Chapter 5. 

5.1.1. 

5.1.2. 

Integrated Health Effects 

5.1. Mode of Action of CO Toxicity 

Introduction 

The diverse effects of CO are dependent upon concentration and duration of exposure as well 

as on 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. 

Hypoxic Mechanisms 

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

pathophysiologic 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. 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) reported changes in vasodilation due to CO 

levels between 500-2,000 ppm (Kanten et al., 1983, 011333; MacMillan, 1975, 012909). In one 

study, the vasodilatory response to CO in cerebral blood vessels was attributed to decreased O2

availability (Koehler et al., 1982, 011341). In another study, exposure of rats to 1,000 ppm CO 

resulted in increased cerebral blood flow which was not triggered by tissue hypoxia since no changes 

in intramitochondrial NADH levels preceded vasodilation (Meilin et al., 1996, 079919). However, 

the response was blocked by the inhibition of NOS indicating a role for the free radical species NO 

in CO-mediated vasodilation (Meilin et al., 1996, 079919). 

Increased cardiac output was also discussed in the 2000 CO AQCD (U.S. EPA, 2000, 000907) 

as a compensatory response to CO-mediated tissue hypoxia. Findings of studies which measured 

hemodynamic alterations following CO exposure were equivocal and sometimes contradictory 

(Penney, 1988, 012519). While most studies reported a positive correlation between COHb and 

cardiac output at COHb levels above 20%, one study demonstrated increased cardiac output in 

humans following acute exposure to 5% CO which resulted in the rapid rise in COHb levels to ~9% 

(Ayres et al., 1973, 193943). However, there was no increase in cardiac output following a more 

gradual increase in COHb levels to ~9% achieved by exposure to 0.1% CO over a longer period of 

time (Ayres et al., 1973, 193943). Increased heart rate and stroke volume (SV) were observed in 

response to CO exposure in one study (Stewart et al., 1973, 012428); however, some experiments 

found no change in SV in humans with 18-20% COHb (Vogel and Gleser, 1972, 010898) or 12.5% 

COHb (Klausen et al., 1968, 193936). The 2000 CO AQCD (U.S. EPA, 2000, 000907) reported that 

blood pressure was generally unchanged in human CO exposure studies, while a number of animal 

studies demonstrated CO-induced hypotension (Penney, 1988, 012519). No changes in forearm 

blood flow, blood pressure, or heart rate were reported in humans with approximately 8% COHb 

 

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 5-1 
(Hausberg and Somers, 1997, 083450). However, high-concentration exposures (3,000-10,000 ppm) 

in animals resulted in diminished organ blood flow (Brown and Piantadosi, 1992, 013441). In-depth 

discussion of hemodynamic changes resulting from CO exposure in recent human clinical studies 

can be found in Section 5.2.4. 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. High-energy phosphate production 

in cardiac myocytes was inhibited when COMb concentrations exceeded 40%, corresponding to an 

estimated COHb level between 20-40% (Wittenberg and Wittenberg, 1993, 013909). Conversely, rat 

hearts perfused with solutions containing 6% CO (60,000 ppm) exhibited no change in high-energy 

phosphate production, respiration rate, or contractile function (Chung et al., 2006, 193987; Glabe et 

al., 1998, 086704). 

5.1.3. Nonhypoxic Mechanisms 

 Nonhypoxic mechanisms underlying the biological effects of CO were discussed in the 2000 

CO AQCD (U.S. EPA, 2000, 000907) and are summarized below. Most of these mechanisms are 

related to CO’s ability to bind heme-containing proteins other than Hb and Mb (Raub and Benignus, 

2002, 041616). Since then, additional experiments have confirmed and extended these findings. 

While the majority of the older studies utilized concentrations of CO far higher than ambient levels, 

many of the newer studies have employed more environmentally-relevant concentrations of CO. 

5.1.3.1. Nonhypoxic Mechanisms Reviewed in the 2000 CO AQCD 

Inhibition of heme-containing proteins such as cytochrome c oxidase and cytochrome P450 

reductases may alter cellular function. CO interacts with the ferrous heme a3 of the terminal enzyme 

of the electron transport chain, cytochrome c oxidase (Petersen, 1977, 193764). Cytochrome c

oxidase inhibition not only interrupts cellular respiration and energy production but can also enhance 

reactive oxygen species (ROS) production. In vivo studies observed CO binding to cytochrome c

oxidase under conditions where COHb concentrations were above 50% (Brown and Piantadosi, 

1992, 013441). It is unlikely that this could arise under physiologic conditions or under conditions 

relevant to ambient exposures. 

A series of studies from the laboratory of Thom, Ischiropoulos and colleagues indicated that 

CO exposure produced a pro-oxidant cellular environment by liberation of NO. Exposure to CO 

concentrations of 10-20 ppm and above caused isolated rat platelets, as well as cultured bovine 

pulmonary endothelial cells, to release NO (Thom and Ischiropoulos, 1997, 085644). This response 

was blocked by treatment with an NOS inhibitor, indicating that the NO released was dependent on 

NOS activity. An increase in available NO was also seen in the lung and brain of CO-exposed rats 

(Ischiropoulos et al., 1996, 079491; Thom et al., 1999, 016757). Reaction of NO with superoxide to 

form the highly active oxidant species, peroxynitrite (Thom et al., 1997, 084337), was thought to 

lead to the activation and sequestration of leukocytes in brain vessels (Thom et al., 2001, 193779) 

and aorta (Thom et al., 1999, 016753), oxidation of plasma lipoproteins (Thom et al., 1999, 016753), 

and the formation of protein nitrotyrosine (Ischiropoulos et al., 1996, 079491; Thom et al., 1999, 

016757; Thom et al., 1999, 016753). NO release by CO was attributed to the displacement of NO 

from nitrosyl-bound heme proteins. The rate of this event was slow; however, it occurred at 

environmentally-relevant concentrations of CO (Thom et al., 1997, 084337). 

CO exposure also increased the production of other pro-oxidant species, including hydrogen 

peroxide (H2O2) and hydroxyl radical (OH). High-level CO exposure (2,500 ppm) increased OH in 

rat brain, and this response was distinct from tissue hypoxia (Piantadosi et al., 1997, 081326). The 

mechanism for enhanced H2O2 production was unclear. The release of H2O2 in the lung of 

CO-exposed rats was dependent upon the production of NO, as it was inhibited by pretreatment with 

an NOS inhibitor (Thom et al., 1999, 016757). It is possible that peroxynitrite formed after CO 

exposure inhibited electron transport at complexes I through III, or that cytochrome c oxidase 

inhibition led to mitochondrial dysfunction and ROS production. 

Evidence was presented for CO-mediated vasorelaxation by three different mechanisms. First, 

CO may inhibit the synthesis of vasoconstrictors by P450 heme proteins (Wang, 1998, 086074). 

January 2010 5-2 
Vasodilation in isolated vessels was demonstrated via this P450-dependent mechanism using high 

concentrations of CO (approximately 90,000 ppm) (Coceani et al., 1988, 040493). In the case of 

cytochrome P450 enzymes, tissue CO levels may need to be abnormally high to elicit a response 

since the Warburg binding coefficients (the ratio of CO to O2 at which half the reactive sites are 

occupied by CO) for cytochrome P450s range from 0.1-12 (Piantadosi, 2002, 037463). P450 

inhibition may reduce the hypoxia-induced expression of mitogens such as erythropoietin (EPO), 

vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and platelet derived growth factor 

(PDGF), which may decrease smooth muscle proliferation in response to hypoxia (Wang, 1998, 

086074). CO also interfered with the metabolism of barbiturates and other drugs; however, this was 

probably due to the hypoxic actions of CO rather than to P450 inhibition (Roth and Rubin, 1976, 

012703; Roth and Rubin, 1976, 012420). 

Secondly, CO has been shown to play a physiological role in vasomotor control and in signal 

transduction by activation of soluble guanylate cyclase (sGC), causing a conversion of GTP to cyclic 

GMP (cGMP). CO reversibly ligates the heme core of sGC, and the resulting protoporphyrin IX 

intermediate triggers cGMP production (Ndisang et al., 2004, 180425). CO caused vascular 

relaxation, independent of the endothelium, in human arterial rings (Achouh et al., 2008, 179918), 

rat tail artery (Wang et al., 1997, 084341), and rat thoracic aorta (Lin and McGrath, 1988, 012773), 

but not in cerebral vessels (Andresen et al., 2006, 180449; Brian et al., 1994, 076283). Activation of 

sGC by CO has been linked to neurotransmission, vasodilation, bronchodilation, inhibition of 

platelet aggregation, and inhibition of smooth muscle proliferation (Brüne and Ullrich, 1987, 

016535; Cardell et al., 1998, 086700; Cardell et al., 1998, 011534; Morita et al., 1997, 085345; 

Verma et al., 1993, 193999). 

CO-mediated vasorelaxation can also be caused by activation of voltage- or Ca2+-activated 

potassium (K+

) channels in smooth muscle cells, which leads to membrane hyperpolarization, 

voltage-dependent Ca2+ channel closing, reduction of resting Ca2+ concentration and vascular tissue 

relaxation (Farrugia et al., 1993, 013826; Wang et al., 1997, 084341). This effect may be linked to 

sGC activity; however, it has also been reported to occur independently (Dubuis et al., 2003, 

180439; Naik and Walker, 2003, 193852). Developmental stage and tissue type will determine 

whether K+

 channels or the sGC/cGMP pathway play more of a role in vasorelaxation (Ndisang et 

al., 2004, 180425). 

