Chapter 2. Integrative Overview 

The subsequent chapters of this ISA present the most policy-relevant information related to 

this review of the NAAQS for CO, including a synthesis of the evidence presented in the 2000 CO 

AQCD (U.S. EPA, 2000, 000907), along with the assessment of more recent studies. This chapter 

integrates important findings from the disciplines evaluated in this current assessment of the CO 

scientific literature, which includes the atmospheric sciences, ambient air data analyses, climate 

forcing effects, exposure assessment, dosimetry, and health effects research (animal toxicological 

studies, controlled human exposure studies, and epidemiologic studies). The EPA framework for 

causal determinations described in Chapter 1 has been applied to the body of evidence evaluated in 

this assessment in order to characterize the relationship between exposure to CO at relevant 

concentrations and health effects. The EPA framework applied here employs a five-level hierarchy 

that classifies the weight of evidence for causation: 

 Causal relationship 

 Likely to be a causal relationship 

 Suggestive of a causal relationship 

 Inadequate to infer a causal relationship 

 Not likely to be a causal relationship 

This evaluation led to causal determinations for several health outcome categories and 

characterization of the magnitude of the response, including responses in susceptible populations, 

over a range of relevant concentrations. This integration of evidence also provides a basis for 

characterizing the concentration-response relationships of CO and adverse health outcomes for the 

U.S. population, given the current state of knowledge. 

This chapter summarizes and integrates the newly available scientific evidence that best 

informs consideration of the policy-relevant questions that frame this assessment, which are 

presented in Chapter 1. Section 2.1 discusses the trends in ambient concentrations and sources of 

CO. Section 2.2 provides an overview of climate forcing related directly and indirectly to CO. 

Section 2.3 provides a brief summary of factors influencing personal exposure to ambient CO. 

Section 2.4 summarizes CO dosimetry and pharmacokinetics and describes what is known regarding 

the modes of action of CO. Section 2.5 integrates the evidence from studies that examined health 

effects related to short- and long-term exposure to CO and discusses important uncertainties 

identified in the interpretation of the scientific evidence. Section 2.6 summarizes policy-relevant 

considerations associated with exposure to CO including evidence of effects in potentially 

susceptible populations and information on the shape of the concentration-response function. Finally, 

Section 2.7 presents an integrated summary of the health effects of CO, reports the levels at which 

effects are observed and discusses important uncertainties to consider in the interpretation of the 

scientific evidence. 

2.1. Ambient CO Sources and Concentrations 

CO is formed by incomplete combustion of carbon-containing fuels and by photochemical 

reactions in the atmosphere. Nationally, on-road mobile sources constituted more than half of total 

CO emissions in 2002, or ~61 of ~117 million tons (MT) of total CO emissions, based on the most 

recent publicly available data meeting data quality objectives from EPA’s National Emissions 

 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and 

Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of 

developing science assessments such as the Integrated Science Assessments (ISAs) and the Integrated Risk Information System (IRIS). 

January 2010 2-1 
Inventory (NEI). In metropolitan areas in the U.S., as much as 75% of all CO emissions result from 

on-road vehicle exhaust. The majority of these on-road CO emissions are derived from gasolinepowered vehicles. When emissions from incomplete combustion of fuels powering nonroad mobile 

sources, such as farm and construction equipment, lawnmowers, boats, ships, snowmobiles, and 

aircraft, are included, all mobile sources accounted for ~80% of total CO emissions in the U.S. in 

2002. Other primary sources of CO include wildfires, controlled vegetation burning, residential 

biomass combustion, and industrial processes. While CO emissions from nonroad mobile sources, 

wild fires, and industry have remained fairly constant, on-road mobile source CO emissions have 

decreased by roughly 5% per year since the early 1990s. Secondary sources of CO include the 

oxidation of both anthropogenic and biogenic hydrocarbons, such as methane and isoprene and other 

carbon containing species including aldehydes and alcohols. During summer when biogenic 

emissions are at their peak, secondary sources of CO are estimated to be a significant fraction of 

total U.S. sources; however, secondary sources are dispersed over the entire country, while direct 

emissions are concentrated near primary sources, such as on-road mobile sources, which are mainly 

in urban areas. Although these estimates are generated using well-established approaches, 

uncertainties are inherent in the emission factors and models used to represent sources for which 

emissions have not been directly measured, and these uncertainties vary by source category, season, 

and region. 

Significant reductions in ambient CO concentrations and in the number of NAAQS 

exceedances have been observed over the past 25 yr, a continuation of trends documented in the 

2000 CO AQCD (U.S. EPA, 2000, 000907). Nationwide ambient CO data from the EPA Air Quality 

System (AQS) for the years 2005-2007 show that the median 1-h daily maximum (max) 

concentration across the U.S. was 0.7 ppm; the mean was 0.9 ppm; the 95th percentile was 2.4 ppm; 

and the 99th percentile was 3.8 ppm. Roughly one-third of the 1-h daily max data fell below the limit 

of detection (LOD) for the majority of CO monitors reporting to AQS. The median 8-h daily max 

ambient CO concentration for the years 2005-2007 was 0.5 ppm; the mean was 0.7 ppm; the 95th 

percentile was 1.7 ppm; and the 99th percentile was 2.6 ppm. Half of the 8-h daily max 

concentrations fell below the LOD for the majority of CO monitors in the field. The current CO 

NAAQS are 35 ppm (1-h avg) and 9 ppm (8-h avg), not to be exceeded more than once per year. 

During the years 2005-2007, 1-h and 8-h CO concentrations did not exceed the NAAQS level more 

than once per year at any monitoring site. Moreover, in these 3 yr, a 1-h avg concentration in excess 

of 35 ppm was reported only once (39 ppm), and there were only 7 reported 8-h avg values 

nationwide in excess of 9 ppm in all 3 yr. Seasonally divided box plots of data from 2005-2007 

compiled for spatially diverse urban metropolitan areas illustrate the tendency for higher median CO 

concentrations and wider variations in concentrations in the winter and fall compared with the spring 

and summer (Section 3.5). 

Policy-relevant background (PRB) concentrations include contributions from natural sources 

everywhere in the world and from anthropogenic sources outside the U.S., Canada, and Mexico. 

PRB concentrations of CO were estimated for this assessment using data for the years 2005-2007 

collected at 12 remote sites in the U.S. which are part of the National Oceanic and Atmospheric 

Administration’s (NOAA) Global Monitoring Division (GMD) and are not part of the EPA national 

regulatory network. The 3-yr avg CO PRB averaged ~0.13 ppm in Alaska, ~0.10 ppm in Hawaii, and 

~0.13 ppm over the contiguous U.S. (CONUS). The analysis for North American PRB in this 

assessment was made by segregating the three Alaska sites based on their high latitude and the two 

Hawaii sites based on their distance from the continent, and then treating the remaining seven sites 

as being more representative of the CONUS PRB. Note that these seven sites are affected by 

anthropogenic emissions in North America to varying degrees. 

2.2. Climate Forcing Effects 

Recent data do not alter the current well-established understanding of the role of urban and 

regional CO in continental- and global-scale chemistry outlined in the 2000 CO AQCD (U.S. EPA, 

2000, 000907) and subsequently confirmed in the recent global assessments of climate change by the 

Intergovernmental Panel on Climate Change (IPCC, 2001, 156587; IPCC, 2007, 092765). CO is a 

weak direct contributor to radiative forcing (RF) and greenhouse warming. Sinha and Toumi (1996, 

193747) estimated the direct RF of CO computed for all-sky conditions at the tropopause to be 

January 2010 2-2 
0.024 W/m2

 based on an assumed change in CO mean global concentrations from 25 to 100 ppb 

since preindustrial times. The direct RF attributed to CO over this time frame is ~1.5% of the direct 

RF for CO2 estimated by the IPCC (Forster et al., 2007, 092936). 

More importantly, CO can indirectly cause increased RF because it reacts with tropospheric 

OH and thus can increase the lifetime of trace gases in the atmosphere including the GHGs CH4 and 

O3. Additionally, the major pathway for removal of CO from the atmosphere is reaction with OH to 

produce CO2. CH4, O3, and CO2 absorb infrared radiation from the Earth’s surface and contribute to 

the greenhouse effect. Indirect RF attributed to 1750-2005 emissions of CO through changes in 

concentration of the GHGs O3, CH4, and CO2 was estimated by Forster et al. (2007, 092936) to be 

~0.2 W/m2, or ~12% of the direct RF of CO2 (Figure 3-7). The future direct and indirect integrated 

RF for year 2000 emissions of CO was estimated to be ~0.2 W/m2

⋅yr with ~50% uncertainty over 

both 20-yr and 100-yr time horizons (Figure 3-8). The RF related to short-lived CO is ~25% of that 

for CO2 for a 20-yr time horizon but only ~7% of that for longer-lived CO2 over a 100-yr horizon. 

