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

-------
                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.

-------
                                  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

-------
                           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

-------
                             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

-------
               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

-------
                                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.

-------
     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

-------
                       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

-------
                                   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

-------
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

-------
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

-------
                                   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.

                                     2-1

-------
     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

-------
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 .


                                     2-3

-------
                            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
                            2-4

-------
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)




                                     2-5

-------
     •  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)
                                   2-6

-------
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.



                                     2-7

-------
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.
                                      2-8

-------
     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.
                                      2-9

-------
     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

-------
 (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

-------
                                    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

-------
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

-------
  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

-------
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

-------
                                  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

-------
                                  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

-------
                                    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

-------
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

-------
    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

-------
                              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

-------
     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

-------
     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

-------
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

-------
     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

-------
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

-------
                                   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

-------
     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

-------
                   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

-------
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

-------
              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

-------
                        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

-------
                                                       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

-------
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

-------
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

-------
                                                         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

-------
                                                 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

-------
                             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

-------
                                                     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

-------
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.
                                     5-79

-------
    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

-------
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

-------
    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

-------
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

-------
                                                            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

-------
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

-------
 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

-------
                                                    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

-------
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

-------
     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

-------
            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

-------
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

-------
(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

-------
   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

-------
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.
                                    5-97

-------
     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

-------
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

-------
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

-------
     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

-------
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

-------
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

-------
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

-------
     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

-------
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

-------
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

-------
              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

-------
    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

-------
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

-------
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

-------
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

-------
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

-------
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

-------
(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

-------
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

-------
                       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

-------
     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

-------
     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

-------
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

-------
                                      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

-------
     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

-------
                          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

-------
                                  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

-------
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

-------
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
                                   5-139

-------
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.
                                   5-140

-------
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

-------
      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%
                                    5-142

-------
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.
                                  5-143

-------
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»   •*»
                                    5-144

-------
                                                           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
                                   5-145

-------
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.





                                     5-146

-------
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.
                                    5-147

-------
                                   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,
                                    6-2

-------
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
                                    6-3

-------
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.   '
                                    6-4

-------
                       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

-------
                                  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
                                    7-1

-------
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.
                                     7-2

-------
     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

-------
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.
                                    7-4

-------
     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.
                                   7-5

-------
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

-------
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

-------
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

-------
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).




                                      7-9

-------
     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.

                                     7-10

-------
     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.
                                   7-11

-------
     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

-------
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.
                                  7-13

-------
     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.
                                     7-14

-------
     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.
                                    7-15

-------
     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

-------
     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

-------
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

-------
                             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

-------
     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

-------
   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

-------
•  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

-------
        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

-------
      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

-------
     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

-------
•  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

-------
•  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.
                              8-9

-------
                                    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

-------
  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

-------
                                     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

-------
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

-------
                                REFERENCES










1.  Abramson, E. , and T. Heyman.  Dark adaptation and inhalation  of  carbon




         monoxide:  Acta Physiol. Scand. 7:303-305, 1944.
 2.  Adams, J. D., H. H. Erickson, and H. L. Stone.  Myocardial metabolism  during




         exposure to carbon monoxide in the conscious dog.  J. Appl. Physiol.




         34:238-242, 1973.




 3,  Allen, T. H., and W.  S. Root.  An improved palladium chloride  method for




          the determination of carbon monoxide in  blood.   J. Biol.  Chem.  '216:




          319-323, 1955.




 4.  Altshuller,  A.  P.,  and J.  J.  Bufalini.   Photochemical aspects of air




         pollution:   A review.   Environ. Sci.  Technol. 5:39-64,  1971.





 5.  Altshuller, A.  P., and J. J. Bufalini.  Photochemical aspects  of air




          pollution:  A review.  Photochem. Photobiol. 4:97-146,  1965.




5a.   Anderson,   J. G.  The absolute concentration of OH  (X2/T) in the earth's




          stratosphere.  Geophys. Res.  Lett.   3:165-168,  1976




 6.   Anderson,  E. W., R.  J.  Andelman,  J. M. Strauch, N. J. Fortuin, and  J. H.




          Knelson.  Effect of low-level carbon monoxide exposure on onset  and




          duration of angina pectoris.   A study in ten patients with ischemic




          heart disease.   Ann. Intern.  Med. 79:46-50, 1973.  •




 6a.  Andrews, J., and J.  M. McGarry.  A community study  of smoking in  pregnancy.




          J. Obstet. Gynaecol. Brit. Commonw. 79:1057-1073, 1972.





 7.   Annau,  Z.  The comparative  effects of hypoxic  and carbon monoxide hypoxia




          on behavior, pp. 105-127.  In B. Weiss  and  V.  G. Laties,  Eds.   Behav-




          ioral Toxicology.  New York:  Plenum Press,  1975.

-------
 fi-   Anthony,  A.,  E.  -Ackcrman,  and G.  K.  Strothor.  Effects of altitude accli-
          matization  on rat myoglobin.  Changes in myoglobin content of skele-
          tal  and  cardiac muscle.   Amer.  J. Physiol. 196:512-516, 1959.
9.    Aronow, W.  S., J.  Cassidy, J. S.  Vangrow, H. March, J. C. Kern, J. R.
          Goldsmith,  M. Khemka, J. Pagano, and M. Vawtek.  Effect of cigarette
          smoking  and breathing carbon monoxide on cardiovascular hemodynamics
          in anginal  patients.   Circulation 50:340-347, 1974.                 	
 10.  Aronow, W. S.,  J.  Dendinger,  and S.  N. Rokaw.  Heart  rate  and  carbon monoxide
           level after  smoking, high-,  low-, and  non-nicotine cigarettes.  Ann.
           Intern.  Med.  74:697-702,  1971.
 11.  Aronow, W. S. , J.  R. Goldsmith, J. C. Kem, J. Cassidy, W. H. Nelson,
          L. L. Johnson, and W. Adams.  Effect of smoking cigarettes on
          cardiovascular hemodynamics.  Arch. Environ.  Health 28:330-332, 1974.
 12.   Aronow,  W.  S.,  C. N. Harris, M.  W.  Isbell, S. N. Rokaw, and B. Imparato.
           Effect  of freeway travel on angina pectoris.  Ann. Intern. Med. 77:
           669-676, 1972.
 13.   Aronow,  W.  S.,  and M. W.  Isbell.  Carbon monoxide effect on exercise-induced
           angina pectoris.  Ann.  Intern. Med. 79:392-395, 1973.
 14.  Aronow, W. S.,  and S.  N.  Rokaw.   Carboxyhemoglobin caused  by smoking non-
           nicotine cigarettes.  Effects  in angina pectoris.   Circulation  44:
           782-788, 1971.
  15.  Aronow, W.  S., E.  A.  Stemmer, and M. W. Isbell.   Effect of  carbon monoxide
           exposure  on intermittent claudication.   Circulation  49:415-417, 1974.
 15a.   Asmussen, I., and K. Kjeldsen.  Intimal ultrastructure of human umbilical
           arteries.   Observations on arteries from newborn children of smoking
           and nonsmoking mothers.  Circ.  Res. 36:579-589,  1975.
15b.   Astrup,  P.   Some physiological and pathological  effects of moderate carbon
           monoxide exposure.   Brit. Med.  J.  4:447-452, 1972.

-------
                      41
I5c.  Astrand, I., P. Ovrum, and A.  Carlsson.  Exposure to methylene chloride.   I.
           Its concentration in alveolar air and blood during rest and exercise
           and its metabolism.  Scand. J. Work Environ. Health  1:78-94, 1975.
 16.  Astrup, P.  Intraerythrocytic 2, 3-diphosphoglycerate and carbon monoxide
           exposure.  Ann. N. Y. Acad. Sci. 174:252-254, 1970.
 17.  Astrup, P., K. Kjeldsen, and J.  Wanstrup.  Enhancing influence of carbon
           monoxide on the development of atheromatosis in cholesterol-fed rabbits.
           J. Atheroscler. Res. 7:343-354, 1967.
18.   Astrup, P., and H.  G.  Pauli,  Eds.   A comparison of prolonged exposure to
           carbon monoxide and hypoxia in man.  -Scand.  J.  Clin Lab.  Invest.
           24(Suppl. 103):1-71, 1968.
 19.  Astrup, P., D. Trolle, H. M.  Olsen, and K. Kjeldsen.  Effect of moderate
           carbon-monoxide exposure on fetal development.  Lancet 2:1220-1222,
           1972.
20.   Ayres,  S.  M.,  A. Criscitiello, and S.  Giannelli,  Jr.   Determination of
           blood carbon monoxide content by gas chromatography.   J.  Appl.
           Physiol.  21:1368-1370, 1966.
 21.  Ayres,  S.  M.,  S. Giannelli, Jr.,  and  H.  Mueller.  Effects of  low concen-
           trations  of carbon monoxide.   Part  IV.  Myocardial and systemic  res-
           ponses to carboxyhemoglobin.   Ann.  N. Y.  Acad. Sci. 174:268-293,  1970.
22.   Astrup, p., H.  M. Olsen,  D. Trolle,  and K.  Kjeldsen.   Effect of moderate
           carbon-monoxide exposure on fetal development.  Lancet  2:1220-1222,
           1972.
23.   Baardsen,  E. L., and R. W.  Terhune.   Detection  of OH in  the  atmosphere
           using a dye laser.   Appl. Phys.  Lett.  21:209-211, 1972.
24.   Baker,  F.  D.,  and C. F. Tumasonis.   Carbon monoxide and avian embryogenesis.
           Arch.  Environ.  Health  24:53-61, 1972.
25.   Baker,  F.  D.,  C. F.  Tumasonis, and J.  Barron.   The effect of carbon monoxide
           inhalation on  the mixed-function oxidase activity in the  chick embryo
           and the adult mouse.   Bull. Environ.  Contam.  Toxicol.  9:329-336,  1973.

-------
 26.  Earth, C. A., A. I. Stewart, C. W. Hord, and  A. L. Lane.  Mariner   9
           ultraviolet spectrometer experiment:  Mars airglow spectroscopy
           and variations in Lyman alpha.  Icarus 17:457-468, 1972.
 27.   Bartlett, D.,  Jr.   Pathophysiology of exposure to low concentrations of car-
           bon monoxide.   Arch.  Environ. Health 16:719-727,  1968.
 28.  Baulch,  D.  L.,  D.  D. Drysdale,  and A. C. Lloyd.  Critical Evaluation of
           Rate Data for Homogeneous, Gas Phase Reactions of Interest in High-
           Temperature Systems,   No.  1.  Leeds University, England, May 1968.

29.   Bates, D. R., and A. E. Witherspoon.  The photo-chemistry of some minor
          constituents of the earth's atmosphere (CO  , CO, CH , NO).  Monthly
          Notices.  Roy. Astron. Soc.  (London) 112:101-124, 1952.
 30.   Bay,  H.  W., K.  F.  Blurton,  H.  C.  Lieb,  and  H.  G. Oswin.   Electrochemical
           measurement of carbon monoxide.   Amer.  Lab. 4(7):57-61,  1972.
31.   Bay,  H.  W., K.  F.  Blurton,  J. M.  Sedlak, and  A.  M.  Valentine.   Electrochem-
           ical technique for the measurement of  carbon monoxide.  Anal.  Chem.
           46:1837-1839,  1974.
32.   Beard, R. R.,  and N. Grandstaff.   Carbon monoxide and human functions,
           pp. 1-26.   In B.  Weiss and V. G. Laties,  Eds.  Behavioral Toxicology.
           New York:   Plenum Press,  1975.
33.   Beard, R. R.,  and N. Grandstaff.   Carbon monoxide exposure and cerebral
           function.   Ann. N. Y.  Acad.  Sci. 174:385-395, 1970.
 34.  Beard,  R.  R., and  G. A. Wertheim.  Behavioral impairment associated  with
            small doses of carbon monoxide.  Amer. J.  Public Health  57:2012-2022,
            1967.
  35.  Beck, H. G.  The clinical manifestations of chronic carbon monoxide  poison-
            ing.  Ann. Clin.  Med.  5:1088-1096,  1927.

-------
36.   Beckman,  A.  0.,  J.  D.  McCullough, and R. A. Crane.  Microdetermination of


          carbon monxide in air.   A portable instrument.  Anal Chem. 20:674-


          677, 1948.
                                                                             i

37.  Bohrmnn,  R. E. ,  D.  E.  Fisher, and J. Pnton.  Air pollution  in  nurseries:


          Correlation with a decrease in oxygen-carrying capacity of hemoglobin.


    .-;.•••• :J. Podiatr.  78:1050-1054, 1971.

33(  Bonder,  W. , M. Gothert', and  G. Malbrny.   Effect of low carbon  monoxide


          concentrations on psychological  functions.   Staub Reinhalt.  Luft


           (Engl. Ed.) 32(4):54-60, 1972.


39.  Bender, W. , M. Gothert,  G.  Malomy, and t>. Sebbcsse.  Wirkungsbild


          neidriger Kohlenoxid-Konzentrationen beim Menschen.  Arch. Toxikol.


          27:142-158,  1971.


 40.  Benesch, R.,  and R. E.  Benesch.  The effect of organic phosphates  from the


           human erythrocyte on the allosteric properties of hemoglobin.   Biochem.


           Biophys. Res. Comm.  26:162-167, 1967.


 41.  Benesch, W. ,  M.  Migeotte,  and L. Neven.  Investigations of atmospheric


           CO  at the  Jungfraujoch.  J. Opt. Soc. Amer.  43:1119-1123, 1953.


 42.  Benson,  F. B.,  J.  J.  Henderson, and D. E. Caldwell.   Indoor-Outdoor  Air


           Pollution Relationships:  A Literature Review.   Publ. AP-112.


           Research Triangle Park, N. C.:  U. S. Environmental Protection


           Agency,  1972.  73 pp.


43. Bergersen,  F. J.   The effects of partial  pressure of oxygen upon respira-


           tion  and nitrogen  fixation by soybean root nodules.   J.  Gen. Micro-


           biol.  29:113-125,  1962.


44.  Bergersen,  F. J.,  and G. L.  Turner.  Comparative  studies of nitrogen


           fixation by soybean root nodules,  bacteroid  suspensions and cell-


           free extracts.   J. Gen. Microbiol. 53:205-220,  1968.

-------
 45.  Bernard,  C.   Lecons  sur les Effets des Substances Toxiques et Medicamen-

           teuses.   Paris:   J.-B. Baillicre et Fils,  1857.   488 pp.

 46.  Bidwoll, R. G. S. , And D.  E. Fraser.  Carbon monoxide uptake and metabo-

           lism by  ]o;ives. Can.  J. Bot. 50:1435-1439,  1972.

46a.  Birnstingl, M.,  L. Hawkins,  and  T. McEvcn.  Experimental atherosclerosis

           during chronic  exposure to  carbon  monoxide.   Eur.  Surg. Res.   2:92-

           93, 1970.   (abstract)

 47.  Blackburn, 11., P. Canner,  W. Krol,  S. Tominaga,  and  J.  Stamler.   The

           natural  history of  myocardial  infarction  in the coronary drug pro-

           ject.  .Prognostic indicators following infarction, pp.  54-64.  In

           G.  Tibblin, A.  Keys and L.  Werko,  Eds. Preventive Cardiology.

           Proceedings of  an International Symposium held  at  Billingehus, Skovde,

           Sweden,  Aug. 21,  1971.  New York:   Halsted  Press,  1972.
 48.  Brieger, H.  Carbon monoxide polycythemia.  J. Ind. Hyg. Toxicol. 26:321-327,

           1944.

48a.  Brief, R. S., R. S. Ajemian, and R. G. Confer.  Iron pentacarbonyl:  Its

           toxicity, detection, and potential for formation.  Amer. Ind. Hyg.

           Assoc. J.  28:21-30, 1967.
                   *
 49.   Brody, J. S.,*and R. F. Coburn.  Effects of elevated carboxyhemoglobin on

           gas exchange in the lung.  Ann. N. Y. Acad. Sci. 174:255-260, 1970.

 50.   Brown, F. B., and R. H. Crist.  Further studies on the oxidation of nitric

           oxide;  the rate of reaction between carbon monoxide and nitrogen

           dioxide.  J. Chem. Phys. 9:840-846, 1941.

50a.  Buncher, C. R.  Cigarette smoking and duration of pregnancy.  Amer. J.

           Obstet. Gynecol. 103:942-946, 1969.

  51.   Burns,  B.,  and  G.  H.  Gurtner.   A specific carrier for oxygen and carbon

            monoxide in the  lung and  placenta.   Drug  Metab.  Depos. 1:374-379,

              73.


