xvEPA
United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-83-033F
August 1984
Final Report
Research and Development
Revised Evaluation of
Health Effects
Associated with
Carbon Monoxide
Exposure:
An Addendum to the
1979 EPA Air Quality
Criteria Document for
Carbon Monoxide
Final
Report
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EPA-600/8-83-033F
August 1984
Revised Evaluation of Health
Effects Associated with Carbon
Monoxide Exposure:
An Addendum to the 1979 EPA
Air Quality Criteria Document for
Carbon Monoxide
Final Report
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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NOTICE
This document has been reviewed in accordance with
U.S. Environmental Protection Agency policy and
approved for publication. Mention of trade names
or commercial products does not constitute endorse-
ment or recommendation for use.
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ABSTRACT
This addendum reevaluates the scientific data concerning health effects
associated with exposure to carbon monoxide (CO) at ambient or near ambient
levels by providing: (1) a concise summary of key health effects information
pertaining to relatively low-level CO exposure; and (2) an overview of the
limited volume of new evidence on the subject. This reevaluation is performed
in light of the diminished value of studies by Dr. Wilbert Aronow on human
health effects of exposure to low levels of CO. These studies figured in to
the preparation of the U.S. Environmental Protection Agency's 1979 Air Quality
Criteria Document for Carbon Monoxide and to the Agency's proposed retention
of the 8-hour and revision of the 1-hour primary standards for CO (45 FR
55066; August 18, 1980).
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CONTRIBUTORS AND REVIEWERS
The following authors contributed to the writing of this addendum.
Dr. Lester D. Grant, Environmental Criteria and Assessment Office,
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. James A. Raub, Environmental Criteria and Assessment Office,
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Vernon A. Benignus, Neurotoxicology Division, Health Effects Research
Laboratory, U.S. Environmental Protection Agency, Building 224H, University
of North Carolina, Chapel Hill, NC 27514.
Dr. David J. McKee, Strategies and Air Standards Division, Office of Air
Quality Planning and Standards, U.S. Environmental Protection Agency,
Durham, NC 27701
A working draft of this addendum was circulated for preliminary peer-review
to the individuals listed below, and comments received were taken into account
in preparing the present addendum. The views expressed in the present addendum
should not be taken, however, as representing those of any single individual or
group listed here.
Dr. Laurence D. Fechter
Department of Environmental Health Sciences
School of Hygiene and Public Health
John Hopkins University
615 North Wolfe Street
Baltimore, MD 21205
Dr. George M. Goldstein,
Clinical Studies Branch, Health
Effects Research Laboratory
U.S. Environmental Protection Agency
Building 224H, University of
North Carolina
Chapel Hill, NC 27514
Dr. Jack D. Hackney
Environmental Health Service
Rancho Los Amigos Hospital
7601 Imperial Highway
Downey, CA 90242
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CONTRIBUTORS AND REVIEWERS
Dr. Stephen M. Horvath
Institute of Environmental
University of California
Santa Barbara, CA 93106
Stress
Dr. Victor G. Laties
Environmental Health Sciences Center
University of Rochester, School of Medicine
Rochester, NY 14642
Dr. Patricia M. Mihevic
Institute of Environmental
University of California
Santa Barbara, CA 93106
Stress
Dr. John J. O'Neil
Clinical Studies Branch, Health
Effects Research Laboratory
U.S. Environmental Protection Agency
Building 224H, University of
North Carolina
Chapel Hill, NC 27515
Dr. David S. Sheps
Department of Cardiology
University of North Carolina
School of Medicine
Chapel Hill, NC 27514
Dr. Jaroslav J. Vostal
Executive Department
General Motors Research Laboratories
Warren, MI 48090
Dr. Jeames A. Wagner
Institute of Environmental
University of California
Santa Barbara, CA 93106
Stress
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CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
The substance of this document was independently peer-reviewed in public
session by the Subcommittee on Air Quality Criteria for Carbon Monoxide, Clean
Air Scientific Advisory Committee, and the Environmental Protection Agency
Science Advisory Board. The Committee's findings and recommendations on the
scientific basis for a revised national ambient air quality standard for carbon
monoxide can be found in Appendix C.
Chairman, Clean Air Scientific Advisory Committee:
Dr. Morton Lippman i
Institute of Environmental Medicine
New York University
New York, NY 10016
Staff Director, Science Advisory Board:
Dr. Terry F. Yosie !
U.S. Environmental Protection Agency
Science Advisory Board
401 M Street, S.W.
Washington, DC 20460
Members and Consultants:
Dr. Stephen M. Ayres
Department of Internal Medicine
St. Louis University Medical Center
1325 S. Grand Blvd.
St. Louis, MO 63104 ;
Dr. Edward Crandall i
Division of Pulmonary Disease
Department of Medicine
University of California
Los Angeles, CA 90024
Dr. Robert Dorfman !
Department of Economics
Harvard University
325 Littauer
Cambridge, MA 02138
Dr. Ronald J. Hall
Ministry of the Environment
Box 39 j
Dorset, Ontario TOA1EO
Dr. Ian T. Higgins
Department of Epidemiology i
University of Michigan ;
109 Observatory Street
Ann Arbor, MI 48109
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CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE (continued)
Dr. Warren B. Johnson, Jr.
Director, Atmospheric Sciences Center
Advanced Development Division
SRI International
333 Ravenswood Avenue
Menlo Park, CA 94025
Dr. Lewis H. Kuller
Professor and Chairperson
Department of Epidemiology
Graduate School of Public Health
University of Pittsburg
130 Desoto Street
Pittsburgh, PA 15260
Dr. Timothy Larsen
Department of Civil Engineering
Mail Stop FC-05
University of Washington
Seattle, WA 98195
Dr. Victor Laties
Environmental Health Sciences Center
School of Medicine, Box RBB
University of Rochester
Rochester, NY 14612
Dr. Lawrence Longo
Division of Perinatal Biology
Loma Linda University
School of Medicine
Loma Linda, CA 92350
Mr. Donald Pack
1826 Opalocka Drive
McLean, VA 22102
Dr. John Seinfeld
Department of Chemical Engineering
206-41
California Institute of Technology
Pasadena, CA 91125
Mr. Bill Stewart
Executive Director
Texas Air Control Board
6330 Highway 290 East
Austin, TX 78723
VI
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CLEAN AIR SCIENTIFIC ADVISORY COMMITEE (continued)
Dr. Michael Treshow
Department of Biology
University of Utah
Salt Lake City, UT 84112
Dr. James Ware
Department of Biostatisties
Harvard School of Public Health
677 Huntington Avenue
Boston, MA 02115
VI I I
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TABLE OF CONTENTS
Page
INTRODUCTION 1
MECHANISMS OF ACTION •; 2
HEALTH EFFECTS OF LOW LEVEL CO EXPOSURES 6
CARDIOVASCULAR EFFECTS 7
NEUROBEHAVIORAL EFFECTS 12
EFFECTS OF CO EXPOSURE ON FIBRINOLYSIS 15
PERINATAL CO EFFECTS 17
POPULATIONS AT RISK 19
SUMMARY AND CONCLUSIONS 23
REFERENCES 27
APPENDIX A A-l
APPENDIX B B-l
APPENDIX C C-l
IX
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INTRODUCTION
On April 30, 1971, the Environmental Protection Agency promulgated (36 FR
8186) national ambient air quality standards (NAAQS) for carbon monoxide (CO)
under section 109 of the Clean Air Act. Identical primary and secondary
standards were set at levels of 9 ppm, 8-hour average, and 35 ppm, 1-hour
average, neither to be exceeded more than once per year. The scientific bases
for these standards are contained in the Air Quality Criteria Document for
Carbon Monoxide (U.S. Department of Health, Education, and Welfare, March,
1970, AP-62). The 1971 standards were primarily based on work by Beard and
Wertheim (1967) suggesting that low-level CO exposures resulting in carboxy-
hemoglobin (COHb) levels of 2 to 3 percent are associated with impairment of
ability to discriminate time intervals, a central nervous system (CNS) effect.
The revised Air Quality Criteria Document for Carbon Monoxide (U.S. EPA, 1979)
indicated that this study is no longer considered to provide credible evidence
for such CNS effects occurring at 2-3% COHB and, therefore, does not represent
a sound scientific basis for the standard as discussed in an August 18, 1980
EPA proposal notice (45 FR 55066). However, medical evidence published since
1970 indicated at the time of proposal that aggravation of angina and other
cardiovascular diseases may occur at COHb levels as low as 2.7 to 2.9 percent.
Assessment of this and other medical evidence led EPA to propose, on August
18, 1980, retention of the 8-hour primary standard level of 9 ppm and revision
of the 1-hour standard level from 35 ppm to 25 ppm (45 FR 55066).
The 1980 proposal was based in part on several health studies conducted
by Dr. Wilbert Aronow (Aronow et al. , 1972; Aronow and Isbell, 1973; Aronow et
al., 1974; Aronow et al., 1974; Aronow and Cassidy, 1975; Aronow et al., 1977;
Aronow, 1978). Based on evaluation of these studies in 1979 by EPA staff,
their expert consultants, and the Agency's Science Advisory Board, it was
concluded that these studies demonstrate human health effects of carbon
monoxide that should be considered by the Agency in reconfirming existing or
proposing new NAAQS for CO. The Aronow studies were an important element in
identifying the blood carboxyhemoglobin (COHb) levels that represent a health
concern for sensitive individuals. This "critical" range was defined as
2.7-3.0 percent. An additional study by Aronow (1981) later reported findings
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suggesting that aggravation of angina symptoms, i.e., small but statistically
significant decreases (~10%) in time to onset of exercise-induced angina, may
occur in angina patients at COHb levels as low as 2.0 percent.
Since the CO standard was proposed by EPA in 1980, news media reports
appearing in early 1983 indicated that the Food and Drug Administration (FDA)
raised questions regarding the technical adequacy of several studies conducted
by Dr. Aronow on experimental drugs, leading to FDA rejection of use of the
drug study data. While there was no specific direct evidence that similar
problems might exist for the CO studies conducted by Dr. Aronow, EPA judged
that an independent assessment of these studies was advisable prior to a f,inal
NAAQS decision on CO. An expert committee was empaneled by EPA and met with
Dr. Aronow to discuss his studies and to examine limited available data and
records from his CO studies. In their report, the committee (chaired by Dr.
Stephen M. Horvath, Director of the Institute of Environmental Stress, Uni-
versity of California-Santa,Barbara) concluded that EPA should not rely on Dr.
Aronow1s data due to concerns regarding problems associated with the studies
which substantially limit the validity and usefulness of those study results
(Horvath et a!., 1983). Dr. Aronow submitted a detailed reply to EPA that
disputed, but did not effectively refute, the major points raised by the com-
mittee report (Aronow, 1983).
The main purpose of the present addendum is to reevaluate the scientific
data base concerning health effects associated with exposure to CO at ambient
or near ambient exposure levels, in light of the diminished value of the
Aronow studies and taking into account any new findings that have become
available beyond those reviewed in the revised Air Quality Criteria Document
for CO (U.S. EPA, 1979). This addendum is, accordingly, organized to provide:
(1) a concise summary of key health effects information discussed in the 1979
document as pertinent to characterization of health effects associated with
relatively low level CO exposures; and (2) an overview of the limited new
evidence bearing on the subject which has become available in the past several
years.