Overall, the evidence reviewed in this assessment is sufficient to conclude that a causal 

relationship exists between current atmospheric concentrations of CO and effects on 

climate. 

2.3. Exposure to Ambient CO 

Very few recent exposure assessment studies involve ambient CO concentration data. The 

studies of personal exposure to ambient CO presented here generally found that the largest 

percentage of time in which an individual is exposed to ambient CO occurs indoors but that the 

highest ambient CO exposure levels occur in transit. In-vehicle CO concentrations are typically 

reported to be between 2 and 5 times higher than ambient concentrations, although peak in-vehicle 

concentrations more than an order of magnitude higher than corresponding ambient monitor 

concentrations have also been reported. Among commuters, exposures were higher for those 

traveling in automobiles in comparison with those traveling on buses and motorbikes and with those 

cycling or walking. Ambient CO exposure in automobiles has been demonstrated to vary with 

vehicle ventilation settings, and a very small portion of that exposure is thought to come from the 

vehicle in which the exposed person travels. High near-road CO concentrations can be important for 

those living in the near-road environment because virtually all of ambient CO infiltrates indoors. 

Hence, indoor exposure to ambient CO is determined by the CO concentration outside the building. 

CO concentration in the near-road environment has been shown to decrease sharply with downwind 

distance from a highway, wind direction, and emission source strength (e.g., number of vehicles on a 

highway); natural and urban topography also influence localized ambient CO concentrations. 

Recent exposure assessment studies support one of the main conclusions of the 2000 CO 

AQCD (U.S. EPA, 2000, 000907), that central site ambient CO monitors may overestimate or 

underestimate individuals’ personal exposure to ambient CO because ambient CO concentration is 

spatially variable, particularly when analyzing exposures in the near-road environment. Exposure 

error may occur when the ambient CO concentration measured at the central site monitor is used as 

an ambient exposure surrogate and differs from the actual ambient CO concentration outside a 

subject’s residence and/or worksite. For example, measurement at a “hot spot” could skew 

community exposure estimates upwards, and likewise measurement at a location with few CO 

sources could skew exposure estimates downwards. Correlations across CO monitors can vary 

widely within and between cities across the U.S. as a function of natural and urban topography, 

meteorology, source strength and proximity to sources. Typically, intersampler correlation ranges 

from 0.35 to 0.65 for monitors sited at different scales within a metropolitan area, although it can be 

greater than 0.8 in some areas. 

Health effects estimates from time-series epidemiologic studies are not biased by spatial 

variability in CO concentrations if concentrations at different locations are correlated in time. 

Exposure assessment in epidemiologic studies is also complicated by the existence of CO in 

multipollutant mixtures emitted by combustion processes, making it difficult to quantify the health 

effects related specifically to CO exposure compared with those related to another combustionrelated pollutant or mix of pollutants. In most circumstances, exposure error tends to bias a health 

effect estimate downward (Sheppard et al., 2005, 079176; Zeger et al., 2000, 001949). Spatial and 

temporal variability not fully captured by ambient monitors and correlation of CO with copollutants 

January 2010 2-3 
are examples of sources of uncertainty that could widen confidence intervals of health effects 

estimates. 

2.4. Dosimetry, Pharmacokinetics, and Mode of Action 

2.4.1. Dosimetry and Pharmacokinetics 

Upon inhalation, CO elicits various health effects by binding to and altering the function of a 

number of heme-containing molecules, mainly hemoglobin (Hb). The formation of COHb reduces 

the oxygen (O2)-carrying capacity of blood and impairs the release of O2 from oxyhemoglobin 

(O2Hb) to the tissues. The 2000 CO AQCD (U.S. EPA, 2000, 000907) has a detailed description of 

the well-established Coburn-Forster-Kane (CFK) equation, which has been used for many years to 

model COHb formation. Since then, models have been developed that include myoglobin (Mb) and 

extravascular storage compartments, as well as other dynamics of physiology relevant to CO uptake 

and elimination. These models have indicated that CO has a biphasic elimination curve, due to initial 

washout from the blood followed by a slower flux from the tissues. The flow of CO between the 

blood and alveolar air or tissues is controlled by diffusion down the pCO gradient. The uptake of CO 

is governed not only by this CO pressure differential but also by physiological parameters, such as 

minute ventilation and lung diffusing capacity that can, in turn, be affected by factors such as 

exercise, age, and medical conditions (e.g., obstructive lung disease). Susceptible populations, such 

as health-compromised individuals, are at a greater risk from COHb-induced health effects due to 

altered CO kinetics, compromised cardiopulmonary processes, and increased baseline hypoxia 

levels. Altitude also may have a substantial effect on the kinetics of COHb formation, especially for 

visitors to high-altitude areas. Compensatory mechanisms, such as increased cardiac output, combat 

the decrease in barometric pressure. Altitude also increases the endogenous production of CO 

through upregulation of heme oxygenase (HO). CO is considered a second messenger and is 

endogenously produced from the catabolism of heme proteins by enzymes such as HO-1 (the 

inducible form of heme oxygenase) and through endogenous lipid peroxidation. Finally, CO is 

removed from the body by expiration and oxidation to CO2. 

2.4.2. Mode of Action 

The diverse effects of CO are dependent upon concentration, duration of exposure, and the cell 

types and tissues involved. Responses to CO are not necessarily due to a single process and may 

instead be mediated by a combination of effects including COHb-mediated hypoxic stress and other 

mechanisms such as free radical production and the initiation of cell signaling. However, binding of 

CO to reduced iron in heme proteins with subsequent alteration of heme protein function is the 

common mechanism underlying the biological responses to CO (see Section 5.1). 

As discussed in the 2000 CO AQCD (U.S. EPA, 2000, 000907), the most well-known 

pathophysiological effect of CO is tissue hypoxia caused by binding of CO to Hb. Not only does the 

formation of COHb reduce the O2-carrying capacity of blood, but it also impairs the release of O2

from O2Hb. Compensatory alterations in hemodynamics, such as vasodilation and increased cardiac 

output, protect against tissue hypoxia. Depending on the extent of CO exposure, these compensatory 

changes may be effective in people with a healthy cardiovascular system. However, hemodynamic 

responses following CO exposure may be insufficient in people with decrements in cardiovascular 

function, resulting in health effects, as described in Section 5.2. Binding of CO to Mb, as discussed 

in the 2000 CO AQCD (U.S. EPA, 2000, 000907) and in Section 4.3.2.3, can also impair the delivery 

of O2 to tissues. Mb has a high affinity for CO, about 25 times that of O2; however, pathophysiologic 

effects are seen only after high-dose exposures to CO, resulting in COMb concentrations far above 

baseline levels. 

Nonhypoxic mechanisms underlying the biological effects of CO have been the subject of 

recent research since the 2000 CO AQCD (U.S. EPA, 2000, 000907). Most of these mechanisms are 

related to CO’s ability to bind heme-containing proteins other than Hb and Mb. These mechanisms, 

which may be interrelated, include alteration in nitric oxide (NO) signaling, inhibition of 

January 2010 2-4 
cytochrome c oxidase, heme loss from proteins, disruption of iron homeostasis, alteration in cellular 

redox status, alteration in ion channel activity and modulation of protein kinase pathways. CO is a 

ubiquitous cell signaling molecule with numerous physiological functions. The endogenous 

generation and release of CO from heme by HO-1 and HO-2 is tightly controlled, as is any 

homeostatic process. However, exogenously-applied CO has the capacity to disrupt multiple hemebased signaling pathways due to its nonspecific nature. Only a limited amount of information is 

available regarding the impact of exogenous CO on tissue and cellular levels of CO and on signaling 

pathways. However, recent animal studies demonstrated increased tissue CO levels and biological 

responses following exposure to 50 ppm CO. Whether or not environmentally-relevant exposures to 

CO lead to adverse health effects through altered cell signaling is an open question for which there 

are no definitive answers at this time. However, experiments demonstrating oxidative/nitrosative 

stress, inflammation, mitochondrial alterations and endothelial dysfunction at concentrations of CO 

within one or two orders of magnitude higher than ambient concentrations suggest a potential role 

for such mechanisms in pathophysiologic responses. Furthermore, prolonged increases in 

endogenous CO resulting from chronic diseases may provide a basis for the enhanced sensitivity of 

susceptible populations to CO-mediated health effects such as is seen in individuals with coronary 

artery disease. 

