EPA-600/1-77-034
September 1977
Environmental Health Effects Research Series
CARBON MONOXIDE
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5. Socioeconomic Environmental Studies
6. Scientific and Technical Assessment Reports (STAR)
7. Interagency Energy-Environment Research and Development
8. "Special" Reports
9. Miscellaneous Reports
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
ances of man for unhealthful substances or conditions. This work is generally
assessed from a medical viewpoint, including physiological or psychological
studies. In addition to toxicology and other medical specialities, study areas in-
clude biomedical instrumentation and health research techniques utilizing ani-
mals — but always with intended'application to human health measures.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.
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EPA-600/1-77-034
September 1977
CARBON MONOXIDE
by
Subcommittee on Carbon Monoxide
Committee on Medical and Biologic Effects of
Environmental Pollutants
National Research Council
National Academy of Sciences
Washington, B.C.
Contract No. 68-02-1226
Project Officer
Orin Stopinski
Criteria and Special Studies Office
Health Effects Research Laboratory
Research Triangle Park, N.C. 27711
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
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DISCLAIMER
This report has been reviewed by the Health Effects Research
Laboratory, U.S. Environmental Protection Agency, and approved for
publication. Approval does not signify that the contents necessarily
reflect the views and policies of the U.S. Environmental Protection
Agency, nor does mention of trade names or commercial products
constitute endorsement or recommendation for use.
NOTICE
The project that is the subject of this report was approved by the
Governing Board of the National Research Council, whose members are
drawn from the Councils of the National Academy of Sciences, the National
Academy of Engineering, and the Institute of Medicine. The members of
the Committee responsible for the report were chosed for their special
competences and with regard for apropriate balance.
This report has been reviewed by a group other than the authors
according to procedures approved by a Report Review Committee consisting
of members of the National Academy of Sciences, the National Academy of
Engineering, and 'the Institute of Medicine.
11
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk
of existing and new man-made environmental hazards is necessary for the
establishment of sound regulatory policy. These regulations serve to
enhance the quality of our environment in order to promote the public
health and welfare and the productive capacity of our Nation's population.
The Health Effects Research Laboratory, Research Triangle Park,
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects. These
studies address problems in air pollution, non-ionizing radiation,
environmental carcinogenesis and the toxicology of pesticides as well as
other chemical pollutants. The Laboratory develops and revises air quality
criteria documents on pollutants for which national ambient air quality
standards exist or are proposed, provides the data for registration of new
pesticides or proposed suspension of those already in use, conducts research
on hazardous and toxic materials, and is preparing the health basis for
non-ionizing radiation standards. Direct support to the regulatory function
of the Agency is provided in the form of expert testimony and preparation of
affidavits as well as expert advice to the Administialor to assure the
adequacy of health care and surveillance of persons having suffered imminent
and substantial endangerment of their health.
To aid the Health Effects Research Laboratory to fulfill the functions
listed above, the National Academy of Sciences (NAS) under EPA Contract
No. 68-02-1226 prepares evaluative reports of current knowledge of selected
atmospheric pollutants. These documents serve as background material for
the preparation or revision of criteria documents, scientific and technical
assessment reports, partial bases for EPA decisions and recommendations
for research needs. "Carbon Monoxide" is one of these reports.
John H. Knelson, M.D.
Director
Health Effects Research Laboratory
iii
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SUBCOMMITTEE ON CARBON MONOXIDE
COMMITTEE ON MEDICAL AND BIOLOGIC EFFKCTS OF ENVIRONMENTAL POLLUTANTS
RONALD F. COBURN, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, Chairman
ERIC R. ALLEN, State University of Hew York Atmospheric Sciences
Research Center, Albany, New York
STEPHEN M. AYRES, St. Louis University School of Medicine, St. Louis,
Missouri
DONALD BARTLETT, JR., Dartmouth Medical School, Hanover, New
Hampshire
EDWARD F. FERRAND, New York City Department of Air Resources,
New York, Now York
A. CLYDE HILL, University of Utah, Salt Lake City, Utah
STEVEN M. HORVATH, University of California Institute of Environ-
mental Stress, Saitta Barbara, California
LEWIS H. KULLER, University of Pittsburgh Graduate School of Public
Health, Pittsburgh, Pennsylvania
VICTOR G. LATIES, University of Rochester School of Medicine and
Dentistry, Rochester, New York
LAWRENCE D. LONGO, Loraa Linda University School of Medicine, Santa
Barbara, California
EDWARD P. RADFORD, JR., The Johns .Hopkins University School of
Hygiene and Public Health, Baltimore, Maryland
JAMES A. FRAZIER, National Research Council, Washington, D.C.,
Statf Officer
HERSC1IEL E. GRIFFIN, University of Pittsburgh, Pitrsburgh, Pennsylvania,
Chairman
RONALD F. COBURN, University, of Pennsylvania School of Medicine, Philadelphia
Pennsylvania
T. TIMOTHY CROCKER, University of California College of Medicine, Irvine,
California
CLEMENT A. FINCH, University of Washington School of Medicine, Seattle,
Washington
SHELDON K. FRIEDLANDER, California Institute of Technology, Pasadena,
California
ROBERT I. HENKIN, Georgetown University Medical Center, Washington, n.C.
IAN T. T. niGCINS, University of Michigan, Ann Arbor, Michigan
JOE W. HIGirrOWER, Rice University, Houston, Texas
HENRY KAMIN, Duke University Medical Center, Durhnm, North Carolina
ORVILLE A. I.EVANDER, Agricultural Research Center, Beltsvlllc, Maryland
DWIGKT F. METZLER, Kansas State Department of Health and Environment, Topeka,
Kansas
I. HERBERT SCHEINBERG, Albert Einstein College of Medicine, Bronx, New York
RALPH G. SMITH, University of Michigann, Ann Arbor, Michigan
ROGER P. SMITH, Dartmouth Medical School, Hanover, New Hampshire
T. D. BOA7., JR., National Research Council, Washington, U.C., Executive Director
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ACKNOWLEDGMENTS
Members of the Subcommittee on Carbon Monoxide, under the Chairmanship of
Dr. Ronald F. Coburn, wrote this report. It is appropriate to mention here
that the same people also wrote the section on carbon monoxide in the report
for the U.S. Senate Committee on Public Works.*
Drs. Coburn and Eric R. Allen wrote the introduction. Dr. Allen also
wrote Chapter 2, on properties and reactions, and Chapter 3, on sources,
occurrence, and fate of atmospheric carbon monoxide. Dr. Edward F. Ferrand
wrote Chapter 4, on environmental analysis and monitoring, and Appendix A,
on methods of monitoring.
For Chapter 5, Dr. Edward P. Radford, Jr., wrote the material on uptake;
Drs. Coburn and Donald Bartlett, Jr., on physiologic effects; Dr. Lawrence D.
Longo, on effects on the pregnant woman, the developing embryo, the fetus, and
the newborn infant; Dr. Lewis H. Kuller, on cardiovascular effects; Dr. Victor G.
Laties, on behavioral effects; Dr. Steven M. Horvath, on effects during exercise
and effects on populations especially susceptible to carbon monoxide exposure
owing to reduced oxygenation at altitudes above sea level; Dr. Bartlett, on the
effects of chronic or repeated exposure; and Dr. Coburn, on dose-response character-
istics in man.
Dr. A. Clyde Hill wrote Chapter 6, on the effects of carbon monoxide on
bacteria and plants.
*National Academy of Sciences, National Academy of Engineering. Coordinating
Committee on Air Quality Studies. Air Quality and Automobile Emission Control.
Vol. 2. Health Effects of Air Pollutants. U.S. Senate Committee Print Serial
No. 93-24. Washington, D. C.: U.S. Government Printing Office, 1974. 511 pp.
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Chapters 7 and 8, the statements in the summary, and recommendations, were
written by the members of the Subcommittee and assembled by Dr. Coburn.
Dr. Radford wrote Appendix B, on measurement in biologic samples.
The Environmental Protection Agency's Air Pollution Technical Information
Center supplied information from its computer data base. Dr. Robert J. M.
Horton of theEPA obtained various technical and scientific documents and other
resource information. The staff of the NRC Assembly of Life Sciences Advisory
Center on Toxicology gave assistance in obtaining resource information and also
reviewed the report.
The report was reviewed by the Academy's Report Review Committee with the
assistance of anonymous reviewers selected by that Committee. The members of
the MBEEP Committee reviewed the report in depth. It was also reviewed by the
Associate Editor, Dr. Henry Kamin, and five anonymous reviewers selected by him.
The staff officer for the Subcommittee on Carbon Monoxide was Mr. James A.
Frazier. We also acknowledge the staff support of Mrs. Renee Ford for editing
the report, Ms. Joan Stokes for preparation and verification of the references,
and Mr. Norman Grbssblatt for his editorial assistance.
vi
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CONTENTS
1. Introduction
2. Properties and Reactions of Carbon Monoxide
3. Sources, Occurrence, and Fate of Atmospheric
Carbon Monoxide
4. Environmental Analysis and Monitoring
5. Effects on Man and Animals
6. Effects on Bacteria and Plants
7. Summary and Conclusions
8. Recommendations
Appendix A: Methods of Monitoring Carbon Monoxide
Appendix B: Measurement of Carbon Monoxide in
Biological Samples
References
vii
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CHAPTER 1.
INTRODUCTION
Man has experienced the effects of carbon monoxide poisoning at least since
that period in prehistory when he first discovered the art of making and utilizing
fire. Numerous accounts of tragic events, circumstances, and phenomena that can
be directly or indirectly attributed to the toxic properties of carbon monoxide
230
have been related in folklore and mythology. Lewin, who traced the early history
of carbon monoxide, was led to the conclusion that this form of poisoning is
unique in its close association with the history of civilization. For example,
carbon monoxide poisonings drastically increased in the fifteenth century when the
use of coal for domestic heating increased. These poisonings were attributed both
to inhalation of carbon monoxide formed by incomplete combustion in the heating of
homes and to the exposure of coal miners to the deadly "white damp," encountered
after underground explosions and mine fires.
The introduction of illuminating gas (a mixture of hydrogen, carbon monoxide,
methane, and other hydrocarbons, also known as carburetted water gas) for domestic
heating purposes further increased the hazard of carbon monoxide poisoning.
Although this fuel is still used extensively in Europe, it has largely been
replaced in the United States with natural gas. More recently, the introduction
of the internal-combustion engine and the development of numerous technological
processes in which carbon monoxide is produced have increased still further the
hazard of exposure to this toxic gas. Despite awareness for many centuries that
human exposure to combustion fumes was hazardous, it was not until 1919 that
industrial production of carbon monoxide was recognized to be an environmental
health problem of national importance. At the First International Congress of
Labor, the rapidly increasing use of the internal-combustion engine as a source of
industrial power was cited as a major contributor of the carbon monoxide being
1-1
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inhaled by workers. The exhaust from the internal-combustion engine is the
principal contemporary anthropogenic source of carbon monoxide. Over the
centuries, the problem of dealing with carbon monoxide exposure has expanded from
dwellings to work environments and now includes the ambient air in cities. This
report reflects our concern with the adverse effects of exposure to carbon monoxide
at the concentrations found in our urban and industrial air.
At the time that the Air Quality Criteria for Carbon Monoxide appeared in 1970,
data was produced which suggested that, when man received an acute carbon
monoxide exposure that produced carboxyhemoglobinemia as low as 3 percent satura-
tion, there were adverse effects on complex mental functions such as vigilance.
There was also epidemiologic evidence relating the incidence of myocardial
infarction and the concentration of carbon monoxide in air. The possibility was
raised that a significant fraction of the urban population might be experiencing
adverse health effects due to carbon monoxide. A major criticism was that it was
not known whether the data could be extrapolated to urban population groups.
Studies on the biologic effects of carbon monoxide on man since 1971
apparently support the conclusion that carboxyhemoglobin levels as low as 3-5%
may have effects on vigilance and aerobic metabolism under conditions of
exercise at maximal oxygen uptake. It is uncertain whether these experimental
results can be extrapolated to urban populations, but it is strongly suspected
that they can. In addition, an awareness of a spectrum of carbon monoxide
susceptible populations is growing, particularly* .in patients with coronary vascular
diseases and the fetus.
This document summarizes the carbon monoxide literature related
to effect's on man and his environment for the consideration of the Environmental
Protection Agency in updating the information in the Air Quality Criteria on
1-2
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Carbon Monoxide. It emphasizes recent major advances in our knowledge of carbon
monoxide: chemical reactions in air; biologic effects on man; problems in
monitoring urban concentrations and relating such data to the exposure of popu-
lations; data concerning the identification of susceptible populations; and
evidence implicating carbon monoxide as a causal factor in disease. We have not
tried to review all published articles but only those deemed to be the important
studies related to carbon monoxide air quality criteria. There is a large
literature on adverse effects of cigarette smoking and some of these effects may
be related to carbon monoxide.
1-3
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CHAPTER 2
PROPERTIES AND REACTIONS OF CARBON MONOXIDE
Carbon monoxide (CO) is an imperceptible poisonous gas, the most common
source of which is the incomplete combustion of carbonaceous materials. It is
probably the most publicized and the best known of all air quality criteria
pollutants* because of the frequency of accidental deaths attributed to its
inhalation over the years. Its toxic and sometimes ?
lethal properties, however, are due to acute effects resulting from exposures
to very high concentrations in confined spaces, generally exceeding 500 ppm for
several hours. In this report we are mainly concerned with the deleterious ef-
fects resulting from human exposures to much lower concentrations over consider-
ably longer periods of time. In the latter context we are also concerned with
the role this oxide of carbon plays as a chemically reactive environmental
pollutant and atmospheric trace constituent. This requires a detailed quantita-
tive understanding of major physical and chemical factors governing production,
control, transformation, and removal of carbon monoxide prior to and during its
atmospheric life cycle. Recently, there has been a renewal of interest in reac-
tions involving carbon oxides because of their fundamental importance in the
genesis and evolution of planetary atmospheres as well as in pollutant-forming
combustion, flame and explosion processes and in terrestrial atmospheric chemistry.
In this report the fundamental scientific and technical knowledge concern-
ing carbon monoxide in its role as an air pollutant affecting public health and
welfare is updated and assessed. Special emphasis is placed on the more recent
advances in our understanding and relevant discoveries made during the last five years.
*Those pollutants for which an air quality.criteria document has been published
as required by the Clean Air Act.
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For a comprehensive review of pertinent literature published prior to 1972,
there are two excellent reports, one commissioned by the National Air Pollution
Control Administration, U.S. Public Health Service^ and the other by the North
Atlantic Treaty Organization, Committee on Challenges of Modern Society,298 pub-
lished in March 1970 and June 1972, respectively. They treat the topic of air quality
criteria for carbon monoxide in considerable detail and provide a basis for this
updated review. In addition, Cooper" has compiled an extensive carbon monoxide
bibliography with abstracts of the literature published prior to 1966, that pro-
vides a further source of information.
General Physical and Chemical Properties
Carbon monoxide, a stable compound, is a heteropolar diatomic molecule.
It absorbs radiation in the infrared region corresponding to the vibrational ex-
citation of the electronic ground state of the molecule, CO (X £ ). Because
thermal population of excited vibrational levels is extremely inefficient, even
at 1000 C less than 1% of all the molecules present will reside in the first
vibrationally excited (v'~l) state above the ground vibrational state (v"=0).
*»
>
Radiation in the visible and near ultraviolet regions of the electromagnetic
spectrum is not absorbed by carbon monoxide, but in the vacuum ultraviolet
region, a structured relatively weak absorption band extends from 155 to 125 nm.
In this so called spectroscopic fourth positive band system of carbon monoxide
the electronic transition COCA^ •<- X1^ ) occurs.167'172 The characteristics of
frequency ^dependent
the absorption spectrum and the/extinction coefficients, as well as the photo-
chemistry of carbon monoxide in the vacuum ultraviolet region, have been reviewed
and discussed elsewhere. ' Interest in carbon monoxide photochemistry has
recently been stimulated by the discovery of this gas at about 0.1% in the Martian
26 197 98 344
atmosphere, ' and by detection in the atmosphere of Venus. ' These
2-2
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discoveries suggest that it plays a significant role in the development of
primitive planetary atmospheres in our solar system.
Carbon monoxide has a low electric dipole moment (0.10 Debye) , short
interatomic distance (1.13 A), and high heat of formation from atoms, or bond
strength (1,072 kj/mole) suggesting that .this diamagnetic molecule is a
309
resonance hybrid of the three structures ;
..
a) :C: 0: b) :C::0: c)
— +
:C:::0:
These structures correspond to forms with single, double;and triple covalent
+ _ _ +
bonds, i.e., C-0, C=0 and C=0. They all apparently contribute about equally
to the normal state of the molecule, thus counterbalancing the opposing effects
of the number of covalent bonds and charge separation. Carbon monoxide is iso-
electronic with molecular nitrogen (N'2) , the nitrosyl cation (NO"*"), and the cyanide
anion (CN ). The similarity to nitrogen causes difficulties in its physical
separation and identification in air. It is a colorless, odorless and taste-
less gas that is slightly lighter than air and difficult to liquefy. Although
an anhydride of formic acid (HCOOH) , it is unreactive with water and is only
slightly soluble. General physical properties of carbon monoxide are presented
in Table 1.
Production and Preparation282 » 308
Carbon monoxide is produced when carbon or combustible carbonaceous ma-
terial is burned in a limited supply of air or oxygen, i.e., under fuel -rich
conditions.
It is manufactured on a large scale by reducing carbon dioxide with carbon
at high temperatures. Below 800 C the reduction is slow but above 1000 C the
conversion, corresponding to the endothermic reaction (1) , is quite fast and
efficient .
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TABLE 2-1
423a
Physical Properties of Carbon Monoxide —
Molecular weight
Critical point
Melting point
Boiling point
Density, at 0 C, 1 atm
at 25 C, 1 atm
Specific gravity relative to air
Solubility in water3-, at 0 C
at 20 C
at 25 C
Explosive limits in air
Fundamental vibrational transition
O
1 -e v" = 0)
Conversion factors:
at 0 C, 1 atm
at 25 C, 1 atm.
28.01
-140 C at 34.5 atm.
-199 C
-191.5 C
1.250 g/liter
1.145 g/liter
0.967
3.54 ml/ 100 ml
(44.3
2.32 ml/100 ml
(29.0 ppmm)
2.14 ml/100 ml
(26.8 ppmm)
12.5 - 74.2%
2,143.3 cm"1
(4.67 urn)
1 mg/m3 = 0.800 ppm £•
1 ppm = 1.250 mg/m3
o
1 mg/m = 0.873 ppm
1 ppnr = 1.145 mg/m3
—Volume of carbon monoxide is at 0 C, 1 atm (atmospheric pressure
at sea level =760 torr)
—Farts per million by mass (ppmm = mg/1)
•^•Parts per million by volume
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C(s) + C02(g) -> 2CO(g) - 163 kJ/mole
(1)
The monoxide is a major constituent of the synthetic fuels, "producer
gas" (25% CO) and "water gas" (40% CO). The former, used mainly for heating
purposes, consists primarily of nitrogen and carbon monoxide and is prepared
by passing air through a bed of incandescent coke, the residue of coal remain-
ing after destructive distillation. If coal is used in place of coke, coal
gas will also be present. This fuel mixture, commonly used for domestic
heating in Europe, has been almost completely replaced by natural gas in the
United States. "Water gas" is made when steam is blown through incandescent
coke at 1100 C. It is a mixture of hydrogen (49%) and carbon monoxide (44%)
H20(g) + C(s) -»• C0(g) + H2(g) (2)
with traces of nitrogen (4%), carbon dioxide (2.7%) and methane (0.3%).
"Semi-water gas" is produced by blowing a mixture of steam and air through
incandescent coke. Carbureted (enriched) water gas, which burns with a lumin-
ous flame, is prepared by mixing water gas with partially unsaturated hydro-
carbons. "Water gas" burns with a blue, nonluminous flame, produces consider-
able heat -In combustion, and may be used with Welsback mantles for illuminating
purposes. The calorific values (available fuel energy) for combustion of pro-
3 6 ^
ducer and semi-water gas are low, of the order 125 Btu/ft (4.4 x 10 J/m ) ,
compared with 350 Btu/ft3 (12.3 x 106 J/m3) for water gas and 600 Btu/ft3
6 3
(21 x 10 J/m ) for coal gas. Carbon monoxide can also be produced by several
other methods , including :
• Reduction of carbon dioxide with zinc dust or iron filings at red heat —
for example, with zinc dust.
C02(g) + Zn(s) ->• C0(g) + ZnO(s) (3)
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• Heating charcoal with either zinc, iron or manganese oxides—
for example, with zinc.
C(s) + ZnO(s) -»• C0(g) + Zn(s) (4)
• Heating carbon with certain alkaline earth carbonates, such
as chalk or barium carbonate—for example, with barium carbonate.
BaC03(s) + C(s) -> BaO(s) + 2CO(g) (5)
On the laboratory scale, carbon monoxide for analytical and other purposes can
be conveniently prepared by the following methods:
• The reaction of concentrated sulfuric acid (H2S04) with formic
acid at 100 C (reaction 6), or oxalic acid at 50 C (reaction 7),
or sodium formate (reaction 8) or potassium ferrocyanide at room
temperature (reaction 9):
H2S04
HCOOH -»• H20 + C0(g) (6)
100 C
' H2S04
(COOH)0 -> H90 + C0(g) + C09(g) (7)
^ 50 C Z
2HCOONa.+ H-SO, Na0SO. + 2H« + 2CO(g) (8)
25 C *
>,SO, (9)
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In the reaction with oxalic acid (reaction 7), note that equal volumes of
carbon dioxide and carbon monoxide are produced. Some sulfur dioxide (S02)
is generated in all the reactions (reactions 6-9) by the reduction of sulfuric
acid as shown in reaction (10):
H2S04 + C0(g) + H20 + S02(g) + C02(g) (10)
• The reaction of chlorosulfonic acid with formic acid also
produces carbon monoxide (reaction 11):
HCOOH + CS03C1 -»• HjSC^ + HC1 + C0(g) UD
In the above procedures the carbon monoxide produced can be purified by bubbling
through caustic soda and then drying over phosphorus pentoxide.
• Thermal decomposition of nickel carbonyl at 200 C yields a high
purity product:
Ni(CO)4(g) -»• Ni(s) + 4CO(g) (12)
Carbon dioxide absorbs solar ultraviolet radiation in its first two
absorption bands between 170 and 120 nm. At wavelengths less than 165 nm,
sufficient energy is available to dissociate the dioxide into the monoxide
and electronically excited atomic oxygen^O according to the spin-conserving
reaction (13).
G00(X1zt) + hv ->- CO(X1£j') + 0(1D) (13)
L 8 *
Here C02(X Eg) is the electronic ground state of carbon dioxide, CO(X zf)
is the electronic ground state of carbon monoxide and (0 D) is an electronically
excited state of atomic oxygen.
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The quantum efficiency (number of molecules of product per absorbed photon of
radiation) of this process is almost unity near 150 nm.
Carbon monoxide is also a product of the pyrolysis or photolysis of many
oxygenated organic compounds. For example, at wavelengths below 340 nm ali-
phatic aldehydes/which are constituents of photochemical smog, may photolyze
directly into hydrocarbon and carbon monoxide as shown in reaction (I4a):
RCHO + hv •> RH + CO (14a)
In the case of formaldehyde (HCHO), the quantum efficiency of this process is
about 0.5 at 313 nm and ambient temperatures, but the efficiency is much less
for higher aliphatic aldehydes. The photolysis of aldehydes also produces
acyl radicals (RCO) according to reaction (14b)|
RCHO + hv + RCO + H (14b)
spontaneously
In the absence of molecular oxygen, acyl radicals can/decompose into hydrocarbon
radicals (R) and carbon monoxide. However, in air this reaction is suppressed
Y
by the dominant formation of acylperoxy radical adducts (RCOo) with oxygen.
dioxide.
Chemical Reactions of Carbon Monoxide
Decomposition
Carbon monoxide is quite stable and chemically inert under normal condi-
tions (25 C and 1 atm) despite a carbon valency of two; At higher tempera-
tures it becomes reactive, behaves as though unsaturated and can act as a
powerful reducing agent—a property used in many metallurgical processes, such
as in blast furnaces.
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At high temperature, in the presence of a catalyst (palladium, iron,
nickel), carbon monoxide undergoes the reversible disproportionation reaction
(15):
2CO + C + C02 +162 kJ/mole'1 (15)
As the temperature is increased the equilibrium fraction of carbon dioxide
decreases, for example, the equilibrium percentages by volume of dioxide
are 90 at 550 C, 50 at 675 C, 5 at 900 C and less than 1 at 1000 C. The
reverse reaction is utilized industrially to manufacture the monoxide (see
reaction 1).
Photolysis of carbon monoxide at 129.5 nm ftenon radiation) results in the
122
disproportionation into carbon dioxide and carbon suboxide (C-C^). Since
the absorption of radiation at wavelengths <£lll nm is required to photodissociate
carbon monoxide into its component atoms it has been postulated that the photo-
chemical reaction involves electronically excited molecules, CO (A ir), and
the following sequence of reactions has been suggested:
CO + hv -»• CO(A1Tr) (16)
CO (A1 IT) + CO ->• C02 + C (17)
C + CO -v C20 (18)
C20 + CO -> C302 (19)
At this wavelength (129.5 nm) the quantum efficiency of carbon monoxide re-
moval is 0.8 ± 0.4 but at 147 or 123.6 nm it is almost zero.15* similar
products are formed by electrical and high frequency discharges in carbon
monoxide.
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Combustion. "° Carbon monoxide burns in air or oxygen with a bright blue
flame but does not itself support combustion (see reaction 20).
2CO + 02 -* 2C02 + 565 kj/mole (20)
Although heat is evolved during combustion, the fuel value is low (320 Btu/ft^
6 o
or 11.3 x 10 J/m ). The blue flames seen on top of a clear fire consist of
burning carbon monoxide. It is presumably produced in fires due to the reduc-
tion of carbon dioxide that is formed in the lower regions of glowing fuel
near the entering air draught as it rises through an incandescent mass of
carbon (see reaction 21). The carbon monoxide burns on top of the fire where
an excess of air is available. An interesting feature of these processes is
that the reaction of carbon with oxygen at temperatures producing carbon
dioxide generates heat (exothermic process—see reaction 21), whereas the
C(s) + 02(g)->- C02(g) + 1109 kJ/mole (21)
reaction of carbon dioxide with carbon at the same temperature absorbs heat
(endothermic process—see reaction 11). Thus, it is possible to adjust the
>
ratio of air* (or oxygen) to carbon dioxide, so that a desired temperature
can be maintained continuously. In industry, large quantities of carbon
monoxide are formed during the incomplete combustion of charcoal or coke,
and to a lesser extent by other carbonaceous fuels, in a limited supply of
under
air,i.e., .fuel-rich conditions. The presence of carbon monoxide in furnace
gases is used as an indicator of improper air supply and its estimation in
flue gases is used as a check on the operating efficiency of the furnace.
Stoichiometric mixtures (2:1 by volume) of carbon monoxide and oxygen
explode upon ignition in the presence of trace amounts of moisture or hydrogen-
ous compounds, such as methane (CH^) or hydrogen sulfide (f^S). These neces-
sary impurities apparently act as a source of oxyhydrogen free radicals
2-10
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(hydroxyl and hydroperoxyl), which provide low energy reaction paths leading
to an explosive chain branching mechanism. Explosive limits in oxygen range
from 15.5 to 93.9% by volume of carbon monoxide. These proportions may be
compared with the limits in air given in Table 2-1.
Heterogeneous Reactions. Carbon monoxide is the anhydride of formic
acid but it does not react with water (liquid or vapor) at room temperature.
However, the forward reaction in the equilibrium with formic acid vapor shown
below (see reaction 22) may be achieved by the application of an electrical
or high frequency discharge in stoichiometric mixtures (1:1) of carbon monoxide
C0(g) + H20(g) * HCOOH(g) (22)
and water vapor. The reverse dehydration process is accomplished by the cata-
lytic action of metallic rhodium. Carbon monoxide at 120 C and 3 to 4 atmospheres
pressure is rapidly and completely absorbed by a concentrated solution of caustic
soda forming sodium formate. This salt is also produced when carbon monoxide is
passed over caustic soda or soda lime heated to 200 C. (See reaction 23.)
NaOH(s) + C0(g) -»• HCOONa(s) (23)
Anhydrous formic acid is manufactured economically in quantity from sodium
formate by distillation with concentrated sulfuric acid.
In the presence of a suitable catalyst, such as freshly-reduced metallic
nickel, carbon monoxide can be hydrogenated to methanol (CHoOH), methane (CH,)
or other organic compounds depending upon the conditions selected. Its conver-
sion to methane is the basis for the flame ionization gas chromatographic separa-
tion procedure used for the detection and estimation of carbon monoxide in ambient
air.
2-11
-------
When carbon monoxide is passed over heated metal oxides such as lead
oxide (PbO) in reaction (24), oxygen is extracted leaving the metal.
PbO(s) + C0(g) + C02(g) + Pb(s) (24)
Rapid and quantitative reaction with various oxides at high temperatures has
been used for the estimation of carbon monoxide; some examples are:
• with cuprous oxide at room temperature or copper-cupric oxide
at 270-300 C t carbon dioxide produced is quantitatively absorbed
by caustic soda solution and the volumetric loss on absorption is
measured in the Orsat-Lunge apparatus.
• with iodine pentoxide at 90 C,iodine vapor is formed stoichiometri-
cally by reaction (25) and the iodine is collected and estimated by
iodometry.
I205(s) + 5CO(g) •> I2(g) + 5C02(g) (25)
• with mercuric oxide at 150 C,mercury vapor is released which is
measured spectrophotometrically at 254 nm.
HgO(s) + C0(g) -»• Hg(g) + C02(s) (26)
The rate of oxidation of carbon monoxide in oxygen, although insignificant
in homogeneous mixtures, is known to be enhanced by metallic catalysts such as
372
palladium on silica gel or a mixture of manganese and copper oxides (Hopcalite).
It has also been shown that carbon monoxide is made catalytically active by ad-
I f\ O
sorption on hot metallic surfaces. The reactions of nitrous oxide (N-O)
with carbon monoxide chemisorbed on copper, charcoal, Pyrex glass or quartz
surfaces at high temperatures (above 300 C) have been studied extensively214,255,369,
and found to be quite efficient in oxidizing carbon monoxide (see reaction 27) .
2-12
-------
C0abs + N2°(g) "" C°2(g) + N2(g) (27)
Carbonyl and Coordination Compounds.282'362 In the presence of light,
equal volumes of carbon monoxide and individual halogens (F2,Cl2,Br2,I2) or
cyanogen (C2N2) react to form the corresponding volatile and highly reactive
carbonyl halides or cyanide . In reaction (28):
CO + X2 -»• COX2 (28)
X is a univalent element. Carbonyl chloride (phosgene), formed by reaction
with chlorine (C12), is the best known of these compounds and is highly
poisonous at a concentration which has been suggested to be considerably less
than that for carbon monoxide. It is used frequently as the solvent in non-
aqueous systems of acids and bases. Phosgene undergoes ammonolysis when passed
into a solution of ammonia in toluene, forming urea (CO(NH2)2) an^ tne salt
COC12 + 4NH3 •»• CO(NH2)2 + 2NH4C1 (29)
ammonium chloride, which provides an effective means of removing the phosgene.
It is also used in the manufacture of urea. Carbonyl fluoride (COF2) is ex-
tremely reactive attacking glass and many metals.
When carbon monoxide is passed over heated sulfur or selenium, carbonyl
sulfide (COS) and selenide (COSe),respectively, are produced. All of the
carbonyl compounds mentioned above are used widely and frequently in industrial
organic syntheses and organic chemical production.
Carbon monoxide forms volatile metallic carbonyl compounds in which the
carbon monoxide molecule exclusively is attached to a single metal atom or
group of metal atoms. These include the carbonyls of chromium, molybdenum
and tungsten in Group VI of the periodic table of the elements; rhenium in
2-13
-------
Group VII; iron, ruthenium and osmium in Group VIIIA; cobalt, rhodium and
iridium in Group VIIIB; and nickel in Group VIIIC. Although these are coordina-
tion compounds, their unusual composition is determined more by their tendency
to form closed (filled) electronic shells rather than by the valence of the
central metal. For example, in simple binary carbonyls, containing one metal
atom (M) in the complex, i.e., (M[CO] ), the carbon monoxide donates two electrons
y
to the shellj thus, the effective atomic number (EAN) of the metal M becomes the
atomic number of the next higher inert gas element for a stable complex.
(Atomic number' of element + 2y.) Thus, the EAN's for some of the metals mentioned
above are: 36 in chromium hexacarbonyl, Cr(CO)/-, iron pentacarbonyl f Fe(CO)ijj
and nickel tetracarbonyl>Ni(CO)^; 54 in molybdenum hexacarbonyl,MO(CO)g, ruthenium
pentacarbonyl Ru(CO)c*and 86 in tungsten hexacarbonyl,W(CO)g,and osmium penta-
carbonyljOs(CO) . Similar considerations apply to the complex carbonyls with
several metal atoms or other co-coordinated groups.
The addition of carbon monoxide to metallic elements, as shown in .reaction
(30) for the case of nickel tetracarbonyl, occurs with a large decrease in
volume and the formation is promoted by employing high pressures (750 atms).
.v
Ni(s) + 4CO(g) •*• Ni(CO)4(l) (30)
In the large scale commercial production of iron pentacarbonyl, reduced iron
is heated at 180 to 200 C under 50 to 200 atmospheres of carbon monoxide.
Cobalt, molybdenum and tungsten carbonyls are prepared on a commercial scale
under similar conditions with sulfur as a promoter. These carbonyl compounds
are used in the separation of metallic elements as a source of highly purified
metals^ and in the manufacture of plastics. Nickel carbonyl is as highly poisonous
as phosgene at concentrations comparable (1 ppm) j these toxicity levels are well
below that
2-14
-------
for carbon monoxide, and these compounds should, therefore, be handled with great care.
At elevated temperatures (>2QO C) the gaseous binary metallic carbonyls decompose
into carbon monoxide and deposit a high-purity metallic element. Similarly,
iron and nickel carbonyls in the gas phase or in solution can dissociate readily
at room temperature when irradiated at 366 nm.
Carbon monoxide can penetrate heated iron and escape through the iron flues
of stoves or furnaces that are operated with an insufficient supply of air. At
high pressures carbon monoxide reacts with solid iron and invariably iron penta-
carbonyl is formed in gas cylinders containing compressed carbon monoxide or
gases such as commercial hydrogen that contain carbon monoxide. This impurity
can lead to erroneous results in reaction studies and in other experiments where
cylinder gases are used.^°a
Other complex carbonyl derivatives that are prepared by partial substitu-
tion of metallic carbonyls are: carbonyl halides such as with iron
(Fe[CO]i ha^); amines of the carbonyls and carbonyl halides, such as with
rhenium (Re[CO]~py2, Re[CO]_pyphal); carbonyl hydrides such as iron carbonyl
hydrides (HgFetCO]^ or Fe[C02][CO.H]2) and their metallic derivatives; mixed
carbonyl-nitrosyl compounds such as iron nitrosyl carbonyl (FefCO^tNOjp) and
compounds with only one carbon monoxide group on the central metal such as
potassium nickel cyanocarbonyl. (K2[Ni(CN)3CO]). Mixed carbonyl halides are
easily prepared by Hiebeh's method, that involves heating metallic halides with
carbon monoxide at high pressure.
The aqueous solubility of carbon monoxide is enhanced by the formation of
coordination compounds with metal atoms, e.g., copper (Cu), silver (Ag), gold
(Au) and mercury (Hg). Owing to this property, the gas can be quantitatively
absorbed by the following solutions."
2-15
-------
• Hydrochloric acid, aqueous ammonia or a potassium chloride
solution of cuprous chloride that produces colorless crystals
with the composition CuCl.CO.H20 and the probable structure:
°\ A
Cu Cu
X \ / \
H20 Cl CO
Silver sulfate solution in concentrated (fuming) sulfuric acid.
Dry aurous chloride, forming benzene soluble Cl-Au-«-CO.
Mercuric acetate in methanolj the product is convertible to the
chloride complex by adding KC1:
CHoCOO.Hg KCL Cl.Hg (31)
^ OCH3 — »- "^ OCR
These coordination compounds can be used to estimate carbon monoxide se-
lefrtivetyor to separate it from other gaseous mixtures.
The toxicity of carbon monoxide is due to its strong coordination bond
JT
formed with the iron atom in heme which is 200 times stronger than that for
molecular oxygen. The molecule (C^E^^^OiFe) , is a ferrous ion complex of
protoporphyrin IX which when combined with the protein, glob in, constitutes
hemoglobin. Hemoglobin consists of a tetramer each with a globin chain and
a single heme group, corresponding to 95% by weight globin. The planar,
macro ring structure of heme is shown below.
CH/;H,COOH
2-16
-------
The purple compound carboxy-
hemoglobin formed by absorption of carbon monoxide in blood has a character-
istic visible and near ultraviolet absorption spectrum, which has been used
in the determination of the amount of carbon monoxide uptake in humans and
animals.
Reactions with Atmospheric Constituents and Trace Contaminants. The
efficiencies of gaseous atmospheric reactions capable of oxidizing carbon
29
monoxide to carbon dioxide were reviewed by Bates and Witherspoon in 1952.
• Reactions with Molecular Species. The homogeneous gas phase reaction
with molecular oxygen (02) freaction (32), is far too slow to be signifi-
cant, even in urban atmospheres where carbon monoxide concentrations
2CO + 02 -»• 2C02 + 565 kj/mole (32)
are relatively high (10-100 ppm). Experimental confirmation has been
provided by the observed long-term stability (7 yrs) of carbon monoxide
in either dry or moist mixtures with oxygen (02) when exposed to sun-
97Q
light. /0 Other possible homogeneous reactions with atmospheric con-
stituents and trace contaminants include those with water vapor (H20),
ozone (0-j) and nitrogen dioxide (NO ).
CO + 02 -* C02 + 0 +33.5 kJ/mole (33)
CO + H20 -> C02 + H2 +41.9 kJ/mole (34)
CO + 0 •> C02 + 02 + 423 kJ/mole (35)
CO + N02 -»• C02 + NO + 226 kJ/mole (36)
2-17
-------
The reactions with molecular oxygen (reaction 33), and water
vapor (reaction 34), may occur in the lower atmosphere but are
very slow and have high energy barriers (activation energies) to
the reactions, 213 and 234 kJ/mole, respectively. Also, at ambient
temperatures (25 C) they exhibit very low molecular reaction colli-
sion efficiencies123'149*403 (<10~15). Reactions 35 and 36, with
ozone and nitrogen dioxide also have been shown.to have high activa-
tion energies^0'133'162'321'457 84 and 117 kJ/mole, respectively.
Therefore, the rates of reactions 33 through 36 become significant
only at substantially high temperatures (above 500 C) and consequently
are unimportant under atmospheric conditions and at ambient concen-
trations at altitudes below 100 km. Above this level in the thermo-
95
sphere, molecular kinetic temperatures increase rapidly with altitude7
from 200 K (-73 C) at 100 km to 1403 K (1130 C) at 200 km and, thus,
reaction (33) can become significant. The increased thermodynamic
probability that this reaction take place above 100 km is at least
partially offset by decreasing atmospheric densities (-^3 x 10 atms)-and
lower molecular collision frequencies (<2 x 103 sec"1). At these high
altitudes competing reactions with atmospheric ions and electrons plus the
solar photodissociation of carbon monoxide are possible.
Gas Phase Reactions with Unstable Intermediates. There is a possi-
bility that rapid reactions can occur between carbon monoxide and
certain reactive intermediates, such as atoms or free radicals,
generated by chemical processes in the natural and polluted atmosphere.
For example^ oxygen atoms are produced by the photolyses of nitrogen
dioxide (A<436 nm) and/or ozone (X<1140 nm) in sunlight near the ground,
2-18
-------
and in the upper stratosphere by the solar photodissociation of
molecular oxygen at wavelengths in the range of 246 to 176 nm
(corresponding to the Herzberg and Schumann-Runge absorption bands)•
Note that significant concentrations (ca. 0.02 ppm) of nitrogen dioxide
and ozone are produced and play important roles in photochemical smog
resulting from atmospheric chemical transformation in automobile
exhaust products.
The probability of reaction between carbon monoxide and atmospheric atomic
oxygen has been discussed by Leighton. Estimates of the rate of reaction
3 i +
(37), in which oxygen atoms, 0( p) and carbon monoxide molecules, COQif-Z^) - both
o
in their electronic ground state and accompanied by a chaperone molecule M
(to remove the excess energy), react to form carbon dioxide, C02(X £• )
electronic ground state show that this spin-forbidden process is insignificant
o l + i +
0(JP) + CO(X EO + M + CO^X1! ) + M + 532 kj/mole (37)
8 g
in air. The predominance of molecular oxygen in the atmosphere and the spin-
conservation rules (which govern the probability of reaction between species
in different spin states) favor instead the formation of ozone by reaction
(38), involving reaction of the electronic ground states of atomic oxygen,
o 3
0( p) and molecular oxygen, 02( £•*). in the presence of a chaperone molecule,
M.
0(3P) + 02(3£r) + M -»• 03(1A) + M (38)
The relative efficiencies* of reactions (37) and (38) at ambient temperatures in
*The rate (R) of any elementary reaction is given by the product of the rate
coefficient (k), at the temperature desired, and the concentrations of the
reactantSj in the same units (dimensions) as used in the rate coefficient,
e.g., for the reaction A + B -»• C
R_A+ R_B - RC - k[A][Bj
where R_^ and R_B refer to the rates of removal of A and B, respectively,
and Rg refers to the rates of formation of C.
2-19
-------
air are given by the ratio of the rates (Ro7, ROD) of reactions (37) and (38),
respectively. Thus, where ko-, and k~0 are the rate coefficients of reaction for
J / JO
*„ k [CO] _6
37.37 = u x 1Q °
reactions (37 and (38) respectively, [CO] = 10 ppm, [02J = 21%. Reaction (37)
is fundamentally important at high temperatures in the combustion (flames and
explosions) of carbonaceous materials and in the photochemistry of planetary
atmospheres.
The kinetics and mechanisms of the reactions of oxygen atoms with carbon
monoxide are reviewed and discussed in considerable detail elsewhere.28,89,160a,2.
Although there have been many studies of this reaction at room temperature and
at the very high temperatures (2300-3600 K) in shock tubes, there still are
large unresolved discrepancies in the reported kinetic measurements. The rate
-7 -5 -9 -1
coefficients at room temperature range from 1.8 x 10 to <5 x 10 ppm min
and activation energies vary from -24 kcal/mole to +4.5 kcal/mole. Some studies
*
found the reaction rate was second order dependent on reactant concentrations,but
order dependence,
others showed a third/ suggesting a termolecular process involving chaperone
molecules (M). Additional studies are required to resolve these difficulties.
The discrepancies may be due in part to: reaction conditions, wall effects,
hydrogenous impurities generating hydroxyl radicals which react rapidly with
carbon monoxide, or iron carbonyl impurities in the carbon monoxide used.
Simonaitis and Heicklen ^"^ have made a recent study of this reaction
employing mercury photosensitization of nitrous oxide and competition for the
oxygen atoms produced by carbon monoxide and 2-trifluoromethylpropene. They
suggested the reaction proceeds via intermediate electronically excited states
2-20
-------
of carbon monoxide, and proposed a mechanism to explain their observation that
the reaction rate was intermediate between second and third order in reactants.
0(3P) + CO + M 2 CO (3B ) + M (39)
C02(3B2) *- CO^Bj) (40)
COj^Bj) + M t CO (1Eg) + M (41)
The reaction was found to be pressure dependent approaching second order
kinetics as the temperature was increased at any pressure. They derived ex-
pressions for limiting low and high pressure rate constants, k and k, re-
spectively; kQ = 5.9 x 109exp[-ItlOO/RT]M~2 sec" (with nitrous oxides as the
chaperone molecule, M) and k = 1.6 x 107exp(-2900/RT) M"1 sec" where kQ = k^-
and k = koQk/n/k ^o (kon and k. are the rate constants for the forward reac-
oo 3? 40 J» 39 40
tions in equations (39) and (40) and k._39 is that for the reverse reaction in
—7 ") _1
equation (39). These values corrrespond to kQ = 5.7 x 10 ppm min"1
and k = 2.9 x 10 ppm min
at ambient temperatures (25 C).
The bimolecular reactions (42) and (43) also have been studied.
C02 + 0(3P) -»• CO + hv (42)
CO + 0(3P) •* C02 (43)
The rate constants evaluated for reactions (42) and (43) are:
k42 = 8.3 x 102exp(-2590/RT) IT1 sec"1 = 2.5 x 10~5 ppm"1 min"1 at 25 C
and
k43 = 1.8 x 107exp(-2530/RT) tT1 sec"1 = 6.1 x 10"1 ppm-1 min"1 at 25 C
Note the similarity between k,~ and k^ in the previous processes (reaction 39 to 41),
2-21
-------
The reaction of carbon monoxide with electronically excited oxygen atoms,
O(-'-D), is permitted by the spin conservation rules and reactions (44) and (45)
would therefore be expected to be considerably faster than the corresponding
o 77 7fi
reactions with the ground state atoms, 0(JP). Clerc and Barat, ">'° using the
COCX^"1") = 0(1D) + M -> CO-CX^*) + M + 720 kJ/mole (44)
g 2 g
CO + 0(XD) ->- C02 (45)
_2
far ultraviolet flash photolysis of carbon dioxide,estimate that k// = 1 ppm
min~ and k^ = 1+0.5 x 10^ ppm min~* at about 300 K. However, the ambient
concentrations of the excited Specie, 0( D), in the lower natural or polluted
3
atmosphere are considerably less than those of the species, 0( P), owing to
a less efficient source of the former species (0 solar photolysis at X<310 nm),
and to efficient removal of 0( D) by processes involving collisional deexcitation wi
molecules of oxygen, nitrogen, water, and argon in air, and by chemical reaction
3 1
with molecular oxygen and water vapor. Oxygen atoms, 0( P) and 0( D), are pro-
duced more efficiently at higher altitudes and it is therefore probable that
atomic oxygen can oxidize carbon monoxide at altitudes in the regions of the upper
stratosphere and in the mesosphere where carbon dioxide itself can be photolysed.
In urban air and the lower stratosphere, the reaction with atomic oxygen is
insignificant, as are the reactions of carbon monoxide with atomic hydrogen and
organic free radicals because of the strong affinity of these transient species
for atmospheric oxygen.
Hydroxyl radicals (OH)are generated by several recognized processes in the
atmosphere, particularly in heavily polluted air resulting from automobile ex-
hausts. These include: the solar photolysis of nitrous acid vapor (HONO) at
X<400 nm, reaction of electronically excited oxygen atoms, 0( D), with water
2-22
-------
vapor by reaction (46); abstraction of hydrogen from hydrocarbons by ground
O^D) + H 0 -» 20H + 117 kJ/mole (46)
state atomic oxygen, 0( P), as in reaction (47); and indirectly by the solar
RH + 0(3P) -* R. + .OH + (59-84) kJ/mole (47)
photolysis of aldehydes (A<350 nm) followed by the reactions of the product
species with atmospheric constituents and trace contaminants, oxygen and
nitric oxide, as shown by the sequence of reactions (48 through 51).
RCHO h£ R.+ .CHO (48)
.CHO -»• .H + CO - 100 kJ/mole (49)
H.+ 02 + M •»• H02-+ M + 197 kJ/mole (50)
HO . + NO -»• N02 +.OH + 38 kJ/mole (51)
Photolysis of aldehyde (reaction 49) is not a significant source of
atmospheric carbon monoxide compared to its production by the internal combus-
tion of gasoline-air mixtures in the automobile. In polluted atmospheres, the
solar photolyses of aldehydes, which are partially oxidized hydrocarbons, by
reaction (48) and specifically that of formaldehyde by reaction (52), are im-
portant sources of transient reactive intermediates such as hydrogen atoms (H),
hv
HCHO *.H +.CHO (52)
hydrocarbon radicals (R, RO, R02, RC-0), hydroperoxyl (H02) and hydroxyl (OH)
radicals. The hydroxyl radical reacts rapidly with carbon monoxide at both
109 152
ambient and sub-ambient temperatures forming carbon dioxide and atomic hydrogen. '
OH + CO -»• CO, + .H + 105 kJ/mole (53)
2
2-23
-------
28
From an evaluation of reported rate constants, the most reliable kinetic
expression for reaction (53) is k53 = 5.6 x 108exp(-1080/RT) M"1 sec~l.
Thus, large rate coefficients at ambient and sub-ambient temperatures may
be derivedji.e., kco - 2.2 x 10^ ppm"1 min"* at 300 K, because of the low
activation energy (4.5 kJ/mole) of this reaction. This fast reaction between the
hydroxyl radical and carbon monoxide is believed to be important in polluted
atmospheres as well as in the upper atmosphere, where hydroxyl radicals are
produced in quantity through reaction (46). In polluted atmospheres, however,
trace contaminants such as hydrocarbons (particularly olefins), sulfur oxides
and nitrogen oxides can compete successfully for available hydroxyl radicals
and thus reduce significantly the probability for reaction with carbon monoxide.