MECHANISMS OF ACTION
The 1979 Criteria Document discussed extensive evidence indicating that
the binding of CO to hemoglobin, producing COHb and decreased oxygen carrying
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capacity, results In decreased oxygen transport and uptake in most body tissues.
The resulting hypoxic state (impairing normal biochemical-physiological cellular
processes as a function of increasing external CO exposure and consequently
increasing blood COHb concentrations), it was concluded, probably represents
the main mechanism of action underlying the induction of toxic effects by low
level CO exposures.
Several important relationships between COHb levels and other physio-
logical parameters discussed in the 1979 Criteria Document have continued to
be the subject of evaluation since then. Of much importance is the relation-
ship between external CO exposure levels and consequent increases in blood
COHb levels. Many factors, discussed in the 1979 Criteria Document, can
affect the rate at which COHb increases above pre-existing endogenous levels
of COHb in response to inhalation of exogenous CO. These include, for example,
the pattern of external CO exposure, as in the case of acute short-term exposures
i
to high CO concentrations versus longer term exposure to relatively low levels
of CO. CO exposure-COHb concentration relationships have been modeled by
Coburn (Coburn et al. , 1965), taking into account several pertinent factors
(see Chapter 9 of the 1979 EPA CO Criteria Document for discussion of the
Coburn model equations). COHb levels predicted by the Coburn equations, as
depicted in Figure 1, are widely accepted as the currently best available
modeled estimates of COHb levels likely to result from varying CO concentra-
tions, exposure durations and exercise levels. It should be noted that some
questions have been raised regarding the specific mathematical approach employed
by Coburn in solving his equations to predict COHb concentration as a function
of time, considering appropriate physiological parameters (Venkatram and Louch,
1979; Ott and Mage, 1980; Marcus, 1980; Goldsmith, 1981; Joumard et al., 1981).
However, the proposed alternative approaches yield very similar estimated COHb
levels to those projected by Coburn's. approach. In addition, actual blood COHb
concentrations observed in response to particular external CO exposure situa-
tions have been consistent with those predicted by Coburn (Peterson and Stewart,
1975), although further experimental verification would be useful to demonstrate
that the Coburn equation accurately predicts uptake and excretion of CO under
widely varying conditions.
The exact mechanisms responsible for the hypoxia induced by CO are not
known. The most widely accepted mechanism of CO toxicity has been attributed
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X
O
O
20 LPM 50 PPM CO •
50 LPM 50 PPM CO
4
HOURS
Figure 1. Blood COHb concentrations predicted by Coburn equations to
occur as a function of exposure duration and ambient carbon monoxide
concentrations under resting (10 LPM), light exercise {20 LPM), or heavy
exercise (50 LPM) conditions. LPM = liters per minute ventilation rate.
Source: U.S. EPA (1979).
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to the preferential binding of CO to hemoglobin which produces hypoxia by re-
ducing 02 transport by red blood cells to the tissues and impedes the dis-
sociation of 02 from hemoglobin in the capillaries. However, other mechanisms
have been postulated for reducing oxygen transport. It is possible for CO to
bind to intracellular hemoproteins such as myoglobin and cytochrome oxidase,
which depends on the relationship of oxygen tension (P02) and CO tension (PCO)
to CO binding constants (Coburn, 1979). The affinity of cytochrome oxidase
for CO is similar to that for oxygen compared to myoglobin (30-50x) and hemo-
globin (220x) which would make it less likely to be responsible for impairment
of facilitated diffusion of oxygen to the mitochondria. However, if steep
oxygen tension gradients exist between the extracellular and intracellular
environment, then the P02 surrounding the mitochondria! terminal oxidase would
be low enough to have increased binding with CO. This hypothesis was tested
by Coburn (1979) in studies on isolated vascular smooth muscle. He concluded
that significant CO binding to cytochrome oxidase was unlikely to be an iji
vivo mechanism of CO toxicity in that particular tissue. Myoglobin was also
unlikely because it is absent or present in only small quantities. It is
possible that CO binds to hemoproteins other than hemoglobin, myoglobin, or
cytochrome oxidase. Cytochrome P-450, tryptophan deoxygenase, and tryptophan
catalase all have high enough binding affinities for CO in specific tissues to
be considered as possible candidates (Coburn, 1979).
the binding of CO to myoglobin in heart and skeletal muscle may be high
enough to reduce intracellular oxygen transport in those tissues (Coburn,
1979; Agostoni et al., 1980). Using a computer simulation of a three-
compartment model (arterial blood, venous capillary blood, and tissue myo-
globin), Agostoni et al. (1980) predicted that conditions would be favorable
for formation of carboxymyoglobin at COHb levels of 5-10%, particularly in
areas where the P02 was physiologically low (e.g., in subendocardium) and when
conditions of hypoxia, ischemia, or increased metabolic demands were present.
This could provide theoretical support for experimental evidence of myocardial
ischemia, such as electrocardiographic irregularities and decrements in work
capacity discussed later. However, it is not known whether binding of CO to
myoglobin could cause health effects (e.g., decreases in maximal oxygen con-
sumption during exercise) occurring at COHb levels as low as 4-5%. Additional
research is needed before this possibility can be more definitively evaluated.
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Whatever the specific biochemical-molecular mechanisms involved in the
induction of CO toxicity in specific tissues or organ systems, it is thought
that COHb concentrations in the blood represent a meaningful and useful
physiological marker by which to gauge the internal CO dose present at a given
time due to the combined cumulative contributions of: (1) baseline endogenous
production of CO by internal body processes; and (2) added CO body burden(s)
resulting from inhalation exposure to exogenous sources of CO.
HEALTH EFFECTS OF LOW-LEVEL CO EXPOSURES
In evaluating CO-induced health effects in humans, a crucial question
that must be addressed concerns blood COHb levels demonstrated to be associated
with effects on specific organ systems. The COHb levels of concern vary with
the patterns and concentrations of external CO exposure pertinent to the
objectives of any particular health risk evaluation. For example, as discussed
in the 1979 CO Criteria Document (U.S. EPA, 1979), some occupations inherently
involve exposure to high levels of CO, at times including frequent exposures
to CO levels well in excess of 100-200 ppm under certain workplace conditions.
On the other hand, it is relatively unusual for members of the general public
to encounter such high CO exposure levels.
As examples of possible extreme CO exposure situations encountered by the
general public, the 1979 Criteria Document noted that the following scenarios
may result in exposure to unusually high ambient levels of CO: (1) On a large
city freeway where traffic has come to a halt, the ambient CO level may exceed
44 ppm; (2) Inside a closed automobile where cigarettes are being smoked, CO
concentrations may exceed 87 ppm; (3) In enclosed, unventilated garages, CO
levels in excess of 100 ppm have been found; and (4) In a heavily traveled
vehicular tunnel, a 1-hour maximum of 218 ppm CO was recorded. Under relatively
mild exercise conditions likely to occur in such exposure situations for any
sustained period of time, the Coburn equations predict COHb blood concentrations
of <10 percent, assuming exposure durations of less than 8 hrs. More often,
the general (non-smoking) population is exposed to substantially lower CO
levels (<20-50 ppm) sustained over 1 to 8 hr. periods, potentially resulting
in maximum COHb levels of 6-7 percent but much more often in COHb levels below
2-3 percent. The present evaluation is, therefore, focused mainly on health
effects observed at blood COHb levels below 10 percent. The latter COHb
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levels are most pertinent for present objectives, i.e., the development of
criteria for ambient air quality standards.
Since the writing of the 1979 Criteria Document, several new studies have
been published that contribute to the CO health effects data base. These new
studies, including both human and animal toxicology data, are concisely reviewed
below within a context of integrating the new information with evidence previ-
ously reviewed in the 1979 Criteria Document.
1. Cardiovascular Effects
The most extensive studies on the cardiovascular effects of CO have been
those involving maximum aerobic capacity (V0_ ). Previous data reviewed in
^max
the revised CO Criteria Document (U. S. EPA, 1979) demonstrated statistically
significant decreases in V02 when COHb levels ranged from 7-20% under con-
ditions of short-term maximal exercise (Ekblom and Huot, 1972; Pirnay et al.,
1971; Vogel and Gleser, 1972). In another study (Horvath et al., 1975), the
critical level at which COHb marginally influenced (P < 0.10) VtL was
approximately 4.3%. In this study, work time to exhaustion was also reduced by
4.9 and 7% when COHb levels had attained 3.3 and 4.3%, respectively. Reductions
in V0_ following exhaustive treadmill exercise have since been confirmed at
5% COHb. In a double blind experiment (Stewart et al. , 1978; Klein et al., 1980),
6 physically fit male fire fighters were randomly exposed to either CO or fil-
tered air twice a week for 3 weeks and exercised to exhaustion. On exposure
days, the subjects breathed a bolus of 20,000 ppm CO for 47 seconds followed by
30 ppm CO for 4 hours. This resulted in a sustained elevation of COHb at 5.0-
5.5% saturation for 4 hours. Similar decrements in maximal exhaustion times were
noted following the acute exposure and at the end of 4 hours. No adaptation to
this hypoxic stress was observed after 4 hours of exposure or over the 3 weeks
of testing. Significant decreases in total exercise time (3.8%) and V0_ (3%)
were also previously reported by Weiser et al. (1978) in a project designed to
determine the effect of 5% COHb exposure on healthy young men residing in Denver
at an altitude of 1610m. Blood COHb concentrations were quickly increased to
5.1% from a resting level of 1.0% by adding a bolus of 100% CO to a closed-
circuit system from which the subjects rebreathed. The decrement in V0_ was
consistent with those reported above and the authors concluded that changes in
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exercise performance following CO exposure at this altitude were similar to,
but not greater than, changes occurring at sea level.
The effects of lower CO exposure levels have also been investigated under
conditions of short-term maximum exercise duration (Drinkwater et a!., 1974;
Raven et a!., 1974a,b). In this; series of studies, a walking test with pro-
gressively increasing grade was used on subjects continuously breathing 50 ppm
CO at either of two ambient temperatures, 25°C or 35°C, with a relative humidity
of 20%. The two populations consisted of young (23+ years) and middle-aged
(48+ years) subjects, both smokers and nonsmokers. During the duration of the
test, COHB levels in nonsmokers increased from 0.6-0.9% to 2.3-2.7%, while levels
in smokers rose from 2.6-3.2% to 4.1-4.5%. Control studies conducted on these
subjects while they breathed filtered air indicated that COHb decreased in both
smokers and nonsmokers in the absence of experimental CO exposures. These stud-
ies did not find any reduction in;maximum aerobic capacity. In fact, the only
statistically significant effect related to CO was a small decrease (<5%) in ab-
solute exercise time consistently observed in the nonsmoking subjects but not in
the smokers (Drinkwater et a!., 1974; Raven et al., 1974a). These observations
extend those found earlier by Ekblom and Huot (1972), who reported a large de-
crease (38%) in work time at 7% COHb.
