effect is found
to have been a decrease in time estimation. The AOV for the Marquette
Test, light stimulus, Estimate/Stimulus (Table 43) shows Benadryl
had a significant effect which, from Table 32, was an increase in time
estimation or the opposite of the effect on the 10-second estimations.
The AOV for the coordination test (Table 46) shows Benadryl had a sig-
nificant effect which, from Table 35, was an increase or improvement
in test performance. The AOV for the arithmetic test shows Benadryl
and the interaction with CO both had significant effects which, from Table 37,
were increases, or improvements, in test performance.
Clinical Tests
The health of all subjects remained excellent throughout the study.
The only effect which correlated with the exposures was in the subject
response list. Table 49 is a summary of the abnormal subjective responses.
®
Benadryl when administered produced drowsiness in the subjects which
commenced within 1 hour after taking the drug and light-headedness which
commenced within 2-3 hours after taking the drug. When CO was ad-
ministered, headaches also commenced 1/2-1 hour into the exposure.
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Neurological Tests
There was no discernible difference between the subjects' ability
to perform the modified Romberg test or the.heel-to-toe test when under
the influence of CO and/or Benadryl at these levels.
There were also no significant changes in either EEG wave fre-
quencies and amplitude or in the VER wave amplitude, latency or configuration.
®
The only exception to this was subject 155 who during one Benadryl
ingestion (Figure 13, upper left) had a reduced amplitude of the VER.
During the second ingestion of Benadryl he did not have an altered VER.
DISCUSSION
Behavioral Tests
Neither of these drugs combined with or without CO had significant
effects on the behavioral tests. The F values from the analysis of variance
which were significant appear random in nature. After phenacetin ingestion,
both the coordination test and arithmetic test showed improvement in
test performance. After Benadryl ingestion, the 10 second estimations showed
a decrease in time estimations, whereas, 30 second estimations did not. Also,
the Estimate/Stimulus parameter for the Marquette Test was significant for
the light stimulus but not for the sound stimulus. If these effects were
real, the effects should have also occurred with the other parameters cited.
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The improvement in test performance of the coordination and arithmetic
®
tests following the administration of phenacetin and Benadryl was not an
unexpected result as these tests have the longest training curve of the
battery of tests and, unfortunately, the experimental order was not randomized
so that training and treatment effects could be examined individually.
Neurological Tests
The recordings of the cortical electrical activity were made under
carefully controlled conditions. In addition, several recordings were made
on every subject each day and each condition was replicated. As a result,
adequate evaluations were made on each subject during each condition. The
primary limitation of this study was the small number of subjects studied.
Consequently, these findings serve primarily as a probe or as a base
for a comprehensive study.
In our previous studies, no EEG changes were noted at COHb
saturation levels of 10—>15%. The observed change in subject 151 of this
study could be an indication of intersubject variability of EEG sensitivity
to the effects of CO, or to a difference in experimental procedure. As
noted previously, the change in subject number 151 did not occur during
this experiment but during a subsequent one where only CO was being
administered but under a different protocol. Also, whereas previously
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no changes in the EEC were noted at COHb saturation levels of 10-15%,
these levels were reached over a period of 2—^4 hours, not 20 minutes.
Therefore, the changes observed could possibly be due to the body's
inability to adapt to such a fast rise in COHb saturation.
The EEG changes in subjects 151 and in 154 following phenacetin
ingestion and CO exposure is classically explained as being cortical
depression. However, we cannot explain why the supposed depression
was not also manifested in appropriate VER changes.
The minimum COHb saturation required to produce EEG or VER
changes is not well defined in the literature. Several authors have found
(8,9,10)
no change in spontaneous activity of even severely poisoned animals.
Several others have found no change in human spontaneous EEG's with
(7,11,12)
up to 33% COHb. However, augmented occurrence of slow wave components
in the spontaneous EEG of workers chronically exposed to 100 ppm CO was
(13)
found by one investigator and another found a decreased amplitude of the
(14)
alpha activity at a COHb of 29%. The average of COHb saturation for each
experiment in this study is presented in Table 2.
Subjective Responses
A COHb saturation of 14% succeeded in eliciting headaches in
5 of the 6 subjects after 1 to 3 hours into the exposure which lasted for
1 to 4 hours. Phenacetin also elicited headaches within 1/2 hour but the
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headaches ameliorated within 1/2 hour. Interestingly, although an
analgesic, phenacetin did not affect the headache produced by the CO
exposure when both phenacetin ingestion and CO exposure were combined.