2.5. Health Effects 

This assessment reviewed health effects evidence regarding the effect of CO on several 

categories of health outcomes. Table 2-1 presents the overall conclusions of the ISA regarding the 

presence of a causal relationship between short-term (i.e., hours, days, or weeks) or long-term (i.e., 

months or years) exposure to relevant CO concentrations (defined in Chapter 1 as generally within 

one or two orders of magnitude of ambient CO concentrations) and health outcome categories. 

Summaries of the evidence supporting each causal determination and considerations relevant to 

application of the causal framework are provided in the following subsections. 

Table 2-1. Causal determinations for health effects categories. 

Outcome Category Exposure Period Causality Determination 

Short-term Likely to be a causal relationship Cardiovascular morbidity Long-term Inadequate to infer a causal relationship 

Central nervous system effects Short- and long-term Suggestive of a causal relationship 

Birth outcomes and Developmental effects Long-term Suggestive of a causal relationship 

Short-term Suggestive of a causal relationship Respiratory morbidity Long-term Inadequate to infer a causal relationship 

Short-term Suggestive of a causal relationship Mortality Long-term Not likely to be a causal relationship 

2.5.1. Cardiovascular Morbidity 

The most compelling evidence of a CO-induced effect on the cardiovascular system at COHb 

levels relevant to the current NAAQS comes from a series of controlled human exposure studies 

among individuals with coronary artery disease (CAD) (Section 5.2). These studies, described in the 

1991 (U.S. EPA, 1991, 017643) and 2000 (U.S. EPA, 2000, 000907) CO AQCDs, demonstrate 

consistent decreases in the time to onset of exercise-induced angina and ST-segment changes 

following CO exposures resulting in COHb levels of 2-6% (Section 5.2.4). No human clinical 

studies have been designed to evaluate the effect of controlled exposures to CO resulting in COHb 

concentrations lower than 2%. Human clinical studies published since the 2000 CO AQCD 

January 2010 2-5 
(U.S. EPA, 2000, 000907) have reported no association between CO and ST-segment changes or 

arrhythmia; however, none of these studies included individuals with diagnosed heart disease. 

While the exact physiological significance of the observed ST-segment changes among 

individuals with CAD is unclear, ST-segment depression is a known indicator of myocardial 

ischemia. It is also important to note that the individuals with CAD who participated in these 

controlled exposure studies may not be representative of the most sensitive individuals in the 

population. It is conceivable that the most sensitive individuals respond to levels of COHb lower 

than those evaluated in controlled human exposure studies. Variability in activity patterns and 

severity of disease among individuals with CAD is likely to influence the critical level of COHb 

which leads to adverse cardiovascular effects. 

The degree of ambient CO exposure which leads to attainment of critical levels of COHb will 

also vary between individuals. Although endogenous COHb is generally <1% in healthy individuals, 

higher endogenous COHb levels are observed in individuals with certain medical conditions. 

Nonambient exposures to CO, such as exposure to environmental tobacco smoke (ETS), may 

increase COHb above endogenous levels, depending on the gradient of pCO. Ambient exposures 

may cause a further increase in COHb. Modeling results described in Chapter 4 indicate that 

increases of ~1% COHb are possible with exposures of several ppm CO depending on exposure 

duration and exercise level. 

Findings of epidemiologic studies conducted since the 2000 CO AQCD (U.S. EPA, 2000, 

000907) are coherent with results of the controlled human exposure studies. These recent studies 

observed associations between ambient CO concentration and emergency department (ED) visits and 

hospital admissions (HAs) for ischemic heart disease (IHD), congestive heart failure (CHF) and 

cardiovascular diseases (CVD) as a whole and were conducted in locations where the mean 24-h avg 

CO concentrations ranged from 0.5 ppm to 9.4 ppm (Table 5-7). All but one of these studies that 

evaluated CAD outcomes (IHD, MI, angina) reported positive associations (Figure 5-2). Although 

CO is often considered a marker for the effects of another traffic-related pollutant or mix of 

pollutants, evidence indicates that CO associations generally remain robust in copollutant models 

and supports a direct effect of short-term ambient CO exposure on CVD morbidity. These studies 

add to findings reported in the 2000 CO AQCD (U.S. EPA, 2000, 000907) that demonstrated 

associations between short-term variations in ambient CO concentrations and exacerbation of heart 

disease. 

The known role of CO in limiting O2 availability lends biological plausibility to ischemiarelated health outcomes following CO exposure. However, it is not clear whether the small changes 

in COHb associated with ambient CO exposures result in substantially reduced O2 delivery to 

tissues. Recent toxicological studies suggest that CO may also act through other mechanisms by 

initiating or disrupting cellular signaling. Studies in healthy animals demonstrated oxidative injury 

and inflammation in response to 50-100 ppm CO, while studies in animal models of disease 

demonstrated exacerbation of cardiomyopathy and increased vascular remodeling in response to 

50 ppm CO. Further investigations will be useful in determining whether altered cell signaling 

contributes to adverse health effects following ambient CO exposure. 

Given the consistent and coherent evidence from epidemiologic and human clinical studies, 

along with biological plausibility provided by CO’s role in limiting O2 availability, it is concluded 

that a causal relationship is likely to exist between relevant short-term exposures to CO 

and cardiovascular morbidity. 

Only two epidemiologic studies were identified that investigated the relationship between 

long-term exposure to CO and cardiovascular effects, and the results of these studies provide very 

limited evidence of an association (Section 5.2.2). Considering the lack of evidence from controlled 

human exposure studies and the very limited evidence from toxicological studies on cardiovascular 

effects following long-term exposure to CO, the available evidence is inadequate to conclude 

that a causal relationship exists between relevant long-term exposures to CO and 

cardiovascular morbidity.

2.5.2. Central Nervous System Effects 

Exposure to high levels of CO has long been known to adversely affect central nervous system 

(CNS) function, with symptoms following acute CO poisoning including headache, dizziness, 

January 2010 2-6 
cognitive difficulties, disorientation, and coma. However, the relationship between ambient levels of 

CO and neurological function is less clear and has not been evaluated in epidemiologic studies. 

Studies of controlled human exposures to CO discussed in the 2000 CO AQCD (U.S. EPA, 2000, 

000907) reported inconsistent neural and behavioral effects following exposures resulting in COHb 

concentrations of 5-20%. No new human clinical studies have evaluated central nervous system or 

behavioral effects of exposure to CO. At ambient-level exposures, healthy adults may be protected 

against CO-induced neurological impairment owing to compensatory responses including increased 

cardiac output and cerebral blood flow. However, these compensatory mechanisms are likely 

impaired among certain potentially susceptible groups including individuals with reduced 

cardiovascular function. 

Toxicological studies that were not discussed in the 2000 CO AQCD (U.S. EPA, 2000, 

000907) employed rodent models to show that CO exposure during the in utero or perinatal period 

can adversely affect adult outcomes, including behavior, neuronal myelination, neurotransmitter 

levels or function, and the auditory system (discussed in Section 5.3). In utero CO exposure, 

including both intermittent and continuous exposure, has been shown to impair multiple behavioral 

outcomes in offspring (75-150 ppm). In utero CO exposure (75 and 150 ppm) was associated with 

significant myelination decrements and neurotransmitter effects (up to 200 ppm). Finally, perinatal 

CO exposure has been shown to affect the developing auditory system of rodents, inducing 

permanent changes into adulthood (12.5-100 ppm), some of which appear to be reactive oxygen 

species mediated. Considering the combined evidence from controlled human exposure and 

toxicological studies, the evidence is suggestive of a causal relationship between relevant 

short- and long-term exposures to CO and central nervous system effects.

2.5.3. Birth Outcomes and Developmental Effects 

The most compelling evidence for a CO-induced effect on birth and developmental outcomes 

is for preterm birth (PTB) and cardiac birth defects. These outcomes were not addressed in the 2000 

CO AQCD (U.S. EPA, 2000, 000907), which included only two studies that examined the effect of 

ambient CO on low birth weight (LBW). Since then, a number of studies have been conducted 

looking at varied outcomes, including PTB, birth defects, fetal growth (including LBW), and infant 

mortality. 