The revised CO Criteria Document (U. S. EPA, 1979) also noted that oxygen
uptake during short exposures and submaximal work was apparently not affected
even at COHb concentrations of 15-20%. Recently, DeLucia et al. (1983) reported
that COHb levels of 7.3% in nonsmokers and 9.3% in smokers did not induce any
effects involving subjective symptoms, pulmonary function, exercise metabolism,
or blood parameters in healthy subjects. In a controlled experimental study
designed to test for potential syhergism between 03 and CO, 24 male and female
volunteers were evaluated while performing moderate aerobic exercise at 50% of
V0_ . After 100 ppm CO exposure for approximately 1 hr., COHb levels in non-
smokers rose from 1.0-2.1% to 6.0-9.6% and COHb levels in smokers rose from
1.9-5.1% to 6.6-11.8%. DeLucia et al. (1983) attributed the lack of CO effects
as possibly being due to large cardiovascular reserves found in healthy subjects.
It should be noted that healthy young subjects were used in most of the
above studies evaluating the effects of CO on work capacity. A recent study
by Calverley et al. (1981) demonstrated a decrease in walking distance in 15
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patients with severe chronic bronchitis and emphysema at a mean COHb concen-
tration of 12.3%. They evaluated 11 men and 4 women with severe reversible
airway obstruction [FEV-j Q = 0.56 ± 0.2 (SD) liters; FVC = 1.54 ± 0.4 (SD)
liters] who were hypoxic [Pa02 = 5.2 ± 4.9 (SD) mm Hg]. All patients were
medically stable at the time of the study and smokers were asked to stop
smoking for 12 hours before each session. Each subject walked while breathing
air and oxygen before and after exposure to 200 ppm CO in air, which raised
their COHb concentrations from 1.1-5.4% to 9.6-14.9%. There was a significant
reduction in walking distance when the patients breathed either air or oxygen
after exposure to CO. A significant increase in walking distance when the
patients breathed oxygen after exercise was abolished by CO exposure. There
was no relationship to normal smoking habits of the patients. It is therefore
quite possible that individuals with hypoxia due to bronchitis or emphysema
are more susceptible to CO during submaximal work loads typical of everyday
exercise.
Other cardiovascular effects of CO are thought to be of greater concern,
i.e., those affecting individuals suffering from chronic angina. However, the
precise COHb levels at which such cardiovascular effects occur in angina patients
are much less well defined than COHb concentrations associated with various
health effects discussed above. Angina pectoris is a symptom of pressure and
pain in the chest produced during mild exercise or excitement because of in-
sufficient oxygen supply to the heart muscle. Angina patients exposed to low
levels of CO while resting have been reported to exhibit statistically sig-
nificantly reduced time to onset of exercise-induced angina at mean COHb levels
of 2.9 (range, 1.3-3.8 percent) and 4.5 percent (range, 2.8-5.4 percent) and to
experience significantly increased duration of angina attacks during exercise at
a mean COHb level of 4.5 percent (Anderson et al., 1973). Certain questions have
been raised regarding the design and conduct of the study, the small number
(N=10) of subjects studied, and the absence of credible independent confirmation
of its findings. A reevaluation of the Anderson et al. (1973) study, addressing
major points of concern, has been conducted recently (see Appendix A), and found
that the study, in fact, provides reasonably good evidence for the hastening of
angina occurring in angina patients at COHb levels of 2.9 to 4.5 percent. The
Aronow et al. (1973) and Aronow (1981) studies were previously accepted as
demonstrating decreased time to onset of angina in exercising patients at COHb
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levels of 2.0-3.0 percent. However, these Aronow findings are now most appro-
priately interpreted as providing, at most, suggestive evidence for such effects
occurring at COHb levels below 3 percent. More conclusive statements regarding
this issue will not be possible until the results of independent studies attempt-
ing to replicate such findings become available.
Another cardiovascular effect of possible concern is that of increased
blood flow that occurs as a compensatory response to CO exposures (Ayres et
a!., 1969; Ayres et a!., 1970; 1979). This response might result in coronary
damage or other vascular effects due to added stress on the cardiovascular
system. However, inconclusive results have been obtained in community epidemi-
ology studies examining the relationship between CO exposure, mortality from
myocardial infarction (heart attack), sudden death due to arteriosclerotic
heart disease, and cardiorespiratory complaints (Goldsmith and Landau, 1968;
Kurt, et a!., 1978; Kurt, et al. , 1979). Hence, the possibility of such an
F
association remains in question, and further research is also needed in order
to clarify this issue.
The results of one controlled human exposure study reported by Davies and
Smith (1980) are suggestive of possible effects on cardiac function at low to
moderate CO exposure in healthy individuals. In a series of replicated experi-
ments, six matched groups of young human subjects lived in a closed-environment
exposure chamber for 18 days. They were exposed continuously to 0, 15, or 50 ppm
of CO in air during the middle 8 days. Standard 12-lead electrocardiograms were
recorded from each subject during the control, exposure, and recovery periods.
Although statistical evaluation of the data was not reported, unequivocal P-wave
changes were observed during the CO exposure period in 3 of 15 subjects at 15 ppm
CO (2.4% COHb) and 6 of 15 at 50 ppm (7.1% COHb) compared to none of 14 at 0 ppm
(0.5% COHb). The changes were evenly distributed among nonsmoking subjects and
subjects who had stopped smoking 3 days before the start of CO exposure. In addi-
tion, one subject, later identified as having evidence of myocardial ischemia,
showed marked S-T changes at 15 ppm. In a separate pilot study by these inves-
tigators with both smokers and nonsmokers at 75 ppm CO (10.9% COHb in nonsmokers;
14.9% COHb in smokers) significant EKG changes were demonstrated in 7 of 10 sub-
jects. In most cases, the CO-induced changes remained 4 days after exposure
ceased. The authors concluded that P-wave abnormalities demonstrated in this
study were due to interference of normal atria! pacemaking or conducting tissue
activity by CO. In addition, they speculate that CO has a specific toxic effect,
10
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on the myocardium rather than (or in addition to) a generalized decrease in 0-
transport to the tissue.
Most animal studies on the cardiovascular effects of CO have been con-
ducted at exposure concentrations resulting in rather .high (>15-20 percent)
COHb levels. Only two studies are relevant for present discussion. Becker
and Haak (1979) exposed 11 adult mongrel dogs to increasing concentrations of
CO 1 hr. after coronary artery ligation. These sequential exposures produced
step-wise increases in the COHb level from 4.9% to 17.0%. Myocardial ischemia,
as indicated by the amount of S-T segment elevation in epicardial electrocar-
diograms, increased significantly at the lowest COHb level and increased
further with increasing CO exposure. These changes occurred in the absence of
altered heart, rate, blood pressure, left atria! pressure, cardiac output, or
blood flow to ischemic myocardium. Flow to non-ischemic myocardium increased
with CO exposure at a rate approximately double the increase in COHb. They
concluded that low level exposure to CO can significantly augment ischemia in
acute myocardial infarction, apparently through a reduction in oxygen supplied
to the ischemic tissue. They suggested, however, that the hypoxia induced by
CO was more severe than could be accounted for by a reduction in tissue 0?
' delivery alone.
Foster (1981) investigated the arrhythmogenic effects of CO during the
initial minutes of acute myocardial ischemia in 8 mongrel dogs. Since each
dog served as its own control, brief occlusions of the coronary artery were
performed sequentially both before and after the administration of 100 ppm CO
which raised COHb levels to 10.4%. Bipolar epicardial electrograms were
recorded in each experiment from the ischemic and non-ischemic myocardial
zones. An additional 6 dogs were used to confirm the reproducibility of
ischemic conduction slowing during successive occlusions in the absence of CO.
There was no significant increase in ischemic myocardial conduction slowing
after CO. This lack of arrhythmogenic effect of CO was supported by the
absence of increased incidence of spontaneous ventricular tachycardia during
ischemia after CO administration. The author concludes that clinically en-
countered COHb levels may not have sufficient arrhythmogenic effect to be of
significant health importance during the initial minutes of myocardial ischemia.
11
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2. Neurobehavloral Effects
•—' ' i
The 1979 CO Criteria Document; noted that statistically significant effects
on central nervous system (CNS) functions have been most clearly shown to occur
at COHb levels of 5-17 percent. This is indicated by studies which demonstra-
ted decrements in vigilance, visual perception, manual dexterity, learning
ability, and performance of complex sensorimotor tasks such as driving
(Bender et al., 1971; Schutte, 1973; O'Donnell et al., 1971; McFarland et al. ,
1944; McFarland, 1973; Putz et al. , 1976; Salvatore, 1974; Wright et al.,
1973; Rockwell and Weir, 1975; Rjummo and Sarlanis, 1974). An evaluative
review by Laties and Merigan (1979) substantially agreed with these conclu-
sions. Also, as reviewed in the 1979 Criteria Document, some studies (Horvath
et al., 1971; Fodor and Winneke, 1972; Groll-Knapp et al., 1972; Putz et al.,
1976) have reported significant decrements in vigilance performance (defined as
the ability to detect small changes in one's external environment occurring at
unpredictable times) to be associated with COHb levels in the 3.0-7.6% range;
and one study by Beard and Grandstaff (1975) reported that vigilance effects may
occur at levels as low as 1.8 percent COHb. The lowest COHb levels at which
vigilance decrements occur, however, are a matter of considerable dispute in ,
view of numerous other studies not finding such effects at COHb levels below
5.0 percent (Haider et al., 1975* Winneke, 1974; Winneke et al. , 1976;
Christensen et al., 1977; Benignus; and Otto, 1977).
Since the writing of the 1979; Criteria Document, several new studies have
been published which contribute to*the data base of CO-related neurobehavioral
effects. In the following, each of the several neurobehavioral endpoints are
re-evaluated by integrating new findings.
I -
Vigilance—Since the 1979 document was written, several new pieces of research
on CO and vigilance have appeared. In an evaluative review of the CO-vigilance
literature, Benignus et al. (1983) concluded that all of the studies (except
one) cited in the 1979 document had serious credibility flaws due to (a) non-
replication of the work, (b) gross statistical abuse, (c) non-concentration-
related effects or (d) combinations of the above.
The single study from the 1979 document which had no serious flaws was
that of Putz et al. (1976), which demonstrated vigilance decrements at 5%
12
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COHb. Since that time the same group of researchers have replicated these
results on independent subjects (Putz et al., 1979) and have reported their
earlier results in peer-reviewed literature (Putz, 1979). The fact that the
experimental design and details of the tasks were not the same in the two
experiments implies that the effects were robust and thus lends further cre-
dibility to these results. The credibility of these findings would be appre-
ciably increased if an independent group of researchers also were to success-
fully replicate the study.
Three other studies on CO and vigilance have appeared since 1979 (Benignus
et al., 1983, Davies et al., 1981, Roche et al., 1981), all of which used
COHb levels of 5-7%. None of the studies found significant effects on vigi-
lance. It is noteworthy that all of them used vigilance paradigms different
from those of Putz et al (1976). Quite possibly the parameters and conditions
under which vigilance was studied are so sensitive that unless the proper con-
ditions exist, the effects of such COHb levels will not be detected.