It has been suggested that the rapid conversion (half-lifesl hr) of
nitric oxide to nitrogen dioxide in photochemical smog can be explained by
the cyclic chain of reactions (50), (51) and (53). In this sequence, hydroxyl
radicals consumed by reaction (53) are subsequently regenerated from the hydrogen
atoms produced in reaction (53) through the consecutive steps, of reactions
(50) and (51). In this way repeated cycles regenerate and maintain ambient
hydroxyl concentrations while simultaneously converting carbon monoxide and
nitric oxide to carbon dioxide and nitrogen dioxide, respectively. The rate
of conversion of nitric oxide to nitrogen dioxide would not be greatly affected
by variations in ambient carbon monoxide concentrations if the carbon monoxide
concentrations were always much higher than the nitric oxide concentra-
tion. This condition is usually met in urban pollution and elsewhere, when the
carbon monoxide concentrations exceed those of nitric oxide by at least two
orders of magnitude. The ambient carbon monoxide concentrations would be
affected very slightly (<1%) and immeasurably by involvement in these processes
2-24
-------
since that amount reacted would be less than the inherent error in standard
monitoring systems, such as nondispersive infrared spectrophotometry.
Reaction (53) is a chemical sink for carbon monoxide in the stratosphere.
Despite the low temperatures near the tropopause (213 K or -60 C), the high
rate of this reaction explains the relatively rapid decrease in the mixing ratio
of carbon monoxide above the tropopause (11 km at mid latitudes). Estimates
of the atmospheric concentrations of hydroxyl radicals required to react with
carbon monoxide by reaction (53) have been made.*226'228 Until recently concen-
—7 —8
trations for these chemical species in the range of 10-10 ppm were below
the limits of detection by the available methods. In 1976, it was reported
that hydroxyl radical concentrations were measured in the upper stratosphere
ranging from 4.5 x 106 c.m at 30 km to 2.8 x 107 c;m~3 at 43 km, by a molecular
resonance fluorescence emission detection instrument. Before mechanisms
such as those cited above can be postulated with any degree of certainty,
the concentrations of these and other reactive intermediates (atoms and free
radicals), such as hydroperoxyl (H02) and nitrate (NO-) have to be determined in
situ in ambient urban atmospheres. Some progress is being made at the present time
oo
in developing techniques and instrumentation for this purpose, but we are
still a long way from being able to measure reproducibly and accurately all
important reactants and products of either photochemical or other types of
pollutants in urban environments. The formidable task of performing similar
measurements at much lower concentrations to determine the background concen-
tration of the relatively clean, natural atmosphere appears, to be impracticable
at this time.
G. J. Doyle, Stanford Research Institute, Menlo Park, California. Unpublished
data. 1968.
2-25
-------
Westenberg and deHaas^° used electron spin resonance detection in a dis-
charge flow system to investigate in the laboratory the competition between
carbon monoxide and hydrogen atoms for hydroperoxyl radicals, by reactions (54)
and (55), respectively.
CO + H02* -> CO + -OH + 264 kJ/mole (54)
•H + H02' -»• 2-OH + 159 kJ/mole (55)
From analysis of their data, they claimed that reaction (54) involving oxida-
tion of carbon monoxide by the hydroperoxyl radical could be faster than oxi-
dation by the hydroxyl radical, reaction (53). Gorse and Volmany*6 on the
other hand, us?d the static photolysis of hydrogen peroxide in the presence
to
of carbon monoxide estimate that the room temperature rate coefficient for
N
reaction (54) is at least ten orders of magnitude less than predicted by
Westenberg and deHaas. This large discrepancy must be resolved before it
can be stated with confidence that a significant reaction exists between
carbon monoxide and hydroxyl, which can effectively compete with the conver-
*
sion of nitric oxide to nitrogen dioxide,**^7 as shown in reaction (51).
There is some evidence that halogen atoms, from the photolysis of fluorine,
chlorine and bromine, may catalyze the oxidation of carbon monoxide^&3'^
in oxygen at ambient temperatures (25 C). At this time, the extent to which
these reactions would be of importance in the atmosphere is uncertain.
Participating halogenated species are produced and exist in the marine
atmosphere as well as in the upper atmosphere, where they are produced by
the decomposition of halocarbon aerosol propellants and refrigerants as well
as natural materials, such as methyl chloride.
2-26
-------
• Chemical Modelling of Carbon Monoxide Reactions. In the previous
section, in which reactions of carbon monoxide were discussed, the
processes described were isolated and studied by suitably selecting
and controlling experimental conditions in order to determine the
kinetic characteristics of the reaction system. In the atmosphere,
however, the situation is complicated by the enormous variety of
competing and consecutive processes and interactions that occur.
As a result, simple assumptions cannot provide a reliable picture
of the transformations occurring; nor can the influence be reliably
assessed of the effects of variations in one contaminant on the rates
of conversion and levels of concentration achieved by the other con-
taminants. In order to assess the influence of varying one or more
parameters in the atmospheric reaction system it has been necessary
to develop theoretical mathematical models that incorporate the
most recent kinetic information on all the significant reactions.
Mathematical models have come to prominence with the advent of high
speed and large capacity computers, which make handling masses of
data efficient and manageable. The initial efforts to develop reliable
the analysis of data obtained by
and realistic models have been in/smog chamber/ simulating synthetic
photochemical pollution reactions at near ambient concentrations of
reactants. As these models are tested and refined, it should be
possible eventually to achieve a reliable predictive model combining
chemistry, physics and meteorology which can be used to assess
the design and impact of various pollution control strategies.
Present models, however, are generally capable of describing reactions
only in simple mixtures under carefully controlled conditions and are
2-27
-------
of limited atmospheric application due to the sensitivity to chemical
input rather than because of the model design. These models make their
greatest contributions by the identification of the limitations of
smog chamber experiments and by indicating the lack of knowledge about
many of the elementary chemical processes involved.
Theoretical considerations suggest that carbon monoxide as well as
hydrocarbons can be involved in the conversion of nitric oxide to nitrogen
dioxide in polluted atmospheres where reactions (50), (51), and (53) can be
represented by reaction (56):
CO + NO + 02 -»• C02 + N02 (56)
Modelling computations indicate that carbon monoxide may play a role
in ozone production. •** Ozone concentrations were determined to be 50% higher
in the presence of 100 ppm carbon monoxide than calculated for the same
hydrocarbon-nitrogen-oxide-air mixture with no carbon monoxide present. This
suggests that substantial reductions in carbon monoxide emissions could reduce
137
ozone production in photochemical smog, but this has been questioned at least for
•v
carbon monoxide concentrations <35 ppm. Also, because these simulations were
performed using a single hydrocarbon reactant, isobutylene, in a controlled
environment, this conclusion cannot be extrapolated with certainty to the
complex blend of organic compounds found in automobile exhausts and the
conditions existing in urban atmospheres.
Calvert et al. have developed a model to simulate a simple analogue
of the sunlight-irradiated auto-exhaust polluted atmosphere. They concluded
that although reactions (50), (51) and (53) constitute a major regeneration
step for hydroperoxyl radicals in the chain oxidation of nitrogen dioxide,
2-28
-------
it is by no means the main source of hydroxyl to hydroperoxyl conversion in
their model. They suggest that reaction of alkoxy radicals with oxygen pro-
vides a more efficient source. In a computer simulation study of the effect
58
of carbon monoxide on the chemistry of photochemical smog the same authors^0
conclude that the presence of small levels of carbon monoxide in a nitric
oxide-containing atmosphere can enhance the photooxidation of nitric oxide
to nitrogen dioxide ultimately forming significant amounts of ozone. Never-
the less, there are still many discrepancies between the effect predicted by
chemical mathematical simulation models and the results from experimental
analyses of reacting mixtures in smog chambers. These discrepancies will be
resolved as our knowledge about these elementary chemical processes increases,
the analytical techniques improve, and as the models are subjected to more
rigorous testing and refinement.
In the last few years several photochemical models of the natural tropo-
sphere have been developed^!»185,226,227,228,422 Using plausible reaction
22fi 99R
schemes,,Levy * has demonstrated that radical reactions are important in
this region of the atmosphere. He has shown specifically that hydroxyl radicals
achieve significant concentrations in the sunlit atmosphere and that their
subsequent reactions with trace gaseous constituents, including carbon monoxide,
could be important. The hydroxyl radical is essentially unreactive with the
major atmospheric components, nitrogen, oxygen, argon and carbon dioxide »this
accounts for the apparent preference for reactions with minor constituents.
McConnell et al. , using a model, similar to that of Levy, estimated that
at noon time the hjcdboxyljcoricentration in '
—8
the lower legions of the troposphere was 8 x 10 ppm- with a daily average
of about 2 x 10~8 ppm. The latter value decreases with increasing altitude to
about 1/3 this concentration in the vicinity of the tropopause.
2-29
-------
226 2?R
According to Levy, » ° the major source of hydroxyl radicals in the
lower troposphere is the reaction of electronically excited oxygen, 0(^0),
with water vapor, shown in reaction (46). The oxygen specif 0( D), is
produced by the efficient solar photolysis of ozone at the long wavelength
at the end of the Hartley absorption band (X=290-350nm). Although most of
1 o
the excited oxygen, 0(^0), atoms are converted to the ground state, 0( P),
by collisions with atmospheric nitrogen and oxygen molecules, a few percent
still are available to react with water vapor. The concentrations of
hydroxyl radicals are maintained by the processes discussed previously
(reactions 46, 47 and 50). An important consequence of .these observations
is that hydroxyl radicals react rapidly with methane (CH ),102,185,228,259
as well as with carbon monoxide, and at a sufficiently high rate which provides
the most significant natural source of carbon monoxide identified thus far.
The primary step in the initiation of atmospheric oxidation of methane involves
hydrogen abstraction by the hydroxyl radical, by reaction (57).
CH + OH -»• CH3 + H20 + 71 kJ/mole (57)
The rate coefficient determined for reaction (57) is kc^ = 12 ppm~l min~l
at 25 C. In conjunction with a methane concentration of 1.4 ppm and the
average hydroxyl concentration given previously, we find the upper limit for
carbon monoxide production, R = 3.4 x 10~' ppm min~ , assuming that all CH*
C#O "
molecules reacted are converted to carbon monoxide. To produce carbon monoxide,
reaction (57) is followed by reaction of the methyl radicals (CH,) produced
with molecular oxygen to produce formaldehyde (CHJD) by reactions (58) and (59a)
and formyl radicals (CHO) by reaction (59b). -The solar photolysis of formaldety
2-30
-------
(M)
CH3 + °2 * CH3°2
CH 02. + CH20 +.OH (59a)
CH302. -> .CHO + H20 (59b)
CH20 +v R2 + CO (60a)
hv
CH0 -»• .H+.CHO (60b)
produced by reaction (59a) is an important natural source of carbon monoxide
by reaction (60a) and of hydrogen atoms and formyl radicals by reaction (60b) .
Formaldehyde is a reactive and photo chemically unstable intermediate which
may, efficiently produce carbon monoxide in the absence of oxygen. Several
authors102 .228,259,428 have estimated that the oxidation of biologically pro-
duced methane leads to a global production rate of carbon monoxide at least
ten times greater than that obtained from anthropogenic sources. Recently,
422
however, Warneck has proposed that Levy's model should be modified to take
into account the possible scavenging of hydroperoxyl radicals (an intermediate
in the hydroxyl recycling process) by atmospheric aerosols.
Numerous photochemical models also have been used to describe stratospheric
processes. These models use sets of sequential reactions similar to those' used
to describe photochemical smog but with appropriate modifications for different
temperatures, pressures, concentrations and solar spectral intensity distributions.
In the stratosphere the dominant scavenging process for removal of carbon
monoxide is the reaction with the hydroxyl radical.
2-31
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CHAPTER 3
SOURCES, OCCURRENCE, AND FATE OF ATMOSPHERIC CARBON MONOXIDE
Carbon monoxide is released into the atmosphere from both natural and
102 228 259 428
anthropogenic sources. Recent theoretical estimates ' ' ' suggest
that on a global basis natural sources contribute at least ten times more
carbon monoxide than manmade sources to the total atmospheric burden. The
228 259
most important natural source that has been suggested ' is that result-
ing from the oxidation of atmospheric methane with lesser contributions from
forest fires, terpene oxidation, and the oceans. The incomplete combustion of
fossil fuels is the principal anthropogenic source of carbon monoxide. At the
present time, carbonaceous fuels are widely used, primarily in transportation
and to a lesser extent in space heating and industrial processing. In con-
trast to natural sources, which are globally widespread, anthropogenic sources
are mainly located in urban and metropolitan areas and concentrated in the
Northern Hemisphere. The influence of naturally produced carbon monoxide on
185
the carbon monoxide concentration in urban air is believed to be negligible,
but recent discoveries indicate that it could be important in determining
the "background" concentrations of carbon monoxide and the mean residence
time (atmospheric lifetime) in the terrestrial atmosphere.
Anthropogenic carbon monoxide production is directly related to man's
technological growth and productivity, as well as to his economic and social
well-being. It is well within our present technologic capability to reduce
the emission of this pollutant, and maintain it at a low level without economic
hardship, despite its being an unwelcome by-product accompanying national
economic growth along with increasing energy requirements. There
3-1
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appears to be no simple panacea, however, for controlling pollutant emissions,
as shown by the new pollution problems that appear when specific controls are
implemented. Much more attention and research have to be devoted in the future
to the indirect as well as the obvious consequences of applying control tech-
niques to both stationary and mobile sources.
It is estimated that the total anthropogenic emission of carbon monoxide
exceeds that of all other man-made pollutants combined. This fact, coupled
with the purported excessive natural emission of carbon monoxide and its long
lifetime (residence time) owing to its stability and apparent lack of chemical
and biologic reactivity, supports the conclusion that carbon monoxide is the
*
most abundant and most commonly occurring of all the atmospheric pollutants
and minor constituents.
Sources of Carbon Monoxide
OQQ A f)£
Contrary to what has been believed ' it is now considered possible that
atmospheric carbon monoxide could be principally of natural origin.228,259
This gas was first discovered as a trace constituent of the terrestrial
atmosphere by Migeotte^?? in 1949. In a study of the solar spectrum, he
attributed specific absorption lines to ambient carbon monoxide originating
*Although carbon dioxide (CC^) is produced and released to the atmosphere
in much greater quantities than carbon monoxide, it is not usually classi-
fied or defined as an air pollutant. Little can be done at this time to
control carbon dioxide emissions despite a regularly observed and signifi-
cant (0.7-1.0 ppur/yr) annual increase in the already large concentrations
of global ambient carbon dioxide ( 330 ppm ) or the associated global cli-
matic implications should the annual-increase trend continue, This gas is a
natural end-product of all combustion processes involving carbonaceous ma-
terials. Thus, not until it is economically and practically feasible to replace
conventional fossil-fuel burning energy sources with non-combustive systems
such as nuclear, solar or geothermal power and provide non-carbonaceous fuels
for transportation will it be possible to markedly reduce carbon dioxide emissii
3-2
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at a wavelength of about 4.7 micrometers (ym) in the infrared region. Similar
observations ' » ' were made during the next decade in the United
States, Canada and Europe which demonstrated that carbon monoxide concentration
levels average about 0.1 mg/m3 (0.1 ppm) in clean air. From these early in-
vestigations, it was concluded by Junge^2 in 1953 that background atmospheric
carbon monoxide concentrations were highly variable and erratic in nature but
generally ranged in concentration from 0.01 to 0.2 ppm.
In 1968, Robinson and Robbins340 estimated that about 2.8 x 108™fonsC
(2.8 x 1011 kg) of carbon monoxide were discharged into the atmosphere
worldwide from anthropogenic sources during the year of 1966. Somewhat more
than half of the / 1.5 x lO^jJtons (l.5 x 10*1 kg) was estimated to be generated
in the continental United States. Transportation is by far the largest single
man-made source of carbon monoxide in this country, accounting for more than
two-thirds of the emissions from all anthropogenic sources in the 1960's.
It has been estimated that the total U.S. emissions of carbon monoxide showed
almost a two-fold increase during the period 1940 through 1968. This dramatic
increase was due almost exclusively to the increasing use of the motor vehicle
during that period. After 1968 there was an initial decline of about 10% in
the carbon monoxide emission followed by a levelling off in mobile source
emission inventories owing to the required installation of emission control
devices in new vehicles. In 1974, there were about 125 million vehicles
registered in the United States,405 which produced annually about 1 x 108™fonsc
(1 x 10 kg) of carbon monoxide.
The magnitude of the problem in controlling internal combustion engine
emissions may be seen from the fact that approximately 3 lb (1.4 kg ) of
3-3
-------
carbon monoxide, along with other pollutants is produced in the combustion
of 1 U.S. gal (3.8 liter) of gasoline. Assuming an average density for gasoline
3
(octane, C0H.0) of 0.7 g/cm , then, on the basis of mass, approximately
o lo
25% of the carbon in gasoline is converted to carbon monoxide in the internal
combustion engine. This corresponds to an oxidation efficiency of 92%, assuming
carbon dioxide and water are the only other products. If the average auto-
mobile (without emission control equipment) travels 15 miles (24 km) per
gallon of fuel consumed, then about 0.2 Ib ( 91 g) of carbon monoxide per
mile (52 g/km) would be released into the surrounding atmosphere, which was
one-
the situation prior to 1968. This average emission is two and/half times greater
than the 1970-1971 automobile emission standard set for carbon monoxide (34 g/miL
20 g/km) but more significantly it is 25 times larger than the pro-
posed standard for 1975-1976 model automobiles (3.4 g/mile, 2.0 g/km), as
prescribed by the 1970 Clean Air Amendments. It should be pointed out here
that the required installation of catalytic converters in 1975 model auto-
mobile exhaust systems in conjunction with the use of unleaded gasoline has
greatly reduced carbon monoxide emissions; but the reduced emissions of
criteria pollutants were achieved at the expense of generating potentially
harmful sulfuric acid aerosol. Apparently there is no simple solution to
the problems of automobile emission control.
Technological Sources. Until recently, anthropogenic sources producing
large quantities of carbon monoxide were considered to be primarily responsi-
bile for the observed ' global concentrations. Although carbon monoxide
produced in urban areas by man's activities far surpasses natural contributions,
it now appears that anthropogenic emissions only approximate natural contribution
3-4
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in the Northern Ifemisphere and on a global scale man's activities contribute
only about 10% to the total worldwide production. Estimates ' of global
tonnages of carbon monoxide produced by anthropogenic sources show a marked
increase in annual emissions which correlates with the worldwide increase
I Qg
in the consumption of fossil fuels. A comparison of a recent estimate of
global carbon monoxide emissions from man-made sources with an earlier esti-
mate^O shows that annual worldwide anthropogenic carbon monoxide emissions
186
have increased by 28% during the period 1966-1970. Jaffe has estimated
that in 1970 the global carbon monoxide emissions from combustion sources
8 11
were about 359 million metric tons (4.0 x 10 short tons or 3.6 x 10 kg).
This estimate is based on an analysis of worldwide fossil fuel usage,
agricultral practice, mining activities and waste disposal in conjunction
with recently revised (1972) carbon monoxide emission factors for various
sources. Table 3-1 gives the estimated worldwide contributions from major
sources plus the corresponding fuel consumption figures. These data show
that as in previous estimates, the internal combustion engine in motor
vehicles still represents the largest single source of carbon monoxide; providing
55% of all anthropogenic emissions. The second most important anthropogenic
sources and industrial processes and certain miscellaneous activities in the
stationery source category, which together contribute almost 257, of the total.
In 1970 the U.S. contribution was 37% of total global production.
During the period 1940-1968, there has been a dramatic increase in carbon
monoxide emissions in the United States due almost exclusively to the increased
use of automobiles. Since 1968, automobile emissions-have leveled off through
1970 and declined from 1970 - 1975 because of the installation of emission
control devices. Trends in the emissions from major sources for the period
3-5
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TABLE 3-1
Estimated Global Anthropogenic Carbon Monoxide Sources for 1970
186
Source
World Fuel
Consumption
10° metric tons/yr
CIO9 kg/yr)
Motor vehicles, gasoline ")
diesel J)
Aircraft (aviation gaso-
line, jet fuel)
Watercraft
Railroads
Other (non-highway) motor
vehicles, construction
equipment, farm tractors,
utility engines, etc.)
Mobile
439
84
World Carbon Monoxide
Emission
10° metric tons/yr
(109 kg/yr)
197
2
5
18
2
26
Coal and lignite;
Residual fuel oil
Kerosene
Distillate fuel oil
Liquefied petroleum gas
Industrial processes
(petroleum refineries,
steel mills, etc.)
. «J.
Solid waste disposal (urban
and industrial)
Miscellaneous (agricultural
burning, coal bank refuse,
structural fires)
Stationary
2983
682
69
411
34
1130
41
23
41
Total anthropogenic carbon monoxide
3-6
359
-------
1940-1975 are shown in Table 3-2. During the 35-year period covered in Table
3-2, transportation in the United States was clearly the dominant contributor
to the total carbon monoxide emissions, as shown by the increasing percentage
from this source, from 41% in 1940 to 77% in 1975. The carbon monoxide emissions
from industrial sources also have been greatly reduced during the period 1940
through 1970, although there has been a rapid industrial expansion during this
period. Agricultural burning and industrial process losses, representing 9.3%
and 7.6%, respectively, of the total carbon monoxide emissions, are two im-
portant sources that remained relatively constant until 1970. A considerable
reduction (77Z) in emissions from stationary sources occurred during the
period from 1940 through 1975, probably owing both to a changeover from solid
fossil fuels to liquid and gaseous fuels and to increased furnace efficiency.
All of the sources listed can be controlled with the exception of those in
the miscellaneous category. These include such essentially uncontrollable
sources as forest fires, structural fires and burning in coal refuse banks.
Table 3-3 gives a more detailed breakdown of emission sources with
estimates of the amounts of carbon monoxide emitted » during calendar
year 1975. These data show that in 1975 the carbon monoxide emissions in
the U.S. from technological sources (all categories except forest fires)
was more than 85 x 106 metric tons (85 x 109 kg, 93 x 10 short tons). The
major source of carbon monoxide in the U.S. in 1975 was the combustion of
9
fossil fuels in vehicles producing about 67 million metric tons (67 x 10 kg,
74 x 10 short tons) annually, with gasoline-burning internal combustion
engines accounting for 65% of the total.
3-7
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TABLE 3-2
Nationwide Estimates of Carbon Monoxide Emissions,
1940-1975
in 106 metric tons*/yr (1Q9 kg/yr)
Source Category 1940 1950 1960 1968 1969 1970 1972 1975
Transportation
Industrial pro-
cess losses
Agricultural
burning
Fuel combustion
in stationary
sources
Solid waste
disposal
Miscellaneous
TOTAL
31.7 50.2 75.7 102.5 101.6 100.6 70.4 66.6
13.1 17.1 16.1
8.3 9.4 11.2
5.6
17.2
5.1
9.1
2.4
1.6 2.4 4.6
5.8
7.7 10.9 10.3 15.8 13.3
12.6 12.5 12.5 1.5
1.8
4.9
1.6 0.7 1.1
7.3 7.2
6.6 4.5
5.7 4.1 4.2
0.8
1.3
3.4
1.6
77.5 93.3 115.8 136.8 139.5 134.8 97.5 87.0
*To convert to U.S. short tons, multiply by 1.1 (1 short-ton = 2000 Ib).
3-8
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TABLE 3-3
Detailed Summary of 1975 Carbon Monoxide Emission Estimates in the United States
Source Category
Fuel combustion in stationary sources
Steam-electric
Industrial
Commercial and institutional
Residential
Total fuel
Transportation
Gasoline vehicles
Diesel vehicles
Total road vehicles
Railroads
Vessels
Aircraft
Other non-highway use
Total transportation
Solid waste disposal
Municipal incineration
On-site incineration
Open burning
Total solid waste
Industrial process losses
Agricultural burning
Total controllable
Miscellaneous
Forest fires
Structural fires
Total miscellaneous
Total all categories
Estimated Carbon Monoxide Emissions
(103 metric tons*/yr 106 kg/yr)
255
468
71
457
1,251
57,226
553
57,779
270
970
778
6,732
66,529
206
1,893
1,307
3,406
13,278
773
85,237
1,640
30
1,670
86,907
Source - U. S. Environmental Protection Agency Data for 1975 National Emissions
Report, National Emissions Data System (NEDS) of the Aerometric and Emissions
Reporting System (AEROS), Research Triangle Park, N.C. U. S. Environmental Pro-
tection Agency, Office of Air and Waste Management. Unpublished, 1976.
"k o
To obtain U.S. short tons, multiply by 1.1 (1 short ton = 2 x 10 Ib).
3-9
-------
At the present time,the remaining sources in order of decreasing contribution are
industrial processes, solid waste combustion, miscellaneous fires and agricultural
burning. Fuel combustion in stationary sources for space heating and power generation
provide less than 2% of the total carbon monoxide emissions and, thus, is of minor
importance. Carbon monoxide is also produced in high concentration by burning
cigarettes, explosions and the firing of weapons, but these point sources are
insignificant in terms of total annual production.
Natural Sources. Prior to the 1970's, the known natural sources of carbon
monoxide were considered to be of minor importance in comparison with technologi-
cal sources, and the principal natural source was thought to be forest fires
resulting from natural causes, such as lightning.340 Other natural emission
sources identified were volcanic activity, natural gases from marshes and coal
mines*2^ and electrical storms.^40 Secondary sources of natural origin included
photochemical degradation of naturally occurring organic compounds, such as
4 5 224
aldehydes, which are alsp involved in photochemical smog formation, * * and the
>
solar photodissociation of carbon dioxide which becomes feasible in the upper
29
atmosphere at altitudes above 70 km.
In the last few years, several potentially large natural sources of geo-
physical or biological origin have been identified. Estimates of the magnitude
of these sources range from 3 to 25 times that of anthropogenic sources, de-
pending upon the data base selected for comparison.
OT C
In 1972, Stevens et^ al. ' reported a comprehensive study made of the
isotopic composition of atmospheric carbon monoxide at numerous locations
at different times of year, which included a comparison with the carbon
monoxide originating from automobile exhausts and from selected natural
3-10
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sources. They found five major iso topic types of carbon monoxide, two con-
taining light oxygen (^O enriched) and three containing heavy oxygen
(*80 enriched). The light oxygen varieties^ which were present throughout
the year, were a predominant fraction of atmospheric carbon monoxide, with
constant concentrations of 0.10-0.15 ppm. The heavy oxygen species were
minor constituents whose production was apparently seasonal. On the basis
that the light oxygen species originate in the atmosphere rather than the
biosphere, they estimated an atmospheric production rate in the Northern
9 19
Hemisphere of more than 3 x 10 metric tons (3 x 10iz kg) . From Robinson
and Moser's*2 estimate that 95% of the global anthropogenic carbon monoxide
emissions originate in the Northern Hemisphere and the total global man-made
carbon monoxide emitted in 1970 given in Table 3-1, the man-made emissions
in the Northern Hemisphere in 1970 are calculated to be about 3.4 x 10**
metric tons, which is ten times lower than the estimate from the isotopic
studies .
an(j formaldehyde^^ have been suggested also as natural
259
atmospheric sources of carbon monoxide. McConnell et^ al . have estimated
that atmospheric oxidation of biologically produced methane can provide a
global source of about 2500 million metric tons (2.5 x 10*2 kg) annually.
This is ten times greater than the previously reported worldwide anthro-
pogenic emission rates and 7 times larger than the estimates for 1970 given
in Table 3-1. In 1972, Weinstock and Niki^2° derived a carbon monoxide produc-
tion rate via methane oxidation based on calculations of hydroxyl radical
concentrations in tropospheric air. They concluded that this mechanism could
provide a source strength about 25 times greater than man-made sources.
3-11
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In some regions, the oceans appear to be a significant source of carbon
monoxide. Independent studies3-^, 388 Q^ Atlantic Ocean surface waters have
shown that the surface layers are supersaturated with carbon monoxide ranging
from about 10 to 40 times the equilibrium water-air ratio. Similar conclusions
have been drawn from subsequent marine air-water interface studies in the
Atlantic221'387'444 and South Pacific Oceans.385 In 1971, Junge, Seiler and
Warneckl94 calculated that the oceans may contribute the equivalent of about
0.3% of the total anthropogenic carbon monoxide production. More recently,
Linnenbom, Swinnerton and Lamontagne241 have revised their previous estimates
of the oceanic carbon monoxide production to a Northern Hemisphere flux of
9 x 10' metric tons per year or about 25% of the man-made output in 1970.
In 1974, Liss and Slater242 developed a mathematical model describing the flux
of various gases across the air-sea interface. Taking a mean atmospheric
carbon monoxide concentration of 0.13 ppm221 and a surface water concentra-
tion of 6 x 10~° cm3 C0/cm%20 in their model, they estimate a total oceanic
flux of 4.3 x 10' metric .tons (4.3 x 10^0 kg) carbon monoxide per year. All
of these recent estimates suggest that the oceans are a source rather than,
as previously thought, a sink for atmospheric carbon monoxide. Biological
organisms including marine algae, siphonophores and microorganisms apparently
are responsible for the large quantities of carbon monoxide in the surface
layers of the oceans.
In 1960, Went434 proposed that atmospheric photochemical reactions in-
volving naturally produced terpene hydrocarbons could be an important source
of atmospheric trace constituents. Revised estimates of natural terpene
production*-" were used by Robinson and Moser338 to calculate that approximately
3-12
-------
54 x 106 metric tons (5.4 x 1010 kg) of carbon monoxide are produced annually
by atmospheric photochemical oxidation. An identical figure (5.4 x 1010 kg/yr)
for carbon monoxide generation from the degradation of chlorophyll was arrived
at by Crespi, e_t _al.100a This source strength was used by these investigators
together with an estimate of production by the bilin biosynthesis, which takes
place in blue-green algae, to show that plants could produce a total of 90
million metric tons (9 x !Cr° kg) of carbon monoxide per year on a global
scale.
Charged particle deposition mechanisms and atmospheric electrical dis-
charge phenomena, including lightning in the troposphere, have been investi-
gated* ^ as potential sources of atmospheric carbon monoxide. However, these
sources appear to be small compared with anthropogenic sources.
Total global emissions of carbon monoxide can be estimated from anthro-
pogenic and natural sources given in Table 3-1 and from the data presented
above. Annual production rates for the major sources are given in Table 3-4.
I O
These estimates show that approximately 3.2 billion metric tons (3.2 x 10 kg)
of carbon monoxide can be released annually into the atmosphere by all processes,
Occurrence of Carbon Monoxide
Community Atmospheres. Carbon monoxide concentrations in metropolitan
areas vary considerably both temporally and spatially. Analysis of aerometric
data collected at continuous air monitoring program (CAMP) stations in selected
cities has revealed distinct temporal patterns in ambient carbon monoxide levels
Diurnal, weekly and seasonal trends have been observed which correlate with
traffic volume, vehicle speed and meteorological conditions.
3-13
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TABLE 3-4
Estimated Carbon Monoxide Production Rates from
Natural and Anthropogenic Sources, 1970
CO Emission rate
Source 10^ metric tons/yr (10* kg/yr) Reference
Anthropogenic
Methane oxidation
Forest fires
359
2,500
10
186
259
340
Terpene oxidation 54 338
Plant synthesis and
degradation 90 186
Oceans 220 241
Total, all carbon
monoxide sources 3,233
3-14
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There is a great variation in the carbon monoxide concentrations in
urban metropolitan areas, ranging from 1 to more than 140 ppm, with the
higher concentrations being observed as brief peaks in dense traffic. As a
result, persons in moving vehicles subject to heavy traffic conditions can
be exposed to carbon monoxide concentrations greater than 50 ppm for sustained
999
periods. Larsen and Burke^" have developed a mathematical model to statisti-
cally analyze and review the extensive aerometric data collected at numerous
sampling locations in many large cities. They estimated that maximum annual
8-hour average carbon monoxide concentrations were approximately 115 ppm
in vehicles in heavy traffic downtown, 75 ppm in vehicles operating on express-
ways or arterial routes, 40 ppm in central commercial and mixed industrial
areas, and about 23 ppm in residential areas. These estimates indicate that
carbon monoxide can achieve levels in heavy traffic on city streets almost
3 times that found in central urban areas and 5 times that found in residential
areas. Mathematical urban diffusion models for carbon monoxide have been
developed at Stanford Research Institute-^04 and elsewhere in order to describe
better the observed spatial and temporal variations of this pollutant.
In special situations, such as in underground garages, tunnels, and
loading platforms, carbon monoxide levels have been found to exceed 100 ppm
for extended periods. To prevent excessive exposure to carbon monoxide,
alarm systems have been installed in newly constructed tunnels which auto-
matically activate auxiliary ventilating units when predetermined undesirable
carbon monoxide levels are reached.
3-15
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Background Levels and Distribution of Carbon Monoxide. Ambient carbon
monoxide concentrations measured in relatively clean air (remote from strong
sources) are quite low but variable. Some of the early measurements of the
infrared solar spectrum absorption by atmospheric carbon monoxide at locations
in Canada,244 Switzerland41.277,278 and in the United States244'359'360 showed
a range of concentrationjfrom 0.03 to 0.22 ppm carbon monoxide, and an average
concentration359 of 0.11 ppm.
Junge^92'!94 reported that background concentrations of carbon monoxide
range from 0.01 to 0.2 ppm. The most extensive measurements of carbon monoxide
background levels at various locations have been made by Robinson, Robbins and
their colleagues. They have found concentrations ranging as low as 0.025 ppm
and up to 0.8 ppm in North Pacific marine air;33" 0.04 to 0.8 ppm carbon
monoxide in non-urban air over California;336 0.06 to 0.26 with an average of
0.09 ppm at Point Barrow, Alaska;64 0.05 to 0.7 with an average of 0.11 ppm
at Inge Lehmann Station in Greenland339 and an average of 0.06 ppm in the Sou then
OOQ
Pacific. Jy They have concluded from these investigations that the observed
variability of carbon monoxide in unpolluted areas is a characteristic of the
•i
air mass in transit and reflects the prior history of the air mass. Background
levels as high as 1.0 ppm are observed when the air mass has recently traversed
densely populated areas. On the basis of data collected on five cruises in the
Pacific Ocean,339 they measured and determined the average background concen-
tration distributed latitudinally over the Pacific. The highest concentrations,
about 0.2 ppm, were found between 30° and 50° N. These were associated with
the high population density at mid-latitudes in the Northern Hemisphere. The
Northern Hemisphere mid-latitude value decreases to about 0.07 ppm in the
Arctic and to 0.09 ppm at the equator. In going south from the equator, the
3-16
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average concentrations fall to a minimum of about 0.04 ppm at 50 S then rise
to about 0.08 ppm in the Antarctic. Based on this work, they suggest average
carbon monoxide concentrations of 0.14 ppm in the Northern Hemisphere, 0.06 ppm
in the Southern Hemisphere and a global average of 0.1 ppm.
Seiler and Junge^55 have measured similar average values over the Northern
(0.18 ppm) and Southern (0.05 ppm) Atlantic Ocean. Generally higher (>30%)
background concentrations have been found over the Atlantic Ocean than over the
Pacific Ocean by several investigators. In general, because of its remoteness
from major polluting sources, the Pacific Ocean may be considered to be more
closely representative of "background" clean air.
The altitude and vertical distributions of atmospheric carbon monoxide
have been reported by Seiler and Junge.339,355 They have found consistent
carbon monoxide concentrations averaging about 0.13 ppm at 10 km altitude in
both the Northern and Southern Hemispheres, in contrast to the large differences
observed near the surface. During polar flights they observed^39 upper
tropospheric concentrations averaging 0.10 ppm, whereas the stratosphere con-
centrations were markedly lower, falling in the range of 0.03 to 0.05 ppm
carbon monoxide. Subsequently, Seiler and Warneck-"" found a decrease in
concentrations from M).15 ppm below the tropopause to ^0.05 ppm above this
357
region of discontinuity. A 1972 investigation of the infrared solar spectrum
made with a balloon-borne spectrometer has shown a gradual decrease in carbon
monoxide concencration with increasing altitude, from ^0.08 ppm at 4 km to
0.04 ppm at 15 km. These observations coupled with those made near the earth's
surface indicate that important contributions to surface carbon monoxide result
from the concentration from Northern Eemisphere industrialization at mid-latitudes
3-17
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Residence times (T = atmospheric mean life) for carbon monoxide in the
atmosphere have been estimated by many investigators using the available data.
An approximate estimate of this temporal turnover parameter can be made using
the global average carbon monoxide concentration to calculate the total amount
in the atmosphere (M ) and the total rate of production from natural and anthro-
oO
pogenic sources (R™) . Thus, TQQ = MQQ/RCQ. Using the global annual production
rate of 3.2 x 10 metric tons, (from Table 3-4) and an average global concen-
tration of 0.1 ppm, corresponding to 580 x 10 metric tons of carbon monoxide
Q
in the atmosphere, then T = 5.8 x 10 ton = Q.18-/yr.
3.2 x 109 ton/yr
sensitive
These rough estimates are /to the variability in and interpretation
of atmospheric concentration measurements and to the current knowledge of source
concentrations. They are however, a useful guide in judging the effectiveness
of natural processes in cleansing the atmosphere of this man-made pollutant
and natural constituent. The early estimates of residence times for atmospheric
carbon monoxide ranged from 2.7 to 5 yrs. 192, 336, 340, 386 However, in 1969,
Weinstock proposed that a residence time could be derived from radiocarbon
data because "hot" carbon-14 (C) nuclei produced from the nitrogen-14 (*N)
(n, p) reaction with cosmic ray neutrons are fixed primarily as carbon monoxide-
C ( ^CO) prior to conversion into carbon dioxide- ^C ( CC^) . From an analysis
of available data on carbon monoxide-^^C (^CO) concentrations in the atmosphere
and estimates of its rate of formation, Weinstock derived a residence time of
0.1 year which is much shorter than the earlier estimates. Such a short atmospherij
mean lifetime suggested that an efficient mechanism for carbon monoxide removal
426
must be operative . and Weinstock proposed reaction with the hydroxyl radical.
In 1971, Levy derived plausible theoretical estimates of tropospheric
3-18
-------
hydroxyl radical concentrations and their reaction with atmospheric carbon
monoxide and calculated a corresponding residence time of 0.2 year. The
reaction of tropospheric hydroxyl radicals with atmospheric methane as the
259
principal natural source of carbon monoxide was used by McConnell et al.
to estimate a residence time of 0.3 year. Subsequently, Weinstock, et al
confirmed their earlier estimate of 0.1 year from an analysis of both radio-
the
active and stable carbon monoxide in/ troposphere. There now is sufficient
evidence to suggest that the residence time of carbon monoxide in the tropo-
sphere is about 0.2 + 0.1 year .
Fate of Atmospheric Carbon Monoxide
On a global basis the average concentration of carbon monoxide in the
atmosphere is about 0.1 ppm (0.12 mg/m^) and it does not appear to have been
increasing substantially in recent time. 336 If efficient natural removal
processes (sinks) were not operative to transform or scavenge this gaseous
atmospheric pollutant, then based on the 1970 estimated total inputs of
carbon monoxide (Table 3-4) , the global average concentration would be in-
creasing by about 0.5 ppm annually. Similarly, using current anthropogenic
production estimates alone . atmospheric carbon monoxide would be expected to
increase at the rate of 0.06 ppm/yr. As this does not appear to be the case,
efficient sinks for carbon monoxide must be present in order to maintain the
present atmospheric concentrations. Several possible natural sinks have been
identified in the upper atmosphere, the biosphere and the chemosphere. These
will be discussed in more detail in the following sections.
3-19
-------
Upper Atmosphere Sink. Carbon monoxide produced at the earth's surface
or in the lower troposphere, could conceivably migrate vertically to the
upper regions of the atmosphere by atmospheric transport, turbulent mixing aand
diffusion. A rapid decrease in carbon monoxide mixing ratio* above the polar
tropopause was first observed by Seller and Junge356 in 1969. They attributed
the reduction in carbon monoxide across the tropopause to the reaction between
carbon monoxide and ambient hydroxyl radicals in the lower stratosphere. In
1970, theoretical estimates of the hydroxyl radical concentrations necessary
to oxidize the flux of carbon monoxide from the troposphere into the strato-
—7
sphere were reported to be 10 ppm . lo:*»J^u Subsequently, flights were
made in the winter of 1970-1971 to measure the gradient of the carbon monoxide
mixing ratio above the tropopause. ' This sink appears to be controlled by
the vertical eddy-type diffusion of carbon monoxide, and accounted for about
13 + 2% of the total annual carbon monoxide based on 1968 estimates. This
sink does not, therefore, appear to be adequate to compensate for carbon
monoxide production at the present time.
Soil as a Sink. Certain microorganisms in the soil> as well as
some terrestrial plant species appear to be the major biological sinks for
carbon monoxide. Soils both produce and absorb carbon monoxide simultaneously,
181
but the net result is they act as a sink. Ingersoll et al. measured soil
-11 9
carbon monoxide uptake rates ranging from 21.1 to 319.4 x 10 g CO/cm /s at
100 ppm carbon monoxide. This study, which was based on investigations in
the field at 59 locations in North America ^0 showed that desert soils took
*The mixing ratio is defined as the fractional volume (mass) of gas in
unit volume (mass) of air under the same conditions of temperature and
pressure.
3-20
-------
up carbon monoxide at the lowest rates and tropical soils at the highest
rates. Agricultural soils had a lower carbon monoxide uptake than un-
cultivated soils presumably because they had less organic matter in the
surface layer. There was also some evidence that soils exposed to higher
carbon monoxide concentrations (such as near a freeway interchange) had a
greater carbon monoxide uptake rate. This was attributed to the development
of a larger or more effective population of carbon monoxide converting micro-
organisms .
Data concerning the effect of temperature on the sink capacity of soils
are limited and contradictory. Ingersoll et^ al. and Seiler agree that
the net uptake rate is drastically reduced as the temperature is increased
from 30 C to 50 C. At temperatures in the range of 10 C to 30 C
181
measured high uptake rates iwhereas Ingersoll ^t al. ° found the maximum
uptake rate to be at 30 C with greatly decreased rates at both 10 C and 20 C.
354
Seiler (1974) calculated the average soil carbon monoxide uptake rate to
be 1.5 x 10"11 g/cm2/sat0.2 ppm carbon monoxide, since the carbon monoxide
concentration used in this study is typical of the concentrations of the gas
found in the Northern Hemisphere, this value appears to be one of the most
reliable estimates of the carbon monoxide uptake rate by soil. The measure-
1 QO . —11 9
ment made by Inman et^ al. of 23.4 x 10 g/cm /s at a carbon monoxide concen-
tration of 100 ppm can not be safely extrapolated to typical ambient concen-
trations because the relationship between carbon monoxide uptake rate and con-
centration is not known over this range. In highly contaminated areas, where
ambient concentrations are particularly high, however, soil carbon monoxide
uptake rates could approach this level. The relationship between uptake rate
and concentration needs to be determined before uptake in the contaminated
areas can be evaluated.
3-21
-------
and Smith et^ al. have shown that production of carbon
monoxide also occurs in soils. It is not clear whether this results from
t
nonbiological processes or from a combination of biological and nonbiological
processes. Apparently the net rate of carbon monoxide removal by soil is
determined by the effects of uptake and production combined. Additional
studies, perhaps using carbon-14 (^C) are needed to clarify this point.
To discover which types of soil microorganisms were most active in
carbon monoxide uptake, Inman and Ingersoll^2 isolated over 200 different
species of fungi, yeast and bacteria from three soil samples. They found
14 species of fungi capable of removing carbon monoxide from an artificial
each
atmosphere. These included four strains .of Penicillium digitatum. Penicillium
each ^
restrieturn; four species.of Aspergillus, Mucor hiemalis; and two strains each
\
of Haplosporangium parvum and Mortierella vesiculata.
Bacteria also have been isolated from soils which utilize carbon
210
monoxide in metabolism or fermentation. Kluyver and Schnellen'iu reported
that under anaerobic conditions the species Methanosarcina barkerii produce
methane utilizing carbon monoxide as the only source of carbon. They presented
evidence that this fermentation proceeds in the following two steps, reactions
(61) and (62):
4 CO + 4 H20 ->• 4 C02 + 4 H2 (61)
C02 + 4 H2 ->• City + 2 H20 (62)
Combining these two equations gives the following net reaction (63):
4 CO + 2 H20 -»• 3 C02 + CHA (63)
3-22
-------
Evidence for the existence of an autotropic aerobic carbon monoxide
323
utilizing bacteria is not conclusive, ' although several isolated species
have been reported to have the capacity to oxidize carbon monoxide to
carbon dioxide. Since many of these organisms also could oxidize hydrogen
or assimilate simple organic compounds^ their true aerobic and autotrophic
nature has been questioned. ^
Vegetation. Some plant species apparently have the ability to remove
carbon monoxide from the atmosphere but the available data are conflicting.
In 1957, Krall and Tolbert^lS exposed excised barley leaves to an artificial
atmosphere containing 60% carbon monoxide- C (CO) and determined the rate
of conversion to serine and other compounds. The conversion at 28 C was
0.038 ymoles/g/h. In 1972, Bidwell and Fraser^ investigated the incorpora-
tion of carbon-14 ( C) from an artificial carbon monoxide atmosphere into
plant carbon compounds (mainly sucrose and serine). The uptake of carbon
monoxide by excised leaves was found in seven out of the nine species studied.
Six species showed a measurable uptake rate at concentrations of 2 ppm or
lower. If we assume that the uptake rate varies linearly with the concentra-
tion in the range 0.2 to 2 ppm, the data for these six species indicate an
n
average uptake rate of 0.003 ymole/dm /h at 0.2 ppm. This would be equivalent
to 0.23 x 10~H g/cm^/s if we assume a leaf area that is 10 times the ground
O C/
surface area. This is 15% of the average value reported by Seller for
soils at this concentration, indicating that soils are probably more important
than plants as a sink for carbon monoxide. In 1973, Kortschak and Nickell^l2
using methods similar to those of Bidwell found the uptake of carbon monoxide
by the leaves of sugar cane to be 1 x 10~^ mg/cm^/h at 2 ppm carbon monoxide.
In contrast, Inman and Ingersoll^-"^ were unable to measure any carbon monoxide
3-23
-------
removal from an artificial atmosphere of 100 ppm by any of the 15 species
of higher plants they tested, although their methods were more than adequate
to establish carbon monoxide uptake rates by different soils. The assessment
of the vegetation as a sink for carbon monoxide will have to wait until this
discrepancy is resolved.
Several workers such as Delwiche,^^^a demonstrated the production of
carbon monoxide by higher plants. The relative importance of plants as a
source and as a sink for carbon monoxide can not be determined from the
available data.
The uptake rate of carbon monoxide needs to be determined for a number
of plant species over the range of atmospheric carbon monoxide concentrations
found in ambient and polluted atmospheres. Also the rates of evolution of
carbon monoxide by plants, if any, need to be known before the overall sink
properties can be ascertained. In addition, the relationship between soil
carbon monoxide uptake and carbon monoxide concentration should be determined,
especially in the range between 0.2 ppm and 50 ppm. The effects of tempera-
ture on the evolution of carbon monoxide by the soil also still remains to
be learned. Knowledge of these parameters will improve the determination of
the carbon monoxide sink properties of soils and vegetation.
Biochemical Removal. The binding of carbon monoxide by porphyrin-type
compounds, found in plants and animals, is analogous to carbon monoxide uptake
by hemoglobin in blood and is a potential sink for carbon monoxide. However,
the carbon monoxide is reversibly bound by the heme compounds found in man
and animals and thus is eventually discharged from the blood, and only a
small fraction of carbon monoxide is retained. *
3-24
-------
Absorption in the Oceans. Unlike carbon dioxide, the oceans can no
194
longer be considered a sink for atmospheric carbon monoxide. In fact,
in the geographical areas studied, the carbon monoxide supersaturation and
the high diurnal variations of carbon monoxide observed in the upper layer
of the ocean provide evidence that the oceans are a significant source of
carbon monoxide that comes from the photobiologic processes of marine algae.
Inland expanses of fresh water have not been adequately assessed at present
but it is doubtful that they can serve as a sink for the large amount of
carbon monoxide injected into the atmosphere.
219
Removal at Surfaces. Kummler et al. have extrapolated the reported
heterogeneous reaction rates of nitrous oxide with carbon monoxide to ambient
temperatures (300 K) and suggest that atmospheric reaction between these
gases in the presence of such common materials as charcoal, carbon black or
glass is a feasible scavenging process for atmospheric carbon monoxide. This
l "\")
mechanism is derived from observations made by Gardner and Petruccilj of the
chemisorption of carbon monoxide at room temperature on the oxide films of
copper, cobalt and nickel using infrared spectroscopy. Also, Liberti^l has
observed from analyses of collected urban particulate material that quantities
of carbon monoxide ranging from 10 to 30 ug/g were associated with the aerosol.
He suggested that absorption by dust may be an important removal mechanism
for ambient carbon monoxide and, through codeposition, it is made available
to soil microorganisms for oxidation. These studies are inconclusive and
additional investigations are necessary. Quantitative evaluation of the
catalytic efficiency and absorbing capacity of common surfaces and atmospheric
particulate materials under ambient conditions is required to determine whether
or not they provide adequate sinks for atmospheric carbon monoxide.