                                   6

-------
 52.   Rurris,  R.  H.,  and P.  W.  Wilson.   Characteristics of the nitrogen-fixing
           enzyme; system in  Nostoc  muscorum.   Dot.  Gazette 108:254-262, 1946.
53.  Butler, N.  R., and E.  D. Alberman, Eds.  Perinatal Problems.   The Second
          Report of the 1958 British Perinatal Mortality  Survey under the
          Auspices of the National Birthday Trust Fund.   Edinburgh:   E. & S.
          Livingston, Ltd., 1969.                                             	
 54.   Butler,  N.  R. ,  and D.  G.  Bonham.   Perinatal Mortality.   The  First Report
           of  the 1958  British  Perinatal Mortality Survey, under  the Auspices
           of  the National  Birthday Trust  Fund.   Edinburgh:   E. &  S. Livingstone,
           Ltd,  1963.   308  pp.                                                	
54a.   Butler,  N.  R.,  and H.  Goldstein.   Smoking in pregnancy and  subsequent
           child  development.   Brit.  Med.  J.  4:573-575, 1973.
55^  Butler, N.  R., H.  Goldstein,  and E.  M.  Ross.  Cigarette smoking in preg-
          nancy:  Its influence  on birth  weight  and perinatal mortality.   Brit.
          Mod. J. 2:127-130, 1972.
 56.  Cahoon,  R.  L.  Simple  decision making at high altitude.  Ergonomics  15:
           157-164, 1972.
 57.   Calvert,  J. G.,  K.  L.  Demerjian,  and J.  A.  Kerr.   Computer  simulation of
           the chemistry of a  simple  analogue to the  sunlight-irradiated auto-
           exhaust polluted  atmosphere.  Environ. Lett. 4:123-140,  1973.
 58.  Calvert, J.  G., K. L.  Demerjian, and J. A.  Kerr.  The effect  of carbon
          monoxide on the chemistry of  photochemical smog systems.   Environ.
          Lett.  4:281-295,  1973.
 59.   Calvert,  J. G. ,  J.  A.  Kerr, K.  L.  Demerjian,  and  R.  D.  McQuigg.  Photo-
           lysis  of  formaldehyde  as a hydrogen  atom source in the  lower atmos-
           phere. Science  175:751-752,  1972.

-------
 SO.  n.ilvort,  .1.  C.. ,  .in»1  j.  N.  Pitts,  Jr.   j_ The oxides of carbon:  C0_7, pp.

           27.2-223.   In  Photochemistry.   Now York:   .Tohn Wiloy & Sons, Inc., 1966.

M.  Campbell, J. A.   Growth, fertility etc. in animals during attempted acclima-

           tization to carbon monoxide.   Q.  J.  Exp.  Physiol.   24:271-281, 1934.

62.  Campbell, J. A.  Hypertrophy of the heart  in acclimatization  to  chronic

          carbon monoxide poisoning.  J. Physiol.  (Lond.)  77:8P-9P,  1933.

 63.  Campbell,  J.  A.  Tissue oxygen tension and carbon monoxide poisoning.   J.

           Physiol.   (Lond.)  68:81-96,  1929.

64.  Cnvanagh, L. A., C.  F.  Schadt,  and  E.  Robinson.   Atmospheric  hydrocarbon

           and  carbon monoxide measurements  at Point  Barrow,  Alaska.   Environ.

           Set. Tcchnol. 3:251-257,  1969.

65.  Cavender, J. II.,  D.  S.  Kircher, and A.  J.  Hoffman.  Nationwide Air

           Pollutant Emission Trends, 1940-1970.  Research Triangle Park, N. C.:

           U.  S.  Environmental Protection Agency, Office of Air and Water
                                                           *
                                                         *r-
           Programs, 1973.  52 pp.

 66.  Chance,  B., M. Erecinska, and  M. Wagner.   Mitochondrial responses  to  car-

           bon monoxide toxicity.   Ann.  N. Y. Acad.  Sci.  174:193-204,  1970.

 67.  Chance,  B., N. .-Oshino, T. Sugano,  and A.  Mayevsky.  "Basic principles  of

           tissue oxygen  determiniation  from mitochondrial signals,  pp.  277-292.

           In H.  I.  Bichcr and  D. F.  Bruley. Oxygen Transport to  Tissue.  Instru-

           mentation, Methods,  and  Physiology.   Advances  in Experimental Medicine

           and Biology.   Volume 37A.  New York: Plenum Press, 19.73.

 68.  Chanutin,  A.,  and R. R. Curnish.   Effect  of  organic  and inorganic  phos-

           phates on  the  oxygen equilibrium of  human erythrocytes.  Arch.

           Biochem.  Biophys. 121:96-102,  1967.

 69.  Ch.ipanis,  A.   The relevance of laboratory studies to practical situations.

           Ergonomics  10:557-577, 1967.
                                   8

-------
 70.  Chapanis, A.  The search for relevance in applied research, pp.  1-14.   In


           W. T. Singleton, J. G. Fox, and D. Whitfield, Eds.  Measurement of


           Man at Work.  An Appraisal of Physiological and Psychological Criteria


           in Man-Machine Systems.  London:  Taylor and Francis Limited, 1971.


 71.   Chevalier,  R.  B.,  R. A. Krumholz,  and  J.  C.  Ross.   Reaction of nonsmokers to


           carbon monoxide inhalation.   Cardiopulmonary  responses at rest  and


           during exercise.   J.A.M.A.  198:1061r 106.4.,  1966.


 72.   Chiodi,  H., D. B.  Dill, F.  Consolazio, and S. M. Horvath.   Respiratory


           and circulatory responses  to  acute carbon  monoxide  poisoning.   Amer.


           J.  Physiol. 134:683-693,  1941.
             • •                      l

 73.   Chovin,  P.  Carbon monoxide;  Analysis of exhaust gas investigations in


            Paris.  Environ.  Res. 1:198-216,  1967.


 74.   City of  Chicago, Department of  Environmental Control.  Engineering Services


           Division.   Chicago 1974 Emission  Inventory Summary.





74a.  City of New York, Bureau of Technical Services,  Department of Air Resources.


           Data Report Aerometric Network.   Calendar Year 1974.  37 pp.


74b.  City of  New York, Bureau of Technical Services.  Department of Air Resources.


           Estimated Emission Inventory Summary.  Technical Service Report 16.


           April  1976.


 75.   Clark, B.  J.,  and  R. F. Coburn.  Mean tnyoglobin oxygen tension  during


           exercise  at maximal oxygen uptake.  J.  Appl. Physiol.  39:135-144,


           1975.


 76.   Clark, R. T.,  Jr., and A.  B. Otis.   Comparative studies  on acclimatization of


           mice to carbon monoxide and  to  low oxygen. Amer. J.  Physiol.  169:285-


            294, 1952.

-------
77.  Clcrc, M., ami F. Barat.  Cinetique des produits  de  decomposition de  CCL
          par photolyse-cclair dans  1'ultraviolet  lointain.   J.  Chim.  Phys.
          63:1525-1529,  1966.
73.  Clerc, M., and F. Barat.  Kinetics of CO formation studies  by  Far-uv
          flash photolysis of C02.   J. Chem. Phys. 46:107-110, 1967.
79.  Coburn,  R.  F.  Enhancement  by phenobarbital and diphenylhydantoinof  carbon
          monoxide  production in normal man.  N,.Erigl* J. Med.  283:512-515,  1970.
80.  Coburn, R. F.  The  carbon monoxide stores.  Ann. N.  Y.  Acad. Sci.  174:
          11-22, 1970.
 81.  Coburn,  R.  F.; G. K.  Danielson, W. S.  Blakemore,  and R. E.  Forster II.
          Carbon monoxide  in blood:   Analytical  method and sources  of error.
          J.  Appl.  Physiol.  19:510-515, 1964.
 82.  Cobu-rn, R. F., R.  E. Forster,  and P. B. Kane.  Considerations of the physio-
           logical variables  that  determine the  blood carboxyhemoglobin concentration
           in man.  J. Clin.  Invest. 44:1899-1910, 1965.   "
 83.  Coburn, R. F., and P.  B. "Kane.  Maximal erythrocyte and hemoglobin catabolistn.
           J. Clin. Invest.  47:14.35-1446, 1968.
 84.  Coburn, R. F., and L. B. Mayers.  Myoglobin 0« tension determined  from
                    »                              ^
           measurements  of carboxymyoglobin in skeletal muscle.  Amer.  J. Physiol.
           220:66-74,  1971.
 85.   Coburn, R. F., F. Ploegmakers, P. Gondrie,  and F. Abboud.  Myocardial myoglo-
           bin oxygen tension.  Amer. J.  Physiol. 224:870-876, 1973.
 86.  Coburn,  R. F., W.  J. Williams, and R. E. Forster.   Effects of erythrocyte
           destruction on  carbon monoxide production in man.  J. Clin.  Invest.
           43:1098-1103, 1964.
 87.  Coburn, R. F., W.  J. Williams, and S. B. Kahn.  Endogenous carbon monoxide
           production in patients with hemolytic anemia.   J. Clin. Invest. 45:460-
           468, 1966.

                                    10

-------
 88.   Cohen,  S.  I.,  M.  Deane,  and  J.  R.  Goldsmith.   Carbon monoxide and survival
           from  myocardial  infarction.   Arch.  Environ.  Health 19:510-517,  1969.
 89.  Cohen, N.,  and L.  Hcicklen.  The oxidation of inorganic non-metallic com-
          pounds, pp. 1-137.  In C. H.  Bamford, and C.  F. H. Tipper, Eds.
          Comprehensive Chemical Kinetics.  Vol. 6.  Reactions of Non-Metallic
          Inorganic Compounds.  New York:  Elsevier Publishing Compnay, 1972.
90.  Cole, P. V., L. H. Hawkins, and D.  Roberts.   Smoking during pregnancy
          and its effects on  the fetus.  J. Obstet. Gynaecol. Brit. Commonw.
          79:782-787, 1972.
91.  Collins, V. G.  Isolation, cultivation and maintenance of autotrophs, pp.
          1-52.  In J.  R.  Norris and D. W. Ribbons, Eds.  Methods in Micro-
          biology.   Vol. 3B.  New York:  Academic Press, 1969.
 92.  Collison,  H.  A.,  F.  L.  Rodkey,  and J.  D.  O'Neal.   Determination of carbon
          monoxide in  blood by gas  chromatography.   Clin.  Chem.  14:162-171,  1968.
 93.  Colmant,  H. J.  Effect of low  carbon monoxide concentrations on the sleep
           and  waking pattern of the albino  rat.   Staub-Reinhalt. Luft (Engl.
           Ed.) 32(4):32-35, 1972.
 94.  Colucci,  J.  M., and  C. R. Begeman.  Carbon monoxide in Detroit, New York
           and  Los  Angeles air.  Environ. Sci.  Technol. 3:41-47,  1969.
 95.  Committee on  Sp^ce Research (COSPAR),  International Council of Scientific
           Unions.   CTRA 1965.  COSPAR International Reference Atmosphere 1965.
           Compiled by  the Members of COSPAR Working Group IV, 1965.  Amsterdam:
           North-Holland Publishing  Company,  1965.   313 pp.
 96.  Comstock, G.  W.,  and F. E. Lundin, Jr.  Parental  smoking and perinatal
           mortality.  Amer. J. Obstet. Gynecol.  98:708-718,  1967.
96a.  Comstock, G.  W.,  F.  K.  Shah, M.  B.  Meyer,  and H.  Abby.   Low birth weight
           and  neonntal mortality rate related  to maternal smoking and socio-
           economic status.   Amer. J.  Obstet. Gynecol.  111:53-59, 1971.
                                  11

-------
  97.  Conlee, C.  J.,  P.  A.  Kenline,  R.  L.  Cummins,  and  V.  J.  Konopinski.




            Motor  vehicle exhausts  at three selected sites.   Arch.  Environ.




            Health 14:429-446,  1967.



  98.  Connes, P.,  J.  Connes, L. D. Kaplan,  and W. S. Benedict.  Carbon monoxide




            in the  Venus  atmosphere.  Astrophys. J.  152:731-743, 1968.



  99.  Cooper, A.  G.   Carbon Monoxide.   A Bibliography with Abstracts.  Public




            Health  Service Publication No.  1503.  Washington,  D. C.:  U. S.




            Department of Health, Education  and Welfare, 1966.  440 pp.



 100.  Coronary Drug Project Research Group.  Factors influencing long-term prog-




            nosis after recovery from myocardial infarction--three-year findings




            of the coronary drug project.  J. Chron.  Dis. 27:267-285, 1974.




lOOa.   Crespi,  H. 1.,  D.  Huff, H. F. DaBoll,  and J. J, Katz.   Carbon Monoxide in




            the Biosphere: CO Emission by Fresh-Water Algae.   Final Report.




            (CRC-APRAC-CAPA-4-68-5)  to Coordinating Research .Council and  Air




            Pollution  Control Office,  Environmental Protection Agency.  Argonne,




            111.:   Argonne National  Laboratory, 1972.  26 pp.




 161.  Crutzcn, p.  J.  A  discussion of the chemistry of  some minor  constituents




            in the  stratosphere and troposphere.  Pure Appl.  Geophys.  106-108:




            1385-1399, 1973.



 102.  Crutzen, P.  J.  Photochemical  reactions initiated by and influencing




            ozone  in unpolluted tropospheric air.  Tellus 26:47-57,  1974.



 103.  Curphey, T.  J., L. P. L. Hood, and N. M. Perkins. Carboxyhemoglobin  in




            relation  to air  pollution and smoking.   Postmortem studies.  Arch.




            Environ.  Health  10:179-185,  1965.



 104.  Dahms, T. E., and  S. M.  Horvath.  Rapid, accurate technique  for determination




            of carbon monoxide in blood.  Clin. Chem. 20:533-537, 1974.
                                   12

-------
 105.  Dahms, T. E., S. M. Horvath, and D. J. Gray.  Technique for accurately
            producing desired carboxyhemoglobin levels during rest and exercise.
            J. Appl. Physiol. 38:366-368, 1975.
 I05a.  Davie, R.,    N. Butler, and H. Goldstein.  From Birth to Seven.  The Second
             Report  of the National Child Development Study.  (1958 Cohort)  London:
            Longman,  1972.   198 pp.
 106.  DeBias, D. A., C. M.  Banerjee,  N.  C.  Birkhead, W.  V. Harrer, and L. A. Kazal.
            Carbon monoxide inhalation effects following myocardial infarction in
            monkeys.  Arch.  Environ. Health 27:161-167, 1973.
106a.  Delwiche, C. C.   Carbonic monoxide production and utilization by higher
            plants.  Ann.  N.  Y.  Acad.  Sci.  174:116-121,  1970.
 167.  deBruin,  A.   Carboxyhemoglobin  levels  due to traffic exhaust.   Arch.
            Environ. Health  15:384-389,  1967.
107a.  Denson, R.,  J.  L. Nanson, and M.  A. McWatters.  Hyperkinesis and maternal
            smoking.  Can. Psychiatr.  Assoc.  J.  20:183-187, 1975.
 108.  Dinman, B. D., J. W. Eaton, and G. J. Brewer.  Effects of carbon monoxide
            on DPG  concentrations in the erythrocyte.  Ann. N. Y. Acad. Sci.  174:
            246-251, 1970.
 108a.  DiVincenzo,  G. D., and M. L. Hamilton.   Fate  and disposition  of    C methy-
             lene chloride in  the rat.  Toxicol. Appl.  Pharmacol.   32:385-393,  1975.
 109.   Dixon-Lewis, G., W.  E. Wilson,  and A. A. Westenberg.  Studies of hydroxyl
             radical kinetics by quantitative ERS.  J. Chem. Phys. 44:2877-2884, 1966.
 110.  Dominquez,  A. M. ,  H. E.  Christensen,  L.  R.  Goldbaum,  and V. A.  Stembridge.
            A sensitive procedure  for determining carbon monoxide in blood or
             tissue  utilizing  gas-solid chromatography.  Toxicol.  Appl. Pharmacol.
             1:135-143,  1959.
 111.  Dorcus, R. M., and G. E. Weigand.  The effect  of exhaust gas  on the per-
            formance in certain psychological tests.  J. Gen. Psychol.  2:73-96,
            1929.
                                     13

-------
112.   Douglas,  C.  G.,  J.  S.  Haldane, and J. B. S. Haldane.  The laws of combination
           of haemoglobin with carbon monoxide and oxygen.  J. Physiol.  (Lond.) 44,
           275-304,  1912.
113.   Drabkin, D. L., and J. H. Austin.  Spectrophotometric  studies.   II.
           Preparations  from washed blood  cells; nitric  oxide hemoglobin
           and sulfhemoglobin.  J. Biol. Chem.  112:51-65,  1935.
114.   Drinkwater, B.  L., P. B. Raven, S. M. Horvath, J. A. Gliner, R. 0.  Ruhling,
            N.  W.  Bolduan, and S.  Taguchi.   Air pollution, exercise, and heat
            s.tress.   Arch. Environ.  Health 28:177-181, 1974.
 115.  Dubois, L., and J.  L. Monkman,   Continuous determination of carbon monoxide
           by frontal analysis.  Anal.  Chem.  44:74-76,  1972.
116.  Dubois, L. , and J.  L. Monkman.   L'emploi  de  1'analyse frontale pour
           I'echnntillonnage et le dosage  de  1'oxyde de carbone dans 1'air.
           Mikrochim. Acta  1970:313-320.
 117,   Duvelleroy, M.  A., H. Mehtnel,  and M. B. Laver.  Hemoglobin-oxygen equilib-
            rium and coronary  blood  flow:  An analog model.  J. Appl. Physiol.
            35:480-484,  1973.
 118.   Eckardt,  R. E., H. N. MacFarland, Y. C. E. Alarie,  and W.  H,  Busey.
            The biologic  effect from long-term exposure  of primates  to carbon
            monoxide.   Arch. Environ. Health 25:381-387,  1972.
 119.   Ehrich,  W.  E.,  S.  Bellet,  and F. H.  Lewey.  Cardiac changes  from  CO
            poisoning.  Amer.  J.  Med. Sci. 208:511-523,  1944.
 120.  Ekblom, B., and R. Huot.  Response  to  submaximal  and maximal exercise at
            different levels of carboxyhemoglobin.   Acta Physiol. Scand.  86:474-
            482,  1972.
I20a.  Essenberg, J. M.,  J. V. Schwind,  and A.  R.  Patras.  The effects of nico-
            tine  and cigarette smoke  on pregnant female albino rats and  their
            offsprings.   J. Lab. Clin.  Med. 25:708-717,  1940.
                                  14