It appears safe to conclude that, at least under some conditions, reliable
but small decrements in vigilance occur at about 5% COHb. The fact that 5% and
higher levels of COHb were not observed to produce vigilance decrements in many
studies is probably a reflection of (a) low experimental test sensitivity in the
those cases or (b) the small effects of CO at these levels coupled with what
is probably a rather low-slope concentration-effects curve in the region of
COHb less than 20%. It must be emphasized that these explanations for the many
no-effect studies are conjectural.
*
Sensory and Time Discrimination—Benignus et al. (1983) concluded that no
highly reliable evidence for time discrimination decrements exists. The ele-
gant concentration-related decrements in dark adaption beginning at 5% COHb
demonstrated by McFarland et al. (1944) remain to be replicated. The importance
of replication should not be overlooked since the decrements were (a) dose-related
and (b) showed a decrement at the lowest non-zero COHb level.
Davies et al. (1981) tested visual sensitivity in dark-adapted subjects
who had been exposed continuously to 50 ppm CO for a total of 5 days (COHb of
7% by the end of each day). They reported no effects of CO. Luria and McKay
(1979) reported that untrained observers showed no decrement in a night vision
test, eye movement, or visual evoked potential at COHb levels of 9 percent. The
13
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fact that McFarland et al. (1944) used bolus exposure methods, whereas the
above investigators used continuous low level exposure, is perhaps significant.
McFarland et al. (1944) also used highly trained observers, which had the effect
of reducing variance and thus increasing the sensitivity of their study. Cer-
tainly the McFarland et al. (1944) study cannot be said to have been invalidated
by newer data.
Some support for visual sensitivity decrements due to CO has been provided
by a study measuring the electroretinogram in anesthetized cats (Ingenito and
Durlacher, 1979). When cats were exposed to 1000 ppm CO the electroretinogram
was decreased in amplitude by 30 minutes after the start of exposure, at which
time the mean COHb was 7.5%. Further decreases were concentration-related.
Complex Sensorimotor Performance and Driving—The conclusion of the 1979
document, that driving-like tasks are impaired at COHb levels of 5% or greater,
has since been substantially strengthened. Three articles have been published
(Putz et al., 1976, 1979; Putz, 1979), using variations of the same task and
experimental design but in two independent groups of subjects. In all cases, it
was reported that 5% COHb produced decrements in compensatory tracking, a hand-
eye-coordination task. In all cases, however, the decrements occurred only during
high task difficulty. Other tasks such as reciprocal tapping and digit manipula-
tion were not affected by COHb levels of up to 5% (Mihevic et al. , 1982).
Sleep and Activity—Although there has been one new publication in this area
(Groll-Knapp et al., 1982), the conclusions remain the same. Marginal increases
in deep sleep and concomitant decreases in rapid-eye-movement sleep were
reported at 8% COHb due to exposure to 100 ppm CO for 8 hrs. during sleep. As
before, the changes did not reach statistical significance when appropriate
corrections were made (Benignus and Muller, 1982).
Central Nervous System Electrical Activity—No significant changes have occurred
in this area of research since 1979. Marginal, nonsignificant effects have
been reported by Benignus et al. (1983) in the electroencephalogram alpha
frequency band and by Groll-Knapp et al. (1982) on evoked potentials. Both
groups of investigators produced COHb levels of 5-6 percent.
14
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3. Effects of CO Exposure on Fibrinolysis
An area of growing interest, which was not extensively discussed in the
1979 Criteria Document, concerns possible effects of CO on fibrinolysis. The
fibrinolytic system is an integral part of homeostatic mechanisms and it has
been suggested that derangement of that system may contribute to the patho-
genesis of thrombosis. The plasminogen activator may be released from the
blood vessel wall by a variety of stimuli, including anoxia, electric shock,
and either local or systemic administration of vasoactive substances such as
epinephrine, acetylcholine, serotonin, or histamine. The finding that anoxia
can release plasminogen activator has suggested to investigators that the
presence of COHb with its associated anoxia could also be associated with
increased plasminogen activator.
Resting fibrinolytic activity is often low and its measurement may yield
conflicting results that do not readily permit intra-individual comparisons.
The relationship of tissue activator to vascular activator suggests that they
are components of two separate fibrinolytic mechanisms: (1) the vascular acti-
vator being part of a humoral system whose main role is maintenance of vascular
patency and (2) the basic activator concerned with tissue repair and wound
healing.
Animal Studies—Fibrinolytic activity was studied in 12 rabbits (6 control
rabbits) continuously exposed for 8 weeks to an ambient concentration of 50 ppm
CO (Kalmaz et al., 1977). The COHb levels reached 30.9% by the end of the
exposure period. Significant increases in whole blood clotting time, serum
fibrin/fibrinogen degradation products•, and acceleration of whole blood clot
lysis occurred. Euglobulin lysis time was significantly accelerated by the end
of the first week of exposure. Although these fibrinolytic activity changes are
of interest, their relationship to CO exposure is far from clear.
In another study, Kalmaz et al. (1978) continuously exposed rabbits to 50
ppm for 8 weeks or intermittently to 300 ppm for 4 weeks. Acceleration of the
whole blood clot lysis and euglobulin lysis times was observed in all CO-exposed
groups. Microscopic examination of large vessels showed endothelial damage —
a possible source for a plasminogen activator release. A more recent study by
Kalmaz et al. (1980) involved exposing rabbits to ambient air, 50 ppm CO for
15
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24 hours/day continuously for 8 weeks, and 300 ppm CO for 8 hours/day, 5 days/
week for 4 weeks. They found a consistent change in circulating platelet
quantity for all CO-exposed rabbits. However, their conclusion that prolonged
exposure to low levels of CO may influence changes in circulating platelet counts
and/or congenital platelet function disorders in man has not been confirmed.
In a recent iji vitro study by Hartiala et al . (1982) a 5-minute exposure to
100% CO was found to have neither an effect on the decrease in prostacyclin
(PGIg) production nor a direct effect on ADP-induced aggregability of human
platelet-rich plasma. This led the authors to conclude that CO is not respon-
sible for the temporary increase :in platelet aggregability after cigarette
smoking.
Human Studies — Workers chronically exposed to high levels of carbon monoxide
(approximately 100 ppm with occasional levels of 200-400 ppm) were studied by
El-Attar and Sairo (1968). They found an accelerated clot lysis time suggestive
of an enhancement of blood fibrinolytic activity. Levels of COHb present were
only crudely determined and were not related to any specific individual. CO
poisoning of 21 workers was suggested by the presence of subjective symptoms,
Headache, blurred vision, etc. Twenty-eight workers, presumably some of the
first group of 21, were restudied after a one day exposure to ambient CO (levels
not given). This group also exhibited accelerated lysis times but to a lesser
degree. In 15 control subjects no fibrinolytic activity could be detected.
This study, although suggestive, jwas too poorly controlled to be of real
value. A similar suggestive study was made by Alexieva et al . (1975) on 100
workers in a coke-chemical plant, i Some increase in fibrinogen was observed in
these chronically exposed individuals. Panchenko et al. (1977) have also
suggested that a relationship between blood coagulation and CO existed. The
data presented are far from conclusive.
The possibility that exposure to other substances in addition to CO
resulted in alterations of fibrinolytic activity was evaluated by Janzon and
Nilsson (1975). Smokers and nonsmbkers were studied by techniques superior to
those used by the above investigators. Smokers and nonsmokers had the same
fibrinolytic activity when smokers were studied after 12 hours abstention from
smoking. Smoking 6 cigarettes during 3 hours was associated with an increased
16
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fibrinolytic activity in blood. They believed that this increase was probably
due to the combined effects of nicotine and carbon monoxide. Mansouri and
Perry (1982) studied the alteration of platelet aggregation by cigarette smoke
and carbon monoxide. Inhalation by healthy adults of CO sufficient to raise
the COHb level to between 4.5% and 11% was found to be responsible for inhi-
bition of platelet aggregation, which returned to normal after five hours.
However, there was no consistent correlation reported between COHb levels and
alterations in platelet aggregation.
Brinkhouse (1977) exposed 23 men (15 nonsmokers) for 4 hours to either 0,
50, or 100 ppm CO. COHb levels on the days of carbon monoxide exposure reached
2.17% (50 ppm) and 4.15% (100 ppm). Platelet count, prothrombin time, partial
thromboplastin time, thrombin time, fibrin split products, factor VIII, and pla-
telet aggregation were determined before and after the exposure. Coagulation
parameters were not significantly affected by the CO exposures. A review by
Haft (1979) discusses the role of platelets in the etiology and natural' history
of coronary artery disease. It is clear thaf smoking increases the activity of
platelets and cigarette smokers have shortened platelet survival time. Endo-
thelial injury may be facilitated by serum CO, by levels of circulating cate-
cholamines, and other factors.
In conclusion, the effects on fibrinolytic activity of exposure to carbon
monoxide are far from clear. The studies on acute exposure to CO do not spe-
cifically implicate this pollutant in the observed alterations in fibrinolytic
activity, and the studies on chronic exposure are too poorly controlled to
confirm any definite effects on the blood coagulation system.
4. Suggestive Evidence for Perinatal CO Effects
The Criteria Document (U.S. EPA, 1979) provides discussion of results
from certain animal toxicology studies which point toward the possibility that
CO exerts perinatal effects on the fetus or newborn. With long-term exposures
of pregnant animals to CO, fetal COHb levels have been shown to be higher than
maternal COHb levels, and fetal elimination of CO was slower than maternal CO
elimination. The ability of CO to decrease the oxygen transport capacity of
maternal and fetal hemoglobin may result in interference in fetal tissue
oxygenation during important developmental stages. Whereas normal adults have
17
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reserve capacity and compensatory responses which enable them to handle moder-
ately high COHb levels without irreversible consequences, the fetus may under
normal situations be operating close to critical levels in terms of tissue
oxygen supply. Thus, even moderate CO exposures may have a deleterious effect
on fetal development (Longo, 1977) but this, too, remains to be demonstrated
along with pertinent dose-response relationships. In several animal studies
in which pregnant females were exposed to CO, deleterious effects were gen-
erally reported in the offspring (e.g., reduced birthweight, increased newborn
mortality, and lower behavioral activity levels) even when no effects on the
mothers were detected. In human studies, similar effects have been reported
in children of mothers who smoked cigarettes during pregnancy, suggesting that
expectant mothers and their unborn children may also represent population
groups at special risk for CO effects, but this remains to be more clearly
defined along with any pertinent dose-response relationships.
i
Sudden infant death syndrome'(SIDS) is characterized by the sudden,
normally unexplained death of an infant. Research has suggested numerous
possible etiological factors (e.g.^ disease, temperature, maternal smoking,
and pollutant levels), but numerous questions remain regarding which are the
most significant factors involved. [Seasonal incidence of SIDS has been studied
in several epidemiological studies (Peterson, 1966; Bergman et al. , 1972;
Bonser et al., 1978). A pattern which appears to be consistent across countries
in the northern hemisphere is increasing incidence in October, peaking in
December and January, remaining high until May, and then declining sharply in
June and remaining low until October.