The occurrence of headaches at this COHb level was also interesting as
in all previous work at this laboratory, CO induced headaches did not
occur until a COHb saturation of 16-18% was reached. As noted above
in the EEG discussion, this could be due to inter subject variability and/
or the rapid rate which the COHb level was reached.
CONCLUSION
At drug dosages normally prescribed for phenacetin and Benadryl,
there were no synergistic effects at COHb saturations commonly experienced
by heavy smokers. Three additional interesting observations were made:
(1) the occurrence of GO induced headaches at COHb saturations of 14%,
(2) the possible effect of CO exposure on EEG activity at this level, and
(3) the finding that phenacetin, as an analgesic, did not lessen the headaches
induced by the CO exposure.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the technical assistance of
D. Crespo, M. D., D. Fleischfresser, S. Graff and K. Kujawski. The
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authors also thank Ms. Susan Kamke for her help in preparation of this
manuscript.
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REFERENCES
1. Beard, R. R., Wertheim, G. A., "Behavioral Impairment Associated
with Small Doses of Carbon Monoxide", Am. J. Public Health,
57:2012-2022, 1967
2. Beard, R. R., Wertheim, G. A., "Behavioral Manifestations of
Carbon Monoxide Absorption", 16th International Congress on
Occupational Health, Tokyo, 1969
3. Stewart, R. D., et al. , "Experimental Human Exposure to Carbon
Monoxide", Arch. Environ. Health. 21:154-164, 1970
4. Stewart, R. D. , et al. , "Effect of Carbon Monoxide on Time
Perception", Arch. Environ. Health, 27:155-160, 1973
5. "Normal Carboxyhemoglobin Levels of Blood Donors in the
United States", Final report to the Coordinating Research Council
and the Environmental Protection Agency by the Department of
Environmental Medicine, The Medical College of Wisconsin,
Report # ENVIR-MED-MCW-CRC-COHb-73-l
6. "Isolation and Identification of Drugs", Edited by E. G. C. Clarke,
The Pharmaceutical Press, London, 1969
7. Hosko,M. J., "The Effect of Carbon Monoxide on the Visual Evoked
Potential in Man", Arch. Environ. Health, 21:174-180, 1970
8. Lewey, F. H. and Drabkin, D. L., "Experimental Chronic Carbon
Monoxide Poisoning of Dogs", Amer. J. Med. Sci., 208:502-511, 1944
9. Lindgren, S.A., "A Study of the Effect of Protracted Occupational
Exposure to Carbon Monoxide with Special Reference to the Occurrence
of So-called Carbon Monoxide Poisonings", Acta. Med. Scand. 167,
Suppl. 356, 1-135, 1961
10. Lindenberg, R. , et al. , "An Experimental Investigation in Animals
of the Functional and Morphological Changes from Single and
Repeated Exposure of Carbon Monoxide", paper presented at AIHA
Conf., Washington, D. C. , 1962
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11. Zorn, H., "A Contribution to the Diagnosis of Chronic CO
Intoxication", Med. Indust. , 33:325-329,1964
12. Shul'ga, T.M., "New Data For Hygiene Evaluation of CO
in Air", U.S.S.R. Literature, 9:73-81, 1964
13. Grudzinska, B., "Electroencephalographic Patterns in Cases
of Chronic Exposure to Carbon Monoxide in Air", Folia Med.
Cracov. 5:493-515,1963
14. Sluijter, M. E., "The Treatment of Carbon Monoxide Poisoning
by Administration of Oxygen at High Atmospheric Pressure",
Progr. in Brain Res. , 24:123-182, 1967
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FIGURE 1
R. Frontal
R. Parietal
^^f^^^^
L. Frontal *
L. Parietal
frHV^^jA-J*^^^
R. Parietal . V
R. Occipital .
M*^wvnn/wvv~WV^^
L. Parietal
L. Occipital
R. Parietal
R. Temporal
L. Parietal
L. Temporal '
»V*-s*f»*f**f*l*'^Wto~^^
I second
Iniort
R-Eor
^tf,d\f*j*A*nnf~~~V*/*+'*^
BASELINE
Subject 151
5/31/73
^^f^/^Y^^^V^^^
/\vs-v^w\vA/vVvi^^
-r^^^^^Nf^^^
.\W*i^rfrJwWN\tV^^
«^/JU*~*\r^/rMW~AsvM^
•f 3 /ITS. No treatment
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FIGURE 2
L Frontal
L Parietal
R. Parietal
R.0ccipitol „,„»...*
^^JW^-vWynw^^
L. Parietal
^^^^AA^^'NV/VN^/'^^
R. Parietal
R. Temporal
L. Parietal
L. Temporal
50/ff
Inion
R-Eor
I second
^^^^f^^f^f^^f^^
BASELINE . . . . .,.