There is limited epidemiologic evidence that CO during early pregnancy (e.g., first month and 

first trimester) is associated with an increased risk of PTB. The only U.S. studies to investigate the 

PTB outcome were conducted in California, and these reported consistent positive associations with 

CO exposure during early pregnancy when exposures were assigned from monitors within close 

proximity of the mother’s residential address. Additional studies conducted outside of the U.S. 

provide supportive, though less consistent, evidence of an association between CO concentration and 

PTB. 

Very few epidemiologic studies have examined the effects of CO on birth defects. Two of 

these studies found maternal exposure to CO to be associated with an increased risk of cardiac birth 

defects. Human clinical studies also demonstrated the heart as a target for CO effects (Section 5.2). 

Animal toxicological studies provide additional evidence for cardiac effects with reported transient 

cardiomegaly at birth after continuous in utero CO exposure (60, 125, 250 and 500 ppm CO) and 

delayed myocardial electrophysiological maturation (150 ppm CO). Toxicological studies have also 

shown that continuous in utero CO exposure (250 ppm) induced teratogenicity in rodent offspring in 

a dose-dependent manner that was further affected by dietary protein (65 ppm CO) or zinc 

manipulation (500 ppm CO). Toxicological studies of CO exposure over the duration of gestation 

have shown skeletal alterations (7 h/day, CO 250 ppm) or limb deformities (24 h/day, CO 180 ppm) 

in prenatally exposed offspring. 

There is evidence of ambient CO exposure during pregnancy having a negative effect on fetal 

growth in epidemiologic studies. In general, the reviewed studies, summarized in Figures 5-7 

through 5-9, reported small reductions in birth weight (ranging ~5-20 g). Several studies examined 

various combinations of birth weight, LBW, and small for gestational age (SGA)/intrauterine growth 

restriction (IUGR) and inconsistent results are reported across these metrics. It should be noted that 

having a measurable, even if small, change in a population is different than having an effect on a 

subset of susceptible births and increasing the risk of IUGR/LBW/SGA. It is difficult to conclude if 

CO is related to a small change in birth weight in all births across the population, or a marked effect 

January 2010 2-7 
in some subset of births. Toxicology studies have found associations between CO exposure in 

laboratory animals and decrements in birth weight (90-600 ppm), as well as reduced prenatal growth 

(65-500 ppm CO). 

In general, there is limited epidemiologic evidence that CO is associated with an increased risk 

of infant mortality during the neonatal or post-neonatal periods. In support of this limited evidence, 

animal toxicological studies provide some evidence that exogenous CO exposure to pups in utero 

significantly increased postnatal mortality (7 h/day and 24 h/day, 250 ppm CO; 24 h/day, 90 or 

180 ppm CO) and prenatal mortality (7 h/day, 250 ppm CO). 

Evidence exists for additional developmental outcomes which have been examined in 

toxicological studies but not epidemiologic or human clinical studies, including behavioral 

abnormalities, learning and memory deficits, locomotor effects, neurotransmitter changes, and 

changes in the auditory system. Structural aberrations of the cochlea involving neuronal activation 

(12.5, 25 and 50 ppm CO) and auditory related nerves (25 ppm CO) were seen in pups after neonatal 

CO exposure. Auditory functional testing using otoacoustic emissions testing (OAE at 50 ppm CO) 

and 8th cranial nerve action potential (AP) amplitude measurements (12, 25, 50, 100 ppm CO) in 

rodents exposed perinatally to CO showed auditory decrements at postnatal day (PND) 22 (OAE and 

AP) and permanent changes in AP into adulthood (50 ppm CO). Furthermore, exogenous CO may 

interact with or disrupt the normal physiological roles that endogenous CO plays in the body. There 

is evidence that CO plays a role in maintaining pregnancy, controlling vascular tone, regulating 

hormone balance, and sustaining normal ovarian follicular maturation. 

Overall, there is limited, though positive, epidemiologic evidence for a CO-induced effect on 

PTB and birth defects, and weak evidence for a decrease in birth weight, other measures of fetal 

growth, and infant mortality. Animal toxicological studies provide support and coherence for these 

effects. Both hypoxic and nonhypoxic mechanisms have been proposed in the toxicological literature 

(Section 5.1), though a clear understanding of the mechanisms underlying reproductive and 

developmental effects is still lacking. Taking into consideration the positive evidence for some birth 

and developmental outcomes from epidemiologic studies and the resulting coherence for these 

associations in animal toxicological studies, the evidence is suggestive of a causal relationship 

between relevant long-term exposures to CO and developmental effects and birth 

outcomes. 

2.5.4. Respiratory Morbidity 

New epidemiologic studies, supported by the body of literature summarized in the 2000 CO 

AQCD (U.S. EPA, 2000, 000907), provide evidence of positive associations between short-term 

exposure to CO and respiratory-related outcomes including pulmonary function, respiratory 

symptoms, medication use, hospital admissions, and ED visits. The majority of the studies evaluated 

have not conducted extensive analyses to examine the potential influence of model selection or effect 

modifiers on the association between CO and respiratory morbidity. A limited number of studies 

have examined the potential confounding effects of copollutants on CO risk estimates, and found 

that CO risk estimates were generally robust to the inclusion of O3, SO2, and PM in two-pollutant 

models, but were slightly attenuated in models with NO2. However, the limited amount of evidence 

from studies that have examined the effect of gaseous pollutants on CO-respiratory morbidity risk 

estimates in two-pollutant models, specifically NO2, has contributed to the inability to disentangle 

the effects attributed to CO from the larger complex air pollution mix (particularly motor vehicle 

emissions), and this limits interpretation of the results observed in the epidemiologic studies 

evaluated. A key uncertainty in interpreting the epidemiologic studies evaluated is the biological 

mechanism(s) that could explain the effect of CO on respiratory health. Animal toxicological studies, 

however, provide some evidence that short-term exposure to CO (50-100 ppm) can cause oxidative 

injury and inflammation and alter pulmonary vascular remodeling. Controlled human exposure 

studies have not extensively examined the effect of short-term exposure to CO on respiratory 

morbidity, with a very limited number of studies reporting inconsistent effects of CO on pulmonary 

function. Although these controlled human exposure studies do not provide evidence to support 

CO-related respiratory health effects, epidemiologic studies show positive associations for COinduced lung-related outcomes and animal toxicological studies demonstrate the potential for an 

underlying biological mechanism, which together provide evidence that is suggestive of a causal 

relationship between relevant short-term exposures to CO and respiratory morbidity. 

January 2010 2-8 
Currently, only a few studies have been conducted that examine the association between longterm exposure to CO and respiratory morbidity, including allergy. Although some studies did observe 

associations between long-term exposure to CO and respiratory health outcomes, key uncertainties 

still exist. These uncertainties include: the lack of replication and validation studies to evaluate new 

methodologies (i.e., Deletion/Substitution/Addition (DSA) algorithm) that have been used to 

examine the association between long-term exposure to CO and respiratory health effects; whether 

the respiratory health effects observed in response to long-term exposure to CO can be explained by 

the proposed biological mechanisms; and the lack of copollutant analyses to disentangle the 

respiratory effects associated with CO due to its high correlation with NO2 and other combustionrelated pollutants. Overall, the evidence available is inadequate to conclude that a causal 

relationship exists between relevant long-term exposures to CO and respiratory 

morbidity.

2.5.5. Mortality 

The recently available multicity studies, which consist of larger sample sizes, along with the 

single-city studies, evaluated reported associations that are generally consistent with the results of 

the studies evaluated in the 2000 CO AQCD (U.S. EPA, 2000, 000907). However, to date the 

majority of the literature has not conducted extensive analyses to examine the potential influence of 

model selection, effect modifiers, or confounders on the association between CO and mortality. 

The multicity studies reported comparable CO mortality risk estimates for total 

(nonaccidental) mortality, with the APHEA2 European multicity study showing slightly higher 

estimates for cardiovascular mortality in single-pollutant models. However, when examining 

potential confounding by copollutants, these studies consistently showed that although CO mortality 

risk estimates remained positive, they were reduced when NO2 was included in the model. But this 

observation may not be “confounding” in the usual sense in that NO2 may also be an indicator of 

other pollutants or pollution sources (e.g., traffic). 