CO has been hypothesized to be associated with seasonal variations in
SIDS incidence rates, based on certain epidemiologic data. Hoppenbrouwers et
al. (1981) have reported that increased seasonal incidence of SIDS in Los
Angeles County during winter may be at least partially explained by higher
levels of CO, sulfur dioxide (SO-), nitrogen dioxide (N02) and hydrocarbons
(HC). They suggest that higher ambient levels of these pollutants may be
implicated in chronic hypoxia, which often precedes death from SIDS. Related
to this hypothesis, they found that SIDS cases in Los Angeles were correlated
to daily mean levels of the above pollutants and peaks in these pollutant
levels preceded seasonal increases in SIDS by seven weeks. The authors further
report that the lifespans of infants dying from SIDS were longer (1) if born
in low rather than high pollution areas and (2) if born in months of low versus
high pollution.
18
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Finally, a direct proportionality was reported between exposure to pollution
for infants from conception to two months of age and bimonthly rate of SIDS,
In an editorial letter assessing the results of the Hoppenbrouwers et al.
study, Goldstein (1982) commented on the presence of indoor sources of CO, NOp
and lead. She further pointed out that during colder months infants spend
most of their time indoors where concentrations of these pollutants can far
exceed ambient levels. Thus, she suggests that the relationship between SIDS
and ambient pollution levels may be only coincidental and the evidence for it
is at best suggestive and in need of further confirmation before any causal
relationships are inferred.
Maternal smoking has been related to SIDS in several studies (Bergman and
Wiesner, 1976; Lewak et al., 1979; Peterson, 1981). Because CO is only one of
numerous pollutants found in cigarette smoke, however, it is difficult to
infer a causal relationship between CO and SIDS. Other factors associated
with SIDS include passive smoking, younger maternal age, short intervals
between pregnancies, gestational age of less than 40 weeks, birth weight of
less than 3000 g., lower socioeconomic status, and male sex. Thus, the number
of potentially confounding factors makes finding an association between CO and
SIDS extremely difficult.
POPULATIONS AT RISK
The 1979 Criteria Document directed attention toward identification of
sensitive population groups at special risk for CO-induced health effects.
One key concept in defining special risk groups for CO effects is the idea
that any preexisting or concomitant physiological or pathological condition
which interferes or interacts with oxygen absorption into blood or its transport
to and perfusion of body tissues can logically be expected to exacerbate
CO-induced health effects associated with the hypoxic effects of CO. Thus,
certain large segments of the general population can be reasonably hypothe-
sized as likely to be at greater risk for experiencing CO-induced health effects
than healthy, non-smoking adults.
These probable risk groups include: (1) fetuses and young infants; (2) the
elderly, especially those with reduced cardiopulmonary functions attributable to
a variety of factors associated with typical aging processes; (3) other, younger
19
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individuals with overt, severe cardiac damage or acutely severe respiratory
diseases, e.g., pneumonia; (4) individuals with chronic bronchitis or emphysema;
(5) individuals with symptoms (e.g.; angina) indicative of chronic cardiovascular
disease; (6) individuals with hematological diseases, (e.g., anemia) that affect
oxygen-carrying capacity or transport in the blood; and (7) persons with geneti-
cally unusual hemoglobin forms associated with decreased oxygen capacity. In
addition to the above, one might reasonably expect that individuals under the
influence of certain drugs, used for recreational or medicinal purposes, may be
at greater risk for CO-induced effects due to interactive effects between CO and
certain pharmacological agents. Lastly, under high altitude conditions (where
reduced levels of atmospheric oxygen exist), increased vulnerability to CO health
effects of both the above sensitive!population groups and otherwise, non-sensitive
healthy individuals might be expected.
As noted in the 1979 Criteria Document, relatively little concrete
experimental or observational evidence currently exists by which most groups
(or conditions) listed above have been clearly demonstrated to be associated
I
with increased risk for CO-induced health effects. Nor have clear-cut
quantitative lowest-observed-effect levels or dose-response relationships been
delineated for the occurrence of ct) effects among the above "at risk" groups
! i
or in conjunction with special interacting circumstances (i.e., drug usage or
high altitude residence) that might exacerbate CO effects. Only very limited
discussion, therefore, can be provided here regarding CO risk factors and
sensitive groups likely at special risk for CO .effects.
In regard to the first group, fetuses and young infants, certain evidence
was alluded to earlier from animaljtoxicology studies indicating that higher
levels of COHb and increased CO excretion time occur among fetuses in compari-
son to their mothers exposed to CO; and some deficits in postnatal growth and
development were noted in the offspring of dams exposed to CO during pregnancy.
Also, analogous perinatal effects were noted in human infants born to mothers
who smoked during pregnancy, and associations between CO exposure and SIDS have
been hypothesized. However, insufficient evidence exists at this time by which
\
to estimate CO exposure levels at which any CO effects on human fetuses or new-
born infants may occur or whether the latter types of effects seen in smoking
mothers are due specifically to CO versus other components of tobacco smoke
either singly or in combination.
20
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Little specific evidence directly demonstrates the increased vulnera-
bility of the elderly for CO health effects in precise quantitative terms.
Given the increased vulnerability of the aged to many different kinds of
stress, including thermal stress (hot or cold) which taxes decreased reserve
capacities to maintain adequate cardiovascular delivery of oxygen to body
tissues, it must be expected that CO exposure would render the elderly more
vulnerable to the effects of other types of cardiovascular stresses. Also,
conversely, it is reasonable to hypothesize that interactive effects involving
other stress factors might lead to exacerbation of CO-induced health effects
or their occurrence at lower external CO exposure levels than in younger>
healthy adults. Similarly, younger individuals with overt, severe cardiac
damage or insufficiency or severe acute respiratory diseases, e.g., pneumonia,
can be expected to be more vulnerable to CO (i.e., either CO exacerbation of
other disease effects or, conversely, increased susceptibility to CO health
effects) due to reduced reserve capacities to cope with stress generally or
increased sensitivity of already compromised organs or tissues, e.g., heart
muscle, to the hypoxia induced by CO.
Turning to individuals with chronic bronchitis and emphysema, again,
reduced reserve capacities for dealing with cardiovascular stresses and al-
ready reduced oxygenation of blood should exacerbate or hasten the onset of
health effects associated with CO-induced hypoxia. Analogously, angina
patients or others with obstructed coronary arteries but not manifesting overt
symptoms such as angina, should be at greater risk for CO health effects. Both
the Anderson et al. (1973) and several Aronow publications on angina patients
reported findings previously accepted as demonstrating the increased vulnera-
bility of angina patients to CO in terms of hastening of the onset of exercise-
induced angina. These papers, furthermore, appeared to confidently establish
2-3% blood COHb as the range of COHb values associated with the onset of statis-
tically significant effects indicative of CO exacerbation of angina and, prob-
ably, associated hypoxic effects on cardiac muscle. It is now clear that the
Anderson findings (as of yet not independently confirmed) can be appropriately
interpreted as providing reasonably good evidence for exacerbation of angina
symptoms occurring at approximately 2.9 to 4.5 percent COHb; and the possibility
of such effects occurring at lower COHb levels cannot be ruled out at this time.
21
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In regard to individuals with|anemia being at special risk for CO health
effects, the 1979 Criteria Document noted that CO poisoning is similar to
anemia, wherein the oxygen capacity of the blood is decreased because the
affinity of hemoglobin (Hb) for binding oxygen is reduced. The 02 dissociation
curve for anemics is similar to that for normals except that it is shifted to
the right. However, when curves from individuals with 50% reductions in Hb con-
tent are compared with dissociation curves for blood with 50% COHb content, there
are striking differences. Consequently, care must be taken to avoid overly
simplistic extrapolations regarding the likely impact of particular CO
exposures on anemia patients due to additional (CO-induced) reductions of 02
carrying capacity beyond the reductions already evident in their blood. The
specific CO exposure levels and associated blood COHb concentrations at which
anemia patients may be at increased risk for specific CO health effects remain
to be clearly delineated, but little doubt exists regarding the likelihood
that the effective CO exposure (and COHb) levels are distinctly lower than for
healthy, non-anemic individuals.
Another logically-hypothesized "at risk" group for CO effects are individuals
with unusual hemoglobin types that;result in chronic elevations of COHb blood
levels even in the absence of external CO exposure. Normal adult hemoglobin
has a relative affinity or equilibrium constant (M) for CO of about 200 for
most animal species, but has been -reported to be as high as 240 to 250 in
humans (Roughton, 1970). There are1 approximately 350 human hemoglobin variants,
including those found in the fetus, sickle cell anemics, and other individuals
with hemoglobinopathy (hemoglobin disorders). Approximately one fourth of the
hemoglobin variants now known are considered unstable, i.e., they denature and
precipitate when red blood cells or hemolyzates are exposed to heat, red
oxdyes, or isopropanol (Bunn et al.,, 1977). One of these variants, hemoglobin
Zurich (HbZ) has been found to have an affinity for CO which is approximately
65 times that of normal hemoglobin (Zinkham et al., 1980; Giacometti et al.,
1980; Zinkham et al., 1983). This !results in chronic elevation of endogenous
COHb levels ranging from 3.9 to 6.7% in nonsmoking HbZ individuals.
As for possible drug-induced enhancement of CO effects, whereas there
exists little specific data directly supporting the idea, it is logical to
suspect that individuals who use certain drugs would be at increased risk for
experiencing health effects associated with CO exposure. For example, drugs
22
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with primary or secondary CNS depressant effects should be expected to exacer-
bate neurobehavioral effects of CO; and drugs which have primary or secondary
cardiac stimulant effects might worsen CO-related cardiac effects. Any vaso-
constrictive drugs would be expected to reduce 0« delivery to various organs,
thus also exacerbating CO effects on exercise, cardiac or neurobehavioral
function. Further speculations about drug-CO interactions are possible, but
it should be emphasized that these are predictions based on theoretical grounds
that rely heavily on our current understanding of hypoxia as the likely
main mechanism underlying the induction of CO-induced health effects. Unfor-
tunately, few data currently exist by which to judge the likely validity of
such speculations.
Hypothesized enhancement or exacerbation of CO health effects under high
altitude conditions, similarly, rests heavily on hypoxia as the key mechan-
ism of CO toxicity. The interactive effects of high altitude hypoxia and CO
exposure, however, appear to be more complex than might be simplistically
expected (Collier and Goldsmith, 1983). For example, the 1979 Criteria Document
notes that adaptation to high altitudes occurs and alludes to the fact that,
analogously, adaptation to CO may alter the position of the 0? dissociation
curve as a function of extensive prior CO exposure. Thus, individuals living
in high altitude situations with frequently elevated ambient air CO levels may
adapt to both the high altitude and CO-induced hypoxia, whereas other indivi-
duals newly entering high altitude and elevated ambient CO conditions might
experience CO effects at concentrations below those effective at lower alti-
tudes.