-------
121.  Estabrook, R.  W. ,  M.  R.  Franklin,  and A.  G.  Hildebrandt.  Factors influenc-
           ing the inhibitory effect of carbon monoxide on cytochrome P-450-
           Ci-italyzcd mixed  function oxidation reactions.  Ann. N. Y. Acad. Sci.
           174:218-232,  1970.
122.   Faltings, K. , W.  Groth, and P. Harteck.  Photochemische Untersuchungen
           im SCIIUMANN-Ultraviolett Nr. 7.   Zur Photochemie  des  Kohlenoxyds.
           Z. Physik. Chem. Abt. B. 41:15-22,  1938.
123.   Fischer,  E. R. , and M. McCarty, Jr.  Study of  the reaction of electronically
           excited oxygen molecules with carbon monoxide.  J.  Chem.  Phys.  45:781-
           784, 1966.
124.   Flury,  F. ,  and F.  Zernik.  Kohlenoxyd, pp.  195-196.   In Schadlich Case.
             it
           Dampfe,  Nebel,  Rauch- und Staubarten.   Berlin:   Verlag von Julius
           Springer,  1931.
125.  Fodor,  G.  G. , and G.  Winneke.  Effect  of low CO concentrations  on resis-
           tance to monotony and on psychomotor capacity.  Staub  Reinhalt. Luft
           (Engl.  Ed.) 32(4):46-54, 1972.
       Forbes, W.  H. ,  D.  B.  Dill, H. DeSilva, and F. M. Van Deventer.  The influ-
            ence of moderate carbon monoxide poisoning upon the ability to drive
            automobiles.   J. Ind. Hyg. Toxicol. 19:598-603, 1937.
 127.   Forbes, W.  H. ,  F.  Sargent, and F.  J.  W.  Roughton.   The rate of carbon
            monoxide uptake  by normal men.   Amer.  J. Physiol. 143:594-608, 1945.
 128.   Forster, R. E.   Carbon monoxide and the partial pressure of oxygen in
            tissue.  Ann. N. Y. Acad. Sci. 174:233-241, 1970.
 129.   Francisco,  D. E. ,  and J. K. G. Silvey.  The effect of carbon monoxide
            inhibition on the growth of an aquatic streptomycete.  Can. J.
            Microbiol. 17:347-351, 1971.
                                     15

-------
 130.  Frazior, T. M.,  G. II. Davis, H. Goldstein, and I. D. Goldberg.  Cigarette
            smoking and prematurity:  A prospective study.  Amor. J. Obstet.  Gynecol
            81:988-996, 1961.
130a.  Fristedt, tt.,  and B.  Akesson.  Health hazards from automobile exhausts  at
            service facitities of multistory garages.  Hyg. Revy  60:112-118,
            1971.  (in Swedish)
 131.   Gaensler, E. A., J.  B. Cadigan, Jr., M. F. Ellicott, R. H. Jones, and
            A.  Marks.  A new method for rapid precise determination of carbon
            monoxide in blood.  J. Lab.  Clin. Med. 49:945-957, 1957.
 132.  Gardner,  R. A., and  R. H. Petrucci.   The  chemisorption of  carbon  monoxide
            on metals.  J.  Amer. Chem. Soc.  82:5051-5053, 1960.
  133.  Garvin,  D.  The oxidation of carbon monoxide in the presence of ozone.  J.
             Amer.  Chem.  Soc.  76:1523-1527, 1954.
  134.   General  Electric Company.   Indoor-Outdoor Carbon Monoxide Study. • EPA-
             R4-73-020.  Philadelphia:  General  Electric Company,  1972.  /~437 pp._7
 134a.   Gennser, G.,  K. Marsf/l,  and B. Brantmark.  Maternal smoking and  fetal
             breathing  movements.  Amer.  J. Obstet.  Gynecol.  123:861-867,  1975.
 134b.   Gilbert, R.,  S. Carlson,  and B.  Bromberger-Barnea.   Comparative effects
             of low pC>2 and  carbon monoxide on myocardial blood flow and oxygen
             consumption.  Amer.  J. Physiol. (in press)
   135.  Gilbert,  G.  J.,  and G. H.  Glaser.   Neurologic manifestations of chronic
             carbon  monoxide poisoning.    N.  Engl.  J.  Med.  261:1217-1220, 1959.
  136.   Gilson,  R. D., F. E.  Guedry,  Jr.,  and A. J.  Benson.  Influence of vestibu-
             lar stimulation and display luminance  on  the  performance of a compen-
             sator:/  tracking task.  Aerosp. Med. 41:1231-1237, 1970.
                                     16

-------
 136.1.  Ginsberg, M. D., and R. E. Myers.  Fetal brain damages following maternal




            carbon monoxide intoxication:  An experimental study.  Acta Obstet.




            Gynecol. Scand.  53:309-317, 1974.



136b.   Ginsberg,  M.  D. ,  and R.  E.  Myers.   Fetal  brain injury after maternal car-




            bon monoxide intoxication:   Clinical and neuropathologic  aspects.




            Neurology   26:15-23,  1976.



 137.  Glasson, W.  A.   Effect  of  carbon monoxide  on atmospheric  photooxidation




            of nitric oxide-hydrocarbon mixtures.   Environ.  Sci.  Technol.  9:




            343-347,  1975.



 138.   Gliner, J.  A.,  P. B. Raven, S. M.  Horvath, B. L.  Drinkwater, and J. -C.




            Sutton.  Man's physiologic response to long-term work during thermal




            and pollutant stress.   J. Appl.  Physiol. 39:628-232, 1975.



 139.   Gold, R. E.,  and L.  L.  Kulak.   Effect of  hypoxia  on aircraft pilot per-




            formance.   Aerosp.  Med.  43:180-183,  1972.




 140.   Goldman, A., D. G.  Murcray, F. H.  Murcray, W. J.  Williams, J.  N. Brooks,




            and C.  M.  Bradford.  Vertical distribution of CO in the atmosphere.




            J. Geophys. Res. 78:5273-5283, 1973.



 141.  Goldsmith, J.  R. , and S. A. Landaw.   Carbon  monoxide  and  human health.




            Science 162:1352-1359, 1968.




 142.  Goldstein, II.  Cigarette smoking and low-birthweight babies.  Amer. J.




            Obstet. Gynecol. 114:570-571, 1972.    (correspondence)



 l42a.  Goldstein, H.  Factors influencing the height of seven year old children  •




            results from the National Child Development Study.  Human  Biol.  43:




            92-111, 1971.




 143.  Gorbatow, 0., and L. Noro.  On acclimatization in connection with  acute




            carbon monoxide poisonings.  Acta Physiol. Scand. 15:77-87,  1948.
                                     17

-------
 1;'*4.   Gordon,.T.   Heart  Disease  in  Adults,  United  States--1960-1962.   U.  S.
           Department  of Health,  Education,  and  Welfare,  Public  Health Service,
           National Center  for Health  Statistics.   Vital  and  Health Statistics
           Series  11,  No. 6.  Washington, D.  C.:   U.  S. Government  Printing
           Office, 1964.    43  pp.
 H5.   Gordon, T. ,  W. ft.  Kannel,  D.  Me Gee, and T. R.  Dawber.   Death  and coronary
           attacks in  men after  giving up cigarette smoking.   Lancet  2:1345-
           1348, 1974.
 1-6.   Gorse,  R.  A.,  and D.  H.  Volman.   Photochemistry of the gaseous hydrogen
           peroxide-carbon  monoxide system:  Rate constants for hydroxyl radical
           reactions with hydrogen peroxide and isobutane by competitive kinetics.
           J.  Photochem. 1:1-10, 1972.
 147.   Gothert, M., F.  Lutz, and  G.  Malorny.   Carbon monoxide partial pressure in
           tissue  of different animals.   Environ.  Res.  3:303-309,1970.
1-7.3.   Goujard, J., C.  Rumeau,  and D.  Schwartz.  Smoking during pregnancy,
           stillbirth  and abruptio placentae.  Biomedicine 23:20-22,  1975.
 "-3.  Grahn,  D.,  and J. Kratchman.  Variations in  neonatal death rate  and
           birth weight in  the United  States  and possible relations to  environ-
           mental radiation, geology,  and altitude.  Amer. J.  Hum.  Genet.  15:
           329-352, 1963.
 149.  Graven,  W.  M.,  and F.  J.  Long.  Kinetics and mechanisms  of the two opposing
           reactions  of the  equilibrium CO +  ^0 = C02 + H£.   J. Amer. Chem. Soc.
           76:2602-2607, 1954.
 150.  Green,  A. E.  S.,  T. Sawada, B. C. Edgar, and M. A. Uman.  Production of
           carbon monoxide  by charged  particle deposition.  J. Geophys. Res.
           78:5284-5292, 1973.

-------
 151.   Gregg, D.  E.,  and 1.  C.  Fisher.   / Blood supply to the heart_7, p. 1547.


            In W. F.  Hamilton and P.  Dow, Eds.  Handbook of Physiology.  Section 2,


            Volume 2.  Circulation.  Washington, D. C.:   American Physiolgical


            Society,  1963.


152.  Greiner, N.  R.   Hydroxyl-radical kinetics by kinetic  spectroscopy.  I.


           Reactions with H2, CO, and CH, at  300°K.   J. Chem. Phys. 46:2795-


           2799, 1967.

153.   Groll-Knapp, E., H. Wagner, H.  Hauck,  and M. Haider.  Effects of low


           carbon monoxide concentrations on vigilance and computer-analyzed


           brain potentials.  Staub Reinhalt. Luft (English ed.) 32(4):64-


           68, 1972.

 154.  Groth,  W.,  W.  Pessara, and H.  J.  Rommel.  Photochemische  Untersuchungen


            im SCHUMANN-Ultraviolett  Nr.  11.   Die  photochemische Zersetzung von

                                                                      ti
            N2 und CO im Lichte  der Xenon- und Krypton-Resonanzwellenlangen.  Z.


            Physik. Chem.  (Frankfurt)  32:192-211, 1962.


155.  Grut,  A.   Chronic Carbon  Monoxide Poisoning.  A Study in  Occupational


            Medicine.  Copenhagen:  Ejnar Munksgaard,  1949.   229 pp.
       Guest, A. D. L., C. Duncan, and P. J. Lawther.  Carbon monoxide  and  pheno-


            barbitone:  A comparison of effects on auditory flutter  fusion  thresh-


            old and critical flicker fusion threshold.  Ergonomics 13:587-594,


            1970.


 157.  Haddon, W.,  Jr., R. E. 1. Nesbitt, and R. Garcia.   Smoking  and pregnancy:


           Carbon  monoxide in blood during gestation  and  at term.  Obstet.  Gynecol.


           18:262-267, 1961.


158.   Haggard, H. W.  Studies in carbon monoxide asphyxia.  I.  The  behavior  of


            the htart.  Amer. J. Physiol. 56:390-403, 1921.
                                    19

-------
158n.   Hnider,  M.,  K.  Croll-Knapp, H. Holler, M. Neuberger, and H. Stidl.
            Effects of moderate CO dose on the central nervous system -—
            electrophysiological and behaviour data and clinical relevance, pp.
            217-232.  In A. J. Finkel and W. C. Duel, Eds.  Clinical Implications
          ~ of Air Pollution Research.  American Medical Association Air Pollu-
            tion Medical Research Conference, 1974.  Acton, Mass.:  Publishing
            Science Group, Inc., 1976.
 159.  Haldane, J.  The action  of carbonic  oxide on man.   J.  Physiol.   (Lond.)
            18:430-462, 1895.
 160.   Halperin, M. H., R. A. McFarland, J. I. Niven, and  F.  J. W. Roughton.
            The time course of the effects of carbon monoxide on visual thresh-
            olds.  J.  Physiol.  (Lond.)  146:583-593,  1959.
160a.   Hampson, R.  F., Jr., and D. Garvin, Eds.  Chemical  Kinetic and Photochemical
            Data for Modelling Atmospheric Chemistry.  NBS Technical Note  866.
            Washington, D. C.:  U. S. Department of Commerce, National Bureau of
            Standards, 1975.  113 pp.
160b.  Haobisch, H,  Die  Zigarette als Kohlenmonoxydquelle.   Arch. Toxic'ol.   26:
            251-261, 1970.
  161.   Hanks,  T.  G.   Human performance of a psychomotor test as a function of
             exposure  to carbon monoxide.   Ann. N.  Y.  Acad. Sci. 174:421-424,
             1970.
  162.   Harteck, P., and S. Dondes.   Reaction of carbon monoxide and ozone.  J.
             Chem.  Phys. 26:1734-1737, 1957.
  163t   Heicklen, J.   Gas  phase oxidation  of perhalocarbons.   Adv.  Photochem.
             7:57-148,  1969.
 1fi4.   Heicklen, J. . K.  Westberg, and N.  Cohen.  The Conversion of NO to N02 in
            Polluted Atmospheres.  Center for Air Environment Studies Publ. 115-
            169.  University Park:  The Pennsylvania State University, 1969. 5 pp.

                                      20

-------
 165.   Hellman, L. M.,  and J. A. Pritchard.  Williams  Obstetrics.   (14th ed.)  New
           York:  Appleton-Century-Crofts,  1971.   1,242 pp.                     	
166.   Heron, H. J.  The effects of smoking  during  pregnancy:  A review with a
           preview.  N. Z. Med. J.  61:545-548, 1962.                        	
167.   Herzberg, G.  Molecular Spectra and Molecular Structure.  I.   Spectra
           of Diatomic Molecules.  (2nd ed.)  New  York:  D. Van Nostrand
   _       Company, Inc., 1950.  658 pp.                                        	
168.   Hesiop-Harrison,  J.,  and  Y.  Heslop-Harrison.   Studies on flowering-plant
           growth  and organogenesis.   II.   The modification of sex expression
           in Cannabis  sativa by carbon monoxide.   Proc.  Roy.  Soc. Edinburgh B
           66:424-434,  1957.                                               	
169.  Hesstvedt, E.  Vertical distribution of CO near the tropopause.  Nature
           225:50, 1970.
 170.  Hill, E.  P., J.  R.  Hill,  G.  G.  Power,  and L.  D.  Longo.   Carbon monoxide in
           human maternal and fetal blood.   A mathematical model.   Amer.  J.
           Physio1.  (in press)
 171.  Honig, C.  R., and  J.  Bourdeau-Martini.   Oj and  the number and arrangement of
           coronary capillaries;   effect on calculated  tissue P02>  pp.  519-524.
           In  H.  I. Bicher  and  D.  F.  Bruley,  Eds.   Oxygen Transport to  Tissue.
           Instrumentation,  Methods  and Physiology.   Advances in  Experimental
           Medicine and  Biology.   Volume 37A.   New York:   Plenum  Press,  1973.
172.  Hopfield, J. J., and R. T. Birge.  Ultra-violet absorption  and  emission
           spectra of carbon monoxide.  Phys. Rev.  29:922, 1927.   (abstract)
 173.  Horvath,  S.  M. ,  T.  E.  Dahms,  and J. F.  O'Hanlon.  Carbon monoxide and
           human vigilance.   A deleterious  effect of present  urban concentra-
           tions.   Arch.-Environ.  Health  23:343-347, 1971.
                                    21

-------
173a.   Horvath,  M.,  and E.  Frantik.  Quantitative interpretation of experimental




            toxicological data:   The use of reference substances, pp. 11-21.  in




            M.  Horvath, Ed.   Adverse Effects of Environmental Chemicals and




            Psychotropic Drugs.   Vol. 1.  Amsterdam:  Elsevier Scientific Publish-




            ing Company, 1973.



174.  Horvath,  S. M.,  P. B. Raven,  T. E.  Dahms,  and D.  J.  Gray.   Maximal




            aerobic capacity at different  levels  of  carboxyhemoglobin.   J.




            Appl. Physiol. 38:300-303, 1975.



175.  Hosko, M. J.  The  effect of  carbon  monoxide on the visual  evoked  response




            in man  and   the spontaneous electroencephalogram.  Arch.  Environ.




            Health 21:174-180, 1970.



176.  Hewlett, L., and R. J.  Shephard.  Carbon monoxide as a hazard  in  aviation,




           J. Occup. Med. 15:874-877, 1973.



177.  Hull,  H.  M.,  and F. W.  Went.   Life processes of plants as affected by air




           pollution,  pp. 122-128.   In-Proceedings of the Second National Air




           Pollution Symposium,  Pasadena,  California, 1952.  Los Angeles:  Natia




           Air Pollution Symposium, 1952.




