Review of the
IMAAQS for
Carbon Monoxide:
Reassessment of
Scientific and
Technical
Information
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EPA-450/5-84-004
Review of the NAAQS for Carbon
Monoxide: Reassessment of Scientific
and Technical Information
July 1984
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park, NC 2771 1
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Disclaimer
This report has been reviewed by the Office of Air Quality Planning
and Standards, U.S. Environmental Protection Agency, and approved for
publication. Mention of trade names or commercial products is not intended
to constitute endorsement or recommendation for use.
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11
ACKNOWLEDGEMENTS
This staff paper is the product of the Office of Air Quality Planning
and Standards (OAQPS). The principal authors include Harvey Richmond,
David McKee, and Mike Jones. The report reflects comments from OAQPS, the
Office of Research and Development, and the Office of General Counsel within
EPA and was formally reviewed by the Clean Air Scientific Advisory Committee
(CASAC) in September 1983. A copy of CASAC's closure letter and report is
included as Appendix A of the staff paper.
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TABLE OF CONTENTS
I. Purpose 1
II. Background 1
A. Legislative Requirements 1
B. Original CO Standards and Proposed Revisions
of the Standards 2
C. Developments Subsequent to Proposal 4
III. Approach 5
IV. Critical Elements in the Primary Standards Review 7
A. Mechanisms of Toxicity 7
B. Reported Effects, Levels of Effects, and
Severity of Effects 8
C. Sensitive Population Groups 15
D. Uncertainty in Estimating COHb Levls 16
E. Exposure Analysis Estimates 22
F. Margin of Safety Considerations 25
V. Factors to be Considered in Selecting Primary Standards. 28
A. Averaging Times 28
B. Form of the Standards 28
C. Level of the Standards 30
D. Staff Conclusions and Recommendations 32
Appendix A. CASAC Closure Memorandum A-l
References
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REVIEW OF THE NAAQS FOR CARBON MONOXIDE:
1983 REASSESSMENT OF SCIENTIFIC AND TECHNICAL INFORMATION
I. PURPOSE
The purpose of this paper is to evaluate the key studies and scientific
information contained in the draft EPA document, "Revised Evaluation of
Health Effects Associated with Carbon Monoxide Exposure: An Addendum to
the 1979 EPA Air Quality Criteria Document for Carbon Monoxide,"1 and to
identify the critical elements that the EPA staff believe should be considered
in the review and possible revision of the current primary and secondary
national ambient air quality standards (MAAQS) for carbon monoxide (CO).
The paper also provides staff recommendations on alternative regulatory
approaches.
II. BACKGROUND
A. Legislative Requirements
Since 1970 the Clean Air Act has provided authority and guidance
for the listing of certain ambient air pollutants which may endanger public
health or welfare and the setting and revising of NAAQS for those pollutants.
Primary standards must be based on health effects criteria and provide an
adequate margin of safety to ensure protection of public health. As several
recent judicial decisions have made clear, the economic and technological
feasibility of attaining primary or secondary standards are not to be
considered in setting them, although such factors may be considered to a
degree in the development of state plans to implement the standards.2>3
The requirement that primary standards provide an adequate margin of
safety was intended to address uncertainties associated with inconclusive
scientific and technical information available at the time of standard
setting as well as to provide a reasonable degree of protection against
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hazards that research has not yet identified.^ Thus in providing an
adequate margin of safety, the Administrator is regulating not only to
prevent pollution levels that have been demonstrated to be harmful, but
also to prevent pollutant levels for which the risks of harm, even if not
precisely identified as to nature or degree, are considered unacceptable.
•
In weighing these risks for margin of safety purposes, EPA considers such
factors as the nature and severity of the health effects involved, the size
of the sensitive population(s) at risk, and the kind and degree of other
uncertainties that must be addressed. The selection of any particular
approach to providing an adequate margin of safety is a policy choice left
specifically to the Administrator.2
Secondary standards must be based on the welfare effects criteria and
must protect the public welfare from any known or anticipated adverse
effects associated with the presence of the pollutant in the ambient air.
Welfare effects are defined in section 302(h) of the Clean Air Act to
include effects on soil, water, crops, vegetation, man-made materials,
animals, weather, visibility, hazards to transportation, economic values,
personal comfort and well-being, and similar factors.
The Clean Ai> Act requires periodic review and, if appropriate, revision
of.existing criteria and standards. If, in the Administrator's judgment,
the Agency's review and revision of criteria make appropriate the proposal
of new or revised standards, such standards are to be revised and promulgated
in accordance with section 109(b) of the Act. Alternatively, the Administrator
may find that revision of the standards is not appropriate and conclude the
review by reaffirming them.
B. Original CO Standards and Proposed Revisions of the Standards
Original CO Standards. On April 30, 1971, the Environmental
Protection Agency promulgated NAAQS for CO under section 109 of the Clean
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3
Air Act (36 FR 8186). 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 and medical bases for
these standards are described in the 1970 document, "Air Quality Criteria
for Carbon Monoxide."4 The standards set in 1971 were primarily based on
work by Beard and Wertheim (1967)5 suggesting that low-level CO exposures
resulting in carboxyhemoglobin (COHb) levels of 2 to 3 percent were associated
with impairment of ability to discriminate time intervals, a central nervous
system affect.
Proposed Revisions of the Standards. In 1979, EPA published a revised
Criteria Document for CO^ and a Staff-Paper*^ in which several key considerations
were identified as major factors in the possible revision of the CO standards.
As discussed in the August 18, 1980 proposal notice (45 FR 55066), the 1979
Criteria Document,6 and the Staff Paper,6a the Beard and Wertheim study^ is no
longer considered a sound scientific basis for the primary CO standards.
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 3.0 percent. Assessment of this
and other medical evidence led r_?\ to propose: (1) retaining the 8-hour
primary standard level of 9 ppm, (2) revising the 1-hour primary standard
leva! from 35 ppm to 25 ppm, (3) revoking the existing secondary CO standards
(since no adverse welfare effects have been reported at or near ambient CO
levels), (4) changing the form of the standard from deterministic to statistical
(i.e., ?.?\ proposed to state allowable exceedances as expected values
rather than as explicit values), and (5) adopting a daily interpretation
for exceedances of the CO standards, so that exceedances would be determined
on t'ne basis of the number of days on which the 8- or 1-hour average concentrations
.V3re .above the standard levels (45 FR 55066).
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C. Developments Subsequent to Proposal
On June 18, 1982, EPA announced (47 FR 26407) an additional public
comment period concerning several key issues and technical documents related
to the review of the CO standards. These issues included: (1) the role of
the Aronow (1981) study,7 (2) consideration of a multiple exceedance 8-hour
standard, (3) the technical adequacy of the revised draft sensitivity
analysis^ on the Coburn model predictions of COHb levels, and (4) the
technical adequacy of the revised exposure analysis.9 The Clean Air
Scientific Advisory Committee (CASAC) met on July 5, 1982 to provide its
advice on these issues. CASAC's recommendations arising from that meeting
are summarized in an August 31, 1982 letter to the Administrator.10
The 1980 proposal (45 FR 55066) was based in part on several health
studies conducted by Or. Wilbert Aronow.H-17 Based largely on evaluation of
these studies in 1979 by EPA staff and CASAC, it was concluded at the time
of proposal that COHb levels of 2.7-3.0 percent represent a health concern
for individuals with angina and other types of cardiovascular heart disease.