SUMMARY AND CONCLUSIONS
As was stated at the outset, the main purpose of the present addendum is
to reevaluate the scientific data base concerning health effects associated
with exposure to CO at ambient or near-ambient exposure levels. The re-
evaluation includes both (1) summarization of information contained in the
revised EPA Air Quality Criteria Document for CO (U.S. EPA, 1979) and (2) new
information and studies that have become available beyond that reviewed in
the 1979 document. The most important points of information reviewed and key
conclusions derived from this evaluation of the CO health effects data base are
summarized below.
23
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Mechanisms of Action—The binding of CO to hemoglobin, producing COHb and de-
creasing the oxygen-carrying capacity of blood, appears to be the main mechanism
of action underlying the induction of toxic effects of low-level CO exposures.
The precise mechanisms by which toxic effects are induced via COHb formation
are not yet fully understood, but likely include the induction of a hypoxic state
in many tissues of diverse organ systems. Alternative mechanisms of CO-induced
toxicity (besides COHb) have been hypothesized, but none have yet been demon-
strated to operate at relatively low (near-ambient) CO exposure levels. Blood
COHb levels, then, are currently accepted as representing a useful physiological
marker by which to estimate internal CO burdens due to the combined contribu-
tion of (1) endogenously derived CO and (2) exogenously derived CO resulting
from exposure to external sources 'of CO. COHb levels likely to result from
particular patterns (concentrations, durations, etc.) of external CO exposure
can be reasonably well estimated from equations developed by Coburn.
CO Exposure Levels—Evaluation of human CO exposure situations indicates that
occupational exposures in some workplace situations can regularly exceed 100
ppm CO, often leading to COHb levels of 10 percent or more. In contrast, such
high exposure levels are much less commonly encountered by the non-occupationally
exposed general public. More frequently, exposures to less than 25-50 ppm CO
for any extended period of time occur among the general population and, at the
low exercise levels usually engaged in under such circumstances, resulting COHb
levels most typically remain below 2-3 percent among non-smokers. Those levels
can be compared to the physiologic norm for non-smokers, which is estimated to
be in the range of 0.3 to 0.7 percent COHb. Baseline COHb concentrations in
smokers, however, often greatly exceed 3 percent, reflecting absorption of CO
from inhaled smoke.
Health Effects of Low Level CO Exposures—Four types of health effects reported
or hypothesized to be associated with CO exposures (especially those producing
COHb levels below 10 percent) were evaluated: (1) cardiovascular effects; (2)
neurobehavioral effects; (3) fibrinolysis effects; and (4) perinatal effects.
In regard to cardiovascular effects, decreased oxygen uptake capacity and
resultant decreased work capacity under maximal exercise conditions have been
clearly shown to occur in healthy young adults starting at 5.0 percent COHb;
24
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and several studies observed small decreases in work capacity at COHb levels as
low as 2.3 to 4.3%. These cardiovascular effects may have health implications
for the general population in terms of potential curtailment of certain physi-
cally demanding occupational or recreational activities under circumstances of
sufficiently high CO exposure. However, of greater concern at more typical
ambient CO exposure levels are certain cardiovascular effects (i.e., aggravation
of angina symptoms during exercise) likely to occur in a smaller, but sizeable,
segment of the general population. This group, chronic angina patients, is pre-
sently viewed as the most sensitive risk group for CO exposure effects, based on
evidence for aggravation of angina occurring in patients at COHb levels of 2.9
to 4.5 percent COHb. Such aggravation of angina is thought to represent an
adverse health effect for several reasons articulated in the 1980 proposal pre-
amble (45 FR 55066), and the Clean Air Scientific Advisory Committee (CASAC)
concurred with EPA's judgment on this matter (see Appendix B). Dose-response
relationships for cardiovascular effects in coronary artery disease patients
remain to be more conclusively defined, and the possibility cannot be ruled out
at this time that such effects may occur at levels below 2.9 percent COHb (as
hinted at by the results of the now-questioned Aronow studies).
No reliable evidence demonstrating decrements in neurobehavioral function
in healthy young adults has been reported at COHb levels below 5%. Much of
the research at 5% COHb did not show any effect even when behaviors similar
to those affected in other studies were involved. However, if any CO effects
on neurobehavioral functions in fact occur below 5% COHb, then none of the sig-
nificant-effects studies would have found such decrements, because none of them
used COHb levels below 5%. Other workers who failed to find CO decrements at 5%
or higher COHb levels may have employed tests not sufficiently sensitive to
reliably detect small effects of CO. From the empirical evidence, then, it can
be said that the COHb levels in the 5% range do produce decrements in neuro-
behavioral function. However, it cannot be said confidently that COHb levels
lower than 5% would be without effect. One important point made in the 1979
document should be reiterated here. Only young, healthy adults have been stu-
died using demonstrably sensitive tests and COHb levels of 5% or greater. The
question of groups at special risk for CNS effects, therefore, has not been
explored. Of special note are those individuals who are taking drugs which have
primary or secondary depressant effects which would be expected to exacerbate
CO-related neurobehavioral decrements. Other groups at possibly increased risk
25
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for CO-induced neurobehavioral effects are the aged and ill but these groups,
also, have not been evaluated for such risk.
In contrast to the data available which demonstrates associations between
cardiovascular and neurobehavioral effects and relatively low-level CO expo-
sures, much less clear evidence exists that other types of health effects are
associated with low-level CO exposures. For example, only relatively weak
evidence points towards possible CO effects on fibrinolytic activity and, then,
generally only at rather high CO exposure levels. Similarly, whereas certain
data also suggest that perinatal effects (e.g. reduced birth weight, slowed
postnatal development, Sudden Infant Death Syndrome) are associated with CO
exposure, insufficient evidence presently exists by which to either confirm
such associations qualitatively or to establish any pertinent exposure-effect
relationships.
Population Groups at Risk for Ambient CO Exposure Effects—Angina patients or
others with obstructed coronary arteries, but not yet manifesting overt symp-
tomatology of coronary artery disease, appear to be best established as a
sensitive group within the general population that is at increased risk for
experiencing health effects (i.e. exacerbation of cardiovascular symptoms) of
concern at ambient or near-ambient'CO exposure levels. Several other probable
risk groups were identified, i.e.: (1) fetuses and young infants; (2) the
elderly (especially those with compromised cardiopulmonary functions); (3)
younger individuals with severe cardiac or acutely severe respiratory diseases;
(4) individuals with chronic bronchitis or emphysema; (5) individuals with
hematological diseases (e.g. anemia) that affect oxygen carrying capacity or
transport in the blood; (6) individuals with genetically unusual forms of hemo-
globin associated with reduced oxygen carrying capacity; and (7) individuals
using medicinal or recreational drugs having CNS depressant properties. However,
little empirical evidence currently is available by which to specify particular
COHb levels at which such individuals are likely to experience specific health
effects associated with ambient or near-ambient CO exposures. Nor does unambi-
guous evidence yet exist which clearly establishes that healthy non-sensitive
individuals or those in the above probable risk categories are affected at lower
CO exposure levels under high altitude conditions than CO exposure concentrations
effective at lower altitudes.
26
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APPENDIX A
EPA HEALTH EFFECTS RESEARCH LABORATORY
REEVALUATION OF ANDERSON ET AL. (1973) STUDY
A-l
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XDW%
QSp
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
HEALTH ERFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK
NORTH CAROLINA 27711
DATE: February 1, 1984
SUBJECT: Evaluation of Anderson et al.. (1973) Study of Carbon Monoxide (CO)
Effects on Angina Patients.
FROM: John J. O'Neil, Ph.D., Chief
Clinical Research Branch, ITD/HERL
TO: Lester D. Grant, Ph.D.
Director, ECAO (MD-52)
THRU: F. Gordon Hueter, Ph.D., Director f
Health Effects Research Laboratory, RTP (MD-58)
This memo replaces one dated August 19, 1983. Changes have been
made to clarify seme points. The discussion of carboxyhemoglobin (COHb)
analysis (section la) and Table 1 have been notably expanded. An analysis
of possible reasons for the differences between the measured values of
COHbreported by Anderson et al. and estimates of COHb calculated using
the Coburn-Forster Kane Equation are also offered. The conclusions at
the memo remain the same. i
Thank you for the opportunity to carment on the paper by Einar Anderson
and his co-workers which is entitled "Effect of Low-Level Carbon Monoxide
Exposure on Onset and Duration of Angina Pectoris." I have re-read it,
have discussed it with several colleagues, especially Dr. Vernon Benignus,
and would offer the following observations by way of review.
This is a good paper. The work appears to be carefully done, the
data seem reasonable, and the paper is well written. Critical review
reveals some flaws in the design and conduct of the research, but this is
typical of most scientific work and, therefore, significance of these
conroents may be interpreted differently by different readers.
DESIGN !
1) ST segment depression reported in this paper is not useful
and does not constitute any physiological support to the observations
regarding the onset and duration of angina. The authors recognize this
shortcoming. The important data in the paper are the measurement of time
to onset of pain and the measurement of the duration of pain.
2) The paper would have been considerably strengthened by more
careful selection of the subject population. For example, 5 subjects
were smokers and 5 were non-smokers and one subject was taking digitalis.
In my opinion, the study would have been strengthened considerably had
the subject population been more homogeneous.
A-2
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3) The number of subjects (n) is very small. Oily ten subjects
were studied and of these there are three for whom there are missing data
points. I have been told anticdotally that this study was intended as
a pilot study. It is unfortunate that it was not possible to design
and complete the proper follow-up study. Given the situation, this is
valuable data to have published and should be used to develop our under-
standing of the response of angina patients to carbon monoxide (CO).
METHODS AND RESULTS
1) It is disconcerting that the measured COHb levels appear to be lower
than we would predict on the basis of our knowledge of CO-COHb kinetics. Why
is this measured value lower than we would expect?
a) Measurement of GOHb. The measurements were done in
triplicate using the Buchwald analysis. As best as I can determine
there is no evidence which causes me to doubt this analysis.
However, this technique is less precise than other methods that are
used today. That is, more scatter occurs in the data for repeated
measurements at a given concentration. At low COHb concentrations
this scatter might have a disproportionately large effect which, in
.turn, might lead to an over-estimation of the "zero" COHb sample analy-
sis. If this occurred, estimations of COHb concentration calculated
using the Coburn-Forster-Kane equation would be over-estimates because
this initial measurement is also used as the initial concentration in the
Coburn-Forster-Kane equation.
b) It is also possible that the exposure mask used in this study
was loose fitting and leaked. This would reduce the exposure level
and the final COHb levels.
c) Though not reported in the paper, the subjects were apparently
allowed to rest ad libitum during the study. This amounted to approxi-
mately 10-15 minutes out of the hour. -This "rest" period would have
reduced the exposure time and the final COHb levels.
Using a minute ventilation of 5 1/min, a blood volume of 5500 ml
and a hemoglobin concentration of 15 g/lOOml, Dr. Benignus calculated a
predicted COHb with the Cobum-Forster-Kane Equation. These data are
presented in Table 1. He concludes that there is an apparent and unex-
plained inconsistency between the predicted value for COHb and that
actually measured.