178.  Hwang, J. C., C.  H. Chen,  and  R.  H.  Burris.   Inhibition  of  nitrogenase-




            catalyzed  reductions.   Biochim.  Biophys.  Acta 292:256-270,  1973.




1794  Ingersoll, R. B.  Soil as  a  Sink  for Atmospheric Carbon  Monoxide.  Final




           Report.  Menlo Park, Calif.:    Stanford Research Institute,  1971.




           40- pp.



180.  Ingersoll, R.  B.  The Capacity of  the Soil as a Natural Sink for Carbon




           Monoxide.   Final Report.  SRI Project LSU-1380.   Menlo Park, Calif.:




           Stanford  Research  Institute,  1972.   38 pp.



181.  Ingersoll, R.  B., R. E. Inman, and W. R. Fishor.  Soil's potential as a




           sink for atmospheric carbon monoxide.  Tellus 26:151-159,  1974.






                                    22

-------
  1S2.  Inman, R. E., and R. B. Ingersoll.  Uptake of carbon monoxide by  soil
            fungi.  J. Air Pollut. Control Assoc. 21:646-647, 1971.
  183.  Inman,  R. E., R.  B.  Ingersoll,  and E.  A.  Levy.   Soil:   A natural sink for
            carbon monoxide.   Science  172:1229-1231,  1971.
 184.  Jaegor, J. J., and J.  J. McGrath.  Effects of hypothermia on heart and
            respiratory responses of chick to carbon monoxide.  J. Appl. Physiol.
            34:564-567,  1973.
 185.   Jaffe,  L.  S.  Ambient carbon monoxide  and  its fate in  the atmosphere.   J.
            Air  Pollut. Control Assoc.  18:534-540, 1968.
 186.   Jaffe,  L.  S.  Carbon monoxide in the biosphere:   Sources, distributions,
            and  concentrations.   J. Geophys.  Res. 78:5293-5305,  1973.
 187.   Jenkins,  C.  E.  The haemoglobin  concentration of workers  connected with
            internal combustion engines.   J.  Hyg. 32:406-408,  1932.
 188,   Joels,  N., and L.  G. C.  Pugh.   The carbon monoxide  dissociation curve of
            human blood.   J.  Physiol.   (Lond.)  142:63-77,  1958.
189.   Johnson, B. L., H.  H.  Cohen, R.  Struble, J. V. Setzer, W. K. Anger, B.  D.
           Gutnik, T. McDonough, and P. Hauser.  Field evaluation of carbon
           monoxide exposed toll collectors,  pp. 306-328.   In C. Xintaras, B.
           L.  Johnson, and I. de Groot, Eds.   Behavioral Toxicology:   Early
           Detection of Occupational Hazards.  HEW Publ. No.  (NIOSH) 74-126.
           Washington, D. C.:  U. S.  Department of Health, Education,  and
           Welfare, 1974.
 190.   Johnson,  K.  L., L. H. Dworetzky,  and A. N. Heller.  Carbon monoxide and
            air  pollution from  automobile  emissions in  New York  City.   Science
            160:67-68, 1968.
 191.  Jones, R.  II., M. F. Ellicott,  J. B. Cadigan,  and E.  A. Gaensler.   The
           relationship between alveolar and blood carbon monoxide concentra-
           tions during breathholding.  Simple estimation of COHb saturation.
           J.  Lab. Clin.  Med. 51:553-564, 1958.

                                   23

-------
102.  Jungo, C. K.  Air Chemistry and Radioactivity.  Now York:  Academic  Press,


          Inc., 1963.  382 pp.


 193 <   Junge,  C.  P..   Residence time and variability of tropospheric trace


            gases.   Tellus  26:477-488,  1974.

                                                                 •* A       1 /
194.   Junge,  C. E., W. Seilor,  and  P.  Warneck.   The  atmospheric  i  CO and  i^CO


           ,budget.  J. Geophys. Res. 76:2866-2879,  1971.


195.   Kagnn,  A., B. R. Harris,  W. Winkelstein,  Jr.,  K.  G.  Johnson, H.  Kato,


           S. L. Syme, G. G.  Rhoads, M.  L. Gay,  M.  Z.  Nichaman,  H. B.  Hamilton,


           and J. Tillotson.  Epidemiologic  studies  of coronary heart  disease


           and stroke in Japanese men  living in Japan,  Hawaii  and  California:


           Demographic, physical, dietary and biochemical  characteristics.   J.


           Chron. Ms. 27:345-364,  1974.                                       	


 196.  Kahn,  A.,  R.  B.  Rutledge, D. L.  Davis, J. A. Altes, G. E. Gantner, C. A.


            Thornton, and N.  D.  Wallace.  Carboxyhemoglobin sources  in the


            metropolitan  St. Louis population.   Arch. Environ. Health 29:127-


            135,  1974.


 197.  Kaplan, L.  D., J. Connes,  and P.  Connes.   Carbon monoxide in the Martian


             atmosphere.  Astrophys. J. 157:L187-L192,  1969.   (letter)


  198.  Kaserer,  H.   Die Oxydation des  Wasserstoffes durch Mikroorganismen.


             Zentralbl.  Bakteriol. Parasitenk. Infektionskrank. Abt. II 16:


             681-696,  1906.

  199.  Kennedy,  A.  C.,  and D. J.  Valtis.  The oxygen dissociation curve  in anemia


             of various  types.  J. Clin. Invest. 33:1372-1381,  1954.


 200.  Kessler, M., H. Lang,  E. Sinagowitz,  R.  Rink,  and  J.  Hoper.  Homeostasis  of


             oxygen  supply in liver and kidney,  pp.  351-360.  In H. I.  Bicher and


             D. F. Bruley.  Oxygen Transport  to  Tissue. Instrumentation,  Methods,


             and Physiology.   Advances  in Experimental  Medicine and Biology.   Volume


             37A.  New York:   Plenum Press, 1973.


                                    24

-------
 201.  Keys, A., Ed.  Coronary Heart Disease in Seven Countries.  American Heart




           Association Monograph Number 29.  Circulation 41 Suppl. 1:1-1-1-211,




           1970.



202.  Killick,  E. M.  The  acclimatization  of mice  to atmospheres  containing  low




           concentrations  of carbon monoxide.  J.  Physiol.  (Lond.)  91:279-292,




           1937.



203.  Killick,  E. M.  The  acclimatization  of the human  subject  to atmospheres




           containing low  concentrations of carbon monoxide.  J.  Physiol.  (Lond.)




           87:41-55, 1936.



204. Killick, E. M.  The nature of the acclimatization occurring during




          repeated exposure of the human subject  to atmospheres containing




          low concentrations of carbon monoxide.  J. Physiol.  (Lond.) 107:




          27-44, 1948.



204a.  Kjeldsen, K.,  P.  Astrup,  and J.  Wanstrup.   Ultrastructural intimal changes




            in the rabbit aorta  after a moderate carbon monoxide exposure.




            Atherosclerosis  16:67-82,  1972.




205.  Kjeldsen, K., and  F. Damgaard.   Influence of prolonged carbon monoxide




           exposure and  high altitude on the composition of blood and urine




           in man.   Scand. J.  Clin.  Lab.  Invest.  22(Suppl.  103):20-25, 1968.



206.  Kjeldsen, K., H. K. Thomsen, and P. Astrup.  Effects of carbon monoxide




           on myocardium.  Ultrastructural changes in rabbits after moderate,




           chronic exposure.  Circ. Res. 34:339-348, 1974.



 207.  Klausen,  K., B. Rasmussen, H. Gjellerod, H. Madsen,  and  E. Petersen.




           Circulation, metabolism and ventilation during  prolonged  exposure




           to  carbon monoxide and to high altitude.  Scand. J. Clin.  Lab.




           Invest. 22(Suppl. 103):26-38,  1968.
                                    25

-------
 203.  Klebha, A. J., J. n. Maurer, and E. J. Glass.  Mortality Trends for  Lead-
            ing Causes of Death, United States--1950-1969.  U. S. Department of
            Health,  Education, and Welfare, National Center for Health Statistics.
            Vital and Health Statistics Series 20, No. 16.  Washington, D. C.:
            U. S. Government Printing Office, 1974.  75 pp.
 209.  Klcndshoj, N. C., M. Feldstein, and A. L. Sprague.  The spectrophotometric
            determination of carbon monoxide.  J. Biol. Chem. 183:297-303, 1950.
 210.  Kluyver,  A.  J., and C.  G. T. Schnellen.  On the fermentation of carbon
            monoxide by pure cultures of methane bacteria.  Arch. Biochem. 14:
            57-70, .1947.
 2ii.  Koob,  G.  F.,  Z.  Annau,  R. J. Rubin, and M. R.  Montgomery.   Effect of
            hypoxic  hypoxia and carbon monoxide on food intake,  water intake,
            and  body weight in two strains of rats.  Life Sci. 14:1511-1520,
            1974.
 212.  Kortschak, H. P., and L. G. Nickell.  Photosynthetic carbon monoxide
            metabolism by sugarcane leaves.  Plant Sci. Lett. 1:213-216, 1973.
 213.  Knight, L. I.,  and W. Crocker.   Toxicity of smoke.  Contributions from the
            Hull Botanical Laboratory 171.  Bot. Gazette 55:337-371, 1913.
 214.  Krause, A.  Mcchanismus  der katalytischen Oxydation von CO mit N«0.  Bull.
            Acad. Pol on. Sci.  Scr. Sci. Chim. 9:5-6, 1961.
 215.  Krall, A. R., and N. E. Tolbert.  A comparison of the  light dependent
            metabolism of carbon monoxide by barley leaves with that of formal-
            dehyde,  formate and carbon dioxide.  Plant Physiol. 32:321-326, 1957.
215a.  Kullander, S.,  and B. Kailen.  A prospective study of smoking and preg-
            nancy.   Acta Obstet. Gynecol. Scand. 50:83-94, 1971.
215b,  Kubic, V. L.  M. W. Anders,  R. R. Engel, C. H. Barlow,  and W. S. Caughey.
            Metabolism of dihalomethanes  to carbon monoxide.  1.  In vivo studies.
            Drug. Metab. Dispos.   2:53-57, 1974.

                                   26

-------
  216.   Kullcr, L. , J. Pcrper,  and M.  Cooper.   Sudden  and  unexplained death due
             to nrteriosclerotic heart disease,  pp.  292-332.   In M.  F.  Oliver,
             Ed.  Modern Trends in Cardiology.   Vol. 3.  London:   Butterworths,
             1974.
 217.  Kullor, L. H., E. P. Radford, D. Swift,  J. A. Perper,  and R.  Fisher.
           Carbon monoxide and heart  attacks.   Arch.  Environ.  Health 30:477-
           482, 1975.
 218.  Kummler, R.  II. , and T.  Baurer.  A  temporal model  of tropospheric carbon-
           hydrogen  chemistry.  J.  Geophys.  Res. 78:5306-5316,  1973.
 219.  Kummler,  R.  II.,  R.  N.  Grenda, T.  Baurer, M.  H.  Bortner, J. H. Davies, and
            J.  MacDowall.   Satellite solution of the carbon monoxide sink  anomaly.
            EOS Trans.  Amer.  Geophys.  Union 50(4):174, 1969.  (abstract)
 220.   Lambert,  J.  L.,  R.  R.  Tschorn, and  P.  A.  Hamlin.   Determination of carbon
           monoxide  in blood.   Anal. Chem. 44:1529-1530,  1972.

 221.   Lamontagne,  R. A.,  J.  W.  Swinnerton,  and V. J. Linnenbom.  Nonequilibrium
            of carbon monoxide and methane at the air-sea interface.  J. Geophys.
            Res. 76:5117-5121,  1971.
 222.   Larsen,  R.  I., and  H.  Burke.   Ambient  carbon monoxide exposures.  Paper
            69-167  Presented  at  62nd  Annual Meeting of the Air Pollution Control
            Association, New  York, 1969.   39  pp.
222a.   Laties,  V.  G.   On the use of reference substances in behavioral toxicology,
            pp. 83-88.   In M.  Horvath,  Ed.   Adverse Effects of Environmental Chem-
            icals  and Psychotropic Drugs.   Vol. 1.  Amsterdam:  Elsevier Scienti-
            fic Publishing Company, 1973.
                                    27

-------
 223.  Ratios, V. G., nnd B. Weiss.  Performance  enhancement  by  the  amphetamines:
           A new appraisal, pp.  800-808.  In  H.  Brill,  J.  0.  Cole,  P.  Deniker,
           II. Ilippius, and P. B. Bradley, Eds.   Neuropsycho-Pharmacology.   Pro-
           ceedings of the Fifth International Congress of the  Collegium Inter-
           nationale Ncuro-Psycho-Pharmacologicum.  Washington, D.  C.,  28-31
           Maxell, 1966.  International Congress  Series No. 129.  Amsterdam: .
           Excerpta Mcdica Foundation, 1967.
 224.   Leighton,  P.  A.   Other reactions of oxygen atoms,  pp.  146-150.   In Photo-
            chemistry of Air Pollution.  New York:   Academic  Press,  1961.
 225.   Lenfant, C.,  J.  Torrance,  E.  English, C.  A.  Finch, C.  Reynafarje,  J.  Ramos,
            and J. Faura.   Effect of altitude on oxygen binding by hemoglobin and
            on organic  phosphate  levels.   J. Clin.  Invest.  47:2652-2656,  1968.
 226.   Levy, H.,  II.  Normal atmosphere:   Large radical and formaldehyde concentra-
            tions predicted.  Science 173:141-143,  1971.
 227.  Levy, H., II.   Photochemistry of the  lower troposphere.   Planet. Space
            Sci. 20:919-935,  1972.
 228.  Levy, H.,  II.  Photochemistry of minor constituents in the troposphere.
            Planet.  Space Sci. 21:575-591,  1973.
 229.  Lewey, F.  11.  , and D. L. Drabkin.  Experimental chronic carbon monoxide
            poisoning of dogs.  Amer.  J. Med. Sci. 208:502-511, 1944.
 230.   Lewin, L.   Die Kohlenoxydvergiftung.  Ein Handbuch  fur Mediziner,
            Techniker und Unfallrichter.  Berlin:  Julius  Springer, 1920.
            370 pp.
230a.   Lewis, J., A. D. Baddeley, K. G. Bonham, and D. Lovett.  Traffic pollution
            and mental efficiency.  Nature 225:95-97, 1970.
 231.  Liberti, A.   The nature of particulate matter.   Pure Appl.  Chem. 24:631-
            642,  1970.
                                     28

-------
  332.  Lichty, J. A.,  R. Y. Ting, P. D.  Bruns,  and  E.  Dyar.   Studies  of babies




             born  nt high altitudes.  I.   Relation of  altitude to  birth  weight.




             A.M.A. J.  Dis. Child. 93:666-669, 1957.



  233.  Liebl, K.  II.   Dor Bodon als Senke und Quell fur das Atm. Kohlcnoxid.




             Diplomarbeit, 1971.  85 pp.




 234.   Lighthart,  B.   Survival of airborne bacteria in a high urban concentration




            of carbon monoxide.  Appl.  Microbiol.  25:86-91, 1973.




 235.  Lilionthal, J.  L., Jr.   Carbon monoxide.  Pharmacol. Rev.  2:234-254, 1950.




  236.  Lilienthal, J.  I.,  Jr., and C. H. Fugitt.  The effect of low concentra-




            tions  of carboxyhemoglobin  on the "altitude tolerance" of man.




            Amer.  J.  Physiol.  145:359-364, 1946.



 237.  Lind,  C.  J. , and P. W. Wilson.  Carbon monoxide inhibition of nitrogen




           fixation  by azotobacter.   Arch. Biochem.  1:59-72, 1942.



238.  Lind,  C. J., and P.  W. Wilson.   Mechanism of biological nitrogen  fixation.




           VIII.   Carbon monoxide as  an inhibitor for nitrogen fixation by red




           clover.  J. Amer.  Chem. Soc. 63:3511-3514, 1941.




 239.   Linderholm, II.,  T. Sjostrand,  and B.  Soderstrom.   A method  for determina-




            tion of  low carbon monoxide concentration in blood.  Acta Physiol.




            Scand. 66:1-8,  1966.



 240.   Link,  W. T.,  E.  A. McClatchie, D.  A.  Watson,  and A.  S.  Compher.  A




            fluorescent source NDIR carbon monoxide  analyzer.   Presented at




            Conference on Methods in  Air Pollution and Industrial  Hygiene




            Studies,  12th,  Los Angeles,  California,  April 6-8, 1971.



241.  Linnenbom,  J.  V., J.  W.  Swinnerton, and R. A.-Lamontagne.  The ocean as




           a source  for atmospheric carbon monoxide.  J. Geophys.  Res.  78:5333-




           5340,  1973.
                                    29

-------
 242.  Liss, P. S., and P. G. Slater.  Flux of gases across the air-sea  interface

            Nature 247:181-184, 1974.

 243.  Lissi,  E.,  R.  Simonaitis, and J. Heicklen.  The bromine atom catalyzed

            oxidation of carbon monoxide.  J.  Phys. Chem. 76:1416-1419, 1972.