Of the studies evaluated, only the APHEA2 study focused specifically on the CO-mortality 

association and in the process examined: (1) model sensitivity; (2) the CO-mortality C-R 

relationship; and (3) potential effect modifiers of CO mortality risk estimates. The sensitivity 

analysis indicated an approximate 50-80% difference in CO risk estimates from a reasonable range 

of alternative models, which suggests that some model uncertainty likely influences the range of CO 

mortality risk estimates obtained in the studies evaluated. The examination of the CO-mortality 

concentration-response relationship found very weak evidence for a CO threshold at 0.5 mg/m3

(0.43 ppm). Finally, when examining a variety of city-specific variables to identify potential effect 

modifiers of the CO-mortality relationship, the APHEA2 study found that geographic region 

explained most of the heterogeneity in CO mortality risk estimates. 

 The results from the single-city studies are generally consistent with the multicity studies in 

that some evidence of a positive association was found for mortality upon short-term exposure to 

CO. However, the CO-mortality associations were often but not always attenuated when copollutants 

were included in the regression models. In addition, limited evidence was available to identify causespecific mortality outcomes (e.g., cardiovascular causes of death) associated with short-term 

exposure to CO. 

The evidence from the recent multi- and single-city studies suggests that an association 

between short-term exposure to CO and mortality exists, but limited evidence is available to evaluate 

cause-specific mortality outcomes associated with CO exposure. In addition, the attenuation of CO 

risk estimates which was often observed in copollutant models contributes to the uncertainty as to 

whether CO is acting alone or as an indicator for other combustion-related pollutants. Overall, the 

epidemiologic evidence is suggestive of a causal relationship between relevant short-term 

exposures to CO and mortality. 

The evaluation of new epidemiologic studies conducted since the 2000 CO AQCD (U.S. EPA, 

2000, 000907) that investigated the association between long-term exposure to CO and mortality 

consistently found null or negative mortality risk estimates. No such studies were discussed in the 

2000 CO AQCD (U.S. EPA, 2000, 000907). The reanalysis of the American Cancer Society (ACS) 

data by Jerrett et al. (2003, 087380) found no association between long-term exposure to CO and 

mortality. Similar results were obtained in an updated analysis of the ACS data when using earlier 

(1980) CO data, but negative associations were found when using more recent (1982-1998) data. 

January 2010 2-9 
These results were further confirmed in an extended analysis of the ACS data. The Women’s Health 

Initiative (WHI) Study also found no association between CO and CVD events (including mortality) 

using the mortality data from recent years (1994-1998), while the series of Veterans Cohort studies 

found no association or a negative association between mean annual 95th percentile of hourly CO 

values and mortality. An additional study was identified that used a cross-sectional study design, 

which reported results for a study of U.S. counties that are generally consistent with the cohort 

studies: positive associations between long-term exposure to PM2.5 and SO4

2- and mortality, and 

generally negative associations with CO. Overall, the consistent null and negative associations 

observed across epidemiologic studies which included cohort populations encompassing potentially 

susceptible populations (i.e., post-menopausal women and hypertensive men) combined with the 

lack of evidence for respiratory and cardiovascular morbidity outcomes following long-term 

exposure to CO; and the absence of a proposed mechanism to explain the progression to mortality 

following long-term exposure to CO provide supportive evidence that there is not likely to be a 

causal relationship between relevant long-term exposures to CO and mortality.

2.6. Policy-Relevant Considerations 

2.6.1. Susceptible Populations 

The examination of populations potentially at greater risk for health effects due to CO 

exposure is an important consideration in setting NAAQS to provide an adequate margin of safety 

for both the general population and sensitive populations (see Section 5.7 for a more detailed 

discussion). During the evaluation of the CO literature, numerous studies were identified that 

examined whether underlying factors increased the susceptibility of an individual to CO-related 

health effects. These types of studies were those that included stratified analyses, examined 

individuals with an underlying health condition, or used animal models of disease. 

The most important susceptibility characteristic for increased risk due to CO exposure is CAD, 

also known as coronary heart disease (CHD). As discussed in Section 5.7, there were approximately 

13.7 million individuals with CHD in the U.S. in 2007. Persons with a normal cardiovascular system 

can tolerate substantial concentrations of CO, if they vasodilate or increase cardiac output in 

response to the hypoxia produced by CO. In contrast, individuals unable to vasodilate in response to 

CO exposure may show evidence of ischemia at low concentrations of COHb. Many of the 

controlled human exposure studies have focused on individuals with CAD, and several studies have 

found that controlled exposures to CO resulting in COHb concentrations of 2-6% result in significant 

decreases in time to onset of exercise-induced angina or ST-segment changes in patients with stable 

angina. Epidemiologic studies found limited evidence for increased hospital admissions for ischemic 

heart disease (IHD) in individuals with secondary diagnoses of dysrhythmias or congestive heart 

failure (CHF). This combined evidence from controlled human exposure and epidemiologic studies 

indicates that individuals with underlying cardiovascular disease, particularly CAD, are a large 

population that is susceptible to increased health effects in response to exposure to ambient CO. 

Additional evidence for increased CO-induced cardiovascular effects is provided by toxicological 

studies that observed altered cardiac outcomes in animal models of cardiovascular disease. 

Other medical conditions that have been linked to increased susceptibility to CO-induced 

health effects include COPD, diabetes, and anemia. Individuals with hypoxia resulting from COPD 

may be particularly sensitive to CO during submaximal exercise typical of normal daily activity. The 

results available from epidemiologic and controlled human exposure studies provide preliminary 

evidence that individuals with obstructive lung disease (e.g., COPD patients with underlying 

hypoxia, asthmatics) may be susceptible to cardiovascular or respiratory effects due to CO exposure. 

Diabetics are known to have elevated exhaled CO concentrations indicative of increased endogenous 

CO production rates. In addition, some recent epidemiologic studies provide preliminary evidence 

for increased associations between short-term CO exposure and ED visits and hospital admissions 

for cardiovascular disease (CVD) among diabetics compared to non-diabetics, as well as associations 

between short-term CO exposure and changes in HRV parameters among subjects with metabolic 

syndrome, but not among healthy subjects. Increased endogenous CO production and the potential 

January 2010 2-10 
for higher baseline COHb concentrations in individuals with diabetes, combined with the limited 

epidemiologic evidence showing cardiovascular effects, suggests that diabetics are potentially 

susceptible to short-term exposure to CO. Individuals with various forms of anemia experience 

lowered hematocrit or produce altered forms of hemoglobin, resulting in decreased arterial O2

content; in addition, individuals with hemolytic anemia exhibit increased endogenous CO production 

rates and COHb levels. This suggests that individuals with anemia who have diminished O2-carrying 

capacity and/or high baseline COHb levels may be more susceptible to health effects due to ambient 

CO exposure, although no studies were identified that evaluated specific CO-related health effects in 

anemic individuals. 

Aging alters physiological parameters that influence the uptake, distribution, and elimination 

of CO. The general impact of these changes over an individual’s lifetime increases the time required 

for both loading and elimination of CO from the blood. As noted in the 2000 CO AQCD (U.S. EPA, 

2000, 000907), changes in metabolism that occur with age, particularly declining maximal oxygen 

uptake, may make the aging population susceptible to the effects of CO via impaired oxygen 

delivery to the tissues. Some epidemiologic studies reported increases in IHD or myocardial 

infarction (MI) HAs among older adults as compared to all-age groups or younger adults in response 

to short-term exposure to CO. Older adults represent a large and growing fraction of the U.S. 

population and have a higher prevalence of CAD and other cardiovascular conditions than the 

general population; combined with the limited evidence available from epidemiologic studies, this 

indicates that older adults are a potentially susceptible population for increased health effects due to 

CO. 

During gestational exposure, fetal CO pharmacokinetics differ from maternal kinetics, in part 

because human fetal Hb has a higher CO affinity than adult Hb. At steady-state conditions, fetal 

COHb concentrations are up to 10-15% higher on a relative basis than maternal COHb levels, and 

these levels are maintained over a longer period since the half-life for fetal CO Hb is approximately 

twice that of maternal COHb (7.5 h versus 4 h). Some epidemiologic studies reported higher 

associations between short-term CO exposure and IHD or MI HAs among older adults as compared 

to all-age groups or younger adults. Epidemiologic studies provide some evidence that CO exposure 

during pregnancy is associated with changes in birth outcomes, including PTB, cardiac birth defects, 

reductions in birth weight, and infant mortality in the postneonatal period. Toxicological studies 

report effects in laboratory animals that lend biological plausibility to outcomes observed in 

epidemiologic studies, including decrements in birth weight, reduced prenatal growth, and effects on 

the heart. Toxicological evidence also exists for additional developmental outcomes which have not 

been examined in epidemiologic or human clinical studies, including behavioral abnormalities, 

learning and memory deficits, locomotor effects, neurotransmitter changes, and changes in the 

auditory system. This evidence suggests that critical developmental phases may be characterized by 

enhanced sensitivity to CO exposure. 