In March 1983 EPA learned that the Food and Drug Administration (FDA)
had raised serious questions regarding the technical adequacy of several
studies conducted by Dr. Aronow on experimental drugs, leading FDA to
reject use of the Aronow drug studies data. While there was no direct
evidence that similar problems might exist for Dr. Aronow's CO studies, EPA
concluded that an independent assessment of these studies was advisable prior
to a final decision on the CO NAAQS. An expert committee was convened by
EPA and met with Dr. Aronow to discuss his studies and to examine the
limited available data and records from his CO studies. In its report,18
the Committee (chaired by Dr. Steven M. Horvath, Director of the Institute
of Environmental Stress, University of California - Santa Barbara) concluded
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that EPA should not rely on Dr. Aronow's data due to concerns regarding
various problems asociated with the studies which substantially limit the
validity and usefulness of the studies results. In early June 1983, EPA
received a detailed reply from Dr. Aronow disputing, but not effectively
refuting, the major points raised by the "Horvath Committee" report.18a
The Environmental Criteria and Assessment Office (ECAO) has prepared a
draft Addendum* to the 1979 CO Criteria Document which re-evaluates the
scientific data base concerning health effects associated with exposure to
CO at 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 1979 CO Criteria Document.
III. APPROACH
The approach used in this paper is to assess and integrate information
derived from the draft Addendum to the 1979 CO Criteria Document and other
staff analyses in the context of those critical elements which the staff
believes should be considered in the review of the primary (health based)
standards. Only the primary standards are addressed, because, as explained
in the proposal notice (45 FR 55066), no standards appear to be requisite
to protect the public welfare from any known or anticipated adverse effects
from ambient CO exposures. Particular attention is drawn to those judgments
that must be based on careful interpretation of incomplete or uncertain
evidence. In such instances, the paper states the staff's evaluation of
the evidence as it relates to a specific judgment, sets forth appropriate
alternatives that should be considered, and recommends a course of action.
Section IV reviews and integrates important scientific and technical
information relevant to review of the primary CO standards. The essential
elements with regard to the primary standards that are addressed in
Section IV include the following:
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(1) identification of possible mechanisms of toxicity;
(2) description of effects of concern including reported effect levels;
(3) identification of the most sensitive population groups and
estimates of their size;
(4) discussion of uncertainties in estimating COHb levels tfiat result
from exposures to CO;
(5) estimates of the number of persons that would reach various COHb
levels upon attainment of alternative standards; and
(6) discussion of margin of safety considerations.
Drawing from the discussion and information presented in Section IV,
Section V identifies and assesses the factors that should be considered in
selecting among alternative regulatory approaches. Preliminary staff
recommendations on alternative policy options also are presented.
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IV. CRITICAL ELEMENTS IN THE PRIMARY STANDARDS REVIEW
A. Mechanisms of Toxlcity
At the time of proposal of the MAAQS for CO, the primary mechanism
for toxic effects from CO exposure was thought to be hypoxia resulting
from COHb formation. Several other possible mechanisms of toxicity were
addressed in the 1979 Criteria Document but at the time of publication
were not considered to be of major importance compared to COHb hypoxia at
ambient CO exposure levels.
Presently, the most important mechanism of CO toxicity at low-level
CO exposures is still thought to be COHb hypoxia. This mechanism involves
diffusion of exogenous CO through the lungs into the blood with resultant
formation of COHb. CO hypoxia results from preferential binding of CO by
hemoglobin, thus reducing the amount available to bind oxygen (03). The CO
bound to hemoglobin affects the binding of 03 to the remaining hemoglobin
and, thus, further reduces the 02 delivery to tissues. Because the
affinity constant for CO is between 200 and 250 times that for 02, blood
levels of 2 to 4.5 percent COHb can result from continued exposure to
concentrations of CO as low as 20 to 150 ppm within two hours for individuals
engaged in moderate activity (ventilation rate = 20 liters per minute).
Models designed to estimate COHb levels arising from CO exposure have
been developed by Coburn et al. (1965).19
Other possible mechanisms of toxicity have been discussed by Coburn
(1979).20 These alternative mechanisms involve binding of CO to such
hemoproteins as cytochrome oxidase, myoglobin, tryptophan deoxygenase,
and tryptophan catalase. Because the affinity constants for these proteins
are much less than that for hemoglobin, it is unlikely that they play a
major role in CO hypoxia. However, in tissues with a high 02 gradient
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between blood and tissue, it is reasonable to assume that the interaction
of CO with these proteins (particularly with myoglobin in heart muscle)
may play a role in CO toxicity. The conclusion drawn in the draft
Addendum1 is that regardless of the mechanism of toxicity, COHb levels
provide a meaningful and useful physiological marker to estimate both
endogenous production of CO and exposure to exogenous sources of CO.
Presently COHb levels provide the best marker available for CO toxicity.
B. Reported Effects, Levels of Effects, and Severity of Effects
Table lisa summary of key clinical studies reporting human health
effects associated with low-level exposures to CO. This table is based
on evidence discussed in the 1979 Criteria Document6 and in the Draft
Addendum1 but excludes a series of studies by Dr. Aronow due to problems
which substantially limit the validity and usefulness of the Aronow
studies.1** Table 1 is intended to be used in conjunction with the following
discussion, but each study should be viewed in light of the qualifications,
if any, discussed in the 1979 CO Criteria Document, in the 1979 staff paper,
in the draft Addendum, and in this staff reassessment.
1. Cardiovascular Effects
The lowest observed CO exposure levels producing human health effects
have been reported in studies involving individuals suffering from chronic
angina pectoris. Angina pectoris, commonly referred to simply as angina,
is a symptom of cardiovascular stress in which mild exercise or excitement
can produce pressure or pain in the chest due to insufficient oxygenation
of heart muscle.
Anderson et al. (1973)^1 reported that experimental subjects with angina
exhibit statistically significant reduced time to onset of exercise-induced
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TABLE 1.
Lowest Observed Effect Levels For Human Health Effects
Associated With Low Level Carbon Monoxide Exposure
Effects
Statistically significant decreased
(~3-73) work time to exhaustion
in exercising young healthy men
Statistically significant decreased
exercise capacity (i.e.,
shortened duration of exercise
before onset of pain) in patients
with angina pectoris ami increased
duration of angina attacks
Statistically significant decreased
maximal oxygen consumption and
exercise time during strenuous
exercise in young healthy men
Mo statistically significant
vigilance decrements after
exposure to CO
Statistically significant impair-
ment of vigilance tasks in
healthy experimental subjects
COHb concen-
tration, (Percent)3
2.3-4.3
2.9-4.5
5-5.5
Below
5
5-7.6
References
Horvath et al., 197530
Drinkwater et al., 197480
Raven et al., 197481
Anderson et al., 197321
Klein et al., 198033
Stewart et al., 197832
Weiser et al., 198078
Haider et al. 197635
Winneke, 197336
Christensen et al ., 197737
Benignus et al., 197738
Putz et al., 197639
Horvath et al., 197144
Groll-Knapp et al., 19724$
Fodor and Winneke, 197246
Putz et al., 197639
Statistically significant diminu-
tion of visual perception, manual
dexterity, ability to learn, or
performance in complex sensorimotor
tasks (such as driving)
5-17
Statistically significant
decreased maximal oxygen
consumption during strenuous
exercise in young healthy men
7-20
Bender, et al.. 197147
Schulte, 197348
O'Donnell et al., 19714?