 244.   Locke,  J. L.,  and L.  Herzberg.  The absorption due to carbon monoxide in

            the infrared solar sprectrum.  Can.  J. Phys.  31:504-516, 1953.

 245.  Lockshin, A.,  and R.  H. Burris.  Inhibitors of nitrogen fixation in

            extracts  from Clostridium pasteurianum.  Biochim.  Biophys. Acta

            111:1-10, 1965.

2"46.   loewus,  M.  W., artd C.  C.  Delwiche.  Carbon monoxide production, by algae.

            Plant  Physiol.  38:371-374, 1963.

246a.  Longo,  L.  D.  Carbon monoxide:  Effects on oxygenation of the fetus in

            utero.  Science   194:523-525,  1976.

 247.  Longo,  L. D.   Carbon  monoxide in the pregnant mother and fetus and its

            exchange  across  the placenta.  Ann.  N. Y.' Acad. Sci.  174:313-341, 1970.

247a.  Longo,  L.  D.  The biologic effects of carbon monoxide on the pregnant woman,

            the fetus and newborn infant.  Amer.  J. Obstet. Gynecol.  (in press)

24?b.  Longo,  L.  D., and K. Ching.  Placental diffusion  capacity for carbon

            monoxide and  oxygen in unanesthetized  sheep.   Amer. J.  Physiol.

            (in press)

 248.  Longo, L. D. ,  and E.  P.  Hill.  Carbon  monoxide uptake  and  elimination
                                                                    !-; '•?
            in fetal  and maternal sheep.   Amer J. Physiol.  (in press)

248a.  Longo,  L.  D. , E. P. Hill, and  G.  G. Power.   Theoretical analysis  of  factors

            affecting placental 02 transfer.  Amer. J. Physiol. 222:7J(X739,  1972.

 249.  Longo,  L. D.,  G. G. Power, and R.  E. Forster, II.   Respiratory fraction-

            of the placenta as determined with carbon monoxide in sheep and

            dogs.   J. Clin.  Invest. 46:812-828, 1967.
                                    30

-------
   250.  Los Angeles County Air Pollution Control District,  1974 Profile  of  Air
             Pollution Control.  Los Angeles:  County of Los Angeles, Air Pollution
             Control District, 1974.  91 pp.
 250a.  Lowe,  C.  R.   Effects  of mothers'  smoking habits  on birthweight of their
             children.   Brit. Med.  J.  2:673-676,  1959.
  251.  Luomanmaki, K.  Studies on the metabolism of carbon monoxide.  Ann.   Med.
            Exp. liiol. Fenniae 44(Suppl. 2): 1-55, 1966.
   252.  Mackworth,  J.  F.   Vigilance and Attention.   Baltimore:   Penguin Books,
             Inc.,  1970.   188 pp.
   253.  Mackworth,  J.  F.   Vigilance and Habituation.  Baltimore:  Penguin Books,
             Inc.,  1969.   237 pp.
  254.  Mackworth,  N.  H.   Researches on the Measurement  of Human Performance.
             Medical Research Council  Special Report Series No. 268.  London:
             His  Majesty's Stationery Office,  1950.   156 pp.
 255.  Madley, D. G.,  and R.  F. Strickland-Constable.  The kinetics of the
            oxidation of charcoal with nitrous oxide.  Trans.  Faraday Soc.
            49:1312-1324, 1953.
 256.  Malenfant, A. L.,  S. R.  Gambino, A.  J.  Waraksa, and E. I.  Roe.   Spectro-
           photometric determination  of hemoglobin  concentration and  per cent
           oxyhemoglobin and carboxyhemoglobin saturation.  Clin.  Chem.  14:789,
           1968.  (abstract)
256a.  Manning, F.,  E.  Wyn Pugh,  and K.  Boddy.  Effect  of cigarette smoking on
            fetal breathing movements  in normal pregnancies.  Brit. Med.  J.
            1:552-553,  1975.
256b.  Manning, F.  A.,  and C. Feyerabend.   Cigarette smoking and fetal breathing
           movements.  Brit. J.  Obstet. Gynaecol.   83:262-270, 1976.
                                     31

-------
25'ic.   Maxwell, J. C. , C. II.  Barlow, J. E. Spallholz,  and W.  S,  Caughey.   The




            utility of  infrared spcctroscopy as  a probe of  intact  tissue:   Deter-




            mination of carbon monoxide and hemeproteins in blood  and  heart muscle.




            Biochem. Biophys. Res. Commun.  61:230-236, 1974.




 257.  McClatchio, E. A.  Development of an Infrared  Fluorescent Gas Analyzer.




            EPA-R2-72-121.   Berkeley, Calif.:  Akron  Scientific Labs,  1972.  7  pp.



 258.  McClatchie, E. A., A. B. Compher, and K.  G. Williams.  A high specificity




            carbon monoxide  analyzer.  Anal. Instrum.  (Symposium)  10:67-69, 1972.



 259.    McConnell, J.  C.,  M.  B.  McElroy,  and S. C.  Wofsy.   Natural sources  of




             atmospheric CO.   Nature 233:187-188, 1971.



 260.  McCortnick, R.  A., and C.  Xintaras.  Variation of carbon monoxide concen-




            trations as related to sampling interval, traffic and meteorological




            factors.   J. Appl. Meteorol. 1:237-243, 1962.



 261.  McCullough, J. D., R. A.  Crane, and A. 0. Beckman.   Determination  of car-




            bon monoxide in  air by use of red mercuric oxide.   Ind. Eng.  Chem.




            Anal. Ed. 19:999-1002, 1947.




 262.  McFarland, R.  A,   Low level exposure to carbon monoxide  and driving




            performance.  Arch.  Environ. Health 27:355-359, 1973.




 263.  McFarland, R. A.  The effects of exposure to small quantities of carbon




            monoxide on vision.  Ann. N. Y. Acad. Sci. 174:301-312,  1970.




 264.  McFarland, R.  A., W.   H. Forbes, H. W. Stoudt, J. D.  Dougherty,  T.  J.




            Crowley,  R.  C. Moore,  and T. J. Nalwalk.  A Study of the Effects  of




            Low Levels of Carbon Monoxide upon Humans Performing Driving  Tasks.




            Final Report, CRC-APRAC Contract CAPM-9-69(2-70), June 15, 1970-




            September 15, 1972.   Boston:  Guggenheim Center  for Aerospace




            Health and Safety, Harvard School of Public Health, 1973.  88 pp.
                                     32

-------
 2f>S.  McFarl.ind, R. A., W. H. Forbos, II. W. Stoudt, J. D.  Dougherty,  A.  J.
           Morandi, and T. J. Nalwalk.  A Study of  the Effects  of  Low Levels
           of Carbon Monoxide upon Humans Performing Driving Tasks.   Final
           Report.  June 15, 1970-June 14, 1971.  Boston:  Harvard School of
           Public Health, Guggenheim Center for Aerospace  Health and  Safety,
           1971.  56 pp.
 266.  McFarl.ind, R. A., D. J. W.  Rough ton, M.  H.  Halperin, and  J.  I.  Niven.
           The  effects  of carbon  monoxide and  altitude on  visual  thresholds.
           J. Aviat. Med. 15:381-394, 1944.                                  _____
 267.  McGrath, J. J., and J. Jaeger.  Effect of iodoacetate on  the carbon monoxide
           tolerance of the chick.  Respir. Physiol. 12:71-76,  1971.
268.   McKee,  H.  C.,  and  R. E.  Childers.   Collaborative  Study  of Reference
           Method  for the Continuous  Measurement  of Carbon Monoxide in the
           Atmosphere  (Non-Dispersive  Infrared  Spectrometry).   EPA-R4-72-009.
           Houston,  Texas:   Southwest  Research  Institute, 1972.   l_ 41 pp._/
269.   McMillan,  C.,  and  J. M.  Cope.  Response to carbon monoxide by geographic
           variants  in Acacia  farnesiana.  Amer. J.  Bot.  56:600-602,  1969.
 270.  McMullen,  T.  B.   Interpreting the eight-hour national ambient air quality
           standard for carbon monoxide.  J. Air Pollut.  Control Assoc. 25:
           1009-1014,  1975.

271.   McNesby, J. R., and H. Okabe.  Vacuum ultraviolet  photochemistry.  Adv.
           Photochem.  3:157-240,  1964.
 272.  Delete

273.   Mellor, J. W.   The chemical properties of carbon monoxide, pp.  926-950.
           In A Comprehensive Treatise on Inorganic and Theoretical Chemistry.
           Vol.  V.   B, Al, Ga, In, Tl, Sc, Ce and Rare Earth Metals, C (Part  1).
           London:   Longmans,  Green and Co., 1924.

                                  33

-------
 274.  Mensor,  H. ,A.,  J.  J.  Grosso,  H.  E.  Heggstad,  and 0.  E.  Street.  Air filtra-




            tion study of "hidden" air  pollution injury to  tobacco plants.  Plant




            Physiol.  39(Suppl.)lviii,  1964.   (abstract)



274.1.  Mover,  M. B. ,  fi.  S.  Jonas,  and J.  A.  Tonascia.  Perinatal events associated




            with mnternnl smoking during pregnancy.   Amer.  J.  Epidemiol.  103:




            464-476,  1976.



 275.  Meyer,  M. B.,  and G.  W.  Comstock.   Maternal cigarette smoking and perinatal




            mortality.  Amcr.  J.  Epidemiol.  96:1-10, 1972.




 276.  Meyer, M. B. , J. A. Tonascia, and C. Buck.  The  interrelationship of




           maternal smoking and increased perinatal mortality with other risk




            factors.   Further analysis  of the Ontario perinatal mortality study,




            1960-1961.  Amer. J. Epidemiol. 100:443-452,  1974.




 277.  Migeotte, M.   The fundamental band of carbon monoxide at 4.7u in the solar




            spectrum.   Phys.  Rev.  75:1108-1109,  1949.




 278.  Migootte, M.,  and L. Neven.  Recents proges  dans  1'observation du spectre




            infrarouge  du soleil  a  la  station scientifique du  Jungfraujoch




            (Suissc).  Mem. Soc.  Roy.  Sci. Liege  12:165-178,  1952.




 279.  Mikulka, P.,  R.  O'Donnell, P. Heinig,  and  J. Theodore.   The effect of




            carbon monoxide  on human performance.   Ann.  N. Y.  Acad. Sci. 174:




            409-420,  1970.



  280.  Minina,  E. G., and L. G. Tylkina.  Physiological  study of  the effect  of




            gases upon sex differentiation in plants.  Dokl. Akad.  Nauk SSSR




            55 (2):165-168, 1947-  (in  Russian)





 281.  Miranda, J.  M., V.  J.  Konopinski,  and R.  I.  larsen.   Carbon monoxide




            control in a high highway tunnel.  Arch. Environ.  Health 15:16-25,




            1967.
                                    34

-------
 232.  Mocllor, T.  Carbon monoxide, pp. 685-687.  In Inorganic Chemistry.   An
           Advanced Textbook.  New York:  John Wiley & Sons, Inc.,  1952.
283.   Montgomery,  M.  R.,  and R.  J.  Rubin.   Adaptation to the inhibitory effect
           of carbon  monoxide inhalation on drug metabolism.  J.  Appl.  Physiol.
           35:601-607,  1973.
 284.  Montgomery, M.  R. , and R. J. Rubin.  Oxygenation during inhalation of drug
           metabolism by carbon monoxide or hypoxic hypoxia.  J. Appl. Physiol.
           35:505-509, 1973.
 285.  Montgomery, M.  R., and R. J. Rubin.  The  effect of carbon monoxide inhala-
           tion on in vivo drug metabolism in the rat.  J.  Pharmacol.  Exp.  Ther.
           179:465-473, 1971.
286.   Mourant,  R.  R.,  and T.  H.  Rockwell.   Strategies of visual search by novice
           and  experienced drivers.   Human Factors  14:325-335, 1972.
287.  Mulhausen,  R. 0., P. Astrup, and K. Mellemgaard.   Oxygen affinity  and
           acid-base status  of human blood during exposure  to  hypoxia  and
           carbon monoxide.  Scand. J. Clin. Lab. Invest. 22(Suppl.  103):9-
           15, 1968.
288.   Muller,  R.  H.   A supersensitive gas detector permits accurate detection
           of toxic  or combustible gases in extremely low concentrations.   Anal.
           Chem.  26(9):39A-42A,  1954.
289.  Murray, J.  F., P. Gold, and B.  L. Johnson, Jr.  Systemic oxygen  transport
           in induced normovolemic anemia and polycythemia.  Amer. J.  Physiol.
           203:720-724, 1962.
290.  Musselman,  N.  P., W. A. Groff,  P. P. Yevich, F. T. Wilinski, M. H.  Weeks,
           and  F.  W.  Oberst.   Continuous exposure of laboratory animals to  low
           concentration of carbon monoxide.   Aerosp. Med. 30:524-529, 1959.
291.   Nasmith,  G.  G. ,  and D.  A.  L. Graham.  The haematology of carbon-monoxide
           poisoning.   J. -Physiol. (Lond.) 35:32-52, 1906.

                                   35

-------
2*2.
             -- use 412.

 293 <   National Research Council.   Division of Medical Sciences.  Committee on
            Effects of Atmospheric Contaminants on Human Health and Welfare.
            Effects of Chronic Exposure to Low Levels of Carbon Monoxide on
            Human Health, Behavior,  and Performance.  Washington, D. C. :
            National Academy of Sciences,  1969.  66 pp.                  ... .  _____
 294.  Keill, U. A.  Effects of arterial hypoxemia  and hyperoxia on  oxygen  avail-
           ability  for myocardial metabolism.  Patients with  and withou-t coronary
           heart disease.  Amer. J. Cardiol.  24:166-171,  1969.
 295.   Delete  -- use 74b.
 296.   Nicholson,  S. E.   A pollution model for street-level air.  Atmos.  Environ.

            9:19-31, 1975.
  297.  Nielsen, B.  Thermoregulation during work in carbon monoxide poisoning.
            Acta Physiol. Scand. 82:98-106, 1971.
2?7a.   X-'.svander,  K. R. , and M.  Gordon.  Cigarette smoking, pp. 72-80.  In The
            Women  and Their Pregnancies.   The Collaborative Perinatal Study of
            the National Institute of  Neurological Diseases and Stroke.  Phila-
            delphia:  W.  15.  Saunders Company,  1972.
 298.  North Atlantic Treaty Organization.  Committee  on Challenges  of Modern
           Society.  Air  Pollution.  Air  Quality Criteria for Carbon  Monoxide.
           N. 10.  Brussels:  North  Atlantic Treaty Organization, 1972. /265 pp._/

  299.  Delete

 299a.  Noyes, W, A.. Jr., and ?. A. teighton.  Appendix CC-1,11, Photochemical
            reactions of carbonyls, p. 449.   In The Photochemistry  of Gases.
            New York:  Dover Publications, Inc., 1966.
                                   36

-------
  300.   O'Donnell,  R.  D., P. Chikos,  and J. Theodore.  Effect  of carbon monoxide




             exposure  on human sleep  and psychomotor performance.  J.  Appl.




             Physiol.  31:513-518,  1971.



  301.   O'Donnell, R.  D. , P. Mikulkn, P. Ileinig, and J. Theodore.  Low level




            carbon monoxide exposure and human psychomotor performance.  Toxicol,




            Appl. Pharmacol. 18:593-602, 1971.



 302.  O'Hanlon,  J.  F.  Preliminary  studies of the  effects  of  carbon monoxide




            on vigilance in man,  pp.  61-72.   In B.  Weiss  and V.  G. Laties,  Eds.




            Behavioral Toxicology.   New York:   Plenum  Press, 1975.



302a.  Ontario Department  of Health.  Perinatal Mortality Study Committee.




            Second Report  of Perinatal Mortality Study in Ten University




            Teaching Hospitals,  Ontario, Canada.  Toronto:   Ontario Department




            of Health, 1967.  274 pp.



302b.  Ontario Department  of Health.   Perinatal Mortality Study Committee.




            Supplement to  the  Second Report of the  Perinatal Mortality Study




            in Ten University  Teaching Hospitals.   Toronto, Canada:   Ontario




            Department of  Health, 1967, pp. 85-275.




 303.  Opitz,  E.   Increased vascularization of the  tissue due  to acclimatization




            to high  altitude and  its  significance for  oxygen transport.   Exp.




            Med.  Surg.  9:389-403,  1951.



 304.  Ott, W. ,  J. H.  Clark, and G.  Ozolins.   Calculating Future Carbon Monoxide




            Emissions  and  Concentrations from Urban Traffic Data.  National Air




            Pollution   Control Administration Publ. 999-AP-41.  Durham,  N.  C.:




  	    u- s- Department of  Health, Education,  and Welfare,  1967.  40 pp.