3-25
-------
CHAPTER 4
ENVIRONMENTAL ANALYSIS AND MONITORING
There are major problems in correlating atmospheric data to the health
effects data for carbon monoxide pollution despite both the financial invest-
ments in monitoring and legal reliance placed on these data. Some of the
problems related to both the nature of the pollutant and the monitoring de-
vices used will be considered in this chapter.
There are varying amounts of a large number of trace substances in the
atmosphere. When the concentration of certain of these increases above a
threshold amount, there is a harmful effect on human health or welfare. When
this happens the atmosphere is considered polluted and the causal agents are
called air pollutants. Most substances considered to be air pollutants
originate from both natural and man-made sources, therefore, origin cannot be
used as a criterion for distinguishing between pollutants and nonpollutants.
The determination of the threshold concentration for each pollutant is
difficult and very often controversial. Therefore, specification of a polluted
atmosphere is based upon concentration standards established by a consensus among
panels of experts designated by air pollution control officials. A distinction
is made between primary standards which are based on health effects and secondary
standards which relate to welfare.
The amount of carbon monoxide emitted into the atmosphere is about ten
times greater from natural than from anthropogenic sources. However, the
natural sources are so widely dispersed that their contribution to atmospheric
pollution can be neglected.. Analyzing pollutant exposure is complicated both
4-1
-------
because people's activity patterns are unpredictable and because there is a
wide concentration variation with respect to location and time for carbon
monoxide from anthropogenic sources.
Carbon monoxide, when taken into the body, is converted into carboxy-
hemoglobin, and then quantitatively eliminated. In a uniform environment,
its concentration in the body reaches a steady state and then remains constant.
Exposure to an environment with a higher carbon monoxide concentration in-
creases the body burden; while exposure to an environment with a lower concen-
tration causes the elimination of carbon monoxide thus decreasing the total
body burden. Such changes characteristically take place over several hours.
Another consideration is the choice of the best way to express the large
number of measurements. Conventionally, the "hourly mean" values and "eight-
hour means" have been expressed as arithmetic means. The "hourly mean" and
the "eight-hour mean" were calculated on the assumption that a significant
number of people will be exposed either for 1 or 8 h. In principle,
the measure of central tendency used should be such that those periods having
the same mean value should also have the same physiologic manifestations.
For any averaging process/however, there are limiting cases in which this
condition cannot be met; for example, exposure to a low concentration for
8 h is not equivalent to a 5 min exposure to a lethal concentration fol-
lowed by 7 h and 55 min at zero concentration. But even in less extreme
cases, exposure periods with the same arithmetic average concentration do
not all stress the receptor equally. Additional study is needed to arrive
at the optimal expression of central tendency. When a large number of hourly
arithmetic means have been collected it is frequently found that they have a
lognormal distribution which permits the expression of the entire data distribu-
tion as a geometric mean and a geometric standard deviation, i.e., the entire
4-2
-------
ensemble of data can be represented by two numbers. This compactness of ex-
pression is very convenient, and is not intrinsically incorrect. Neverthe-
less the limitations of the data must be kept in mind so that the researcher
does not do further statistical analyses that ignore the character of the
data. For example, when using these statistical data to compute the optimum
number of sampling stations within a monitoring network and the optimum
sampling frequency the individual sample data taken at sequential times and
adjacent locations should be checked for correlation. It is possible to reduce
the number of sampling stations if good correlation can be shown. Furthermore,
the data on each pollutant must be evaluated separately owing to differences
in source-receptor relationships that affect the correlations for pollutants
other than carbon monoxide.
To summarize, it is convenient to use statistical measures of central
I
tendency and dispersion to represent aerometric data; these measurements are
so closely correlated in space and time that it is disadvantageous to use
additional statistical manipulations that depend on the randomness or inde-
pendence of successive measurements. As yet, the ideal spacing of monitors
has not been achieved.
Emission of Carbon Monoxide
Motor vehicles are the largest anthropogenic source of atmospheric carbon
monoxide. Diesel-powered vehicles emit a much lower amount than those using gasoline
as a fuel. A 1972 gasoline-powered light-duty vehicle emits 59,0 g/km
(36.9 g/m) as compared to a pre-1973 diesel-powered light-duty vehicle that
emits 2.7 g/km (1.7 g/m) .-^ A compilation of the estimated man-made emissions
of the major pollutants for the United States and for three major cities is
4-3
-------
given in Table 4-1. The breakdown of carbon monoxide emissions by source,
both nationally and for New York City, given in Table 4-2, shove the pre-
ponderance in the mobile sources.
In individual locations,however, stationary sources can be equally
important. For example, proximity to a poorly-controlled petroleum refinery
could, under certain circumstances, result in exposures to significant concen-
trations of carbon monoxide.
Emission factors for a number of sources are listed in Table 4-3.
The industrial factors are multiplied by appropriate measures of industry
size to obtain the total emissions. To obtain the total emissions for
motor vehicles, the emission factor adjusted by the appropriate speed correc-
tion factor is multiplied by the total vehicle miles travelled. Figure 4-1
has been calculated from data in the reference and gives the speed correction
factor for 1975 with the additional assumption that 88% were autos and 12%
were light-duty trucks. "
Vehicle speed has long been recognized as a critical variable in pre-
dicting motor vehicle emissions. It is only recently with the introduction
of sophisticated emission control systems such as catalysts and stratified
charge systems that the importance of ambient temperature and hot/cold weighting
(a measure of the relative mileage contribution of warmed-up vehicles) has been
recognized. This has led to the quantification of the corresponding emission
adjustment factors. Calculations based upon USEPA's emission factor report
indicate that carbon monoxide emissions from conventional vehicles not equipped
with catalytic exhaust control devices are three times greater during cold
starts at -7C (20F) than at 27C (80F).1 Over this same ambient temperature
range the carbon monoxide emissions of catalyst-equipped vehicles during cold
starts differ tenfold. As these improved pollution-control systems become more
prevalent, it will be particularly necessary to take adjustment factors into
consideration.
4-4
-------
TABLE 4-1
3
Estimated Man-Made Emissions for Year 1973, 10 Tons/Yr
CITY
U.S. TOTAL (1972 )X
NEW YORK CITY2
LOS ANGELES3
CHICAGO4
SULFUR
DIOXIDE
33,210
131
133
99
PARTICULATES
19,800
47
47
74
NITROGEN
OXIDES
24,640
317
407
112
HYDRO-
CARBONS
27,820
197
281
93
CARBON
MONOXIDE
107,301
495
2,664
364
U. S. Environmental Protection Agency
2 New York City Department of Air Resources 74b
3 Los Angeles County Air Pollution Control District 250
^ City of Chicago Department of Environmental Control 74
4-5
-------
TABLE 4-2
3
Carbon Monoxide Emissions, 10 Tons/Yr
STATIONARY SOURCES
Fuel Combustion
Coal
Fuel Oil
Natural Gas
Wood
Other
Industrial Processes
Solid Waste Disposal
Miscellaneous
MOBILE SOURCES
Motor Vehicles
Gasoline
Diesel
Aircraft
Vessels
Railroads
Other (Off-Highway)
TOTAL
USA1
1972
24,276
1,180
772
96
171
49
92
17,469
4,982
645
77,288
69,560
68,850
710
976
437
149
6,296
101,564
Percent of
Total
23.9
1.2
0.8
0.1
0.2
0.1
17.2
4.9
0.6
76.1
68.4
67.7
0.7
1.0
0.4
0.1
6.2
100.0
NYC2
1973
28
24
18
4
2
trace
4
469
455
440
15
14
497
Percent of
Total
5.6
4.8
3.6
0.8
0.4
0.1
0.7
94.4
91.5
88.5
3.0
2.8
100.0
1. Environmental Protection Agency
2. New York City Department of Air Resources
4-6
-------
TABLE 4-3
SELECTED CARBON MONOXIDE EMISSION FACTORS
409
ACTIVITY
Bituminous Coal Combustion
Combustion
Combustion
Combustion
Fuel Oil Combustion
Carbon Black Manufacturing
Charcoal Manufacture
Meat Smokehouses
Sugar Cane Processing
Coke Manufacture
Steel Mills
Foundries
Petroleum Refineries
Highways*
1965
1970
1972
1973
1974
1975
1980
1990
CONDITIONS
Utility and large industrial
boilers
Large commercial and general
industrial boilers
Commercial and domestic
furnaces
Hand-fired unit
l
Power plants
Industrial, commercial, and
domestic
Channel process
Thermal process
Furnace process
Pyrolysis of wood
Field burning
Without controls
Uncontrolled
Gray iron cupola
Uncontrolled fluid
catalytic cracking
Uncontrolled moving
bed cracking
FACTOR
1 Ib/ton coal (0.5 kg/t)
2 Ib/ton coal (1.0 kg/t)
10 Ib/ton coal (5.0 kg/t)
90 Ib/ton coal (45 kg/t)
3 lb/103 gal (0.36 kg/103l)
4-5 lb/103 gal (0.47-0.6 kg/103l)
33,500 Ib/ton (16,750 kg/t)
Negligible
5,000 Ib/ton (2500 kg/t)
320 Ib/ton (160 kg/t)
0.6 Ib/ton meat (0.3 kg/t)
225 Ib/acre burned (253 kg/ha)
0.6 Ib/ton (0.3 kg/t)
1,750 Ib/ton (875 kg/t)
145 Ib/ton (72.5 kg/t)
13,700 lb/103 bbl (38.63 kg/103l)
3,800 lb/103 bbl (10.7 kg/103l)
Approximately 20 mph(32 km/h)
for each of the years
89
78
76.5
71.5
67.5
61.1
31.0
11.3
g/mi (55.3 g/km)
11 (48.5 g/km)
11 (47.6 g/km)
" (44.4 g/km)
(40.6 g/km)
" (38.0 g/km)
(19.3 g/km)
" (7.02 g/km)
*Average emission factors for all vehicles on the road in given year
* ,- -N
4-7
-------
9
4J
o m
P. *
NEW YORK CITY
•DENVER
WASHINGTON, D.C.
LOS ANGELES
CHICAGO
.JACKSONVILLE
...— HONOLULU
-------
TABLE 4-4
CARBON MONOXIDE (PPM) HOURLY READINGS
STREET LEVEL STATIONS*
Calendar Year, 1974
8 HOURS 7 AM - 3 PM EST
STATION NUMBER OF ARITHMETIC PEAK NUMBER OF NUMBER OF AVERAGE PEAK NO. > 9
READINGS AVERAGE HOURS > 35 8 ». AVGS
1973 1974 1973 1974 1973 1974 1973 1974 1973 1974 1973 1974 1973 1974 1973 1974
•t ,.
00-121 Street 6018 5473 4.5 4.1 35 26 00 213 192 4.5 4.5 13.0 15.6 8 5
Laboratory
94 59th Street 7140 8463 18.5 16.2 70 57 384 89 277 335 21.7 18.5 49.6 37.4 276 334
•f Bridge
N>
96 Canal Street 7635 7698 8.8 9.3 36 45 1 1 302 309 10.4 11.0 21.5 20.5 184 217
98 45th Street 8503 8698 11.3 12.6 61 43 29 5 349 355 13.6 14.6 25.3 25.8 264 307
and
Lexington
Avenue
74a
*City of New York, Bureau of Technical Services, Dapatrtaaent of Air Resources
-------
TABLE 4-5
CARBON MONOXIDE, HOURLY READINGS, PPM
ROOFTOP STATIONS*
Calendar Year, 1974
8 HOURS 7
STATION
NUMBER OF
READINGS
CITY WIDE
1 -Bronx HS of Science
3-Morrisania
,L 14- Queens College
w
30- Springfield Gardens
5 -Central Park Arsenal
10-Mabel Dean Bacon
11-Greenpoint
18 -Brooklyn Public
Library
26 Sheepshead Bay HS
3 4- Sea view Hospital
1973
68,280
7079
6381
7657
5759
6866
6708
8210
6720
5521
7379
1974
59,443
7069
7081
7755
1889
5673
5543
7329
2843
7408
6853
ARITHMETIC
PEAK
NUMBER OF
AVERAGE
1973
3.7
3.6
3.4
3.8
5.2
4.1
3.6
3.7
3.4
3.3
2.9
1974
3.3
4.2
2.6
3.5
4.3
2.9
3.1
3.6
3.7
2.5
2.5
1973
34
21
20
20
28
34
16
22
20
20
11
1974
23
19
13
19
23
15
13
18
18
20
8
AM - 3 PM EST
AVERAGE
PEAK
NO. >
9
8 H» AVGS
1973
2782
342
292
325
184
289
232
266
241
283
328
1974
2406
314
288
311
77
224
214
293
117
292
276
1973
3.8
3.6
3.6
4.0
5.3
3.8
3.9
3.8
3.8
3.5
3.2
1974
3.4
4.2
2.6
3.5
4.6
3.0
3.3
3.5
3.9
2.6
2.6
1973
15
9
12
11
11
14
10
15
14
14
9
1974
12
8
10
8
12
10
10
10
8
8
6
1973
24
2
3
2
6
4
2
3
1
1
0
1974
6
0
1
0
2
1
1
1
0
0
0
*City of New York, Bureau of Technical Services, Department of Air Resources^3
-------
Temporal Variations. A lognormal plot (normalized logarithmic probability
190
plot) of data separated both by season and by day of the week for a station
in New York City is shown in Figure 4-3. Seasonal differences are small com-
pared with the difference between Sundays and weekdays. This is probably not
surprising since there is little seasonal difference in New York City's traffic
density. Sunday traffic however, is significantly lighter than weekday traffic,
and this correlation shows up clearly.
The correlation between carbon monoxide concentration and traffic is still
more apparent in Figure 4-4.^ These plots of the diurnal course of both traffic
and carbon monoxide reveal their typical patterns and show their similarity. Cities
with a marked rush-hour traffic peak in the morning and afternoon tend to show
similar carbon monoxide patterns. Cities such as New York that experience saturation
traffic throughout business hours tend to show a plateau during the day rather than
a mid-day minimum.
Spatial Variations. In narrow canyon-like streets, most of the carbon
monoxide is emitted at ground level. Dilution is largely through mechanical
turbulence induced by the movement of the traffic and possibly by convection
from the excess heat produced by the vehicles. The resulting vertical distribution
(Figure 4-5) shows smoothed vertical profiles up the sides of two high-rise buildings
in New York City. The data are given by season to distinguish between the heating
and nonheating seasons. The differences shown are probably not significant. One
conclusion that can be drawn is that the concentrations measured at a given station
are very sensitive to the height of the intake tube. This point is discussed further
below.
4-14
-------
FIGURE 4-3. 1967 Cumulative Distributions of Hourly Average Concentrations of Carbon Monoxide
(110 East 45th Street, Manhattan)
Ui
I
a
5(
40
30
20
10
9
8
7
6
0.5
WEEKDAY 1/6 - 5/17
.WEEKDAY 7/30 - 9/14
SUNDAY 1/6 - 5/17
SUNDAY 7/30 - 9/14
January 6- May 17: 1936 weekday hours
360 Sunday hours
July 30- Sept. 14: 731 weekday hours
144 Sunday hours
1 ppm = 1.145 mg CO at 25° C
10 20 30 40 50 60 70 80 90 95
Percent of values £ ordinate value
98 99
99.8
-------
I
i
CM
I
H
s
CM
o
B*
M
10
8
2
0
FIGURE 4-4
DIURNAL VARIATION OF
CARBON MONOXIDE AND TRAFFIC
CARBON VONOXIOE
TRAFFIC
J—l
I — I — I _ I _ i i » i i _ I
L_l — I _ i
8
10
N
1 1 I
10
LODGE-FORD FREEWAY INTERCHANGE
CORRELATION COEFFICIENT 0.92
8
10 N
8 10
M
COLUMBUS CIRCLE
CORRELATION COEFFICIENT 0.86
§
-------
35 i—
OUTDOOR
30 r-
C
O
at
n
•u
g
u
u
-------
Meteorological Effects. An additional complication occurs when a pre-
vailing wind blows across a deep street-canyon. Studies have shown that this
induces a downward air motion on the side of the street facing the wind, a
flow across the street in the opposite direction to the prevailing wind, and
an upflow on the upwind side of the street. This reverse eddy causes low
carbon monoxide concentrations on the downwind side of the street and high
296
concentrations on the upwind side.
Local wind behavior combined with the configurations of nearby structures
can be responsible for significant differences in the measurements reported
by closely adjacent monitors. For example, differences as great as twofold
were found at different corners of the same intersection in Tokyo. Ola
Indoor-Outdoor Relationships. Because carbon monoxide is relatively
inert, there is little adsorption on surfaces. Therefore,
with the possible exception of a brief time lag, a close relationship would
be expected between concentrations in the open air and those inside buildings.
Figure 4-6,which gives indoor and outdoor concentrations and adjacent traffic
count for a third-floor apartment in a high-rise building in New York City,
shows that this is true in many cases.13^ The daily course of carbon monoxide
for a detached suburban home (Figure 4-7), where leakage from an attached
garage and the effects of gas-cooking and smoking largely obscure the outdoor
influences^,is in marked contrast.^2 The effects of indoor sources including
tobacco smoking predominate over the influence of the outside atmosphere.
Indoor-outdoor combined effects will be increased if windows and doors are
open and decreased if the house is tightly closed^as is the case during the
heating season.
4-18
-------
I
I-1
vo
o
*™r^
1
25 r
20
15
10
2400
Traffic
Inside 3rd Floor
-Outside 3rd Floor
Heating Weekdays
I I I I
12000
9600
7200
4800
2400
200 400 600 800 1000 1200 1400
TIME OF DAY
1600
1800
2000
2200
2400
i
I
ro
en
O
Figure 4-6 - Diurnal Carbon Monoxide & Traffic - Site 1 - Heating Season - 3rd Floor - Weekdays.
134
-------
Q.
a
O
<
O
u
I I I
CAR BEING TAKEN FROM GARAGE
CAR BEING PUT IN GARAGE
KITCHEN
. FAMILY ROOM
• — OUTSIDE
2.0
1.0
1200 1700 2200 I 1300
MARS
1300 1800
MAR 6
TIME, hours
400
900 1400
MAR 7
Figure 4-7 - Indoor-Outdoor Diurnal Variation in Carbon Monoxide.
42
4-20
-------
Summary . Urban carbon monoxide concentrations are at least ten times
higher than background concentrations; seasonal differences are small; concen-
trations on Sundays are almost invariably less than those on weekdays; diurnal
concentration patterns follow diurnal traffic patterns, with a tendency to
peak during morning and evening rush hours (the intervening period may or
may not show a decrease depending on the nature of nearby traffic) ; concen-
trations decrease steeply with increasing height and are also affected, even
when averaged over the long-term, by persistent air circulation patterns.
Because carbon monoxide emission decreases and mechanical turbulence increases
with increasing vehicle speed; high speed roads tend to yield lower ambient
carbon monoxide concentrations in their vicinity even though the traffic
density is increased. In addition, because high speed roads tend to be built
in open spaces and on elevated roadbeds they are less subject to canyon effects.
Measurement of Carbon Monoxide
Several of the techniques used for monitoring carbon monoxide are dis-
cussed in detail in the Appendix. The previous discussion has pointed out a
number of measurement problems common to all monitoring techniques. There
are however, additional problems specific to the measurement of carbon monoxide.
The Environmental Protection Agency has set ambient air quality standards for
carbon monoxide based on the resulting concentrations of carboxyhemoglobin in
human blood. These were supposed to remain below 2% in nonsmokers, which
o
corresponds to carbon monoxide concentrations of 40 mg/m (35 ppm) for 1 hour,
or 10 mg/m3 (9 ppm) for 8 hours. ^ Since there is a finite probability of
exceeding any given concentration the statistical status of these standards
was further defined by stating that they could be exceeded by experiencing
one higher concentration per year without constituting a violation. That is
to say, these standards refer to the second highest concentration measured in
4-21
-------
any year. It has recently been argued that using three fixed periods per day
(0000-0800, 0800-1600, and 1600-2400) for the 8-hour averages leads to under-
estimating concentrations. Therefore, 8-hour moving averages of one-hour
97ft
average concentrations should be used instead. " The number of violations
which result if running averages are used should be limited by counting only
nonoverlapping 8-hour averages as violations.
These standards have had a profound effect on both the measurement and
reporting of carbon monoxide concentrations. Whether or not the selection of
concentrations has been completely accurate it can be seen from the foregoing
discussion that a typical mobile individual may experience a history of carbon
monoxide exposure very different from that recorded by either one or several
stationary monitoring devices. A situation can be pictured in which a monitor
at the second-floor level would measure one concentration, while a person
on the curb directly beneath would experience ten times that concentration,
and another person on an upper floor would be exposed to significantly less
than the measured concentration. A sampling probe can always be located so
that much higher concentrations are measured than a person in the vicinity could
reasonably experience for any extended period.
The statistical problem of the optimal theoretical design for sampling
systems has not yet been solved. Consequently* to obtain reliable data first
the number and locations of the sampling stations must be decided and then
many trials must be made to minimize any distortion of the data because of one
or two anomalous locations.
Assuming optimal locations have been selected and tested the quality
control of the individual monitoring instruments remains a problem. All
carbon monoxide monitoring instruments have features in common; they contain coopl
electronic circuits; they are operated near the sensitivity limits set by
4-22
-------
inherent noise; and most significant of all their calibration is arbitrary.
None of the available instruments can be calibrated solely from consideration of
its operating principle. For this reason the instruments must be calibrated
using standard gas mixtures. Their accuracy is thus limited by the accuracy
of available standards. Additional potential sources of error are the
electronic circuits that add the possibility of malfunction or calibration
drift not necessarily obvious from inspection of the output data and unless a
program of frequent calibration, preferably daily, is instituted. Much of the
carbon monoxide monitoring in the past has been performed by nondispersive
infrared instruments, wfaich are very susceptible to water vapor, and which
require highly-trained technicians. Thus, some of the data generated have
been unreliable.
Simulation Modelling
The preceding discussion has pointed out the inherent difficulties in
obtaining carbon monoxide concentration data in order to calculate accurately
human exposures. Ideally, the individuals being tested should carry a personnel
monitor that would continuously record the concentrations to which they are
exposed. Alternately, a detailed record of their movements combined with moni-
toring data representative of each location could be used to calculate ex-
posures and rate of carbon monoxide uptake. For technical and economic reasons
neither of these alternatives is feasible at present.
A major step towards the ability to characterize the concentration in
a complex area has been the development of simulation models* Once a successful
model has been achieved, estimates of concentrations at a particular location can
be made, given the intensity.of emissions and their spatial and temporal patterns,
the micrometeorology, and the structural configurations bounding the area. In
combination with a relatively small number of strategically located monitoring
4-23
-------
stations, such models can be used to depict the concentrations at many locations
in a large area. Unavailability of such sophistication in the past necessitated
using oversimplified models. The pressures created by the cost of pollution
control require investing in the development of more effective models. Modelling
has also become important in the preparation of environmental impact statements.
Therefore, there is an increased effort to develop successful air quality models.
The models for pollutants such as sulfur dioxide are usually long-term. Be-
cause of the difficulty in depicting meteorological conditions over extended
periods., these can be in error by as much as 100% or more.
Short-term models for urban carbon monoxide conditions are currently
under development in order to meet state implementation plan requirements and
to prepare environmental impact statements. These short-term models are
Q
capable of calculating concentrations within 25% of measured values.
Because of the short-term relation between carbon monoxide exposure and health
effects, concentration models have primarily emphasized hourly averages.
4-24
-------
MONITORING CARBON MONOXIDE IN THE ENVIRONMENT BY BIOLOGIC TECHNIQUES
Carbon monoxide is not significantly altered metabolically when taken
into the body. It binds reversibly with heme pigments, principally hemoglo-
bin, the red pigment of the blood. A direct indication of the amount of
human exposure can therefore be obtained by hemoglobin measurements. From
the standpoint of health these are more significant than ambient air measure-
ments, since the concentration of carboxyhemoglobin (HbCO) in the blood is
related to the physiologic effects of carbon monoxide on people.
There are practical limits to the value of biologic sampling for
carbon monoxide uptake. Carbon monoxide is taken up relatively slowly by
the body from ambient sources. Since the rate of uptake is dependent on
several physiologic factors, the interpretation of measurements in terms of
ambient sources may not be simple. Because cigarette smoking is a major
source of carbon monoxide exposure, widely prevalent in the urban population,
ambient air sources can be evaluated only in nonsmokers. Occupational sources
of carbon monoxide exposure, for example in garages, may also contribute to
its presence in urban dwellers.
Routine sampling of blood has two additional practical limitations; the
first is that the discomfort of taking a blood sample by any method would
make random sampling in the general population unacceptable, and the second,
is that analytical techniques for determining low concentrations of carboxy-
hemoglobin are as yet not sufficiently reliable. At the time of the previous
National Academy of Sciences report (1969) rapid spectrophotometric methods
were not considered accurate for measuring very low carboxyhemoglobin concen-
trations. 293 Accuracy is crucial if the blood carboxyhemoglobin is used to
indicate exposure to the low concentrations in urban air. The methods currently
used to measure carboxyhemoglobin are described in Appendix A.
4-25
-------
Carboxyhemoglobin can also be estimated indirectly by measuring alveolar
gas, which is the gas present in the deep regions of the lungs. Using subjects
with normal lungs and properly applying this technique, good results are
achieved with a minimum of discomfort. The subject's cooperation and well-
trained personnel are required. Therefore, the wide applicability of this
technique for routine sampling of carbon monoxide exposure is unlikely. This
technique is described in the Appendix. Because a small amount of carbon
monoxide is generated within the body, there is about 0.4% carboxyhemoglobin
present even when no carbon monoxide is in the inspired air, which adds a
further complication to biologic sampling for carbon monoxide exposure. The
production rate of carboxyhemoglobin can be increased by certain diseases and
Qf
physiologic conditions such as hemolytic anemias. These can increase the
carboxyhemoglobin 2 to 3% above normal endogenous production. It is also
increased by ingesting drugs that induce the hepatic oxidizing enzyme, cyto-
79
chrome P-450. For example, barbiturates slightly increase carbon monoxide
production.?9
We can add the effects of carbon monoxide produced in the body to that
of the carbon monoxide from the ambient air.^2 The expected carboxyhemoglobin
concentration at equilibrium,calculated using an endogenous carbon monoxide
production rate of 0.4 ml/h, is shown in Table 4-6. For comparison there is
a calculation based on the empirical equation, % carboxyhemoglobin = 0.4 + (p/7),
where p is the inspired carbon monoxide concentration in ppm. Table 4-6 shows
that if equilibrium is achieved (for comment see the section on uptake) 2%
carboxyhemoglobin should result from inspired carbon monoxide of about 12 ppm,
and 3% carboxyhemoglobin from about 18 ppm.
4-26
-------
TABLE 4-6
Calculated Carboxyhemoglobin at Equilibrium with Inspired Carbon Monoxide
Concentration, Pressure in Parts Per Million
(Applicable to nonsmokers only)
% Carboxyhemoglobin
Inspired Carbon Monoxide % Carboxyhemoglobin from empirical equation pn
ppm from Coburn, et al. ~ ~ . ----- « * . _ CO,.,**
0
5
8.7
10
15
20
30
40
50
0.36
1.11
1.66
1.85
2.57
3.29
4.69
6.05
7.36
_ - u
0.4
1.1
1.6
1.8
2.5
3.3
4.7
6.1
7.5
82
*Assumptions used in the equation of Coburn, Forster & Kane: the carbon monoxide pro-
duction = 0.4 ml/h STPD; the diffusion capacity, D_CO = 20 ml/min/torr; the barometric
L
pressure, 760 torr; the alveolar ventilation, 3,500 ml/min STPD; the Haldane constant =
342
220; the mean pulmonary capillary oxygen pressure, C00 = 100 torr and the fraction
of unbound hemoglobin is constant at 3%.
**PtCO is the inspired carbon monoxide concentration in ppm. This equation is applicable
up to 50 ppm.
4-27
-------
The most extensive study of carboxyhemoglobin in the general public has
been carried out by Stewart and his associates, who sampled blood drawn from
about 31,000 individuals by blood donor mobile units in 17 urban areas and
378
also in some small towns in New Hampshire and Vermont. Their results showed
that smokers' blood contained a much higher percent of carboxyhemoglobin than
nonsmokers. They found however, that in all regions studied a large percentage
\
of the nonsmokers had over 1.5% carboxyhemoglobin, indicating significant ex-
posure. Frequency distributions for each of these regions indicated that a
small percentage (1-2%) of the nonsmokers^ despite claiming to be exsmokers, were
actually still smoking. Their inclusion as nonsmokers does not change the
results significantly. In addition, some of the high values found in non-
smokers in four of the cities may have been due to special occupations
in which unusual exposures to high carbon monoxide concentrations occurred in
377
enclosed areas.
The effect of occupationally related carbon monoxide sources was emphasized
by Kahn and associates who did a similar analytical study of more than 10,000
blood samples from nonsmokers and 6,000 samples from smokers in the St. Louis
area.1^ For the nonsmokers classified as "industrial workers" the mean car-
boxyhemoglobin concentration was 1.4% and for those classified as "other than
industrial" the mean was 0.8%. The overall mean for both employed and un-
196
employed was 0.9%. The conclusions drawn from the results of Kahn et_ al.
377 378
differ markedly from those of Stewart e£ al. ' Whereas Stewart and his
coworkers concluded that 35% of nonsmokers in St. Louis were exposed to ambient
carbon monoxide causing their carboxyhemoglobin to be greater than 1.5%, Kahn
196
et al.Lyv concluded that only a small percentage of nonsmokers (many of whom
were industrial workers), had values greater than 2%. Of the nonindustrial
workers, 5.7% had values above 2%, but some of these were unquestionably smokers.
4-28
-------
196
Kahn et al. did show that a small urban-rural gradient for carboxy-
hemoglobin existed in the St. Louis area. Three areas, "highly urban,"
"urban," and "rural" were designated according to the 1970 census data. The
mean carboxyhemoglobin for nonsmokers who were not industrial workers was
0.8%, 0.7% and 0.6% for the highly urban, urban and rural areas respectively.
These very small differences do not support the conclusion that carbon monoxide
uptake from ambient sources in the urban air is physiologically significant.
The discrepancy in the conclusions of these two studies is important
with respect to current air quality control strategies. Both studies empha-
size the significance of smoking and occupational exposures. Stewart's group,
however, infers that in cities with such different meteorological conditions
and population densities as New York, Los Angeles, Denver, New Orleans,
Phoenix, Anchorage, St. Louis and Washington, one-fourth to three-fourths of
the nonsmokers are consistently exposed to carbon monoxide concentrations
above the current standard of 8.7 ppm (which would result in carboxyhemoglobin
196
above 1.5%, see Table 4-6). Kahn et^ al_. conclude^, contrarily, that the
carbon monoxide in the urban environment of St. Louis contributes only negligibly
to carbon monoxide uptake by the general population.
Other measurements have been made that apply to the questions raised by
these studies. Aronow ^ ^1. ' ' found carboxyhemoglobin values around
1.0% in 25 nonsmoking subjects in the Los Angeles control area which rose
to 5.1% when these subjects were driven in a car on freeways for one and
one-half hours. Ambient carbon monoxide was reported to be 1 to 3 ppm in
the laboratory and about 50 ppm in the car. Radford et. ^i.- (unpublished
observations) found values of 0.9% carboxyhemoglobin in the blood of 19
4-29
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laboratory workers and other personnel in Baltimore, who had never smoked,
and values of 0.6% carboxyhemoglobin In 32 nonsmoking residents of Hagerstown,
Md., a small rural city. The carbon monoxide concentrations observed in
Baltimore are comparable to those reported in St. Louis, and these results
resemble those of the St. Louis study. Horvath (unpublished observations),
in Santa Barbara, California>has found 0.6% carboxyhemoglobin in the blood
of approximately 150 nonsmokers, indicating low carbon monoxide exposures
for this city, even though high ambient air values have been recorded in
Santa Barbara. Ayres et al.2* reported that 26 nonsmoking hospitalized
patients in New York City had a mean value of 1.0% carboxyhemoglobin. The
carbon monoxide concentrations in the hospital were similar but slightly below
those found outdoors at the same time. These last two studies are particularly
important because the carboxyhemoglobin was measured by gas chromatography
rather than by the spectrophotometric techniques used by the other invest!-
»
gators.
Carboxyhemoglobin concentration in smokers depend*on the number of cigarettes
smoked, degree of inhalation and other factors. The carbon monoxide content of
160B
cigarette smoke is up to 5% by volume and about 80% of carbon monoxide
produced by smoking cigarettes is retained. Carboxyhemoglobin levels
as high as 15% have been reported in chain smokers, but values are usually in the
3-8% range in most smokers.
4-30
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CHAPTER 5
EFFECTS ON MAN AND ANIMALS
UPTAKE OF CARBON MONOXIDE
Carbon monoxide In the body comes from two sources; endogenous, from the
breakdown of hemoglobin and other heme-containing pigments; and exogenous, from
inhalation. The catabolism of pyrrole rings is the source of the endogenous
production of carbon monoxide, which in adults normally leads to carbon monoxide
86
production of about 0.4 ml/h (STP). This can be increased by hemolytic
Q ^ T/\
anemias and the induction of hepatic cytochromes from taking drugs. Dihalo-
methanes may have increased endogenous carbon monoxide production and markedly
elevated carboxyhemoglobin.
Inhalation is the first step in the process of exogenous carbon monoxide
uptake,followed by an increase in carbon monoxide concentration in the alveolar
gas with diffusion from the gas phase through the pulmonary membrane and into
the blood. The rate of uptake into the body is limited by the rate of diffusion
from the alveoli and the combination with the blood. When the concentration of
carbon monoxide is very high the rate of uptake may be partially limited by the
amount that can be inhaled with each breath.
Using modern concepts of the physiologic factors that determine carbon
82
monoxide uptake and elimination, Coburn, Forster, and Kane developed an
equation for calculating the blood carboxyhemoglobin as a function of time.
The basic differential equation was:
d(CO) = ' [HbCO] ^ PC°2 v 1 . Pi00
dt CO [HbO?] A M 1 + PD - 47 1 + P - 47
*• —— o 7T- »
^ \ * —
where d(CO) is the rate of change of carbon monoxide in the body
, dt
5-1
-------
V^Q is the carbon monoxide production rate
[HbCO] is the concentration of carbon monoxide in the blood
[HbC^J is the concentration of oxyhemoglobin
*C 2 is the mean pulmonary capillary oxygen pressure
M is the Haldane constant (220 for pH 7.4)
Dr is the diffusion capacity of the lungs
Pfi is the barometric pressure
•
V^ is the alveolar ventilation rate
p-j-CO is the inspired carbon monoxide pressure.
This equation was designed to investigate the measurement of blood
carboxyhemoglobin as an indicator of the rate of carbon monoxide production.
Its solution could therefore be based on the assumption that the mean pul-
monary capillary oxygen pressure, Pr®2> an(* t*ie concentrati°n °f oxyhemo-
globin, [HbC^^were constant and independent of the concentration of carboxy-
hemoglobin, [HbCO]. With these assumptions a solution of the equation be-
>
came possible. Researchers who have used the Coburn, Forster, Kane solution
have accepted these assumptions.
In the general case however, the oxyhemoglobin concentration depends
on the carboxyhemoglobin concentration in a complex way and a solution is
only possible using special computer methods. A second approximation solution
of the Coburn, Forster, and Kane equation permits the evaluation of the
kinetics of the washing in and washing out of carbon monoxide over a fairly
wide range of carboxyhemoglobin concentrations.* The basic assumptions on
which the differential equation and its solutions are developed are described
e are indebted to Dr. Alan Marcus and Mr. Philip Becker of the University
of Maryland at Baltimore County for providing both this solution and the
computer printouts.
5-2
-------
in the original paper by Coburn et^ al.^2 These assumptions are not re-
strictive however, and therefore the solutions are applicable generally.
The inspired gas is assumed to be ambient air to which carbon monoxide is
added.
Besides the carbon monoxide production rate, the principal factors
that determine the rate of uptake or release of carbon monoxide from the
body are: the concentration of carbon monoxide inspired; the diffusion
capacity, DL, a function of body size and to some extent the level of
exercise; the alveolar ventilation, v^, also dependent on the amount of
exercise; the mean pulmonary capillary oxygen pressure, P,^, a function
both of the barometric pressure and the health of the lungs; and the blood
volume, determined by the body size. Thus, the principal factors relating
the change in carboxyhemoglobin concentration, after exposure are: concentration
of carbon monoxide inspired; endogenous carbon monoxide production; amount
of exercise; body size; lung health (including diffusion capacity, DA; and
barometric pressure.
In addition to exposure from ambient sources, tobacco smoking, particu-
larly of cigarettes, is an important special case of carbon monoxide exposure.
The theory predicts that a smoker with a normal concentration of carboxyhemo-
globin during the day frpm ambient carbon monoxide sources will have an
additive amount cf carboxyhemoglobin from smoking. Recent measurements by
Smith (unpublished data) in Calgary, Alberta,of ambient exposures and alveolar
carbon monoxide concentrations have shbwn that the theory predicts end-of-day
carboxyhemoglobin with reasonable accuracy as long as the ambient carbon
monoxide does not fluctuate rapidly during the day as it does with certain
occupational exposures.
5-3
-------
As illustrated in the figures, the theory can also be applied to the
influence of various factors such as cigarette smoking, lung health, duration
of exposure and altitude on the rate of change of carboxyhemoglobin during the
daily activity cycle and to its concentration at night during sleep.
In the following graphs the variables used in the Coburn, Forster,
Kane equation are for adult subjects at sea level. Any modifications are
indicated in the legends to the figures.
The values assumed for the general case are:
Haldane constant = 220 (for pH 7.4)
= 0- (mean pulmonary capillary oxygen, partial pressure) = 95 torr
c !
D (diffusion capacity) = 20 ml«min torr"1
LI
Sleeping V. (alveolar ventilation) * 3 liters»min
A
4 -1
Light work V (light exercise) - 5 liters*min
A
V (blood volume) - 5 liters
b
5-4
-------
HbCO
XConc.
CO
PPM
100
0
-
r-
f~~
1
, 7
1 1 1 f
i i i i
P. __. _ __
i
r r i i
— »
'~~i
1 i i i
0
10
20
TIME (H)
30
40
50
FIGURE 5-1.
Upper graph: carboxyhemoglobin in a nonsmoker exposed to
carbon monoxide during the period 8 AM to 6 PM and not exposed
at other times; sleep from 10 PM to 6 AM, light exercise when
awake. Zero time is midnight on the first day. The initial
carboxyhemoglobin is an arbitrarily chosen value.
Solid line: Ambient carbon monoxide 10 ppm during day4
Dashed line: Ambient carbon monoxide 20 ppm during day.
Lower graph: this shows the carbon monoxide exposure pattern
used to calculate above carboxyhemoglobin -
5-5
-------
The peak values reached are less than the equilibrium values (Table 4-6).
For 10 ppm the peak percent of carboxyhemoglobin reached on the second day
(when the initial conditions no longer are important) is 1.5% compared to
1.85% predicted for equilibrium. At 20 ppm the peak value reached at the
second day is 2.86% compared to 3.29% for equilibrium. These results show
that if exposure to carbon monoxide occurs only during the working day from
ambient or occupational sources, the carboxyhemoglobin reached will be well
below equilibrium for persons not doing heavy work.
5-6
-------
HbCO
% Cone.
o
125
150
175
TIME (H.)
150
CO
PPM
-
-
f>-*i '"V
•f
• /*i*^*
Ri
i i
J«?'l*".J1r-J-
-"-vf"
it* •''!•'
,^^-..-;'
8
dill
tppSfff**
\*£*-~.
t §^^*" ]
&"'-•/?••* i
ml
*
T i i i
i' ••We .' ... ^
». -r-\ .
•
'
^
0 25 50 75 100 125 150 17^
TIME (E)
FIGURE 5-2. Upper graph: Carboxyhemoglobin in a smoker during one week,
smoking 48 cigarettes per day, but with relatively light in-
halation. Sleep and awake conditions as in Figure 5-1. At
zero time (midnight), the initial carboxyhemoglobin is assumed
to be 0.4%, which is consistent with endogenous production only.
Lower graph: The pattern of exposure to carbon monoxide appli-
cable to the upper graph. Each single vertical line represents
a cigarette smoked for 5 min, with a mean alveolar pCO of 100
* X
ppm during that five minute interval (light inhalation)*
5-7
-------
By the second day, a consistent daily pattern of carboxyhemoglobin
has been achieved. The peak carboxyhemoglobin reached in the evening in
this light inhaler is 4.5%. The carboxyhemoglobin remains well above that
from endogenous production even when smoking is stopped during sleep.
5-8
-------
HbCO
%Conc.
10 ,
8
6
4 '
2
0 .
0
10
i i iii i r
20 30
TIME
-------
HbCO
'•Cone.
TIME
-------
PHYSIOLOGICAL EFFECTS
General
The respiratory and cardiovascular systems working together transport
oxygen from the ambient air to the various tissues of the body at a rate
sufficient to maintain tissue metabolism. In one step in this overall
process, oxygen is carried by the blood from the lungs to extrapulmonary
tissues. Nearly all the oxygen in the blood is reversibly bound to the
hemoglobin contained in the red blood cells. The most important chemical
characteristic of carbon monoxide is that it too, is reversibly bound by
hemoglobin, competing with oxygen for the binding sites on the hemoglobin
molecule. Hemoglobin's affinity for carbon monoxide is more than 200 times
greater than for oxygen. Therefore, carbon monoxide can seriously impair the
transport of oxygen even when present at very low partial pressures.
The proportion of hemoglobin combined with carbon monoxide at any time
is determined not only by the partial pressure of carbon monoxide, but also
by that of oxygen. The approximate relation stated by Haldane and his associ-
112
ates, in 1912, showed that the ratio of the concentrations of
carboxyhemoglobin (HbCO) and oxyhemoglobin (Itt^) is proportional to the ratio
of the partial pressures of carbon monoxide and oxygen:
[HbCO] = M (pCO)
] (Po2r
5-11
-------
The constant M is about 210 for human blood. The accuracy of this expression
has been questioned, particularly when a large fraction of the hemoglobin present
is not combined either with oxygen or with carbon monoxide.188 The equation
approximates the actual relationship closely, however, and has proven very useful
for quantitatively analyzing the influence of carbon monoxide on oxygen trans-
port by the blood.
The oxyhemoglobin dissociation curve (Figure 5»^F) describes
oxygen transport. Under normal conditions when the arterial blood has been
equilibrated in the lungs with a° oxygen partial pressure (p02) of 90-100 mm Hg,
it contains slightly less than 20 vol % of oxygen bound to hemoglobin (point a).
As the blood flows through the various tissues of the body, oxygen diffuses out
of the capillaries to meet metabolic needs. The p02 falls as the oxygen content
of the blood is reduced by an amount determined by the metabolic rate of
the tissue and the capillary blood flow. For a typical tissue or for
the entire body, the venous oxygen content is about 5 vol % lower than the
arterial,and the venous pOn is about 40 mm Hg (point V).
The normal oxygen transport by the blood may be impaired by a variety of
factors. In Figure 5-5 the effects of carbon monoxide on venous p02 are shown
and compared to the normal state and to the —?
effects of a decrease in blood hemoglobin content (anemia). Arterial p02
are
and oxygen content A indicated by the symbols ^ and a/ and the symbols v,
v|, and v£ indicate venous p02 and oxygen content assuming the arteriovenous
(A-V) oxygen content difference remains constant at 5 ml/100 ml. This figure
shows that there are two consequences of increasing carboxyhemoglobini an affect
like anemia that results in decrease of p02 in tissue capillary blood, and a shift to
the left of the oxyhemoglobin dissociation curve, which further decreases the p00
5-12
-------
BOKAncml*
/ (0, Hb Cipicltv - 10 ml/100 ml)
100
Figure 5-5. Oxyhemoglobin dissociation curves of normal human
blood, of blood containing 50% carboxyhemoglobin, and of blood
with a 50% normal hemoglobin concentration due .tq anemia.
O'gAg 34-4-3
(Derived from Rahn and Fenn and Roughton and Darling )
5-13
-------
in the capillary blood in peripheral tissues. For the sake of clarity an
example of severe carbon monoxide poisoning has been used in this discussion.
Under conditions of mild carbon monoxide poisoning as shown in Figure 5-6,
the effects are qualitatively similar but less severe.
The ultimate indicator
-------
20r
16
g 14
60
12
-
8
,0
10
20
30
40
60
60
70
80
90
Figure 5-6. Oxyhemoglobin dissociation curve of normal human
blood containing 10% carboxyhemoglobin and blood with 10% de-
crease in hemoglobin concentration (10% anemia).(Symbols v, V]
and v*2 feave same meaning as in Figure 5-5).
5-15
-------
PERCENT OF Hb COMBINED WITH CO
6 10 IS 20
n
I
GO
40
30
20
10
T
1
BO 100 160
CO CONCENTRATION (ppm)
200
Figure 5-7. Effect of carbon monoxide on venous p02* The arterio-
venous oxygen content difference with normal blood flow and oxygen
consumption is assumed to be 5 vol %. (Modified slightly from
Figure 3 of reference 27).
5-16
-------
This analysis assumes that alveolar ventilation, metabolic rate, and
blood flow all remain constant and that little or no mixed venous blood is
shunted through the lungs without being equilibrated with alveolar air. It
is well known, however, that 1-2% of the cardiac output is shunted past the
alveolar capillaries in normal subjects, and much larger right-to-left shunts
exist under disease conditions. Mixed venous blood flowing through these
right-to-left shunts combines with blood that has undergone gas-exchange in
the pulmonary capillaries to form the mixed arterial blood. Because the
oxygen content of the shunted blood is lower than that of the end-capillary
blood with which it mixes, the resulting oxygen content of the arterial blood
is lower than that of the end-capillary blood, and arterial pC is somewhat
lower than mean alveolar pC^. Brody and Coburn, * have pointed out that if
the oxygen content of the mixed venous blood is abnormally low, as in anemia
or carbon monoxide poisoning, the effect of the shunted blood in lowering the
arterial pOn will be greater than normal, resulting in a small increase in the
alveolar-arterial oxygen pressure difference (A-a 002). If the mixed venous
pC^ and the right-to-left shunt remain constant, the change in the shape of
the oxyhemoglobin curve due to the presence of carbon monoxide also increases
the A-a DC^. A similar phenomenon occurs when some lung regions have non-
uniform ventilation perfusion ratios, the case in many types of cardiopulmonary
disease. Figure 5-$^ taken from the work of Brody and Coburn, " shows that
slight increases in carboxyhemoglobin concentration have little or no influence
on the alveolar-arterial oxygen pressure difference (A-a DC^) in normal sub-
jects but in patients with large intracardiac right-to-left shunts or with
chronic lung disease and mismatching of ventilation and perfusion of carbon
monoxide increases the A-a D0«. This phenomenon adds a component of arterial
hypoxia to the effect of carbon monoxide on oxygen transport in such patients.
5-17
-------
a
o
o
60
55
50
45
40
35
20
15
10
5
0
4 6 12 16
HbCO (%)
Figure 5-8., Effect of carbon monoxide administration on the
alveolar arterial^pO^ difference in normal subjects (•)» in
patients with VA/Q abnormalities due to chronic lung disease (o),
and in patients with intracardiac right-to-left shunts (x).
(Reprinted with permission from Brody and
5-18
-------
It has been suggested that cytochrome P~^50is important in oxygen trans-
port in cells and that one effect of increased carbon monoxide tension is to
block transport facilitated via this mechanism. At present, however , there
is no convincing evidence to support this postulate.
Intracellular Effects of Carbon Monoxide
Tissue Carbon Monoxide Tension. Intracellular effects of carbon monoxide
depend on the carbon monoxide partial pressures (pCO) in the tissues. Calcula-
tions have been made of tissue pCO from blood carboxyhemoglobin and an assumed
mean capillary oxygen partial pressure pO^, using the Haldane equation. At a
*)
blood carboxyhemoglobin concentration of 5%, pCO is 2 x 10 mm Hg (assuming
the mean capillary pO^ is 40-50 mm Hg) , about 5 times greater than when the
carboxyhemoglobin is normal. This is about 60-70% of the inspired pCO for a
steady state condition.
Gothert and coworkers^^ have recently (1970) estimated tissue pCO in
the rabbit peritoneum from measurements of pCO in an air pocket in the peritoneal
cavity. Measurements were made with rats, guinea pigs or rabbits breathing
carbon monoxide at 86-1,000 ppm. The pCO in the gas pocket was 42-69% of
the partial carbon monoxide pressure in the alveolar air. This figure probably
underestimates tissue pCO in tissues where the ratio of oxygen extraction to
blood flow is less than in peritoneum. Campbell •*• made similar measurements
of pCO in a gas bubble in the peritoneum of mice.
Intracellular pQ
The pOo in proximity to intracellular compounds which bind carbon monoxide
is a critical factor in possible intracellular effects of carbon monoxide,
since oxygen and carbon monoxide binding are competitive. In general, recent
5-19
-------
research is pointing to the presence of a lower intracellular p02 than previously
thought. Studies using polarographic microelectrodes in liver (Kessler
demonstrated a tissue p02 of < 10 mm Hg in 10-20% of their penetrations.