McFarland et al... 194441
McFarland, 197350
Putz et al., 197639
Salvatore, 197451
Wright et al., 197352
Rockwell and Weir, 197553
Rummo and Sarlanis, 197454
Putz et al.. 197942
Putz, 1979«
Ekblom and Huot, 197229
Pi may et al. 197176
Vogel and Gleser, 197277
aThe physiologic norm (i.e., COHb levels resulti
of hemoglobin and other heme-containing material
in the range of 0.3 to 0.7 percent (Coburn et al
from the
has been
1963).28
normal catabolism
estimated to be
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angina after exposure to low levels of CO resulting in mean COHb levels
of 2.9 (range 1.3-3.8 percent) and 4.5 percent (range 2.8-5.4 percent).
In the same study, it was reported that subjects experienced statistically
significant increases in duration of angina attacks during exercise at a
mean COHb level of 4.5 percent. As discussed in the draft Addendum*, the
Anderson et al. (1973)21 study provides reasonably good evidence for the above
effects occurring in angina patients at mean COHb levels of 2.9 to 4.5
percent. There remain some concerns about the study findings due to
ambiguities regarding the design and conduct of the study and the small
number of subjects (M=10) examined.
In similar studies Aronow et al. (1973)12 and Aronow (1981)? report
decreased time to onset of angina for exercising subjects with reported
COHb levels in the range of 2 to 3 percent. In addition, Aronow et al.
(1974)13 reported that subjects with peripheral vascular disease had
reduced time to onset of leg pain at similar COHb levels. As discussed
earlier, however, these results should be considered only in developing
»
a margin of safety for effects below 3 percent COHb. Until independent
studies attempting to replicate the Aronow studies have been completed,
more conclusive statements are not possible concerning effects on individuals
with angina or peripheral vascular disease at COHb levels below 2.9
percent COHb.
In another controlled human experimental study, Davies and Smith
(1980)22 reported possible effects on cardiac function in healthy individuals
exposed continually to 0 ppm CO (0.5 percent COHb), 15 ppm CO (2.4 percent
COHb), or 50 ppm CO (7.1 percent COHb) for 8 days. P-wave changes taken from
EKG tracings were reported.in 3 of 15 subjects at 15 ppm CO, in 6 of 15
at 50 ppm CO, and 0 of 14 at 0 ppm CO. In addition, one subject who was
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later identified as having evidence of heart damage, showed marked S-T
segment changes at 15 ppm CO. It was suggested by the authors that
P-wave changes reported were due to interference by CO of normal atria!
pacemaking or conducting tissue activity. Although they hypothesize that
CO specifically affects the myocardial tissue as well as reduces blood
oxygenation, the P-wave changes reported in this study have not yet been
clearly identified as adverse health effects. While no statistical
analysis of these results is reported in the study, it is highly unlikely
that the P-wave changes in 3 of 15 subjects or the S-T segment change in
1 of 15 subjects at the 2.4 percent COHb level are statistically significant.
Increased blood flow was reported by Ayres et al. (1969, 1970,
1979).23,24,79 jnis effect occurs as a compensatory response to CO exposure
and may be related to coronary damage or cerebrovascular effects at very
high blood flow rates due to the added stress on the vascular system.
Community epidemiology studies which may have provided supporting evidence
for these effects, however, have instead provided inconclusive results.
In the Goldsmith and Landau (1968),25 Kurt et al. (1978),26 and Kurt et
al. (1979)27 studies, the relationships between CO exposure and mortality
from myocardial infarction (heart attack), sudden death due to atherosclerotic
heart disease, and cardiorespiratory complaints remain in question.
Maximum aerobic capacity (?02max) and exercise capacity are
indirect measures of cardiovascular capacity which have been reported to
be reduced in several carefully conducted studies involving normal healthy
adults exposed to CO. These effects, while not as serious as the possible
impact of CO on angina, are still a matter of some concern since they
have been found to occur in healthy individuals.
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A decline in ?02niax f°r healthy individuals with COHb levels
ranging from 5-20 percent was reported in a series of studies (Ekblom and
Huot, 1972;29 Weiser et al., 1980;78 Stewart et al., 1978;32), reviewed
in the 1979 Criteria Document°. Horvath et al., (1975)30 f0unc| decreases
(p <.10) in 702max when COHb levels were 4.3 percent. Also COHb levels
of 3.3 percent and 4.3 percent reduced work time to exhaustion by 4.9 and
7 percent respectively. Similar results were also found (Stewart et al.,
1978;32 Klein et al., 198033) following exhaustive treadmill exercise at
5 percent COHb.
The effects of lower CO exposure levels in healthy individuals have
also been investigated under conditions of short-term, maximum exercise
duration (Drinkwater et al., 1974;80 Raven et al. 1974a,b81*82-). In this
series of studies a walking test with progressively 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 percent. The
two populations tested consisted of young (23+ years) and middle-aged
(48+ years) subjects, both smokers and nonsmokers. During the study,
COHb levels in nonsmokers increased from 0.6-0.9 to approximately 2.3-2.7
percent COHb, while levels in smokers rose from 2.6-3.2 percent to 4.1-5.2
percent COHb. While no reduction in maximum aerobic capacity was observed
for either group, small (3-5 percent) but statistically significant
decreases in absolute exercise time were observed in the non-smoking
subjects but not in the smokers.80,81
The effects of CO on the fibrinolytic system have been reported in
numerous publications and may be related to heart attacks and strokes,
although evidence at this time is very limited. In a series of studies
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Kalmaz et al. (1977;55 1978;56 198057) concluded that prolonged exposure of
rabbits to low levels of CO may change circulating platelet counts and/or
congenital platelet function disorders, however, this has not been confirmed
in man. Accelerated clot lysis time suggestive of enhanced blood fibrinolytic
activity in humans was reported by El-Attar and Sairo (1968),53 while
others reported relationships between CO exposure and increases in fibrinogen
and blood coagulation (Alexieva et al., 1975;59 Panchenko et al., 197760).
Haft (1979)^1 reported that smoking increases the activity of platelets and
that cigarette smokers have shortened platelet survival time. Neither
this study nor others clearly implicate acute CO exposure in observed
alterations in fibrinolytic activity and chronic exposure studies of
humans are too poorly controlled to confirm coagulation system effects.
Thus, this area of cardiovascular effects research needs to be developed
far beyond the present state of knowledge before being acceptable even as
suggestive evidence.
2. Neurobehavioral Effects
Central nervous system (CMS) effects have been reported in numerous
studies (Bender et al., 1971*7; Schulte, 197348; O'Donnell et al., 197149;
McFarland et al., 1944;41 McFarland, 1973;50 Putz et al., 1976;39
Salvatore, 1974;51 Wright et al., 1973;52 Rockwell and Weir, 1975;53 and
Rummo and Sarlanis, 197454) for co exposures resulting in COHb levels of
5-17 percent. The range of effects included impaired vigilance, visual
perception, manual dexterity, learning ability, and performance of complex
tasks.