 305.  Palanos,  P.  N.   A practical design  for an ambient  carbon monoxide  mercury




            replacement analyzer.  Anal. Instrum.  (Symposium)  10:117-125,  1972.
                                   37

-------
  306.   Pfllck,  J.,  V.  Hrabcc,  L.  Mircovova",  V.  Volok,  and B.  Friedmann.   Rod cell
             carbohydrate metabolism in primary refractory anemias.   Clin.  Chim.
             Acta  18:39-45,  1967.
  307.  Park, C. D., I. Mela, R. Wharton, J. Reilly, P. Fishbein, and E. Aberdeen.
            Cardiac mitochondrial activity  in  acute and chronic cyanosis.   J.  Surg.
            Res/ 14:139-146, 1973.
 308.  Partington,  J.  R.   Carbon monoxide,  pp.  686-696.  In Textbook of Inorganic
            Chemistry for University Students.  (5th ed.)  London:   MacMil-lan &
            Co.,  Limited, 1937.
 309.  Pauling, L.   / Resonant energy of carbon monoxide_/, pp. 194-195.  In The
            Nature of the Chemical Bond and the Structure of Molecules and Crys-
            tals:   An Introduction to Modern Structural Chemistry. (3rd ed.)
            Ithaca, N. Y.:  Cornell University Press,  1960.
 310.  Penney,  D.,  M.  Benjamin,  and  E.  Dunham.   Effect of carbon monoxide on
            cardiac weight as  compared  with  altitude effects.   J.  Appl.  Physiol.
            37:80-84,  1974.
  311.  Penney, D., E. Dunham,  and M. Benjamin.   Chronic carbon monoxide exposure:
            Time course of hemoglobin, heart weight and lactate dehydrogenase
            isozyme changes.  Toxicol.  Appl. Pharmacol. 28:493-497; 1974.
  312.   Permutt, S.,  and  L.  Farhi.   Tissue hypoxia  and carbon monoxide,  pp.  18-24.
             In National  Research Council.   Division of Medical  Sciences.  Committee
             on Effects of Atmospheric  Contaminants on Human Health and  Welfare.
            Effects of Chronic Exposure to  Low Levels  of Carbon Monoxide on Human
            Health, Behavior, and Performance.  Washington, D. C.:  National
     _      Academy of Sciences, 1969.
312a.  Pernoll, M.  I., J. Metcalfe,  T.  L.  Schlenker,  J. E.  Welch,  and J. A.
            Matsumoto.  Oxygen consumption  at rest  and during exercise in preg-
            nancy.   Respir.  Physiol.  25:285-293,  1975.
                                    38

-------
  .313.  Perper, J. A. , 7,. II. Kuller, and M. Cooper.  Arteriosclerosis of coronary
            arteries in sudden, unexpected deaths.  Circulation 52(6 Suppl.  3):
            27-33, 1975.
  314.  Peterson, W.  F. , K. N. Morese, and D. F. Kaltreider.  Smoking and prema-
            turity.  A preliminary report based on study of 7740 Caucasians.
            Obstet.  Gynecol. 26:775-779, 1965.
  315.   Pierce,  J.  0., and  R.  J.  Collins.   Calibration of an infrared analyzer
             for continuous measurement  of carbon  monoxide.   Amer.  Ind. Hyg.
            Assoc.  J. 32:457-462,  1971.
  316.   Pirnay,  F.,  J.  Dujardin,  R. Deroanne, and J.  M. Petit.  Muscular exercise
             during intoxication by carbon monoxide.   J. Appl. Physiol. 31:573-575,
             1971.
  317.  Pitts, G. C., and N. Pace.  The  effect  of  blood carboxyhemoglobin concen-
            tration  on hypoxia tolerance.  Amer.  J. Physiol.  148:139-151,  1947.
              s                  /'
  318.  Plevova, J.,  and E. Frantik.  The influence of various  saturation rates
            on motor performance of rats exposed  to carbon monoxide.   Activ.
            Nerv. Super. 16:101-102, 1974.
  319.  Porter, K., and D.  H. Volman.  Flame ionization detection of carbon monox-
            ide for gas  chromatographic analysis.  Anal. Chem. 34:748-749,  1962.
319a.  Power,  G.  G.,  and L. D.  longo.   Fetal circulation times and their implica-
            tions for tissue oxygenation.   Gynecol.  Invest.  6:3420355,  1975.
  320.  Pressman, J., and P. Warneck.  The stratosphere as a chemical sink for
            carbon monoxide.  J.  Atmos.  Sci. 27:155-163, 1970.
  321.  Pressman,  J.,  I.  M.  Arin,  and P.  Warneck.   Mechanisms for Removal of Carbon
            Monoxide from  the Atmosphere.   Report  GCA TR-70-6-G.   Bedford,  Mass.:
            GCA Corporation,  1970.   45 pp.
                                    39

-------
 322.  Primary  prevention  of  the atherosclerotic  diseases,  pp.  15-56.   In I.  S.
           Wright  and  D.  T.  Fredrickson,  Eds.  Cardiovascular  Diseases.   Guide-
           linos  for Prevention and  Care.   Reports  of the  Inter-Society  Commission
           for Heart Disease Resources.  Washington,  D.  C.:  U.  S.  Government
           Printing Office,  1973.
 323.  Quayle,  J. R.  The  metabolism  of one-carbon compounds  by micro-organisms.
           Adv. Microb. Physiol. 7:119-203,  1972.
 324.  Radford, E.  P.,  and E. Kresin.  Red cell diphosphoglycerate after exposure
           to  carbon monoxide.   Fed. Proc. 32:350,  1973.  (abstract)
324a.  Rahn,  H., and W. 0. Fenn.  A Graphical Analysis of the Respiratory Gas
           Exchange.   The C^-CO^ Diagram.   Washington, D.  C.:   American
           Physiological  Society,  1955.   38 pp.
 325.  Ramsey,  J. M.  Carbon  monoxide,  tissue hypoxia, and  sensory psychomotor
           response in hypoxaemic  subjects.   Clin.  Sci.  42:619-625, 1972.
 326.  Ramsey,  J.  M.  Carboxyhemoglobinemia in parking garage employees.   Arch.
           Environ. Health 15:580-583,  1967.
 327.  Ramsey,  J. M.  Effects of single exposures of carbon monoxide on sensory
           and psychomotor response. Amer.  Ind. Hyg. J. 34:212-216,  1973.
 328.  Raven, P. B., B.  L.  Drinkwater, S. M.  Horvath,  R.  0. Ruhling, J. A.  Gliner,
           J.  C. Sutton,  and N.  W. Bolduan.   Age, smoking  habits, heat stress,
           and their interactive effects with  carbon  monoxide  and peroxyacetyl-
           nitrate on  man's  aerobic  power.   Int.  J. Biometeorol.  18:222-232,  1974.
 329.  Raven, P. B., B.  L.  Drinkwater, R.  0.  Ruhling,  N.  Bolduan,  S. Taguchi,  J.
           Gliner, and S.  M.  Horvath.  Effect  of carbon  monoxide and  peroxyacetyl
           nitrate on  man's  maximal  aerobic  capacity. J.  Appl.  Physiol. 36:288-
           293, 1974.
                                   40

-------
  313.  Torpor, J. A., I. II. Kuller, and M. Cooper.  Arteriosclerosis of coronary


            arteries in sudden, unexpected deaths.  Circulation 52(6 Suppl.  3):


            27-33, 1975.

  314.  Peterson, w. F., K. N. Morese, and D. F. Kaltreider.  Smoking and prema-


            turity.  A preliminary report based on study of 7740 Caucasians.


            Obstet. Gynecol. 26:775-779, 1965.                                   _


  315.   Pierce,  J.  0.,  and  R.  J.  Collins.   Calibration of an infrared analyzer


             for continuous  measurement  of carbon  monoxide.   Amer.  Ind. Hyg.


             Assoc. J.  32:457-462,  1971.

  316.   Pirnay,  F.,  J.  Dujardin,  R. Deroanne, and  J.  M. Petit.  Muscular exercise


             during intoxication by carbon monoxide.   J. Appl. Physiol. 31:573-575,


             1971.

  317.  Pitts, G. C., and N. Pace.  The  effect  of  blood carboxyhemoglobin  concen-


             tration on hypoxia tolerance.  Amer.  J. Physiol.  148:139-151,  1947.

              s                  /'
  318.  Plevova, J., and E. Frantik.  The influence of various  saturation  rates


            on motor performance of rats exposed  to carbon monoxide.   Activ.


            Nerv. Super. 16:101-102, 1974.


 319.  Porter, K., and D.  H. Volman.   Flame ionization detection of carbon monox-


            ide for gas chromatographic analysis.   Anal. Chem. 34:748-749, 1962.
                                                           <

319a. '  Power,  G.  G.,  and L.  D.  longo.   Fetal circulation times and their implica-


            tions  for tissue oxygenation.   Gynecol.  Invest.  6:3420355,  1975.


 320.  Pressman, J.,  and P.  Wameck.   The stratosphere as a chemical sink for


            carbon monoxide.  J.  Atmos.  Sci. 27:155-163, 1970.


 321,  Pressman,  J.,  L.  M.  Arin,  and  P.  Warneck.   Mechanisms for Removal of Carbon


            Monoxide  from  the Atmosphere.   Report  GCA TR-70-6-G.   Bedford, Mass.:


            GCA Corporation,  1970.  45  pp.
                                    39

-------
?22.  Primary  prevention  of  the  atherosclerotic  diseases,  pp.  15-56.   In I.  S.




           Wright  and  D.  T.  Fredrickson,  Eds.  Cardiovascular  Diseases.   Guide-




            linos  for Prevention  and  Care.   Reports  of the  Inter-Society  Commission




            for Heart Disease Resources.   Washington,  D.  C.:  U.  S.  Government




           Printing Office,  1973.




323.  Quayle,  J.  R.  The  metabolism  of  one-carbon compounds  by micro-organisms.




           Adv. Microb. Physiol.  7:119-203,  1972.



324.  Radford, E.  P.,  and E. Kresin.  Red cell diphosphoglycerate after exposure




            to  carbon monoxide.   Fed. Proc.  32:350,  1973.  (abstract)




324o.  Rahn,  H.,  and W. 0. Fenn.   A Graphical Analysis of the Respiratory Gas




            Exchange.   The CU-CO^ Diagram.  Washington, D.  C.:   American




            Physiological  Society, 1955.  38 pp.



 325.  Ramsey,  J.  M.  Carbon  monoxide,  tissue hypoxia, and  sensory psychomotor




            response  in hypoxaemic subjects.  Clin.  Sci.  42:619-625, 1972.



 326.  Ramsey,  J.  M.   Carboxyhemoglobinemia in parking garage employees.   Arch.




            Environ.  Health 15:580-583,  1967.



 327.  Ramsey,  J.  M.  Effects of  single  exposures of carbon monoxide on sensory




            and psychomotor response.  Amer. Ind. Hyg. J. 34:212-216,  1973.



 328.  Raven, P.  B., B. I. Drinkwater, S.  M.  Horvath,  R.  0. Ruhling, J. A.  Gliner,




            J.  C.  Sutton,  and N.  W.  Bolduan.   Age, smoking  habits,  heat stress,




            and their interactive effects  with carbon monoxide  and  peroxyacetyl-




           nitrate on  man's  aerobic  power.   Int. J.  Biometeorol.  18:222-232,  1974.




329.  Raven,  P.  B.,  B. L. Drinkwater,  R.  0. Ruhling, N.  Bolduan,  S. Taguchi,  J.




            Gliner, and S. M. Horvath.   Effect of carbon monoxide and peroxyacetyl




            nitrate on  man's  maximal  aerobic capacity.  J.  Appl. Physiol. 36:288-




            293,  1974.
                                   40

-------
  330.   Ravenholt,  R.  T.,  M.  J.  Levinski,  D.  J.  Nellist,  and M.  Takenaga.  Effects
             of  smoking  upon  reproduction.   Amor.  J.  Obstet. Gynecol.  96:267-281,
             1966.
  331.   Ray,  A.  M.,  nnd  T.  H.  Rockwell.   An exploratory study of automobile driv-
             ing performance  under the  influence of low levels of carboxyhemoglo-
             bin.   Ann.  N.  Y.  Acad.  Sci.  174:396-408,  1970.
 332.   Regan, D.  Evoked Potentials in Psychology, Sensory Physiology and Clini-
            cal  Medicine.   New York:  John Wiley & Sons, Inc., 1972  328 pp.
  333.   Rikans,  L.  E., and  R.  A. van Dyke.   Evidence  for a different CO-binding
             pigment  in  solubilized  rat hepatic  microsomes.   Biochem.  Pharmacol.
             20:15-22, 1971.
  334.  Ringold,  A., J. R. Goldsmith, H. L. Helwig, R.  Finn, and  F.  Schuette.
             Estimating recent carbon monoxide exposures.  A rapid method.
             Arch. Environ. Health 5:308-318, 1962.
 335.   Rissancn, V., K.  Pyorala, and 0. P. Heinonen.  Cigarette  smoking  in rela-
            tion to coronary and aortic atherosclerosis.  Acta Path. Microbiol.
            Scand. A 80:491-500, 1972.
 336.   Robbins,  R. C., K.  M.  Borg, and E. Robinson.  Carbon monoxide in  the
            atmosphere.   J. Air Pollut. Control Assoc. 18:106-110,  1968.
 337.   Roberts,  W. C.  Coronary arteries in fatal acute myocardial  infarction.
            Circulation 45:215-230, 1972.
338.   Robinson, E.,  and C. W.  Moser.   Global gaseous pollutant emissions and
            removal mechanism,  pp.  1097-1101.   In H.  M. Englund and W.  T. Beery,
            Eds.  Proceedings of the Second International Clean Air Congress,
            Washington,  D.  C.,  1970. New York:   Academic Press, Inc.,  1971.
 339.   Robinson, E.,  and R. C.  Robbins.   Atmospheric  background concentrations
            of carbon monoxide.  Ann. N.  Y.  Acad.  Sci.  174:89-95, 1970.
                                    41

-------
  --0.  Rolinsor., F,. , ;,vt  R. C.  \:bv-:-c.   ~0'.:rc£-r.  .V urbaneo, *nd Fate- ,--f  ~      <;


            Ai-i.v^spheric Poilv.i :--rs.   SRI  I'rcjfct PR-6755.  Huntsville,  Ala..


            Stanford Research  ]>•:;_ itate,  19(>8.   i^3 pp.

 '*!.   Rodkey,  F.  L.   i-'inct ic  r.spects of  cy.uirTiC'Lhcy.iogl^Mn  formation  from c^r^oxy--


            hc.,oglobin.   Clin.  Chem.  13:2-5, 1967.

  342.  Rodkey,  F.  L. ,  J.  D. O'\'ea1, H*. A. Collison,  and  D.  E.  Uddin.   Relative


             affinitv of hemc^globin S and hemoglobin  A  for carbon monoxide and


             oxygen.  Clin. Chem. 20:83-84,  1974.

                                             /•               •*»
  343.   Rondia, D.  Abaisse.ment  de  1'activite de la benzopyrene-hydroxylase


             hepatique in vivo  apres  inhalation d'oxyde de carbone.  C. R. Acad.


             Sci.  D 271:617-619,  1970.

 343a.   Roth, R. P., R. T. Drew,  R. J. Lo,  and  J.  R.  Fouts.   Dichloromethane inhal-


             ation, carboxyhemoglobin concentrations, and drug metabolizing  enzymels


             in rabbits.  Toxicol. Appl.  Pharrcacol.   33:427-437, 1975.


  344.  Rottman, G. J., and H.  W. Moos.   The ultraviolet  (1200-1900 angstrom)


             spectrum  of  Venus.   J.  Geophys. Res.  78:8033-8048,  1973.


 344a.   Roughton,  F. J. W., and R. C. Darling.   The  effect of carbon monoxide on


             the oxyhemoglobin dissociation  curve.   Amer. J.  Physiol.   141:17-31,


             1944.

344b.  Roth, R. A.,  Jr.,  snd  R.  J.  Rubin.  Role of blood flow  in carbojn monoxide-


             and hypoxic hypoxia-induced alterations  in nexobarbital metabolism


             in  rats.   Drug. Metab.  Dispos.  4:460-467, 1976.


344c.  Roth, R. A., Jr.,  and  R.  J.  Rubin.  Comparison  of the  effect of carbon  n.on-


             oxide  and  of  hypoxic hypoxia.  T.   In ± i v_o ;,i.-1 .jbol ism,  distribution


             and action of hexobarbi tal.   J. i'hannacol. Exp. Ther.  199:53-60, 1976,
                                     42

-------
 34^d.   Roth,  R.  A.,  Jr.,  and  R.  J.  Rubin.   Comparison of the effect of carbon mon-

             oxide and of  hypoxic hypoxia.   II.   Jk-xobarbital metabolism in the iso-

             lated,  perfused rat  liver.   J.  Pharmacol. Exp.  Ther.   199:61-66, 1976.
                 >
 345.   Rummo, N., and K. Sarlanis.  The  effect of carbon monoxide  on  several

            measures  of vigilance in a simulated driving task.  J.  Safety  Res.

            6:126-130, 1974.

 346.   Rush, D.   Examination of  the relationship between birthweight,  cigarette

            smoking during pregnancy   and maternal weight  gain.   J.  Obstet.

            Gynaecol. Brit. Commonw. 81:746-752, 1974.

 347.   Russell,  M.  A. H. ,  P.  V.  Cole,  C. Wilson, M.  Idle,  and C.  Feyerabend.

             Comparison of increases  in carboxyhe-r.oglobin .?fter smoking

             "extra-mild"  and  "non-mild"  cigarettes.   Lancet 2:687-690, 1973.