Collectively, these older studies demonstrated that exposures to high concentrations of CO 

resulted in altered functions of heme proteins other than Hb and Mb. Decreased cellular respiration 

and energy production and increased ROS following cytochrome c oxidase inhibition would likely 

predispose towards cellular injury and death. The release of NO from sequestered stores could 

contribute to the pro-oxidant status if superoxide levels are simultaneously increased. Furthermore, 

increased ROS and reactive nitrogen species are known to promote cell signaling events leading to 

inflammation and endothelial dysfunction. An inappropriate increase in vasorelaxation due to 

inhibition of vasoconstrictor production or to activation of vasodilatory pathways (sGC and ion 

channels) could potentially limit compensatory alterations in hemodynamics. Alternatively, 

CO-binding to sGC could result in decreased vasorelaxation by interfering with the binding of NO to 

sGC. NO can also activate sGC, and with a 30-fold greater affinity than CO, is 1,000-fold more 

potent with respect to vasodilation and sGC activation (Stone and Marletta, 1994, 076455). CO 

could further contribute to endothelial dysfunction by this mechanism. Although the 2000 CO 

AQCD (U.S. EPA, 2000, 000907) made no definitive links between these nonhypoxic mechanisms 

of CO and CO-mediated health effects, it did document the potential for CO to interfere with basic 

cellular and molecular processes that could lead to dysfunction and/or disease. 

5.1.3.2. Recent Studies of Nonhypoxic Mechanisms 

Since the 2000 CO AQCD (U.S. EPA, 2000, 000907), new studies have provided additional 

evidence for nonhypoxic mechanisms of CO which involve the binding of CO to reduced iron in 

heme proteins. These mechanisms, which may be interrelated, are described below and include: 

 Alteration in NO signaling 

 Inhibition of cytochrome c oxidase 

 Heme loss from protein 

January 2010 5-3 
 Disruption of iron homeostasis 

 Alteration in cellular redox status 

Recent studies have also demonstrated nonhypoxic mechanisms of CO which are either 

indirectly linked to heme protein interactions or not yet understood. These mechanisms are described 

below and include: 

 Alteration in ion channel activity 

 Modulation of protein kinase pathways 

This assessment evaluates these nonhypoxic mechanisms in terms of their potential to 

contribute to health effects associated with environmentally-relevant CO exposures. As discussed 

above, CO at high concentrations may promote oxidative stress, cell injury and death, inflammation 

and endothelial dysfunction. Whether lower CO concentrations trigger these same processes is of 

key interest since they may potentially contribute to adverse health effects following ambient 

exposures. 

In addition, a large number of studies published since the 2000 CO AQCD (U.S. EPA, 2000, 

000907) have focused on the role of CO derived from HO-catalyzed heme metabolism as an 

endogenous signaling molecule and on the potential therapeutic effects of exogenous CO 

administered at high concentrations. This assessment addresses aspects of these topics pertaining to 

the evaluation of health effects associated with environmentally-relevant CO exposures. 

Alteration in NO Signaling 

Work by Thorup et al. (1999, 193782) demonstrated altered NO signaling in isolated rat renal 

resistance arteries. In one set of experiments, rapid release of NO was observed in response to 

exogenous CO. This response was biphasic, peaking at 100 nM CO in the perfusate and declining at 

higher concentrations. It was also NOS-dependent as it required L-arginine and was blocked by a 

NOS inhibitor. The authors attributed the effects of CO on NO release to either stimulated eNOS or 

to displacement of preformed NO from intracellular binding sites. These findings are similar to those 

of Thom and colleagues (Ischiropoulos et al., 1996, 079491; Thom and Ischiropoulos, 1997, 085644; 

Thom et al., 1994, 076459; Thom et al., 1997, 084337; Thom et al., 1999, 016753; Thom et al., 

1999, 016757; Thom et al., 2000, 011574; Thom et al., 2006, 098418) who demonstrated NO 

release, presumably from sequestered stores in platelets, endothelial cells, aorta and lung in response 

to CO (see above). Furthermore in a second set of experiments, Thorup et al. (1999, 193782) 

demonstrated inhibition of agonist-stimulated NOS activity in isolated rat renal resistance arteries. 

Here rapid NOS-dependent release of NO following carbachol stimulation was blocked by 

pretreatment with 100 nM CO or by upregulation of intracellular HO-1. Additional experiments 

using blood-perfused isolated juxtamedullary afferent arterioles demonstrated a biphasic response to 

CO with rapid vasodilation observed at lower, but not higher, concentrations of CO. These same 

higher concentrations of CO inhibited agonist-stimulated vasodilation in the arterioles. In order to 

determine whether CO had a direct effect on the activity of NOS, which is a heme protein, purified 

recombinant eNOS was exposed in vitro to CO in the presence of the necessary substrates and 

cofactors. A dose-dependent inhibition of NOS by CO was observed, suggesting that CO-mediated 

NO release in the isolated vessels was not due to stimulated NOS activity. The authors concluded 

that CO effects on vascular tone were due to the liberation of NO from intracellular binding sites at 

lower concentrations and to the inhibition of NOS at higher concentrations. 

These findings illustrate the potential of CO to alter processes dependent on endogenous NO 

either by enhancing intracellular concentrations of free NO (increased vasodilatory influence) or by 

inhibiting agonist-induced NO production by NOS (decreased vasodilatory influence). In addition, 

CO may compete with NO for binding to sGC as discussed above. Since NO activates sGC to a 

greater extent than CO, NO-dependent vasodilation may be significantly impaired in the presence of 

CO. In fact, a recent study in transgenic mice demonstrated that chronic overexpression of HO-1 in 

vascular smooth muscle resulted in attenuated NO-mediated vasodilation and elevated blood 

pressure (Imai et al., 2001, 193864). Results of this study suggested that decreased sensitivity of sGC 

to NO contributed to the changes in vascular function. The considerations mentioned above, 

however, do not preclude an important role for CO in maintaining vasomotor tone in vessels where 

January 2010 5-4 
CO and NO do not compete for available heme sites on sGC. This could occur when both mediators 

are present at low concentrations compared with sGC or in situations where NOS does not colocalize with sGC, as discussed by Thorup et al. (1999, 193782). 

Inhibition of Cytochrome c Oxidase 

High concentrations of CO are known to inhibit cytochrome c oxidase, the terminal enzyme in 

the mitochondrial electron transport chain, resulting in inhibition of mitochondrial respiration and 

the formation of superoxide from mitochondrial substrates. Several recent studies demonstrated 

CO-mediated decreases in cytochrome c oxidase activity in model systems ranging from isolated 

mitochondria to whole animals. In a study by Alonso et al. (2003, 193882), exposure of isolated 

mitochondria from human skeletal muscle to 50-500 ppm CO for 5 min decreased cytochrome c

oxidase activity. Similarly, exposure of cultured macrophages to 250 ppm CO for 1 h inhibited 

cytochrome c oxidase (Zuckerbraun et al., 2007, 193884). In this latter study, increased ROS were 

observed following exposure to 250 ppm CO, as well as to CO concentrations as low as 50 ppm, for 

1 h. Animal studies demonstrated that exposure of rats to 250 ppm CO for 90 min inhibited 

cytochrome c oxidase activity in myocardial fibers (Favory et al., 2006, 184462). Exposure of mice 

to 1,000 ppm CO for 3 h, resulting in COHb levels of 61%, decreased cytochrome c oxidase activity 

in heart mitochondria (Iheagwara et al., 2007, 193861). 

Heme Content Loss from Proteins 

In addition to decreasing the activity of cytochrome c oxidase, exposure of mice to 1,000 ppm 

CO for 3 h resulted in decreased protein levels and heme content of cytochrome c oxidase in heart 

mitochondria (Iheagwara et al., 2007, 193861). CO-mediated heme release was also seen in a study 

by Cronje et al. (2004, 180440) and was followed by increased endogenous CO production through 

the activation of HO-2 and the induction of HO-1. Loss of heme from proteins leads to loss of 

protein function and often to protein degradation. 

Disruption of Iron Homeostasis 

Exposure of rats to 50 ppm CO for 24 h increased levels of iron and ferritin in the 

bronchoalveolar lavage fluid (BALF), decreased lung non-heme iron and increased liver non-heme 

iron (Ghio et al., 2008, 096321). Furthermore in this same study, exposure of cultured human 

respiratory epithelial cells to 10-100 ppm CO for 24 h caused a dose-dependent decrease in cellular 

non-heme iron and ferritin. Heme loss, which was observed in other studies (Cronje et al., 2004, 

180440; Iheagwara et al., 2007, 193861), may also contribute to disruption of iron homeostasis. Iron 

homeostasis is critical for the sequestration of free iron and the prevention of iron-mediated redox 

cycling which leads to ROS generation and lipid peroxidation. 

Alteration in Cellular Redox Status 

Recent studies demonstrated that exposure to low, moderate, and high levels of CO increased 

cellular oxidative stress in cultured cells (Kim et al., 2008, 193961; Zuckerbraun et al., 2007, 

193884). A dose-dependent increase in dichlorofluorescein (DCF) fluorescence (an indicator of 

ROS) occurred following 1-h exposure to 50-500 ppm CO in macrophages and following 1-h 

exposure to 250 ppm CO in hepatocytes. NOS inhibition had no effect on the increase in DCF 

fluorescence in CO-treated macrophages, indicating that the effects were not due to an interaction of 

CO and NO (Zuckerbraun et al., 2007, 193884). Mitochondria were identified as the source of the 

increased ROS since mitochondria-impaired cells (rho zero cells and treatment with antimycin A) 

did not respond to CO with an increase in DCF fluorescence. Furthermore, 1-h exposure to 250 ppm 

CO inhibited mitochondrial cytochrome c oxidase enzymatic activity in macrophages (Zuckerbraun 

et al., 2007, 193884). Recently, inhibition of cytochrome c oxidase was demonstrated in HEK-293 

cells transfected with HO-1 and in macrophages with induced HO-1; this effect was attributed to 

January 2010 5-5 
endogenously produced CO (D'Amico et al., 2006, 193992). In hepatocytes, exposure to 250 ppm 

CO for 1 h resulted in Akt phosphorylation and nuclear translocation of nuclear factor kappa B 

(NF-κB), effects which were blocked by antioxidants (Kim et al., 2008, 193961). Significant 

increases in apoptosis were also observed in this model. Thus in this study, CO exposure led to 

uncoupled mitochondrial respiration and ROS-induced programmed cell death. 