Subject 151
6/5/73
~\/tfv^^^^
iVv-'..A-
+ 3hrs. drug only
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FIGURE 3
R. Frontal
R. Parietal
~^vV\>--^~^^^
L. Parietal
L. Occipital
R Parietal
R. Temporal
50 uv
L. Parietal
L. Temporal
/*v**/v/\Mrwvvv''*''vwvV^^
tnion
R-Eor
I second
^H~M^-W^W^^
BASELINE
\.~^j^^^l+AS*~^tyW^^
Y\^W^MS*^-\ytfV^^
^jWJV\j\r*J\f\i(^^ • • '
*-\pfil/WV\/VAj\fyv**JW^'^^
/•A/VWxA'W
+ 3hrs. CO
6/18/73
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FIGURE 4
R. Frontal
R. Parietal
/^^^
L Frontal
L. Parietal
R. ftvieto/
R. Occipita,
*^Jv^^
L. Parietal
L. Occipital
•*vAv>^yv^^^M/\y\y\n/\^^
R. Parietal
R. Temporal
Inion
R-Eor
I second
^t^^^f^l^
BAS£LINE Subject 151
6/6/73
^
/'~''v^
+ 3/>rs. Drug* CO
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-22-
FIGURE 5
R. Frontal
R. Parietal
ff*wyv\/~jf*j**«*f^j'f^^
L. Frontal
L. Parietal
\jtf~f**(v\s*^fW\r*JW*~>li^
R. Parietal
R Occipital
vvvv^Jy\/Vvl/\/^/v-^/v^^/v^^
L Parietal
L. Occipital
\f^^/^(M\^f^^^
R. Parietal
R. Temporal
L. Parietal
{..Temporal
Inion
R-Ear
i-
I second
**\
BASELINE
JWvo/\/W\y\/SY^^-^^
J\i\^l^M\r^^^
\pl\pt^!^
YVVvv/lM/^^^
J\P^rArt\f^/\l\rf^p/W$^^
wiWAArjy\^^
+ 3hn.CO
Subject 151
6/15/73
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-23-
FIGURE 6
R. Frontal
R. Parietal
V\AfA/v^
L Frontal
L. Parietal
Is^^^f**^^
R. Parietal
\n(fyW^]u^^
L. Parietal
L. Occipital .
^jv\p+\fs\/»*s+fl(r«^jj^^
R. Parietal
R. Temporal
L. Parietal
L.Temporal
^v»N«w^N/-»A^«A>>«^^V^V>^**AAs^
Inion
R-Eor
I second
fT'cor
.^fj^f^^f^f^^^^^^l^^^
BASELINE
l^y*w\Wr^sf*-\^
[(/fif*™l\w^^
^J\J^^^^
f^l\f^^/^l\J^^
\jJ\l\f^^f^f^^
ifAf\,fis$^^
Subject 151 +3 tin CO
6/11/73
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-24-
FIGURE 7
R. Frontal
/?. Parietal
p/\/\J^^rJ!/!^
L. Parietal
^/\^/^/v\^M^^
R. Parietal
R. Temporal
L Parietal
L. Temporal
—V^-
/n/on
R-Eor
SOfLV
I second
H^^Vw^'WW^
^\/U/\A^^V^^^^
BASELINE
Subject 154
6/4/73
r\fs+vtfj.