Whalen439 found that intracellular p02 in skeletal and cardiac muscle averaged
5-6 mm Hg. Computing mean myoglobin p02 from carbon monoxide binding to myo-
globin also give a normal p02 value of 4-7 mm Hg (Coburn85). Tissue p02
levels in brain are somewhat higher. Since we have no idea about either p02
gradients or compartmentalization in cells it is possible that intracellular
p02 at the site of carbon monoxide binding compounds are considerably below
these levels.
Chance at al. indicate that the p02 in mitochondria under conditions
of tight respiratory coupling and presence of ADP (state 3) is inhibited 50%
at 0.01-0.05 mm Hg. Since it is possible that the p02 in mitochondrial cristae
is as low as 0.01 mm Hg even though mean cytoplasmic p02 is 4-6, later in
this chapter we used this low value in calculations of possible effects
of carbon monoxide on cytochrome ag function.
Zorn studied the effects of carbon monoxide inhalation on brain and
liver p02> using Lubbers' platinum electrode and surface electrodes. It was
found in both tissues that tissue pO« fell, even at carboxyhemoglobin of 2%
saturation, and that the fall was almost directly related to the increase in
carboxyhemoglobin. For a 1% fall in oxyhemoglobln saturation due to an increase
in carboxyhemoglobin, pO. decreased 0.2 to 1,8 mm Hg. This is a particularly
nice approach since, if carbon monoxide had only an intracellular effect, tissue
p02 would be expected to increase. When the experimental animal breathed air
not containing carbon monoxide, tissue pO« returned toward normal.
5-20
-------
Weiss and Cohen431 have reported similar effects of breathing 80 and 160 ppm
carbon monoxide saturation g.^
for 20 minutes (resulting in carboxyhemoglobin of less than J.J/6; on
A /*
rat brain cortex p02 and rat biceps brachii muscle, as measured with a bare
platinum electrode.
Direct Carbon Monoxide Effects on Intracellular Processes _- Cytochrome
a^ and Mitochondrial Electron Chain Transport. Carbon monoxide affinity to
intracellular compounds has customarily been given in terms of the Warburg
partition coefficient:
K = [n/l-n] [C0/02]
where n is the fraction bound to carbon monoxide and CO/02 -*-s t*ie ratio of
carbon monoxide to 02 . The data are usually given where n=0.5/ which gives
the ratio of carbon monoxide to oxygen for 50% saturation with carbon monoxide.
There is apparently no new information about K for aj which has been widely
quoted to be 2.2-28. In the normal aerobic steady state in the rapidly
respiring State 3, the concentration of reduced cytochrome 33 is very low,
probably less than 0.1%. Because only reduced cytochrome 33 binds carbon
monoxide, the affinity of carbon monoxide for cytochrome 33 under this condition
is small. In coupled mitochrondia at low ADP concentration (State 4), the
steady-state concentration of reduced cytochrome 33 may be even lower.
Earlier studies of Chance^ have not been appreciated in previous publi-
cations concerning possible effects of carbon monoxide on mitochondria. He
studied the transient from anoxia to normoxia in pigeon heart mitochondria in
both the absence and presence of carbon monoxide. It was found in un-
coupled mitochondria that CO/02 ratios of 0.2 caused a marked delay in this
transient. Thus these mitochondria were markedly more sensitive to the
effects of carbon monoxide, when studied in this state. Chance also points
5-21
-------
out that the dissociation of carbon monoxide from reduced a$ is so slow that
it should take 3-4 minutes for one-half unloading to occur; thus after a
hypoxic episode, cytochrome a3 function can be influenced by much lower tissue
pCO.
Recent data have suggested that mitochondrial respiration may be more
sensitive to carbon monoxide under some conditions than previously indicated,
however, there is no solid evidence for implicating this system at low blood
carboxyhemoglobin levels. Even using C0/02 ratios of 0.2 for 50% binding to
33 which Chance found in uncoupled mitochondria during transients, and a pC>2
__o
of 0.01 mm Hg, computed tissue pCO at 5% carboxyhemoglobin of 2 x 10 * mm Hg
is slightly below that necessary to cause 50% binding to a^, however at a
carboxyhemoglobin of 10%, tissue pCO is high enough. There is a probability
that binding of carbon monoxide to a~ is physiologically significant during
tissue hypoxia at very low blood carboxyhemoglobin levels. Previous reviews
of possible effects of carbon monoxide on a3 have failed to point out that
the chemical constants and investigations are never performed at 37 C but at
25 C or less.
A recent line of investigation has revealed that heart
mitochondria isolated after chronic arterial hypoxemia have a higher State
3 mitochondrial oxygen uptake, per gram protein, than mitochondria isolated
from an animal which was not chronically hypoemic. These data may be pertinent
to acclimatization to carbon monoxide,which has been demonstrated in experimental
animals.
Cytochrome P-450. The Warburg coefficient for6 Cy*°chrOtne P"45has been
A-
quoted by Estabrook121 to be 1-5. Calculations similar to those performed
for cytochrome 33 in the preceding section suggest, using values of 5 to
5-22
-------
10 mm Hg for microsomal p02, that tissue pCO is 1 to 2 orders of magnitude
too low for carboxyhemoglobin at less than 15% saturation to have an effect
on the cytochrome P-450 system.
Recent advances in our knowledge of the effects of carbon monoxide on
Q
the cytochrome P-450 system are discussed below. Estabrook e£ al. found
that under conditions of rapid electron transport through the cytochrome
P-450 system, sensitivity to carbon monoxide increased. In the presence of
high concentrations of reducing equivalents and substrate, the C0/02 ratio
necessary for 50% binding was as low as 0.2 whereas with slow electron trans-
port the system becomes almost completely refractory to carbon monoxide.
Since carbon monoxide sensitivity does vary under changing conditions, it
is possible that in some conditions carbon monoxide sensitivity might increase
to levels where the cytochrome P-450 system is influenced by carbon monoxide
tension in tissues at low carboxyhemoglobin.
Data are now available on the effects of elevated carboxyhemoglobin on
the cytochrome P-450 system. Rondia^ found that in rats exposed to 60 ppm,
there was a decreased ability of liver to metabolize 3-hydroxybenzo[a]pyrene.
284 285
Montgomery and Rubin * found prolonged sleeping time in the presence of
20% carboxyhemoglobin in rats given hexobarbital. However, when they compared
these effects owing to carbon monoxide poisoning to those of hypoxic hypoxia,
looking at the effects with an equivalent arterial oxyhemoglobin percent
saturation, it was discovered the effects on sleeping time were greater owing
to hypoxic hypoxia than to carbon monoxide poisoning. In subsequent studies, Roth
34.4 344c "344(1
and Rubin '* have found that the greater effect with hypoxic hypoxia
was due to a decrease in hepatic blood flow. The effect of carbon monoxide is
probably due to a fall in capillary pO-, rather than carbon monoxide binding to
83
cytochrome P-450. Coburn and Kane found that 10-12% carboxyhemoglobin concentration
5-23
-------
in anesthetized dogs resulted in inhibition of loss of hemoglobin- haptoglobin
from the plasma. It is now known that catabolism of hemoglobin-hepatoglobin
is mediated by a cytochrome P-450 linked system but this could be due to a
blood flow effect. Rikans333 has reported evidence for a carbon monoxide bind-
ing compound in solubilized rat hepatic microsomes that is distinct from cyto-
chrome P-450, however, the chemistry and relative affinities for carbon monoxide
and oxygen, as well as its function, have not been delineated.
Myoglobin. The Warburg partition coefficient for the reaction of carbon
monoxide with oxymyoglobin is 0.04. Myoglobin is probably the intracellular
hemoprotein most likely to be involved in toxic effects of carbon monoxide,
Coburn et al.85 have measured the ratio MbCO/HbCO and found it to be
approximately 1 and Constant, even with increases in blood carboxyhemoglobin,-exceed-
ing 20% saturation. Thus, at 5 percent concentration of carboxyhemoglobin, 5
percent of the myoglobin should be bound to carbon monoxide. It is difficult
to interpret this in terms of toxic effects of carbon monoxide on skeletal
muscle, smooth muscle or heart muscle since the function of myoglobin is not
clearly defined, nor is it known where it is located in the cell. In the
heart, there is evidence that myoglobin buffers changes in oxygen tension
in close proximity to mitochondria during muscle contraction.-.Another
possible function of these compounds is to facilitate oxygen transport across
the cytoplasm from cell membrane to mitochondrion. Like other intracellular
hemoproteins, carbon monoxide binding is markedly increased in the presence
of tissue hypoxia.
There is evidence (by Clark and Coburn75) of significant carbon monoxide
shifts out of blood, presumably into skeletal muscle, during short-term bicycle
exercise at maximal rate of oxygen uptake.
5-24
-------
EFFECTS OF CARBON MONOXIDE ON THE PREGNANT WOMAN, DEVELOPING EMBRYO, FETUS,
AND NEWBORN INFANT
Insufficient knowledge exists about the biological effects of carbon
monoxide during intrauterine development and the newborn period.
Several studies report decreased birthweights and increased mortality
in the progeny of animals exposed to relatively high carbon monoxide concen-
trations, but few studies have reported on the more subtle effects at
lower concentrations. Most of the evidence supporting carbon monoxide effects
on the fetus is inferred from data on maternal smoking rather than from studies
of its effects per se. This section reviews both what is known and what is
not known about carbon monoxide effects on the developing embryo, fetus and
newborn infant; carbon monoxide exchange between the mother and the fetus
under both steady state and non-steady state conditions*and the mechanisms by
which it interferes with oxygenation of the fetus.
The Interrelations of Carboxyhemoglobin Concentrations in the jlother and Fetus
Maternal Carboxyhemoglobin Levels. The carboxyhemoglobin concentration
19 247
in the blood of normal nonsmoking pregnant women varies from 0.5 to 1%. '
In addition to those factors affecting carboxyhemoglobin in the nonpregnant
82
person f maternal carboxyhemoglobin concentration, [HbCOm], reflects the
endogenous carbon monoxide production by the fetus and its rate of exchange
across the placenta.^49 Fetal endogenous carbon monoxide production accounts
for about 3% of the total carboxyhemoglobin present in the blood of a normal
pregnant woman.
Fetal Carboxyhemoglobin. Under steady state conditions, the concentration
of human fetal carboxyhemoglobin, [HbCOf], is greater than that in maternal
blood (g ee Figure 5-9). The wide disparity in the reported values of both
5-25
-------
40 , .60
COVppm)
80
100
0.01 0.02 0.03 0.04 0.05 0.06 0.07
FIGURE 5-9. The relation of human maternal and fetal carboxyhemoglobin
concentrations under steady state conditions as a function
of both carbon monoxide partial pressure (mm Hg) an(i inspired
air concentrations in parts per million. (Reprinted with
permission from Hill jit al. )
5-26
-------
human fetal carboxyhemoglobin concentrations and the ratio of fetal to maternal
carboxyhemoglobin concentrations, [HbCOf ] /[HbCOm],247 probably results from a
number of factors. These include collecting the samples under non-steady
state conditions and using different methods to analyze for carbon monoxide.
While the fetal carboxyhemoglobin concentration varies as a function of the
concentration in the maternal blood, it also depends upon the rate of fetal
carbon monoxide production, placental carbon monoxide diffusing capacity, the
relative affinity of both fetal and maternal hemoglobin for carbon monoxide
as compared to its affinity for oxygen, and the relative affinity of blood
for these two gases.
The relation of the fetal to maternal carboxyhemoglobin concentrations
during the steady state depends on several factors. Assuming that the carbon
monoxide partial pressure in maternal blood, pCOm, equals the carbon monoxide
partial pressure in fetal blood, pCOf , the Haldane equation pCO = ([HbCO] x
x M) may be equated for maternal and fetal blood. The result when
rearranged becomes:
[HbCO,:] [Hb07 ] pOo Mf
Zf ^
(1)
[HbCOm] p02f [HbO^] Mm
where the ratios of oxyhemoglobin concentration to the oxygen partial pressure
for both fetal and maternal blood equal oxygen affinities of fetal and maternal
blood determined from the oxyhemoglobin saturation curves at the mean oxygen
tension of blood in the placental exchange vessels; and M£ and ^ are the relative
affinities of fetal and maternal blood. respectively for carbon monoxide as com-
pared to oxygen. Thus, the ratio of the concentrations of fetal to maternal
carboxyhemoglobin, [HbCOf ]/[HbCOm] , during the steady state depends on both the
relative affinities of fetal and maternal hemoglobin for oxygen and the ratio of
5-27
-------
the relative affinity of fetal and maternal blood for carbon monoxide and
oxygen,
Time Course of Changes in Fetal and Maternal Carboxyhemoelobin. The
relation of carboxyhemoglobin concentrations to inspired carbon monoxide
concentrations in adult humans has been experimentally determined in several
studies. Recently, Longo and Hill248 studied these relations in pregnant sheep
with catheters chronically implanted in both maternal and fetal blood vessels.
They exposed ewes to inspired carbon monoxide concentrations of up to 300 ppm.
At 30 ppm, maternal carboxyhemoglobin concentrations increased over a period
of 8 to 10 hr equilibrating at about 4.6 + 0.3 (SEM)%. The fetal carboxy-
hemoglobin concentration increased more slowly, equilibrating in 36 to 48 hr
at about 7.4 + 0.5 % (Fig. 5-10). At 50 ppm, the time courses were similar
with maternal and fetal steady values of 7.2+ 0.5 % and 11. 3 + 1.1 % re-
spectively. At 100 ppm, maternal and fetal steady state values were 12.2
+1.2 %and 19.8;+ 1.4 %, respectively. For all three concentrations, the
half-times for carbon monoxide uptake by maternal and fetal blood were about
2.5 and 7.5 hr respectively.
For ethical and technical reasons, such experiments cannot be carried
out with humans. This same group examined the experimental data and
theorized a mathematical model of the interrelations of human fetal and
maternal carboxyhemoglobin concentrations. The predicted changes in the
carboxyhemoglobin concentrations as a function of the time of exposure to
inspired carbon monoxide concentrations ranging from 30 to 300 ppm are
shown in Figure 5-11.
5-28
-------
j-i-M-*w/t
0 4 8 12 16 20 24 0 4 8 12 18 24
0 4 8 12 16 20 24 0 4 8 12 W 24
300 ppm for 3 hrt.
Ui
u
J.
20
16
12
8
4
100 ppm
~
0 4 8 12 16 20 24 0
TIME (hours)
8 12 18 24
4 8 12 U 20 24
TIME (hour*)
FIGURE 5-10. Time course of carbon monoxide uptake in maternal and fetal sheep exposed to
varying carbon monoxide concentrations. The experimental results for the ewe
(•) and fetal lamb (o) are the mean values (± SEM) of 9 to 11 studies at each
inspired carbon monoxide concentration, except in the case of 300 ppm. Only
3 studies were performed at that concentration. The theoretical predictions
of the changes in maternal and fetal carboxyhemoglobin concentrations for the
ewe and lamb are shown by the solid and interrupted lines, respectively.
(Reprinted with permission from Longo and Hill * )
-------
Maternal
Fetal
0
4 8 12
16
20 24 «oO 4
TIME (Hours)
8 12 16 20 24
FIGURE 5-11. The predicted time course of human maternal and fetal earboxy-
hemoglobin concentrations during prolonged exposures to 30,
50, 100, 200 and 300 ppm inspired carbon monoxide concentra-
tions, followed by a washout period when no carbon monoxide
is inspired. Note the fetal carboxyhemoglobin concentrations
lag behind that of the mother, but eventually reach higher
values in most cases. (Reprinted with permission from Hill
, 170v
et al. )
5-30
-------
Several points of interest are: The equilibration for fetal carboxy-
hemoglobin was not achieved for about 30 to 36 hr ; the half-time of the
increase in fetal carboxyhemoglobin concentration was about 7.5 hr for all
concentrations; the time for fetal carboxyhemoglobin to equal the maternal
value varied from 12 to 15 hr ; and finally, under steady state conditions,
fetal carboxyhemoglobin concentration was about 15% greater than the maternal.
The theoretical relations in humans and the experimental data in sheep are
therefore in reasonably good agreement.
Theoretical Prediction of Fetal._Carboxyh_emogfobin Concentration During
Intermittent Maternal Carbon Monoxide Exposure. Mothers who smoke cigarettes
or are exposed to excessive amounts of carbon monoxide in the air are sub-
jected to fluctuating concentrations of inspired carbon monoxide. The
previously described mathematical model^™ was used to simulate such condi-
tions and to predict the changes in fetal and maternal carboxyhemoglobin
concentrations during exposure to various carbon monoxide concentrations for
different durations. The time course of carboxyhemoglobin concentrations
i
anticipated if the mother breathed 50 ppm carbon monoxide for a 16 hr period
or smoked one and a half packs of cigarettes a day is shown in Figure 5-12.
The peak fetal carboxyhemoglobin concentrations were greater than the maternal
concentrations and the mean carboxyhemoglobin concentrations were 6% and
5.4% respectively. Similar patterns would be produced by exposure of the
mother (and fetus) to other carbon monoxide concentrations with the values
reflecting the concentrations. While peak fetal carboxyhemoglobin concen-
trations were only about 10% greater than maternal, the mean values were
about 20% greater. (This difference ranged from 25% greater at 5 ppm to 15%
greater at 50 ppm). The implications for the fetus of this greater carbon
monoxide exposure are unknown.
5-31
-------
50-
8
to
Z
*""• c
O 5
u
-O
I
MATERNAL
12
18 24 30
TIME (HOURS)
36
42
48
FIGUKF- 5-12. The predicted maternal and fetal carboxyhemoglobin concentrations
when a mother breathes 50 ppm carbon monoxide for a 16-hour
period followed by 8 hours during which no carbon monoxide
is breathed. This level of carbon monoxide exposure is
equivalent to smoking about 1 -1% packs of cigarettes per
day, followed by an 8-hour sleep period. (Reprinted with permission
from Hill et al.17°)
5-32
-------
This mathematical model also has been used to predict fetal and maternal
carboxyhemoglobin changes following more complicated exposure patterns. Data
on carbon monoxide concentrations obtained from the Los Angeles Air Pollution
Control District were measured at numerous sites in that city. Figure 5-13
shows the data for a typical site in southern Los Angeles (site number 76 in
Torrance) during January 22, 23, and 24, 1974, a Tuesday, Wednesday, and
Thursday. The inspired carbon monoxide concentration fluctuated between 0
and 48 ppm (upper curve). The values plotted represent hourly averages.
The lower curve shows the calculated maternal and fetal carboxyhemoglobin
concentrations, assuming a pregnant women breathed this air, with no additional
source of carbon monoxide^ such as cigarette smoke. ™ Following the peaks of
inspired carbon monoxide, the fetal carboxyhemoglobin concentration averaged
3%, while the maternal concentration averaged 2.6%.
These relatively low carboxyhemoglobin concentrations may seem too
small to be of much significance. However, several investigators (reviewed
in other sections of this report). have demonstrated significant reductions
in a number of physiologic functions with blood carboxyhemoglobin levels in
the range of 4 to 5%. For the case of a pregnant mother who smoked 1 to 2
packs of cigarettes per day, exposure to these elevated ambient carbon monoxide
concentrations would be nearly additive. Thus, it can be calculated that the
fetal carboxyhemoglobin concentration would be 6 to 7% in the pregnant mother
who smoked one pack of cigarettes per day and was exposed to this level of air
pollution. Similarly, if the exposed subject smoked two packs of
cigarettes per day, the fetal carboxyhemoglobin concentration may reach 10 to
11%.
5-33
-------
Maternal Smoking and Other Carbon Monoxide Exposure. Perhaps the most
common source of fetal exposure to greater than normal carbon monoxide concen-
trations is maternal smoking. Several studies have reported the carboxyhemo-
globin concentrations in the blood of mothers that smoke and their newborn
(Table 5-1). Carboxyhemoglobin concentrations of thefetusesranged from 2 to
10%, and those of the mothers ranged from 2 to 14%.
The blood samples were obtained at the time of vaginal delivery or
cesarean section and probably did not accurately reflect the normal values
of carboxyhemoglobin for several reasons: the number of cigarettes smoked
during labor may have been less than the number normally consumed; blood
, \M*
samples were collected at varying time intervals following the cessation of
smoking; and many samples were probably taken in the morning before the
carboxyhemoglobin concentrations had built up to the values reached after
prolonged period of smoking. Therefore, the concentrations measured in both
maternal and fetal blood may have been lower than average values for normal
smoking periods.
The relation between maternal smoking and low birthweight recently has
been reviewed. » > a» 5 The reports relating perinatal mortality to
-maternal smoking habits disagree. Several report an increased Incidence
of spontaneous abortion and of fetal neonatal and post-neonatal deaths
associated with maternal smokin8.53'54'96'130'275»276»330»348,349
314 404 454
Others- ' ' 'reported finding little correlation of these prob-
lems with smoking, but this conclusion probably was based on inadequate sample
size.
All recent studies using data from large population groups have concluded
that perinatal mortality is increased in the infants of mothers who smoke.
5-34
-------
Q-
— 50
r—i
§
o
ULJ
5-
O
u
_Q
I
.___,xFETAL
MATERNAL
JANUARY 22
JANUARY 23
TIME (DAYS)
JANUARY 24
FIGURE 5-13.
Measured carbon monoxide concentrations in inspired air
(upper curve) and calculated maternal and fetal carboxy-
hemoglobin concentrations (lower curves) during a 3-day
period in southern Los Angeles. Note that fetal carboxy-
hemoglobin concentrations rise slightly higher than maternal
concentrations following each peak in carbon monoxide ex-
posure and that the fetal carboxyhemoglobin concentrations
take longer to decline afteij^he peaks. (Reprinted with
permission from Hill et al. )
5-35
-------
TABLE 5-1
The Relation of the Concentrations of Fetal to Maternal Carboxyhemoglobin
in Mothers Who Smoke During Pregnancy
Fetal
Carboxyhemoglobin
Concentration %
7.6 (SEM + 1.14)*
3.1 (+ 0.84)**
5.0 (+ 0.48)
2.4 (+ 0.30)
5.3 (+ 0.22)
7.3
3.6 (+ 0.7)
7.5 +
Maternal
Carboxyhemoglobin
Concentration %
6.2 (+ 0.75)*
3.6 (+ 1.06)**
6.7 (+ 0.61)
2.0 (+ 0.31)
5.7 (+ 0.24)
8.3
6.3 (+1.7)
4.1
Fetal/Maternal
Carboxyhemoglobin
Ratio
1.2 (+ 0.2)*
0.9 (+ 0.14)
0.7 (+ 0.04)
1.2 (+ 0.08)
0.9 (+ 0.06)
0.9
0.6 (+ 0.15)
1.8
Reference
Haddon et al.
157
Heron
166
455
Young and Pugh
Tanaka390
Younoszai and Haworth^
90
Cole et al.
* one or more cigarettes 1 h or less prior to delivery
** one or more cigarettes 1 to 24 h prior to delivery
+ calculated from [HbCO ] and the ratio of [HbCO,;] to [HbCO ]
m
5-36
-------
This increased perinatal mortality is independent of, rather than due to,
birthweight reduction5.3 ,55,96a,276,297a,302a,274a while the mean duration
of pregnancy of smoking mothers is slightly shorter than normal, 30,250a,5Ua
the proportion of preterm births increased significantly. 53»^5^a Goldstein
has pointed out that the lower perinatal mortality among infants weighing
less than 2500 g of women that smoke probably reflects the increased mean
birthweight of the smokers' babies compared with those of the
nonsmokers. Meyer and her colleagues conclude from the Ontario, Canada data
that the independent effect of maternal smoking increases the perinatal
mortality risk 20% for light smokers (less than 1 pack per day) and 35% for
heavy smokers (1 pack or more per day) .
Several causes have been suggested for the low birth weights and in-
creased perinatal mortality: decreased food intake associated with smoking""
decreased placental blood flow due to the action of pharmacologic agents in
the smoke, and the effects of carbon monoxide on tissue oxygenation. While
carbon monoxide probably adversely affects fetal growth and development,
other factors such as various chemicals in tobacco smoke and the psychologic
make-up of the mother make it difficult to assess the specific effects of
carbon monoxide per se.
Several reports have analyzed the incidence of complications of pregnancy
and labor in smoking mothers. There are increases in the incidence of
abruptio placenta with resulting stillbirth, !47a,274a placenta previa and
other causes of bleeding during pregnancy. 215a,302b,274a The incidence of pre-
mature rupture of the fetal membranes is also increased^0 while that of the
hypertensive disorders of pregnancy is decreased. oa,53,215a,348,404
5-37
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Recently, it has been observed that "breathing" movements by the fetus
are a normal component of intrauterine development. Both the proportion of
time the fetus makes breathing movements and the character of these movements
indicate the condition of the fetus. In women with normal pregnancies,
cigarette smoking caused an abrupt and significant decrease from a control
value of 65% to 50% in the proportion of time that the fetus made breathing
134a,256a
movements. Carbon monoxide may not play an important role causing
these acute changes, however, since marked decreases in breathing were not
256b
observed in the fetuses of women who smoked non-nicotine cigarettes.
166
Heron reported a delayed onset of crying immediately after birth in the
infants of smoking mothers. Several infants showed definite evidence of
asphyxia with irregular respiration and cyanosis.
Long-term effects in surviving children owing to maternal smoking are
not well documented. In a multifactorial analysis of data from over 5,000 childrei
in the British National Child Development Study, Davie et al_. and Goldstein
found highly significant differences in reading attainment at 7 years between the
children of mothers who smoked and those who did not. Butler and Goldstein
restudied these children at 11 years of age. Significant differences in the
offspring of mothers who smoked 10 or more cigarettes a day —>
included: 3,4,and 5 months of retardation in general ability,reading, and
mathematics, respectively, and a mean height 1 cm less.Tlieir data suggest a
decrement in intelligence quotient, but the difference was not statistically
107a
significant. Finally, Denson £t al. reported a syndrome of minimal
brain dysfunction in the infants of mothers who smoke. These findings re-
quire confirmation as their implications are great.
5-38
-------
As noted in other portions of this report, there is a high correlation
between smoking and the development of coronary and peripheral artery disease.
Several studies indicate that carbon monoxide in tobacco smoke injures
arterial blood vessels.*•* Exposure to low doses of carbon monoxide accelerated
athrogenesis in cholesterol-fed animals-^.46a,423 pro(jucing significant ultra-
structural changes in the aortic and coronary epithelium of rabbits and
primates399,423 indistinguishable from early artherosclerosis. Asmussenand
KjeldsenlSa used the human umbilical artery as a model to evaluate vascular
damage caused by tobacco smoking. In comparison with the vessels from babies
of non-smoking mothers, the umbilical arteries from babies of smoking mothers
showed pronounced vascular intimal changes. Scanning electromicroscopy dis-
closed swollen and irregular endothelial cells with a peculiar cobblestone
appearance and cytoplasmic protrusions or blebs on their surface. Trans-
mission electromicroscopy showed degenerative changes including endothelial
swelling, dilation of the rough endoplasmic reticulum, abnormal appearing
lysosomes, and extensive subendothelial edema. In addition, the basement
membrane was markedly thickened, a change probably indicating reparative
change. Finally, the vessels showed focal openings of intercellular junctions
and loss of collagen fibers. This study underscores the vulnerability of the
fetus to the effects of smoking by the mother.
Animal studies showed fetal growth retardation and increased perinatal
mortality in pregnant rats120a»^56a and rabbits351a exposed to tobacco smoke.
Schoeneck^Sla exposed rabbits to tobacco smoke for several generations. The
original doe weighed 3.5 kg. One female of the first generation weighed
2.8 kg.j another one from the second generation weighed only 1.53 kg and all
5-39
-------
attempts to breed the doe were either totally unsuccessful or resulted in
stillbirths or neonatal deaths.
Of course, factors other than carbon monoxide in tobacco smoke may also
45 6a
result in fetal growth retardation. Younaszai, et al. exposed rats to
several types of smoke, including: the smoke of tobacco leaves,
smoke from lettuce leaves plus nicotine, and smoke from lettuce leaves alone.
The body weight of rat fetuses exposed to lettuce leaf smoke decreased 9%.
Body weight of the fetuses exposed to lettuce leaf smoke plus nicotine de-
creased about 12%, while the decrease in those animals exposed to tobacco
smoke was about 17%. The carboxyhemoglobin concentration was maintained at
from 2 to 8% in all animals, but the data were not given.
Biologic Effects of Carbon Monoxide on the Developing Embryo, Fetus, and Newborn
Experimental Studies of Mammalian Fetal Growth and Survival. Few studies
have reported the effects of carbon monoxide on fetal growth.
Wells^3^ exposed pregnant rats to 1.5% (15,000 ppm carbon monoxide) for from
5 to 8 min 10 times on alternate days during their 21 day pregnancy. This
resulted in maternal unconsciousness and abortion or absorption of most fetuses.
The surviving newborns did not grow normally. Similar exposure to 5,900 ppm
affected only a small percentage of animals. This is a brief report lacking
quantitative data on the number of experimental animals and number and weight
of the fetuses. Williams and Smith^3 exposed rats to 0.34% (3,400 ppm)
carbon monoxide for 1 hr daily for 3 months. Peak carboxyhemoglobin concen-
trations in these animals varied from 60 to 70%. The number of pregancies known to
occur amoung the 7 exposed animals were half the number in the controls. The
number of rats born per litter decreased and only 2 out of 13 newborns survived
to weaning age. No pregnancies resulted in the 5 females exposed for 150 days-
5-40
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19
Aatrup, et al. reported quantitative data on fetal weights of 2 groups of
pregnant rabbits exposed to carbon monoxide continuously —=>
for 30 days. Exposure to 90 ppm resulted in maternal carboxyhemoglobin con-
centrations of 9 to 10%. Birthweights decreased 11% from 57.7 to 51.0 g and
neonatal mortality increased to 10%, from a control value of 4.5%. Mortality
of the young rabbits during the following 21 days increased to 25% from a
control value of 13%. Following exposure to 180 ppm carbon monoxide, with
resulting maternal carboxyhemoglobin concentrations of 16 to 18%, birthweights
decreased 20% from 53.7 to 44.7 g, and neonatal mortality was 35% compared
with 1% for the controls. Mortality during the following 21 days was 27%,
the same value as the controls.
Carbon Monoxide Effects on Avian Embryogenesis. Baker and Tumasonis^^ con-
tinuously exposed fertilized chicken eggs to various carbon monoxide concen-
trations from the time they were laid for up to 18 days of incubation. Hatch-
ability correlated inversely with carbon monoxide concentration. At 425 ppm,
the apparent "critical level", only about 75% of the eggs hatched. The embryos
of these eggs weighed almost the same as those of the controls and no congenital
anomalies were noted. Since 0 and 100 ppm were the only lower carbon monoxide
concentrations tested, the conclusion that 425 ppm represents a "critical level"
may not be justified. In eggs exposed to 425 ppm, the carboxyhemoglobin con-
centrations varied from 4 to 16%. The lowest values were reported on the 15th
to 16th day of incubation. At 650 ppm carbon monoxide, the percent of eggs
hatching decreased to 46%, and developmental anomalies of the tibia and meta-
25
tarsal bones were noted. Subsequently, Baker et jil. exposed embryonated
eggs 12 and 18 days old to 425 ppm for 24 hr. The carboxyhemoglobin concen-
I
trations averaged 7% in 12 to 14 day chick embryos, 16% in the 16-day embryos,
5-41
-------
and 36% in the 18-day embryos. It is not clear why the carboxyhemoglobin
increased so markedly with embryonic age. The activities of two hepatic
mixed-function oxidase enzymes, hydroxylase and 0-demethylase increased
about 50% in the livers of the older chicks. Chick eggs 13 days old did
not show significant enzyme increases. The authors interpreted these results
as indicating that the increased hepatic mixed-function oxidase enzymes repre-
sent an adaptation to carbon monoxide induced tissue hypoxia in the more mature
embryo.
Exposure to Excessively High Carbon Monoxide Concentrations During the
Newborn Period. Behrman et al.37 reported that in 16 normal human newborns
in a nursery in downtown Chicago, the carboxyhemoglobin concentration in-
creased from about 1% to 6.98± 0.55% and the blood oxygen capacity
decreased 13.8i 0.57 % (control values were not given). The authors
correlated the decreases of blood oxygen capacity with carbon monoxide con-
centrations at a Chicago air pollution station about 1.5 miles distant.
On days when the ambient carbon monoxide concentration was ^ess than 20 ppm,
blood oxygen capacity was decreased 8.4+ 1*1 % in infants aged 24 hr old
or younger and 11.0+0.73 % in infants over 24 hr old. On days when the
atmospheric carbon monoxide was greater than 20 ppm, blood oxygen capacity
decreased 11.4+ 1.1% in the newborns and 13.0± 0.65 % in babies over
24 hr old. The carboxyhemoglobin concentrations varied as a function
of both the concentrations of inspired carbon monoxide and the duration of
exposure. While these observations are of interest, certain problems inherent
the study were not clarified. A close correlation between the carbon monoxide
concentrations in the nursery and at the monitoring station 1.5 miles distant
is questionable.
5-42
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The authors noted that the decrease in oxygen capacity was greater than could
be accounted for by carbon monoxide alone, although the error in the method
of carboxyhemoglobin determination with the spectrophotometer used probably
invalidates such a conclusion. No untoward clinical effects were observed
either from these carboxyhemoglobin concentrations or from the decrease in
blood oxygen capacity.
Apparently the only study in newborn animals is that of Smith et al.
They exposed rats to mixtures of illuminating gas in air, such that inspired
carbon monoxide concentrations equaled 0.43%. In 22 newborn rats 12 to 48 br
old exposed to carbon monoxide, the average survival time was about 196 min
in contrast to an average survival of about 36 min in mature animals. McGrath
and Jaeger26' also noted that 507o of newly hatched chicks oould withstand exposure
to 1% (10,000 ppm) carbon monoxide concentration for about 32 min. This initial
resistance to carbon monoxide decreased rapidly. By day one, mean survival time
decreased to about 10 min, by day 4 it was 6 min, and by day 8 it was 4 min,
where it remained for all ages tested up to 21 days. Subsequently, Jaeger and
McGrath18^ showed that decreasing the body temperature increased the time to
last gasp from a mean value of 9.8 + 0.5 min at 40 C to 20.7 + 0.1 min at 30 C.
They noted that hypothermia caused markedly reduced heart and respiratory rates
and suggested that its major benefit was a reduction in energy requiring functions.
Possible Mechanisms by Which Carbon Monoxide Affects the Fetus and
Newborn. Several mechanisms probably account for the effects of carbon monoxide
on developing tissue. Undoubtedly the most important of these is the inter-
ference with tissue oxygenation.27'* ^ As first observed by Claude Bernard
in 1857,^-> carbon monoxide decreases the capacity of blood to transport oxygen
by competing with it for hemoglobin. When carbon monoxide binds to hemoglobin,
the oxygen affinity of the remaining hemoglobin is increased. This shift to
the left of the oxyhemoglobin saturation curve means that the oxygen tension
5-43
-------
of blood must decrease to lower than normal values before a given amount of
oxygen will be released from hemoglobin. This effect may be particularly
significant for the fetus because the oxygen tension in the arterial blood
is normally relatively low, about 20-30mmHg, as compared to adult values of
about lOOmmHg. Carbon monoxide also interferes with oxygen transport by dis-
placing oxygen from the hemoglobin in arterial blood, thus decreasing the blood
oxygen capacity. For the pregnant woman, these effects on blood oxygenation pose
a special threat. Not only is her oxygen consumption increased 15-25% during
^ 1 OQ
pregnancy, but her blood oxygen capacity is decreased 20 to 30% or more due
to the decreased concentration of hemoglobin. The woman with a significant
anemia faces even more severe compromise of her oxygen delivery.
The theoretical basis for understanding the consequences of carbon
monoxide interaction with oxygen in humans is shown in Figure 5~14, in which
blood oxygen content is plotted as a function of the oxygen partial pressure.
The oxygen affinity of fetal blood is greater than that of maternal blood,
hence its oxyhemoglobin saturation curve is shifted to the left. In addition,
human fetal blood contains more hemoglobin than maternal (16.3 vs. 12 g/100 ml),
it therefore has a greater oxygen capacity. Under normal circumstances, ma-
ternal arterial oxygen tension is about 16.1 ml/100 ml of blood (point A.-, in
Fig. 5-14). The placental exchange of oxygen extracts about 5 ml 02/100 ml
blood, producing a uterine mixed venous oxygen tension of about 34 mmHg (point
V^). When the maternal blood contains carboxyhemoglobin, the oxygen capacity
is decreased and the oxyhemoglobin curve shifts to the left (as indicated by
the curve labelled 9.4% [HbCOm]. While arterial oxygen tension remains
essentially the same as under normal conditions, the oxygen content is reduced
to 14.5 ml/100 ml (point A^) • With the same placental oxygen transfer of
5 ml/100 ml blood, the venous oxygen tension would be about 27mm Hg (point V )>
M2
a decrease from normal of about 7 mm Hg.
5-44
-------
Ul
4>
Ul
22
20
90
100
Figure 5-14. Oxyhemoglobin saturation curves (plotted as blood oxygen content vs.
partial pressure) of human fetal blood with 0% and 10% carboxyhemoglobin and of
maternal blood with 0 and 9.47» carboxyhemoglobin concentrations. This figure depicts
the mechanism accounting for the reduction of umbilical artery and vein oxygen partial
pressures and contents resulting from elevated earboxyhemoglobin concentrations.
(See text for details.) (Reprinted with permission from Longo246a)
-------
In the fetus, oxygen partial pressure in the descending aorta is normally
about 20mm Hg and oxygen content is about 12 ml/100 ml fc oint Apl) > With an
oxygen consumption of 5 ml/100 ml, inferior vena caval oxygen tension would be
16 mm. Hg (pointv ) • With elev*ted fetal carboxyhemoglobin concentrations,
both arterial (.point Ap2 ) and venous (point V J» oxygen tensions are reduced.
This contrasts to the adult in which the arterial oxygen tension remains normal.
This is because of the lowered oxygen tension of maternal placental capillaries
with which fetal blood equilibrates. With normal fetal oxygen consumption,
the venous blood oxygen content is 5 ml/100 ml less than arterial content pro-
ducing a venous oxygen tension of about llmm Hg, a decrease from normal of
5 mm Hg.
The oxygen tension of venous blood is roughly indicative of the adequacy
of tissue oxygenation and the mean capillary partial pressure driving oxygen
into the tissues is probably related to the oxygen partial pressure at 50%
oxyhemoglobin saturation, the p50. Figure 5-15 shows the changes in P50 for
maternal and fetal blood as a function of the blood carboxyhemoglobin concen-
trations .
While the effects of carbon monoxide on venous oxygen tensions have been
considered from a theoretical standpoint, there has been essentially no experi-
mental validation of these effects in either adults or the fetus. Longo and
Hill248 recently examined the changes in oxygen tension in response to various
carboxyhemoglobin concentrations in sheep in which catheters were chronically im-
planted in maternal and fetal vessels. About a week following their recovery
from anesthesia and surgery the ewes were exposed to various concentrations of
carbon monoxide.
5-46
-------
[HbCO]
Figure 5-15» The partial pressure at which the oxyhemoglobin satura-
tion is 50%, p50, for human maternal and fetal blood as a function of
blood carboxyhemoglobin concentration. (Reprinted with permission
from Longo2^73)
5-47
-------
Figure 5-16 shows the oxygen tensions in the descending aorta and the
inferior vena cavae below the ductus venosus as a function of carboxyhemo-
globin concentration in the fetus. Maternal and fetal carboxyhemoglobin
levels were in quasi-steady state equilibrium. In contrast to the adult in
which arterial oxygen tension is relatively unaffected by changes in carboxy-
hemoglobin concentrations, fetal arterial oxygen tension is particularly
sensitive to increases in maternal or fetal carboxyhemoglobin concentrations.
This is because fetal arterial oxygen tension varies with the oxygen
tension in fetal placental end-capillary blood, which in turn varies with
the oxygen tensions in maternal placental exchange vessels. The oxygen
partial pressure in the fetal descending aorta decreased from a control value
of about 20 mmHg to 15.5 mmHg at 10% fetal carboxyhemoglobin concentration
(Figure 5-16). The regression equation for this relation was: p02 = 20.1 - 0.4
[HbCOf], (R = -0.96).
Figure 5^-16 also shows the relation of oxygen tension of the inferior
vena cava, below the ductus venosus. to carboxyhemoglobin concentration of
the fetus. At 10% carboxyhemoglobin concentration, inferior vena caval oxygen
tension decreased from a control value of about 16 to 12.5 mmHg. The regres-
sion equation for this relation was: p02 = 15.8 - 0.3 [HbCO-J. (R = -0.96).
Strictly speaking, the oxygen tension of fetal venous blood is affected both
by the decreased maternal placental venous oxygen tension resulting from in-
creased maternal carboxyhemoglobin concentration and the increased fetal
carboxyhemoglobin concentration. Since these oxygen tensions were obtained
when maternal and fetal carboxyhemoglobin concentrations were in a quasi-steady
state condition, a relation between fetal inferior vena caval oxygen
5-48
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20
Fetal Descending Aorta
0 2 4 6 8 10 12 14 16 18
FIGURE 5-16.
Fetal values of oxygen partial pressure as a function of
carboxyhemoglobin concentrations during quasi-steady state
conditions. Fetal inferior vena cava oxygen tension is a
function of both maternal and fetal carboxyhemoglobin con-
centrations. The oxygen partial pressure of fetal arterial
blood is chiefly a function of maternal carboxyhemoglobin
concentrations. During steady state conditions, however,
it will also be related to the fetal carboxyhemoglobin con-
centration. Each point represents the mean + SEM (vertical
bars) of 6-20 determinations at each concentration of blood
loglobin. (Reprinted with permission from Longo
a)
et al.
5-49
-------
tension and maternal carboxyhemoglobin concentration would be expected. If
one plots this relation,2488 the decrements in fetal oxygen tension appear
greater when plotted as a function of maternal carboxyhemoglobin than when
plotted as a function of fetal carboxyhemoglobin concentration. This follows
because the carboxyhemoglobin concentration of the fetus exceeds that of the
mother during equilibrium conditions.
These oxygen partial pressures in sheep are not identical with those values
anticipated in humans, because of differences in oxygen affinities and capacities
of maternal and fetal blood between the species. Differences however^are
estimated to be no more than 2-3 mmHg.
About 577. of the sheep fetuses in this study died when fetal carboxyhemoglobin
values were greater than 15% for 30 minutes or longer (5 of 11 died at 100 ppm,
and 3 of 3 died at 300 pprn).2^3 These deaths presumably resulted from hypoxia
of vital tissues. There are probably two major reasons for this. Firstly, in
the adult, elevation of carboxyhemoglobin concentrations to 15-20% results in a
6-10 mmHg decrease in venous oxygen tension. While this decrease is substantial,
the resultant oxygen partial pressures probably remain well above critical values
for maintaining oxygen delivery to the tissues. a In contrast, in the fetus
with normal arterial and venous oxygen tension probably close to the critical
levels, a 6-10 mmHg decrease in oxygen tension can result in tissue hypoxia or
anoxia. Furthermore, adult subjects and animals subjected to carbon monoxide
hypoxia show increases in cardiac output, coronary blood flow, and presumably
of tissue blood flow. Apparently, such compensatory adjustments are not available
to the fetus to any great extent. The decreases in blood oxygen tensions measured
experimentally were similar to those predicted, assuming no increase in tissue
blood flow. In addition, the fetus probably cannot increase its cardiac output
significantly.as fetal cardiac output normally is about 2 to 3 times that of the
319a
adult on a per weight basis,, Thus, the fetus probably normally operates
near the peak of its cardiac function curve.
5-50
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136a,136b
Ginsberg and Myers studied the effects of carbon monoxide
exposure on near-term pregnant monkeys and their fetuses. They acutely
exposed anesthetized animals to 0.1 to 0.3% carbon monoxide, resulting in
maternal carboxyhemoglobin concentrations of about 60%. During the 1 to
3 hr studies, fetal blood oxygen content decreased to less than 2 ml/100
ml blood. Fetal heart rate decreased in proportion to the blood oxygen
values. These fetuses also developed severe acidosis (pH less than 7.05),
hypercarbia (pCK^ = 70 mmHg or greater), hypotension and electrocardio-
136a
graphic changes such as T-wave flattening and inversion.
In cases of acute carbon monoxide poisoning, the mother will develop a
high carboxyhemoglobin concentration with a shift to the left of her oxyhemo-
globin saturation curve while the carboxyhemoglobin concentration in the
fetus remains normal or low. Nonetheless, the fetus experiences a decrease
136a,247b
in pOn values, because of the shift in the maternal dissociation curve.
O 1 O
In a theoretical analysis, Permutt and Farhiji calculated the effect
of elevated carboxyhemoglobin in lowering oxygen tension in the venous blood
of an otherwise normal adult. Hill et^ al. used this approach to calculate
the effect of various carboxyhemoglobin concentrations on fetal tissue oxygena-
tion. The equivalent reduction in umbilical arterial oxygen tension required
to maintain normal placental oxygen exchange, or the equivalent increase in
blood flow necessary for oxygen exchange was calculated. The results are
plotted in Figure 5-17. A 10% carboxyhemoglobin concentration would be
equivalent to a 27% reduction in umbilical arterial p(>2 (from 18 to 13 mm-Hg.
It would also be equivalent to a drastic reduction in blood flow. Fetal
blood flow would have to increase 62% (from 350 to 570 ml/min) to maintain
normal oxygen exchange. Higher levels of fetal carboxyhemoglobin require
even more dramatic compensations.
A further carbon monorxide effect is its relation to oxygen consumption
OQf)
by placental tissue. Tanaka used a Warburg apparatus to measure oxygen
consumption in placental slices from non-smoking and smoking mothers. With
5-51
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Umbilical
vein
Umbilical
artery
[HbCOm]
10
[HbCOf]
10
15
Figure 5-17. upper panel. The umbilical arterial oxygen partial
pressure drop necessary to maintain normal oxygen exchange at
various carboxyhemoglobin concentrations allowing no change in
maternal or fetal blood flows or maternal arterial oxygen partial
pressures.
Lower panel. The increase in fetal blood flow necessary to main-
tain oxygen exchange (with no change in umbilical arterial oxygen
tension). These curves indicate the degree of compensation neces-
sary to offset the effects of elevations in carboxyhemoglobin con-
centrations. (Reprinted with permission from Hill et al. )
5-52
-------
tissues from normal non-smoking mothers, the oxygen consumption was about
1.9pl/mg placenta per hour. With the tissue from smoking mothers, the rate
of oxygen consumption decreased in proportion to the concentration of carboxy-
hemoglobin in the maternal blood. For example, it decreased about 30% to
1.3 jal/mg per hr at a maternal carboxyhemoglobin concentration of 8%.
Hypoxia owing to carbon monoxide may further interfere with tissue
oxygenation by increasing the concentration of carboxymyoglobin, [MbCO], in
relation to carboxyhemoglobin. As shown by Coburn and his coworkers, when
arterial oxygen tension decreases to 40 mm Hg or lower, the ratio of carboxy-
myoglobin to carboxyhemoglobin increases from a normal value of 1.0 to about
84 85
2.5 in the resting dog skeletal muscle and myocardium of dogs. If a
similar relation exists in the fetus, where arterial pO_ is normally 30 mm
Hg -or less, then carboxymyoglobin concentration would be 12.5% when
carboxyhemoglobin is 5%. The effect of this degree of carboxymyoglobin
saturation on oxygenation of the fetal myocardial cells may be significant.
Similarities of High Altitude Hypoxia andCarbon Monoxide Hypoxia. The
interference with tissue oxygenation caused by carbon monoxide is somewhat
similar to hypoxia at high altitudes. Both can result in lower oxygen
tensions in end-capillary blood and therefore tissue hypoxia. The
effect of smoking on newborn birthweight is strikingly similar to the effects
of high altitude. A study by the Department of Health, Education,and Welfare
reported in 1954 that in the Rocky Mountain states mean birthweights were
lower, there were a larger proportion of babies weighing less than 2500 g and
fewer weighing greater than 4000 g, and neonatal mortality was higher than in
O CO
the country as a whole. ~>0 A comparison of infants born in Lake County, Colorado,
elevation about 3000-3600 m (9,800-11,800 ft), with those born in Denver, about
1585 m (5,200 ft), showed that mean birthweight of the Lake County babies
5-53
-------
f\ o n
was 290 g less than that of those born in Denver. In Lake County, 48.3%
of newborns weighed less than 2500 g compared with 11.7% in Denver.
A more precise analysis of the relation between altitude and birthweight
can be derived from the work of Grahn and Kratchman.1^8 These workers showed
that the proportion of low birthweights increased with increasing elevation.
The number of infants weighing less than 2500 g increased to 10.1% at 1500-1580
(4,920-5; 180 ft) from a control value of 6.6% at sea level. At 2,760 m (9,055
ft), the number of such newborns further increased to 16.6%. The decrease in
the duration of gestation, a mean difference of 0.4 week,was not enough to
explain the 190 g birthweight difference between Colorado and Illinois-Indiana
148
infants.