Further evidence for cellular redox stress is provided by studies in which glutathione stores 

were altered following CO exposure in vitro (Kim et al., 2008, 193961; Patel et al., 2003, 043155). 

In addition, mitochondrial redox stress was observed in livers of rats exposed to 50 ppm CO 

(Piantadosi et al., 2006, 180424). Furthermore, an adaptive increase in intracellular antioxidant 

defenses (i.e., superoxide dismutase) was observed in endothelial cells exposed to 10 ppm CO for 

40 min (Thom et al., 2000, 011574), and mitochondrial biogenesis was observed in hearts of mice 

exposed to 250 ppm CO for 1 h (Suliman et al., 2007, 193768). 

Several mechanisms could contribute to the cellular redox stress elicited by CO exposure. 

First, inhibition of cytochrome c oxidase could result in increased mitochondrial superoxide 

generation. Secondly, interactions of CO with heme proteins could lead to the release of heme and 

free iron and subsequently to the generation of ROS. As mentioned above, increased ROS generation 

has been linked to cellular injury and death, inflammation, and endothelial dysfunction. 

 Two of the above-mentioned studies demonstrated that CO-mediated mechanisms were 

unrelated to hypoxia by showing that hypoxic conditions failed to mimic the results obtained with 

CO. Hence, the mitochondrial redox stress and mitochondrial pore transition observed in livers from 

rats exposed to CO (Piantadosi et al., 2006, 180424) and the cardiac mitochondrial biogenesis 

observed in mice exposed to CO (Suliman et al., 2007, 193768) were attributed specifically to 

nonhypoxic mechanisms of CO. 

Alteration in Ion Channel Activity 

Work by Dubuis et al. (Dubuis et al., 2002, 193911) demonstrated increased current through 

Ca2+-activated K+

 channels in smooth muscle cells from pulmonary arteries of rats exposed to 

530 ppm CO for 3 wk. These findings provide further evidence for non-cGMP-dependent 

vasodilatory actions of CO. 

Modulation of Protein Kinase Pathways 

Endogenously produced CO is a gaseous second messenger molecule in the cell. Work from 

numerous laboratories has demonstrated the potential for CO to be used as a therapeutic gas with 

numerous possible clinical applications since it can produce anti-inflammatory, anti-apoptotic, and 

anti-proliferative effects (Durante et al., 2006, 193778; Ryter et al., 2006, 193765). These studies 

generally involved pretreatment with CO followed by exposure to another agent 12-24 h later. There 

is extensive literature on this topic as reviewed by Ryter et al. (2006, 193765), Durante et al. (2006, 

193778) and others. A number of these processes are mediated through cGMP while others involve 

redox-sensitive kinase pathways, possibly secondary to CO-dependent generation of ROS. For 

example, 250 ppm CO inhibited growth of airway smooth muscle cells by attenuating the activation 

of the extracellular signal-regulated kinase 1/2 (ERK 1/2) pathway, independent of sGC and other 

MAP kinases (Song et al., 2002, 037531). A second example is provided by the study of Kim et al. 

(2005, 193959) where 250 ppm CO inhibited PDGF- induced smooth muscle cell proliferation by 

upregulating p21Waf1/Cip1 and caveolin-1, and down-regulating cyclin A expression. In this case, 

effects were dependent upon cGMP and the p38 MAPK pathway (Kim et al., 2005, 193959). Thirdly, 

rat endothelial cells exposed to 15 ppm CO escaped anoxia/reoxygenation-induced apoptosis via 

modulation of the signaling pathways involving phosphoinositide 3-kinase (PI3K), Akt, p38 MAP 

kinase, Signal Transducers and Activators of Transcription (STAT-1) and STAT-3 (Zhang et al., 

2005, 184460). In a fourth study, Akt was found to be responsible for the CO-induced activation of 

NF-κB, protecting against hepatocyte cell death (Kim et al., 2008, 193961). While research focusing 

on therapeutic applications of CO generally involves high-level short-term exposure to CO (i.e., 250-

1,000 ppm for up to 24 h), some studies found effects below 20 ppm (Zhang et al., 2005, 184460). 

Few if any studies on the therapeutic effects of CO have explored the dose-response relationship 

January 2010 5-6 
between CO and pathway activation/deactivation, so it remains unclear how these effects may be 

related to environmentally-relevant exposures. 

Concentration-Response Relationships 

In many cases, the concentrations of exogenous CO required for these nonhypoxic effects 

were much higher (Alonso et al., 2003, 193882; Favory et al., 2006, 184462; Iheagwara et al., 2007, 

193861; Thorup et al., 1999, 193782) than concentrations of CO in ambient air. However, in some 

studies the effects were mimicked by upregulation of HO-1 which would result in increased local 

production of CO as well as of iron and biliverdin (D'Amico et al., 2006, 193992; Imai et al., 2001, 

193864; Thorup et al., 1999, 193782). For example, HO-1 upregulation or overexpression attenuated 

carbachol-mediated NO release and NO-mediated vasodilation, similar to the effects of exogenous 

CO in these same models (Imai et al., 2001, 193864; Thorup et al., 1999, 193782). In the study by 

D’Amico et al. (2006, 193992), overexpression of HO-1 in cells inhibited cellular respiration by 

12% and decreased cytochrome c oxidase activity by 23%. It is not clear how comparable these 

conditions involving increased intracellular concentrations of endogenous CO are to increased 

intracellular concentrations of CO resulting from exogenous CO exposures. Neither is it clear what 

concentrations of intracellular CO are generated locally within cells as a result of HO-catalyzed 

heme metabolism. However, a small amount of a relatively high local concentration of endogenous 

CO produced in a regulated manner by HO-1 and HO-2 may be sufficient to react with local targets 

(e.g., heme proteins), while a larger amount of exogenous CO may be required to reach the same 

targets. This may be due to indiscriminate reactions of exogenous CO with other target proteins or to 

other issues related to compartmentalization. It is conceivable that acute or chronic exposures to 

ambient CO could “sensitize” (or “desensitize”) targets of endogenous cellular CO production, but 

there is no experimental evidence to support this mechanism. 

There is a growing appreciation that nonhypoxic mechanisms may contribute to the effects 

associated with CO toxicity and poisoning (Ischiropoulos et al., 1996, 079491; Thom et al., 1994, 

076459; Weaver et al., 2007, 193939). On the other hand, recent studies suggest that exogenous CO 

at lower concentrations may have beneficial anti-inflammatory, anti-proliferative and cytoprotective 

effects under certain circumstances (Durante et al., 2006, 193778; Ryter et al., 2006, 193765). Since 

the focus of this assessment is on mechanisms which are relevant to ambient exposures, it is 

important to understand which mechanisms may occur at “low” (50 ppm and less) and “moderate” 

(50-250 ppm CO) concentrations of CO. Hence, both recent animal studies and relevant older ones 

which add to the understanding of mechanisms in this range of CO concentrations are briefly 

summarized in Table 5-1. It should be noted that most of the above-mentioned nonhypoxic 

mechanisms were demonstrated at CO concentrations of 50 ppm and less. 

January 2010 5-7 
Table 5-1. Responses to CO exposures at low and moderate concentrations. 

Study Model System CO Exposure Response Notes 

IN VITRO 

Alonso et al. (2003, 

193882) 

Human muscle 

mitochondria 

50, 100, 500 ppm 

5 min Decreased cytochrome c oxidase activity 

Thom and Ischiropoulos 

(1997, 085644) 

Rat 

platelets 10 ppm Increased free NO 

Thom et al. (1997, 

084337) 

Bovine pulmonary artery 

endothelial cells 

20 ppm 

30-60 min Increased free NO and peroxynitrite Reported to correspond to 7% COHb 

Thom et al. (2000, 

011574) 

Bovine pulmonary artery 

endothelial cells 

10 ppm 

40 min 

Increased MnSOD and protection against 

toxic effects of 100 ppm CO Adaptive responses 

Song et al. (2002, 

037531) 

Human aortic smooth 

muscle cells 

50-500 ppm 

24 h Inhibition of cellular proliferation 

Blocked activation of ERK1/2 pathway, 

independent of sGC and other MAP 

kinases 

Kim et al. (2005, 

193959) 

Rat pulmonary artery 

smooth muscle cells 

250 ppm 

1 h 

Inhibited PDGF- induced smooth muscle cell 

proliferation 

Upregulated p21Waf1/Cip1 and caveolin1, and down-regulated cyclin A 

expression. 

Kim et al. (2008, 

193961) Rat hepatocytes 

250 ppm 

1 h 

2x per day 

250 ppm 

1 h 

Blocked spontaneous apoptosis 

Increased mitochondrial ROS generation, 

increased mitochondrial glutathione 

oxidation, and decreased cellular ascorbic 

acid 

CO induced Akt phosphorylation via 

ROS production 

CO activated NFκB 

Zhang et al. (2005, 

184460) 

Rat pulmonary artery 

endothelial cells 

15 ppm 

0.5-24 h 

Blocked anoxia-reoxygenation mediated 

apoptosis 

Modulation of PI3K/Akt/p38 MAP 

kinase and STAT-1 and STAT-3 

Zuckerbraun et al. 