A' '>
43/irs. COon/y
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-25-
FIGURE 8
R. Frontal
R. Parietal
R. Parietal
. . R.0ccipital
\l(^\l^%f^^^
L. Parietal
L Occipital
•AA/V>*~V^A/^^—VA^/^IV^U--
R. Parietal
R. Temporal
to/cm
R-Eor
/second
'WfiJ\F\/vV+»*Aj^Vv^
BASELINE
\ri\j^W*>^
JVwMwJwv-^^
~*jfWfr^[V(^W/^{^^
Subjecf 154
6/5/73
+3 firs. Drug only
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-26-
FIGURE 9
R. Frontal
R. Parietal
L Frontal
L Parietal
R. Parietal
^J^J\M^^^
L. Parietal
L.Occipital . . .
i^^r^/^i^^
R. Parietal
R Temporal
I second
R-Ear
'v\vAv/V'*''M'vA'v>~'WV^^
BASELINE
Subject 154
6/6/73
rtfi
-'-•<« V.^-^V-v^V
+3hrs. -Drug + CO
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-27-
FIGURE 10
P. Frontal
R. Parietal
L. Frontal
L. Parietal
R. Parietal
R. Occipital
V^^Art/v/A^
L. Parietal
L. Occipital
R. Parietal
R. Temporal
L. Parietal
L.Temporal
Infon
R-Ear
SOjtv
I second
\J\KJI/A4\frJ^V*wA^^
BASELINE
AA^l/^VI/^/^^
^^^^
VW^M/HA^/\^^^
+ 3 tin.-Drug* CO
Subject 154
6/8/73
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-28-
FIGURE 11
SUBJECT 151 .
40
VCR
Amphi hide
20
10
40
30
20
10
lip mln.
M
%+
l
r
I
Wavtl
^
n
+
-t-
rjn
m
I
1
t
1
m
i
COHb-4jO%. COHb~l5% COHb-4.0% COHb-15%
No Drug No Drug •Phenocttin 'Phenocttin
COHb-4.0% COHb-15% COHb-4.0% COHb-15%
No Drug No Drug «Ph«noc(tln »Phenocttin
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-29-
FIGURE 12
SUBJECT 154
WanS
VER
Amplitude
(mVI
30
20-
10
20
K>
Prt'SVWS'S'M
Exp. mln.
Wave 2
rff
i
No Drug No Drug
C0-Hb<2% CO-HO-II% COHb<2% COHb-11%
»Phenocet!n »Ph»twc«tin *B«nodryl tBenodryl
-------
o
CO
I
CO
I—I
W
ti
t>
O
VER
Amplitude
(mV)
Wave 5
40-
(0
40-
30-
20-
10-
Pre »55'l:55«3=20
Exp min »
Wave 3
SUBJECT 155
-£-,
55J2C
Wove 4
COHb-2.0%
* Benadryl
COHb-15%
*Benadryl
COHb-2.0%
tBenadryl
COHb~l5%
•••Benadryl
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-31-
TABLE 1
PHYSICAL CHARACTERISTICS OF SUBJECTS
Subject
K.K.
K.M.
E.S.
D.J.
I.K.
D.N.
W.F.
AVERAGE
No.
150
151
152
153
154
155
156
Age, yrs.
22
24
23
25
23
23
11
22.7
Ht. , cm.
181
177
183
186
185
180
171
180.4
.Wt., kg.
73.6
71.3
88.1
78.1
83.5
61.4
72.0
75.4
-------
-32-
TABLE 2
CHRONOLOGICAL LISTING OF EXPERIMENTS
Experiment CO Concentration
No. Mean S. D.
1 <1
2 <1
[1,011.3
I 141.5
4 <1
5 f 983.0
I 123.9
6 <1
' /1, 001.1
t 128.1
o f 968.8
1 117.6
9 <1
10 5 980'°
L 104.6
11 <1
12 f 988.1
1124.3
--
_ _
45.5
108.3
--
74.9
45.9
--
32.8
81.4
102.3
41.1
__
91.3
52.1
--
70.6
50.7
Duration
Hr.
3.5
3.5
0.5
3.0
3.5
0.5
3.0
3.5
0.5
3.0
0.5
3.0
3.5
0.5
3.0
3.5
0.5
3.0
Drug
_ -
--
Phenacetin
Phenacetin
Phenacetin
Phenacetin
Benadryl
Benadryl
Benadryl
Benadryl
Average
% COHb
1.58
1.68
13.49
1.80
11.36
0.93
14.10
13.10
1.90
14.78
2.48
14.58
-------
-33-
TABLE 3
PROTOCOL: CARBON MONOXIDE PLUS DRUG
C.D. T. Elasped :-
Time
9:00 A.M. -I'OO" Subjects arrive (Breakfast of 8 oz. orange juice,
2 slices toast w/butter and jam at home prior
-2'30").