While Beard and Grandstaff (1975)34 have suggested vigilance effects
may occur at levels of COHb as low as 1.8 percent COHb, several other
studies (Haider et al., 197635; winneke, 197336; Christensen et al., 197737;
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Bem'gnus et al., 197738; and Putz et al., 197639) have not found any
vigilance decrements below 5 percent COHb. Measurement methods used
to detect effects may have been too insensitive to detect changes in the
latter vigilance studies, but in the Addendum,1 it was concluded that, at
least under some conditions, small decrements in vigilance occur at
5 percent COHb.
Bem'gnus et al. (1983)^0 concluded that no reliable evidence for time
discrimination decrements caused by exposure to low levels of CO exists.
Concentration-related decrements in dark adaptation at COHb levels as low
as 5 percent were reported by McFarland et al. (1944).41 TJiis effect, however,
is not considered to be adverse at ambient levels of CO exposure.
Studies by Putz et al. (1976),39 putz (1979)42, and Putz et al. (1979)43
reported that 5 percent COHb produced decrements in compensatory tracking,
a hand-eye coordination task. These effects are not considered to be of
major concern because nonsmokers rarely attain 5 percent COHb due to ambient
CO exposure levels.
3. Perinatal Effects
The 1979 Criteria Document suggests that based on limited animal
toxicology data CO may produce perinatal effects on the fetus or newborn.
Long-term exposures to CO may result in a slower elimination of CO by the
fetus and may lead to interference with fetal tissue oxygenation during
development. Because the fetus may be developing at or near critical -
tissue oxygenation levels, even exposures to moderate levels of CO may
produce deleterious effects on the fetus (Longo, 1977).62 Although this
has not yet been demonstrated in humans, evidence from smoking mothers is
suggestive of fetal and newborn effects (Peterson, 1981).63
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Research on sudden infant death syndrome (SIDS) recently has suggested
a possible link between ambient CO levels and increased incidence of SIDS
(Hoppenbrouwers et al., 1981).64 it has been pointed out by Goldstein
(1982)65 -t^t in,joor sources of CO, as well as other pollutants (e.g.,
nitrogen dioxide, lead), may be at least as important as CO in causing
SIDS and that the relationship between SIDS and ambient pollution levels
may be only coincidental. Because the number of potentially confounding
factors makes finding an association between CO and SIDS extremely difficult,
further confirmation is needed before any causal relationship can be
inferred.
C. Sensitive Population Groups
This section identifies those groups most likely to be particularly
sensitive to low-level CO exposures based on the health effects evidence
and considerations presented in the Addendum^ and Section 8 of this
paper. Those groups include: (1) individuals with angina, peripheral
vascular disease, and other cardiovascular diseases, (2) persons with
chronic respiratory disease (e.g., bronchitis, emphysema, and asthma),
(3) elderly individuals, especially those with reduced cardiopulmonary
functions, (4) fetuses and young infants, (5) individuals suffering from
anemia and/or those with abnormal hemoglobin types that affect oxygen
carrying capacity or transport in the blood. In addition, individuals
taking certain medications or drinking alcoholic beverages may be at greater
risk for CO-induced effects based on some limited evidence suggesting
interactive effects between CO and some drugs. Visitors to high altitude
locations are also expected to be more vulnerable to CO health effects due
to reduced levels of oxygen in the air they breathe. Finally, individuals
with some combination of the disease states or conditions listed above
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(e.g., individuals with angina visiting a high altitude location) may be
particularly sensitive to low-level CO exposures, although there is no
experimental evidence to confirm this hypothesis.
Table 2 briefly summarizes the rationale for the judgments that these
groups are more likely to be affected by low-level CO exposures and presents
population estimates for each group. For most of the groups listed in Table 2
there is little specific experimental evidence to clearly demonstrate that
they are indeed at increased risk for CO-induced health effects. However,
it is reasonable to expect that individuals with preexisting illnesses or
physiological conditions which limit oxygen absorption into blood or its
transport to body tissues would be more susceptible to the hypoxic (i.e.,
oxygen starvation) effects of CO.
In our judgment, the available health effects evidence still suggests
that persons with angina, peripheral vascular disease, and other types of
cardiovascular disease are the group at greatest risk from low-level, ambient
exposures to CO. This judgment is based principally on the Anderson et al.
(1973) studyZl which indicates that individuals with angina may be affected
at COHb levels in the range 2.9-4.5 percent. In addition, while there is
less confidence in the results reported in Aronow et al . (1974),13 this
study still suggests that individuals with peripheral vascular disease may be '
at risk from ambient exposures to CO.
D. Uncertainty in Estimating COHb Levels
The health effect studies discussed above report the effects observed
at varying COHb levels. In order to set ambient CO standards based on
these studies, it is necessary to estimate the ambient concentrations of
CO that are likely to result in COHb levels at or near those observed in the
studies. A model known as the Coburn equation^ has been developed to
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Table 2. Summary of Potentially Sensitive Population Groupsa
Group
Rationale
Coronary Heart
Disease
Angina Pectoris
Chronic Obstructive
Pulmonary Diseases
Bronchitis
Emphysema
Asthma
Anderson et al. (1973) suggests
reduced time until onset of
exercise-induced angina in
2.9-4.5% COHb range.
Reduced reserve capacities for
dealing with cardiovascular
stresses and already reduced
oxygen supply in blood likely
to hasten onset of health effects
associated with CO-induced
hypoxia.
Fetuses and
Young Infants
Several animal studies (Longo,
1977) report deleterious effects
in offspring (e.g., reduced
birth weight, increased newborn
mortality, and lower behavioral
activity levels).
Population
Estimates
Percent of
Population
7.9 million (in 1979)
6.3 million (in 1979)
6.5 million (1970)
1.5 million (1970)
6.0 million (1970)
3.1 million live
births/year (1975)
5.0 (of the adult
population)
4.0 (of the adult
population)
Reference
DHEW, 197566
DHEW, 197367
3.3
0.7
3.0
DHEW, 197868
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is already reduced increasing
likelihood of CO-induced hypoxia
effects at lower CO exposure
levels than for non-anemic
individuals.
Pernicious and
Deficiency Anemias
.15 million (1973)
0.07
Peripheral
Vascular Disease
Elderly
Aronow et al. (1974)13 suggests
reduced time until onset of
exercise-induced leg pain after
exposure to CO.
0.75 million (in 1979)
0.3
DHEW, 197470
CO exposures may increase
susceptibility of elderly
individuals to other
cardiovascular stresses due
to already reduced reserve
capacities to maintain
adequate oxygen supply to
body tissues.
24.7 million (in 1979)
> 65 years old
DOC, 198071
aAll subgroups listed are not necessarily sensitive to CO exposure at low levels.
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estimate COHb levels resulting from CO concentrations as a function of
time and various physiological factors (e.g., blood volume, endogenous CO
production rate). Table 3 presents baseline estimates (i.e., a typical set
of physiological parameters was used) of COHb levels expected to be reached
by nonsmokers exposed to various constant concentrations of CO for either
1 or 8 hours based on the Coburn model.
There are, however, at least two uncertainties involved in estimating
COHb levels resulting from exposure to CO concentrations. First, even
among otherwise "normal" (non-anemic) persons with cardiovascular heart
disease, there is a distribution for each of the physiological parameters
used in the Coburn model in the population. These variations are sufficient
to produce noticeable deviations from the COHb levels in Table 3 that were
predicted using the typical set of physiological parameters. Second,
predictions based on exposure to constant CO concentrations inadequately
represent the responses of individuals exposed to widely fluctuating CO
concentrations that typically occur in ambient exposure situations.