(2007, 193884) Mouse macrophages 50 and 250 ppm 

1 h 

Increased ROS generation (dose dependent 

response for 50-500 ppm CO) 

Mitochondrial derived ROS and 

cytochrome c oxidase inhibition 

demonstrated for 250 ppm 

Ghio et al. (2008, 

096321) 

Human bronchial epithelial 

cells 

10-100 ppm 

24 h 

Dose-dependent decrease in cellular nonheme iron (effect at 10 ppm was significant, 

effect at 50 ppm maximal) 

Dose-dependent decrease in cellular ferritin 

at 50-100 ppm 

50 ppm blocked iron uptake by cells 

50 ppm increased iron release from cells 

Compare with in vivo experiments in 

same paper 

IN VIVO 

Ghio et al. (2008, 

096321) Rats 50 ppm 24 h 

Mild neutrophil accumulation in BALF 

Increased lavage MIP-2, protein, LDH 

Lavage iron and ferritin were increased by 

CO 

Lung non-heme iron was decreased by CO 

Liver non-heme iron was increased by CO 

Compare with in vitro experiments in 

same paper 

Thom et al. (1999, 

016753) Rats 

50 ppm 

1 h 

100 ppm 

1 h 

Increased nitrotyrosine in aorta 

Leukocyte sequestration in aorta after 18 h 

Albumin efflux from skeletal muscle 

microvasculature 3 h after CO 

LDL oxidation 

Effects blocked by NOS inhibitor 

Thom et al. (1999, 

016757) Rats 

100 ppm 

1 h 

50 ppm 

1 h 

Elevated free NO during CO exposure 

(EPR) 

Elevated nitrotyrosine in lung homogenates 

Lung capillary leakage 18 h after exposure 

Inhibition of NOS abrogated CO 

effects 

Sorhaug et al. (2006, 

180414) Rats 200 ppm 

72 wk 

No changes in lung morphology 

No pulmonary hypertension 

No atherosclerotic lesions in systemic 

vessels 

Ventricular hypertrophy 

Loennechen et al. 

(1999, 011549) Rats 100 and 200 ppm 

1-2 wk 

Increased ET-1 mRNA in the heart 

ventricles, increased right and left 

ventricular weight 

12 and 23% COHb 

Favory et al. (2006, 

184462) Rats 250 ppm 

90 min 

Complex IV inhibition in myocardial fibers 

Inhibition of vasodilatory response to 

acetylcholine and SNP, Increased coronary 

perfusion pressure and contractility 

11% COHb 

Piantadosi et al. (2006, 

180424) Rats 

50 ppm CO or 

hypobaric hypoxia for 

1, 3, or 7 days 

Liver mitochondrial oxidative and nitrosative 

stress, altered mitochondrial permeability 

pore transition sensitivity 

CO effects not mimicked by hypobaric 

hypoxia 

Suliman et al. (2007, 

193768) Mice 250 ppm 

1 h Cardiac mitochondrial biogenesis 

Activation of GC involved. No role for 

NOS. Increased mitochondrial H2O2

and activation of Akt proposed 

Wellenius et al. (2004, 

087874) 

Rats 

Model of MI 

35 ppm 

1 h 

Decreased delayed ventricular beat 

frequency Altered arrhythmogenesis 

Wellenius et al. (2006, 

156152) 

Rats 

Model of MI 

35 ppm 

1 h Decreased supraventricular ectopic beats Altered arrhythmogenesis 

January 2010 5-8 
Study Model System CO Exposure Response Notes 

Carraway et al. (2002, 

026018) 

Rats 

Model of hypoxic 

pulmonary vascular 

remodeling 

Hypobaric hypoxia 

± 50 ppm CO 

3 wk 

CO promoted remodeling and increased 

pulmonary vascular resistance 

Gautier et al. (2007, 

096471) 

Rats 

Model of right ventricle 

hypertrophy secondary to 

chronic hypoxia 

3 wk of hypobaric 

hypoxia with 50 ppm 

CO during last week 

Rats with pulmonary hypertension were 

more sensitive to CO which altered the right 

ventricular adaptive response to pulmonary 

hypertension leading to ischemic lesions 

Melin et al. (2005, 

193833) 

Rats 

Model of right ventricle 

hypertrophy secondary to 

chronic hypoxia 

50 ppm 

10 wk 

CO increased cardiac dilation and 

decreased left ventricular function 

Melin et al. (2002, 

037502) 

Rats 

Model of right ventricle 

hypertrophy secondary to 

chronic hypoxia 

50 ppm 

10 wk 

CO increased right ventricular hypertrophy, 

decreased right ventricular diastolic function 

and increased left ventricular weights 

5.1.3.3. Implications of Nonhypoxic Mechanisms 

A key issue in understanding the biological effects of environmentally-relevant exposures to 

CO is whether the resulting partial pressures of CO (pCO) in cells and tissues can initiate cell 

signaling which is normally mediated by endogenously generated CO or perturb signaling which is 

normally mediated by other signaling molecules such as NO. 

Several aspects need to be considered. First of all, during a period of exogenous CO uptake, 

Hb acts as a buffer for most cells and tissues by limiting the availability of free CO. Nevertheless, 

COHb delivers CO to cells and tissues. This delivery involves CO’s dissociation from Hb followed 

by its diffusion down a pCO gradient. Hence, greater release of CO from COHb will occur under 

conditions of low cell/tissue pCO. Conversely, higher cell/tissue pCO in cells/tissues than in the 

blood will lead to the egress of CO from cells/tissues. 

A second consideration is the role played by O2 in competing with CO for binding to 

intracellular heme protein targets. In general, heme proteins (e.g., cytochrome c oxidase) are more 

sensitive to CO when O2 is limited. Hence, hypoxic conditions would be expected to enhance the 

effects of CO. This concept is demonstrated in the study by D’Amico et al. (2006, 193992). NO, 

which also competes with O2 and CO for binding to heme proteins, may have a similar impact. 

A third consideration is whether certain cell types serve as primary targets for the effects of 

CO. Besides the blood cells (including leukocytes and platelets), the first cells encountering CO 

following its dissociation from Hb are the endothelial cells which line blood vessels. An exception to 

this situation is in the lungs where epithelial and inflammatory cells found in airways and alveoli are 

exposed to free CO prior to CO binding to Hb. These lung cells may also serve as unique targets for 

CO. Processes such as pulmonary microvascular endothelial dysfunction, inflammatory cell 

activation, and respiratory epithelial injury may ensue as a result of preferential targeting of these 

cell types. 

Since there is potential for exogenous CO to affect endogenous pools of CO, the 

concentrations of CO in cells and tissues before and after exogenous exposures are of great interest. 

Table 5-2 summarizes findings from four recent studies relevant to this issue. It should be noted that 

exposure to 50 ppm CO resulted in a three- to fivefold increase in tissue CO concentration. 

January 2010 5-9 
Table 5-2. Tissue concentration of CO following inhalation exposure. 

Study CO Exposure Tissue CO Concentrations COHb Notes 

Cronje et al. (2004, 

180440) 

Rat 

2,500 ppm 

45 min 

Blood: 27,500 (800) pmol/mg 

Heart: 800 (300) pmol/mg 

Muscle: 90 (80) pmol/mg 

Brain: 60 (40) pmol/mg 

Control levels in parentheses 

66-72% 

CO concentration increased in the heart but not in brain or 

skeletal muscle after CO exposure 

A later report stated that these tissue CO values were too 

high due to a computational error (Piantadosi et al., 2006, 

180424) 

Vreman et al. (2005, 

193786) 

Mice 

500 ppm 

30 min 

Blood: 2648 ± 400 (45) pmol/mg 

Heart: 100 ± 18 (6) pmol/mg 

Muscle: 14 ± 1 (10) pmol/mg 

Brain: 18 ± 4 (2) pmol/mg 

Kidney: 120 ± 12 (7) pmol/mg 

Spleen: 229 ± 55 (6) pmol/mg 

Liver: 115 ± 31 (5) pmol/mg 

Lung: 250 ± 2 (3) pmol/mg 

Intestine: 9 ± (4) pmol/mg 

Testes: 6 ± 3 (2) pmol/mg 

Control levels in parentheses 

28% 

CO concentration relative to 100% blood: 

Lung: 9.4% 

Spleen: 8.6% 

Kidney: 4.5% 

Liver: 4.3% 

Heart: 3.8% 

Brain: 0.7% 

Muscle: 0.5% 

Intestine: 0.3%, 

Testes: 0.2% 

Piantadosi et al. (2006, 

180424) 

Rats 

50 ppm 

1-7 days 

Liver: 30-40 pmol/mg 

Control liver 10 pmol/mg 

4-5% 

Control 1% 

CO concentration reached a plateau after 1 day 

Vreman et al. (2005, 

193786) 

Mice 

50, 250 and 

1,250 ppm 

1 h 

Heart (left ventricle) 

50 ppm: 50 pmol/mg 

250 ppm: 95 pmol/mg 

1250 ppm: 160 pmol/mg 

Control heart: 9 pmol/mg 

No mention of COHb% but exposures were similar to those 

in Cronje et al. (2004, 180440) 

Data is expressed as pmol CO/mg tissue wet weight 

Furthermore, endogenous CO production is known to be increased during inflammation, 

hypoxia, increased heme availability and other conditions of cellular stress where HO-1 or HO-2 

activity is increased. A few studies reported cell and tissue concentrations of CO along with 

accompanying COHb levels resulting from enhanced endogenous CO production; Table 5-3 summarizes these findings. Additional measurements of CO levels in cells and tissues following 

increased endogenous production and following inhalation of exogenous CO may provide further 

insight into the relationship between the CO tissue concentration and biological responses. 

January 2010 5-10 
Table 5-3. Tissue concentration of CO following increased endogenous production. 