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Table 1. Concentrations of Carboxyhemoglobin Reported by Anderson
et al. and Estimated Using the Coburn-Forster-Kane Equation
Exposure Concentration (ppm)
Initial measurement (% COHb)
Final measurement (% COHb)
Coburn-Forster-Kane Calculated Value
(% COHb) 1
Difference (% COHb)
50
1.4
2.9
3.3
+0.4
100
1.6
4.5
5.8
+1.3
d) The Cobum-Forster-Kane equation was derived to deal with endo-
genously produced CO. Its application to situations involving exogenous
CO, though widely done, may be inappropriate.
e) There exist, therefore, at least three possible explanations
for the differences in the reported COHb measurements and the estimates
derived using the Coburn-Forster-Kane equation.
1) The final measurement of COHb in the study by Anderson
et al. underestimates the true COHb concentration.
2) The initial measurement of COHb in the study by Anderson
et al. overestimates the true COHb concentration and when
"this number is used in the Cobum-Forster-Kane equation, it
results in an overestimation of the final COHb concentration.
3) The Coburn-Forster-Kane equation over-estimates COHb
concentrations in the range of interest for this study.
2) There is considerable variability in the data reported. The following
table gives the mean and range of the time to onset of pain for each day of
the study.
Table 2. Time to Onset of Pain
Mean (Range)
Mon (Air)
Air (Control)
50 ppm
100 ppm
Friday (Air)
294 (215-480)
325 (220-435)
264.5 (65-390)
263.5 (85-425)
300 (185-485)
A-4
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The exposures on Monday and Friday were included to demonstrate the com-
parison of two air exposures separatead by the study itself. The air
control and the exposures to 50 or 100 ppm CO were randomized on Tuesday
Vfednesday> and Thursday. The data for Monday and Friday are both considerably
closer to the data for 50 and 100 ppm CO exposure than to that for the air
control. This is, I believe, associated with the small number of subjects
used in the study. Dr. Benignus and his colleagues analyzed the data for
the different air days and did not show any significant differences
between these days.
STATISTICAL ANALYSIS
Dr. Benignus has developed an analysis of the paper by Anderson et
al. and I have excerpted part of his critique here.
Critique of the Study by Anderson et al. (1973)
Vernon A. Benignus
The statistical tests used in the study were anticonserv-
ative (Benignus and Muller, 1982) and thus would have tended
toward showing a significant effect even if none were present
in the population.
The data of Anderson et al. were reanalized using one
multivariate analyses of variance for each of the two measures
(time to onset of angina and duration of angina). Multivariate
tests were used because the data for 0, 50 and 100 ppm exposure
were collected from the scjme subjects. Since two separate
significance tests were to be run (one for time to onset and
one for duration) Bonferroni corrections were used to keep
experimentwise a = .05. Each test would then be evaluated
at a/2 = .025.
Table A. Overall Test Results
Variable
Time to Onset
Duration
F
7.72
3.10
df
2,8
2,7
P<
.014
.11
Table A shows the results of the overall tests. This table
agrees with Anderson et al. that time to onset of angina
would have been significantly affected by CO exposure but
does not agree with Anderson et al. that duration of Angina
is affected by CO exposure. Stepdown tests of the time to
onset data revealed that the 50 ppm exposure showed a CO
A-5
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effect, p<.017 and the 100 ppm exposure showed a CD
effect p<.002.
Table B. Means of Time to Onset Data
CO Level Mean time to onset of Angina
0 ppm
50 ppm
100 ppm
310
265
264
Table B shows the mean times to onset for the 0, 50, and
100 ppm exposure days. While both the 50 and 100 ppm
exposures produced shorter ^.imes to onset, they did not
differ among themselves. (The fact that the p value for
the 100 ppm day was lower than for the 50 ppm day was due
to the fact that the data on -the 100 ppm day were more
closely correlated with the 0 ppm values. Thus Table B
shows a puzzling non-dose-related finding.)
Inspection of Table 1 in Anderson et al. (1973),
reveals that all COHb values were related to the exposure
level so that the non-dose-related findings in time to
onset remain unexplained. To be sure, the variability
was high on all days and with the small number of subjects,
such non dose related findings can occur even if the effects
are dose related in the population. This is especially
true since the COHb values were both close to the lower
limits for CO effects and the general dose-effects curve
can be plausibly argued to have a rather low slope.
The tests of significance employed in this critique are
quite conservative. Thus, the fact that significant results
would have been reported even if appropriate and conservative
tests had been done, lends (credibility to the study. On the
other hand, the non dose related findings are mildly disturbing.
Considering (1) the small number of subjects, (2) the high
variability of the data, (3) 'the fact that both doses were
near the no-effects level and (4) the low p values on the
significance tests, the data are strongly suggestive of an
effect but are sorely in need of replication and extension.
More subjects should be run and a wider dose range
should be studied to be able adequately to quantify a
dose-effects curve.
Conclusions
Several aspects of the study were of above average quality. The study
was conducted in a double-blind fashion; very commendable, especially by
comparison to the extant literature. Only a small number of variables
A-6
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were studied, thus minimizing the chances of finding sane spurious variable
which accidentally covaried with CD exposure; another positive quality. v
When compared to an ideal study the study by Anderson et al. has
several flaws in its design and execution and the results have inconsistencies.
However, when compared to the extant literature, the design and execution
of this study is commendable. None of the inconsistencies are of a major
nature and several plausible explanations exist for them. The results of
this study suggest that angina is exacerbated by small increases in COHb.
This study is sorely in need of replication and extension. More subjects
should be run and a wider dose range should be studied to be able to adequately
quantify the dose response relationships. Even if no inconsistencies were
present in this study, it would be rash to rely entirely upon one study
with 10 subjects. It would be equally irresponsible to disregard these
findings. The greatest imprudence would be to fail to do the follow-up
studies suggested by these results.
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APPENDIX B
CASAC LETTER (AUGUST 31, 1982) TO
EPA ADMINISTRATOR CONCERNING ISSUES
INVOLVED IN SETTING OF NAAQS FOR CO
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
\August 31, 1982
OFFICE OF
THE ADMINISTRATOR
Mrs. Anne M. Gorsuch \
Administrator
U.S. Environmental Protection Agency
Washington, D.C. 20460
Dear Mrs. Gorsuch: !
The Clean Air Scientific Advisory Committee (CASAC) met
on July 6 to provide its advice on several issues related to
the ambient air quality standard for carbon monoxide. The
Committee had previously ajavised the Administrator of the
scientific adequacy of the criteria document and staff paper
in a closure memorandum dated October 9, 1979.
At its most recent meeting the Committee provided advice
to the Agency on .four issues. These included: 1) setting a
revised eight-hour carbon monoxide standard that includes five
allowable exceedances; 2) the role and significance of the 1981
study published by Dr. Wilbert Aronow; 3) sensitivity analysis
and exposure analysis predictions of carboxyhemoglobin (COHb)
levels and ambient CO concentrations under alternative air
quality standards;. 4) range of scientifically acceptable
alternative standards for CO.
I would like to briefly summarize for you the Committee's
views on each of these issues.
1. Development of a Multiple Exceedance 8-Hour Standard.
The CASAC reached a consensus that a multiple exceedance
standard has both scientific as well as administrative merit.
From a scientific point of view this approach recognizes the
stochastic or random-like (character of meteorological events;
administratively, it reduces the element of chance in determining
compliance with the standard. In recommending that you adopt
a multiple exceedance standard, the Committee notes that an
increase in the number of allowable exceedances will, in effect
relax the existing standard if the standard level 'remains
unchanged. In order to provide protection to the public health
with an adequate margin of safety you should consider the impact
of a multiple exceedance standard upon ambient CO concentrations
and levels of blood COHb.
B-2
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2. Role of the 1981 Aronow Study.
CASAC reached no overall consensus on the significance
which the Agency ought to attribute to the Aronow study. The
study reported a 10 percent reduction in the time to onset of
angina during treadmill exercise at blood carboxyhemoglobin
levels of 2 percent. CASAC discussed the fact that the response
observed at 2.0% COHb was more subtle than that observed at
higher levels (2.7 - 2.9% COHb) and speculated that even more
subtle responses might be found at COHb levels below 2.0%. The
Committee concluded that there may be no physiological response
threshold for carbon monoxide. One CASAC consultant, while
noting that the study data are solid and irrefutable, concluded
that activity and exposure patterns of angina patients are far
different from the general population. He also observed that
there is no reason to believe that changes in the time of
onset of angina during treadmill exercise are a valid biologic
endpoint for the determination of an adverse health effect.
Another Committee consultant, however, concluded that shortening
of exercise time prior to the onset of an angina attack clearly
is an adverse health effect.
While reaching no consensus on the role of this study, the
Committee's earlier position as stated in the October 9, 1979
closure memorandum —• that.the critical effects level for COHb
occurs between 2.7% — 3.O% and that the onset of angina represents
an adverse effect — remains as the CASAC consensus on this
issue.
3. Scientific and Technical Adequacy of Sensitivity and
Exposure Analyses.
The sensitivity and exposure analyses were prepared by the
Agency to compare the relationship between ambient CO concentrations
and various levels of blood COHb. In addition, the analyses
estimated the number and distribution of individuals who were
projected to experience various COHb levels under alternative
CO standards.
CASAC has reviewed the exposure and sensitivity analyses
and has concluded that both are scientifically acceptable given
the current state-of-the-art of the scientific community's
ability to model physiological and other parameters related to
this pollutant. Specifically, the Committee would draw to your
attention two of its conclusions on these analyses: 1) the
Agency's use of the Haldane constant with a value set at 218 is
a reasonable selection among a variety of physiological parameters
B-3
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discussed in the sensitivity analysis; and 2) the draft preamble
states that an Agency objective is to keep 99% of the population
below a COHb level of 2.5%. Since there may be no threshold
concentration level for carbon monoxide below which no adverse
effects will be experienced by anyone, and since one hundred
percent protection is not feasible, a social policy choice must
be made to limit societal risk from this pollutant. From a
scientific standpoint the 99% objective is within the realm of
reason, but there may be other than scientific factors you wish
to consider in reaching a decision on this particular issue.
4. Scientifically Acceptable Range for the 8-Hour CO
Standard. ;
In commenting upon the staff's proposals for a revised
8-hour CO standard set at 9 parts per million (p.p.m.) with
five exceedances, or 12 p.p.'m. with one exceedance, the Committee
made the following consensus observations:
o a standard set at 12 p.p.m.
is not scientifically acceptable
with 5 exceedances
o a standard established at 12 p.p.m. with 1
would provide a very small margin of safety
exceedance
o the scientific evidence alone cannot identify an
exact level at which to set a standard for carbon monoxide.
Given the need to protect sensitive members of the population
from this pollutant, the Committee advises you to choose a
standard level and a corresponding number of exceedances that
will limit COHb below tihe critical effects level of 2.7 - 3.01,
with an adequate margin of safety.
The Committee appreciates the opportunity to advise you on
the carbon monoxide standard and hopes that its comments will
be useful as you finalize tlie standard. We urge you to proceed
expeditiously in this matter because the criteria document and
staff paper, reviewed by CASAC more than three years ago, will
be increasingly subject to challenge because of any newly published
literature on this pollutant. In addition, both the private
sector and individual citizens need to know the standard level
for the next five years for [planning purposes and for reassurance
that public health is being adequately protected.