347a.  Russell, M. A. H.   P.  V. Cole, and E. Brown.  Absorption by non-smokers

            of carbon monoxide from room air polluted by tobacco smoke.  Lancet

            1:576-579, 1973.

 348.   Russell, C. S., R.  Taylor, and C.  E.  Law.   Smoking in pregnancy, maternal

            blood pressure, pregnancy outcome, baby weight and growth, and related

            factors.  A prospective study.   Brit.  J. Prev.  Soc. Med. 22:119-126,

            1968.

 349.   Russell,  C.  S., R.  Taylor,  and  R. N.  Maddison.   Some effects of smoking

             in pregnancy.  J.  Obstet.  Gynaecol. Brit.  Co-iriionw.  73:742-746, 1966.
                                   43

-------
     .   Ssy&rs,  R.  R. ,  W.  P.  Yant,  E.  Levy,  and W.  B.  Fulton.   Effect of Rtpr.-ate-d
                                                            i

             Daily Exposure of Several Hours to Small  Amounts  of Automobile


             Exhaust Gas.   Public Health Bulletin No.  186.   Washington, D.  C.:


             U.  S.  Government Printing Office,  1929.   58 pp.


350a.  Schmeltz, I., D. Hoffmann, and E. I. Wynder.  The influence of  tobacco


            smoke on indoor atmospheres.  Prev. Med.  4:66-82,  1975.



 351.   Schnellen, C. G. T.   Research  on Methane  Fermentation.   Ph.D. Thesis.


            Delft,  The Netherlands:   Technische  Hoogeschool te  Delft,  1947.


            137 pp.   (in  Dutch,  summary in  English)


351a.   Schoeneck,  F. J.   Cigarette  smoking  in  pregnancy.  N.  Y.  State  J. Med.


            41:1945-1948,  1941.



 352.   Scholander,  P.  F.,  and F. J. W.  Roughton.   Micro gasoroetric  estimation  of


             the blood  gases.   II.   Carbon monoxide.   J. Biol.  Chem.  148:551-563,


             1943.



 353.   Schulte, J.  H.  Effects of mild  carbon  monoxide  intoxication.   Arch.


            Environ.  Health  7:524-530,  1963.



  354.  Seiler, W.   The cycle of  atmospheric CO.  Tellus 26:116-135,  1974.
                                  44

-------
 355.   Seller, W. ,  and  C.  Junge.  Carbon monoxide  in the  atmosphere.   J.  Geophys.
            Res.  75:2217-2226,  1970.
 356t   Seller, W. ,  and  C.  Junge.  Decrease  of carbon monxide mixing ratio above
            the  polar tropopause.  Tellus 21:447-449,  1969.
 357.   Seller, W.,  and  P. Warneck.  Decrease of carbon monoxide ratio  at  the
            tropopause.  J. Geophys. Res. 77:3204-3214, 1972.
 358.   Shapiro,  S.,  and J. Unger.  Weight at Birth and Survival of  the Newborn.
            United  States, Early 1950.  Vital and  Health  Statistics Series  21,
            No.  3.   Washington, D. C.:  U.  S. Department  of Health,  Education,
            and  Welfare, 1965.  33 pp.
 359.   Shaw, J. H.   A Determination of the Abundance of Nitrous Oxide,  Carbon
           Monoxide and Methane in Ground Level Air at Several Locations Near
           Columbus, Ohio.  Scientific Report No. 1 on Contract AF19(604)2259.
           Air  Force Cambridge Research Laboratory AFCRC-TN-59-428.   Columbus:
           Ohio State  University, Research Foundation, 1959.  44 pp.
 360.   Shaw, J. H.   The abundance of atmospheric carbon monoxide above Columbus,
           Ohio.   Astrophys. J. 128:428-440, 1958.
361.   Shurtleff, D.  Some characteristics related to the incidence of cardiovascular
           disease  and death:  Framingham Study,  16-year follow-up.   Section 26.
           In W. B.  Kannel  and T.  Gordon,  Eds.  The Framingham Study.  An Epidem-
           iological Investigation of Cardiovascular Disease.   Washington, D. C.:
           U. S. Government Printing Office, December 1970.
 362.   Sidgwick, N.  V.   Carbon monoxide, pp. 545-546.  In The Chemical Elements
            and  Their Compounds.  Vol. 1.   Oxford, England:  Clarendon Press,  1950.
 363.   Sitnonaitis,  R.,  and J.  Heicklen.   Kinetics  and  mechanism of the reaction
            of 0(3P) with  carbon monoxide.   J.  Chem. Phys.   56:2004-2011, 1972.
363a.   Simpson,  W.  J.  A preliminary report on cigarette smoking and  the incidence
            of prematurity.   Amer.  J. Obstet.  Gynecol. 73:808-815, 1957.
                                 45

-------
        £ •
        Sjostrand, T.  A method  for  the  determination  of  carboxyhaemoglobin  con-




            centrations by  analysis of  the  alveolar air.   Acta  Physiol.  Scand.




            16:201-210, 1948.



  365.  Small, K. A., K. p.  Radford,  J.  M. Frazicr, F. I.  Rodkey,  and  H.  A.




            Collison.  A  rapid  method for simultaneous measurement  of carboxy-

                 x


            and mcthcmoglobin in blood.  J. Appl. Physiol.  31:154-160,  1971.



365a.  Smith,  E.,  E. McMillan,  and L. Mack.   Factors  influencing the lethal




            action of illuminating gas.   J.  Ind. Hyg.  17:18-20,  1935.



 366.  Smith,  F.,  and A. C.  Nelson,  Jr.   Guidelines  for Development of a Quality




            Assurance Program.   Reference Method for  the Continuous Measurement




            of Carbon Monoxide  in the Atmosphere.  EPA-R4-73-028a.  Research




            Triangle Park, N.C.:  Research Triangle Institute,  1973.  110 pp.



 367.  Smith,  K. A.,  J. M.  Bremner,  and  M. A.  Tabatabai.   Sorption of  gaseous




            atmospheric pollutants by soils.   Soil Sci.   116:313-139,  1973.




 368.  Smith,  I.,  Jr.,  and E. H. C.  Sie.  Response of luminescent bacteria to




            common atmospheric  pollutants.   Inst. Environ. Sci.  15:154-157, 1969.




 369.  Smith,  R.  N., and J.  Mooi.  The catalytic oxidation of carbon monoxide by




            nitrous  oxide  on carbon surfaces.   J. Phys.  Chem. 59:814-819, 1955.




369a.  Stainsby,  W.  N., and A.  B. Otis.   Blood flow,  blood oxygen tension, oxygen




            uptake,  and oxygen transport in skeletal  muscle.,  Amer. J. Physiol.




            206:858-866, 1964.



 370.  Stalker, W. W.,  and R. C. Dickerson.  Sampling  station and time require-




            ments  for urban air  pollution surveys. Part  II:   Suspended particu-




            late matter and  soiling  index.   J.  Air Pollut.  Control Assoc. 12:111-




            128, 1962.



371.  Stebbins, W.  C. ,  Ed.   Animal Psychophysics:  The Design and Conduct of




           Sensory Experireents.   New York:  Appleton-Century-Crofts, 1970.




           433 pp.
                                    46

-------
 372.  Stecher, P.  G.,  Kd.  Carbon monoxide, p. 212.  In The Merck Index of Chem-
            icals and Drups.  (7th ed.)  Rahway, N. J.:   Merck & Co., Inc., 1960.
372o.  Stechor, P.  G. ,  Ed.  Carbon monoxide, pp. 208-209.  In The Merck Index.
            An Encyclopedia of Chemicals and Drugs.   (8th ed.)  Rahway, N. J.:
            Merck & Co.,  Inc., 1968.
 373.  Stcdman, D.  H. ,  E.  D.  Morris,  Jr.,  E. E. Daby,  H.  Niki, and B. Weins.tock.
            The role of OH radicals in photochemical smog reactions.   Abstract
            WATR 026.  In Abstracts of Papers.  160th National Meeting, American
            Chemical Society,  Chicago, Illinois, September 14-18,  1970.
 374.  Stephenson,  M.  Bacterial Metabolism.   (3rd ed.)   New York:  Longmans,
            Green and Co., 1949.  398 pp.
375.  Stevens, C. M., L. Krout, D. Walling, A.  Venters,  A. Engelkemeir,  and
           L.  E. Ross.  The isotopic  composition of atmospheric carbon monoxide.
           Earth Planet. Sci. Lett.  16:147-165, 1972.
 376. Stewart,  R. D.,  E.  D. Baretta,  L. R.  Platte,  E. B.  Stewart,  H.  C.  Dodd,
            K.  K. Donohoo,  S.  A. Graff,  J.  H. Kalbfleisch,  C.  L.  Hake, B.  van
            Yserloo,  A. A.  Rimm, and  P.  E.  Newton.   "Normal"  Carboxyhemoglobin
            Levels of Blood Donors  in the  United States.   Report  No.  ENVIR MED
            MCW CRC-COHb-73-1.   Milwaukee:   The Medical College of Wisconsin,
            1973. /~252 pp._7
 377.  Stewart, R-,  D. ,  E.  D.  Baretta, L. R.  Platte,  E. B. Stewart,  J.  H.
            Kalbfleisch,  B.  van Yserloo, and A. A.  Rimm.   Carboxyhemoglobin
            concentrations  in  blood from donors in  Chicago, Milwaukee, New
            York, and Los  Angeles.   Science 182:1362-1364,  1973.
378.  Stewart, R. D.,  E. D. Baretta,  L. R.  Platte,  E. B. Stewart,  J.  H.
           Kalbfleisch, B. van Yserloo, and A.  A. Rimm.  Carboxyhemoglobin
            levels in American blood  donors.  J.A.M.A. 229:1187-1195,  1974.
                                     47

-------
378a.  Stewart, R. I)., T. N. Fisher, M. J. Hosko, J. E. Peterson, E.  D,  Baretta,

            and II. C. Dodd.  Experimental human exposure to methylene chloride.

            Arch. Environ. Health  25:342-348, 1972.

 379.  Stownrt, R. D., P. E. Newton, M. J. Hosko, and J. E. Peterson.  Effect

            of cnrhon monoxide on time perception.  Arch. Environ. Health  27:
                  \
      __    155-160, 1973.

 380.  Stewart, R. D., P. E. Newton, M. J. Hosko, J. E. Peterson, and J. W.

            Mellender.  The effect of carbon monoxide on time perception,

            manual coordination, inspection, and arithmetic, pp. 29-55.  In

            B.  Weiss and V. G.  Laties, Eds.  Behavioral Toxicology.   New York:

            Plenum Press, 1975.

 381.  Stewart, R. D., J. E. Peterson, E. D. Baretta, R. T. Bachand,  M.  J.  Hosko,

            and A. A. Herrmann.  Experimental human exposure to  carbon monoxide.

            Arch. Environ. Health 21:154-164, 1970.

 382.  Stewart, R. D. , J. E. Peterson, T. N. Fisher, M. J. Hosko, E.  D.  Baretta,

            H.  C. Dodd, and A.  A. Herrmann.  Experimental human  exposure to high

            concentrations of carbon monoxide.  Arch. Environ. Health 26:1-7, 1973.

 383.  Strickland-Constable, R. F.  Part played by surface oxides in  the oxida-

            tion of carbon.  Trans. Faraday Soc. 34:1074-1080, 1938.

 384.  Stupfel, M.,  and  G.  Bouley.  Physiological and biochemical effects  on

            rats  and mice  exposed to  small concentrations of carbon monoxide

            for long periods.  Ann. N. Y. Acad. Sci. 174:342-368, 1970.

 385.  Swlnnerton, J. W., and R. A. Lamontagne.  Carbon monoxide in the  South

            Pacific Ocean.  Tellus 26:136-142, 1974.

 386.  Swinnerton, J. W., V. J. Linnenbom, and C. H. Cheek.  Distribution  of

            methane and carbon monoxide between the atmosphere and natural

            waters.  Environ. Sci. Technol. 3:836-838, 1969.
                                    48

-------
 387.   Swinnerton, J. W. , V. J. Linnenbom, and  R. A. Lamontage.   Distribution
            of cnrbon monoxide between  the atmosphere  and  the  ocean.   Ann.
            N. Y.  Acad. Sci. 174:96-101, 1970.
 388.   Swinnorton, J. W., V. J. Linnenbom, and  R. A. Lamentagne.   The ocean:
            A natural source of carbon  monoxide.  Science  167:984-986, 1970.
 389.   Syvertson,  C. R., and J. A.  Harris.   Erythropoietin production in dogs
            exposed  to  high altitude  and  carbon monoxide.  Amer.  J.  Physiol.
            225:293-299, 1973.
 390.   Tanaka,  M.   Studios  on the etiological mechanism of fetal developmental
            disorders  caused  by maternal smoking during pregnancy.  J. Jap. Obstet.
            Gynecol. Soc.  (Nippon.  Sanka-Fujinka Gakkai Zasshi) 17:1107-1114,
            1965.   (in Japanese)
 391.   Taylor, 0.  C.  Air pollution with  relation to agronomic crops:   IV.
            Plant  growth suppressed by  exposure to  air-borne oxidants (smog).
            Agron. J. 50:556-558, 1958.
 392.   Teichner, W.  H.,  Carbon monxide and  human performance:  A methodologi-
            cal  exploration, pp.  77-103.  In B. Weiss  and  V. G. Laties,  Eds.
            Behavioral  Toxicology.  New York:   Plenum  Press, 1975.
 393.   Teichner, W.  H.   Recent studies  of simple reaction  time.   Psychol. Bull.
            51:128-149, 1954.
  394.  Teichner, W.  H., and M.  J. Krebs.  Laws of  the  simple visual reaction
            time.  Psychol. Rev.  79:344-358, 1972.
 395.   Tenney, S. M., and L. C. Ou.   Physiological  evidence  for increased tissue
            capillarity in rats acclimatized to high altitude.  Respir.  Physiol.
            8:137-150,  1970.
396.  Theodore,  J.,  R.  D.  O'Donnell,  and K.  C. Back.   Toxicological evaluation
           of carbon monoxide in humans and other mammalian species.  J. Occup.
           Med.  13:242-255,  1971.
                                   49

-------
 397.  Thomas Jefferson University.  Jefferson Medical College, Department of



            Physiology.  The Effect of Carbon Monoxide Inhalation on Induced



            Ventricular Fibrillation in the Cynomologus Monkey.  Technical



            Report.  Philadelphia:  Thomas Jefferson University, 1973.  31 pp.


 398.   Thompson,  C.  R. ,  0.  C.  Taylor, M.  D.  Thomas,  and J.  0.  Ivie.   Effects  of



            air  pollutants  on  apparent  photosynthesis  and water use  by citrus



            trees.   Environ. Sci.  Technol.  1:644-650,  1967-


 399.   Thomsen,  H.  K.   Carbon  monoxide-induced atherosclerosis in primates.   An



            electron-microscopic  study  on the coronary arteries of Macaca irus



            monkeys.   Atherosclerosis  20:233-240,  1974.


 400.   Thomsen,  H.  K., and K.  Kjeldsen.  Threshold limit for carbon monoxide-



            induced myocardial damage.   An electron microscopic study in



            rabbits.  Arch. Environ. Health 29:73-78,  1974.


 401.  Tjepkema, J. D., and C. S. Yocum.  leghemoglobin facilitated oxygen



            diffusion in soybean nodule slices.  Plant Physiol. 46(Suppl.):



            44, 1970.   (abstract)



401a.  Tokyo Metropolitan Research Institute for Environmental Protection.  Annual



            Report of the Tokyo Metropolitan Research Institute for Environmental



            Protection.  1971.  68 pp.-
                                                         i

 402.  Trapnell, B. M. W.  Chemisorption.  London:  Butterworths Scientific



            Publications, 1955.  265 pp.


 403.   Tunder,  R.  S.,  S. W.  Mayer,  E.  A.  Cook, and L.  Schieler.  Compilation of



            Reaction Rate Data for Non-Equilibrium Performance and Reentry Calcu-



            lation  Programs.   Aerospace Report No.  TR-1001(9210-02)-!.  El



            Segundo,  Calif.:   Aerospace Corporation,  1967.   68 pp.



 404.  Underwood, P. B., K. F. Kesler,  J. M. O'Lane, and D. A. Callagan.  Paren-



            tal smoking empirically related to pregnancy outcome.  Obstet. Gynecol.



            29:1-8, 1967.


                                    50

-------
405.  U.  S.  Bureau  of  the Census.   Social  and  Economic  Statistics  Administration.




           Department  of Commerce.   Statistical Abstract  of  the  United  States




           1974.  95th Annual  Edition.  Washington, D.  C.:   U. S.  Government




           Printing Office,  1974.   1028 pp.



 406.  U. S. Department  of  Health,  Education,  and Welfard.   Public Health Service.




            Environmental Health Service.   National Air Pollution Control Adminis-




            tration.   Air Quality Criteria for Carbon Monoxide.   NAPCA Publication




            No.  AP-62. Washington,  D. C.:   U. S.  Government Printing Office,




            1970.   /.~166 pp. ~J




407.   U. S. Department  of  Health,  Education and  Welfare.  Public Health Service.




            Vital  Statistics of the United States, 1968.   Volume 1.  Natality.