Study Exposure Tissue CO COHb Notes 

Carraway et al. (2000, 

021096) 

Rats 

Hypobaric hypoxia for 21 days 

1.5-2.8% 

Control 0.5% 

COHb highest after days 1 and 21 

at three- to fourfold higher than controls 

Piantadosi et al. (2006, 

180424) 

Rats 

Hypobaric hypoxia 

1-7 days 

Liver: 5-12 pmol/mg 

Control liver 10 pmol/mg 

1-1.25% 

Control 1% 

CO concentration reached a plateau after 1 day 

Vreman et al. (2005, 

193786) 

Mice 

30 μM heme 

Blood: 88 ± 10 (45) pmol/mg 

Heart: 14 ± 3 (6) pmol/mg 

Muscle: 7 ± 1 (10) pmol/mg 

Brain: 2 ± 0 (2) pmol/mg 

Kidney: 7 ± 2 (7) pmol/mg 

Spleen: 11 ± 1 (6) pmol/mg 

Liver: 8 ± 3 (5) pmol/mg 

Lung: 8 ± 3 (3) pmol/mg 

Intestine: 3 ± 1 (4) pmol/mg 

Testes: 2 ± 0 (2) pmol/mg 

Control levels in parentheses 

0.9% 

CO concentration relative to 100% blood: 

Heart: 16% 

Spleen: 13% 

Lung: 9% 

Liver: 9% 

Kidney: 8% 

Muscle: 8% 

Intestine: 3% 

Brain: 2% 

Testes: 2% 

Data is expressed as pmol CO/mg tissue wet weight 

It should be noted that increased cellular and tissue concentrations of biliverdin and iron 

accompany the increased endogenous production of CO by HO-1 and HO-2. Biliverdin and iron 

have known biological effects, with biliverdin exhibiting antioxidant properties and iron exhibiting 

pro-oxidant properties (Piantadosi et al., 2006, 180424), which could complicate interpretation of 

results from studies in which HO-1 and HO-2 activities are increased. In addition, indiscriminate 

reactions occurring in the case of exogenous CO would likely lead to less specific responses than 

those mediated by reactions of endogenously-produced CO with local targets. Hence, the situations 

of increased endogenous CO production and of exogenous CO exposure are not equivalent. 

A further consideration is that in the numerous conditions and disease states where HO-1 is 

induced, increased levels of endogenously produced CO may represent an adaptive response to stress 

(Durante et al., 2006, 193778; Piantadosi, 2008, 180423). These increases and the accompanying 

increases in COHb generally fall in the range of 1.5- to 4-fold, with the exception of some situations 

of hemolytic anemia and hemoglobin disorders (see Figure 4-11 for results in humans). The resulting 

excess endogenous CO may react intracellularly with heme proteins or diffuse into the blood 

according to the gradient of pCO in the cell/tissue and blood compartments. In many cases, 

beneficial effects or compensatory mechanisms may result as a result of short-term induction of 

HO-1, as reviewed by Ryter et al. (2006, 193765) and Durante et al. (2006, 193778). Longer term 

increases in HO-1 are sometimes associated with protective responses, as in the case of 

atherosclerosis (Cheng et al., 2009, 193775; Durante et al., 2006, 193778), and sometimes with 

pathophysiologic responses as demonstrated in hypoxic pulmonary vascular remodeling (Carraway 

et al., 2002, 026018) and models of salt-sensitive hypertension (Johnson et al., 2003, 193868; 

Johnson et al., 2004, 193870) and metabolic syndrome (Johnson et al., 2006, 193874). Increased 

endogenous CO in hearts of individuals with ischemic heart disease and in lungs of individuals with 

various forms of inflammatory lung disease might also be expected (Scharte et al., 2006, 194115; 

Yamaya et al., 1998, 047525; Yasuda et al., 2005, 191953) (Figure 4-12). It is conceivable that 

prolonged increases in endogenous CO production in chronic disease states may result in less of a 

reserve capacity to handle additional intracellular CO resulting from exogenous exposures, but there 

is no experimental evidence to support this mechanism. Perhaps these circumstances lead to 

dysregulated functions or toxicity. Thus, CO may be responsible for a continuum of effects from cell 

signaling to adaptive responses to cellular injury (Piantadosi, 2008, 180423), depending on 

intracellular concentrations of CO, heme proteins and molecules which modulate CO binding to 

heme proteins. 

January 2010 5-11 
5.1.3.4. Summary

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 

heme-based 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. 

Figure 5-1. Direct effects of CO. The dashed line refers to uptake of inhaled CO by 

respiratory epithelial cells and resident macrophages in the lung. The uptake of 

CO by all other cells and tissues is dependent on COHb. 

5.2. Cardiovascular Effects 

5.2.1. Epidemiologic Studies with Short-Term Exposure 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) examined the association between short-term 

variations in ambient CO concentrations and cardiovascular morbidity. While the results presented 

by these studies did provide suggestive evidence of ambient CO levels being associated with 

exacerbation of heart disease, the AQCD determined that the evidence was inconclusive. The reasons 

January 2010 5-12 
for this conclusion were given as: internal inconsistencies and lack of coherence of the reported 

results within and across studies; the degree to which average ambient CO levels derived from fixedsite monitors are representative of spatially heterogeneous ambient CO values or of personal 

exposures that often include nonambient CO; and the lack of biological plausibility for any harmful 

effects occurring with the very small changes in COHb levels (from near 0 up to 1.0%) over typical 

baseline levels (about 0.5%) that would be expected with the low average ambient CO 

concentrations reported in the epidemiologic studies (generally <5.0 ppm, 1-h daily max) (U.S. EPA, 

2000, 000907). These reasons were also cited in the discussion of the effects of short-term exposure 

to CO on mortality and other types of morbidity. The AQCD posited that ambient CO concentrations 

used as exposure indices in epidemiologic studies may be surrogates for ambient air mixtures 

produced by combustion sources and/or other constituents of such mixtures. In addition, the AQCD 

noted that the epidemiologic evidence was stimulating increased scientific interest regarding ambient 

CO exposures as a potential risk factor for exacerbation of heart disease and other health effects, 

although the epidemiologic studies were subject to considerable biological and statistical uncertainty. 

The following section reviews the literature since the 2000 CO AQCD, including numerous 

new studies on relevant cardiac endpoints and biomarkers and additional studies of daily hospital 

admissions for heart disease. New epidemiologic evidence addresses some of the aforementioned 

uncertainties, including consistency and coherence of results and the possibility that CO may be 

acting as a surrogate for other combustion-derived air pollutants. 

5.2.1.1. Heart Rate and Heart Rate Variability 

Heart rate variability (HRV) refers to the beat-to-beat alterations in the heart rate (HR) and is 

generally determined by analyses of time and frequency domains measured by electrocardiograms 

(ECG). The time domains often analyzed are (a) normal-to-normal (NN or RR) time interval 

between each QRS complex, (b) standard deviation of the normal-to-normal interval (SDNN), and 

(c) mean squared differences of successive difference normal-beat to normal-beat intervals (rMSSD). 

Shorter time domain variables results in lower HRV. The frequency domains often analyzed are (a) 

the ratio of low energy frequency (LF) to high energy frequency (HF), and (b) the proportion of 

interval differences of successive normal-beat intervals greater than 50 ms (PNN50), reflecting 

autonomic balance. Decreased HRV is associated with a variety of adverse cardiac outcomes such as 

arrhythmia, myocardial infarction (MI), and heart failure (Deedwania et al., 2005, 195134; De Jong 

and Randall, 2005, 193996; Huikuri et al., 1999, 184464; Rajendra et al., 2006, 193787). 

Three studies investigated the association between ambient air pollution, including CO, and 

HRV in Boston, MA and reported inconsistent results. The earlier of these studies recruited 21 active 

residents aged 53-87 yr and performed up to 12 ECG assessments on each subject over a period of 4 

mo (summer 1997). Particles (PM10, PM2.5) and several gaseous pollutants (O3, NO2, and SO2) were 

monitored at fixed sites (up to 4.8 mi from the study site), while CO was monitored 0.25 mi from 

each participant's residence. Lag periods for the preceding 1 h, 4 h, and 24 h before each subject’s 

HRV assessment were analyzed, and results showed that only PM2.5 and O3 were associated with 

HRV parameters (Gold et al., 2000, 011432). 

A similar study by the same group of researchers 2 yr later involved 28 older subjects (aged 

61-89 yr) who were living at or near an apartment complex located on the same street as the Harvard 

School of Public Health. The subjects were seen once a week for up to 12 wk, and HRV parameters 

(SDNN, r-MSSD, PNN50, LF/HF ratio) were measured for 30 min each session. Data for PM2.5, BC, 

and CO were recorded at the Harvard School of Public Health (<1 km from the residence) while data 

for NO2, O3, and SO2 were collected from government regulatory monitoring sites. There were 

moderate correlations between CO and PM2.5 (r = 0.61) and between CO and NO2 (r = 0.55) but not 

with SO2 (r = 0.18) or O3 (r = 0.21). Similarly, PM2.5 was associated with HRV, whereas in contrast 

to the previous study, CO was associated1

 with a negative change in SDNN (% change: -13 

[95% CI: -24.06 to -1.88]), r-MSSD (% change: -31.88 [95% CI: -38 to -7.5]), and PNN50

(% change: -46.25 [95% CI -103.95 to -9.38] per 0.5 ppm increase in 24-h avg CO concentration) 

(Schwartz et al., 2005, 074317). 

 

1

 The effect estimates from epidemiologic studies have been standardized to a 1 ppm increase in ambient CO for 1-h max CO 

concentrations, 0.75 ppm for 8-h max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations throughout this section (text, 

tables, and figures). 

January 2010 5-13 
An additional Boston, MA study examined HRV parameters (SDNN, LF, HF, LF/HF ratio) 

among 603 persons from the Normative Aging Study, a longitudinal study that originally recruited 

2,280 men in the greater Boston area during 1963. The cohort members were examined (November 

2000-October 2003) and the ECG data were linked to air pollution data for PM2.5, particle number 

concentration, BC, O3, NO2, SO2, and CO. Lagged pollutant effects for a 4-h, 24-h, and 48-h ma 

were examined. The main pollutant effects were with PM2.5 and O3, while CO was not associated 

with HRV (Park et al., 2005, 057331). 