COHb concentrations are generally higher in males than in females, and the COHb half-life is 

longer in healthy men than in women of the same age. However, women experience fluctuating 

COHb levels through the menstrual cycle due to variations in the endogenous CO-production rate. 

Only a limited number of epidemiologic studies have examined gender differences, and found some 

evidence for larger effects in males compared to females when examining the association between 

short-term CO exposure and IHD HAs. The limited epidemiologic evidence combined with known 

gender-related differences in endogenous CO production do not provide sufficient basis for 

determining whether CO disproportionately affects males or females. 

Increased altitude induces a number of physiological changes as compensatory mechanisms to 

counteract the effects of decreased barometric pressure and the resulting altitude-induced hypobaric 

hypoxia (HH). These changes generally increase both CO uptake and elimination, with increased 

COHb levels observed in subjects at rest and decreased COHb observed in individuals exposed to 

CO during exercise. In addition, baseline COHb levels increase due to increased endogenous CO 

production. A controlled human exposure study observed an additive effect of CO exposure and 

simulated high altitude on the reduction in time to onset of angina among a group of individuals with 

CAD. Acclimatization occurs as the length of stay at high altitude increases, indicating that visitors 

to high-altitude locations may have an increased risk of health effects due to CO exposure and 

represent a potentially susceptible population. 

Physiological changes associated with exercise tend to increase both uptake and elimination of 

CO. In a controlled human exposure study, healthy subjects exposed to CO and achieving COHb 

levels of ~5% observed a significant decrement in exercise duration and maximal effort capability 

January 2010 2-11 
during heavy exercise. Due to the counterbalancing effects of increased COHb formation and 

elimination rates, it is unclear whether individuals engaging in light to moderate exercise represent a 

population potentially susceptible to ambient CO exposure. 

CO concentrations on and adjacent to heavily traveled roadways are several times higher than 

concentrations measured at fixed-site monitors not located adjacent to roadways. In addition, studies 

of commuters have shown that commuting time is an important determinant of CO exposure for 

those traveling by car, bicycle, public transportation, and walking. Census data indicate that 17.9 

million occupied homes nationwide (16.1%) are located within approximately 90 m of a freeway, 

railroad, or airport, and that 5.5 million U.S. workers (5%) commute 60 min or more to work in 

automobiles. This evidence for elevated on-road and near-road CO concentrations combined with 

residential and commuting data indicates that the large numbers of individuals who spend a 

substantial amount of time on or near heavily traveled roadways are an important population that is 

potentially susceptible to increased health risks due to ambient CO exposure. 

Endogenous CO production can be altered by medications or other substances, including 

nicotinic acid, allyl-containing compounds (acetamids and barbiturates), diphenylhydantoin, 

progesterone, contraceptives, and statins. One epidemiologic study observed an association between 

short-term CO exposure and an increase in SDNN for CAD patients not taking beta blockers; 

however, this association did not persist in CAD patients taking beta blockers. Other compounds 

such as carbon disulfide and sulfur-containing chemicals (parathion and phenylthiourea) increase CO 

following metabolism by cytochrome p450s. The p450 system may also cause large increases in CO 

produced from the metabolic degradation of dihalomethanes such as methylene chloride. Minor 

sources of endogenous CO include the auto-oxidation of phenols, photo-oxidation of organic 

compounds, and lipid peroxidation of cell membrane lipids. Taken together, this evidence indicates 

that individuals ingesting medications and other substances that enhance endogenous or metabolic 

CO production represent a population that is potentially susceptible to increased health effects due to 

additional exposure to ambient CO. 

Overall, the controlled human exposure, epidemiologic, and toxicological studies evaluated in 

this assessment provide evidence for increased susceptibility among multiple populations. Medical 

conditions that increase endogenous CO production rates may also contribute to increased 

susceptibility to health effects from ambient CO exposure. Although the weight of evidence varies 

depending on the factor being evaluated, the clearest evidence indicates that individuals with CAD 

are most susceptible to an increase in CO-induced health effects. 

2.6.2. Concentration- and Dose-Response Relationships 

Currently, very limited information is available in the human clinical and epidemiologic 

literature regarding the CO concentration- or dose-response (C-R, D-R) relationships and the 

potential existence of a CO threshold. Two human clinical studies described in the 1991 (U.S. EPA, 

1991, 017643) and 2000 (U.S. EPA, 2000, 000907) CO AQCDs have evaluated the D-R relationship 

between percent COHb (a measure of internal dose of CO) and onset of exercise-induced angina 

among individuals with CAD. Anderson et al. (1973, 023134) exposed 10 adult men with stable 

angina (5 smokers and 5 nonsmokers) for 4 h to CO concentrations of 50 and 100 ppm, which 

resulted in average COHb concentrations of 2.9% and 4.5%, respectively. Both exposures 

significantly decreased the time to onset of exercise-induced angina relative to room air control 

(1.6% COHb). However, there was no difference in response between the two exposure 

concentrations of CO. In a much larger study, 63 adults with stable angina were exposed for 1 h to 

2 concentrations of CO (average exposure concentrations of 117 and 253 ppm) resulting in average 

COHb concentrations in the range of 2.0-2.4% and 3.9-4.7% (Allred et al., 1989, 013018; Allred et 

al., 1989, 012697; Allred et al., 1991, 011871). Relative to control (average COHb 0.6-0.7%), COHb 

concentrations of 2.0-2.4% and 3.9-4.7% were observed to decrease the time required to induce STsegment changes indicative of myocardial ischemia by 5.1% (p = 0.01) and 12.1% (p < 0.001), 

respectively. Increasing COHb concentration was similarly shown to decrease the time to onset of 

exercise-induced angina. As described in Allred et al. (1989, 013018; 1989, 012697; 1991, 011871), 

the observed dose-response relationship was further evaluated by regressing the percent change in 

time to ST-segment change or time to angina on actual COHb concentration (0.2% - 5.1%) using the 

three exposures (air control and two CO exposures) for each subject. Regression analyses were 

conducted separately for each individual and the averages of the intercepts and slopes across subjects 

were reported. This analysis demonstrated statistically significant decreases in time to angina and 

January 2010 2-12 
ST-segment change of approximately 1.9% and 3.9%, respectively, per 1% increase in COHb 

concentration, with no evidence of a measurable threshold. The findings of Allred et al. (1989, 

013018; 1989, 012697; 1991, 011871) provide evidence of a significant D-R relationship over a 

range of COHb concentrations relevant to the NAAQS. While several other laboratory studies have 

evaluated cardiovascular effects of CO exposure among adults with CAD, differences in study 

protocols and analytical methods do not allow for an informative pooled or quantitative metaanalysis of the D-R relationship across studies (Section 5.2.4). 

Two studies in the epidemiologic literature attempted to examine the C-R relationship at the 

low end of CO concentrations through a threshold analysis. Samoli et al. (2007, 098420) in their 

examination of the association between short-term exposure to CO and mortality conducted an 

ancillary analysis to examine the potential presence of a CO threshold. In this analysis the authors 

compared city-specific models to the threshold model, which consisted of thresholds at 0.5 mg/m3

(0.43 ppm) increments. Samoli et al. (2007, 098420) then computed the deviance between the two 

models and summed the deviances for a given threshold over all cities. While the minimum deviance 

suggested a potential threshold of 0.43 ppm (the lowest threshold examined), the comparison with 

the linear no-threshold model indicated weak evidence (p-value > 0.9) for a threshold. However, 

determining the presence of a threshold at the very low range of CO concentrations (i.e., at 

0.43 ppm) in this data set is challenging, because, in 7 of the 19 European cities examined, the 

lowest 10% of the CO distribution was at or above 2 mg/m3

 (1.74 ppm). By only using the 12 cities 

in the analysis that had minimum CO concentrations approaching 0.5 mg/m3

 (0.43 ppm), a limited 

number of observations were examined around the threshold of interest, which subsequently 

contributed to the inability to draw conclusions regarding the potential presence of a threshold with 

any certainty. In addition to the time-series analyses investigating the association of CO 

concentrations with hospital admissions due to CVD among Medicare enrollees, Bell et al. (2009, 

193780) performed subset analyses using datasets that included only days with CO levels below 

certain specified values, ranging from 1 to 10 ppm (in 1 ppm increments). When these various COlimit values were evaluated, there were positive associations between cardiovascular health effects 

and CO concentrations at each level investigated in this study, thus providing no evidence for the 

existence of a threshold. The investigators also estimated an exposure-response curve allowing a 

nonlinear relationship between CO concentration and risk of CVD hospital admissions, and reported 

no evidence of departure from a linear exposure-response curve. 