            Washington,  D.  C.:  U.  S.  Government  Printing Office,  1970.  /254 pp._/



 408.  U.  S. Environmental  Protection  Agency.  Ambient  air monitoring reference




            and  equivalent  methods.  Federal Register 40:7042-7070, 1975.




409.   U.  S. Environmental  Protection Agency.  Supplement No. 5  for Compilation




            of Air Pollutant Emission Factors.  (2nd  ed.) AP-42.   Research




            Triangle Park,  N.  C.:  U. S.  Environmental Protection  Agency, 1975.




            /~158 PP._7




410.   U.  S. Environmental  Protection Agency.  Guidelines for Air  Quality Main-




            tenance Planning and  Analysis.   Vol.  9.   Evaluating  Indirect  Sources.




            EPA 450/4-75-001.  Research Triangle  Park,  N. C.:  U.  S.  Environmental




            Protection Agency, Office of Air Quality, Planning and Standards,




            1975.   /~557 pp._7




411.  U.  S. Environmental Protection Agency.  National  primary and secondary




           ambient  air quality standards.   Federal Register 36:8186-8201, 1971.
                                    51

-------
 Alln.   U.  S.  Environmenta1 Protection Agency.  1973 National Emissions Report.




             National Emissions Data System (NEDS) of the Aerometric and Emissions




             Reporting System (AEROS).  EPA-450/2-76-007.  Research Triangle Park,




             N.  C.:   U.  S. Environmental Protection Agency, Office of Air and




            W.-istu  Management,  1976.  423 pp.




  412.  U.  S.  Environmental Protection Agency.  1972 National Emissions Report:.,




             National Emissions Data System (NEDS) of the Aerometric and Emis-




             sions  Reporting System (AEROS).  EPA-450/2-74-012.  Research Triangle




            Park,  N.  C.:   U. S.  Environmental Protection Agency, 1974.   422 pp.




4l2a.  U. S. Environmental Protection Agency.  Ambient air monitoring reference




            and equivalent methods.  Federal Register 40:7042-7070, 1975.




 413.   van  Kampen,  E. J., and W.  G.  Zijlstra.   Standardization of hemoglobin-




            ometry.   II.   The hemoglobincyanide method.   Clin. Chim. Acta 6:




            538-544,  1961.



 414.   van  Slyko, D.  D.,  A.  Hiller,  J.  R.  Weisiger,  and  W.  0.  Cruz.   Determination




            of carbon monoxide  in blood and of total and active hemoglobin by




            carbon  monoxide capacity.   Inactive hemoglobin and methemoglobin




            contents  of normal  human blood.  J. Biol.  Chem. 166:121-148, 1946.




 415.  Vaughan,  B.  E., and N. Pace.   Changes in myoglobin content of the high




            altitude  acclimatized rat.  Amer.  J. Physiol. 185:549-556,  1956.




 416.  Vogel,  J. A.,  and M. A.  Gleser.  Effect of carbon monoxide on oxygen




            transport during exercise.  J. Appl. Physiol. 32:234-239, 1972.



 417.  Vogel, J. A., M. A.  Gleser,  R. C. Wheeler, and B. K. Whitten.  Carbon  mon-




            oxide and physical work capacity.  Arch. Envir. Health  24:198-203,  1972.



 418.  Vollmer, E.  P., G. B. King,  J. E. Birren, and M. B. Fisher.  The  effects




            of carbon monoxide on three types  of performance,  at simulated  alti-




            tudes of 10,000 and 15,000 feet.   J. Exp. Psychol. 36:244-251,  1946.





                                     52

-------
 419.  Wnlcl, N., S. Howard. ?. G. Smith, and K. Kjeldsen.  Association between  ather-
            osclerotic diseases and carboxyhaemoglobin levels in tobacco smokers.
            Brit. Mod. J. 1:761-765, 1973.
 4?0.  Wallace,  N.  n.   C.  L.  Davis,  R.  B.  Rutledge,  and A.  Kahn.   Smoking and
            carboxyhomoglobin  in  St.  Louis Metropolitan population.   Theoretical
            and  empirical  considerations.  Arch.  Environ.  Health  29:136-142,  1974.
 421.  Wanstrup, J., K. Kjeldsen,  and P. Astrup.  Acceleration of spontaneous
           intitnal-subintimal changes in rabbit aorta by a prolonged moderate
           carbon monoxide exposure.  Acta Path. Microbiol. Scand. 75:353-
           362, 1969.
 422. Warneck,  P.   On the role of OH and  H02 radicals in the troposphere.
            Tellus  26:39-46,  1974.
 423.  Webster, W. S.,  T.  B. Clarkson,  and H.  B.  Lofland.   Carbon monoxide-
            aggravated  atherosclerosis  in  the squirrel monkey.  Exp.  Molec.
            Path. 13:36-50, 1970.
423a. Weast,  R.  C., Ed.   Handbook of Chemistry and Physics.   (56th ed.)
            Cleveland, Ohio:   The Chemical Rubber Company, 1975.
 424. Weinblatt, E., C. W. Frank, S. Shapiro, and R. V.  Sager.   Prognostic
            factors in  angina pectoris--a prospective study.  J.  Chron. Dis.
            21:231-245, 1968.
 425. Weinblatt, E.,  S.  Shapiro,  C.  W.  Frank, and  R.  V.  Sager.   Prognosis  of men
            after first myocardial  infarction:  Mortality and first recurrence in
            relation to selected  parameters.   Amer.  J. Public Health 58:1329-1347,
            1968.
 426. Weinstock, B.  Carbon monoxide:  Residence time in  the atmosphere.
            Science 166:224-225, 1969.
 427. Weinstock, B.,  and  T. Y. Chang.  The global balance of carbon monoxide.
            Tellus 26:108-115,  1974.

                                    53

-------
 428.   Weinstoclc, B.,  and H.  Niki.  Carbon monoxide balance in nature.  Science 176:

            290-292,  1972.
 429.  Weir,  F.  W. ,  and T. H.  Rockwell.   An Investigation of the Effects of Car-

            bon  Monoxide on Hum.-ms in the Driving Task.   Final Report.  Columbus:

            The  Ohio  State University Research Foundation, 1973.  170 pp.
                  \ ;
430.  Weiss, B., and V. G. Laties.  Enhancement of human  performance  by caffeine
                 /
           and  the amphetamines.  Pharmacol. Rev. 14:1-36,  1962.

 431.   Weiss, H. R., and J. A.  Cohen.  Effects  of low levels of carbon monoxide

            on rat brain and muscle  tissue PQ_.   Environ.  Physiol.  Biochem.  4:

            31-39, 1974.
 432.  Wells, L. L.  The'prenatal effect  of carbon monoxide on  albino rats  and  the

            resulting neuropathology.  Biologist  15:80-81,  1933.

 433.   Went,  F.  W.   On the nature of Aitken condensation nuclei.  Tellus 18:

            549-556,  1966.
 434t  Went, F.  W.   Organic matter in the atmosphere and  its possible relation

            to petroleum  formation.   Proc. Nat. Acad. Sci.  U.S.A. 46:212-221,

            1960.
 435.  Westberg, K., and  N. Cohen.  The Chemical  Kinetics of Photochemical  Smog

            as  Analyzed by Computer.  Aerospace Report No.  ATR-70  (8107)-!.  El

            Segundo, Calif.:  Aerospace Corporation, 1969.   29  pp.

 436.  Westberg, K., N. Cohen, and K. W.  Wilson.  Carbon  monoxide:  Its role in

            photochemical smog formation.  Science 171:1013-1015,  1971.

 437.   Westenberg, A. A.  Carbon monoxide and nitric oxide  consumption  in polluted

            air.  The carbon monoxide-hydroperoxyl reaction.  Science 177:255-256,

            1972.
 438.  Westenberg,  A.  A.,  and N.  deHaas.   Steady-state intermediate concentra-

            tions and  rate constants.  Some H0« results.   J. Phys.  Chem. 76:

            1586-1593,  1972.
                                     54

-------
439.  Who Ion, W. J.  Intracellular P02 in heart and skeletal muscle.  Physiologist

            14:69-82, 1971.
440.  White, J.  J.   Carbon monoxide and its relation to aircraft.  U. S. Nav.
           Med.  Bull. 30:151-165, 1932.
441.  Wilmer, W. H.  Effects of carbon monoxid  upon the eye.  Amor. J.  Ophthalmol.
           4:73-90, 1921.
442.  Wilks, S.  S., J.  F. Tomashefski, and R. T. Clark, Jr.  Physiological effects
           of chronic exposure to carbon monoxide.  J. Appl. Physiol. 14:305-310,
           1959.
443.  Williams,  I.  R., and E. Smith.  Blood picture, reproduction, and general
           condition during daily exposure to illuminating gas.  Amer. J. Physiol.
           110:611-615,  1935.
444.  Wilson, D. F.,  J.  W.  Swinnerton, and R. A. Lamontagne.   Production of car-
           bon monoxide and gaseous hydrocarbons in seawater:  Relation  to dis-
           solved organic carbon.  Science 168:1577-1579,  1970.
445.  Winnekc,  G.  Behavioral effects of methylene chloride  and  carbon monoxide
            as assessed by  sensory  and psychomotor performance, pp.  130-144.   In
           C. Xintaras,  B. L. Johnson, and I. de Groot, Eds.   Behavioral Toxicol-
           ogy:  Early Detection of Occupational Hazards.  HEW Publ. No.  (NIOSH)
           74-126.  Washington,  D. C.:  U. S. Department of  Health,  Education,
           and Welfare,  1974.
      Wittenberg, J. B., C. A. Appleby, and B. A. Wittenberg.  The kinetics of
           the reactions of leghemoglobin with oxygen and carbon monoxide.  J.
           Biol. Chem. 247:527-531, 1972.

 447.  wofsy, S. C., J. C. McConnell, and M. D. McElroy.  Atmospheric CH4, CO a
            and C02.  J. Geophys. Res. 77:4477-4493, 1972.
                                    55

-------
 448. Wohlrah,  H. ,  and G.  B.  Oguntnola.   Carbon monoxide binding studies of cyto-

            chrome  a  hemes in intact rat liver mitochondria.  Biochemistry 10:

            1.103-11.06, 1971.

 449. Wright,  G.,  P.  Randell, and R. J.  Shephard.  Carbon monoxide and driving


            skills.   Arch.  Environ. Health 27:349-354, 1973.

450.  Xintaras, C.,  B.  L.  Johnson, C.  E. Ulrich,  R.  E.  Terrill, and M. F.

            Sobecki.   Application of the  evoked response technique in air pollu-
                         --..
            tion toxicology.   Toxicol.  Appl.  Pharmacol.  8:77-87, 1966.


 451.  Delete -- use 450.


452.  Xintaras, C.,  C.  E.  Ulrich, M. F.  Sobecki,  and R. E. Terrill.  Brain

            potentials studied by computer analysis.   Arch. Environ. Health


            13:223-232,  1966.


 453.  Yamate, N., and A.  Inoue.  Continuous analyzer for  carbon monoxide in

            ambient air by electrochemical technique.   Kogai to Taisaku  (J.

            Public Nuisance)  9:292-296,  1973.   (in Japanese)

  454.  Yerushalmy,  J.  Mother's cigarette smoking and survival of infant.   Amer.

            J.  Obstet.  Gynecol. 88:505-518,  1964.

454a.  Yerushalmy, J.  The relationship  of parents' cigarette smoking  to outcome

            of pregnancy - implications  as to  the problem  of inferring causation

            from observed  associations.  Amer. J. Epidemiol. 93:443-456, 1971.

 455.  Young,  I. M., and L. G.  C. Pugh.  The carbon monoxide content  of  foetal

            and maternal blood.  J. Obstet. Gynaecol. Brit.  Commonw.  70:681-


            684, 1963.

 456.  Younoszai,  M. K., and J. C. Haworth.  Placental dimensions and  relations


            in preterm, term and growth-retarded  infants.  Amer. J. Obstet.


            Gynecol. 103:265-271, 1969.
                                   56

-------
-'>56a.  Youaaszai,  M.  K. ,  J.  Peloso,  and J.  C.  Haworth.   Fegal growth retardation
            in rats  exposed  to cigarette smoke during pregnancy.   Amer.  J. Obstet.
            Gynecol.  104:1207-1213,  1969.
 457.   ZatsiorskU, M. , V. Kondrateev,  and  S.  Solnishkova.   Radiation of the flame
            of carbon monoxide and ozone and the mechanism  of this  reaction.  Zh.
            Viz. Khim.  (Leningrad) 14:1521-1527, 1940.   (in Russian)
 458.  Zimmerman, P.  W., W. Crocker,  and A.  E.  Hitchcock.  Initiation and stimu-
           lation of roots from exposure of plants to carbon monoxide.  Contrib.
           Boyce Thompson Inst. 5:1-17, 1933.
 459.  Zimmerman, P.  W., W. Crocker,  and A.  E.  Hitchcock.  The effect of carbon
           monoxide on plants.  Contrib. Boyce Thompson Inst. 5:195-211,  1933.
 460.Zorn, H.   The partial oxygen pressure  in  the brain and  liver at  subtoxic
           concentrations of  carbon monoxide.  Staub Reinhalt. Luft   (Engl. Ed.)
           32(4):24-29,  1972.
                                     57

-------
                                   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
 U.S. Environmental Protection  Agency
 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
 8. DISTRIBUTION STATEMENT

 RELEASE!TO PUBLIC
19. SECURITY CLASS (ThisReport)
  UNCLASSIFIED
21. NO. OF PAGES
20. SECURITY CLASS (Thispage}

  UNCLASSIFIED	
22. PRICE
EPA Form 2220-1 (9-73)
                                           352

-------
                                                         INSTRUCTIONS

   1.   REPORT NUMBER
        Insert the EPA report number as it appears on the cover of the publication.

   2.   LEAVE BLANK

   3.   RECIPIENTS ACCESSION NUMBER
        Reserved for use by each report recipient.

   4.   TITLE AND SUBTITLE
        Title should indicate clearly and briefly the subject coverage of the report, and be displayed prominently.  Set subtitle, if used, in smaller
        type or otherwise subordinate it to.main title. When a report is prepared in  more than one volume, repeat the primary title, add volume
        number and include subtitle for the specific title.

   5.   REPORT DATE
        Each report shall carry a date indicating at least month and year.  Indicate the basis on which it was selected (e.g., date of issue, date of
        approval, date of preparation, etc.).

   6.   PERFORMING ORGANIZATION CODE
        Leave blank.

   7.   AUTHOR(S)
        Give name(s) in conventional order (John R. Doe, J. Robert Doe, etc.}. List author's affiliation if it differs from the performing organi-
        zation.

   8.   PERFORMING pRGANIZATION REPORT NUMBER
        Insert if performing organization wishes to assign this number.

   9.   PERFORMING ORGANIZATION NAME AND ADDRESS
        Give name, street, city, state, and ZIP code. List no more than two levels of an organizational hirearchy.

   10.  PROGRAM ELEMENT NUMBER
        Use the program element number under which the report was prepared. Subordinate numbers may be included in parentheses.

   11.  CONTRACT/GRANT NUMBER
        Insert contract or grant number under which report was prepared.

   12.  SPONSORING AGENCY NAME AND ADDRESS
        Include ZIP code.

   13.  TYPE OF REPORT AND PERIOD COVERED
        Indicate interim final, etc., and if applicable, dates covered.

   14.  SPONSORING AGENCY CODE
        Leave blank.

   15.  SUPPLEMENTARY NpTES
        Enter information not included elsewhere but useful, such as: Prepared in cooperation with, Translation of. Presented at conference of,
        To be published in, Supersedes, Supplements, etc.

   16.  ABSTRACT
        Include a brief (200 words or less} factual summary of the most significant information contained in the report. If the report contains a
        significant bibliography or literature survey, mention it here.

    17.  KEY WORDS AND DOCUMENT ANALYSIS
        (a) DESCRIPTORS - Select from the Thesaurus of Engineering and Scientific Terms the proper authorized terms that identify the major
        concept of the research and are sufficiently specific and precise to be used as index entries for cataloging.

        (b) IDENTIFIERS AND OPEN-ENDED TERMS  - Use identifiers for project names, code names, equipment designators, etc.  Use open-
        ended terms written in descriptor form for those subjects for which no descriptor exists.

        (c) COSATI FIELD GROUP - Field and group assignments are to be taken from the 1965 COSATI Subject Category List. Since the ma-
        jority of documents are multidisciplinary in nature, the Primary Field/Group assignment(s) will be specific discipline, area of human
        endeavor, or type of physical object. The application(s) will be cross-referenced with secondary Field/Group assignments that will follow
        the primary posting(s).

    18.  DISTRIBUTION STATEMENT
        Denote releasability to the public or limitation for reasons other than security for example "Release Unlimited."  Cite any availability to
        the public, with address and price.

    19.  &20. SECURITY CLASSIFICATION
        DO NOT submit classified reports to the National Technical Information service.

    21.  NUMBER OF PAGES
        Insert the  total number of pages, including this one and unnumbered pages, but exclude distribution list, if any.

    22.  PRICE
        Insert the  price set by the National Technical Information Service or the Government Printing Office, if known.
EPA Form 2220-1 (9-73) (Reverse)

-------