As discussed in the proposal preamble (45 FR 55066), EPA attempted
to represent these uncertainties in a draft Sensitivity Analysis. This
analysis used the Coburn model to examine the effects of fluctuating CO
concentrations and variations in physiological parameters on COHb estimates.
Since proposal, EPA has revised the Sensitivity Analysis73 to address
concerns raised in several public comments. Table 4 presents estimates
of the distribution of COHb levels in the adult population based on
variations in physiological parameters upon exposure to three different
patterns of CO levels which just meet a given CO standard. The estimates
given in Table 4 and others contained in the Sensitivity Analysis report73
are based on the assumption that the entire adult population is exposed
to CO levels just meeting a given standard.
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Table 3. Predicted CQHb Response to Exposure to Constant CO Concentrations
Percent COHb Based on Coburn Equation3
Exposure Time
CO
(ppm)
7.0
9.0
12.0
15.0
20.0
25.0
35.0
50.0
1 hour
Intermittent
Rest/Light
Activity
0.7
0.7
0.8
0.9
1.1
1.2
1.5
2.0
exposure
Moderate
Activity
0.7
0.8
0.9
1.1
1.3
1.5
2.0
2.7
8 hours
Intermittent
Rest/Light
Activity
1.1
1.4
1.7
2.1
2.7
3.4
4.6
6.4
exposure
Moderate
Activity
1.1
1.4
1.8
2.2
2.9
3.6
4.9
6.9
a
Assumed parameters: alveolar ventilation rates = 10 liters/min (intermittent
rest/light activity) and 20 liters/min (moderate activity); hemoglobin =
15 g/100 ml (normal male); altitude = sea level; initial COHb level = 0.5 percent;
endogenous CO production rate = 0.007 ml/min; blood volume = 5500 ml, Haldane
constant (measure of affinity of hemoglobin for CO) = 218; lung diffusivity
for CO = 30 ml/min/torr.
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Table 4. Percentage of Persons with Carboxyhemoglobin Greater
than or Equal to Specified Peak Value When Exposed to
Air Quality Associated with Alternative Eight-Hour Daily
Maximum Carbon Monoxide
9 ppm, 8-hr 12 ppm, 8-hr
Peak
COHb
%
3.7
3.5
3.3
3.1
2.9
2.7
2.5
2.3
2.1
1.9
1.7
1.5
1.3
1.1
1 Expected Exceedance
Low
Pattern
<0.01
0.05
3
39
97
100
Midrange
Pattern
<0.01
0.02
0.4
5
35
88
100
100
High
Pattern
<0..01
0.02
0.2
2
10
53
98
100
100
100
1 Expected Exceedance
Low
Pattern
<0.01
0.01
0.2
4
36
91
100
100
100
Midrange
Pattern
<0.01
0.01
0.2
2
12
49
88
99
100
100
100
High
Pattern
<0.01
0.01
0.1
0.6
2
9
36
84
100
100
100
100
100
100
aCOHb responses to fluctuating CO concentrations were dynamically evaluated
using the Coburn model prediction of the COHb level resulting from one
hour's exposure as the initial COHb level for the next hour. The series of
1-hour CO concentrations used were from 20 sets of actual air quality data.
Each pattern was proportionally rolled back or up so that its peak 8-hour
CO concentration equalled the level of the 8-hour standard. Of the 20
selected patterns, results from 3 patterns are presented here. The low
pattern tends to give the lowest peak COHb levels, the midrange pattern
tends to give a midrange value, and the high pattern tends to give the
highest value.
^Haldane constant = 218. Alveolar ventilation rate = 10 liters/min.
Altitude = 0.0 ft.
cThe estimation of distributions for each of the physiological parameters
used in the Coburn model and the Monte Carlo procedure used to generate
these estimates are discussed in Appendix C of the Sensitivity Analysis.?3
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The impact of fluctuating air quality levels on COHb uptake can be
roughly estimated by comparing the result of a constant 9 ppm exposure
for 8 hours (1.4 percent COHb from Table 3) with a "typical" (50th percentile)
adult exposed to several different air quality patterns that result in
the same maximum 8-hour dose (i.e., 9 ppm, 8-hour average). The various
•
patterns examined in the Sensitivity Analysis indicate COHb levels ranging
from 1.4 to 1.9 percent (from Table 4) can be reached for the "typical"
adult exposed to air quality reaching a 9 ppm, 8-hour average. A similar
comparison of the results for air quality with a 12 ppm, 8-hour average
peak exposure, indicates that the impact of fluctuating CO levels can
increase the peak COHb value by up to 0.5-0.6 percent COHb.
The Sensitivity Analysis results in Table 4 also illustrate the
effect of using distributions for each physiological parameter rather
than just a representative set of physiological parameters in applying
the Coburn model. For any given air quality pattern, the effect of the
distribution of physiological parameters is to generate a distribution
that is fairly tight around the 50th percentile individual. For example,
95 percent of the population is estimated to be within +_ 0.3 percent COHb
of the median adult value after exposure to the midrange pattern with a
peak 9 ppm, 8-hour average. .
Since proposal, EPA has made considerable improvements in its exposure
analysis methodology which, unlike the Sensitivity Analysis, treats
movement of people and variation of CO concentration levels through time
and space. EPA staff believes that the revised Exposure Analysis,74 described
below, represents the best available tool for estimating the percentage
of the population who would reach various CO concentrations and COHb
levels upon attainment of alternative CO standards. Since the
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Exposure Analysis model simulates the exposure of individuals on an
hourly basis and simulates actual air quality patterns, the impact of
fluctuating CO levels is taken into account in the Exposure Analysis
results. The results of the revised Sensitivity Analysis are useful,
however, in characterizing the uncertainties resulting from variations in
physiological parameters in the population which at this time are not
fully accounted for in the Exposure Analysis.
E. Exposure Analysis Estimates
EPA's revised exposure analysis report, "The NAAQS Exposure
Model (NEM) Applied to Carbon Monoxide,"74 contains estimates qf the
numbers and percentage of urban American adults that would be exposed to
various ambient CO levels if alternative 8-hour CO standards were just
attained. In addition, estimates have been made of the percentage of
this population that would exceed selected COHb levels each year. These
latter estimates were derived by applying the Coburn model, which relates
patterns of CO exposure to resultant COHb levels, to the exposure model
outputs using a typical set of physiological parameters for men and for
women.
In contrast to the Sensitivity Analysis,73 the Exposure Analysis?4
simulates pollutant concentrations and the activities of people with regard
to time, place, and exercise level. In the exposure model, the" population
is represented by an exhaustive set of "cohorts" (i.e., 'age-occupational
groups that tend to "track together" in time and space). For each hour of
the year each cohort is located in one of five "microenvironments." A
microenvironment is a general physical location such as indoors-at-home or
inside a transportation vehicle. Since attainment of a standard is defined
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in terms of the monitoring system, CO levels in each of the microenvi ronments
are estimated by the use of multiplicative "transformation factors,"
which relate CO levels recorded at the nearest monitor to estimated CO
levels for each microenvironment. Values for the multiplicative
•
transformation factors that would give the best exposure estimates are
uncertain. The values used for these factors were estimated making
use of the available literature on (1) indoor and inside-motor-vehicle air
pollution and (2) statistical analyses of monitoring data (e.g., how
ambient values change with height and distance from a monitor). A more
detailed description of the approach, input data, and assumptions used to
derive exposure estimates appears in the Exposure Analysis report.^4
The exposure analysis model described above was applied to four
urban areas: Chicago, Los Angeles, Philadelphia, and St. Louis. Exposure
estimates for the adult population living in urban areas in the United
States were obtained primarily by associating each urban area in the
United States having a population greater than 200,000 with one of the
four cities mentioned above. The association was made on the basis of
geographic proximity to one of the base areas, average wind speed, peak
CO concentrations, observed climate, and general character of the area.