A study in Mexico City selected 30 subjects from the outpatient clinic at the National Institute 

of Cardiology and followed them for ~10 h (starting at 9:00 a.m.) (Riojas-Rodriguez et al., 2006, 

156913). Each subject was connected to a Holter ECG monitor (e.g., a portable ECG monitor) and 

also given personal PM2.5 and CO monitors. The subjects went about their usual daily activities, and 

the personal PM2.5 and CO data were linked to various ECG parameters (HR, R-R, LF, HF) at 

various lags. In copollutant models with PM2.5, personal CO exposure for the same 5-min period was 

significantly associated with a decrease in LF and very low energy frequency (VLF) parameters with 

coefficients equal to -0.024 (95% CI: -0.041 to -0.007) and -0.034 (95% CI: -0.061 to -0.007), 

respectively, for a 1 ppm increase in 1-h CO concentration. 

In an additional study conducted in Mexico City, 34 residents from a nursing home underwent 

HRV analysis every other day for 3 mo (Holguin et al., 2003, 057326). Exposure assessment for 

ambient PM2.5 was based on data recorded at a monitor on the roof of the nursing home, while 

exposures to ambient O3, NO2, SO2, and CO were derived from data recorded at a fixed site 3 km 

from the nursing home. Exposures for the same day and 1-day lags were analyzed, and only O3 and 

PM2.5 were positively associated with HRV. 

Wheeler et al. (2006, 088453) examined 18 individuals with COPD and 12 individuals with 

recent MI living in Atlanta, GA. Morning ECG readings were collected by a Holter system by a field 

technician in the subjects’ homes. Ambient air pollution exposures for PM2.5, O3, NO2, SO2 and CO 

were derived from data recorded at fixed sites throughout metropolitan Atlanta. Three exposure 

periods were analyzed: the hour of the ECG reading, 4-h mean, and 24-h mean before the reading. 

While positive effects were reported for NO2 and PM2.5, no quantitative results were reported for 

CO. 

After reviewing 2,000 patient charts, Dales (2004, 099036) recruited 36 subjects with CAD 

from the Toronto Western Hospital’s noninvasive cardiac diagnostic unit. HR and HRV (SDNN, NN, HF, LF, HF/LH ratio) were assessed 1 day each week for up to 10 wk by a Holter monitoring 

system. Personal air sampling for PM2.5 and CO was carried out for the same 24-h period while 

subjects went about their usual daily activities for that period. Stratified results showed that among 

those not on beta-receptor-blockers, personal CO exposure was positively associated with SDNN (p

= 0.02). However, in the group taking beta blockers, there was a negative association (p = 0.06). 

Personal exposure to PM2.5 was not associated with HRV. 

Peters et al. (1999, 011554) examined HR among a sub-sample of the Monitoring of Trends 

and Determinants in Cardiovascular Disease (MONICA) study (n = 2,681) in Augsburg, Germany. 

Total suspended particles (TSP), SO2, and CO data were collected from a single monitoring station 

located in the center of the city and linked to each subject to estimate exposures on the same day and 

5 days prior. A 0.5 ppm change in 24-h CO concentration was associated with an increase in HR of 

approximately 1 beat per minute, whereas CO based on a 5-day exposure had no effect on HR. 

Thirty-one subjects with CHF had their pulse rate recorded daily over a 2-mo period, and the 

correlation between pulse rate and air pollutants was examined (Goldberg et al., 2008, 180380). 

There was weak evidence for a decrease in pulse rate associated with the lag 1 SO2 concentration 

after adjustment for personal and meteorological factors and no evidence for an effect associated 

with any of the other air pollutants (adjusted mean difference for CO: 0.245 [95% CI -0.209 to 

0.700] lag 0-2). 

Liao et al (2004, 056590) investigated men and women aged 45-64 yr from the Atherosclerosis 

Risk in Communities (ARIC) study (Washington County, MD; Forsyth County, NC; and selected 

suburbs of Minneapolis, MN). The sample sizes were 4,899, 5,431, 6,232, 4,390 and 6,784 for 

analyses involving PM10, O3, CO, NO2, and SO2, respectively. County-level exposure estimates for 

24-h CO were calculated for 1, 2, and 3 days prior to clinical examination. A 0.5 ppm increase in 

24-h CO concentration (at lag 1) was associated with an increase in HR (beats/minute) (β = 0.357, 

p < 0.05). CO was not significantly associated with changes in SDNN. 

The Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) 

study was carried out in three European cities: Amsterdam, The Netherlands; Erfurt, Germany; and 

January 2010 5-14 
Helsinki, Finland; a panel of subjects with CAD was followed for 6 mo with biweekly clinical visits, 

which included an ECG reading to assess HRV (Timonen et al., 2006, 088747). The time-domain 

measures of HRV (SDNN and rMSSD) were analyzed along with frequency-domain measures, 

which included power spectrum densities for LF and HF. Exposures to ambient air pollution (PM2.5, PM10, NO2, CO) were derived from data recorded at fixed-monitoring site networks within each city. 

Correlation coefficients for NO2 and CO ranged from 0.32 to 0.86 in the three cities. CO was 

moderately correlated with PM10 in Helsinki (r = 0.40), with PM2.5 in Amsterdam (r = 0.58), and 

more highly correlated with PM10 in Erfurt (r = 0.77). Various lag periods were examined, including 

lag 0 (24 h prior to the clinical visit) through a 0- to 2-day avg lag and a 0- to 4-day avg lag. In total 

there were 1,266 ECG recordings used in the final analyses. In the pooled analyses (e.g., across 

cities) a 0.5 ppm increase in 24-h CO concentration was associated with a decrease in LF/HF ratio at 

lag 1-day (β -16.4 [95% CI: -29.9 to -0.3]), and a decrease in SDNN and HF at lag 2-day (β -3.4 

[95% CI: -6.1 to -0.4]; β= -17.6 [95% CI: -34.4 to -0.9], respectively). However, the same study 

reported no effect for CO on BP and HR (Ibald-Mulli et al., 2004, 087415). 

A small panel study in Kuopio, Finland, which was designed as the pilot study for the ULTRA 

study, examined simultaneous ambulatory ECG and personally monitored CO readings among 

6 male patients with CAD (Tarkiainen et al., 2003, 053625). The patients were asked to follow their 

usual daily activities, but data were recorded only three times with 1-wk intervals. The CO exposures 

were divided into low (≤ 2.7 ppm) and high (>2.7 ppm) and during the high CO exposure r-MSSD 

increased on average by 2.4 ms; however, there was no effect on RR or SDNN. 

A study in Taiwan recruited 83 patients (aged 40-75 yr) from the National Taiwan University 

Hospital, Taipei, and conducted ambulatory ECG readings using a Holter system (Chan et al., 2005, 

088988). Ambient air pollution exposures for PM10, NO2, SO2, and CO were derived from 12 fixedsite monitoring stations across Taipei. Lag periods of 1 h to 8 h prior to the ECG reading were 

analyzed, and only NO2 was associated with HRV parameters (SDNN and LF); CO was not 

associated with HRV. 

Min et al. (2009, 199514) investigated the effects of CO on cardiac autonomic function by 

measuring HRV in patients with and without metabolic syndrome. Several criteria were used to 

classify metabolic syndrome, including waist circumference, triglycerides and cholesterol levels, 

blood pressure, and fasting glucose level. The group classified as having metabolic syndrome 

showed significant decreases in SDNN and HF, and those declines were significantly associated with 

CO exposure with a 1- to 2-day lag. Copollutant models with PM10 and NO2 gave similar results. 

In summary, few studies have examined the effect of CO on HR, and while two of the three 

studies reported a positive association, further research is warranted to corroborate the current 

results. Similarly, while a larger number of studies have examined the effect of CO on various HRV 

parameters, mixed results have been reported throughout these studies. Furthermore, with several 

HRV parameters often examined, there are mixed results across the studies as to the HRV parameters 

that are positively associated with CO exposure. Table 5-4 presents a summary of the reviewed 

studies. Due to the heterogeneity of endpoints (see column “cardiac endpoint” in Table 5-4), these 

studies do not lend themselves to a quantitative meta-analysis or inclusion in a summary figure. 

January 2010 5-15 
Table 5-4. Summary of studies investigating the effect of CO exposure on HRV parameters. 

Study Location 

Sample Size Cardiac Endpoint

Upper CO 

Concentrations 

from AQSa

 in 

ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

Copollutants 

Gold et al. (2000, 011432) Boston, MA 

(n = 21) 

HR, SDNN, 

r-MSSD 

98th%: 0.80-2.48 

99th%: 0.89-2.57 

(24 h)t 

Mean: 0.47(24 h) 

Range: 0.12-0.82 

PM10, PM2.5, O3, NO2, 

SO2

Schwartz et al. (2005, 074317) Boston, MA 

(n = 28) 

SDNN, 

r-MSSD, PNN, LF/HF 

98th%: 0.95-2.14 

99th%: 0.96-2.60 

(24 h) 

25th, 50th, 75th 

percentiles: 

0.38, 0.45, 0.54 

PM2.5, BC, NO2, O3

Park et al. (2005, 057331) Boston, MA 

(n = 4 97) SDNN, LF, HF, LF/HF 

98th%: 0.92-1.45 

99th%: 0.99-1.66 

(24 h) 

Mean: 0.50 (24 h) 

Range: 0.13-1.8 

PM2.5, BC, O3, NO2, 

SO2

Riojas-Rodriguez et al. (2006, 

156913) 

Mexico City, Mexico 

(n = 30) HF, LF, VLF, HR, R-R NA Mean: 2.9 (11 h) Range: 0.1-18 PM2.5

Holguin et al. (2003, 057326) Mexico City, Mexico 

(n = 34) HF,LF, LF/HF NA Mean: 3.3(24 h) Range: 1.8-4.8 PM2.5, O3, NO2, SO2

Wheeler et al. (2006, 088453) Atlanta, GA 

(n = 30) 