2.7. Integration of CO Health Effects 

This section summarizes the main conclusions of this assessment regarding the health effects 

of CO and the concentrations at which those effects are observed. It also discusses important 

uncertainties that were considered in interpreting the health effects evidence. The clearest evidence 

for health effects associated with short-term exposure to CO is provided by studies of cardiovascular 

morbidity. The combined health effects evidence supports a likely causal relationship for this 

outcome. Controlled human exposure studies provide strong evidence of independent effects of CO 

on cardiac function, with effects being observed in patients with CAD following short-term CO 

exposures resulting in 2.0-2.4% COHb. Epidemiologic studies of ED visits and hospital admissions 

for ischemic heart disease report consistent positive associations with additional preliminary 

evidence for an increase in cardiovascular-related mortality provided by a multicity study. This 

epidemiologic evidence is coherent with ischemia-related effects observed in controlled human 

exposure studies. Recent toxicological evidence suggests that other mechanisms involving altered 

cellular signaling may play a role in cardiovascular disease outcomes following CO exposure. 

Consistent decreases in time to onset of exercise-induced angina, along with ST-segment 

changes indicative of myocardial ischemia, were observed in individuals with CAD following 

controlled CO exposures resulting in COHb concentrations of 2-6%, with no evidence of a threshold 

at the lowest levels tested. Modeling results described in Chapter 4 indicated that increases of ~1% 

COHb are possible with exposures of several ppm CO, depending on exposure duration and exercise 

level. Baseline COHb levels are <1% in healthy individuals, with higher endogenous CO production 

observed in individuals with certain medical conditions. The volunteers who participated in these 

studies were diagnosed with moderate to severe CAD, although they may not be representative of 

the most sensitive individuals in the population. Variability in activity patterns and severity of 

January 2010 2-13 
disease combined with daily fluctuations in baseline COHb levels may influence the critical level of 

increased COHb which leads to adverse cardiovascular effects in a particular individual. In addition, 

arterial COHb is transiently higher than venous COHb for several minutes following a rapid increase 

in inhaled CO concentration. Transient increases in ambient CO have the potential to elevate COHb 

to higher levels in the coronary arteries than in other vascular beds, possibly increasing heart CO 

levels and cardiovascular symptoms in diseased individuals. Quantification of the magnitude of 

effects at ambient concentrations from the results of controlled human exposure studies is difficult 

due to the gap between ambient concentrations and the higher concentrations used in these studies 

(i.e., experimental studies have not been conducted at levels within the range of current maximum 

ambient concentrations). 

Epidemiologic studies consistently show associations between ambient CO concentrations and 

cardiovascular endpoints other than stroke, particularly hospitalizations and ED visits for ischemic 

heart disease, MI, and angina. These effects are robust to adjustment for copollutants. Since the 

heterogeneity of endpoints in these studies does not lend itself to a quantitative meta-analysis, a 

forest plot was used to summarize the results. Figure 2-1 presents unadjusted health effect estimates 

from U.S. and Canadian studies of short-term CO exposure and CVD hospitalizations, along with 

mean and 99th percentile concentrations during the study periods. Table 2-2 summarizes the range of 

mean and 99th percentile concentrations observed in the studies presented in Figure 2-1. This 

evidence for ischemia-related outcomes is coherent with effects observed in controlled human 

exposure studies, although uncertainty regarding the extent of reduced O2 delivery to tissues 

following exposure to ambient CO concentrations contributes to the uncertainty in quantitative 

interpretation of effect estimates. 

Study Location Mean*a,b Avg Time Lag Outcome/ 

Group 

Effect Estimate (95% CI) 

 Non-Stroke CVD Endpoint

Symons et al. (2006, 091258) Baltimore, MD 0.4 (2.3) 8-h max 0-3 CHF 

Szyszkowicz (2007, 193793) Montreal, Can 0.5 24-h avg 0 IHD 

0 IHD, 65+ 

Wellenius et al. (2005, 087483) Pittsburgh, PA 1.03 (1.6-3.9) 24-h avg 0 CHF 

Bell et al. (2009, 193780) 126 U.S. Counties 1.3 (1.2-22.1)c 1-h max 0 CVD, 65+ 

Fung et al. (2005, 074322) Windsor, Can 1.3 1-h max 0-2 CVD, <65 

0-2 CVD, 65+ 

Metzger et al. (2004, 044222) Atlanta, GA 1.8 (5.5-5.9) 1-h max 0-2 IHD 

0-2 CHF 

Tolbert et al. (2007, 090316) Atlanta, GA 1.6 (5.3-5.4) 1-h max 0-2 CVD 

Peel et al. (2007, 090442) Atlanta, GA 1.8 (5.5-5.9) 1-h max 0-2 IHD 

0-2 CHF 

Koken et al. (2003, 049466) Denver, CO 0.9 (1.3-2.0) 24-h avg 3 CHF 

0-3 IHD 

0-3 IHD, sCHF 

Mann et al. (2002, 036723) California, US 2.07 (1.3-15.9) 8-h max 

0-3 IHD, sARR 

0 MI 

0 CHF 

Linn et al. (2000, 002839) Los Angeles, CA 1.5 (1.1-8.3) 24-h avg 

0 CVD 

0-2 IS, 65+ Stroke

0-2 CIS, 65+ 

Villeneuve et al. (2006, 090191) Edmonton, Can 0.8 24-h avg 

0-2 HS, 65+ 

Wellenius et al. (2005, 088685) Multicity, US 1.02** (1.2-7.1) 24-h avg 0-2 IS, 65+ 

0-2 HS, 65+ 

Linn et al. (2000, 002839) Los Angeles, CA 1.5 (1.1-8.3) 24-h avg 0 IS 

*CO Mean and (99th percentile) concentrations in ppm. ** Median 

a

 Mean concentrations (ppm) are presented as reported in the references. Studies are arranged in approximate order of 

increasing mean concentration, with adjustment for different averaging times using a 4:3:2 ratio of 1-h max, 8-h max, 

and 24-h avg values based on relationships derived from the national AQS CO distribution. b

 99th percentile concentrations (ppm) were obtained from the AQS database for durations and locations chosen to match 

those of the U.S. studies. When multiple monitors were available at the study location, the range of monitor specific 99th 

percentile concentrations during the study period is presented. No 99th percentile data are presented for Canadian studies. c

 For the Bell et al. (2009, 193780) study, the concentration statistics represent the 1999-2005 average of daily county-specific 

values. The central estimate is the median county-average across the U.S. The 99th percentile values represent the 

counties with the lowest and highest 99th percentile concentrations. Additional cause-specific effect estimates adjusted for 

NO2 are presented in Section 5.2.1. 

 

 Excess Risk 

Figure 2-1. Excess risk estimates from epidemiologic studies of short-term CO exposure and 

CVD hospitalizations along with author-reported mean and AQS-derived 99th 

percentile CO concentrations. See the footnotes related to concentration data. 

January 2010 2-14 
Table 2-2. Range of mean and 99th percentile concentrations (ppm) in US and Canadian studies of 

short-term CO exposure and CVD hospitalizations. See the notes in Figure 2-1 for 

sources of concentration data. 

Metric 1-h daily max 8-h daily max 24-h avg 

Mean 1.3-1.8 0.4-2.07 0.5-1.5 

99th percentile 1.2-22.1 1.3-15.9 1.1-8.3 

 

Additional studies provide evidence for associations between CO exposure and other health 

outcomes, including CNS effects, birth outcomes and developmental effects, respiratory effects, and 

mortality. Although inconsistent results were reported in controlled human exposure studies on 

neural and behavioral effects, toxicological studies in rodents found that perinatal exposure to CO 

can have a range of effects on the adult nervous system. This combined evidence is suggestive of a 

causal relationship between both short- and long-term CO exposure and CNS effects. Differences in 

fetal pharmacokinetics from those of the mother result in fetal COHb levels that are up to 10-15% 

higher than maternal COHb levels. Epidemiologic studies provide some evidence that CO exposure 

during pregnancy is associated with changes in birth outcomes, including increased risk of PTB, 

cardiac birth defects, small reductions in birth weight, and infant mortality in the postneonatal 

period. This evidence, in conjunction with developmental effects observed in toxicological studies, is 

suggestive of a causal relationship between long-term exposure to CO and birth and developmental 

effects. 