Sincerely yours,
cc: Dr. John W. Hernandez
Kathleen Bennett
Dr. Terry F. Yosie
Sheldon K. Friedlander
Chairman, Clean Air Scientific
Advisory Committee
B-4
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APPENDIX C
CASAC LETTER (MAY 7, 1984) TO EPA ADMINISTRATOR
CONCERNING FINDINGS AND RECOMMENDATIONS ON THE
SCIENTIFIC BASIS FOR A REVISED NAAQS FOR CARBON MONOXIDE
C-l
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
May 17, 1984
OFFICE OF
THE ADMINISTRATOR
Honorable William D. Ruckelshaus
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Dear Mr. Ruckelshaus:
The Clean Mr Scientific Advisory Committee (CASAC) has completed its
review of two documents related to thb development of revised primary
National Ambient Air Quality Standards (NAAOS) for Carbon Monoxide (CO).
Ihe documents were the Revised Evaluation of Health Effects Associated with_ ,
Carbon Monoxide Exposure; An Addendum to the 1979 Air Quality Criteria
Document for Carbon Monoxide written by the staff of the Office of Research
and Development (ORD), and a staff pajpef entitled Review of the NAAQS for
Carbon Monoxide; 1983 Reassessment of Scientific and Technical Information
prepared by the Office of Air Quality! Planning and Standards (OAQPS). The
Committee unanimously concluded that both documents represent a scientifically
balanced and defensible summary of the current basis of our knowledge of
the health effects literature for this pollutant.
As you know, the latest CASAC review of the CO documents took place in
an atmosphere of great scientific uncertainty and controversy due to the
fact that a group of scientists condupting a revi-ew of the protocols for a major
series of peer reviewed studies, carried' out by Dr. Wilbert Aronowr had "shortly
before concluded that adequate standardized procedures for scientific
research were not utilized in those studies. Confronted with this situation,
Agency staff in both ORD and OAQPS moved quickly and resolutely to analyze
the remaining scientific basis for the Clean Air Act requirement to finalize
a revised CO standard. Hie CASAC concludes that, even without the use of
the Aronow studies to determine a critical effects level from CO exposures,
there remains a sufficient and scientifically adequate basis on which to
finalize the CO standard.
As a result of its review of the information contained in these docu-
ments, the CASAC recommends that you consider choosing the 8-hour and
1-hour carbon monoxide standards to maintain approximately current levels
of protection. A more extended analysis of the factors that led to this
reconmendation is contained in the enclosed report.
C-2
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Thank you for the opportunity 'to present the Committee's views on this
important public health issue.
Sincerely,
Morton Lippnanry1; Chairman
Clean Air Scientific
Advisory Canmittee
Enclosure
cc: Mr. Alvin Aim
Mr. Joseph Cannon
Dr. Bernard Goldstein
Dr. Tterry Yosie
C-3
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CASAC Findings and Recommendations on the Scientific Basis for
a Revised NAAQS for Carbon Monoxide
Addendum to the CO Air Quality Criteria Document
1. A key issue in the evaluation of public health risks from carbon
monoxide (CO) exposures concerns the relation between CO in air and its
displacement of oxygen .in blood hemoglobin. The index for this displacement,
known as carboxyhemoglobin (COHb), is expressed as a percentage of the
blood hemoglobin. There is a scientific consensus that relatively low
levels of COHb are associated with critical (i.e., health impairing) health
effects. The discussion of the scientific evidence thus centers on what
percentage of, COHb causes a critical effect.
On October 9, 1979, CASAC submitted a report to the Administrator
concluding that the critical COHb level occurred within a range of 2.7—3.0%.
The Cornittee reached this finding following an extensive review of the
scientific literature, including a series of studies performed by Dr. Wilbert
Aronow. CASAC expressed some reservations about one of these studies
(Aronow, 1978 which reported effects at levels [1.8%] well below the 2.7-
3.0% range) in view of the fact that some confounding factors in the study
protocols were not appropriately accounted for. The Committee further
recommended that "given the uncertainties stemming from the methodological
approach, [the Agency].. .should utilize the [1978 Aronow] study for margin
of safety considerations rather than using it for the determination of a
threshold value" (CASAC report, October 9, 1979, p.5). On August 31,
1982 CASAC sent a follow-up report on several issues related to the NAAQS
for carbon monoxide. In that report the Committee reaffirmed its prior
findings on the critical COHb effects level. It should be noted that
CASAC1 s 1982 recommendations were reached after the Committee members
i
C-4
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had an opportunity to review an additional (1981) study by Dr. Aronow which
concluded that a 10% reduction in the time to onset of an angina attack
occurred during treadmill exercise with 2% CDHb.
A review of the most recent update of this scientific literature in
the August 1983 draft EPA Addendum to the 00 Air Quality Criteria Document
persuades CASAC that there is no significant reason to substantively alter
its previous findings. An elaboration of CASAC's current reasoning on
several issues will clarify the Committee's position, These include:
A, The role of the Aronow studies
A key question raised about Aronow's work was" whether or not the
procedures used insured that the studies were double blind. A double
blind protocol is one in which neither the subjects nor the laboratory
technicians conducting the experiments and collecting the data are aware of
key parameters of the study (exposure conditions, timing, etc.) and the
results of the responses by the experimental grsap and the-control group.
It is apparent that such double blind procedures were not applied in Aronow's
work because technicians who were directly involved with the subjects knew
some of the important parameters of the study. The lack of quality assurance
checks represents another issue of concern. In these respects, the results
of Aronow's work do not meet a reasonable standard of scientific quality
for a study of the kinds of responses of interest, and therefore, they should
not be used by the Agency in defining the critical COHb level.
B. Ihe role of the Anderson study
The 1973 study by Anderson et al. reported that angina patients exposed
to low CO levels while at rest experienced a statistically significant reduction
in time to onset of exercise induced angina at average COHb levels of 2.9% and
4.5%. Ihe study further concluded that there was a significantly lengthened
C-5
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angina attack during exercise at an average COHb level of 4.5%. The 1983
CO criteria document addendum noted concerns expressed by some parties
about the study due to the small number of subjects studied, apparent
inconsistencies between predicted and observed COHb levels, the possibility
that the protocols were not .truly double blind, and the lack of subsequent
confirmatory findings.
CASAC reached several conclusions concerning this study. It was trou-
bled that so few patients were included in the study design and that there was
uncertainty about the exposures to which the patients were subjected. The
Ccnroittee agreed that it is important to replicate such a study, but the notion
that a study has no validity until it's been replicated is flawed. Based
I
upon its current knowledge of how the study was conducted, CASAC presumes
that double blind protocols were, in fact, observed and that discrepancies
between observed and predicted COHb levels are not as great or as serious
as originally suggested. In summary; while CASAC treats the Anderson et
al. study with caution, it can find no substantive reason at this tine to
dispute the reported values, and it reccmnends that the Agency not disregard
its findings. j
C. Additional studies [
CASAC wishes to point cut two sets of additional studies which lend
support to concerns about low level CO exposures. In 1974, both Raven et al.
and Drinkwater et al. reported statistically significant decreases (less
than 5%) in exercise time for work capacity in healthy, nonsmoking young
and middle aged ran at approximately 2.3 - 2.8% COHb. Also, a 1980 controlled
human exposure study by Davies & Smith, observed changes in electrocardiogram
(EKG) measurements in a small number of healthy nonsmoking young men at
2.4% COHb. Such CO induced changes are a cause for public health concern
and should be factored into the Agency's thinking for setting a standard
with an adequate margin of safety.
; c-e
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D. Use of the Coburn-Fcster-Kane (CFK) equation
The CFK model is the most important available tool for analyzing a
number of physiologically important variables (blood volume and endogenous
CO production rate, for example) in order to project a relationship
between ambient CO exposures and resulting COHb levels. Wiile this
model, like any model, is subject to the need for additional evaluation
of COHb in different population groups, it is reasonable to conclude that
the CFK equation accurately predicts CO uptake under differing exposure
conditions.
E. Summary of cardiovascular effects
The Committee unanimously agrees that: 1) the key mechanism of CO toxicity"
is the decreased oxygen carrying capacity resulting frcm the greater af-
finity of blood hemoglobin for carbon monoxide than for oxygen; 2) reduction
in time to the onset of an angina attack is a medically significant event
and should be considered an adverse health effect; and 3) following a
review of the peer reviewed scientific literature (not including the Aronow
studies), the critical effects level for NAAOS setting purposes is
approximately 3% COHb (not including a margin of safety).
2. A second important public health issue in setting a NAAQS for carbon
monoxide concerns CD-induced central nervous system effects. Decreased
vigilance or sensory-motor function is a health effect which the standard
ought to protect against. CASAC's position is that such behavioral effects
are observed between 5-8% COHb.
3. The Committee was asked to address the issue of the role of CO in
Sudden Infant Death Syndrome (SIDS). A review of the current scientific
C-7
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literature leads to the conclusion that there is not a sufficient scientific
basis to establish a connection between a CO exposure level and SIES.
OftOPS Staff Paper Review of the NAA05 For Carbon Monoxide
Based upon the addendum to the revised Air Quality Criteria Document
for Carbon Monoxide, QAOPS developed a staff paper analyzing alternative
ranges of concentration levels for a final promulgated standard. The current suite
of primary standards is set at 9 parts per million (ppm) for the 8-hour averaging
time and 35 ppm for the 1-hour average.
CASAC was asked to advise the Agency on several issues associated with
the proposed ranges. The following discussion responds to the Agency request.
1. CASAC reaffirms the judgment it reached in its October 1979 report
that reduction in the time to onset of angina aggravation represents
an adverse health effect.
2. The Committee concurs with the Agency that R-hour and 1-hour
standards are the appropriate averaging times, but it recommends
that there be additional discussion and more explicit comparison
in the regulatory package concerning the relationship between the
two averaging times, particularly in terms of what attainment of
the 8-hour standard portends for the health protection provided by
the 1-hour standard.
3. The factors identified by OAOPS for margin of safety
consideration are appropriate. Underlying CASAC's view of
the margin of safety, however, is its traditional belief that
C-8
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where the scientific data, as in this case, are subject to large
uncertainties, it is desirable for the Administrator to consider a
greater margin of safety than the numerical values of OOHb generated
by the Coburn equation might otherwise suggest.
4. The QAQPS staff recommends that the Administrator retain or
select an 8-hour primary standard in the range of 9 to 12 ppm.
With regard to the 1-hour primary standard, the staff recomnends
that a selection be made within the range of 25 to 35 ppm. CASAC
concurs that the proposed ranges for both the 8-hour and 1-hour
primary standards are scientifically defensible. Given the uncer-
tainties within the scientific data base and Discussion of margin
of safety issues, the Committee reconmenrts that you consider
choosing standard limits that maintain approximately current
levels of protection.
C-9
•&U. S. GOVERNMENT PRINTING OFFICE: 1984/759-102/10639.
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