SDNN, r-MSSD, PNN, 

LF, HF, LF/HF 

98th%: 2.8-3.1 

99th%: 2.9-3.8 

(8 h) 

Mean: 362 ppb (4h) 

25th, 50th, 75th 

percentiles: 

221.5, 304.3, 398.1 

PM2.5, O3, NO2, SO2

Dales (2004, 099036) Toronto, Canada 

(n = 36) 

SDNN, HF, LF, LF/HF, 

N-N NA Mean: 2.4b

Range: 0.4-16.5 PM2.5

Peters et al. (1999, 011554) Augsburg, Germany 

(n = 2681) HR NA Mean: 3.6 Range: 1.5-7.1 TSP, SO2

Goldberg et al. (2008, 180380) Montreal, Canada 

(n-31) Pulse rate NA NR; IQR: 1.8 ppm NO2, O3, SO2, PM2.5

Liao et al. (2004, 056590) 

Maryland, 

North Carolina, 

Minnesota, 

(n = 4899-6784) 

HR, SDNN, LF, HF 

98th%: 0.39-2.29 

99th%: 0.43-2.66 

(24 h) 

Mean: 0.65 (24 h) PM10, O3, NO2, SO2

Timonen et al. (2006, 088747) 

Amsterdam, 

The Netherlands; 

Erfurt, Germany; 

Helsinki, Finland 

(n = 131) 

SDNN, HF, LF/HF NA Mean: 0.35-0.52 

Range: 0.09-2.17 PM2.5, PM10, NO2

Ibald-Mulli et al. (2004, 

087415) 

Amsterdam, 

The Netherlands; 

Erfurt, Germany; 

Helsinki, Finland 

(n = 131) 

BP, HR NA Mean: 0.35-0.52 

Range: 0.09-2.17 

UFP, PM10, PM2.5, NO2, 

SO2

Tarkiainen et al. (2003, 

053625) 

Kuopio, Finland 

(n = 6) PNN, SDNN, r-MSSD NA Mean: 4.6 Range: 0.5-27.4 None 

Chan et al. (2005, 088988) Taipei, Taiwan 

(n = 83) 

SDNN, 

r-MSSD, LF NA Mean: 1.1 Range: 0.1-7.7 PM10, NO2, SO2

Min et al. (2009, 199514) South Korea 

(n=986) SDNN, HF, LF NA Mean: 0.45 Range: 0.10-7.20 PM10, NO2, SO2

NA: Not Available 

a Includes range across individual monitors in study site; AQS data available for U.S. studies only b 95th percentile of 24-h levels 

5.2.1.2. ECG Abnormalities Indicating Ischemia 

The ST-segment of an ECG represents the period of slow repolarization of the ventricles and 

ST-segment depression can be associated with adverse cardiac outcomes, including ischemia. Gold 

et al. (2005, 087558) recruited a panel of 28 older adults living at or near an apartment complex 

located within 0.5 km of a monitoring site in Boston, MA. Each subject underwent weekly ECGs for 

12 wk in summer 1999 with the main outcome of interest being the ST-segment. Air pollution data in 

the form of PM2.5, BC, and CO were collected from a central site within 0.5 km of the residences of 

the subjects and averaged over various lag periods (1- to 24-h, 12-h, and 24-h ma) before the ECG. 

The final analyses included 24 subjects with 269 observations, and results showed consistent 

negative associations of ST-segment change with increased BC with the strongest association with 

the 5-h lag. CO during the same lag period also showed a negative association with ST-segment 

change; however, only BC remained significant in multipollutant models. 

The most recent study by this group of researchers utilized a repeated-measures study to 

investigate the associations between ambient air pollution and ST-segment level changes averaged 

over 30-min periods in patients with coronary artery disease (CAD) (Chuang et al., 2008, 155731). 

January 2010 5-16 
The authors reported that increases in mean PM2.5, BC, NO2 and SO2 concentrations predicted 

depression of 30-min averaged ST-segment levels. No association of ST-segment depression was 

observed with CO or O3. 

5.2.1.3. Arrhythmia 

Cardiac arrhythmia refers to a broad group of conditions where there is irregular electrical 

activity in the heart. The main types of arrhythmias are fibrillation, tachycardia, and bradycardia, all 

resulting from dysfunction of the upper (atria) and lower (ventricle) chambers of the heart. Briefly, 

fibrillation refers to when a chamber of the heart quivers chaotically rather than pumps in an orderly 

fashion, tachycardia refers to a rapid heart beat (e.g., >100 beats/min), while bradycardia refers to a 

slow heart beat (e.g., <60 beats/min). A few air pollution panel studies have examined the occurrence 

of cardiac arrhythmias by analyzing data recorded by implantable cardioverter defibrillators (ICDs) 

among cardiac patients. The majority of these studies were conducted in North America, with the 

main outcome investigated being tachycardia. Results of these studies provide little evidence for an 

association between cardiac arrhythmia and ambient CO. 

For example, Dockery and colleagues (2005, 078995) analyzed the relationship between 

ambient air pollution and the daily incidence of ventricular tachyarrhythmia among 203 patients with 

ICDs in Boston, MA. An hourly city average for the Boston metropolitan area was calculated for 

CO, O3, NO2, SO2, SO4

2-, BC, and PM2.5. Although positive associations between ventricular 

arrhythmic episode days were found for all mean pollutant levels on the same day and previous days, 

none of these associations approached statistical significance. However, when the analyses were 

stratified by patients who had a previous incidence of ventricular arrhythmia within 3 days or greater 

than 3 days to the day of interest, a 0.5 ppm increase in 24-h CO concentration was positively 

associated with incidence of ventricular arrhythmia (OR: 1.68 [95% CI: 1.18-2.41]) among those 

who had a ventricular arrhythmia within the last 3 days. 

A similar study in eastern Massachusetts examined cardiac arrhythmia by analyzing 

defibrillator discharges precipitated by either ventricular tachycardia or fibrillation among 100 

cardiac patients (Peters et al., 2000, 011347). Exposure to ambient CO was estimated for the same 

day, 1-day, 2-day, 3-day, and a 5-day mean lag period. CO was moderately correlated with PM10

(r = 0.51) and PM2.5 (r = 0.56) and more highly correlated with NO2 (r = 0.71). When analyzing 

patients who had at least one defibrillator discharge (n = 33), there was no association with CO. 

However, when analyzing patients who had at least 10 discharges (n = 6), a 0.5 ppm increase in 24-h 

CO concentration (lag 0-4) was associated with an increased odds of a defibrillator discharge (OR: 

1.66 [95% CI: 1.01-2.76]). 

In contrast, other air pollution panel studies conducted in St Louis, MO (among 56 subjects) 

(Rich et al., 2006, 089814), Atlanta, GA (among 518 subjects) (Metzger et al., 2007, 092856), 

Boston, MA (among 203 subjects) (Rich et al., 2005, 079620), and Vancouver, Canada (Rich et al., 

2004, 055631; Vedal et al., 2004, 055630) (among 34 and 50 subjects respectively) did not find an 

association between short-term changes in ambient CO and occurrence of cardiac arrhythmia in 

patients with implantable defibrillators. The study in Boston also examined atrial fibrillation 

episodes among the same group of subjects and did not find an association with ambient CO (Rich et 

al., 2005, 079620). 

An alternative method used to assess the relationship between cardiac arrhythmia and ambient 

air pollution is to analyze cardiac data recorded via ECG. Two studies have employed this method 

and reported inconsistent results. A study in Steubenville, OH, which is located in an industrial area, 

examined weekly ECG data among 32 nonsmoking older adults for 24 wk during summer and fall 

(Sarnat et al., 2006, 090489). Ambient exposures for up to 5 days prior to the health assessment 

(based on a 5-day ma) were calculated for PM2.5, SO4

2-, elemental carbon (EC), O3, NO2, SO2, and 

CO from data recorded at one central monitoring site. Increases in ambient CO were not associated 

with increased odds of having at least one arrhythmia during the study period. 

In contrast, a study in Germany examined the relationship between ambient air pollution and 

the occurrence of supraventricular (atria) and ventricular tachycardia recorded via monthly 24-h 

ECGs among 57 subjects over a 6-mo period (Berger et al., 2006, 098702). Exposure estimates were 

calculated for ambient ultrafine particles, PM2.5, CO, NO, NO2, and SO2 for various lag periods 

(0-23 h, 24-47 h, 48-71 h, 72-95 h, and 5-day avg) prior to the ECG. Results showed that a 0.5 ppm 

increase in ambient 24-h CO concentration (lag 0-4 days prior to ECG) was positively associated 

January 2010 5-17 
with the occurrence of supraventricular tachycardia (OR: 1.36 [95% CI: 1.08-1.74]). However, 

ambient CO was not associated with ventricular tachycardia. 

In summary, the studies that have examined associations between CO and the occurrence of 

cardiac arrhythmias provided little evidence of a CO effect on cardiac arrhythmias. While most 

studies analyzed data from ICDs, very few reported significant associations, which is similar to the 

studies that analyzed ECG data to evaluate cardiac arrhythmias in association with CO exposures. 

Table 5-5 summarizes the reviewed studies. 

Table 5-5. Summary of studies investigating the effect of CO exposure on cardiac arrhythmias. 