Table 5 provides estimates for 1987 of the percentage of the adult
population living in urban areas who would exceed various COHb levels
upon attainment of two alternative 8-hour standards. For example,
less than 0.1 percent of the adult population in urban areas is estimated
to exceed 2.1 percent COHb due to CO exposures associated with attainment
of a 9 ppm standard with 1 expected exceedance allowed per year and
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Table 5. Cumulative Percent of Adult Population in Urban
Areas Whose COHb Levels Would Exceed Specified COHb Values
Upon Attainment of Alternative 8-Hour Standards3'^*0
8-Hour Standards
9 ppm 12 ppm 15 ppm
1 Expected 1 Expected 1 Expected
Exceedance Exceedance Exceedance
COHb Level
Exceeded (Percent)
3.0
2.9
2.7
2.5
2.3
2.1
<.01
.02
0.1
0.8
<0.1 4.1
0.1 8.6
1.1
2.5
5.9
9.7
14
20
Projected cardiovascular and peripheral vascular disease population
in all urbanized areas in the United States for 1987 is 5,300,000 adults.
bjhese exposure estimates are based on air quality distributions which
have been adjusted to just attain the given standards.
cThese exposure estimates are based on best judgments of microenvironment
transformation factors. Projections for one urban area based on lower
and upper estimates of the microenvironment transformation factors are
provided in the Exposure Analysis report.74
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approximately 20 percent of the adult population is estimated to exceed
2.1 percent COHb upon attainment of a 15 ppm standard with 1 expected
exceedance allowed per year. It should be noted that the estimates given
in Table 5 are based on air quality distributions which have been adjusted
to just attain the given standards.
Several factors make the accuracy of the nationwide exposure estimates
uncertain. They include: (1) the paucity of information on several of
the needed inputs (e.g., some of the microenvironment multiplicative
transformation factors) and (2) the fact that nationwide estimates were
extrapolated from only four urbanized areas. The results of the Coburn
Model Sensitivity Analysis,?3 discussed previously in Section D, suggest
that the uncertainty introduced by the use of two representative sets of
physiological parameters (one for men and one for women), rather than the
distributions of the physiological parameters, in applying the Coburn
model to derive COHb estimates is not very large. The Exposure Analysis
report?4 describes some limited sensitivity analysis runs for one urbanized
area to give a rough idea of the range of possible actual exposures.
F. Margin of Safety Considerations
In determining which standards will provide an adequate margin of
safety, the Administrator must consider uncertainties regarding the lowest
levels at which adverse health effects occur, as well as uncertainties
about the levels of COHb that will result from CO exposure at the levels
associated with attainment of alternative standards. The staff recommends
that the following factors and sources of uncertainty be considered in
selecting the primary standards:
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1. Human susceptibility to health effects and the levels at which
these effects occur varies considerably among individuals, and EPA cannot
be certain that experimental evidence has accounted for the full range of
susceptibility. In addition, for ethical reasons, clinical investigators
have generally excluded from their studies individuals who may be especially
sensitive to CO exposure, such as those with myocardial infarction or
multiple disease states (e.g., angina and anemia). Another factor is that,
apart from the Aronow et al. studies,7,12,13 there are neither positive nor
negative human exposure studies testing cardiovascular effects at COHb
levels below the 2.9 percent level reported by Anderson et al.21
2. Several Aronow et al. studies^.12,13 report decreased time to
onset of angina and peripheral vascular disease at COHb levels in the range
of 2.0-3.0 percent. In view of the concerns expressed in the Horvath
Committee report,^ the findings from these Aronow studies are questionable.
Therefore, EPA staff recommends that the Aronow et al. findings be considered
only as a margin of safety consideration. The Aronow studies suggest the
possibility of effects at lower levels of CO but the results remain to be
confirmed.
3. There is some animal study evidence indicating that there may
be detrimental effects on fetal development (e.g., reduced birth weight,
increased newborn mortality, and behavioral effects) associated with CO
exposure. Similar types of effects have also been found in studies of the
effects of maternal smoking on human fetuses. However, it is not possible
at this time to sort out the confounding influence of other components of
tobacco smoke in causing the effects observed in the human studies. While
human exposure-response relationships for fetal effects remain to be
determined, these findings denote a need for caution in evaluating the
margin of safety provided by alternative CO standards.
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Other groups that may be affected by ambient CO exposures but for which
there is little or no experimental evidence providing exposure-response
relationships include: anemic individuals, persons with chronic respiratory
diseases, elderly individuals, visitors to high altitude locations, and
individuals on certain medications.
5. Uncertainties regarding the uptake of CO, including those related
to the accuracy of the Coburn equation in assessing variations in the
population due to differing physiological parameters and exposure to
varying air quality patterns, should be considered in judging which
standards provide an adequate margin of safety.
6. There are several factors contributing to uncertainties about the
estimates provided by the Exposure Analysis^ of the expected number of
individuals achieving various COHb levels upon attainment of alternative
standards. These factors include: the paucity of information on several
of the needed inputs, the fact that nationwide estimates were extrapolated
from only four urbanized areas, and the use of two representative sets of
physiological parameters (one for men and one for women) rather than the
distributions of physiological parameters in applying the Coburn model to
derive COHb estimates. The Exposure Analysis report^ describes some
limited sensitivity analysis runs for one urbanized area to give a rough
idea of the degree of uncertainty involved.
7. Uncertainty regarding adverse health effects that may result from
very short duration, high-level CO exposures (the bolus effect). However,
this factor is probably not a critical consideration because, as discussed
in the proposal notice (45 FR 55077), existing air quality data indicate
that attainment of an 8-hour averaging time standard should limit the
magnitude of short-term peak concentrations.
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8. There is some concern about possible interactions between CO and
other pollutants, although there is little experimental evidence to document
such interactions at this time.
V. FACTORS TO BE CONSIDERED IN SELECTING PRIMARY STANDARDS
This section draws on the previous evaluation of scientific information
and summarizes the principal factors bearing on selection of primary CO
standard levels and on designating appropriate averaging times and forms.
Preliminary staff recommendations for each of these choices also are
presented.
A. Averaging Times
Currently there are primary CO standards for both 1-hour and 8-
hour averaging times. The original 8-hour averaging time was selected
primarily because most individuals achieve equilibrium or near equilibrium
levels of COHb after 8 hours of continuous exposure. Another reason for
the 8-hour averaging time is that many people are exposed in approximately
8-hour blocks of time (e.g., work, sleep). The 8-hour averaging time
provides a good indicator for tracking continuous exposures that occur
during any 24-hour period. The 1-hour averaging time provides an
appropriate time frame for evaluating health effects from short-term
exposures. As discussed in the June 1979 staff paper,^a the 1- and 8-
hour averaging time standards can also provide reasonable protection
against high spikes of less than 1-hour duration ("the bolus effect") in
the urban ambient environment. The staff recommends both the 1- and 8-
hour averaging times be retained for the primary standards.