A given carboxyhemoglobin concentration may cause a more profound effect
on tissue oxygenation at high altitudes than at sea level. Thus, individuals
at high altitudes would be expected to be more sensitive to the effects of
carbon monoxide. This would be particularly true of the pregnant mother, whose
312a
oxygen requirement is greater than when not pregnant, as well as for the
newborn infant.
5-54
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CARDIOVASCULAR RESPONSES TO CARBON MONOXIDE EXPOSURE
The heart requires a continuously available supply of oxygen in order
to maintain electrical and contractile integrity. The glycolytic response
to hypoxia in the myocardium is much less than that observed in skeletal
*
muscle and is unable to prevent a rapid depletion of high energy phosphates.
Ectopic electrical activity, decline in contractile force and ventricular
fibrillation soon follow the induction of myocardial hypoxia. As discussed
earlier carbon monoxide decreases the oxygen-carrying capacity of hemoglobin
and shifts the oxyhemoglobin dissociation curve to the left reducing the
oxygen tension in both the capillaries and cells (5 ee Figure 5-18).
The concept that any alteration in intracellular oxygen tension is
rapidly corrected by an appropriate increase or decrease in coronary blood
flow is central to an understanding of the effects of carboxyhemoglobinemia
on myocardial oxygenation. Peripheral tissues respond to increased oxygen
needs by increasing oxygen extraction and reducing venous oxygen content
and tension. Increased myocardial oxygen extraction is almost never seen
in the normal heart and, when present, is considered evidence of myocardial
hypoxia.
The capacity for increased coronary blood flow in the normal heart is
demonstrated by increases of up to 300% in the coronary flow during exercise,
in severe anemia or in individuals exposed to arterial hypoxemia. •
The myocardium probably also adapts to hypoxia by increasing "functioning"
capillary density. The capacity of the normal heart to maintain its
oxygenation at relatively high carboxyhemoglobin concentrations is analogous
to the situation in which a normal man climbs to high altitudes or a patient
with chronic anemia sustains a 70% reduction in circulating hemoglobin.
5-55
-------
Coronary Blood Flow,
ml/IOOg/min
200i Capacity
1501
IOCH
50
MVg , ml/min/IOOg
Capacity, ml/100 ml
p50, mmHg
5
5
18 20
10
10
22
24
15
15
26
28
20
20
30
FIGURE 5-18. Analogue model illustrating theoretical relationships between
coronary blood flow and myocardial oxygen consumption (MV_ ),
°2
hemoglobin oxygen carrying capacity (Capacity), and the position
of the oxyhemoglobin dissociation curve (p50). Point A on the
p50 and capacity curves represents coronary blood flow at normal
p50 and hemoglobin capacity; Point B illustrates theoretical
effect of increasing carboxyhemoglobin from 0 to 20% saturation
on coronary blood flow. The assumptions used in computing this
theoretical model are given by Duvelleroy. Adapted from
Duvelleroy et al.
5-56
-------
The importance of coronary blood flow in the maintenance of myocardial
oxygen tension is emphasized in a recent theoretical model presented by
Duvelleroy et^ al. ' Increasing myocardial oxygen consumption (by increasing
heart rate, arterial blood pressure, or contractile force), decreasing oxygen
capacity, or shifting the oxyhemoglobin dissociation curve to the left all
lead to a decrease in myocardial oxygen tension unless coronary blood flow
is increased commensurately. Figure 5-18 shows that each alteration can
independently produce a change in coronary blood flow which restores myo-
cardial oxygen tension to normal. Increasing carboxyhemoglobin concentra-
tions increase coronary blood flow both by decreasing the oxygen capacity
of hemoglobin and by shifting the oxyhemoglobin curve to the left, shown
in the figure as a decrease in the oxygen tension at 50% concentration, p50.
Points A and B show the effects of 0 and 20% carboxyhemoglobinemia, re-
spectively. Note that the relationships are curvilinear so that progressively
greater alterations call forth disproportionately greater increases in
coronary blood flow. The implications of this type of response curve for
«-*»o
elevated baseline conditions discussed elsewhere in this chapter. The
cardiovascular response of the intact organism to carbon monoxide inhalation
depends on the ability of the entire coronary vascular bed to dilate and in-
crease coronary blood flow. The random occurrence of coronary atherosclerosis
in the general population explains the variation in myocardial responses ob-
served both in humans and among different species. It also provides a physiologic
explanation for the clinical observations described in the next section.
The manifestations of carbon monoxide toxicity were shown to be closely
related to the carboxyhemoglobin concentration by John Haldane15' in 1895.
5-57
-------
He did not observe serious symptoms at rest until his own hemoglobin was at
least one-third saturated with carbon monoxide. Exertionfhowever, produced
mild dyspnea and palpitations when as little as 14% carboxyhemoglobin was
present. Haggard158 in 1921 and Chiodi and coworkers72 in 1941 observed
increase in pulse rate and cardiac output with carboxyhemoglobin concentra-
tions between 16 and 20%.
Ayres e£ ail.21 studied the systemic hemodynamic and respiratory re-
sponse to acute increases in carboxyhemoglobin in man, by means of measure-
ments performed during diagnostic cardiac catheterization. Carboxyhemoglobin
concentrations between 6 and 12% were achieved by the breathing of either
5% carbon monoxide for 30-45 s or 0.1% carbon monoxide for 8-15 min. In men
with no evidence of heart disease, cardiac output increased from 5.01 to 5.56
1/min, the minute ventilation increased from 6.86 to 8.64 1/min, and arterial
carbon dioxide pressure pCC^, decreased from 40 to 38 mm Hg. Systemic oxygen
extraction ratios increased from 0.27:jto 0.32:1, indicating more complete
extraction of oxygen from perfusing arterial blood. Mixed venous oxygen
tension decreased from 39 to 31 mm Hg as a result of the leftward shift of
the oxyhemoglobin dissociation curve and arterial pOo unexpectedly decreased
from an average of 81 to 76 mm Hg. The decrease is probably due to enhance-
ment of the venoarterial shunt effect and is more prominent in patients who
initially have a low arterial pOo.
Observations such as this suggest that carbon monoxide inhalation would
have a significant effect on arterial p02 in those patients with preexisting
lung disease, in those individuals who are heavy smokers, and in patients in
coma owing to severe carbon monoxide poisoning. These studies were repeated
with the lower concentration of carbon monoxide (0.1% for 8-15 min). Cardiac
5-58
-------
output did not change significantly, although pC02 decreased, indicating hyper-
ventilation. Changes in arterial and mixed venous pO^ were similar to those
observed with the higher concentrations.
Myocardial studies were performed before and after the administration
of either 5 or 0.1% carbon monoxide for 30-45 s or 8-15 min,respectively.
Patients were divided into two groups, those with coronary arterial disease
and those with other cardiopulmonary disorders. In the patients with other
cardiopulmonary diseases, the lowest concentration of carbon monoxide decreased
the myocardial arteriovenous oxygen difference by an average of 6.6% and
in the patients with coronary arterial disease by 7.9%. The higher concentra-
tion decreased the difference by 25% and 30.5%, respectively. Coronary blood flow
increased in all but two of the studies, regardless of the dose delivered.
These changes were statistically significant.
Neither the presence of coronary arterial disease nor the concentration
of carbon monoxide appeared to alter this reponse to increasing carboxyhemo-
globin. Failure of the increase in coronary blood flow to compensate for the
decrease in oxygen delivery produced by carbon monoxide was suggested by a
decrease in coronary sinus oxygen tension in all but two of the 26 patients
studied. Nine of 14 patients with coronary arterial disease had decreased
lactate extraction with increasing carboxyhemoglobin, a finding suggestive
of anaerobic metabolism. In four of these patients, lactate extraction ceased
and the myocardium produced lactate, indicating severe anaerobic metabolism.
The increase in their carboxyhemoglobin concentration averaged 5.05%. These
studies were performed in patients with arteriographically demonstrated
coronary arterial disease. The abnormal changes occurred while the patients
were, at rest.
5-59
-------
Adams et^ al.2 also found that low concentrations of carboxyhemoglobin
increased coronary blood flow. These workers exposed conscious dogs to
carbon monoxide at increasing concentrations and observed a 13% increase
in coronary blood flow with a 4% increase in carboxyhemoglobin. At 20%
carboxyhemoglobin, coronary blood flow had increased by 54%. Coronary blood
flow measurements at 4 carboxyhemoglobin concentrations suggested a linear
relation between carboxyhemoglobin concentration and blood flow. A threshold
value was not observed, although measurements were not made below 5% carboxy-
hemoglobin.
Studies in experimental animals with presumably normal coronary vascular
beds are useful models for the effects of carbon monoxide on individuals with-
out coronary disease. Since myocardial oxygen tension is maintained by in-
creasing coronary blood flow, in these studies dose-response relationships
cannot be directly used for establishing threshold levels for man.
An interesting study of the effect of relatively low concentrations of
carbon monoxide in the cynomolgus monkey has been reported by DeBias et_ al.^97
They observed that chronically increased carboxyhemoglobin (to an average of
12.4%) produced polycythemia with an increase in hematocrit from 35 to 50%
of the volume of packed red blood cells. All animals developed increased
amplitude of the P-wave in the electrocardiogram and some developed T-wave
inversions suggestive of myocardial ischemia. Electrocardiographic abnormalities
5-60
-------
were more severe in the monkeys with experimental myocardial infarction and
increased carboxyhemoglobin than in those with experimental infarction who
were breathing ambient air.
In a later study, DeBias et al.^97 showed that increasing the carboxy-
hemoglobin concentration to an average of 8.5% in five cynomolgus monkeys
reduced the ventricular fibrillation threshold. Fibrillation could be produced
by an average of 45 V AC delivered for 150 msec during the vulnerable period
compared to 79 V while breathing ambient air (p < 0.01). This observation
in normal monkeys is particularly relevant to the problem of sudden death in
atheromatous man.
The study of ultrastructural changes following exposure is another
approach to the evaluation of the myocardial toxicity of carbon monoxide.
Thomsen and Kjeldsen^OO observed myofibrillar degeneration and myelin body
formation in the mitochondria of rabbits exposed to carbon monoxide at 100 ppm
for 4 hours, an exposure sufficient to raise carboxyhemoglobin concentrations
to 8 or 9%.
While the currently available physiologic data are insufficient by
themselves to formulate dose-response data, they emphasize the multifarious
nature of the human response. Sudden exertion in an individual with carboxy-
hemoglobinemia requires a substantial increase in coronary blood flow in
order to overcome the effects of increased myocardial oxygen requirements,
decreased oxygen-carrying capacity of hemoglobin, and rightward shift of the
oxyhemoglobin dissociation curve (Figure 5-18). Should an appropriate in-
crease in blood flow be limited in any region of the myocardium by a rigid
vascular bed, myocardial hypoxia may occur. Such a multivariate formulation
emphasizes the difficulty of identifying a single threshold concentration
capable of protecting the entire population.
5-61
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THE RELATION BETWEEN CARBON MONOXIDE AND CORONARY ARTERY DISEASE
Arteriosclerotic heart disease (ASHD) is the leading cause of death in
the United States,208 with approximately 35% of all deaths directly attributable
to this disease. It is also a major cause of morbidity. Some of its clinical
and epidemiologic characteristics are particularly pertinent for establishing
a causal relationship between carbon monoxide exposure and ASHD. The patho-
logic basis of the clinical disease is a severe, diffuse narrowing of the
coronary arteries.337 Neither the frequency nor the prevalence of coronary
arterial stenosis in the population is known. There are, however, many people
with asymptomatic severe coronary arterial stenosis due to atherosclerosis.
They are at high risk with respect to developing clinical ASHD.
The underlying atherosclerosis is considered to be a chronic disease
but the clinical manifestations are usually acute. Approximately 25-30%
of the individuals die suddenly, from several minutes to 24 hours after their
216
first heart attack. Certain risk factors for clinical disease have been
322
identified. They appear to act primarily in the development of the severe
underlying atherosclerotic disease and the consequent coronary stenosis.
Very little is known about the specific factors that precipitate the clinical
disease, such as myocardial infarction, angina pectoris and sudden death.
Agents that decrease the available oxygen supply to the myocardium, including
carbon monoxide, are primary suspects as precipitating factors in heart attacks.
Most persons who experience either angina or myocardial infarction have
severe coronary arterial stenosis.313 They are at high risk compared to the
rest of the population for recurrent heart attacks and sudden death.^7 About
20% of the men who survive the first months after a myocardial infarction will
5-62
-------
die within 5 years.-> Most of these deaths will be due to recurrent heart
attacks, and about 60% of the deaths will be sudden. The specific environ-
mental and host factors that determine survival following a heart attack have
not been clearly determined.
Environmental exposure to carbon monoxide and ASHD may be related in two
ways. One of these is that exposure to carbon monoxide can enhance the develop-
ment of underlying atherosclerosis and subsequent coronary arterial stenosis
when associated with other risk factors such as increased cholesterol levels
and hypertension. The other is that in the presence of severe underlying
coronary arterial stenosis due to atherosclerosis, carbon monoxide may be a
major precipitant of myocardial infarction, angina pectoris or sudden death.
Such a relation is very plausible in the light of what is known about the
epidemiology of heart disease and the possible pathophysiologic mechanisms.
The relation between carbon monoxide and the precipitation of heart
attacks can be extended further to include new cases among individuals with
pre-existing but silent underlying atherosclerosis; an increase in mor-
bidity}such as greater frequency and severity of chest pain,in patients with
angina pectoris:j or a reduction in survuval amoung individuals with clinical
atherosclerotic heart disease such^as decreased life expectancy following a
myocardial infarction.
The Relation Between Exposure to Carbon Monoxide, Severity of Coronary
Atherosclerosis and Possible Precursor Vascular Lesions
Studies of the association between the underlying coronary atherosclerosis
and exposure to carbon monoxide have been limited to laboratory investigations
with animal models (Table 5-2).17,206,399,421,423 in these studies the
5-63
-------
experimental animals are exposed to various concentrations of carbon monoxide
either continuously or intermittently, while the controls breathe ambient air.
For some of the experiments both the experimental and the control animals are
fed a diet high in cholesterol and/or fat, and either the cholesterol content
of the artery or the extent of vascular disease is measured. Several studies
in rabbits and primates have reported that animals exposed to relatively high
doses of carbon monoxide (170-180 ppm) for extended periods of time have either
a higher cholesterol content in their arteries or enhanced vascular disease.
Animals in another type of study were exposed to large doses of carbon monoxide
but were not fed a high cholesterol or fat diet. These studies in both pri-
mates and rabbits have reported finding subendothelial edema and gaps between
the endothelial cells with increased infiltration of the cells with lipid
droplets. (These lesions might be the early precursors of atherosclerotic
disease.)
There are no studies in humans describing the relation between exposure
to carbon monoxide and the rate of development of atherosclerotic disease.
Evidence that such a relation exists is based on the observation that
cigarette smokers, who have higher carboxyhemoglobin concentrations than
nonsmokers, also have more advanced atherosclerosis than nonsmokers.^^
There is also evidence(however, that exposure to carbon monoxide may not be
causally related to the underlying atherosclerosis. Heavy cigarette smokers
in countries, such as Japan, where the diets are low in fat and cholesterol
do not seem to have a high risk of heart attacks and probably do not have
195
severe coronary atherosclerosis.
5-64
-------
TABLE 5-2
The Relation Between Atherosclerosis and Carbon Monoxide
Ul
i
Ui
Animal
Rabbit
Rabbit
Primates &
Squirrel
Monkey
Primates :
Macaca Iris
Rabbit
Exposure
Experimental
CO at
0.009%
Cholesterol &
170 ppm CO for
7 weeks
Atherogenic diet
plus 200-300 ppm
CO for 4 hr
5 days per week for
7 months
250 ppm CO
continuously
250 ppm every
12 hours
180 ppm CO for
2 weeks
Results
Control
Ambient air Increased focal degenerative and
reparative changes in intimal and
subintimal coats in CO-exposed
animals
Cholesterol and Cholesterol content of aorta
ambient air 2 . 5 times higher than in control
Atherogenic diet Enhanced atherosclerosis in
only and com- monkey exposed to carbon
pressed air monoxide
Ambient Air Experimental group subendothelial
edema and infiltration of cells,
lipid droplets in coronary arteries
Air Exposed, local areas of partial
or total necrosis of myofibrils
and degenerative changes of
mitochondria
Reference
421
Wans tr up et al.
Astrup et al.
Webster e_t al.^23
Thomsen3^
Q/-V/T
Kjeldsen et al.
-------
The enhancement of atherosclerosis due to carbon monoxide exposure might
take place only in the presence of a high fat, high cholesterol diet. Since
much of the United States population eats such a diet, exposure to carbon
monoxide could be an important determinant of the extent of coronary athero-
sclerosis. However, because the data for such an association are preliminary
in nature, any current conclusions would be speculative.
The Relation Between Exposure to Carbon Monoxide and the Incidence of
Clinical Arteriosclerotic Heart Disease
The relation between ambient carbon monoxide concentrations and the
incidence of clinical disease in man has been studied in two ways. One of
these was by comparing the spatial or temporal distribution of ambient carbon
monoxide concentrations with the occurrence of new cases (Table 5-3). The
other was by measuring the post-mortem carboxyhemoglobin concentrations among
ASHD sudden death subjects and those of subjects who died suddenly from other
causes and comparing the values with those of normal living controls. ~ ~
In two community studies (Los Angeles^l and Baltimore^!?) a relation
between the incidence of heart attack and ambient carbon monoxide concentrations
has not been demonstrated. The Los Angeles study was based on hospital admissions
for myocardial infarctions and the Baltimore study was based on sudden and
more prolonged deaths due to ASHD and patients admitted to the hospital because
of their first transmural myocardial infarction.
The major problem with this type of study is the difficulty in determining
the dose of carbon monoxide that a heart attack subject may have received owing
to exposure to the ambient carbon monoxide concentrations in the community.
The onset of the acute event, myocardial infarction, or sudden death, is not
5-66
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TABLE 5-3
The Relation Between Ambient Carbon Monoxide Levels and Incidence and Survival of Coronary Heart Disease
Study
Method
CO Range
Results
Los Angeles
Comparison of admissions and case-
fatality from heart disease in
high and low CO areas.
Above or below 8 ppm CO; 2,484
admissions in high, 596 in low
areas.
5-14 ppm weekly
basin average
No difference in admission rates.
Increased fatality rates in high CO
areas only during times of high
pollution (8.6+ mean weekly ppm CO)
Oi
Baltimore Incidence of sudden death,
myocardial infarction, total
ASHD deaths compared with
ambient CO concentrations
at one station.
0-4 ppm compared
to 9+ ppm CO
24-hour average
No relation between the incidence of
sudden death, myocardial infarction
or total ASHD deaths, and the ambient
CO concentrations.
-------
well-defined except perhaps for instantaneous deaths.335 For many myocardial
infarction cases and sudden deaths, there is a prodromal period which may last
for several days prior to hospitalization or death. Therefore, the ambient
carbon monoxide concentrations on the day of admission or death may have little
relation either to the onset of the myocardial infarction or to sudden death.
Can the values reported by a field-monitoring station be used to estimate the
dose or change in dose for an individual living in the community but not in the
immediate vicinity of the sampling station? Perhaps it would be advisable to
consider the reported values as a crude estimate of changes in exposure from
day-to-day rather than as an individual dose.
Comparing carboxyhemoglobin concentrations between subjects and controls
partially eliminates the problem of estimating specific individual doses.
Carboxyhemoglobin concentrations in subjects experiencing sudden death due
to ASHD were compared with those in subjects whose sudden death resulted from
other causes or with the concentrations in living controls. For sudden death
the time between onset of the event and death is usually relatively brief.
Since carboxyhemoglobin concentration is stable after death, the concentration
determined at post-mortem may be a good estimate of the concentration at the
time of death.
The first such study took place in Los Angeles where carboxyhemoglobin
measurements were made at post-mortem on a 20% sample of the subjects (2,207
deaths) from the Los Angeles County Chief Medical Examiner/Coroner's cases.
Questionnaires about smoking habits were returned from the next-of-kin of
1,078 of the subjects (Table 5-4).l03 The cause of death was determined at
the post-mortem examination. Carboxyhemoglobin concentrations were higher
5-68
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TABLE 5-4
The Relationship Between Carboxyhemoglobin and Cause of Death
Study
Method
Results
Los Angeles County <"!hief
Medical Examiner/
Coroner 103
Ul
VO
Baltimore Office of the
Chief Medical Examiner217
20% sample, Los Angeles County Chief
Medical Examiner/Coroner's case load:
November 1950 - June 1961, blood
samples 2,207 cases; smoking
questionnaire
Comparison of carboxyhemoglobin
concentrations in relation to cause
of death. Age, race, sex for ASHD
deaths by smoking history detailed
pathology and length of survival;
2,366 deaths
High carboxyhemoglobin levels in
cigarette smokers
Younger smokers higher carboxyhemo-
globin than older cigarette smokers
Greater the. amount of smoking,
higher the carboxyhemoglobin levels
Relationship between postmortem
carboxyhemoglobin and ambient carbon
monoxide among nonsmokers in most
polluted areas
Cause of death had little or no relation>
ship to the carboxyhemoglobin concent-
ion at post-mortem
Carboxyhemoglobin higher for ASHD
sudden-death subjects than in
those of sudden-death owing to
other natural causes, but no dif-
ference in comparison with
traumatic deaths
Among ASHD death subjects, carboxy-
hemoglobin higher in younger than
older age group
Among smokers, carboxyhemoglobin
higher in controls than ASHD death
subjects. For non-smokers, carboxy-
hemoglobin greater in ASHD sudden
death than controls
No relation of ASHD death subjects'
pathology, place of activity at
onset, length of survival and
carboxyhemoglobin levels
-------
in smokers than nonsmokers. In the most polluted areas there was a relation
between the ambient carbon monoxide concentrations on a specific day and the
mean post-mortem carboxyhemoglobin concentrations. The causes of death showed
little or no relation with the carboxyhemoglobin values taken at post-mortem.
The Baltimore Study (Table 5-5)217 measured the carboxyhemoglobin concen-
trations at post-mortem for 2,366 subjects. These were compared by age, race,
sex and cause of death. The post-mortem carboxyhemoglobin concentrations were
higher in those who died suddenly owing to ASHD than in subjects
whose sudden death resulted from other natural causes. This was true for all
of the age-group comparisons. Differences between the median concentrations
of the groups were relatively small. No differences were noted between people
who died mASHD and people who died suddenly from traumatic causes such as
accidents or homicides.
Smoking histories were obtained from a sample of the ASHD-sudden-death
subjects only and carboxyhemoglobin concentrations were found to be substantially
higher for smokers than nonsmokers. ASHD-sudden-death subjects were compared
with living controls. Living controls who were cigarette smokers had higher
carboxyhemoglobin concentrations than ASHD-sudden-death subjects who smoked
cigarettes prior to death. For nonsmokers the levels were higher for the
ASHD-sudden-death subjects than for living controls. However, when exsmokers
were excluded there were no differences in carboxyhemoglobin concentrations
between individuals experiencing ASHD sudden death who were life-time non-
smokers and similar living controls. There were also no differences in post-
mortem carboxyhemoglobin concentrations in the ASHD-sudden-death subjects that
were related to place of death, activity at onset, length of survival and
whether the deaths were witnessed or not.
5-70
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TABLE 5- 5
Median and Mean Carboxyhemoglobin Levels by Age and Cause of Death
Baltimore Sudden Death Study
Cause of Death
ASHD
Other Natural
Auto Accident
Other Accidents
Homicide
AGE
25-34
Median Mean
1.5 2.0
1.2 1.6
2.0 3.2
1.0 5.4
2.4 2.9
AGE
35-44
Median Mean
1.6
0.8
2.3
1.2
2.0
2.6
1.5
2.2
3.9
2.7
AGE
45-54
AGE
55-64
Median Mean
1.9
0.7
0.4
1.4
2.9
2.6
1.3
1.8
7.1
3.7
Median
0.7
0.6
1.2
0.5
1.2
Mean
1.6
1.0
2.2
1.4
2.1
-------
A detailed pathology study was done of 120 ASHD-sudden-death subjects
whose post-mortem carboxyhemoglobin concentrations were measured. Practically
all of them had severe coronary artery stenosis. There was no relation between
the post-mortem carboxyhemoglobin concentrations among the ASHD-sudden-death
subjects and the extent of coronary artery stenosis, the presence of acute
pathologic lesions such as a thrombosis or hemorrhage in the plaque, or recent
myocardial infarction.
Neither of the two incidence studies, Los Angeles or Baltimore, revealed
a relation between ambient carbon monoxide concentrations and the number of
new ASHD cases. These two studies reported that there was a strong relation
between carboxyhemoglobin concentrations and prior smoking history, but little
or no relation to the cause of sudden death.
The Relation Between Ambient Carbon Monoxide and Survival Following a
Myocardial Infarction
There has been only one study of the relation between ambient carbon
monoxide concentration and case-fatality following a myocardial infarction.
Case-fatality rates were compared for patients admitted with a myocardial
infarction to 35 Los Angeles hospitals during 1958. The carbon monoxide
measurements were reported from monitoring stations operated by the Los
217
Angeles County Air Pollution Control District.
The hospitals were divided into those located in the low and those in
the high carbon monoxide pollution areas. The low area was outside the 8 ppm
isopleths for 1955. The majority of hospitals were located in the high area,and
2,484 patients with myocardial infarction were admitted in the high areas as
compared to 596 admitted in the low areas. The areas more highly polluted
with carbon monoxide had a greater case-fatality percentage than those less pollutedl
5-72
-------
during the weeks when the average carbon monoxide concentrations were in the
highest quintile, 8.5 to 14.5 ppm weekly mean basin carbon monoxide concentrations.
In 12 of the 13 weeks, the case-fatality percentage was greater in the higher
carbon monoxide areas (Tables 5-g and 5-7).
A further analysis of the data suggests that the differences in case-
fatality may not be a function of a change in ambient carbon monoxide concen-
trations. During times of high pollution, the median percentile of case-
fatalities in the high-polluted area was 30% and it was 20% in the low-polluted
area. When the average basin pollution was low the median percentile for
case-fatalities was 26% in the high- and 27% in the low-polluted areas. Thus,
as the mean basin carbon monoxide concentration increased, the case-fatality
percentage increased slightly in the high-polluted areas but decreased in
the low-polluted areas. It would be very unlikely that the case-fatality
percentage would be inversely related to the carbon monoxide concentrations
in the less polluted areas. Practically all of the high mean basin carbon
monoxide concentrations were reported in the winter while the low concentra-
tions occurred in the spring and summer. Because of the relatively small
number of hospital admissions per week (12) in the low pollution areas,
there was a wide variation in mean case-fatality percentages (0-58%). These
three factors suggest that the relation between ambient carbon monoxide con-
centrations and case-fatality percentages during high pollution episodes may
be related to a seasonal factor such as an influenza epidemic, changes in
the number of hospital admissions in relation to the number of available
beds, or other undetermined variables.
5-73
-------
TABLE 5-6
Case-Fatality Percentage in High and Low Carbon Monoxide Pollution Areas
for the 13 Weeks in which the Average Basin Weekly Mean Carbon Monoxide
Concentrations were Lowest °°
Week
of
Year
10
11
14
17
19
20
23 -
24
27
29
30
35
46
Carbon
Monoxide
Average,
ppm
5.8
•
5.8
5.9
5.8
5.6
5.8
5.4
5.8
5.6
5.5
5.6
5.8
5.6
High Pollution Area
Case-Fatality
(50)*
27
29
28
22
21
27
24
45
29
23
21
19
26
Low Pollution Area
Case-Fatality
(12)*
14
10
36
14
58
29
20
33
22
08
0
27
29
MEDIAN:
26
27
* Estimated number of patients with mycardial infarction admitted to
hospitals per week
5-74
-------
TABLE 5'.7
Case Fatality Percentage in High and Low Carbon Monoxide Pollution
Areas for the Thirteen Weeks in Which the Average Basin Weekly Mean
Carbon Monoxide Concentrations Were Highest:
Week
of
Year
1
2
3
6
38
44
45
47
48
49
50
51
52
Carbon
Monoxide
Average
ppm
9.6
9.2
9.4
8.6
8.5
9.5
9.0
12.0
8.6
10.5
10.4
14.5
9.3
High Pollution Area
Case-Fatality
(50>*
21
27
31
30
23
30
30
29
29
31
41
59
29
Low Pollution Area
Case-Fatality
(12)*
50
0
14
23
17
18
22
08
14
25
27
20
08
MEDIAN: 30 20
* Estimated number of patients with myocardial infarction admitted
to hospitals per week
5-75
-------
Seventy percent of all ASHD deaths take place outside of the hospital.
The percentage of case-fatalities among hospital admissions is an inadequate
measure of the relation between environmental factors and the number of short-
term fatalities following a heart attack. The percent of case-fatalities
within a hospital is a function of the incidence of heart attacks, and their
severity, and the rapidity of transfer to the hospital. When there is fast
transportation to the hospital after heart attack, the number of case-fatalities
within the hospital might increase while the over-all percentage of case-
fatalities decreases.
Because of the significance for public health of a possible relation
between case-fatality and ambient carbon monoxide concentrations, particularly
during periods of high pollution, replications of both the Baltimore and
Los Angeles studies should be implemented. Such studies need to include the
number of both in-hospital and out-of-hospital case-fatalities, a description
of the criteria both for diagnosing heart disease and for the demographic
characteristics of the subjects, and effective methods for monitoring carbon
monoxide.
Clinical/Experimental Studies of the Relation of Carbon Monoxide and
Morbidity Due to Heart Disease
Another approach to the study of the relation between exposure to carbon
monoxide and the natural history of ASHD is to identify high-risk subjects
and observe the effect of either natural or artificial carbon monoxide exposure.
Such studies usually involve a technique for inducing symptoms in the subjects,
such as exercise testing (Table 5.-8).6'12'13*14*15
The first studies in 1971 compared subjects with angina pectoris before
and after smoking nicotine-free cigarettes.^ Ten male angina pectoris subjects
5-76
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TABLE S.-8
Clinical Studies of the Relation between Carbon Monoxide and Angina Pectoris
Study
Method
Sample Size
Case Control
Carboxy-
hemoglobin,%
Case Control
Results
Reference
Ul
Carboxy-
hemoglobin
Non-nicotine
cigarette
(1971)
Freeway
travel on
angina
pectoris
(1972)
Carbon
monoxide on
exercise in-
duced angina
pectoris
(1973)
Carbon
monoxide
exposure and
onset and
duration of
angina
pectoris
(1973)
Low level
carbon
monoxide
onset & dura-
t ion inter-
mittent claud-
ication
(1973)
Evaluation of patients
with angina following
smoking non-nicotine
cigarettes, exercise
on bicycle ergometer
Comparison of breath-
ing freeway travel in
air (high carbon
monoxide) with carbon
monoxide free com-
pressed air, exercise
bicycle
50 ppm carbon monoxide
2 hr for 2 mornings;
carbon monoxide free
compressed air 2
mornings; exercise
bicycle
Carbon monoxide free
compressed air,
50 ppm carbon monoxide,
100 ppm carbon monoxide
50 ppm carbon monoxide
2 hr compared to carbon
monoxide free compres-
sed air
10 subjects;
2 smoked in
morning,
2 non-smoking
10 patients with
angina pectoris,
cross-over ex-
periment
10 patients,
angina cross
over, blind
study
10 patients
cross-over
10 men cross-
over
7.54 0.76
8.03 1.06
5.08 0.75
2.91
2 hr later
2.68 0.77
50 ppm (2.8)
100 ppm (4.51)
2.97 0.90
Reduction in exercise
time to development
of angina following
smoking of cigarettes.
No ECG changes
Reduction in mean
exercise time, inter-
val after freeway air,
3 patients with ST-T
depression
Breathing freeway
air reduction in
length of time ex-
ercise until onset
of angina; no ECG
changes
Reduct ion in t ime
to chest pain after
exercise, no differ-
ence 50-100 ppm; S-T
depression, ECG
earlier
Reduction in time to
develop claudication;
exercise on bicycle
Aronow and Rokaw
14
Aronow etal.
12
Aronow and Isbell
13
Anderson etal.
Aronow et al.
-------
smoked 8 nicotine-free lettuce leaf cigarettes on two of four mornings.
Following the smoking and/or nonsmoking mornings, the subjects exercised
on a bicycle ergometer. Their carboxyhemoglobin concentrations rose about
8.0% after smoking the cigarettes as compared to about 1% during the non-
smoking periods.
The duration of exercise prior to the onset of angina was reduced
following cigarette smoking (TableS -8). Chest pain also occurred at a
lower systolic blood pressure and heart rate than for the nonsmoking mornings.
Although prior to pain there was a wide difference in the duration of exercise,
the duration was reduced for every man who smoked.
The next approach was to determine the effect of exposure to the high
OA
carbon monoxide concentrations on the Los Angeles freeway. u Ten patients
with angina pectoris rode on the L.A. freeway for 90 minutes and then were
brought to the laboratory for exercise testing. Exercise testing was done
prior to the freeway trip, then immediately after it and finally two hours
later. Approximately three weeks later the ten subjects followed the same
testing schedule except during the 90-minute freeway trip they breathed
carbon monoxide free compressed air. Breathing carbon monoxide-polluted
ambient air the mean carboxyhemoglobin increased to 5% during the freeway
trip ancr*279T~two hours later. Ischemic ST-T changes in the electrocardiogram
occurred in 3 out of 10 subjects while breathing carbon monoxide polluted
freeway air. There was a substantial decrease in the duration of exercise
time before the onset of angina (both immediately after the trip and 2 hours
later) in comparison to the exercise time prior to the freeway trip (Table
5-8). Breathing carbon monoxide-free compressed air, there were no changes
5-78
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in exercise time before or after freeway travel. The subjects exercised longer
after breathing the compressed air than after breathing carbon monoxide polluted
freeway air. Systolic blood pressure and pulse were lower at the onset of
angina after breathing the freeway air. No EGG differences were noted during
the exercise testing, before the freeway trip, after it or when breathing
compressed air. These were not blind studies. The investigators and subjects
both knew about the exposure to carbon monoxide. The subjects might even
have suspected the possible occurrence of a harmful effect.
A double-blind study was done.21 Ten subjects with angina pectoris
were exposed either to carbon monoxide at 50 ppm for two hours on two mornings,
or to compressed air for two mornings. They then exercised on a bicycle
ergometer. The mean carboxyhemoglobin after two hours of the carbon monoxide
exposure was 2.68% as compared to 0.77% with compressed air. Even at relatively
low carboxyhemoglobin concentrations, the exercise time was reduced prior to
the onset of angina pectoris. There was also a decrease in systolic blood
pressure and heart rate at the time of onset of angina.
Anderson, et al.6 in North Carolina did a similar double-blind study.
Ten subjects with angina pectoris were exposed to air with carbon monoxide
at either 50 or 100 ppm for 4 hours. After exposure the subjects exercised
on a Collins treadmill. The duration of exercise before the onset of chest
pain was significantly shorter after exposure to carbon monoxide either at
100 ppm (mean carboxyhemoglobin 4.5%) or at 50 ppm (mean carboxyhemoglobin
2.8%). There was however, no difference in exercise times after exposure
to either 50 and 100 ppm of carbon monoxide. The S-T segment depression of
the electrocardiogram generally appeared earlier and was deeper after breathing
carbon monoxide. Other measures of cardiac function such as systolic time
intervals, left ventricular ejection time, pre-ejection period index, and pre-
ejection peak to ejection time ratio were within normal limits.
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Subjects with intermittent claudication have also been studied with this
approach. In a double-blind study, they were exposed for 2 h either to carbon
monoxide at 50 ppm or to compressed air then they exercised. Time until
pain, in this case intermittent claudication rather than angina pectorls, was
reduced after breathing carbon monoxide.
Only one experimental animal study of the effects of carbon monoxide on
the natural history of heart disease has been reported. DeBias et al. °°
studied the effects of continuous exposure to 100 ppm carbon monoxide (115 mg/m3)
for 24 weeks in the cynomolgus monkey. They observed that carboxyhemoglobin
chronically raised to an average of 12.4% produced polycythemia and the
hematocrit increased from 35 to 50%. All animals showed an increased P-wave
amplitude and T-wave inversion in their electrocardiogram suggestive of
myocardial ischemia. Animals in which an experimental myocardlal infarction
was produced who were next exposed to carbon monoxide had more severe electro-
cardiographic changes than animals that breathed ambient air.
These studies of heart disease morbidity after carbon monoxide exposure
have important Implications. The first question that needs to be investigated
is whether the experimental model in man, angina pectoris subjects exposed
to low doses of carbon monoxide followed by exercise on a bicycle or treadmill,
has relevance to the situation in a community. It has been suggested that a
carboxyhemoglobin concentration as low as 2.5% has a deleterious health
QTO A20
effect.-"0'^" All cigarette smokers and about 10% of the nonsmokers in the
United States frequently have carboxyhemoglobin concentrations higher than
2.5%. Thus a large percentage of the United States population may be poten-
tially at risk. The National Health Survey Examination reported that there
were 3,125,000 adults, aged 18 to 79, with definite coronary heart disease
t
A complex of symptoms characterized by absence of pain or discomfort in a
limb when at rest, the commencement of pain, tension, and weakness, after
walking is begun, intensification of the condition until walking becomes
impossible, and the disappearance of the symptoms after a period of rest.
5-80
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and another 2,410,000 who were suspect. Many people who have severe
coronary artery stenosis without any apparent clinical disease would also
be at high risk when the concentrations of carbon monoxide in the air
are relatively low.
If the results of the clinical studies are applicable to this large
population at risk, then a major public health problem exists. Taking the
current results at face value suggests only that when patients with angina
are exposed to low carbon monoxide concentrations for short periods they
cannot exercise as long on a bicycle or treadmill before developing chest
pain as those breathing compressed air. There is no evidence from these
results that the exposure to carbon monoxide increases the frequency and
severity of chest pain or the development of other complications, or that
it shortens life expectancy among patients with angina pectoris or other
clinical manifestations of heart disease. We can only infer the existence
of such a relationship.
Evidence for this association based on observations is equivocal. People
with angina pectoris who smoke cigarettes can be expected to have higher
carboxyhemoglobin concentrations and poorer prognosis than those who do not
smoke cigarettes. ^ The harmful effect could be due both to carboxyhemoglobin
and to other chemicals in cigarette smoke. A recent study has shown, on
the other hand, that relatively few heart attacks occur while an individual
is cigarette smoking and is thus exposed to higher carbon monoxide concen-
trations. 216 There is no evidence of an increased heart attack risk, in-
cluding myocardial infarction and sudden death^ while driving an automobile,
and there no data showing the occurrence of angina pectoris pain episodes
A
in relation to specific activities.
5-81
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There is also no evidence suggesting a higher incidence, prevalence,
or prognosis of heart disease among industrial workers who are exposed to
high carbon monoxide concentrations.
And finally, there is little positive or negative evidence indicating
that high ambient carbon monoxide concentrations in a community are associ-
ated either with the prevalence of angina pectoris or the natural history
of heart disease. Furthermorej within communities, there is no evidence that
there is a relation between the frequency of angina pectoris pain episodes
and changes in the ambient carbon monoxide concentrations. Without such
evidence, although the clinical experimental studies suggest important relation-
ships between carbon monoxide and heart disease, ambient carbon monoxide cannot
be implicated as a major causative factor of heart disease in a community.
The Relation Be.tween Cigarette Smoking and Clinical Coronary Arterial Disease
The association between cigarette smoking and clinical coronary arterial
disease is much closer for myocardial infarction and sudden death than it
oq
is for angina pectoris. y At present it is not completely clear why this
is so but it may be related to specific precipitating factors rather than
to the underlying atherosclerosis. The association of cigarette smoking
with clinical coronary arterial disease apparently depends on other risk
factors, particularly a high-fat diet and increased serum cholesterol.
This association is relatively weak in populations with low serum cholesterol
content, but is apparently stronger in younger than in older people.201
Cigarette smoking appears to increase the risk of sudden death and
myocardial infarction among subjects with pre-existing angina pectoris.424
On the other hand, the relation between smoking after a myocardial infarction
and subsequent survival is less clear.100'425 If cigarette smoking did not
increase the mortality risk after a myocardial infarction, specifically
5-82
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among those who have survived for a month or so after the initial myocardial
infarction, then the association between carbon monoxide and heart disease
would be substantially weakened. A critical problem has been to try to
separate the carbon monoxide effects of cigarette smoking from the effects
of other harmful substances in cigarette smoke. After individuals free of
clinical coronary disease cease smoking their risk of heart attacks is re-
duced. This reduction in risk takes place very soon after the cessation of
cigarette smoking.1^5
The above observations suggest that a major effect of cigarette smoking
may be as a precipitant of heart attack rather than in the development of
the underlying atherosclerosis. There is a small amount of data suggesting
that cigarette smokers have more extensive atherosclerosis than nonsmoking
age-related controls. Such studies;however, do not have data adjusted for
serum cholesterol levels or other risk factors. The effects of cigarette
smoking on the incidence or clinical history of ASHD do not necessarily have
to be due to carbon monoxide inhalation. Other factors in cigarette smoke,
including nicotine, cyanide, or trace elements may be important.
Studies relating carbon monoxide, smoking and heart disease include
10 angina pectoris subjects who smoked cigarettes and who had blood pressure,
heart-rate, and expired carbon monoxide measurements taken before and after
smoking high-, low-,and no-nicotine cigarettes. ^ After they smoked these
cigarettes, their expired carbon monoxide concentrations increased with little
difference among the three types of cigarettes. There was a significant in-
crease in heart rate and systolic blood pressure after smoking the high- and
low-nicotine cigarettes, but no effect after smoking nicotine-free cigarettes.
Another study compared the effects of carbon monoxide and nicotine on
5-83
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911
cardiovascular dynamics in 8 men with angina pectoris. » Right and
left heart catheterizations were done before and after smoking cigarettes
and then repeated after breathing carbon monoxide at 150 ppm so thau coronary
sinus carbon monoxide would be similar to that after the smoking of 3 cigarettes.
None of the subjects developed symptoms of angina pectoris either after
smoking or after exposure to carbon monoxide. Smoking caused increases in
the aortic systolic and diastolic blood pressure and in the heart rate.
These changes were not observed after breathing carbon monoxide. The
left ventricular end diastolic pressure increased after both smoking and
carbon monoxide inhalation, the stroteindex was reduced with both procedures,
and the cardiac index did not change after smoking but declined after carbon
monoxide inhalation. Smoking and carbon monoxide exposure also reduced the
coronary sinus oxygen. Most of the effects disappeared or were substantially
reduced within 30 minutes after the exposures. Therefore, after smoking,
nicotine apparently increased the systolic and diastolic blood pressure
and the heart rate, while carbon monoxide caused a negative inotropic
effect, an increase in left ventricular end diastolic pressure and a decrease
in the stroke index.
Wald e± _al.419 have attempted to determine whether cigarette smokers
with clinical coronary disease have higher carboxyhemoglobin concentrations
than smokers without disease, after adjusting for the amount of cigarette
smoking. Volunteers (1,085) were recruited from several firms in Copenhagen,
Denmark. They completed a questionnaire concerning their ASHD history.
All who gave a positive history of heart disease were examined and the history
validated both by examination and review of the medical records. Smoking
histories were obtained from all of the subjects and their carboxyhemoglobin
5-84
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measured. A higher prevalence of ASHD was found with increased cigarette
smoking. Men whose cigarette smoking was moderate to heavy and who had
higher carboxyhemoglobin concentrations had a greater prevalence of ASHD.
The relation persisted after adjusting for age, sex, duration of smoking
history, serum cholesterol levels and cigarette consumption. Although these
results suggest a specific carboxyhemoglobin effect, they might also just
be a measure of the inhalation of smoking products and not necessarily only
a function of carbon monoxide inhalation.
" The significance of carbon monoxide inhalation from smoking cigarettes
is often dismissed when the effects of cigarette smoking on cardiovascular
disease are evaluated. There is a good correlation with the amount of tar
and nicotine in cigarettes, but not necessarily with the amount of carbon
monoxide produced. A controversy exists about the effect on the increase in
carboxyhemoglobin concentrations of smoking low-as compared to high-nicotine
cigarettes. Several investigators have suggested that the carbon monoxide
production of a cigarette be included on the package. A safe cigarette
should be low in tar, nicotine, and carbon monoxide production. A low-carbon
monoxide-producing cigarette has been made.
Cigarette smoking is the chief source of the high carboxyhemoglobin
concentrations in the population. To effect major reductions in the mean
carboxyhemoglobin in the population will require both a significant reduction
in smoking and the modification of cigarettes to deliver lower doses of
carbon monoxide.
The potentially harmful effects of low doses of carbon monoxide with
respect to cardiovascular disease should provide further impetus to efforts
5-85
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to reduce cigarette smoking. People exposed to carbon monoxide from other
sources,such as their occupations or concentrations in the ambient community
air, may be at particularly high risk from cigarette smoking. The cigarette
smoker exposed to high carbon monoxide concentrations in the ambient air
will also have a greater carboxyhemoglobin concentration and a concomitant
increased risk of heart attack.
The studies on cigarette smoking and cardiovascular disease are
summarized in Table 5-9.
5-86
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TABLE 5-9
Cigarette Smoking, Carbon Monoxide and Cardiovascular Disease Studies Summarized
Study
Population
Methods
Results
Wald et al.
419
1,085 volunteers, several
firms, including tobacco
companies
Aronow et al.
10
Comparison of nicotine
and carbon monoxide
effects; 10 men with
ang ina; high,low-,and
no-nicotine cigarettes
00
Aronow et al.
Cigarette smoking
and breathing
carbon monoxide;
cardiovascular
hemodynamic in
anginal patients
8 men with angina
pectoris
History of ASHD, validated by
records and exam, smoking
history and carboxy-
hemoglobin concentrations
Higher prevalence of ASHD with
increased tobacco smoking, with
increase in carboxyhemoglobin,
slight effect on carboxyhemoglobin
within smoking groups
At older ages, carboxyhemoglobin
most powerful discriminator
(1) Significant increase in peak systolic and diastolic blood
pressure from smoking high-or low-nicotine cigarettes.
(2) Significant increase in heart rate with high or low nicotine
cigarettes.
(3) No change in heart rate or systolic blood pressure after
smoking nicotine-free cigarette.
8 men with angina, right and
left cardiac catheterization
before, after smoking 1,2,3,
cigarettes, replicate after
150 ppm - until coronary
sinus carbon monoxide is
same as after cigarette 3
None of the patients developed
angina pectoris. Smoking aortic
systolic and diastolic blood
pressure. Blood pressure, no change
after breathing carbon monoxide
Heart rate increased with smoking,
not with carbon monoxide.
Left ventricular end diastolic
pressure increased after smoking also
after breathing carbon monoxide.
Cardiac index unchanged after smoking>
decreased with carbon monoxide.
Stroke index decreased after both smoking
and breathing carbon monoxide.
Increase in coronary sinus xygen
after smoking cigarettes or after
carbon monoxide. Most of the hemo-
dynamic changes reduced after 30
minutes.
-------
TABLE 5-9 continued
Russell et al.347 22 cigarette smokers Comparison of increase in Carboxyhemoglobin increase after smoking
Effects of changing carboxyhemoglobin after single strong cigarette was 1.45%, 1.09%
to low-tar, low- smoking extra for small brand, and 0.64% for extra-mild
nicotine cigarettes strong cigarettes brand
In
i
oo
00
-------
BEHAVIORAL EFFECTS
The experimental studies of carbon monoxide's effects on human behavior
are reviewed under seven topical headings; vigilance, driving, reaction time,
time discrimination and estimation, coordination and tracking, sensory
processes, and complex intellectual behavior. Although carbon monoxide is
probably the most widely studied of all toxic substances, our knowledge of
its effect on behavior is limited.
Vigilance
Psychologists study vigilance by examining how well an individual per-
forms when detecting small changes in his environment that take place at un-
predictable intervals and so demand continous attention.2^2»253 vigilance
A
was first explicitly studied during World War II, when the
British government became concerned about the performance
of men who spent long hours searching for submarines or aircraft. This was a
monotonous task and it was found that after a while the men would miss signals
that they would not have missed at the start of their vigil.
There have been a series of reports of carbon monoxide's effects on such
a task. Groll-Knapp £t al.**3 exposed "20 subjects of both sexes" to carbon
monoxide at 0, 50, 100 or 150 ppm for a 2-hour period. Whether the subjects
smoked is not stated. Carboxyhemoglobin concentrations were not measured
directly but rather it was estimated that by the end of exposure their
values would have reached about 3% at 50 ppm, 5.4% at 100 ppm and about 7.6%
at 150 ppm. The subjects began an acoustic vigilance test one-half hour after
exposure started. At this time the carboxyhemoglobin concentrations would
V
have reached only about 1.5, 2, and 2.5%, respectively. Pairs of short tones,
5-89
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1.1 s apart;were presented in a regular sequence. Over the 90-minute test-
period, 200 of these pairs were transformed into signals by making the second
tone "slightly weaker" than the first. The subject reported their presence
by pressing a button. Thus, signals occurred irregularly 2.2 times per
minute. Every subject was exposed to tich of the four conditions once with
the sequence systematically changed.