VER on 2 subjects (smoker and non-smoker)
All subjects-physical, blood, urine, EKG and
electrodes ECG strip
9:55 -0'05" All subjects - take medication
10:00 0 All subjects - enter chamber, subjective response
All subjects - Romberg & heel-to-toe
10:50 0'50" All subjects - subjective response
2 subjects - VER
11:00 I'OO" All subjects - behavioral tests, EKG strip
11:30 1'30" All subjects - subjective response
2 subjects - VER
11:40 1'40" All subjects - EKG strip
1:10 P.M. 3'10" All subjects - subjective response, blood, Romberg
& heel-to-toe
2 subjects - VER
1:20 3'20" All subjects - exit chamber, EKG strip
All subjects - lunch
Subjects should have no coffee or alcohol after midnight of the :'night prior
to the experiment. Smokers should smoke no more than 2 cigarettes in the
morning prior to the experiment.
-------
-34-
TABLE 4
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
10 SECOND ESTIMATIONS
No
CO
CO
R
E
P
R
E
P
R
P
1_
R
E
P
PLACEBO
10.56
9.86
10.10
10.41
10 mg/kg
PHENACETIN
9.86
10.84
10.28
10.62
-------
-35-
TABLE 5
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
30 SECOND ESTIMATIONS
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
30.91
31.42
30.45
32.53
10 mg/kg
PHENACETIN
30.43
33.04
32.18
31.49
-------
-36-
TABLE 6
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Estimate/Stimulus; Sound)
No
CO
CO
R
E
P
1
R
E
P
2
R
. E
P
1
R
E
P
2
PLACEBO
1.05
1.01
1.02
1.13
•10 mg/kg
PHENACETIN
1.04
1.08
1.05
(
1.07
, 1
-------
-37-
TABLE 7
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQ'UETTE TEST (| Estimate-Stimulus |; Sound)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.28
0.36
0.35
0.50
10 mg/kg
PHENACETIN
0.38
0.43
0.34
0.39
-------
-38-
TABLE 8
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Reaction Time; Sound)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.24
0.27
0.25
0.23
10 mg/kg
PHENACETIN
0.25
0.25
0.26
0.25
-------
-39-
TABLE 9
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Estimate/Stimulus; Light)
. R
E
P
No 1
CO
R
E
P
2
R
: E
P
1
CO
R
E
P
2
PLACEBO
0.93
0.98
0.94
0.95
10 mg/kg
PHENACETIN
0.99
0.96
0.97
1.01
i
-------
-40-
TABLE 10
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| Estimate/Stimulus |; Light)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.35
0.31
0.41
0.28
10 mg/kg
PHENACETIN
0.28
0.36
0.35
0.34
-------
-41-
TABLE 11
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Reaction Time; Light)
No
CO
CO
R
E
P
1
R
E
P
2
R
P
1
R
E
2
PLACEBO
0.30
•
0.3.1
0.31
0.27
10 mg/kg
PHENACETIN
0.31
0.30
0.32
0.30
,
-------
-42-
TABLE 12
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE COORDINATION TEST
No
CO
CO
R
E
P
1
R
E
P
2
R
E
P
1
R
E
P
2
PLACEBO
103.86
106.43
111.43
101.38
10 mg/kg
PHENACETIN
115.57
114.29
115.29
110.86
,
-------
-43-
TABLE 13
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE INSPECTION TEST
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
64.86
65.28
62.00
54.88
10 mg/kg
PHENACETIN
64.86
57.29
66. 14
61.71
-------
-44-
TABLE 14
THE EFFECT OF PHENACETIN AND CARBON MONOXIDE ON
THE ARITHMETIC TEST
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
85.86
91.43
81.57
75.00
10 mg/kg
PHENACETIN
86.00
85.71
89.43
88.86
-------
-45-
TABLE 15
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON 10-SECOND ESTIMATION
Source
Carbon
of Variation
Monoxide
Phenacetin
C x P
SS
0.
0.
0.
Oil
056
001
DF
1
1
1
MS
0.
0.
0.
Oil
056
001
F
0.
0.
0.