B. Form of the Standards
The current CO standards are stated in a deterministic form,
allowing only one exceedance per year. The general limitations of the
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29
deterministic form are discussed in Biller and Feagans (1981).75
Recognition of these limitations has led EPA to promulgate a statistical
form for the ozone standards (44 FR 8202) and to propose a statistical
form for the CO standards (45 FR 55066). The statistical form of the
standard (e.g., stating an allowable number of exceedances of the standard
level as an average or expected number per year) offers a more stable
target for control programs and is less sensitive than a deterministic form
to very unusual meteorological conditions. The emissions reductions to
be achieved in the required control implementation program would be based
on a statistical analysis of the monitoring data over a multi-year period
(e.g., the preceding 3-year period).
EPA has considered the possibility of setting a multiple expected
•
exceedances standard (47 FR 26407). At a July 6, 1982 public meeting,
the CASAC discussed several advantages and liabilities of setting a
multiple expected exceedances standard for CO. Based on the discussion
at that meeting, the Chairman of CASAC sent a letter to the Administrator
recommending adoption of a multiple expected exceedances standard with a
standard level suitably adjusted to provide adequate protection of public
health.10 Subsequent to the CASAC meeting, the Agency received a number of
comments both for and against multiple exceedances standards. In particular,
the State and Territorial Air Pollution Program Administrators (STAPPA)
sent a resolution to EPA expressing the view that a single exceedance CO
standard would be preferable to a multiple exceedance standard because the
former (1) is more directly related to the health effects of concern and
(2) is more clearly understood by the public than a multiple expected
exceedances standard. The staff recommends that for the CO decision the
standards be stated in terras of a single expected exceedance based on
(1) the comments made by State air pollution control agencies and others
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regarding the advantages of a single exceedance standard and (2) the
advantages of a statistical (i.e., expected exceedance) standard discussed
above.
C. Levels of the Standards
The principal conclusions derived from the scientific evidence
described in Section IV of this paper and in the draft Addendum to the
1979 Criteria Document^ that are relevant to the standard selection process
are summarized below:
(1) Cardiovascular effects are judged to be the health effects of
greatest concern that have been associated with CO exposure levels observed
in the ambient air. In particular, there is no change in the staff's judgment
as stated in the 1980 proposal that decreased time to onset of angina and
prolonged duration of angina attacks should be considered adverse health
effects. The staff concludes from its review of the scientific evidence
that aggravation of angina is likely to occur at COHb levels in the range
3.0-4.5 percent. This judgment is based principally on the Anderson
et al. (1973)21 study. The Aronow studies^»12,13 report that aggravation
of angina and peripheral vascular disease may occur at levels below 3.0
percent COHb. However, in view of the concerns expressed by the Horvath
Panel^S about the design and conduct of the Aronow studies, further experimental
confirmation is needed on the question of whether these effects occur at
levels below 3.0 percent COHb. The Aronow studies should be considered
only in developing a margin of safety.
(2) Several controlled human exposure studies^O,80-81 nave reported
effects on maximum aerobic and exercise capacity for healthy vigorously
exercising adults exposed to CO. The staff's assessment of these studies is
that small (3-7 percent) reductions in work time are likely to occur at
COHb levels in the range 2.3-5.0 percent. It should be noted, however, that
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31
the effects observed at these levels are not clearly of health significance.
At higher COHb levels (7 percent), one study29 reported a 38 percent decrease
in work time for healthy adults engaged in heavy exercise.
At submaximal exercise levels there appear to be little if any effects
on aerobic or work capacity for healthy individuals exposed to COHb levels
up to 15-20 percent. However, the possibility that individuals with severe
chronic respiratory disease may be affected at COHb levels below 5 percent
has not been investigated. The possible impairment of work capacity for
individuals with chronic respiratory disease should, therefore be included
as a margin of safety consideration in selection of the final standards.
(3) Additional factors which we believe should be considered in
selecting CO primary standards which provide an adequate margin of safety
include:
(a) there are no valid human controlled experimental studies
reporting no adverse health effects at COHb levels below 2.9 percent for
cardiovascular effects,
(b) concern about animal study evidence indicating that there
may be detrimental effects on fetal development,
(c) concern about other potentially sensitive population groups
that have not been adequately tested such as the elderly, anemics, and
visitors to high altitude,
(d) uncertainties regarding the uptake of CO and the accuracy of
the Coburn equation in assessing uptake under varying conditions,
(e) uncertainties about the Exposure Analysis^ estimates of the
expected number of individuals achieving various COHb levels upon attainment
of alternative standards,
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32
(f) uncertainty regarding adverse health effects that may result
from very short duration high-level CO exposures (the bolus effect), and
(g) concern about possible interactions between CO and other
pol1utants.
All of the above factors were previously discussed in greater detail in
Section IV-F of this paper.
D. Staff Conclusions and Recommendations
Based on the assessment of the scientific evidence discussed in the
draft Addendum^ and in previous sections of this paper, the staff remains
concerned that adverse health effects may be experienced by large numbers
of sensitive individuals at COHb levels in the range S.Ojto 5.0 percent.
Unless the primary standards are set to keep most of the sensitive population
somewhat below these levels, we believe that the Agency would not be
exercising the degree of prudence called for by the Clean Air Act requirement
that primary standards be set to provide "an adequate margin of safety."
Based on the revised Exposure Analysis^ estimates summarized in Table 5,
8-hour standards with one expected exceedance allowed per year in the range
of 9 to 15 ppm are estimated to keep 99 percent or more of the sensitive
population below 3.0 percent COHb. Standards within this range would
provide different levels of protection. For example, a 9 ppm, 8-hour
average standard is estimated to keep more than 99 percent of the adult
population below 2.1 percent COHb and a 15 ppm standard would keep almost
99 percent of the adult population below 3.0 percent COHb. In using
the Exposure Analysis estimates to evaluate the protection afforded by
alternative standards, it should be noted that the above exposure estimates
are based on best judgments of certain key inputs to the analysis. The
uncertainty associated with these estimates should, therefore, also be
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33
considered in evaluating alternative standards. To the extent that the
uncertainty may lead to overestimates of the protection afforded by any
particular standard, selection of a more protective standard is appropriate,
In view of the lack of negative controlled human exposure evidence
concerning the impact of COHb levels below 3.0 percent on individuals with
cardiovascular disease, the margin of safety considerations discussed in
Section IV-F of this paper, and the precautionary nature of the Clean Air
Act, the staff is concerned that 8-hour standards at the upper end of the
range 9 to 15 ppm would provide little or no margin of safety. Therefore,
the staff recommends that the Administrator retain or select an 8-hour
standard in the range 9 to 12 ppm. With regard to the 1-hour primary
standard the staff recommends that 1-hour standards in the range 25 to 35
ppm be retained or set to provide a comparable level of protection.
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APPENDIX A. CASAC CLOSURE LETTER
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Arl
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C. 20460
May 17, 1984
OFFICE OF
THE AOMINIST* A TOW
Honorable William D. Puckelshaus
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Eear Mr. Ruckelshaus:
The Clean Air Scientific Advisory Ccmmittee (CASAC) has completed its
review of two documents related to the development of revised primary
National Ambient Air Quality Standards (NAA3S) for Carbon Monoxide (CO).