The mean number of signals missed during the test was 26 at 0" ppm (control),
35 at 50 ppm, 40 at 100 ppm and 44 at 150 ppm. Apparently even the smallest
difference was significant. (A failure to replicate these findings is reported
but not described in detail in a recent symposium paper from the same laboratory. *
Fodor and Winneke^S carried out a second auditory signal study. They used a
broad band noise that las ted 0.36 s and was repeated at 2.0 s intervals. About threa
of the noises out of every hundred were made to be slightly less intense.
These were the signals the subjects reported by pressing a button. Twelve
subjects (male and female nonsmokers, 22-35 years old) were tested at carbon
monoxide concentrations of both 0 and 50 ppm, half with each order of presenta-
tion. Exposure lasted 80 min before the first 45-mlnute vigilance test. A five-
minute visual task followed the first vigilance test after which there was a
second 45-oinute vigilance test. Following another five-minute visual task,
a third vigilance test was presented. The signals occurred randomly, 44 of
them occurring within any one 45-minute period, or about 1/min. Carboxyhemoglobin
concentrations were not determined directly but were predicted to be 2.3 and
3.12 at the beginning and end of the first vigilance test. The values for
the second test were 3.12 and 3.72, and 3.72 and 4.32 for the last test.
Background carbon monoxide was neglected.
5-90
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The percentage of signals missed is shown in Figure 5-19. Exposure
to carbon monoxide caused the subjects to miss signals during the first
vigilance test. This effect was not apparent during the next two vigilance
test periods and the interaction between carbon monoxide concentrations and
time was statistically reliable. The data for the speed of response to the
detected signals also showed a trend toward a maximum effect during the
first period, but this time the interaction was not significant.
125
Fodor and Winneke note that the "variation in performance after the
125th minute of exposure is hardly consistent with existing theoretical and
experimental knowledge" and go on to speculate that "an organism exposed to
carbon monoxide possesses the capability of compensation, which can, within
certain limits, counterbalance a drop in performance." However, they recognize
that "published data give little support to this ex post facto hypothesis,
which urgently needs corroboration by replication experiments."
Winneke reported another study of the effect of carbon monoxide on
auditory vigilance in which the carbon monoxide data were collected along
with data on methylene chloride, a compound suspected of exerting at least
some of its behavioral effects by increasing carboxyhemoglobin concentrations.
Eighteen subjects, nine male and nine female, were exposed to carbon monoxide
at 0, 50, and 100 ppm on different occasions for almost four h and then
tested with the same ajudttory vigilance task used by Fodor and Winneke.125
The results were completely negative^with differences not even in the expected
direction (see Figure 5-20). Winneke^5 estimated that the subjects had an
average carboxyhemoglobin concentration of about 9% after the 100 ppm exposure.
At first glance the positive results with methylene chloride reinforce confidence
5-91
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70 r-
J3
4-1
o
o
i>
s ?5°
2 790
cfl
11
2
K'
Periods of observation
30' «5' 75' 30' V5' X' 30' VS'
~r
K' 110'
L.J 1 j._
130' W ISO'
•--• Control
. CO
Minutes after beginning of exposure
1S5' 210'
Figure 5-19. Effects of carbon monoxide on an acoustic vigilance
test. Top, number of signals missed after exposure to carbon
monoxide at zero and 50 ppm. Bottom, latencies of responses to
the detected signals. The panels show results from three successive
45-minute vigilance tests. Reprinted with permission from Fodor and
Winneke.125
5-92
-------
83
to
10
to
O
So
&,
s
77
75^
VIGILANCE- PERFORMANCE
LJQ- 75 aO-125 130-175 l8ff-225'\
• Control N=20
D 300ppm N=12
V SOOppm N=14
• 800ppm N= 6
CO
K-125 ISO-US' 180-225}
• Control N=16
0 SOppm N=18
A 100ppm N=1d
?i
^ S
o
p
Co
8
»G5
h72 S
•u
;e
7«
3
MINUTES AFTER ONSET OF EXPOSURE
Figure 5-20. Vigilance performance after exposure to methylene
chloride (left) and carbon monoxide (right). Reprinted from
Winneke.445
5-93
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in the reliability of the carbon monoxide data and are particularly welcome
to an area where data are rare for substances that can serve as positive
controls or reference substances.173a'222a However, this confidence is
diminished by the inversion of the 300 ppm and 500 ppm curves and the irregular
carbon monoxide control curve.
Horvath ^t al.173 and O'Hanlon301'302 studied carbon monoxide's effects
on a visual vigilance task. A disk with a one-inch diameter about 3 ft (0.9 m)
from the subject was lit for 1 s every 3 s. The signal was a slightly brighter
pulse. The subject pressed a button whenever he saw this brighter light.
Before starting the test, each of 10 nonsmoking, "healthy male volunteers"
21-32 years old were exposed via a mouthpiece for 1 h to the same carbon
monoxide concentration used during the test. The subjects were then brought
to the experimental room where they were exposed further to carbon monoxide
via another mouthpiece. Preceding the one-hour main vigilance task, there
was a short pre-test called an "alerted" test, during which 10 out of 60 light
pulses were the randomly>-interspersed, slightly-brighter pulses that were the
signal. These were presented at a signal rate of 3.3/min.
The 1-hour main vigilance task began after a 1-minute rest. Twelve
hundred light pulses were shown 40 of which were the slightly brighter
signals. These were distributed so that there were 10 among the 300 light
pulses presented during each 15-minute period. Therefore the signal rate
was 0.67/mi*. Since each subject was exposed at 3 different times to carbon
monoxide concentrations of 0, 26, and 111 ppm, he served as his own control.
The experiment was 4 single-blind study, with the subjects being unaware of the
experimental treatment. The carboxyhemoglobin concentration of the controls
5-94
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(0 ppm) was the same, 0.8% after the initial-hour exposure as at the experiment's
end. For the exposure to 26 ppm the carboxyhemoglobin concentration was 1.6%
after the first hour and 2.3% at the end; and for the 111 ppm exposure the
concentration was 4.2% after the first hour and 6.6% at the end. Performance
on the pre-test, when the signal rate was 3.3/min, was approximately the same
for all 3 exposures. The carbon monoxide apparently had no effect. During
the 1-hour vigilance test, subjects exposed to carbon monoxide at 111 ppm
made significantly fewer correct signal identifications than did those same
subjects exposed to either 0 or 26 ppm. The data are summarized in Figure
5-21. When the signal rate was 0.67/min performance accuracy was reduced
at a carboxyhemoglobin concentration of about 5%. However, during the pre-
test, when the signals appeared 5 times as frequently, there was no such
effect. No measures of variability are given. The sudden increase in detec-
tion rate sometimes seen near the end of the hour may be an example of the end
spurt often reported in vigilance work when subjects have been told when to
254
finish their task.
Beard and Grandstaff^2 examined the effect of carbon monoxide on a
visual vigilance task also. In their double-blind experiment, the signal was
a slightly shorter flash of light than that usually programmed to occur.
The subject was seated in a small audiometric booth and faced a 3 in.(7.6 cm)
electroluminescent panel 2 ft (0.6 m) from his eyes. Every 2 s this panel
was lit. On most occasions the panel lit up for 0.5 s but once in a while
it remained lit for only 0.275 s; these were the signals to be reported by
Pressing a button. The subjects monitored the light flashes for four 30-minute
Periods during the first day's session. The first of these periods was a control
5-95
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90 r
CO
o
80
70
to
o
Ul
cc
0£
O
O
60
50
[CO]
1
1
0
ALERTED
TEST
15
30
VIGIL (min)
45
60
Figure 5-21. Vigilance performance after exposure to carbon monoxide.
Reprinted with permission from Horvath et al.l?3
5-96
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period. Carbon monoxide was then administered at concentrations of 0, 50,
175, or 250 ppm. A second 30-minute vigilance task was begun after 10 minutes
of exposure to carbon monoxide. This was followed by a 10-minute rest period,
after which there was a third 30-minute vigilance test. The carbon monoxide
was then shut off and after another 10-minute break, the final 30-minute
vigilance test was given. During each of the vigilance tests, 10 signals
were randomly distributed among a total of 722 non-signal light flashes/
making the signal rate 0.33/min.
Nine nonsmoking male and female students, 18-25 years old^were each tested
in random order eight timesV twice under each condition. Carboxyhemoglobin
concentrations were estimated from alveolar breath samples taken both before
testing and after the last vigilance test, 30 min after the cessation of the
carbon monoxide exposure. The pretest concentrations were all below 1%.
Post-test they averaged 1.8% for exposure to 50 ppm, 5.2% for 175 ppm and
7.5% for 250 ppm. About 73% of the signals were detected by subjects exposed
only to room air, during the last 3 tests. The detection rate was about 64% for
exposure to both 50 and 175 ppm and 70% for exposure to 250 ppm. The decreases
following exposure to 50 and 175 ppm, while small, were statistically signifi-
cant at the 0.05 level (one-tailed test). The decrease following the 250 ppm
exposure was not significant.
Further analysis of the data, " within a framework provided by signal
detection theory, showed that the significant changes in performance were
related tcJ 1iot:h an increased "degree of caution In making decisions and a
decreased sensitivity (i.e., beta increased and d_ decreased). Interpretation
°f the peculiar results found with 250 ppm would be easier if levels high
enough to produce pronounced effects had been included.
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An experiment by Lewis et al.230a should also be noted. These investi-
gators examined the effects of traffic pollution on vigilance by exposing
subjects to air pumped from the roadside of a busy street into the automobile
that served as the experimental "room." Carbon monoxide levels were not
measured during the testing but sometime after the test the experimenter de-
termined that they were above 10 ppm about 40% of the time, above 30 ppm more
than 4% of the time. The air was not analyzed for other noxious constituents.
It is not clear how long subjects were in the immediate environment and there-
fore exposed to the flow of pollution before starting on these tasks. While
seated in the test car they performed on an auditory vigilance task in which
they were presented 0.5 s tones every 2s. On 9 occasions during a 45-minute
session the tone was slightly shorter. Thus the tones occurred at the rate
of about 0.2/min.
Subjects performed on the vigilance task twice, working on a number of
other psychological tasks between runs. The sixteen subjects used were
18-28 years old. Order of testing was counterbalancedxwith half first being
exposed to pure air while the other half was first exposed to the polluted
air. The subjects detected 73% of the signals while being given pure air
from a metal cylinder but only 60% while breathing polluted air from the
roadside. This difference was reported to be reliable but, as the authors
realize, given the almost complete lack of knowledge of what the subjects
were exposed to, one can conclude nothing about the specific effects of
carbon monoxide. For instance, Fristedt and Akesson130a found that workers
in service stations located in multistory garages reported headaches and
general fatigue at only slightly elevated lead and slightly elevated
5-98
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carboxyhemoglobin levels. They point out that exposure to neither substance
was
"of a magnitude such as to constitute a primary toxicological
hazard. The combination of these in combination with other
substances existing in automobile exhausts, such as acrolein
and other aldehydes, alcohols, phenols, acetone, partially
burned hydrocarbons, oxides of nitrogen, sulfur dioxide,
and organic lead compounds, may pose a hazard to health,
or a sanitation problem, manifesting itself in the form
of discomfort. There never has been an exhaustive investi-
gation of the biological reaction to chronic exposure to
small quantities of a mixture of these substances."
Several investigators have looked for changes in physiological re-
sponses that may be related to vigilance. O'Donnell et al examined how
overnight exposure to low carbon monoxide concentrations.with carboxyhemo-
globin concentrations reaching 12.7%, affected sleep. They reported small
and unreliable changes that were interpreted as a possible reduction in
central nervous system activation. Their observations agreed with the
450 452
findings of Xintaras et al. ' on the evoked response in the rat and
93
with Colmant's data on disturbed sleep patterns in the rat. Xintaras
un-
®t al. ,452 foun(j that effects on the visual evoked response of the
restrained, unanesthetized rat were similar for both carbon monoxide and
pentobarbital, the classic reference standard for depression of reticular
activity. They concluded that the changes induced by both substances re-
sembled those recorded during- the normal transition from wakefulness to
5-99
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sleep. In man it has also been possible to find carbon monoxide-induced changes
in the visual evoked response. Carboxyhemoglobin concentrations of 20 to 28%
were required,175'380 which are much higher than those associated with vigilance
changes in the studies previously cited. It is uncertain whether recent
332
advances in the techniques for its measurement and analysis will show an
increase in this response's sensitivity to carbon monoxide.
153
In addition to studying behavioral vigilance Groll-Knapp et al. measured
the slow-wave brain potentials presumed to correlate with anticipatory reactions
to an oncoming signal. For their vigilance task subjects were presented with a
pair of brief tones. They had to respond if the second tone was weaker than the
first. The researchers recorded for a 4-second period starting with the first
pair of tones presented. They reported that during a 90-minute test period that
started 30 min after exposure to a carbon monoxide concentration as low as
50 ppm, both the height reached by the anticipation wave after the first tone and
the drop after the second tone were reliably reduced.
With vigilance as with other functions that will be discussed below, the
interpretation of negative results with small amounts of carbon monoxide
frequently cannot be made unambiguously. Before attacking the question of
thresholds, investigators should demonstrate the sensitivity and specificity of
their behavioral tests by employing doses high enough to produce measurable
effects. They should also consider using previously studied drugs as reference
substances. a»17 a Only after sensitivity and specificity have been established,
can one have confidence in negative findings with low concentrations.
Driving
In the earliest reported study (1937) of simulated automobile driving
T26
Forbes et al. exposed five subjects to enough carbon monoxide to produce
carboxyhemoglobin concentrations as high as 30%. They reported very little effect
on a series of reaction-time, coordination and perceptual tasks, presented within
the context of a driving skills test. The only control observations were made
just before exposure and there was no attempt to ascertain how much performance
would have changed if room air alone had been administered. Consequently, their
results cannot be interpreted and are only interesting historically.
5-100
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McFarland and co-workers262.264,265 have recently (1973) studied actual
driving performance, focusing on two aspects of driving. One of these is the
amount of visual information required by a driver. This was measured by asking
the subject to maintain a constant speed while looking at the road as infre-
quently as possible. The subject wore a helmet with a shield that was placed
in front of his eyes so that he was prevented from seeing the road. By de-
pressing a foot switch he could briefly raise the shield. He was instructed
to do this sufficiently often to keep his car within a 12-foot-wide marked
lane on a deserted superhighway while maintaining a constant speed, of either
30 or 50 mi/h (48 or 80 km/h) in different trials.265 The number of steering
wheel reversals was also monitored. Ten subjects were used in these experi-
ments with each acting as his own control. They were either exposed only to
air or to enough carbon monoxide at a concentration of 700 ppm (via a mouth-
piece) to produce a carboxyhemoglobin concentration level of 17%. McFarland
reported that carboxyhemoglobin did not produce a differential effect on the
frequency of steering wheel reversals. His conclusion concerning visual
interruption data is less clear. From a significant interaction term in an
analysis of variance, McFarland concluded that those subjects exposed to
carbon monoxide while driving at the higher speed required more roadway viewing
than those exposed only to air.
•jo 1
Ray and Rockwell0-'1 examined the driving performance of three subjects
with carboxyhemoglobin concentrations of 10-20% from carbon monoxide exposure.
In this study the subject rode in a car yoked by a taut wire to a second car
driven ahead of it. Information concerning relative-velocity.and the distance
between the two vehicles was transmitted via the wire. In some experiments the
5-101
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subject drove while in others he was a passenger. The authors only reported
for an experiment in which , ., .
data the subject attempted to detect slight changes in the relative
r
velocity of the 2 vehicles when the lead vehicle was 200 ft (61 m) ahead of
the car in which he rode as a passenger. The time required to respond to a
velocity change of 2.5 mi/h (4 km/h) was approximately 1.3 s for control con-
ditions, 3.3 s when the subjects had a carboxyhemoglobin concentration of
about 10%, and 3.8 s when it was about 20%. These differences were statisti-
cally significant for a group of three subjects, each of whom had been exposed toi
wisely
three conditions. In view of the small sample size, the authors considered
A
these results as only exploratory.
AOQ
Weir and Rockwell have made extensive observations of driving behavior.
This as yet unpublished research also utilized yoking one car to another by
a thin wire. Gas pedal positions, brake pedal applications, steering wheel
reversals, actual velocity^ and separation of the lead and following vehicles
were recorded. The results were negative for carboxyhemoglobin concentrations
of 7% and 12%. These were the concentrations studied with the largest numbers
of subjects and the tightest experimental designs.
Another study of carbon monoxide's effects on driving performance used
449
"a standard driving simulator," a. device that simulated a 10-minute drive
through traffic, giving the subjects a brake pedal, an accelerator, and a
steering wheel with which to react to various realistic driving conditions
shown on a film. Forty-four adult volunteers were used. Half of these were
randomly allocated tc a group receiving only air and half to a group receiving
enough carbon monoxide to produce carboxyhemoglobin concentrations about 3.4%
N,
higher than they had when tested before exposure. Half of the experimental
-------
group were smokers and their carboxyhemoglobin concentrations just before the
second driving simulator test averaged about 7.0% (up from about 4.4%) whereas
the nonsmokers averaged 5.6% (up from about 1.3%). An 80 ml dose of pure
carbon monoxide was introduced into the breathing system that was also used
to make carboxyhemoglobin determinations. The subjects breathed this as a
carbon monoxide concentration of 2%.— The carbon monoxide was not found to
affect the overall performance on the driving simulator.
The experimenters divided the various individual activities that had
been scored during the simulation task into 2 categories; "emergency actions,"
and "careful driving habits." No difference could be detected in the way the
experimental and control subjects reacted on the category "emergency actions."
With the "careful driving habits," the group working under the influence of
carbon monoxide showed more deterioration than the control group. The change
is only marginally statistically reliable,however, the relevant data shown in the
a
-Administering carbon monoxide at a high concentration for a short time
may produce greater effects on performance than the customary method of
exposing subjects to low concentrations for longer times. While the
carboxyhemoglobin concentration is usually thought to be the most important
physiological stimulus for determining carbon monoxide's effects, there is
• *
some evidence that the rate of saturation is also important (see other section
on page 5-145). Plevova and Frantik3 recently (1974) demonstrated that
exposing rats to 700 ppm for 30 min produced a greater decrease in the
length of a forced run on a treadmill than did exposure to 200 ppm for 24 h,
* ' f - ^
even though both exposures brought the average carboxyhemoglobin concentration
at the start of the experimental task to approximately 20%.
5-103
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researchers' table*|ave a chi-square of 5.84, which with 2 degrees of freedom
yields a probability between 0.10 and 0.05. Consequently, this finding can
only be regarded as suggestive support for their conclusion that a 3.4%
59
increase in carboxyhemoglobin is sufficient to prejudice safe driving.
Runnno and Sarlanis345 also used a driving simulator to examine the effects
of approximately 7% carboxyhemoglobin concentration. Carbon monoxide at
800 ppm was administered for 20 min prior to a 2-hour simulated drive. By
also dosing the subjects in the same manner with air before one of the two
kept the subjects
experimental sessions.they4 unaware of when they received the carbon
' r
monoxide. The experimenter knew,however, which gas treatment was in effect.
The 7 subjects (6 nonsmokers, 1 smoker) tried to maintain a specified distance
between the automobile that they were "driving" and one that appeared to be
in the same lane ahead of them. They were instructed to respond as quickly
as possible to any changes in this separation. Both increases and decreases
in the separation were programmed to occur at random intervals 10 times
every half-hour. Steering wheel reversals and braking responses to a red
warning-light that appeared on the dashboard for a few seconds 8 times every
half-hour were also recorded. An increase in the response time to changes
in the speed of the car ahead was associated with the carbon monoxide treatment.
The mean response time increased from 7.8 s to 9.6 s, a statistically significant
effect. It was also observed that fewer steering wheel reversals were made
after carbon monoxide administration. The lone smoker showed the opposite
effect. The change was statistically significant only when that subject's
data were not included in the calculations. Several other measures - reaction
5-104
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time to the dashboard light, how much space the subjects kept between cars, and
ability to maintain lateral position on the simulated road— showed no reliable
changes. The authors pointed out one factor that may have helped them observe a
reliable decrease in the rapidity with which changes in the distance between the
two cars were detected. The task "was designed as a vigilance task that closely
simulated a real-life situation of prolonged driving on a little traveled road under
twilight conditions. Nearly all the subjects remarked that the driving was
34 5
realistic but boring."-3"
The paucity of published research on driving and carbon monoxide is somewhat
puzzling, given the longstanding interest in the question by strong political and
economic groups. Perhaps one impediment has been the relative difficulty in
devising both suitable and safe experimental preparations. In light of the strong
preference on the part of some that experimenters work with the precise behavior
at issue, rather than with laboratory analogues, ' the field is probably await-
ing the development of adequate field methods (cf., e.g., 286).
Reaction Time
Reports on the effects of carbon monoxide on reaction time have been con-
flicting. In the last few years several well-controlled studies were completely
negative, whereas several others equally well-controlled were positive.
449 381
Negative studies were reported by Wright et al., Stewart et: al.,
125 445 345
Fodor and Winneke, Winneke, and Rutnmo and Sarlanis. The last study was
described above.
449
In another driving simulator study also described above, Wright et al.
had subjects release the accelerator pedal and depress the brake pedal as quickly
as possible when a red light was lit by the experimenter. No reliable difference
was found in performance on this task at carboxyhemoglobin concentrations about
3.4% higher than the subjects (both smokers and nonsmokers) had at the onset of
the experiment.
5-105
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Stewart e£ al.381 used the American Automobile Association driving
simulator in a reaction-time study. The subject was presented one of 3
stimuli,each of which signaled a different response; turning the steering
wheel left or right or removing the foot from the accelerator and depressing
the brake pedal. Carboxyhemoglobin concentrations as high as about 16%
did not change the reaction time.
During their study of vigilance, Fodor and Winneke125 carried out three
different reaction-time tests: one in which the subject kept his finger
directly above a response button; one in which the subject had to move 25 cm
from where his finger rested between trials to the button; and one dis-
criminative reaction-time test in which 5 buttons in a circle were paired
with 5 different signals. No significant differences were found for any
of these at carboxyhemoglobin concentrations estimated to be 2.3 and 5.3%.
The same procedures also produced negative results in a study by Winneke
in which carboxyhemoglobin concentrations were an estimated 10%.
Ramsey325,32Jep0rted two studies in which longer reaction times with
carbon monoxide were observed. In one study, ^ 60 subjects were exposed via a
face mask to 300 ppm for 45 min while 20 controls breathed only air from a
tank through the mask. The mean carboxyhemoglobin concentration of the
exposed group reached about 4.5%. The reaction-time test is described by
the author only as "reaction-time to a visual stimulus." Subjects exposed
to carbon monoxide showed a very-small but statistically significant increase
in reaction-time. In this experiment, the 60 experimental subjects were
of three different types; one subgroup of 20 subjects were patients with
"mild anemia;" a second 20 subjects suffered from emphysema? and the remaining
5-106
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20 subjects were in normal health. There was no difference in the changes
induced by carbon monoxide in these subgroups. In a second experiment,
327
Ramsey exposed 20 healthy male subjects to 650 ppm for 45 min and another
20 subjects to 950 ppm for the same time. The carboxyhemoglobin concentrations
increased by 7.6% in the first case and 11.2% in the second. Twenty other
subjects received only pure air. A discriminative reaction-time task was
used in which the subject had to respond to various colored lights on different
buttons. The increases in reaction-time shown by the two experimental groups
were both statistically significant.
The interpretation of many of the reaction time studies is difficult
because the experimental procedures have not been fully described. Even
though stimulus intensity, intertrial interval, and the precise response
required have all long been known to be important in react ion-time work-
OQO QQA
they are frequently unspecified. '
Time Discrimination and Estimation
f\ i
In 1967 Beard and Wertheim published an account of an experiment in
which they examined the effects of carbon monoxide on the ability of human
subjects to discriminate between the lengths of two tones. In each case the
first tone;which was 1 s longjserved as the standard. The second tone was
presented one-half s later and varied in duration from 0.675 s to 1.325 s.
The subject's task was to report whether the second tone was shorter, longer
°r the same length as the first tone. He was given three buttons with which to
report his judgment. The pairs were presented in sets of 50 with approximately
7-5 s elapsing between the initiation of pairs. Within each half of this
5-107
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set one-third of the comparison stimuli were identical to the standard, one-
third were longer and one-third were shorter. These were scrambled in a
nonsystematic sequence. It took 6 to 7 min to complete the 50 trials. The
subject then had about 13 min during which he could either read, rest or
watch television while remaining in the small audiometric booth used as an
exposure chamber. The next set of 50 trials was signaled by a warning light
and a tone. This cycle of working approximately one-third of the time and
resting the other two-thirds was repeated 3 times per hour for 4 hours, so
the subject made a total of 600 judgments during each experimental session.
Eighteen university students were each exposed 3 times to each of the
following carbon monoxide concentrations; 0, 50, 100, 175 and 250 ppm. The
subjects were unaware of the concentrations being used but the experimenter
knew. The experimenters presented their results in terms of "mean percent
correct responses." Their analysis of greatest interest concerns the amount
of carbon monoxide exposure necessary to produce a marked performance decre-
ment. Under control conditions subjects averaged about 78% correct at 0 ppm
(see Beard and Wertheim,3^ Figure 1), with a standard deviation of approximately
5 percentage points. The authors presented data on how long an exposure to
various carbon monoxide levels was needed to produce a decrement in performance
more than two standard deviations in magnitude (Figure 5-22). A decrease
from 78% correct to approximately 68% incorrect was produced by 50 ppm carbon
monoxide in about 90 minutes, by 100 ppm in about 50 minutes, by 175 ppm in
about 32 minutes, and by 250 ppm in 23 minutes. Note that the subject had
been in the booth and working for 30 minutes before the exposure began.
5-108
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0>
&
£
|TO
i
O
$30
-------
Carboxyhemoglobin levels were not given so they can only be estimated at this
time. According to Coburn e£ al.82 these levels would have ranged from
approximately 2-1/2 to 4%.
Beard and Wertheim3^ also plotted correct responses versus carbon
monoxide concentration in the booth. They found a linear function with
subjects exposed to 250 ppm getting fewer than 30% correct, whereas control
subjects scored nearly 80% correct, these figures being derived from a two-
hour carbon monoxide exposure starting one hour after the subject had been
&c _ f.
placed in the booth to start the task ana^one-ftali nour after exposure had begun.
Thus, they refer to Carboxyhemoglobin concentrations estimated to average 2%,
4%, 6% and 9% for the 50, 100, 175 and 250 ppm exposures, respectively.
Although this experiment which showed deleterious effects from rather
short duration exposures to low carbon monoxide concentrations was reported
one decade ago, only three groups have attempted to replicate its findings.
In each case, the replication has been less than satisfactory.
In 1970 Beard and Grandstaff33 reported that "the earlier work with
tone duration had been confirmed in 7 additional subjects." No new data
were presented in their paper, however. In 1971 O'Donnell e£ al.3*50 studied
the effects of overnight carbon monoxide exposure on a temporal discrimination
task patterned after that used by Beard and Wertheim3.4 A 1-second standard
tone was delivered one-half second before a tone that varied in length between
0.675 and 1.325 s. Neither the duration of the task nor the total number of
tone pairs was reported. This task was given twice during a 1.5 hour battery
of tests that included 2 other tests of time-estimation, 2 tracking and moni-
toring tasks, and measures of critical flicker frequency, and mental arithmetic.
5-110
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tests were done in the morning after the subject had spent approximately
7-1/2 h in a special chamber exposed to the carbon monoxide concentration
level at which he was being tested. This was a double-blind study in which
neither the subjects nor the experimenters knew which exposure was being
studied. There were 4 subjects each of whom produced data on 3 out of 9
nights spent in the experimental chamber. On the first 4 nights the subjects
adapted to the experimental procedures. On the fifth night they were exposed
to carbon monoxide at either 75 ppm or 150 ppm. On the sixth and eighth
nights they went through all the experimental procedures but were not exposed.
Data for these nights were not reported. On the seventh night they were ex-
posed to the concentration alternate to that used on the fifth night and on
the ninth night to zero concentration. Because the subjects went through
the experimental conditions at either 75, 150, 0, or 150, 75, 0 ppm, only the
two higher carbon monoxide concentrations can be compared statistically.
The carboxyhemoglobin concentrations were 5.9% for the 75 ppm and 12.7% for
the 150 ppm exposure. No difference was found between the subjects' temporal
discrimination scores for" the two concentrations; the means were 6.13± 1.53
at 5.9% carboxyhemoglobin and 6.50 + 1.03 at 12.7%.
The third experiment on carbon monoxide's effects on auditory duration
379
discrimination was carried out by Stewart and co-workers. The subjects were
exposed to carbon monoxide at different concentrations for varying lengths
°f time. This was also a double-blind study. Four different time estimation
methods were investigated. One was an auditory time-discrimination task
modeled after the one used by. Beard and Wertheim.34 Stewart e* al.380 ex-
amined performance on this task under three different conditions: 24 subjects
5-111
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were tested while seated along one side of a table in an experimental room
measuring 20 x 20 x 8 ft (6 x 6 x 2.4m );5 subjects were tested one at a
time in the experimental room; and 9 subjects were tested in an audiometric
booth placed inside the larger experimental room. Seventy-five pairs of
tones were presented in sets of 25 with 30-second pauses between the sets.
The time between the tone-pairs is not reported. However, since the model
was Beard and Wertheim's experiment, it is assumed that similarly the pairs
were 7.5 s apart. According to the authors, the task took approximately 15
min. Other tasks probably took another 10 min to carry out. Since the en-
tire task group was usually carried out once per hour during the carbon
monoxide exposure, the subjects were free to interact with one another for
at least part of every hour. This situation was quite different from the
one in which Beard and Wertheim's subjects found themselves, alone in the
small booth working on their single task approximately one-third of the time
and resting the remaining time.
oon
Stewart et^ a^. presented their results in two ways. In one., they
combine all the pre-exposure data with the data collected after exposure to
the control concentration, described as air containing carbon monoxide at
less than 2 ppm. They then contrasted the score at this "base line1! concentratioa
with the mean score on the tone discrimination task at carboxyhemoglobin
concentrations as high as 20%, which were reached after exposure to various
carbon monoxide concentrations. With this approach there was no apparent
effect. This method of presentation does not take into consideration that
the subjects were being used as their own controls by producing both a pre-
test and a post-test for each carbon monoxide exposure. Therefore the
5-112
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experimenters could more precisely characterize each subject's reaction to
the different exposures. Stewart et al.380 also presented this type of analysis,
not presenting means but presenting the results of t-tests. The changes were
not statistically significant for the 2 measurement conditions in which the
subjects were not tested in the small booth. The t-test was significant for
the 9 subjects who were tested in the booth. These subjects had a 2.9% mean
decrement in the number of correct responses. With 8 degrees of freedom the
t-value of 2.75 was significant at the 0.05 level. The authors reported
that this decrement was associated with a 9.7% mean carboxyhemoglobin con-
centration. Beard and Wertheim's3^ subjects showed a much greater reduction
in performance at much lower carboxyhemoglobin concentrations. However, the
results may not be comparable because their experiment was not exactly
duplicated.
Two other methods of studying carbon monoxide's effects on time percep-
tion have been used. In one, the subject was requested to respond at speci-
fied regular intervals. Beard and Grandstaff33 studied the subject's ability
to estimate the passage of either 10 or 30 s in this way. They reported that
exposure to as little as 50 ppm for 64 min impaired the judgment of a 30-second
period. Estimating a 10-second period however, was not modified by longer
exposures to as much as 250 ppm. Not enough experimental detail was reported
to evaluate the data, and carboxyhemoglobin concentrations were not determined
directly.
o f\1
O'Donnell et al. and Mikulka et al.279 studied the effects of low
carbon monoxide concentrations on the ability of men to space button presses
10 s apart. The subjects received no feedback concerning their accuracy.
5-113
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Data are reported for 9 subjects, each exposed 3 times to 0, 50, or 125 ppm
for a 3-hour period. The carboxyhemoglobin concentrations at the end of the
exposures were 1.0, 3.0 and 6.6%, respectively. Time estimates were made for
3 minutes every half-hour. This task was part of a 15-minute-long battery
that included some tests of tracking and ataxia. It was a double-blind study
in that both the experimenters and the subjects were not informed about the
exposures used. The mean time-estimates were found to be higher under the
influence of carbon monoxide.
The experimenters carefully counterbalanced exposure to the three condi-
tions and did analyses of variance for each of the 6 time-periods. Only one
at 135 to 150 min after the beginning of exposure yielded a reliable difference.
There was also no apparent trend over time toward greater differences between
the control and experimental conditions, which would be expected if the
carboxyhemoglobin concentrations were rising with carbon monoxide exposure.
This, plus the greater difference found with exposure to 50 ppm than to 125
ppm, led the investigators to conclude that they had not demonstrated con-
sistent carbon monoxide effects on this type of performance.
O'Donnell et al. studied the discrimination of one-second tones
after overnight exposures and also studied discrimination of 10-second intervals.
Because they did not counterbalance zero exposure,which was always last^only
their results with exposure to 75 and 150 ppm can be compared. These were
completely negative.
379
Stewart and co-workers also investigated the effect of carbon monoxide
on the discrimination of 10-second time intervals. Their general technique
is described above. In the 10-second time-estimations, similar to those for
5-114
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30-second intervals, the subject held down a push-button for what he thought
was the appropriate time. The mean of two such judgments was taken every hour
during exposure. The results for both the 10- and 30-second tests were negative.
Stewart and his associates^'9,381 ftave examined carbon monoxide's effects
when the subject had to reproduce an interval of time by depressing a button
the
for the same length of time as just-presented auditory or visual signal. The
stimuli lasted either 1, 3, or 5 s, and were presented in random order.
constituted
Three stimuli of each duration a test. The test lasted approximately
/
7 min. In one experiment, the subjects were tested immediately after enter-
ing the experimental chamber after either 4 or 7 h exposure to carbon monoxide •,
or if the exposure was for less than 4 h, during the last half-hour of the
exposure. There were no apparent effects at carboxyhemoglobin concentrations
as high as 25%. In a later experiment in which carboxyhemoglobin concentrations
rose to 20%, the results were only slightly less negative.-*'* The earlier
study had been done with the subjects working in one large room. Part of the
later experiment was carried out under more controlled conditions. The sub-
jects worked either alone in a large room or in a small audiometric booth.
This reduced the influence of factors extraneous to the study. The data were
not presented in the published paper. The results of the t-tests were cited
that led the researchers to reject the possibility of a carbon monoxide effect.
Both experiments were conducted under double-blind conditions.
34
\...t-.nou;>-. in Bea:on and Wertheim's original experiment the researchers
knew which exposure a subject received (it was not a double-blind study
no direct measurements
5-115
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of the carboxyhemoglobin concentrations were made, this experiment's demonstration
of the effects of very low carbon monoxide concentrations on time discrimination
and estimation of behavior has not been refuted. Neither has it been confirmed or
repeated by other workers. However, since either very small or no effects on other
timing-behavior tests have been reported with carbon monoxide doses larger than
those used by Beard and Wertheim, the effect they found may have been due to aspects
of their task other than those associated with time perception. Judging from the
frequent positive results reported by researchers studying vigilance (see above),
it is possible that Beard and Wertheim1 s use of isolated subjects who were given a
prolonged exposure to the tone-duration discrimination task was crucial to their
positive findings. Both the research groups at Marquette University379*380'381
and at Wright-Patterson Air Field300'301 minimized boredom in their tiiaing~behavior
studies. For instance, O'Donnell and co-workers301 reported that, "Following
90 min of exposure, the subject was allowed to walk around and stretch in order to
reduce the possibility of fatigue and boredom from being in a constant position
for 3 hr." On the other hand, the Stanford researchers32>33,34 invariably mini-
mized external influences and ran their experiments for longer periods of time
(cf. 297), thereby turning them into vigilance experiments. Thus, both groups may
be correct in what they are reporting, with external stimulation being the variable
that determines sensitivity to the effects of carbon monoxide.
Coordination and Tracking
The conclusions of most of the coordination, steadiness, dexterity and track-
38T
ing tests examined were negative. Stewart et al. used several tests of
manual dexterity in which, for example, subjects had to pick up small pins, place
them in little holes, and then put collars over the pins. No effects were found,
even at carboxyhemoglobin concentrations of about 15%. Changes in manual
dexterity were seen in a separate series of observations on two subjects when
concentrations of almost 30% were reached. Wright et al.^49 also found
no effects on hand-steadiness at carboxyhemoglobin concentrations of 77..
125
Fodor and Winneke also reported negative results on a series of coordination
tasks performed at carboxyhemoglobin concentrations estimated to be about 5%
5-116
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(from exposure to carbon monoxide at 50 ppm for about 4-1/2 hours).
also reported no change in similar task performance after doubling the exposure
level to 100 ppm for about the same length of time.
OQ OQ
Bender _e_t al . ' reported some positive results with a coordination
task on which 42 students were tested. Each subject was exposed to both 0 and
100 ppm. The experimenter but not the subjects was informed which exposure was
being studied. At carboxyhemoglobin concentrations estimated to be about 7%
(2.5 h exposure to 100 ppm), small but significant decrements were observed
in how skillfully the subjects worked on the Purdue peg board, on
which pegs, bushings, and rings had to be assembled.
In 1929 Dorcus and Weigandm reported that steadiness was the only
characteristic tested that showed any apparent effect after 5-hour exposures
to exhaust gas containing carbon monoxide at up to 400 ppm. More recently,
189
in 1974, in a study of toll booth operators, Johnson et aJL. found that a test
of eye-hand coordination correlated significantly with the increase in carboxy-
hemoglobin concentration produced by exposure to automobile exhaust.
O'Donnell e± al. 279»301 stu
-------
had been carried out for longer than one minute. In psychopharmacology
studies it has been found that prolonged task performances are more likely
to be sensitive to change by chemical agents.°0,26
Both O'Donnell and Mikulka279»301 studied a tracking task in which
subjects reacted with corrective movements to needle deflections, which
became more difficult to compensate with time. The length of time the
subject could keep up with this increasingly difficult task was measured.
Nine nonsmoking male students were each exposed for 3 periods of 3 h duration
to 0, 50 and 125 ppm. At the end of 3 h, the carboxyhemoglobin concentrations
were 1.0, 3.0 and 6.5%, respectively. Although there was a significant
decrement in performance about half-way through the exposure, when the authors
examined the individual curves they concluded that the differences were not
statistically reliable. Hanks^l using the same tracking task reported no
effects at up to 100 ppm for 4-1/2 h. His report contains no data, however.
O'Donnell et_ al.301 gave their subjects the Pensacola Ataxia Battery when
they had completed the tracking task. At carboxyhemoglobin concentrations
up to 6.6% no effects were observed on such measures of ataxia as standing
on one leg or walking a straight line both with closed eyes.
Sensory Processes
Vision is the only sensory function that has received much attention.
The early literature abounds with case histories of the sequelae of both
acute and chronic carbon monoxide poisoning^* but there have been surprisingly
160,263,23
few experimental studies. During World War II, McFarland and co-workers
studied brightness discrimination. They made very careful measurements with
5-118
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a small group of well-trained subjects, thereby minimizing the variability
that usually makes the detection of small differences difficult. Figure 5-23
shows data from an experiment that compared a simulated altitude of 4£94
(15,400 ft)
meters, with various carboxyhemoglobin levels produced by graded doses of
carbon monoxide. Also shown are the effects of administration of pure
oxygen
oxygen and a combination of 7% and 93% carbon dioxide (carbogen).
Carbon monoxide was given via a face mask. It is clear that even slight
to
increases in carboxyhemoglobin level, about 4.5%, increased the measured
visual threshold, indicating that the subject's ability to distinguish an
increase in the intensity of a dimly lit field was diminished. In 1970
Beard and Grandstaff-" reported that Wertheim found statistically significant
increases in the brightness thresholds of four young adults and a decrease
in vernier visual acuity at a carboxyhemoglobin concentration of 3% produced
by carbon monoxide exposure.
327
Conversely Ramsey failed to detect any changes in brightness dis-
crimination in a study of 60 young adults, 20 of whom were exposed to enough
carbon monoxide to produce a carboxyhemoglobin concentration of about 8%,
20 to enough to produce a concentration of about 12%, and 20 controls who
received only air. Using carbon monoxide concentrations that produced
carboxyhemoglobin percentages approximately 3.4% above those at the beginning
f o
of exposure, Wright et al^. did not find any effect on several measures of
visual function; night vision, glare vision, glare recovery, and depth percep-
tion. A possible change in the speed of dark adaptation was studied in 1973
r)f\') ")f\ti
by McFarland and co-workers ' and earlier in 1944 by Abramson and Heyman,2
with negative results in both'experiments. McFarland's study used carboxy-
hemoglobin concentrations as high as 17%. However, none of these negative
5-119
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4-5 "9-4 "15-8" 197
8-0 %COHb
90 120 150
Time (min)
Figure 5-23. The effect of progressive increases in carboxyhemo-
globin percentage in blood on brightness discrimination thresholds.
Each point represents the mean of 10 measurements and the vertical
bars represent plus and minus one standard deviation. Carbon
monoxide was administered at times indicated by th*» horizontal Hnes
between arrowheads. Reprinted with permission from Halperin et al
5-120
-------
studies presented evidence of experimental control comparable to that shown
in the earlier work by McFarland and his colleagues.160>263»266
Several investigators have examined the effects of low carbon monoxide
concentrations on critical flicker fusion frequency (CFF), the frequency
above which an intermittent light appears not to flicker. In 1946 Lilienthal
2"^fi
and Fugitt reported detecting the effects of carboxyhemoglobin concentrations
of 5 to 9% when subjects had also been kept at a simulated pressure correspond-
ing to an altitude of 1,524 or 1,829 m (5 or 6 thousand ft). No such effect was
observed at sea level, even at carboxyhemoglobin concentrations as high as
17%. The actual data were not reported*rathertthe subjects' performance
was characterized as "depressed" or "constant1,1 which makes evaluation difficult.
In another study reported the same year^Vollmer et^ al_. found no effect for
carboxyhemoglobin concentrations of 22% with subjects at simulated altitudes
of 4,724 m (15,500 ft). Fodor and Winneke in 1972,125 Guest e± al. in 1970,156
O'Donnell et al. in 1971,30° Ramsey in 1973327 and Winneke in 1974445 all
reported finding no effect on CFF at carboxyhemoglobin concentrations ranging
from 10% to 12.7%.
Besides the auditory vigilance and time perception studies discussed
above '' only one other study of the effects of small amounts of
carbon monoxide on auditory function has been reported. In 1970 Guest
et al.I56 used an auditory analogue of CFF, an auditory "flutter fusion"
threshold. Their subjects were required to distinguish the point at which
an intermittently presented sound was no longer heard as intermittent.
They found that a carboxyhemoglobin concentration of 10% had no effect on
this threshold.
5-121
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The work by Guest et^ _al.156 is especially noteworthy in that it is one
of the few studies with carbon monoxide that included within its design
provision for gathering data on another agent with known effects, thereby
providing for some internal validation of the sensitivity of its procedures.
Complex Intellectual Behavior
Dorcus and Weigand used three tests of complex learned-behavior in
their 1929 study of the effects of automobile exhaust gas. No effects were
qcrq
found for carboxyhemoglobin concentrations up to 35%. In 1963 SchulteJJJ
studied firemen carrying out a series of complex tasks, none of which is
described in detail. He was able to produce large and regular changes.
For example, in one test subjects underlined all the plural nouns in
certain prose passages. Between carboxyhemoglobin concentrations of 0 and
7% they averaged about 150 s to complete this task; between 10 and 15%
they averaged about 210 s. Subjects averaged slightly less than 800 s to
complete an arithmetic test at concentrations of 8%, but took about 1,000 s
at 15%.
Both Stewart j^t al. and Mikulka et al. have suggested that
Schulte's-"-* measurements of carboxyhemoglobin concentrations were probably
low since he reported a zero value under control conditions in a population
consisting mainly of smokers. Both Guest et al.2^ and Stewart £t al.^81
have questioned the reported concentrations of 20% after exposures to carbon
monoxide at only 100 ppm. Stewart £t al.381 suggested the possibility that
353
Schulte's analytic techniques were unreliable.
5-122
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O'Donnell es£ al. ° also examined carbon monoxide's effects on ability
to do a short series of mental arithmetic problems. Their 4 subjects took
a mean of 89.8 s (SE=10.56) after overnight exposure to 75 ppm and 98.6S
(SE=11.52) after exposure to 150 ppm. The data from the control (0 ppm) measure-
ments are not included here since they were always taken during the last of
a series of three experimental sessions. The difference between the scores
of the 4 subjects after the 2 different exposures (carboxyhemoglobin concen-
trations of 5.9% and 12.7%) is not reliable.
Bender et^ jal.3°»39 investigated the effects of a moderate amount: of
carbon monoxide on several complex tasks. One of these was learning 10
meaningless syllables so that they could be recited without error. Exposure
to 100 ppm carbon monoxide for about 2.5 h (average carboxyhemoglobin
concentration 7%) produced a reliable decrease in accuracy. Repeating a
series of digits in reverse order was also tested. It too showed a reliable
decrease. Negative results were found for several other tasks involving
calculation problems, analogies, shape selection, dot counting, and letter
recognition.
In view of the recent surge of interest among psychologists in human
perception, learning, and memory — all of which now go to make up cognitive
psychology — as well as in human operant conditioning — it is surprising
that more work has not been done on these topics with carbon monoxide. It
would be illuminating, for instance, to see what effects carbon monoxide has
upon such diverse behaviors as simple decision making and the complex per-
, 126 139
tormance of aircraft pilots, ' both of which have been shown to be sensitive
to hypoxic hypoxia.
5-123
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EFFECTS OF CARBON MONOXIDE DURING EXERCISE
It has long been known that when carboxyhemoglobin exceeds 45%, the
capacity to perform physical work is drastically reduced. The subjects
studied by Chiodi et al.72 were unable to carry out tasks that required
low to moderate physical exertion when their carboxyhemoglobin was 40-45%.
Attention has been directed recently to determining the influence of various
carboxyhemoglobin concentrations on maximal aerobic power (maximal oxygen
uptake*). Most of the relatively small number of experiments carried out to
date have studied a limited population of healthy young males (see Table
5-10). The majority of these studies have induced the requisite carboxy-
hemoglobin concentration in their subjects by first exposing them to a
relatively high concentration of carbon monoxide and then proceeding with
the maximal aerobic capacity tests while administering supplementary carbon
monoxide; alternatively it was assumed that the carboxyhemoglobin concentra-
tion remained unchanged during the test. There have been only a few experi-
ments in which the subjects breathed carbon monoxide at the low ambient con-
centrations encountered in urban areas. Some studies failed to separate
the data from smoking and nonsmoking subjects.
Within the carboxyhemoglobin concentration range of 5-35% there is a
linear relation between the decrease in aerobic capacity or power (V0?)
and the carboxyhemoglobin concentration (Figure 5-24). This decrement
*
Maximal aerobic power: The highest oxygen uptake that an individual can
attain during physical work breathing air at sea level (0 meters).
5-124
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TABLE 5-10
The Influence of the Presence of Carboxyhemoglobin
on Maximum Aerobic
Capacity (V09 max) *
Subjects were all male
S = smokers
; NS = nonsmokers
HbCO = Carboxyhemoglobin
Subjects
(n)
2
2
8 (S,NS)
16 (S,NS)
10 (S,NS)
5
10 (S,NS)
1
7 (S)***
7 (S)***
10 (S)
10 (S)
10 (NS)
10 (NS)
9 (NS)***
9 (NS)***
4 (NS)
4 (NS)
Duration of
Max Test**
(min)
3-5
3-5
4-5
4-5
3-5
2-3
3-5
3-5
15
15
21
20
22
21
20
19
23
23
%
HbCO
31
25
20.5
20.3
19.2
15.4
7.1
4.8
5.2
5.1
4.5
4.1
2.7
2.5
2.3
2.3
3.2
4.3
% Decrease
in V02 max
32
18
23
23
23
15
9
9
0
0
3.0
0
3.3
2.0
3.4
5.7
4.9
7.0
Comments
Bolus plus supplementation
Bolus plus supplementation
Bolus plus supplementation
Bolus plus supplementation
Bolus plus supplementation
Bolus
Bolus plus supplementation
Bolus plus supplementation
50 ppm for duration 25 C
50 ppm for duration 35 C
50 ppm for duration 25 C
50 ppm for duration 35 C
50 ppm for duration 25 C
50 ppm for duration 35 C
50 ppm for duration 25 C
50 ppm for duration 35 C
75 ppm for duration 25 C
100 ppm for duration 25 C
Reference
297
297
417
416
120
316
120
120
328
328
329
114
329
72
328
328
174
174
**.
Significant decreases observed at 4.8 and greater HbCO levels.
Duration of exercise time for NS to point of fatigue was consistently
in all tests when carbon monoxide was present in the ambient air.
reduced
***
Middle-aged subjects—all others younger adults.
5-125
-------
40 r-
30
in
tt
o>
M
O
V
20
10
% Decrease V0, m „ - 0.91 (% HbCO) + 2|
, i max
15
25
35
% HbCO
Figure 5-24.
Relationship between percent carboxyhemoglobin and decrement
in maximum aerobic power the linear regression
decrease
V02
max
= °-91
+ 2.2] obtained only
from 5 to 36% carboxyhemoglobin.