Evidence regarding the effect of short-term exposure to CO on respiratory morbidity is 

suggestive of a causal relationship, based on associations observed in epidemiologic studies and 

animal toxicological studies which indicate the potential for an underlying biological mechanism, 

while the evidence on long-term exposure and respiratory morbidity is inadequate to infer the 

presence of a causal relationship. 

An evaluation of epidemiologic studies that examined the effect of short-term exposure to CO 

on mortality provides evidence that is suggestive of a causal relationship. Epidemiologic studies that 

examined mortality and long-term exposure to CO reported consistent null associations, which, 

combined with the lack of respiratory and cardiovascular morbidity or a proposed biological 

mechanism for mortality following long-term exposure, indicate that there is not likely to be a causal 

relationship between long-term exposure to CO and mortality. 

Issues such as exposure error and isolation of the independent effect of CO as a component of 

a complex air-pollutant mixture contribute to uncertainty in interpreting the results of epidemiologic 

studies. Studies published since the 2000 CO AQCD (U.S. EPA, 2000, 000907) have provided 

insight regarding the nature and magnitude of these uncertainties. Exposures in near-road and onroad microenvironments are likely to be higher than concentrations measured at community-oriented 

regulatory monitors, which may result in over- or underestimation of the magnitude of ambient 

exposure for some individuals. Individuals who are susceptible to CO-induced health effects, such as 

those with CAD, may be at additional risk when experiencing elevated on-road CO concentrations. 

However, as discussed in Section 2.3 and in more detail in Section 3.6, spatial variability in absolute 

concentration will not introduce error into time-series epidemiologic studies if the concentrations are 

correlated in time. A recent study by Sarnat et al. (2009, 180084) found that associations between 

CO and cardiovascular ED visits were similar when based on different monitors within an urban 

center, regardless of monitor location or distance to population, while an association was not 

observed when using a rural monitor outside the urban area. This may have been related to the 

similarity of driving patterns and peak rush-hour times in the urban center as compared to the area 

around the rural monitor, where the temporal driving patterns were different. Simulations of ambient 

and nonambient exposures to a nonreactive pollutant indicated that nonambient exposure has no 

effect on the association between ambient exposure and health outcomes for the case where ambient 

and nonambient concentrations are independent, although variability is introduced. Nonambient 

exposure to CO is not expected to be temporally correlated with ambient CO concentrations, and 

therefore nonambient CO will not act as a confounder in epidemiologic associations with ambient 

CO. Exposure error is not likely to affect the magnitude of the population-averaged effect estimates 

observed in epidemiologic studies, although it would tend to widen the confidence intervals. 

January 2010 2-15 
Epidemiologic studies consider the effects of CO as a component of a complex mixture of air 

pollutants that varies across space and time, with moderate to high correlations observed between 

CO concentrations and those of other combustion-related pollutants. On-road vehicle exhaust 

emissions are a nearly ubiquitous source of combustion pollutant mixtures that include CO, NO2, and PM2.5, and these emissions are the most important contributor to ambient CO in near-road 

locations. Correlations between CO and NO2 reported in epidemiologic studies of short-term 

exposure to CO generally ranged from 0.3 to 0.86, with correlations reported in US studies ranging 

from 0.55 to 0.86. Correlations between CO and PM2.5 reported in all studies ranged from 0.17 to 

0.74, with correlations in US studies ranging from 0.43 to 0.62. This complicates the quantitative 

interpretation of effect estimates in these studies to apportion the relative extent to which CO at 

ambient concentrations is independently associated with cardiovascular or other effects, and the 

extent to which CO acts as a marker for the effects of another combustion-related pollutant or mix of 

pollutants. 

As summarized in Tolbert et al. (2007, 090316), when toxicological or controlled human 

exposure studies of two correlated pollutants provide evidence that each exerts an independent health 

effect, two-pollutant models may be appropriate to adjust the effect estimate for each pollutant for 

confounding by the other pollutant. PM2.5 and NO2 have each been linked to cardiovascular health 

effects in epidemiologic studies. In two-pollutant models in which one of the pollutants is linked to 

the measured outcome and the other is a surrogate for the first pollutant, the copollutant model can 

help identify which is the better predictor of the effect, particularly if the etiologically linked 

pollutant is measured with more error than the second pollutant. Uncertainty is introduced in the size 

of the effect estimate and the portion of the effect size represented by each of the coefficients in the 

model by correlation between the two pollutants and by differential exposure measurement error. 

Since the spatial variability of CO is a larger contributor to measurement error than for other more 

homogenously distributed pollutants such as PM2.5, robustness of CO effect estimates indicates that 

CO is the better predictor of effects in copollutant models. Although this complicates quantitative 

interpretation of the effect estimates reported in epidemiologic studies, the epidemiologic evidence 

for cardiovascular morbidity summarized in this assessment indicates that CO associations generally 

remain robust in copollutant models (Figure 5-6 and Figure 5-7), which, combined with the 

consistency of effects observed across studies, the coherence of epidemiologic health outcomes with 

effects observed in controlled human exposure studies, and the emerging evidence on the potential 

role for cell signaling effects at low tissue CO concentrations, supports an independent effect of 

short-term CO exposure on cardiovascular morbidity. This combined evidence supports a 

determination that the relationship between CO and cardiovascular morbidity is likely causal, while 

still recognizing that CO is a component of a mixture of combustion-related pollutants. 

Evidence from controlled human exposure and epidemiologic studies indicates that individuals 

with underlying CVD, specifically CAD, are an important susceptible population at increased risk of 

health effects due to ambient CO. Potentially susceptible populations include those with other 

underlying diseases, including anemia, obstructive lung disease, or diabetes; older adults and fetuses 

during critical phases of development; commuters and those living near heavily traveled roadways; 

visitors to high-altitude locations; and individuals ingesting medications and other substances that 

enhance endogenous or metabolic CO production. Limited evidence is available from controlled 

human exposure studies of CAD patients indicating a statistically significant inverse relationship 

between COHb concentration and time to ST segment change or time to exercise-induced angina. 

Epidemiologic analyses investigating the exposure-response relationship for mortality and 

cardiovascular morbidity did not find evidence for a departure from linearity or a threshold for CO 

effects. 

The new evidence reviewed in this ISA builds upon the health-effects evidence summarized in 

the 2000 CO AQCD (U.S. EPA, 2000, 000907), with many new epidemiologic studies adding to the 

body of evidence showing associations between acute cardiovascular effects and CO measured at 

ambient monitors. Controlled human exposure studies reviewed both in this ISA and the 2000 CO 

AQCD (U.S. EPA, 2000, 000907) show definitive evidence of cardiovascular effects among 

individuals with CAD following short-term CO exposure, resulting in COHb concentrations as low 

as 2.0-2.4%. Emerging toxicological evidence points to the potential role for CO in modes of action 

not directly related to COHb’s role in O2 delivery. In evaluating the several epidemiologic studies 

available at the time that reported associations between ambient CO and cardiovascular effects, the 

2000 CO AQCD (U.S. EPA, 2000, 000907) considered those findings to be inconclusive for multiple 

reasons, including: questions regarding the consistency of the results among studies; the ability of 

January 2010 2-16 
community fixed-site monitors to represent spatially variable ambient CO concentrations and 

personal exposures; the small expected increase in COHb due to ambient CO concentrations; the 

lack of biological plausibility for health effects to occur at such COHb levels, even in diseased 

individuals; the potentially greater impact of non-ambient exposure on COHb; and the possibility 

that ambient CO is serving as a surrogate for a mixture of combustion-related pollutants. Some of 

these uncertainties remain and complicate the quantitative interpretation of the epidemiologic 

findings, particularly regarding the biological plausibility of health effects occurring at COHb levels 

resulting from exposures to ambient CO concentrations measured at AQS monitors. New research 

summarized in this assessment reduces several of the other uncertainties noted in the 2000 CO 

AQCD (U.S. EPA, 2000, 000907) and demonstrates the lack of influence of nonambient exposure on 

effect estimates in epidemiologic studies, the consistency of epidemiologic study results, their 

robustness in copollutant models, and the coherence of ischemia-related outcomes with evidence 

from controlled human exposure studies. This consistent and coherent evidence from epidemiologic 

and human clinical studies, along with biological plausibility provided by the role of CO in limiting 

O2 availability, is sufficient to conclude that a causal relationship is likely to exist between relevant 

short-term CO exposures and cardiovascular morbidity. 

January 2010 2-17 
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