054
269
007
Subtotal 0.069 3
Within Treatments 0.834 4 0.208
TOTAL 0.903 7
-------
-46-
TABLE 16
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON 30-SECOND ESTIMATION
Source
Carbon
of Variation
Monoxide
Phenacetin
C x P
SS
0.
0.
0.
087
425
027
DF
1
1
1
MS
0.
0.
0.
087
425
027
F
0.
0.
0.
059
286
018
Subtotal 0.539 3
Within Treatments 5-935 4 1.484
TOTAL 6.474 7
-------
-47-
TABLE 17
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (ESTIMATE/STIMULUS; SOUND)
Source of Variation
Carbon Monoxide
Phenacetin
C x P
Subtotal
Within Treatments
SS DF
0.001 1
0.000 1
0.001 1
0.002 3
0.008 4
MS F
0.001 0.433
0.000 0.077
0.001 0.498
•
TOTAL . 0.010 7
-------
-48-
TABLE 18
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| ESTIMATE - STIMULUS |; SOUND)
Source of Variation
Carbon Monoxide
Phenacetin
C x P
Subtotal
Within Treatments
SS
0.002
0.000
0.010
0.013
0.016
DF
1
1
1
3
4
MS F
0.002 0.502
0.000 0.040
0.010 2.539
0.004
TOTAL . 0.029 7
-------
-49-
TABLE 19
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (REACTION TIME; SOUND)
Source of Variation SS DF MS F
Carbon Monoxide 0.000 1 0.000 0.102
Phenacetin 0.000 1 0.000 0.139
C xP 0.000 1 0.000 1.128
Subtotal 0.000 3
Within Treatments 0.001 4
TOTAL . .0.001 7
-------
-50-
TABLE 20
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (ESTIMATE/STIMULUS; LIGHT)
Source of Variation •
Carbon Monoxide
Phenacetin
C x P
Subtotal
Within Treatments
SS
0.000
0.002
0.000
0.003
0.002
DF
1
1
1
3
4
MS F
0.000 0.092
0.002 4.273
0.000 0.626
TOTAL . 0.005
-------
-51-
TABLE 21
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| ESTIMATE - STIMULUS]; LIGHT)
Source of Variation
Carbon Monoxide
Phenacetin
C xP
Subtotal
Within Treatments
SS
0.001
0.000
0.000
0.001
0.013
DF MS F
1 0.001 0.292
1 0.000 0.014
1 0.000 0.002
3
4 0.003
TOTAL . 0.014
-------
-52-
TABLE 22
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE MARQUETTE TEST (REACTION TIME; LIGHT)
Source of Variation
Carbon Monoxide
Phenacetin
C x P
SS DF MS F
0.000 1 0.000 0.176
0.000 1 0.000 0.668
0.000 1 0.000 0.469
Subtotal 0.000 3
Within Treatments 0.001 4
TOTAL , 0.001 7
-------
-53-
TABLE 23
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE COORDINATION TEST
Source of Variation SS DF MS F
i
Carbon Monoxide K 0.172 1 0.172 0.011
Phenacetin 135.375 1 135.375 8.397*
C x P 4.875 1 4.875 0.302
Subtotal 140.422 . 3
Within Treatments 64.484 4 16.121
TOTAL , 204.906 7
*Significant, P<.05
-------
-54-
TABLE 24
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE INSPECTION TEST
Source of Variation SS DF MS
Carbon Monoxide
Phenacetin
C x P
7.
1.
45.
133
117
039
1
1
1
7.
1.
45.
1
1
33
17
039
0.
0.
2.
446
070
818
Subtotal 53.289 3
Within Treatments 63.941 4 15.985
TOTAL 117.230 7
-------
-55-
TABLE 25
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF PHENACETIN AND CARBON MONOXIDE ON
THE ARITHMETIC TEST
Source of Variation
Carbon Monoxide
Phenacetin
C x P
Subtotal
Within Treatments
TOTAL
SS DF MS F
25.008 1 25.008 2.681
32.578 1 32.578 3.493
93.070 1 93.070 9.979*
150.656 3
37.305 4 9.326
187.961 1
#Significant, p<.05
-------
TABLE 26
Recorded Abnormal Subjective Responses for CO and Phenacetin
Exp. #
1
2
3
4
5
6
7
8
CO
N
N
Y
N
Y
N
Y
Y
DRUG
N
N
N
Y
Y
Y
Y
N
IMMEDIATE 1/2 HOUR
'
-
-
headache
(155,156)
headache
(153)
drowsy
(155)
headache
(153)
-
1 HOUR
-
-
headache
(152)
headache
(153)
-
headache
(153)
- .