5-126
-------
in the maximum aerobic capacity can be predicted from the equation:
% decrease V02 max =0.91 [HbCO] +2.2.
Aerobic power was not significantly decreased in young nonsmokers until a
carboxyhemoglobin concentration above 4% was attained. In these experiments
the number of subjects studied was small. If greater numbers had been used,
some significant differences would probably have been noted at lower carboxy-
hemoglobin concentrations. There were considerable differences between the
responses of young smokers and nonsmokers, especially at lower carboxyhemo-
globin concentrations. Even though smokers had higher carboxyhemoglobin
concentrations than nonsmokers, they often did not show any decrease in
aerobic capacity. The significance of these observations is not understood.
Too few middle-aged subjects were studied to permit drawing conclusions.
OOQ T9Q
In the studies reported"3 »J * it was noted that these 41-56 year-old men
were not typical of the population. Because of the stringent testing, subjects
were carefully screened to eliminate those with cardiovascular or pulmonary
disabilities. Over half the subjects were eliminated in the initial screening
process. The data represent the responses of a highly special population.
Therefore conclusions cannot be extended to the general middle-aged population,
which has a risk factor related to the high incidence of cardiovascular disease.
Furthermore, even though middle-aged smokers did not exhibit clinical signs of
cardiopulmonary disability, they had a much lower aerobic capacity (in filtered
air) than would have been predicted on the basis of age-related norms and so
again are different from the .general population. Changes in ambient temperature
(25-35 C) appear to have only a minimal influence on aerobic capacity at the
low carboxyhemoglobin concentrations studied, >328 other than that anticipated
°n the basis of an increased thermal load.
5-127
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Recent research7 has indicated that 4.3% is a critical concentration at
which carboxyhemoglobin reduces maximum aerobic capacity. This was also
accompanied by a reduction in total work time until maximum aerobic capacity
was reached. Two procedures were used to raise the carboxyhemoglobin to
appropriate concentrations; a build-up method in which carboxyhemoglobin
was incrementally increased by administering ambient air containing carbon
monoxide at 75 or 100 ppm CO; and a high initial carbon monoxide exposure
followed by continued carbon monoxide inhalation to maintain the carboxy-
hemoglobin at the concentration reached in the build-up method, regardless
of the magnitude of ventilation. The decrease in maximum aerobic capacity
was found to occur at the same carboxyhemoglobin concentration and was there-
fore independent of the procedure followed. This observation indicated that
even low ambient carbon monoxide concentrations (23.7 ppm) would result in a
reduced maximum aerobic capacity if the individual had been previously
exposed to sufficient carbon monoxide to raise his carboxyhemoglobin concen-
tration to the critical value, 4.3%. Clark and Coburn^ have suggested that
intracellular carbon monoxide effects may be responsible for the decrease in
aerobic capacity.
The available data concerning the influence of various carboxyhemoglobin
concentrations on the ability of young males to perform light to moderate work
are
* summarized in Table 5 -11. The only observable effect is a slight increase
in heart-rate when the work is performed under conditions in which carboxy-
hemoglobin is increased. Because in all but one of the studies there was
a minimal duration of effort (minutes) and relatively high percentages of
maximal capacity, it will be necessary to separate these factors in order to
5-128
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TABLE 5-11
The Influence of Carboxyhemoglobin on the Capacity
to Perform Submaxlmal Work
S = Smokers; NS = Nonsmokers
HbCO = Carboxyhemoglobin
Subjects
(n)
3
8 (S,NS)
8 (S,NS)
5
5
16 (S,NS)
16 (S,NS)
5
8
32 (S,NS)
24 (S,NS)
% HbCO
25-33
23
23
20
20
20
20
15
15
14
3-6
% Maximum
Capacity*
40-68
50
75
30
70
45
70
50
50
75
35
Duration
of Exer-
•
cise (min)V09 Uptake Reference
60
8
8
-
-
7
7
15
13
5
240
No change
No change
No change
No change
No change
No change
No change
No change
No change
No change
No change
297
417
417
120
120
416
416
316
207
71
138
These figures represent the work load at certain percentages
of the subjects'maximal aerobic capacity, i.e., submaximal work.
5-129
-------
interpret the influence of higher carboxyhemoglobin concentrations on such
performance.
Studies conducted with both young (22-26 yr) and older (45-55 yr) subjects,
smokers and nonsmokers, have indicated that at 35% of their maximal aerobic
capacity prolonged periods of activity (3.5 h within a 4-hour period) could
be performed with minimal changes in their physiologic responses, even though
carboxyhemoglobin concentrations were as high as 10.7 and 13.2%, for nonsmokers
1 3ft
and smokers respectively (see Table 5-12). However, heart rates were higher
during this activity of walking while breathing polluted air (ambient carbon
monoxide = 50, 75, or 100 ppm) than when walking while breathing carbon
monoxide-free air, (0 ppm).
Previous investigations have indicated that a man could work at 35% of
his maximum aerobic capacity for a period of 8 h without evidence of physio-
logical stress,such as an increasing heart rate. In this carbon monoxide
study, the heart rate began to increase after 2 ^indicating that the physio-
logic strain had started at an earlier time when carbon monoxide was present
in the ambient air. Cardiac output remained constant but since there was an
increased heart rate, the heart beat volume decreased. This alteration in
volume was enhanced when work and carbon monoxide exposures were conducted in
a warm environment (35 C).
In summary» maximal aerobic capacity is readily affected even at fairly
low carboxyhemoglobin concentrations (5%), whereas submaximal efforts (30-
75% of maximum) can be carried out with minimal changes in efficiency, even
at relatively high carboxyhemoglobin concentrations (30%).
5-130
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TABLE 5-12
Carboxyhemoglobin Concentrations Prior to and at Completion of
4 Hours of Activity (35% maximum aerobic capacity)
at Different Concentrations of Ambient
1 O Q
Carbon Monoxide (2 Smokers and 2 Nonsmokers)
Ambient
CO (ppm)
0
50
75
100
Nonsmokers*
Pre Post
%HbCO
0.63 0.32
0.67 4.88
0.85 10.27
0.78 12.56
HbCO = Carboxyhemoglobin
Mean
QO Uptake
llters/min
1.29
1.31
1.26
1.21
Smokers**
Pre Post
Mean***
0? Uptake
% HbCO
4.64
6.23
5.48
4.41
1.80
6.88
10.68
13.18
liters /mil
0.85
0.72
0.86
0.94
*Minute ventilation during walking periods averaged 17.93 liters.
fcft
Minute ventilation during walking periods averaged 28.06 liters.
Smokers had significantly smaller maximum aerobic capacity values, V02 max.
5-131
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POPULATIONS ESPECIALLY SUSCEPTIBLE TO CARBON MONOXIDE EXPOSURE OWING TO
REDUCED OXYGENATION AT ALTITUDES ABOVE SEA LEVEL
Precise data on the potential scope of the problems caused by carbon
monoxide^residents and visitors at high altitude are not available. There
are approximately 2.2 million people living at altitudes above 1,524 m (5,000
ft) -in the United States (see Table 5-13). Most live in nine states,
with Colorado having the largest number. The majority of high-altitude
residents (95%) live at 1,524-2,134 m (5,000-7,000 ft). The actual number of
people exposed to carbon monoxide at these altitudes may be much larger
because the tourist population in these states is high both in summer and
winter. Since proper tuning of automobiles for high-altitude traveling is
uncommon, the influx of visitors with cars^accompanied by an increase in the
emission of carbon monoxide and other contaminants, may be an important
factor in increasing air pollution to an unacceptable point.
Ambient air standards set at sea level are not applicable to high-
altitude sites. The Environmental Protection Agency's primary standards
are expressed in milligrams per cubic meter of air. In Denver, at 1,524 + m
(5.,000 + ft), each cubic meter contains about 18% less air than at sea
level. Therefore, permissible concentrations of carbon monoxide in Denver
air would be 18% higher (a 10-mg/m^ maximal permissible 8-hour average is
equivalent to 8.7 ppm at sea level but 10.3 ppm at Denver's altitude)
(see Table 5-14).
The effects of carbon monoxide and of hypoxia induced by high altitude
are similar. Carbon monoxide produces effects that aggravate the oxygen
deficiency present at high altitudes. When high altitude and carbon monoxide
5-132
-------
exposures are combined, the effects are apparently additive. Each of
these •-a decrease in the partial pressure of oxygen in the air and in-
creased carboxyhemoglobin- produce different physiologic responses. They
have different effects on the partial pressure of oxygen in the blood, on
the affinity of oxygen for hemoglobin, on the extent of oxyhemoglobin satura-
tion (carbon monoxide hypoxemia shifts the oxyhemoglobin dissociation curve
to the left, and a decrease in the alveolar oxygen partial pressure shifts
it to the right), and on ventilation drive-
The actual influence of a combination of increased carboxyhemoglobin
and decreased oxyhemoglobin has not been adequately documented by experi-
mental data. The few available studies refer only to acute exposures to a
decreased oxygen partial pressure and an increased carbon monoxide partial
pressure. The best available information on the additive nature of this
combination comes from psychophysiologic studies, but even they are inadequate.
are
There . no data on the effects of carbon monoxide on residents at high
altitudes or on their reactions when they are suddenly returned to sea level
and higher ambient carbon monoxide concentrations.
jf-f.
McFarland £t al., °° in conjunction with their studies on the exposure
of young males to high altitudes, showed that changes in visual threshold
took place at carboxyhemoglobin concentrations as low as 5% or in. a simulated
altitude of approximately 2,438 m (8,000 ft). These observations were confirmed
by Halperin et^ al.f 16° who further observed that recovery from the detrimental
effects on visual function lagged behind the carbon monoxide elimination.
However, there were very few actual data given and neither the variability
among the four subjects nor the day-to-day variations v'ere reported. Vollmer
5-133
-------
/ 1 Q ' '
et_ a^. studied the effects of carbon monoxide at simulated altitudes of
3,048 and 4,572 m (10,000 and 15,000 ft) and did not observe any additive
effects of carbon monoxide and altitude. They suggested that carbon monoxide's
effects were masked by some compensatory mechanism. The data reported were
not convincing.
Lilienthal and Fugitt236 indicated that a combination of altitude
1,524 m (5,000ft) and 5-9% carboxyhemoglobin caused a decrease in flicker
fusion frequency, although either factor by itself had no effect. They also
reported that a carboxyhemoglobin concentration of 8-10% reduced altitude
127
tolerance by about 1,219 m (4,000 ft). Forbes et al. found that during light
activity at an altitude of 4,877 m (16,000 ft), carbon monoxide uptake was
increased. This was probably the result of hyperventilation at high altitude
caused by the respiratory stimulus of a decreased oxygen partial pressure.
317
Pitts and Pace stated that if the subjects were at altitudes of 2,134 to 3,048
m (7,000-10,000 ft), every 1% increase in carboxyhemoglobin (up to 13%) was
equivalent to a 108.2 m (355 ft) rise in altitude. Their observations were
based on changes in the heart-rate response to work. These studies were
contaminated in general by such factors as poor control and the presence of
unidentified subjects who smoked.
Two groups of investigators have reported data comparing physiologic
responses to high altitude and carbon monoxide where the hypoxemia due to
altitude and the hypoxemia due to the presence of carboxyhemoglobin were
approximately equivalent. In one study,18 the mean carboxyhemoglobin con-
centration was approximately 12% (the method of carbon monoxide exposure
resulted in a carboxyhemoglobin variation of from 5 to 20%) and the altitude was
3,454 m (11,333 ft). The second study9 compared responses at an altitude of
5-134
-------
4,000 m (13,125 ft) and a carboxyhemoglobin content of 20%. In both these
studies, the carboxyhemoglobin concentration greatly exceeded that anticipated
for typical ambient pollution. They both suggested,however, that the effects
attributable to carbon monoxide and altitude were equivalent.
The precise measurement of the possible additive effects of carbon
monoxide exposures and altitudes has not received much attention. What
little information is available has been obtained by assuming simple additive
effects^'° but these have not been verified by direct experiments. In the
construction of tunnels at 3,353 m (11,000 ft) it was recommended, on theo-
retical grounds, that the ambient carbon monoxide in the tunnel not exceed
281
25 ppm. To elucidate this question research is needed following both
physiologic and psychophysiologic approaches.
5-135
-------
TABLE 5-13
Estimated U.S. Population Living at High Altitudes (9 States)
1,524-2,134 m 2,134-2,743 m 2,743-4,572 m ^
5,000-7,000 ft 7,000-9,000 ft 9,000-15,000 ft
Urban 1,833,442 69,362. 4,314
Rural* 321,100 16,770 1,150
Total 2,154,542 86,132 5,464
Figures based on ratio of rural to urban population.
Total number living above 1,524 m (5','000 ft) = 2,246,140 or
approximately 6.7% of the total population of these nine
states.
NOTE: Total U.S. population in 1970 was 203,235,000.
TABLE 5-14
Approximate Physiologically Equivalent Altitudes at
Equilibrium with Ambient Carbon Monoxide Concentrations
Ambient Actual Altitude
Carbon Monoxide ft m ft m ft m
Concentration(ppm)'Q (sea level) 0 5,000 1,524 10,000 3,048
Physiologically Equivalent Altitudes with Carboxyhemoglobin
0 0 (sea level) 0 5,000 1,524 10,000 3,048
25 6,000 1,829 8,300 2,530 13,000 3,962
50 10,000 3,048 12,000 3,658 15,000 4,572
100 12,300 3,749 15,300 4,663 18,000 5,486
5-136
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EFFECTS OF CHRONIC OR REPEATED CARBON MONOXIDE EXPOSURE
In the course of chronic or repeated carbon monoxide exposure over
periods of several weeks or months, a variety of structural and functional
changes develop. Some of these changes serve to offset the impairment brought
about by carbon monoxide and thus can reasonably be taken to represent adaptation.
Other changes, however, are of uncertain value to the organism, and a few are
frankly disadvantageous. In this review, adaptive and nonadaptive changes
are considered separately. The reader should recognize, however, that the
separation is somewhat arbitrary and that further information may lead to re-
classification .
Adaptation
The best evidence for adaptation is that animals chronically or re-
peatedly exposed to moderate concentrations of carbon monoxide can tolerate,with-
out apparent harm, acute exposure to higher concentrations , which cause collapse
or death in animals not exposed previously.63,143,202,291,442 in addition^
animals chronically exposed to carbon monoxide develop tolerance for acute
exposure to simulated high altitudes, as well as the converse.'" This suggests
that common mechanisms are involved.
Whether there is symptomatic adaptation in man is much less clear; the
evidence consists mainly of anecdotal reports of industrial workers exposed
to unknown concentrations of carbon monoxide and of extensive studies con-
ducted 40 years ago by Killick^who herself was the subject.203'20^ She
reported that in the course of several months of 6-hour exposures at 5-8
day intervals to carbon mono'xide at 110-450 ppm, slie became "acclimatized."
5-137
-------
This was manifested by diminished symptoms and a smaller pulse rate response
during exposure. She reported that after acclimatization, the equilibrium
carboxyhemoglobin concentration reached during exposure to any given inspired
carbon monoxide concentration was 30-50% lower than before. Because "accli-
matized blood" equilibrated jin vitro showed normal relative affinities for
carbon monoxide and oxygen, and closed circuit breathing experiments appeared to
exclude the rapid metabolism of carbon monoxide, Killick suggested that after
acclimatization, carbon monoxide was actively transported from pulmonary
capillary blood to alveolar air. It is unfortunate that this type of experi-
ment has not been repeated with human subjects using modern analytical teCh-
AQ 99Q
niques. Both the results of animal experiments^ ' and current evidence
that pulmonary gas exchange occurs by passive diffusion suggest that there
may have been a systematic technical error in Killick1s data.
The mechanisms responsible for the development of symptomatic adapta-
tion are not fully understood, but it is clear that hematologic changes are
important. Chronic or repeated exposure to carbon monoxide causes an increase
in both the hemoglobin concentration and the hematocrit (polycythemia) in a
variety of experimental animala17'48'63'76'106'143'202'229'290'291'389*442
In most studies there is a rough correspondence between the severity of the
carbon monoxide exposure and the extent of the polycythemic response. Man
has a similar response but neither the threshold nor the time course has
been accurately quantitated. Industrial workers exposed to high but un-
measured amounts of carbon monoxide have been found to be significantly
1 R7
polycythemic. Kjeldsen and Damgaard,205 in a study of eight healthy volunteers
exposed to 0.5% carbon monoxide intermittently for 8 days (mean carboxyhemo-
globin concentration was 13%), found no change in hemoglobin or hematocrit
5-138
-------
values. This suggests that-more severe or more prolonged exposure may be
necessary to elicit this response in man. There is some evidence that cigarette
smokers have higher hematocrits than nonsmokers, and in a recent survey of blood
donors, hemoglobin concentration was correlated with carboxyhemoglobin concen-
376
tration in both smokers and nonsmokers.
An increase in hemoglobin concentration increases the oxygen capacity
of the blood and improves oxygen transport to some extent. The improvement
may be limited owing to the increase in blood viscosity that accompanies the
increased hematocrit. °9
A second possible hematologic adaptation involves 2,3-diphosphoglycerate
(2,3-DPG), a phosphorylated by-product of glycolysis that is found in the
red blood cells of man and most other mammals. An increase in the concentra-
tion of 2,3-DPG shifts the oxygen-hemoglobin equilibrium in the direction of
deoxygenation, * which lowers the effective oxygen affinity of hemoglobin
(shifts the oxyhemoglobin dissociation curve to the right). This shift is of
theoretical benefit during hypoxic stress because oxygen is "unloaded" into
the tissues with a smaller drop in capillary oxygen partial pressure than
would be possible with the normal dissociation curve.
Red cell 2,3-DPG concentrations are increased and the dissociation curve
is shifted to the right in anemia and during residence at high altitudes.199,225,306
Several investigators have looked for a similar effect from carbon monoxide ex-
posure^with inconclusive results. Dinman et al.108 reported small increases
in 2,3-DPG in humans after 3 h at approximately 20% carboxyhemoglobin and in
rats after exposure to variable higher concentrations of carbon monoxide.
Conversely, Astrup16 found a small decrease in red cell 2,3-DPG in human
subjects maintained with 20% carboxyhemoglobin for 24 h. Radford and
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Kresin324 found that 2,3-DPG concentrations in rats were unaffected by 2 or
287
24 h exposures to carbon monoxide at 500 and 1,000 ppm. Mulhausen et al.
studied blood from human subjects maintained for 8 days at an average carboxy-
hemoglobin concentration of 13% and found no change in the dissociation curve
from that predicted from the immediate carbon monoxide effect. A shift
of the dissociation curve does not appear to be an important adaptation to
carbon monoxide exposure.
Except for Killick's20^ observation that her pulse rate at any given
carboxyhemoglobin concentration was slower after acclimatization, there is
little or no information about possible adaptation of the cardiovascular
system. Data are not available about whether tissue capillarity increases
with prolonged carbon monoxide exposure, as it does during high altitude
residence. 03,39.) Muscle myoglobin concentration especially in the heart
has been shown to increase at high altitude. ' Although a similar in-
crease might be expected owing to prolonged carbon monoxide exposure, no
measurements have been made.
OQO
Montgomery and Rubin OJ in 1973 reported an example of adaptation. In
285
a 1971 study they demonstrated that exposing rats briefly (90 min) to
carbon monoxide at 250-3,000 ppm resulted in a concentration-related slowing
of the in vivo metabolism of certain drugs and a prolongation of their pharma-
cological effects. Hypoxia produced similar effects. When carbon monoxide
exposure was prolonged the effect on drug metabolism became less pronounced,
and by 24 h had almost disappeared. Similar adaptation occurred during ex-
posure to low inspired oxygen when hypocapnia was prevented. The mechanism
of the adaptation is presently unknown.
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Detrimental Effects of Chronic Exposure
The general category of chronic exposure effects comprises those that
result from prolonged or repeated carbon monoxide.exposure, but which are not
caused by acute exposure to carbon monoxide concentrations in the same range.
Most of the effects discussed are irreversible or slowly reversible. The
effects that do not appear to be of benefit to the organism—and thus are not taken
to represent adaptation—are in this section, but whether or not an effect is
beneficial is questionable in some cases.
Prolonged exposure to carbon monoxide concentrations higher than en-
countered in ambient air pollution in the community environment has been
ft 1 7fi 90?
shown to retard growth in experimental animals. »» The mechanism of
growth retardation has not been extensively studied, but reduced food intake
211
may be involved. The effects of carbon monoxide on fertility and on fetal
development are reviewed elsewhere in this chapter.
A syndrome of chronic carbon monoxide intoxication has been described
by several authors,35'135'155 but is far from being established.
A wide variety of symptoms - such as: weakness, periodic loss of
consciousness with twitching, insomnia, personality changes, loss of libido,
and clinical and hematologic changes similar to those of pernicious anemia
have all been attributed to chronic or repeated carbon monoxide exposure.
Dogs exposed intermittently to carbon monoxide at 100 ppm during 11 weeks
developed a broad-based gait and other subtle neurologic abnormalities "
but since there were no controls the results are questionable.
Cardiac enlargement, first reported in carbon monoxide-exposed mice
f\")
"lore than 40 years ago,0^ has recently received renewed attention. Theodore
5-141
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396
et al. reported an increase in heart weight in rats exposed at total
pressure of 5 psi to 460 mg/nr* of carbon monoxide for 71 days, followed by
575 mg/nP for 97 days. These unusual exposure conditions resulted in carboxy-
hemoglobin concentrations of 33-39% in dogs simultaneously exposed with the rats,
O 1 Q ^11
but carboxyhemoglobin was not measured in the rats. Penney et al. »
studied rats continuously exposed at sea level pressure to carbon monoxide
at 500 ppm (41% carboxyhemoglobin) and found that heart weight was significantly
increased within a few days. After 2 weeks the heart weight was 35-40%
greater than the value for control animals of the same body weight. Both
the right and left ventricles were enlarged after 11 weeks of exposure.
This contrasts with the predominance of right ventricular enlargement in
rats exposed at high altitude. Heart weight was also increased in rats
exposed to carbon monoxide for 30 days at 200 ppm (16% carboxyhemoglobin).
In agreement with earlier reports, 118,290,384 anjjjiais that were exposed for
46 days to 100 ppm (9% carboxyhemoglobin) did not develop significant
cardiac enlargement.
Histologic examination of myocardial tissue from animals exposed to
90-100 ppm of carbon monoxide for long periods has revealed edema, degenera-
tion of muscle fibers and fibrosis.119'421 Kjeldsen et^ al.206 in 1974 de-
scribed a variety of ultrastruetural changes in the hearts of rabbits exposed
to carbon monoxide at 180 ppm (17% carboxyhemoglobin) for 2 weeks. The func-
tional significance of these anatomic changes is not known.
During the past several years, Astrup e£ al. have studied the influence
of chronic carbon monoxide exposure on vessel walls. In cholesterol-fed
rabbits, 8 weeks' exposure to carbon monoxide at 170 ppm (15-20% carboxyhemo-
globin), followed by 2 weeks' exposure to carbon monoxide at 350 ppm (33%
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carboxyhemoglobin), increased the cholesterol content of the aorta and
caused subendothelial edema. Similar effects were produced in normally fed
monkeys exposed to carbon monoxide at 250 ppm (21% carboxyhemoglobin) for
399
2 weeks. The significance of this observation in the pathogenesis of
human vascular disease remains to be determined.
Significance for Human Health
Nearly all the available data on the effects of chronic CO exposure are
derived from animal experiments. This is true both of adaptive changes and
of effects that do not seem to be of benefit. Whereas many of these effects
are of considerable interest, it is not justifiable at present to conclude
that human beings are similarly affected. Existing data neither establish
nor disprove a significant influence of chronic CO exposure on human health.
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SUMMARY OF DOSE-RESPONSE CHARACTERISTICS IN MAN
This section summarizes present knowledge about the relationship of dose-
response to adverse effects in man of acute carbon monoxide exposure.
Threshold for Adverse Carbon Monoxide Effects
Whether there is a threshold carboxyhemoglobin concentration for an
adverse effect is still unknown. The question is of practical importance
in setting carbon monoxide air standards. If there are adverse carbon monoxide
effects at any carboxyhemoglobin concentration (no threshold), such effects
could not be entirely prevented by legislation. The mechanism for
adverse carbon monoxide effects is a fall in capillary oxygen partial pressure
(pO^) due to carbon monoxide binding to hemoglobin^ a pertinent question then
is whether any fall in capillary pO£, no matter how small, results in an adverse
effect on tissues. It is known that many tissues, in order to keep intracellular
pO2 nearly constant, can adapt to acute falls in arterial pO,, with resultant falls
in capillary pO^. The major adaptation mechanism in many tissues is probably
recruitment of capillaries to give a decrease in^ diffusion distance between
/*
capillary blood and mitochondria. If such a mechanism occurs as carboxyhemoglobia
increases» it is unlikely that adverse carbon monoxide effects occur at carboxy-
hemoglobin concentrations near zero, and more probable that a threshold exists at
a carboxyhemoglobin concentration where adaptation can not compensate.
As indicated earlier in this chapter, the tissues most sensitive to the
adverse effect of carbon monoxide appear to be heart, brain and exercising
skeletal muscle. Evidence has been obtained that carboxyhemoglobin concen-
trations in the 3-5% saturation range may adversely affect the ability to
15 33 125 153
detect small unpredictable environmental changes (vigilance). ^»JJ» •*»
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to
There is evidence that acute increases of carboxyhemoglobin^above 4-5%
in patients with cardiovascular disease can exacerbate their symptoms »••••*»
173
when the carboxyhemoglobin is as low as 5%. Maximum oxygen consumption
in exercising healthy young males has been shown to decrease when the carboxy-
hemoglobin is as low as 5%.1^^ In the studies of the effect of carbon monoxide
on vigilance and cardiovascular symptoms, there was no attempt either to
determine the effect of lower carboxyhemoglobin concentrations or to look for
a threshold. When the aerobic metabolism of exercising skeletal muscle was
studied an apparent threshold was found. At a carboxyhemoglobin concentration
below 5%, a measurable effect on oxygen uptake could not be demonstrated.
Dose-Response Relationships in Man
In recent yearSj the direction of research has been to look for adverse
effects at low carboxyhemoglobin concentrations. Little effort has been made
to investigate dose-response relationships at carboxyhemoglobin concentrations
higher than those demonstrated to have an adverse effect. It is important to
define dose-response relationships in order to determine whether an increase
in carboxyhemoglobin will have the same adverse effect in a subject with a
normal carboxyhemoglobin as it does in a subject with a higher baseline
carboxyhemoglobin concentration, such as a smoker or a patient with an in-
creased rate of endogenous carbon monoxide production. If the dose-response
curve is concave upward, a given incremental increase in carboxyhemoglobin will
have a greater adverse effect on a subject with higher baseline carboxyhemo-
globin than on! a subject with a normal one. Such a subject would have a
greater risk of experiencing adverse effects from environmental carbon
monoxide. The research mentioned above that showed the effects of sudden
small increases in carboxyhemoglobin on vigilance and on the myocardium
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did not investigate the adverse effects over a wide range of carboxyhemoglobin
concentrations. In the study of the effect of increasing carboxyhemoglobin on
aerobic metabolism in exercising muscle (referred to above), it has been demon-
strated that over a concentration range of 5 to 30%, there was an almost linear
relationship between carboxyhemoglobin and the fall in maximal oxygen uptake.
This dose-response relationship cannot be extrapolated to carboxyhemoglobin
effects on other tissues, since under conditions of exercise at maximum
oxygen uptake it is unlikely that adaptation to carboxyhemoglobin could occur;
the maximum recruitment of capillaries has probably already taken place because
of exercise.
It is likely that dose-response relationships for the adverse effect of
carbon monoxide on a given tissue are different in the presence of disease
or in the fetus. Mechanisms of adaptation to carbon monoxide hypoxia may be
altered or the tissue may be functioning under borderline hypoxia conditions
andj theref ore} be more susceptible to the effects of increased carboxyhemoglobin.
Dose-response relationships may also be different when there is acute rather
than chronic carbon monoxide exposure.
At the present time we know that when there are sudden increases in
carboxyhemoglobin concentrations exceeding 20%, there are gross adverse effects
on the functioning of several organ systems. Conversely, as discussed above,
there is evidence of adverse effects on brain, myocardium, and skeletal muscle
function at relatively low carboxyhemoglobin. But virtually no data are available
in man for other dose-response relationships. Additional information about
threshold carboxyhemoglobin concentrations and dose-response relationships for
various tissues in normal and carbon monoxide-susceptible populations would be
valuable in understanding the biologic effects of carbon monoxide on man.
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Ambient Air Standards for Carbon Monoxide
The current EPA standard for carbon monoxide is 9 ppm maximum for 8 hours
average exposure, or 35 ppm maximum for one hour average exposure. Approximate
calculated carbon monoxide uptakes for varying levels of activity after exposure
to these concentrations are given below.
Heavy
Resting Moderate Activity Activity
9 ppm 8 hours 1.3% sat 1.4% sat 1.4% sat
35 ppm 1 hour 1.3% 2.2% 2.9%
82
These [HbCO] are calculated with the Coburn Forster Kane equation, using
appropriate values for carbon monoxide diffusing capacity, alveolar ventilation,
alveolar pC^ and endogenous carbon monoxide production for resting,
moderate or heavy activity* The current EPA standard is mainly justified
t_
on the basis of adverse carbon monoxide effects in patients with cardiac
and peripheral vascular disease and effects of carbon monoxide on oxygenation
of skeletal muscles in exercising normal human subjects. There appears
to be an adequate safety factor between the lowest carboxyhemoglobin concentration
which has been demonstrated to cause adverse effects and the maximal carboxy-
hemoglobin concentration which can occur at 9 ppm carbon monoxide for 8 hours
or 35 ppm for one hour. However, the existing data base on the adverse effects
of carbon monoxide exposure is not adequate to allow a precise setting of the
carbon monoxide concentrations in ambient air due to the uncertainties discussed
.. that.
throughout this report, and it is probable as more information becomes available,
there can be justification for altering the present standards.
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CHAPTER 6
EFFECTS ON BACTERIA AND PLANTS
BACTERIA
The limited data available indicate that relatively high carbon monoxide
concentrations can have an effect on certain airborne and soil bacteria. But
there is no evidence that concentrations normally found in polluted atmospheres
have an effect. Lighthart studied carbon monoxide's effect on the survival
of airborne bacteria. Vegetative cells of Serratia marcescens 8 UK, Sarcina
lutea, and the spores of Bacillus subtilis var. niger were held in aerosols
at 15 C and exposed to 85 ppm for up to 6 hours. The relative humidity (RH)
was varied from 1 to 95%. At 88% RH and above, carbon monoxide appeared to
protect the cells of
-------
The luminescence of some strains of aquatic bacteria has been reported
to be affected by carbon monoxide.3^ Suspensions of bacteria spotted on
luminescence sensor discs and exposed to atmospheres containing carbon
monoxide gave a detectable response with concentrations as low as 3 ppm.
Lind and Wilson237 reported that nitrogen fixation by Azotobacter
veinlandii (a free-living nitrogen-fixing bacterium) was inhibited by carbon
monoxide concentrations from 1,000 to 2,000 ppm and totally suppressed by
concentrations from 5,000 to 6,000 ppm. Nitrogen fixation by Nostoc muscorum
was inhibited by 1,000 ppm and it approached complete inhibition with concen-
trations of 2,500 ppm. Bergersen and Turner^ reported that exposures to
86 ppm suppressed the nitrogen fixation of bacterial suspensions of Rhizobium
japonicum obtained from soy bean root nodules. Higher concentrations were
required to inhibit nitrogen fixation by the intact nodules.
Soils exposed to high carbon monoxide concentrations develop the ability
to convert it more rapidly. °* This may be due to changes in the population
of carbon monoxide-assimilating organisms in the soil and indicates that
carbon monoxide could have an effect on the ecology of some soil organisms.
") 10 181
Both bacteria^1" and fungi * are known to be able to oxidize it.
PLANTS
Plants are relatively resistant to carbon monoxide. Much higher concen-
trations are required to cause injury or growth abnormalities than for pollutants
such as sulfur dioxide, ozone and hydrogen fluoride. For this reason data
concerning its effects on plants are extremely limited and most of the studies
have been conducted with much higher concentrations than those to which plants
are exposed in nature. Possible damage to vegetation could be caused in three
ways: the production of leaf injury or growth abnormalities which reduce yield,
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growth or quality; the suppression of nitrogen fixation in the soil or root
nodule resulting in a deficiency of nitrogen for plant growth; and suppression
in the rate of photosynthesis over a sufficiently long time-period to cause
a significant reduction in the plant's growth rate.
The available data indicate that carbon monoxide does not cause visible
effects on plants at concentrations found in the ambient air but at high con-
213
centrations it can produce various abnormalities. Knight e_t al. measured
a growth suppression of the etiolated epicotyl of sweet pea at 5,000 ppm.
From this study they showed that ethylene^ and not carbon monoxide , was the
major toxic component of smoke. Zimmerman et^ _al. °» y conducted extensive
studies of carbon monoxide effects on plants. Their interest was not in carbon
monoxide as an air pollutant but rather in finding a chemical that could induce
root initiation and stimulate the growth of other plant parts. They exposed
over 100 species to artificial atmospheres containing high carbon monoxide
concentrations for periods of up to 23 days (most of the data presented are
for 10,000 ppm). At 10,000 ppm they found a growth reduction in a number of
the species. But the species varied widely both in their susceptibility to
carbon monoxide and in their symptom expression. The most important responses
observed at these high concentrations were leaf epinasty and hyponasty,
leaf chlorosis; stimulation of the abscission of leaves, flower buds, and
fruits; hypertrophied tissue on stems and roots; retardation of stem growth;
reduction of leaf size; initiation of adventitious roots from young stem or
leaf tissue; and modification of the natural response to gravity, causing the
roots to grow upward out of the soil. Minina e_t ad. °" and the Heslop-
Harrisons found that 'cucumbers and hemp exposed during critical stages of
development to carbon monoxide at 10,000 ppm induced a modification of sex
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expression, even to the point of total sex reversal in genetically male hemp
96Q
plants. McMillan et^ al. reported that a concentration of 20,000 ppm for
24 hours caused up to 100% leaf drop in certain geographic variants of Acacia
farneniana. They did not find this response in the two other acacia species
studied.
It has been shown that high carbon monoxide concentrations can inhibit
nitrogen fixation of red clover plants and soy bean root nodules ' but
the available data do not indicate that ambient concentrations would have an
adverse effect. Lind et^ al_- exposed red clover inoculated with Rhizobium
trifolii to carbon monoxide for periods of up to one month. No effect was
observed at 50 ppm, there was a 20% reduction in nitrate production at 100 ppm,
andat 500 ppm nitrogen fixation was essentially halted. Carbon monoxide com-
bines rapidly with the root nodule hemoglobin (leghemoglobin) at a rate 20
times faster than it combines with myoglobin, and apparently inhibits oxygen
transport to the interior of the nodule. Leghemoglobin facilitates oxygen
diffusion into the interior of the nodule. The oxygen concentration appears
to be important for nitrogen fixation.^3
Carbon monoxide also can limit bacterial nitrate production through
inhibiting the enzymatic process of nitrogen fixation. Free-living nitrogen-
fixing bacteria and bacteria isolated from soy bean root nodules can be inhibited
by high concentrations^9*237 but Bergersen et _aJL.44 reported that higher con-
centrations were required to inhibit an intact soy bean root nodule than
to inhibit a bacterial suspension prepared from nodules. Inhibition of
nitrogen fixation by carbon monoxide has in some cases been reported to be
competitive52'245 and in others to be noncompetitive. '
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46
Bidwell and Fraser reported a carbon monoxide-induced growth suppres-
sion. In their studies on carbon monoxide uptake by detached leaves they
measured a reversable reduction in photosynthesis in several plant species
exposed to relatively low concentrations. For example, there was strong
inhibition of the net carbon dioxide uptake rate (a measure of the growth
rate) of grapefruit at a concentration of 1.6 ppm and complete inhibition
at 7 ppm. These data indicate that photosynthesis might be inhibited at
concentrations commonly measured in the atmosphere. If this is true,
carbon monoxide could be one of the major pollutants measured in ambient
air in or near large cities responsible for the suppression of plant
growth.177,274,391,398 These results reported by Bidwell and Fraser
have not been confirmed and additional studies should be conducted.
6-5
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CHAPTER 7
SUMMARY AND CONCLUSIONS
Properties and Reactions
Carbon monoxide is a colorless, odorless gas that is chemically stable at
ordinary temperature and pressure. Its molecule is heteropolar, diatomic, and
diamagnetic. It has a low electric dipole moment, short interatomic distance,
and high heat of formation from atoms. These characteristics suggest that the
molecule is a resonance hybrid of three valence structures. The poisonous
nature of carbon monoxide is due to the strength of the coordination bond formed
with the iron atom, which is stronger than that of oxygen in protoheme (a ferrous
ion complex of protoporphyrin IX that constitutes part of the hemeprotein molecules
that bind carbon monoxide).
Chemical reactions of carbon monoxide are critical to its formation or loss
in the atmosphere. Its reactions with oxygen, water, nitrogen dioxide, ozone,
atomic hydrogen, and organic free radicals are probably not important. A number
of reactions with unstable intermediates, such as atomic oxygen and hydroxyl
radicals, are important in atmospheric carbon monoxide chemistry. It is likely
that reactions with atomic oxygen in the upper atmosphere play a role in oxidizing
carbon monoxide. Hydroxyl radicals are generated in the atmosphere, particularly
in air heavily polluted by automobile exhausts and in the natural atmosphere. The
major reaction generating hydroxyl radicals is believed to be solar photolysis of
aldehydes. Carbon monoxide is also formed during solar photolysis of aldehydes,
but this is not an important source, compared with carbon monoxide production from
internal combustion of gasoline-air mixtures in the automobile. The generation of
hydroxyl radicals is important, because they are known to react rapidly with carbon
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monoxide at ordinary temperatures. However, such trace contaminants as hydro-
carbons, sulfur oxides, and nitrogen oxides will compete successfully for avail-
able hydroxyl radicals and thus reduce the significance of reaction with carbon
monoxide. Theoretically, the rate of conversion of nitric oxide to nitrogen
dioxide by hydroperoxyl radicals could be affected by ambient carbon monoxide con-
centrations, but carbon monoxide concentrations are affected to only a very small
extent by nitric oxide conversion. Hydroxyl radical reaction with methane pro-
duces carbon monoxide, and this may be the most important natural source of carbon
monoxide.
Sources and Sinks
There is evidence that perhaps 10 times as much carbon monoxide is formed
by natural processes as by processes related to the activities of man. The anthropo-
genic sources are due to incomplete combustion processes. The total anthropogenic
carbon monoxide emission is much greater than the total anthropogenic emission of
all other criteria pollutants. Anthropogenic carbon monoxide emission is estimated
to have increased by about 28% in the period 1966-1970. Global carbon monoxide
emission from combustion sources was estimated at 359 million metric tons (tonnes)
in 1970. Of the total anthropogenic carbon monoxide formed, the internal-combustion
engine contributes by far the largest fraction. There was a great increase in
carbon monoxide emission from 1940 to 1968, paralleling the increase in motor
vehicles; since 1968, the emission has decreased, owing to installation of emission
control devices. Other sources include industrial processes, agricultural burning,
fuel combustion in stationary sources, and solid-waste disposal. It is estimated
that 95% of the global anthropogenic carbon monoxide emission originates in the
northern hemisphere.
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Natural sources of carbon monoxide include volcanic activity, natural
gases, photochemical degradation of such organic compounds as aldehydes,
methane oxidation, and possibly solar photodissociation of carbon dioxide at
high altitudes. Calculations of carbon monoxide formation by methane oxidation
(based on estimations of hydroxyl radical concentration in the troposphere air)
suggest this reaction contributes about one-fourth as much carbon monoxide as
man-made sources. The oceans are also a significant source of carbon monoxide.
Endogenous carbon monoxide production by man and animals is probably insignificant,
compared with other carbon monoxide sources, in terms of total global carbon monoxide
formation.
Average global background concentration of 0,1 ppm carbon monoxide in iir
removal rate. , , , . , n
reflect a balance between formation and/ Background carbon monoxide as low
as 0.025 ppm is found in northern Pacific air and in the range of 0.04-0.08 ppm
in nonurban air in California. Background carbon monoxide concentrations in
unpolluted areas reflect the history of the air mass. The residence time for
carbon monoxide in the atmosphere has been crudely estimated at approximately
0.2 yr.
If there were no removal of carbon monoxide the average atmospheric concen-
tration would increase at the rate of 0.06 to 0.5 ppm/yr. The sinks include oxida-
tion by hydroxyl radicals (probably the major sink); biologic sinks, such as
microorganisms in soil, vegetation, and metabolism in animals; and removal at the
surfaces of such materials as charcoal and carbon.
Environmental Analysis and Monitoring
There are many problems in the monitoring of any atmospheric pollutant that
are related to variation in concentration and to analytic error. Carbon monoxide
concentration can be shown to be variable on the time and space scale of the
7-3
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smallest atmospheric eddies and on all larger scales. Furthermore, for almost
any pollutant, a monitoring device may well not record the same concentrations
as are present at a receptor a few meters away. Carbon monoxide is taken up by
the lungs of man very slowly; after an increase in inspired carbon monoxide con-
centration, it takes nearly 24 h to reach an "equilibrium" blood carboxyhemoglobin
content. The same is true after a decrease in inspired carbon monoxide concentra-
tion. Because carbon monoxide concentrations in a typical urban environment are
variable in all three spatial dimensions, as well as in time, exposure of a typical
highly mobile urban dweller to carbon monoxide will vary greatly in the course of
effects on the
a day's activity, and the relationship between the/human health and concentrations
measured at monitoring stations is complex. These complexities are partly responsi-
reliable
ble for the dearth of / epidemiologic data on the health effects of chronic
carbon monoxide exposure. The situation is exacerbated by the general tendency of
pollutants to vary together, owing to meteorologic factors.
Carbon monoxide concentrations in cities exceed background concentrations
by at least an order of magnitude. Seasonal differences are small. Diurnal con-
centration follows diurnal traffic patterns and tends to peak during morning and
evening rush hours.
Concentrations decrease steeply with increasing
altitude and are also affected by persistent air circulation patterns. Mathe-
matical models, have led to some success in computing concentrations at loca-
tions not covered by monitoring stations. The problem is made more difficult by
the absence of a general theory of optimal placement of monitoring devices; anthro-
pogenic emission is invariably concentrated, whereas natural emission is usually
diffuse.
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Carbon monoxide concentrations normally found in open air influence man
and animals on a rather long-term. Since the turnover time or exchange rate,
or biological half-life are in hours in man, selection of brief measuring
periods (averaging times) is not necessary.
There are a number of analytic methods for atmospheric carbon monoxide,
but only the nondispersive infrared analyzers and the electrochemical analyzer
(Ecolyzer) are in wide use. The method consisting of catalytic reduction of
carbon monoxide to methane and gas chromatography with flame ionization detec-
tion is specific and sensitive, but it is inherently discontinuous, and most
commercial units based on this method have not been highly dependable. Non-
dispersive infrared analyzers operate continuously, but they are significantly
less sensitive and somewhat less specific. Specificity problems are reduced,
but apparently not totally controlled, by gas pretreatment systems. Some of
the data generated with the nondispersive infrared analyzers have been unreli-
able. Electrochemical methods (Ecolyzer) of monitoring carbon monoxide appear
to be highly satisfactory in regard to reliability and precision.
Although blood carboxyhemoglobin is an almost unique biologic indicator of
exposure to carbon monoxide air pollution, its accurate measurement at low
concentrations is not easy and requires well-trained personnel. In addition,
of course, if the plan is to sample the general public for carbon exposure,
there is a practical limitation on the willingness of people to cooperate. For
these reasons, use of blood samples for routine monitoring of carbon monoxide
exposure of the general public is considered to be impractical.
The efficacy of carbon monoxide monitoring networks as indexes of the
human health effects of this pollutant has not been demonstrated. It would be
ideal to compare uptake, as determined by blood carboxyhemoglobin measure-
ments, with measurements of carbon monoxide in air.
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Effects on Man and Animals
Carbon monoxide in the body may come from two sources: it may be endogenous,
owing to the breakdown of hemoglobin and other heme-containing pigments; and it
may be exogenous, owing to the inhalation of carbon monoxide. Endogenous carbon
monoxide results in blood carboxyhemoglobin saturation of approximately 0.4% in
a normal human. Uptake of exogenous carbon monoxide adds to this value. The
process of uptake of exogenous carbon monoxide consists of inhalation, increase
in alveolar carbon monoxide concentration, and diffusion through the pulmonary
membrane and into the blood. Generally, the rates of diffusion and ventilation
limit carbon monoxide uptake. Equations developed to describe carbon monoxide
uptake in the lung include the following quantities: diffusing capactiy of the
lung, alveolar ventilation, oxygen tension in pulmonary capillary blood, and pul-
monary capillary blood volume. Because the carbon monoxide diffusing capacity and
pulmonary capillary blood volume vary with age and exercise, carbon monoxide up-
take at a given inspired carbon monoxide concentration also varies with age and
exercise. Body size also influences total body hemoglobin; with a larger pool of hemo-
globin available for carbon monoxide binding, the rate of increase in carboxy-
hemogloMn will be smaller at a constant pulmonary uptake. Obviously, the health
of the lung is important: with decreased diffusing capacity or alveolar ventila-
tion, carbon monoxide uptake resulting from an increase in inspired-air carbon
monoxide concentration or carbon monoxide excretion resulting from a decrease in
inspired-air carbon monoxide concentration will be delayed. Barometric pressure
is a factor, because of the effect on inspired and alveolar pO^, pulmonary capil-
lary p02, and pCO at a given carbon monoxide concentration.
Several important questions are related to biologic effects of carbon monoxide.
For example, will a smoker with a usual carboxyhemoglobin concentration resulting
7-6
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from inhalation of cigarette smoke have carboxyhemoglobin from ambient carbon
monoxide simply additive to that present from smoking? The theory predicts that
this would be the case. What is the influence of various parameters on the rate
at which carboxyhemoglobin changes during the daily cycle of activity? Answers
predicted from the theory are given in Chapter 5.
With regard to physiologic effects of carbon monoxide, the most important
chemical characteristic of carbon monoxide is that, like oxygen, it is reversibly
bound by hemoglobin and competes with oxygen for binding sites on the hemoglobin
molecule. Because the affinity of hemoglobin for carbon monoxide is more than
200 times that for oxygen, carbon monoxide, even at very low partial pressures,
can impair the transport of oxygen. That is, the presence of carboxyhemoglobin
decreases the quantity of oxygen that can be carried to tissues and shifts the
oxyhemoglobin dissociation curve to the left and changes the shape of this curve,
so that capillary oxygen tensions in tissues are decreased; this is believed to
hinder oxygen transport from blood into tissues. Although not proved, it is possible
that carbon monoxide exerts deleterious effects by combination with the intra-
cellular hemoproteins, myoglobin, cytochrome oxidase, and cytochrome PATO- The
evidence is best for myoglobin: it has been demonstrated that the degree of
carboxymyoglobin saturation increases with increases in blood carboxyhemoglobin.
Recent evidence that mitochondrial respiration is more sensitive to carbon monoxide
during tissue hypoxia and that binding of carbon monoxide to myoglobin increases
during tissue hypoxia at the same blood carboxyhemoglobin content suggests an
intracellular mechanism of carbon monoxide toxicity under this condition.
Effects on the Fetus. It has recently become obvious that the fetus may be
extremely susceptible to effects of carbon monoxide carried in maternal blood.
7-7
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The fetal carboxyhemoglobin content is chiefly a function of maternal carboxy-
hemoglobin and fetal endogenous carbon monoxide production, but in addition
is a function of placental carbon monoxide diffusing capacity and the factors
that affect maternal carboxyhemoglobin content. Under steady-stage conditions,
fetal carboxyhemoglobin is about 10-15% greater than the corresponding maternal
carboxyhemoglobin concentration. The rates of fetal uptake and elimination of
carbon monoxide are relatively low, compared with those of the mother. After a
step change in inspired carbon monoxide concentration, the time for maternal
carboxyhemoglobin to reach half its steady-state value is about 3 h. In con-
trast, fetal carboxyhemoglobin requires about 7.5 h to reach half its steady-
state value, and final equilibrium is not approximated for 36-48 h. Because
of this lag in change in fetal carboxyhemoglobin and because the ratio of
fetal to maternal carboxyhemoglobin is greater than unity under steady-state
conditions, the mean fetal carboxyhemoglobin content is greater than that of
the mother under a wide variety of circumstances.
Few studies have explored the effects of carbon monoxide on the growth and
development of the embryo and fetus. Most of these used high carbon monoxide
concentrations. The only study with a moderate carbon monoxide content showed
decreased birthweight and increased neonatal mortality in rabbits.