The 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 paper 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 (OAOPS). The
Comittee unanimously concluded that both documents represent a scientifically
balanced and defensible .summary of the current basis of cur 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 conducting a review of the protocols for a major
series of peer reviewed studies, carried' out by Dr. Wilbert Aronow," 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 OFD and OAQPS moved quickly and resolutely to analyze
the remaining scientific basis for the Clean Air Act requirement to finalize
a revised CO standard. The 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
recommendation is contained in the enclosed report.
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A.2".
Thank you for the opportunity to present the Cornrni ttee ' s vievs on this
important public health issue.
Sincerely,
Enclosure
cc: Mr. Alvin Aln
Mr. Joseph Cannon
Dr. Bernard Goldstein
Dr. Terrv Ycsie
Morton LipprTanns Qiaiman
Clean Air Scientific
Advisory Ccnroittee
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A-3
CASAC Findings and Recannnendations on the Scientific Basis for
a Revised NAAQS for Carbon Monoxide
Addendum to the CO Air Oualitv 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 Committee reached this finding following an extensive review of the
scientific literature, including a series of studies performed by Dr. Wilbert
Aronow. CASAC expressed seme 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 seme confounding factors in the study
protocols were not appropriately accounted for. The Conmittee further
reccmended that "given the uncertainties stemming fron 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 NAAOS
for carbon monoxide. In that report the Conmittee reaffirmed its prior
findings on the critical COKb effects level. It should be noted that
CASAC's 1982 reccmmendations ware reached after the Conmittee members
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A-4
had an opportunity to review an additional (1981) study by Dr. Aroncw which
concluded that a 10% reduction in the time to onset of an angina attack
occurred during treadmill exercise with 2% ODHb.
A review of the most recent update of this scientific literature in
the August 1983 draft EPA Addendum to the CD 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 Conmittee's position. These include:
A. The role of the Aroncw studies
A key question raised about Aroncw's work was" whether or net 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 grscp and the-control group.
It is apparent that such double blind procedures were not applied in Aroncw1 s
work because technicians who were directly involved with the subjects kne-7
seme of the iirportant parameters of the study. The lack of quality assurance
checks represents another issue of concern. In these respects, the results
of Aroncw's work do net 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 CQfib level.
B. The role of the Andersen study
The 1973 study by Anderson et al. reported that angina patients exposed
to low CD levels while at rest experienced a statistically significant reduction
in time to onset of exercise induced angina at average COfib levels of 2.9% and
4.5%. The study further concluded that there was a significantly lengthened
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angina attack during exercise at an average OOHb level of 4.5%. The 1983
CO criteria document addendum noted concerns expressed by scrne 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
Committee 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
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 time to
dispute the reported values, and it reconmends that the Agency not disregard
its findings.
C. Additional studies
CASAC wishes to point cut two sets of additional studies which lend
support to concerns about low level CO exposures. In 1.974, 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 nen at approximately 2.3 - 2.8% CDHb. 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.
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A-6
D. Use of the Coburrrroster-Kane (CFK) equation
The CFK model is the most important available tool for analyzing a
number of physiologically important variables (blood volume and endogenous
CD production rate, for example) in order to project a relationship
between ambient CO exposures and resulting COKb levels. While this
model, like any model, is subject to the need for additional evaluation
of ODKb 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 Cormittee unanimously agrees* that: 1) the key mechanism of CO toxicity"
is the decreased oxygen carrying capacity resulting fron the greater af-
finity of blood hemoglobin for carbon monoxide than for oxygen; 2) reduction
in tine 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 paer reviewed scientific literature (not including the Aroncw
•
studies), the critical effects level for NAACS setting purposes is
approximately 3% COHb (not including a margin of safety).
2. A second important public health issue in setting a NAACS 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 issu*» of the role of CO in
Sudden Infant Death Syndrome (SIDS). A review of the current scientific
-------
literature leads to the conclusion that there is not a sufficient scientific
basis to establish a connection between a CD exposure level and SIES.
OAOPS Staff Paper Review of the NAAOS For Carbon Monoxide
Based upon the addendum to the revised Air Quality Criteria Document
for Carbon Monoxide, QPOPS 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 fl-hour and 1-hour
standards are the appropriate averaging times, but it reccmmends
that there be additional discussion and more explicit conparison
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 QftOES for margin of safety
consideration are appropriate. Underlying CASAC's view of
the margin of safety, however, is its traditional belief that
-------
A-8
where the scientific data, as in this case, are subject to large
uncertainties, it is rtesirable for the Administrator to consider a
greater margin of safety than the numerical values of CDKb generated
by the Coburn equation might otherwise suggest.
4. The QAOPS staff reconnEnds 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 recamrends
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 anrf Discussion of margin
of safety issues, the Committee recommends that you consider
choosing standard limits that maintain approximately current
levels of protection.
-------
REFERENCES
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-------
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of fibrinolysis in rabbits exposed to low and moderate levels of carbon
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Research Triangle Park, N.C. November 1982.
74. Johnson, T. and R.A. Paul. The NAAQS Exposure Model (NEM) Applied to
Carbon Monoxide (Draft) Prepared by PEDCo Environmental, Inc. for
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August 1983.
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-------
TECHNICAL REPORT DATA .
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-450/5-84-OU4
3. RECIPIENT'S ACCESSION MO.
4. TITLE AND SUBTITLE
Review of the NAAQS for Carbon Monoxide;
Reassessment of Scientific and Technical
5. REPORT DATE
July 1984
Information
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
. PERFORMING ORGANIZATION NAME AND ADDRESS
Office of Air and Radiation
Office of Air Quality Planning and Standards
U.S. Environmental Protection Agency
Research Triangle Park; North Carolina 27711
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Final
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This paper evaluates and interprets the available scientific and technical
information that EPA staff believes ts most relevant to the review of the primary
(health), national ambient air quality standards for carbon monoxide and presents
staff recommendations on alternative approaches to revising the standards. The
assessment ts intended to bridge the gap between the scientific review in the EPA
criteria document and criteria document addendum for carbon monoxide and the judgments
required of the Administrator in setting ambient air quality standards for carbon
monoxide.
The major recommendations of the staff paper include the following:
1). that the 8-hour primary standard level be set in the range 9 to 12 parts
per million;
2) that the 1-hour primary standard level be set in the range 25 to 35 parts
per million to provide a comparable level of protection.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
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Carbon Monoxide
Air Pollution
Air Quality Standards
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53
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ended terms written in descriptor form for those subjects for which no descriptor exists.
(c) COS ATI FIELD GROUP - Field and group assignments are to be taken from the 1965 COSATI Subject Category List. Since the ma-
jority of documents are multidisciplinary in nature, the Primary Field/Group assignment(s) will be specific discipline, area of human
endeavor, or type of physical object. The application(s) will be cross-referenced with secondary Field/Group assignments that will follow
the primary posting(s).
18. DISTRIBUTION STATEMENT
Denote releasability to the public or limitation for reasons other than security for example "Release Unlimited." Cite any availability to
the public, with address and price.
19. & 20. SECURITY CLASSIFICATION
DO NOT submit classified reports to the National Technical Information service.
21. NUMBER OF PAGES
Insert the total number of pages, including this one and unnumbered pages, but exclude distribution list, if any.
22. PRICE
Insert the price set by the National Technical Information Service or the Government Printing Office, if known.
EPA Form 2220-1 (Rev. 4-77) (Reverse)
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