2 HOUR
-'
-
headache
(151,153)
headache
(151)
-
headache
(152,153)
headache
(153)
3 HOUR
-
-
-
Ui
headache '
(152, 154)
-
headache
(152, 153)
headache
(151, 152, 153)
(154, 155, 156)
Subject numbers given in parenthesis
-------
-57-
TABLE 27
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
10 SECOND ESTIMATIONS
No
CO
CO
R
E
P
1
R
E
P
2
R
E
P
1
R
E
P
2
PLACEBO
10.56
'
9.86
10.10
10.11
50 mg.
BENADRYL
9.30
9.81
9.37
9.02
-------
-58-
TABLE 28
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
30 SECOND ESTIMATIONS
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
30.90
31.42
30.45
32.27
50 mg.
BENADRYL
30.99
30.31
29.09
29.46
-------
-59-
TABLE 29
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Estimate/Stimulus; Sound)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
1.05
1.01
1.02
1. 16
50 mg.
BENADRYL
1.20
1. 18
1.11
1.11
-------
-60-
TABLE 30
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| Estimate-Stimulus |; Sound)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.28
0.36
0.35
0.55
50 mg.
BENADRYL
0.62
0.51
0.41
0.45
-------
-61-
TABLE 31
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Reaction Time; Sound)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.24
0.27
0.25
0.26
50 mg.
BENADRYL
0.28
0.22
0.24
0.24
-------
-62-
TABLE 32
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Estimate/Stimulus; Light)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.93
0.98
0.94
0.96
50 mg.
BENADRYL
1.04
1.08
1.09
1.03
-------
-63-
TABLE 33
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| Estimate-Stimulus |; Light)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.35
0.31
0.41
0.31
50 mg.
BENADRYL
0.43
0.40
0.33
0.37
-------
-64-
TABLE 34
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (Reaction Time; Light)
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
0.30
0.31
0.31
0.31
50 mg.
BENADRYL
0.35
0.27
0.35
0.32
-------
-65-
TABLE 35
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE COORDINATION TEST
No
CO
•
CO
R
E
P
1
R
E
P
2
R
E
P
1
R
E
P
2
PLACEBO
103.86
106.43
111.43
112.87
50 mg.
BENADRYL
115.75
123.00
121.25
124.00
,
-------
-66-
TABLE 36
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE INSPECTION TEST
No
CO
CO
R
E
P
R
E
P
R
E
P
R
E
P
PLACEBO
64.86
65.29
62.00
59.22
50 mg.
BENADRYL
64.25
54.50
60.25
52.25
-------
-67-
TABLE 37
THE EFFECT OF BENADRYL AND CARBON MONOXIDE ON
THE ARITHMETIC TEST
No
CO
CO
R
E
P
R
E
P
R
E
P
1_
R
P
2
PLACEBO
85.86
91.43
81.57
82.71
50 mg.
BENADRYL
86.25
94.00
101.50
100.25
-------
-68-
TABLE 38
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON 10-SECOND ESTIMATION
Source of Variation
Carbon Monoxide
Benadryl
C x B
Subtotal
Within Treatments
N
TOTAL
SS
0.109
1.225
0.032
'1.366
0.436
1.802
DF MS F
1 0.109 0.999
1 1.225 11.250*
1 0.032 0.293
3
4 0. 109
7
-"Significant, P< . 05
-------
-69-
TABLE 39
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON 30-SECOND ESTIMATION
Source of Variation
Carbon Monoxide
Benadryl
C x B
ss
0.693
3.348
1.236
DF MS
1 0.695
1 3.348
1 1.236
F
1. 331
6.407
2.366
Subtotal
Within Treatments
5.279 3
2.090 4 0.522
TOTAL
7.369 7
-------
-70-
TABLE 40
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (ESTIMATE/STIMULUS; SOUND)
Source of Variation
Carbon Monoxide
Benadryl
C x B
SS DF
0.000 1
0.015 1
0.010 1
MS F
0.000 0.105
0.015 5.393
0.010 3.688
Subtotal 0:026 3
Within Treatments 0.011 4 0.003
TOTAL 0.037 7
-------
-71-
TABLE 41
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| ESTIMATE - STIMULUS); SOUND)
Source of Variation SS DF MS
Carbon Monoxide
Benadryl
C x B
0.