As indicated above, carbon monoxide interferes with tissue oxygenation,
both by decreasing the capacity of blood to transport oxygen and by shifting
the blood oxyhemoglobin saturation curve to the left. Blood oxygen tension
must therefore decrease to lower than normal before a given amount of oxygen
will unload from hemoglobin. Thus, blood carboxyhemoglobin lowers tissue end-
capillary or venous p02. This may result in tissue hypoxia if the pO- is below
a critical point and tissue blood flow does not increase appropriately. Some
7-8
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theoretical effects of blood carboxyhemoglobin on tissue oxygenation and the
effective changes in blood flow and arterial p02 values required to maintain
normal oxygen delivery are reviewed in Chapter 5. These mechanisms may operate
either individually or together to compromise oxygen delivery to developing
cells. If present briefly at critical periods of embryonic or fetal development
or if continued for long periods, these effects may interfere with normal
development.
The hypoxic effects of carbon monoxide are similar to the hypoxic effects
of high altitude; and the fetus, as well as the pregnant woman, at high altitude
may be particularly sensitive to the effects of carbon monoxide.
The effects of carbon monoxide on fetal growth and development are of con-
siderable interest and importance, but there is a dearth of experimental data
available on them. Because of both the short-term effects of carbon monoxide
on fetal oxygenation itself and the possible long-term sequelae (damage to the
brain and central nervous system), fundamental research in this subject is urgent.
Maternal smoking is associated with increased blood carboxyhemoglobin in
both mother and fetus. The decrease in mean birthweight of the infants of
smoking mothers, compared with that of infants of normal nonsmokers, may result
from relative hypoxia caused by carbon monoxide, but this is not established.
Nicotine and other chemicals in tobacco smoke may affect birthweight.
Much of the excessive exposure of the fetus and newborn infant to carbon
monoxide results from smoking by the mother. There is considerable evidence
that smoking during pregnancy results in increased incidences of abortion, such
bleeding problems as placenta praevia and abruptio placentae, stillbirths, and
neonatal deaths. It is thus apparent that there is no place for cigarette-
smoking during pregnancy (it must be noted that the results of smoking during
pregnancy include not only the effects of carbon monoxide, but also the effects
of nicotine and other constituents of tobacco smoke).
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Cardiovascular Effects. It has become clear in recent yuars that the cardio-
vascular system, particularly the heart, is susceptible to adverse effects of carbon
monoxide at low blood carboxyhemoglobin concentration.
Considerable evidence has been obtained with experimental animals that carboxy-
hemoglobin at 6-12% saturation results in a shift from aerobic to nonaerobic metab-
olism in the myocardium and that tissue oxygen tension may be compromised. In
addition, there apparently are ultrastructural changes in the myocardium of experi-
mental animals exposed to carbon monoxide that produces carboxyhemoglobin at 8-9%
saturation for 4 h. There is strong evidence that patients with coronary arterial
disease are more susceptible to small increases in blood carboxyhemoglobin, in
that their physiologic responses are different from those of normal subjects.
Arteriosclerotic heart disease is the leading cause of death and morbidity
in the United States. Many asymptomatic people have extensive coronary athero-
sclerosis. Experimental and clinical studies have suggested that exposure to
carbon monoxide is important in the development of atherosclerotic disease, later
heart attacks, and the natural history of heart disease.
Persons with angina pectoris exposed to relatively low doses of carbon
monoxide for short periods—doses that raised their hemoglobin content to about
2.5%—were found to be able to exercise for a shorter peiod before the onset of
chest pain. Similarly, exposure to the air on the Los Angeles freeway resulted
in an increase in carboxyhemoglobin concentration (mean, 5.08%) and a decrease
in exercise tolerance among angina patients, compared with those in patients who
breathed compressed air while driving on the freeway. Patients with "intermittent
claudication"* who breathed carbon monoxide at 50 ppm for 2 h developed leg pain
sooner after the start of leg exercise and had greater duration of pain than when
they had not been exposed to carbon monoxide.
"c
A complex of symptoms characterised by absence of pain or discomfort in a limb
when at rest, the conpenefiment a£ pain, tenpio?!, and weakness, §f£sr walking is
begun, intensification of the condition until walking becomes impossible, and
the disappearance of the symptoms after a period of rest.
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Patients with angina pectoris who continue to smoke, and therefore might
have higher carboxyhemoglobin contents than nonsmokers, have a poorer prognosis
than patients with angina pectoris who do not smoke cigarettes.
After the cessation of cigarette-smoking by people free of clinical coronary
arterial disease, there is a reduction in their risk of heart attack. This re-
duction in risk occurs fairly rapidly after the cessation of smoking and suggests
that cigarette-smoking (and perhaps carbon monoxide) precipitates heart attack.
It is not known whether results obtained in studies of effects of carbon
monoxide on patients with cardiovascular disease are pertinent to large numbers
of people with these diseases in our population.
Exposure of selected animals, especially rabbits and primates, to carbon
monoxide and a high cholesterol diet has led to a higher incidence of athero-
sclerosis than a cholesterol diet alone. No data are available on the increase
in atherosclerosis after carbon monoxide exposure in man. A recent report, how-
ever, noted atherosclerotic changes in the umbilical arteries of newborns of
smoking mothers.
Epidemiologic studies in Baltimore and Los Angeles have failed to show any
relationship between the number of heart attacks per day (including both myo-
cardial infarction and sudden death) and the daily ambient carbon monoxide con-
centrations in the community. The case-fatality percentage was reported to be
greater in areas within the Los Angeles basin with high ambient carbon monoxide
content than areas with low content during the time when the ambient carbon
monoxide in the basin was increased. Further analysis of these studies suggests,
however, that other factors might have accounted for the difference between case-
fatality percentages.
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People who died suddenly from coronary arterial disease had higher postmortem
carboxyhemoglobin concentration than other sudden-death victims and living con-
trols. The differences were related primarily to the extent of cigarette-smoking
among the different groups. No difference in the pathologic findings between
smoking and nonsmoking people who died suddenly from arteriosclerotic heart disease
(ASHD) was noted in the Baltimore study.
Behavioral Effects. The behavioral effects of low concentrations of carbon
monoxide are small and variable. The effects found most reliably in the labora-
tory are those on vigilance tasks, in which subjects are asked to report the
occurrence of occasional signals over long periods. Four recent studies reported
a higher incidence of missed signals at very low carboxyhemoglobin—between 2%
and 5%—than under control conditions; but one study, in which the carboxyhemo-
globin was 9%, did not. These studies all used relatively small numbers of young,
healthy subjects. In addition, all but one relied on indirect measures of carboxy-
hemoglobin, either alveolar breath samples or estimates made from knowledge of the
duration of the exposure to carbon monoxide. Nevertheless, taken as a group, these
studies argue that carbon monoxide does have an effect on human behavior at carboxy-
hemoglobin saturations even lower than those reached by chronic smokers.
The finding by Beard and Wertheim in 1967, that carboxyhemoglobin estimated
at less than 5% was associated with deficits in a subject's ability to discriminate
between short tones still stands, not yet having been repeated by other workers in
a fashion that would truly challenge it. But this finding now appears to be more
relevant to questions of vigilance than to time perception, inasmuch as some in-
vestigators have minimized the role of boredom and fatigue and others have done
the opposite—i.e., have excluded external influences and studied their subjects
7-12
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for relatively long periods. The former method has usually yielded negative
results; and the latter, positive. Other tests of time perception have been
almost uniformly negative, so time perception itself is probably not affected
by very, low carbon monoxide content.
Only the most tentative conclusion—that carbon monoxide has perhaps a slight
deleterious effect on driving performance—can be drawn from the few preliminary
attempts to study actual or simulated driving. The lack of clear-cut evidence
is especially unfortunate in view of the importance of automobile drivers in any
consideration of the behavioral effects of carbon monoxide.
Low concentrations of carbon monoxide may impair brightness discrimination;
however, this finding dates to World War II and has not been adequately repeated.
There are some hints that various verbal and arithmetic abilities and motor
coordination are lessened by carbon monoxide, but the evidence is unsatisfactory.
Carbon monoxide may modify effects produced by other substances. People
drive automobiles under the influence of sedatives, tranquilizers, alcohol, anti-
histamines, and other drugs. What would be innocuous amounts of such drugs if
taken alone may become important determinants of behavior in the presence of low
carboxyhemoglobin concentrations. Interactions with the other constituents of
automobile exhaust may also occur.
Carbon Monoxide Effects During Exercise. Data on effects of increased carboxy-
hemoglobin during exercise indicate that aerobic capacity is compromised readily
even at fairly low carboxyhemoglobin saturation, whereas submaximal efforts
(30-75% of maximum) can be carried out with minor change in efficiency, even at
relatively high carboxyhemoglobin saturation—i.e., 30%. The available data were
obtained for the most .part from studies on young male subjects.
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Altitude and Carbon Monoxide Effects. Precise data on effects of carbon
monoxide in high-altitude residents and visitors are not available. Some 2.2
million people live at altitudes above 5,000 ft in the United States. Ambient-
air standards set at sea level are not applicable for high-altitude sites. EPA
primary standards are expressed in milligrams per cubic meter of air, and at high
altitudes each cubic meter of space contains less air than at sea level; therefore,
allowable carbon monoxide concentrations are higher. As noted in a previous sec-
tion, carbon monoxide and oxygen are competitive, so adverse effects of carbon
monoxide should occur at lower carbon monoxide concentrations if tissue pC>2 is
less in subjects at high altitude. Carbon monoxide uptake during transient high
carbon monoxide concentration will be more rapid, owing to the lower alveolar pC^-
There are some data that suggest that effects of carbon monoxide are additive to
effects of hypoxia. The most important information on carbon monoxide exposures
at altitude—the preciseness of potentially additive effects—has not received
much attention, and what little information there is has not been verified by
direct experiments.
Chronic Carbon Monoxide Exposure. Animals subjected to prolonged or repeated
exposure to carbon monoxide at concentrations higher than those associated with
community air pollution undergo adaptive changes, which enable them to tolerate
acute carbon monoxide exposures that cause collapse or death in animals not
previously exposed. Polycythemia develops in the course of chronic carbon
monoxide exposure, and this probably contributes to the symptomatic adaptation.
Other compensatory mechanisms are likely, but they have not been demonstrated.
Limited evidence suggests that chronically exposed humans also develop symptomatic
adaptation.
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Prolonged carbon exposure also leads to detrimental effects, including growth
retardation, cardiac enlargement, and an increased rate of development of athero-
sclerosis in some experimental animals. The extent to which similar changes occur
in humans is unknown.
Dose-Response Relationships. Whether there is a threshold concentration of
carboxyhemoglobin for an adverse effect is still unknown. The question is of
practical importance in setting carbon monoxide air standards, because, if there is no
threshold and there are adverse carbon monoxide effects at any blood carboxyhemo-
globin content, it is impossible to prevent all adverse effects by legislating air
standards, but, of course, more severe effects could be prevented.
As indicated in this document, the tissues most sensitive to adverse effects
of carbon monoxide appear to be heart, brain, and exercising skeletal muscle.
There is evidence that carboxyhemoglobin at 3-5% saturation has an adverse effect
on ability to detect small unpredictable environmental changes (vigilance). There
is evidence that acute increases in carboxyhemoglobin to above 5% saturation in
patients with cardiovascular disease can result in exacerbation of symptoms. Car-
boxyhemoglobin as low as 5% saturation has been shown to decrease the maximal
oxygen consumption during exercise in healthy young males. In the studies of
effects on vigilance or cardiovascular symptoms, no attempt was made to determine
effects of lower carboxyhemoglobin saturation and to look for a threshold. In
the studies on aerobic metabolism of exercising skeletal muscle, an apparent
threshold was found: measurable effects on oxygen uptake could not be demon-
strated with carboxyhemoglobin at less than 5% saturation, but it is possible
that effects were present at lower carboxyhemoglobin saturation.
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Recent research has been directed at adverse effects of low carboxyhemoglobin
saturation, and little effort has been made to investigate dose-response relation-
ships at carboxyhemoglobin saturations greater than that demonstrated to have an
adverse effect. Defining dose-response relationships, however, is important in
considering the question of whether increases in carboxyhemoglobin have the same adverse
effects in a subject with a normal carboxyhemoglobin as in a subject with baseline
increased carboxyhemoglobin (such as a smoker) or a patient with increased endogenous
carbon monoxide production. The studies referred to above, showing effects of
acute small increases in carboxyhemoglobin on vigilance or the myocardium did not
explore adverse effects over a wide range of carboxyhemoglobin saturation. It
has been demonstrated in the study of effects of increasing carboxyhemoglobin on
aerobic metabolism in exercising muscle that over about 5-30% saturation there was
an almost linear relationship between carboxyhemoglobin and the fall in maximal
oxygen uptake.
It is likely that dose-response relationships for adverse effects of carbon
monoxide on a given tissue are different in the presence of disease. Mechanisms
of adaptation to carbon monoxide hypoxia may be altered or the tissue may operate
under conditions of borderline hypoxia and therefore be more susceptible to effects
of increased carboxyhemoglobin. Dose-response relationships in acute carbon
monoxide exposure may be different from those in chronic exposure.
There are gross adverse effects on function in several organ systems with
acute increases in carboxyhemoglobin to over 20% saturation. At the other end
of the spectrum, there is evidence of adverse effects on brain, myocardium, and
skeletal muscle function at relatively low carboxyhemoglobin. But almost no data
on other dose-response relationships in man are available. The data base is in-
adequate for determination of air quality criteria standards for carbon monoxide
with a reasonable degree of certainty.
7-16
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A great deal is known about adverse effects of e.irbon monoxide- on nomi.jJ «md
abnormal man, and much of this knowledge supports the setting of rather stringent
air carbon monoxide standards. The present EPA standards are designed to prevent
carboxyhemoglobin over about 2.5% saturation; this gives an adequate safety factor,
in that adverse effects of "acute" carbon monoxide exposures under experimental
conditions are demonstrated at carboxyhemoglobin above 4-6% saturation.
This review made no attempt to survey the literature related to the possible
role of carbon monoxide in the adverse effects of cigarette-smoking. Carboxyhemo-
globin in smokers is frequently greater than saturations that have been implicated
as having adverse effects on normal or abnormal man. A major conclusion of this
report is that it is imperative to determine the effects of carbon monoxide in
smokers and to determine the possible role of carbon monoxide in the excess
morbidity of carbon monoxide in cigarette smokers.
Carbon Monoxide Effects on Bacteria and Plants
Carbon monoxide reacts readily with cytochrome oxidase, and this reaction and
the resulting effect on energy transport may be responsible for some of the observed
effects of this pollutant on plants and bacteria. Carbon monoxide also reacts with
leghemoglobin, affecting the oxygen transport system in the legume root nodule, and
at least some plants appear to be able to metabolize carbon monoxide.
Carbon monoxide at 85 ppm can increase or decrease the survival rate of some
airborne bacteria, depending on the relative humidity and the organism. Luminescence
of some strains of marine bacteria can be inhibited by carbon monoxide when they
are exposed to a carbon monoxide atmosphere on sensor disks.
Carbon monoxide at about 10,000 ppm can produce various leaf, stem, flower,
and root abnormalities in higher plants. These abnormalities include retardation
7-17
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of growth, epinasty and chlorosis of leaves, abscission of leaves and other
plant parts, initiation of adventitious roots from stem or leaf tissue, modifica-
tion of the response to gravity, and modification of sex expression. Carbon
monoxide at about 100 ppm can inhibit nitrogen fixation in root nodules, and
carbon monoxide at about 1,000 ppm can inhibit nitrogen fixation of free nitrogen'
fixing bacteria.
Inhibition of apparent photosynthesis (a measure of the growth rate) has
been measured in excised leaves exposed to typical urban ambient concentrations
of carbon monoxide. Carbon monoxide at 1-10 ppm inhibited the apparent photo-
synthetic rate of coleus, cabbage, grapefruit, and Phoenix palm. Inhibition of
apparent photosynthesis, if it occurs in the field, is probably the only important
effect of carbon monoxide on plants at ordinary concentrations.
Closing Comments
We would be remiss if we did not reemphasize the importance of the issues
associated with exposure to carbon monoxide. Little research has been done on
these problems, compared with that in many other important subjects. And the
quality of this research has sometimes been less than excellent. Unfortunately
the public and legislatures often do not recognize that the roots of understand-
basic mechanism of the
ing of many of the problems of clinical relevance, such as the.effects of carbon
monoxide on the human organism, lie in fundamental research.
7-18
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CHAPTER 8
RECOMMENDATIONS
• We recommend that studies be supported to determine the role
of carbon monoxide in deleterious effects of cigarette-smoking.
The estimation of populations that are influenced by
adverse effects of carbon monoxide is confounded by
the lack of information about the cause of adverse
effects of cigarette-smoking and the possible role
of carbon monoxide.
• We recommend that effort be directed toward greater public
awareness of the hazards of cigarette-smoking during pregnancy.
Although there is public awareness of the hazards of
cigarette-smoking related to lung cancer and other
diseases, there has been little publicity about
hazards to the fetus. There is growing evidence of
serious deleterious effects of maternal cigarette-
smoking on the fetus.
• We recommend expansion of the data base related to adverse
effects of carbon monoxide on vigilance, on oxygenation of
exercising skeletal muscle, and in atherosclerotic heart disease,
and in peripheral vascular disease.
Carbon monoxide standards are now set on the basis of
available data in these fields. Experiments in each of
these fields have been performed on a relatively small
number of human subjects. There is a need for replica-
tion of studies by other laboratories. Carbon monoxide
exposure should be varied in duration and concentration.
8-1
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Dose-response relationships should be determined.
Studies of adverse effects on vigilance and on
oxygen uptake during exercise should be performed
on susceptible populations. In studies on patients
with atherosclerotic heart disease, it would be
particularly useful to study: patients with ex-
tensive coronary arterial disease as determined by
coronary angiography, the effects of positive exercise
testing in people without clinical symptoms, and
people with high risk of heart attack.
We recommend that studies be performed to determine whether
heart, brain, and exercising skeletal muscle adapt to effects
of small increases in blood carboxyhemoglobin (less than
about 5-10% saturation).
The entire data base related to deleterious effects
of carbon monoxide on the heart, brain, and exercising
skeletal muscle was obtained from acute experiments.
\
•i>
Yet exposure of the population to carbon monoxide can
be chronic or intermittent. It is necessary to de-
termine whether subjects can adapt and therefore be-
come less susceptible to intermittent or chronic in-
creases in carbon monoxide in ambient air. Susceptible
populations should be studied.
We recommend rapid expansion of the data base relating physiologic
and ambient carbon monoxide measurements, continuation of the re-
cent approach of monitoring human exposure to carbon monoxide in
8-2
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urban communities with blood carboxyhemoglobin and alveolar
carbon monoxide measurements, acquisition by the EPA of a
trained team capable of measuring blood carboxyhemoglobin.
One of the uncertainties in evaluating effects of
environmental carbon monoxide on health is the
relationship of environmental exposure to carbon
monoxide uptake. Existing methods of monitoring
environmental carbon monoxide can be improved.
The spacing patterns of individual measurement
stations within a monitoring network need to be
studied. Comparison of air monitoring data with
blood carboxyhemoglobin measured either directly
or as alveolar carbon monoxide concentration,
would allow study of the efficiency of air
monitoring systems.
• We recommend an increase in the information on mechanisms
of adverse carbon monoxide effects in man.
It is not clear how very small decreases in hemo-
globin oxygen-carrying ability and computed mean
capillary pC^ resulting from 3-5% carboxyhemo-
globin can cause significant effects on tissue
oxygenation. Studies of intracellular effects
of carbon monoxide should be performed at 5-10%
carboxyhemoglobin.
8-3
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• We recommend studies aimed at identifying susceptible popula-
tions .
Patients with respiratory insufficiency or anemia
should particularly be studied.
• We recommend research to determine the possible role of carbon
monoxide in the increased incidence of abortion, stillbirth,
and neonatal death associated with mothers who are heavy smokers
and in the small-for-gestational-age infants of smoking mothers.
• We recommend research to determine fetal susceptibility to
carbon monoxide.
It is known that carbon monoxide can be concentrated in
the fetal circulation and that blood oxygen tensions in
the fetus are very low; these factors are expected to
increase susceptibility to the adverse effects of carbon
monoxide.
• We recommend studies to determine whether increased carboxyhemo-
globin is a factor in sudden deaths due to coronary arterial
disease.
In previous studies, it was shown that people who died
suddenly from coronary arterial disease had higher post-
mortem carboxyhemoglobin saturation than other sudden-
death victims and living controls. The differences were
related primarily to the amount of cigarette-smoking in
the ASHD subjects who died suddenly. No difference in
the pathologic findings between smoking and nonsmoking
8-4
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people who died suddenly from ASHD was noted in the
Baltimore study. Studies should be performed to
assess whether these effects are in fact relevant
to large numbers of urban people with coronary
disease.
• We recommend studies aimed at determining the relationship
between carbon monoxide exposure in some industries and
morbidity and mortality from heart disease.
This information should give insight into the re-
lationship between atherosclerotic heart disease
and carbon monoxide. A better determination of
industrial carbon monoxide exposure is needed.
Measurement of either carboxyhemoglobin or
expired-air carbon monoxide among employees in
various "high-risk" industries should be completed.
• We recommend further research to establish the extent of
carbon monoxide-induced decrements in vigilance.
Much work remains before it will be possible
to determine which aspects of performance are
most sensitive to carbon monoxide. For example,
decreasing the rate of signal presentation leads
to poorer performance, as does increasing the rate
of unwanted signals or increasing the length of the
experimental session. It would be illuminating to
find out how carboxyhemoglobin saturation inter-
acts with these variables. In addition, modern
8-5
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advances in psychophysics, particularly in signal-
detection theory, promise to help to elucidate the
effects of agents like carbon monoxide.
We recommend further studies of effects of increased carboxy-
hemoglobin saturation on driving performance.
Automobile drivers probably constitute the most
important target population when one considers the
behavioral effects of carbon monoxide. The task of
driving an automobile resembles a vigilance task in
many ways. In the light of the findings on vigilance,
studies on driving performance may uncover deleterious
effects of low concentrations of carbon monoxide,
provided that experimenters with sensitive methods
study their subjects for a long enough period. Two
main targets here are probably the long-distance
truck-driver, who performs a job that combines monotony
8-6
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with danger, and the taxi-driver, who is continuously
exposed to some of the highest urban carbon monoxide
concentrations. An epidemiologic study of automobile
accidents needs to be performed to determine the possi-
ble role of carbon monoxide.
We recommend studies aimed at elucidating possible adverse
effects of carbon monoxide on sensory functions.
Definitive work on the sensory effects of carbon
monoxide has not yet been done, despite a history
of more than 30 years of sporadic effort. The
important conflicts among early experimental
findings were described by Lilienthal 25 years
ago; they remain unresolved. Questions concerning
motor
complex intellectual behavior and coordination are
f^
also largely unanswered, after almost 50 years of
experimentation.
We recommend studies of interactions between carbon monoxide
and other agents.
Carbon monoxide may modify effects produced by other
substances. People drive automobiles under the in-
fluence of sedatives, tranquilizers, alcohol, anti-
histamines, and other drugs. Amounts of such drugs
that would be innocuous alone may become important
determinants of behavior in the presence of low
carboxyhemoglobin saturation. Interactions may
also occur with the other constituents of auto-
mobile exhaust.
8-7
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• We recommend continuing research aimed at determining potentially
additive effects of carbon monoxide and low oxygen tension.
What little information is available has been ob-
tained by assuming simple additive effects, but
has not been verified by direct experiments.
Studies involving both physiologic and psycho-
physiologic approaches are recommended, in order
to clarify this issue. This information will
allow a more rational approach to setting carbon
monoxide air standards at high altitude. Studies
of effects of low carbon monoxide concentration
on man, adapted and nonadapted to high altitude,
are needed.
a We recommend study of the effect of typical urban ambient
carbon monoxide concentrations on several airborne bacteria.
• We recommend studies on intact plants to determine the degree
of suppression of growth or apparent photosynthesis at dif-
ferent carbon monoxide concentrations in combination with other
smog-induced reactions.
• We recommend more work related to natural sources and sinks
of carbon monoxide.
The natural sources and sinks of atmospheric carbon
monoxide are not well understood. Carbon monoxide
production occurs in soil, but little is known about
it. Natural sources and sinks should be measured on
a global basis.
8-8
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• We recommend that animal research be encouraged.
It is at this level that the behavioral, as well as
physiologic, mechanisms of action will most likely
be ascertained. Emphasis on mechanisms of action
is warranted, because such emphasis makes possible
intelligent extrapolation to human behavior that
may not lend itself to direct study. The recent
growth of sophisticated animal psychophysics has
made possible a concerted attack on questions in-
volving sensory and perceptual effects of carbon
monoxide in animals.
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APPENDIX A
METHODS OF MONITORING CARBON MONOXIDE
Nondispersive Infrared Spectrometry (NDIR)
In 1971 the Environmental Protection Agency (EPA) designated nondispersive
infrared spectrometry (NDIR) as the reference method for continuous measurement
of carbon monoxide. 4H This relatively reliable procedure that has been used
for many years is based on the absorption of infrared radiation by carbon
monoxide. First infrared radiation from an emitting source passes alternately
through a reference and a sample cell, and then through matched detector cells
containing carbon monoxide. Since the carbon monoxide in the detector cells
absorbs infrared radiation only at the characteristic frequencies of this com-
pound, the detector becomes sensitive to those frequencies. The wall between
the detector cells is a flexible diaphragm with an electrical position trans-
ducer attached to it. When there is a nonabsorbing gas in the reference cell,
and carbon monoxide-free air in the sample cell, the signals from the detectors
are balanced electronically. The carbon monoxide introduced into the sample
cell reduces the radiation reaching the sample detector, lowering the tempera-
ture and pressure in the detector cell,and displacing the diaphragm. This
electronically detected displacement is amplified to produce an output signal.
Such a monitoring system for carbon monoxide is shown in Figure A-l.366
Because water is the principal interfering substance the moisture
control system is particularly important. Carbon monoxide data obtained
using the nondispersive infrared techniqueare questionable without information
about water removal. At 4.6 ym the absorption-bands of water and carbon
dioxide overlap the carbon monoxide band. A concentration of 2.5% by volume
of water vapor can produce a response equivalent to 6.4 ppm carbon monoxide.315
A-l
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SAMPLE INTRODUCTION SYSTEM
ANALYZER SYSTEM
INTAKE
MANIFOLD
FIRST STAGE
PRESSURE
GAUGE
CYLINDER
PRESSURE
VALVE
DATA RECORDING
AND
DISPLAY SYSTEM
STRIP CHART
RECORDER
SECOND STAGE
PRESSURE GAUGE
SECOND STAGE
PRESSURE VALVE
ZERO OAS
SPAN GAS
366
Figure A-l Carbon Monoxide Monitoring System Diagram
-------
To reduce water vapor interference, water can be removed by drying agents, by
cooling, or its effect reduced by optical filters. A combination of these is
recommended. Selective ion exchange resins in a "heatless air drier" system
can also be used. In a collaborative study of the NDIR method reported by
McKee and Childers, a maximum reproducibility of + 3.5 ppm in the 0 to 50 ppm
968
range was found. The minimum detectable concentration was 0.3 ppm. The
instruments are large owing both to the long cells required for accuracy at
low concentrations and to the air cooling and drying systems for water re-
moval .
Since the data produced by the federal, state, and local monitoring
agencies are used to make decisions which can be very costly, procedures
for validating and maintaining data quality have been developed. Because
of the requirements of the Clean Air Act, the EPA has issued specifications
"•$66
for instruments, methods, calibration, and data quality. The performance
specifications for automated carbon monoxide determinations are shown in
Table A-l, and the specifications for concentrations of interfering
substances used to.check the effects in automated analytical methods for
carbon monoxide are summarized in Table A-2.
A-3
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TABLE A-l
Performance Specifications for Automated Analytical Methods for Carbon
Range 0-50 ppm
Noise 0.50 ppm
Lower detectable limit 1.0 ppm
Interference equivalent
Each interfering substance +1.0 ppm
Total interfering substances 1.5 ppm
Zero drift
~\
12 h +1.0 ppm
24 h +1.0 ppm
Span drift, 24 h
20% of upper range limit +10.0%
80% of upper range limit +2.5%
Lag time 10 min
Rise time 5 min
Fall time 5 min
Precision
20% of upper range limit 0.5 ppm
80% of upper range limit 0.5 ppm
Definitions:
Range: Nominal minimum and maximum concentrations which a method
is capable of measuring.
Noise: The standard deviation about the mean of short duration
deviations in output which are not caused by input concen-
tration changes.
A-4
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Definitions - continued
Lower Detectable Limit*
The minimum pollutant concentration which produces a signal
of twice the noise level.
Interference Equivalent•
Positive or negative response caused by a substance other
than the one being measured,
Zero Drift;
The change in response to zero pollutant concentration during
continuous unadjusted operation.
Span Drift:
The percent change in response to an up-scale pollutant concen-
tration during continuous unadjusted operation.
Lag Time;
The time interval between a step change in input concentration
and the first observable corresponding change in response.
Rise Time:
The time interval between initial response and 95 percent of
final response.
Fall Time!
The time interval between initial response to a step decrease
in concentration and 95 percent of final response.
Precision!
Variation about the mean of repeated measurements of the same
pollutant concentration expressed as one standard deviation about
the mean.
A-5
-------
TABLE A-2
Test Concentrations (In Parts Per Million) of Interfering Substances
for Automated Analytical Methods for Carbon Monoxide
Carbon Water
Measuring principles Ammonia Nitric oxide dioxide Ethylene vapor Methane Ethane
Infrared photometric
(other than reference
method) - _ 750 - 20,000
Gas chromatography—
flame —ionization
detection - - - - 20,000 - 0.5
Electrochemical - 0.5 - 0.2 20,000
Catalytic combustion - - - _ _ _
Thermal detection 0.1 - 750 0.2 20,000 5.0 0.5
Infrared fluorescence - - 750 - 20,000 - 0.5
Mercury replacement
Ultraviolet photometric - - - 0.2 - - 0.5
-------
Dual Isotope Fluorescence
This instrumental method utilizes the slight difference in the infrared
spectra of isotopes. The sample is alternately illuminated with the character-
istic infrared wavelengths of carbon monoxide-16 (CO ) and carbon monoxide-18
(CO18). The carbon monoxide in the sample that has the normal isotope ratio,
nearly 100% carbon monoxide-16, absorbs only the carbon monoxide-16 wavelengths.
Therefore, there is a cyclic variation in the intensity of the transmitted light
O/O 0 ^ "7 O^fl
that is dependent on the carbon monoxide content of the sample. ' '
Full scale ranges of 0 to 20 ppm and up to 0 to 200 with a claimed sensi-
tivity of 0.2 ppm are available in this instrument. The response time (90%)
is 25 s, but a 1-second response time is also available. An advantage of this
technique is that it minimizes the effects of interfering substances.
Catalytic Combustion - Thermal Detection
Determination of carbon monoxide by this method is based on measuring
the temperature rise resulting from catalytic oxidation of the carbon monoxide
in the sample air.
The sample air is first pumped into a furnace which brings it to a pre-
set, regulated temperature and then over the catalyst bed in the furnace. A
thermopile assembly measures the temperature difference between the air leaving
the catalyst bed and the air entering the catalyst bed. The output of the
thermopile, which is calibrated with known concentrations of carbon monoxide
in air, is read on a strip-chart recorder as parts of carbon monoxide per
million parts of air. The sensitivity is about 1 ppm. Most hydrocarbons
are oxidized by the same catalyst, and will interfere unless removed.
A-7
-------
Electrochemical
Carbon monoxide is measured by the means of the current produced in
aqueous solution by its electro-oxidation at a catalytically active-
electrode. The concentration of carbon monoxide reaching the electrode
is controlled by its rate of diffusion through a membrane. This is dependent
on 01
on its concentration in the sampled atmosphere. y> Proper selection of
both the membrane and such cell characteristics as the nature of the electrodes
and solutions make the technique selective for various pollutants. (£. similar
/CO
technique has been reported by Yamate et al. )
The generated current is linearly proportional to the carbon monoxide
concentration from 0 to 100 ppm. A sensitivity of 1 ppm and a 10-second
response time (90%) is claimed for a currently available commercial instrument.
Acetylene and ethylene are the chief interfering substances; one part
acetylene records as 11 parts carbon monoxide and one part ethylene as 0.25
parts carbon monoxide. For hydrogen, ammonia, hydrogen sulfide, nitric oxide,
nitrogen dioxide, sulfur dioxide, natural gas and gasoline vapor, interference
is less than 0.03 part carbon monoxide per one part interfering substance.
Gas Chromatography - Flame lonization
Measured volumes of air are delivered 4 to 12 times/h: to a hydrogen
flame ionization detector that measures the total hydrocarbon content (THC).
A portion of the same air sample, injected into a hydrogen carrier gas stream,
is passed through a column where it is stripped of water, carbon dioxide, and
hydrocarbons other than methane. Methane is separated from carbon monoxide by
a gas chromatographic column. The methane, which is eluted first, is unchanged
after passing through a catalytic reduction tube into the flame ionization de-
tector. The carbon monoxide eluted into the catalytic reduction tube is reduced
A-8
-------
o 1 q
to methane before passing through the flame ionization detector.JJ-y Between
analyses the stripping column is flushed out. Nonmethane hydrocarbon concen-
trations are determined by subtracting the methane value from the total hydro-
carbon value. There are two possible modes of operation. One of these is a
complete chromatographic analysis showing the continuous output from the de-
tector for each sample injection. In the other, the system is programmed
for both automatic zero and span settings to display selected elution peaks
as bar graphs. The peak height is then the measure of the concentration.
The first operation is referred to as the chromatographic or "spectro" mode
and the second as the barographic or "normal" mode.
Since measuring carbon monoxide entails only a small increase in cost,
instrument complexity, and analysis time, these instruments are customarily
used to measure three pollutants; methane, total hydrocarbons and carbon
monoxide.
The instrumental sensitivity for each of these three components
(methane, total hydrocarbons and carbon monoxide) is 0.02 ppm. The lowest
full scale range available is usually from 0 to 2 up to 0 to 5 ppm, although
at least one manufacturer provides a 0 to 1 ppm range. Because of the com-
plexity of these instruments, continuous maintenance by skilled technicians
is required to minimize excessive downtime.
Frontal Analysis
Air is passed over an adsorbent until equilibrium is established between
the concentration of carbon monoxide in the air and the concentration of
carbon monoxide on the adsorbent. The carbon monoxide is then eluted with
hydrogen, reduced to methane on a nickel catalyst at 250 C, and determined
by flame ionization as methane.
A-9
-------
Concentrations of carbon monoxide as low as Q.I ppm can be measured.
This method does not give instantaneous concentrations but does give averages
over a six-minute or longer sampling period. '
Mercury Replacement
Mercury vapor formed by the reduction of mercuric oxide by carbon
monoxide is detected photometrically by its absorption of ultraviolet light
at 253.7 nm. It is potentially a much more sensitive method than infrared
absorption because the oscillator strength of mercury at 253.7 nm is 2000
times greater than that of carbon monoxide at 4.6 ym.
Hydrogen and hydrocarbons also reduce mercuric oxide to mercury and
there is some thermal decomposition of the oxide. Operation of the detector
at constant temperature results in a regular background concentration of
mercury from thermal decomposition. McCullough et al. recommended a tempera-
ture of 175 C to minimize hydrogen interference.36,261 ^ commercial instrument
288
employing these principles was made and used during the middle 1950's.
The technique has been recently used for measuring background carbon monoxide
concentrations. Robbins et^ al.^36 have described an instrument in which the
mercuric oxide chamber is operated at 210 C, and the amount of hydrogen inter-
ference was assessed by periodically introducing a tube of silver oxide into
the intake air stream. At room temperature silver oxide quantitatively oxidizes
carbon monoxide but not hydrogen. Thus the baseline hydrogen concentration can
be determined. Additional minor improvements are discussed by Seiler and
055
Junge, who gave the detection limit for carbon monoxide as 3 ppb with a 5%..
standard deviation of the calibration at 0.2 ppm.
A-10
-------
305
More recently Palanos described a less sensitive model of this
instrument intended for use in urban monitoring. It has a range of 0 to
20 ppm, a sensitivity of about 0.5 ppm, and a span and zero drift of less
than 2% per day. As in other similar instruments specificity is achieved
by removal of the potentially interfering substances other than hydrogen
(which is less than 10%).
All of these instruments assume a constant hydrogen concentration.
In unpolluted atmosphere the hydrogen concentration is roughly 0.1 ppm.
Howeverfthe automobile is not only a source of carbon monoxidefbut also of
hydrogen. Therefore, if this technique is used in polluted areas, it will be
necessary to measure the hydrogen concentration frequently.
A-ll
-------
APPENDIX B
MEASUREMENT OF CARBON MONOXIDE IN BIOLOGICAL SAMPLES
Carbon monoxide is bound chemically to a number of heme proteins in the
body, any of which could act as a measure of exposure. But because hemoglobin
in the red blood cells binds carbon monoxide much more strongly in relation to
oxygen than do any of the other proteins, and because blood is more easily ob-
tained in a pure state than the other sources of heme proteins, blood is ob-
viously the tissue of choice for sampling carbon monoxide exposure. Its
188 342
affinity for hemoglobin is 220 times greater than for oxygen; ' about
40 for myoglobin and about 1 for cytochrome P-450. For routine monitoring,
however, blood samples can be taken only under special conditions. A more
practical method for estimating carboxyhemoglobin is to measure alveolar gas.
The most meaningful expression for the evaluation of carbon monoxide uptake
is the percent concentration of carboxyhemoglobin [HbCO]. Alveolar carbon mon-
oxide and the fraction of total hemoglobin unavailable for oxygen transport are
both directly related to carboxyhemoglobin concentration. The carboxyhemoglobin
concentration may be determined directly using spectrophotometric procedures
without releasing the carbon monoxide bound with the hemoglobin. Also, it can
be determined by measuring total hemoglobin separately and then measuring the
amount of carbon monoxide present by liberating it as a gas. Venous blood can
be taken by venipuncture or by pricking the earlobe or finger. The sample should
be collected in a closed container containing an anticoagulant in the dry form,
such as disodium ethylene diaminetetraacetic acid, EDTA (1 mg/ml of blood)
B-l
-------
or dry sodium heparin USP (0.05 mg/ml of blood). Use of commercial anti-
coagulant Vacutainer tubes is satisfactory. Blood samples can be preserved
on ice (about 4 C) for several days until analyzed. Methods which measure
gaseous carbon monoxide and hemoglobin separately require complete mixing
before aliquots are taken, which is not always easy with small blood samples".
Carboxyhemoglobin Measurement
The amount of carbon monoxide in the blood can be determined by spectro-
photometric procedures without liberating the bound carbon monoxide from the
hemoglobin. These techniques are designed to give the percent of carboxyhemo-
globin directly. Alternatively, the carbon monoxide content of the blood can
be estimated by freeing all the carbon monoxide from the carboxyhemoglobin,
extracting the gas, and assaying it by one of several techniques; classical
volumetric methods, methods based on the reducing action of carbon monoxide,
infrared absorption, or combinations of these. Many of the methods used are
quite adequate when tl\e carboxyhemoglobin percentage is greater than 20%.
>
The difficulty has been to develop a method that is accurate for low concen-
trations of carboxyhemoglobin, particularly in the presence of other hemo-
globin forms such as methemoglobin.
Spectrophotometric Methods. These methods have been popular because
they are quick and simple, but they are frequently inaccurate at low concen-
trations. The spectrophotometric determination of carboxyhemoglobin is
dependent on the difference between the carboxyhemoglobin absorption curve
and the absorption curve for other forms of hemoglobin that are present at
certain wavelengths of electromagnetic radiation. Spectrophotometry can be
as simple and qualitative as observing the color of diluted blood. More
B-2
-------
precise and objective procedures are used to estimate the quantity of carboxy-
hemoglobin and the degree of saturation. A number of spectrophotometric pro-
cedures have been developed that vary in sophistication and accuracy.
70Q
Klendshoj jit. _al. diluted blood 1:100 with dilute ammonia, added solid
hydrosulfite and measured the absorbance at both 555 and 480 nm. The addition
of the hydrosulfite prevents presence of any other but the two pigments,
carboxyhemoglobin and reduced hemoglobin. Both of these have the same ab-
sorbance at 555 nm but different absorbances at 480 nm. The ratio of ab-
sorbance, 550/480, decreases with increasing carboxyhemoglobin. It is evalu-
ated using a standard curve prepared by analyzing known standards. This
method.which is simple, rapid, and sufficiently accurate to determine a
2-5% change in carboxyhemoglobin concentration, has not proven satisfactory
at low concentrations.
O/T C
Small et al. , using blood diluted about 1:70 in dilute ammonia, made
absorbance measurements in the Soret region (410-435 nm) at 4 wavelengths with
a 1 mm light-path. A series of simultaneous equations were used to estimate
the percent carboxyhemoglobin, the percent methemoglobin, and by difference
the percent oxyhemoglobin. The accuracy of this is + 0.6% at low carboxy-
hemoglobin concentrations and + 2% methemoglobin at concentrations below 20%.
This method has now been successfully adopted by other laboratories.
Probably the most convenient spectrophotometric procedure is automated
differential spectrophotometry carried out with a carbon monoxide-oximeter
(manufactured by the Instrumentation Laboratory Co.) described by Malenfant
?"5fi
£t_ al^. In this method measurements of the three-component system con-
taining reduced hemoglobin, oxyhemoglobin and carboxyhemoglobin are made at
three appropriate wavelengths; 548,568 and 578 nm. The instrument carries out
B-3
-------
three simultaneous absorbance measurements at the three wavelengths on an
automatically diluted, hemolyzed blood sample. The signals are then processed
by an analog computer and displayed in digital form as total hemoglobin and
the percent concentration of oxy- and carboxyhemoglobin. Although this instru-
ment is commercially available and widely used, accurate measurements at low
carboxyhemoglobin concentrations (less than 5%) can be carried out only after
careful calibration.
Measurement of carboxyhemoglobin in blood using infrared spectroscopy
of blood (rather than of carbon monoxide extracted from blood as described
o tifir*
below)'has been recently described. This method appears to have a very
high specificity for carbon monoxide bound to hemoglobin and a precision that
is in the same range as the most precise methods in common use.
Volumetric Methods. A variety of methods are used to free bound carbon
monoxide from hemoglobin before measuring the amount of released carboxyhemo-
globin. Carbon monoxide liberation has been carried out by acidification
with various acids (sulfuric, lactic, hydrochloric, acetic, phosphoric)
either with or without the addition of oxidizing agents (potassium ferricyanide,
potassium biiodate). The carbon monoxide released may be determined gaso-
metrically ' or by reaction with palladium chloride. '
There are three methods currently available that have sufficient accuracy
and sensitivity to detect small changes in blood carbon monoxide content on
the order of 0.02 vol % or less. Of these, the infrared analyzer"^»^^ and
the Hopcalite carbon monoxide oxidation meter •" both require blood samples
of one ml or more. In the infrared or Hopcalite analyzer, a maj-or problem
is the necessity for an accurate gas-phase dilution before analysis.
The most satisfactory current method is that of gas-solid chromatography
on molecular sieve columns. Procedures employing thermal conductivity de-
tectors 20,110 require a gas-sample size of 1 ml or more and the detectors
must be operated at the highest sensitivity.
B-4
-------
319
Porter and Volman showed that hydrogen f larae-ionization detection can
be used to measure carbon monoxide after in-line catalytic reduction to methane.
This technique has been applied both to the analysis of carbon monoxide both
92 4
in blood and in respiratory gases and is about 10 times more sensitive than
other chromatographic techniques.
To calculate percent carboxyhemoglobin, total hemoglobin must be determined,
113
This is done by reaction to form cyanmethemoglobin. The most satisfactory
413
procedure is to use Van Kampen and Zijlstra reagent taking precautions both
to prevent the gradual loss of hydrogen cyanide from the acid reagent and to
341
allow sufficient time for total conversion of the carboxyheraoglobin.
The data derived from the analysis of carbon monoxide in the blood by
various techniques are given in Table B-l.
Measurement of Alveolar Gas. The theory of measuring carboxyhemoglobin
by measuring alveolar gas is based on the idea that under certain conditions
the gas in the lungs will equilibrate with the blood. Measurements of the
gas-phase can then be applied to determine carboxyhemoglobin by use of the
Haldane relationship:
[HbCO] = M [Hb02]
To get pO_, the oxygen partial pressure in the arterial blood can either
be measured or assumed; pCO, the carbon monoxide partial pressure, is the
measured quantity, M is the Haldane constant (equal to 220 with very little
342
individual variation at physiologic pH) ; and oxyhemoglobin concentration
is assumed to be approximately 1 - carboxyhemoglobin concentration.
The problem in using this method is to approximate equilibrium conditions
when the gas composition is actually changing at all times. Two maneuvers
B-5
-------
TABLE B-l
Comparison of Representative Techniques for the
Reference
Gasometric
365
342
Optical
188
352
256
Chromatographic
3
209
220
104
Analysis
Method
Van Slyke
syringe-
capillary
infrared
spectrophoto-
metric
CO-oximeter
thermal
conductivity
flame
ionization
thermal
conductivity
thermal
conductivity
of Carbon Monoxide in Blood
Sample
vol. (ml)
1.0
0.5
2.0
0.1
0.4
1.0
0.1
1.0
0.25
Resolution3
(ml/dl)
0.03
0.02
0.006
0.08
0.10
0.005
0.002
0.001
0.006
Sample analysis ,
time (min) CV.%b'
15 6
30 2-4
30 1.8
10
3
20C 1.8
20 1.8
30 2.0
3 1.7
aSmallest detectable difference between duplicate determinations.
Calculated based on samples containing less than 2.0 ml CO per deciliter.
c
Estimated from literature.
Coefficient variation.
B-6
-------
have been tried to achieve equilibrium conditions, rebreathing and breath-
holding. With rebreathing, the subject breathes in and out into a bag. A
gas sample is taken after a specified number of breaths. Since oxygen is
being continuously removed and carbon monoxide concentrations are a function
of both the oxyhemoglobin present as well as the total volume of the lungs
and bag, this is a complex system with equilibrium difficult to achieve. For
this reason the rebreathing method has been replaced by the breathholding
method.191
191
Jones et al. have shown that when a subject holds his breath, alveolar
carbon monoxide concentration increases initially as carbon monoxide leaves
the blood to equilibrate. As the alveolar oxygen falls however, carbon monoxide
is reabsrorbed into the blood due to the fall of oxyhemoglobin and the Haldane
relationship. Thus alveolar pCO will go through a maximum depending on the
191
duration of breathholding. Jones et^ a]^. concluded that 20 s was the
optimum period of time for both practical and theoretical reasons. This
technique is now standard.
The subject expires to residual volume, inspires maximally, holds his
breath for 20 s and then breathes out as far as possible. With the aid of
a 3-way valve, the first 500 ml of expirate is discarded and the remaining
gas is collected by turning the valve to an air-tight bag. The gas in the
bag is then analyzed with standard gas analyzers. For field use the Ecolyzer
has proved to be a rugged and reliable instrument.
ft 7
Theoretically based on the Coburn— Forster.—Kane equation, the slope
of the graph relating the percent concentration of carboxyhemoglobin to alveolar
pCO in ppm should be about 0.155 at sea level for carboxyhemoglobin percent
concentration values equivalent to between 0 and 50 ppm, and progressively
B-7
-------
lower for higher concentrations. Various researchers have reported discrepancies
1 *?7
in the results. Forbes et al. found a ratio of 0.14, Sjostrand364 found 0.16,
and Ringold et al. found 0.20. Smith (unpublished observations) showed
that the. slope was about 0.18 and did not decrease at higher carboxyhemoglobin
percent concentrations as would be expected because equilibrium was reached
less effectively.
This method cannot be used with persons that have chronic lung disease,
in whom the alveolar gas composition tends to be extremely variable. Moreover,
the subject's cooperation is essential. Despite these difficulties, skilled
personnel can achieve reliable data.
B-8
-------
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
REPORT NO.
EPA-600/1-77-034
2.
3. RECIPIENT'S ACCESSION NO.
TITLE AND SUBTITLE
CARBON MONOXIDE
5. REPORT DATE
September 1977
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
Subcommittee on Carbon Monoxide
8. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME AND ADDRESS
Committee on Medical and Biologic Effects of
Environmental Pollutants
National Academy of Sciences
Washington, D.C. 20460 ._
10. PROGRAM ELEMENT NO.
11. COfJTffAtnYGRANT NO.
68-02-1226
2. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory
Office of Research and Development
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Research Triangle Park. N.C. 27711
13. TYPE OF REPORT AND PERIOD COVERED
RTP,NC
14. SPONSORING AGENCY CODE
EPA-600/11
5. SUPPLEMENTARY NOTES
6. ABSTRACT
This document summarizes the carbon monoxide literature related to effects
on man and his environment for the consideration of the Environmental Protection
Agency in updating the information in the Air Quality Criteria for Carbon Monoxide,
It emphasizes recent major advances in our knowledge of carbon monoxide: chemical
reactions in air; biologic effects on man; problems in monitoring urban
concentrations and relating such data to the exposure of populations; data
concerning the identification of susceptible populations; and evidence implicating
carbon monoxide as a causal factor of disease.
Not all published articles have been reviewed, but only those deemed
to be important studies related to carbon monoxide air quality criteria. There
is a large literature on adverse effects of cigarette smoking and some of these
effects may be related to carbon monoxide.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
Carbon monoxide
Carbon monoxide poisoning
Air pollution
toxicity
health
ecology
chemical analysis
06 F, H, T
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