0.
0.
000
023
036
1
1
1
0.
0.
0.
000
023
036
0.
3.
4.
002
117
839
Subtotal '0.059 3
Within Treatments 0.030 4 0.007
t
TOTAL 0.089 7
-------
-72-
TABLE 42
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (REACTION TIME; SOUND)
Source of Variation
Carbon Monoxide
Benadryl
C x B
SS
0.000
0.000
0.000
DF
1
1
1
MS
0.000
0.000
0.000
F
0.066
0. 347
0. 143
Subtotal 0.000 3
Within Treatments 0.002 4
TOTAL 0.002 7
-------
-73-
TABLE 43
ANALYSIS OF. VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (ESTIMATE/STIMULUS; LIGHT)
Source of Variation
SS
DF MS
Carbon Monoxide
Benadryl
C x B
0.000 1
0.023
0.000
0.000 0.012
0.023 25.507*
0.000 0.023
Subtotal
Within Treatments
0.023 3
0.004 4 0.001
TOTAL
0.027 7
"Significant, P< . 01
-------
-74-
TABLE 44
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (| ESTIMATE - STIMULUS]; LIGHT)
Source of Variation
Carbon Monoxide
Benadryl
C x B
ss
0.001
0.003
0.005
DF
1
1
1
MS
0.001
0.003
0.005
F
0. 176
1.539
2.283
Subtotal
Within Treatments
0.008
0.008
3
4
TOTAL
0.016
-------
-75-
TABLE 45
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE MARQUETTE TEST (REACTION TIME; LIGHT)
Source of Variation
Carbon Monoxide
Benadryl
C x B
SS
0.000
0.001
0.000
DF
1
1
1
MS
0.000
0.001
0.000
F
0.376
0.569
0. 180
Subtotal
Within Treatments
0.001 3
0.004 4
TOTAL
0.005
-------
-76-
TABLE 46
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE COORDINATION TEST
Soxu-ce of Variation
Carbon Monoxide
Benadryl
C x B
Subtotal
Within Treatments
TOTAL
SS
52.
305.
7.
364.
34.
399.
531
391
047
969
391
359
DF
1
1
1
3
4
7
MS F
52.531 6.110
305.391 35.520*
7.047 0.820
^Significant, P< . 005
-------
-77-
TABLE 47
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE INSPECTION TEST
Source of Variation
Subtotal
Within Treatments
SS
DF
MS
Carbon Monoxide
Benadryl
C x B
26. 937
53.090
0.586
1
1
1
26.937
53.090
0.586
1.310
2. 582
0.029
80.613 3
82.234 4
20.559
TOTAL
162.848 7
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-78-
TABLE 48
ANALYSIS OF VARIANCE TABLE FOR THE EFFECT
OF BENADRYL AND CARBON MONOXIDE ON
THE ARITHMETIC TEST
Source of Variation
Carbon Monoxide
Benadryl
C x B
Subtotal
Within Treatments
TOTAL
SS
9.0Z3
204. 313
148.805
362. 141
46.984
409. 125
DF MS F
1 9.023 0.768
1 204.313 17.394*
1 148.805 12.668*
3
4 11.746
7
-^Significant, P< .025
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TABLE 49
Recorded Abnormal Subjective Responses for CO and Benadryl
Exp. # CO DRUG IMMEDIATE 1/2 HOUR 1 HOUR
•IN N - - -
2 N N - - -
7 Y- N - headache headache
(153) (153)
8 Y N - . -
9 N Y - - drowsy
(151,154)
10 Y Y - - drowsy
(151)
11 N Y
12 Y Y - - headache
(151,152,
153)
2 HOUR
-
-
headache
(152,153)
headache
(153)
drowsy
(151, 152, 154)
drowsy
(151,152)
dizzy
(151)
drowsy
(151)
drowsy
(151, 152, 153)
headache
3 HOUR
-
-
headache
(152, 153)
headache
(151, 152,153,
154, 155)
drowsy
(151, 152,154)
dizzy
(153)
drowsy
(152,153)
dizzy
(151)
-
drowsy
(151, 152, 153)
headache
(152,153) (152,153)
Subject numbers are given in parenthesis
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