Study Location, 

Sample Size 

Cardiac 

Endpoint 

Upper CO 

Concentrations 

from AQSa in ppm

CO Concentrations 

Reported by Study 

Authors 

 in ppm 

Copollutants 

ARRHYTHMIAS (AMONG PATIENTS WITH ICDS) 

Dockery et al. (2005, 

078995) 

Boston, MA 

(n = 203) 

Ventricular 

tachycardia 

98th%: 0.89-2.33 

99th%: 0.99-2.55 

(24 h) 

25th, 50th, 75th, 95th, 

percentiles: 0.53, 0.80, 1.02, 

1.37 (2-day) 

PM2.5, BC, O3, NO2, SO2, SO4

2-

Peters et al. (2000, 

011347) 

Massachusetts, US 

(n = 100) Ventricular 

fibrillation or 

tachycardia 

98th%: 1.60-2.58 

99th%: 1.75-2.71 

(24 h) 

Mean: 0.58 (24 h) 

Max: 1.66 

PM2.5, PM10, BC, O3, NO2, SO2, 

SO4

2-

Rich et al. (2006, 

089814) 

Boston, MA 

(n = 56) Ventricular 

arrhythmia 

98th%: 0.89-2.33 

99th%: 0.99-2.55 

(24 h) 

25th, 50th, 75th percentiles: 

0.4, 0.5, 0.6 (24 h) 

PM2.5, EC, O3, NO2, SO2

Metzger et al. (2007, 

092856) 

Atlanta, GA 

(n = 518) Ventricular 

tachycardia 

98th%: 5.0 

99th%: 5.6 

(1 h) 

Mean: 1.7 (1 h) 

Range: 0.1-7.7 

PM10, PM2.5, O3, NO2, SO2

Rich et al. (2005, 

079620) 

Boston, MA 

(n = 203) Atrial fibrillation 

98th%: 0.89-2.33 

99th%: 0.99-2.55 

(24 h) 

25th, 50th, 75th, 95th, 

percentiles: 0.53, 0.80, 1.02, 

1.37 (2-day) 

PM2.5, BC, O3, NO2, SO2

Rich et al. (2004, 

055631) 

Vancouver, 

Canada 

(n = 34) 

ICD discharge 

due to 

arrhythmia 

NA Mean: 0.55 (24 h) 

IQR: 0.16 

PM2.5, PM10, EC, O3, NO2, SO2, 

SO4

2–

Vedal et al. (2004, 

055630) 

Vancouver, Can 

(n = 50) 

ICD discharge 

due to 

arrhythmia 

NA Mean: 0.6 (24 h) 

Range: 0.3-1.6 

PM10, O3, NO2, SO2

ARRHYTHMIAS (VIA ECG) 

Sarnat et al. (2006, 

090489) 

Steubenville, OH 

(n = 32) 

Atrial or 

ventricular 

tachycardia 

98th%: 1.42 

99th%: 1.81 

(24 h) 

Mean: 0.2 (24 h) 

Range: 0.1, 1.5 

PM2.5, O3, NO2, SO2, SO4

2–, EC 

Berger et al. (2006, 

098702) 

Erfurt, Germany 

(n = 57) 

Atrial or 

ventricular 

tachycardia 

NA 

Mean: 0.45 (24 h) 

Min, Med, Max 

0.10, 0.38, 1.68 

PM10, PM2.5, NO2, NO, SO2, UF 

NA: Not Available 

a

 Includes range across individual monitors in study site; AQS data available for U.S. studies only. 

5.2.1.4. Cardiac Arrest 

Cardiac arrest refers to the abrupt loss of heart function due to failure of the heart to contract 

effectively during systole, which can lead to sudden cardiac death if not treated immediately. Very 

January 2010 5-18 
few studies have investigated the association between ambient CO exposure and the risk of cardiac 

arrest, and none reported a significant association between increased CO exposure and the 

occurrence of cardiac arrest. 

Two studies (Levy et al., 2001, 017171; Sullivan et al., 2003, 043156) were evaluated that 

examined the association between ambient CO and cardiac arrest. Both studies were conducted in 

Seattle, WA, using a case-crossover study design and found no association between short-term 

exposure to CO and cardiac arrest. 

 These studies examined air pollution exposures for black smoke particles (BSP), PM10, SO2, 

and CO. The correlation coefficient for PM10 and CO was 0.8 in both studies. The first of these 

studies examined paramedic-attended out-of-hospital primary cardiac arrests among 362 cases 

(1998-1994) in Seattle and King County, WA, whereby lags of 0-5 days were analyzed (Levy et al., 

2001, 017171). There was no indication of association between CO and out-of-hospital primary 

cardiac arrest (RR 0.99 [95% CI: 0.83-1.18]). The second of these studies examined out-of-hospital 

primary cardiac arrest for a 10-yr period (1985-1994) among subjects within a health organization 

database (the Group Health Cooperative of Puget Sound), whereby 0- through 2-day lags were 

analyzed (Sullivan et al., 2003, 043156). The relative risk of primary cardiac arrest was 0.95 

(95% CI: 0.85-1.05; lag 0). 

5.2.1.5. Myocardial Infarction 

As previously stated, MI is commonly referred to as “heart attack” and is another cardiac 

outcome that has received limited attention within the area of air pollution research. Only one study 

has investigated the association between short-term changes in ambient CO and the onset of MI. 

Peters and colleagues (2001, 016546) employed a case-crossover study design to analyze short_term 

exposures (0-5 h and 0-5 days before the onset of MI) to particles (PM10, PM2.5, PM10-2.5, BC) and 

gases (CO, O3, NO2, SO2) among 772 patients with MI in the greater Boston area. While all 

pollutants showed positive associations with the onset of MI, only PM2.5 reached statistical 

significance with the main exposure period (2 h before the onset) (OR for CO: 1.22 [95% CI: 

0.89-1.67]). 

5.2.1.6. Blood Pressure 

Only two studies have investigated whether short-term exposure to CO influences BP. The 

earlier of these two studies examined BP among 2,607 men and women aged 25-64 yr who 

participated in the Augsburg, Germany, MONICA study (Ibald-Mulli et al., 2001, 016030). 

Exposures to ambient TSP, SO2 and CO (from one monitor in the center of the city) during the same 

day as the BP reading and an average over the 5 days prior were examined. Results showed that 

ambient CO had no association with BP. 

Similarly, the second of these studies extracted baseline and repeated measures of cardiac 

rehabilitation data from a Boston, MA, hospital for 62 subjects with 631 visits and analyzed ambient 

air pollution exposures (with particular focus on PM2.5) averaged over various periods up to 5 days 

before the visit (Zanobetti et al., 2004, 087489). While results showed significant associations 

between increased BP and ambient PM2.5, SO2, O3, and BC, there was no significant effect for CO 

(results not presented quantitatively). 

5.2.1.7. Vasomotor Function 

Gaseous pollutants, including SO2, NO and CO, were found to affect large artery endothelial 

function among 40 healthy white male nonsmokers in Paris, France, whereas PM was found to 

exaggerate the dilatory response of small arteries to ischemia (Briet et al., 2007, 093049). Changes in 

amplitude of flow-mediated dilatation were highly dependent on changes in 5-day lag concentrations 

of SO2, NO and CO, but not NO2, PM2.5 or PM10. The effect attributed to CO (β coefficient: -0.68 

[95% CI: -1.22 to -0.15]) was the smallest in magnitude when compared to those for SO2 and NO, 

but overall the effect estimates were similar and all were statistically significant. Similarly, PM2.5, 

PM10, NO2 and CO were positively correlated with small artery reactive hyperemia, and the effect 

attributed to CO was the smallest in magnitude when compared to those for PM2.5, PM10, and NO2; 

but overall, the effect estimates were similar and all were statistically significant. 

January 2010 5-19 
5.2.1.8. Blood Markers of Coagulation and Inflammation 

Several studies have investigated the association between ambient CO and various blood 

markers related to coagulation and inflammation. The main endpoints analyzed have been plasma 

fibrinogen, B-type natriuretic peptide (BNP), endothelial function, Factor VII, C-reactive protein 

(CRP), prothrombin, intercellular adhesion molecule (ICAM-1), and white blood cell count (WBC). 

Delfino et al. (2008, 156390) measured blood plasma biomarkers in a panel of 29 nonsmoking, 

elderly subjects with a history of CAD living in retirement communities in the Los Angeles, CA, air 

basin, in order to identify associations with systemic inflammation. The blood plasma biomarkers 

included CRP, fibrinogen, tumor necrosis factor-α (TNF- α) and its soluble receptor-II (sTNF-RII), 

interleukin-6 (IL-6) and its soluble receptor (IL-6sR), fibrin D-dimer, soluble platelet selectin 

(sP-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble ICAM-1, and 

myeloperoxidase (MPO). Overall, there were statistically significant associations for many of the 

biomarker and pollutant combinations, with some of the strongest effects for CRP, IL-6 and sTNFRII with indoor and outdoor concentrations of NO2 and CO. Only the outdoor concentrations 

indicated an effect of PM for these three biomarkers of inflammation. There was weak evidence for 

an effect of outdoor and indoor CO on the biomarker of platelet activation (sP-selectin), and for an 

effect of many of the air pollutants examined on fibrinogen, TNF- α, sVCAM-1, sICAM-1, and 

MPO. Parameter estimates for fibrin D-dimer were close to zero for most models. Overall, the 

results suggest that traffic related pollutants, including PM2.5, UFPs, OC and CO, lead to increases in 

systemic inflammation and platelet activation in elderly people with a history of CAD. 

Delfino et al. (2009, 200844) added a second year of data from 31 additional subjects to data 

used in their previous analysis of 29 subjects (Delfino et al., 2008, 156390). This updated panel 

study of 60 elderly individuals with CAD investigated the relationship of air pollutants to changes in 

circulating biomarkers of inflammation, platelet activation and antioxidant capacity. The updated 

analysis focused on the biomarkers that were most informative in the previous analysis (Delfino et 

al., 2008, 156390) and included IL-6, TNF-α, sTNF-RII, CRP, and sP-selectin. Additionally, frozenthawed erythrocyte lysates were assayed spectrophotometrically for activities of two antioxidant 

enzymes, glutathione peroxidase-1 (GPx-1) and copper-zinc superoxide dismutase (Cu,Zn-SOD). 

Hourly outdoor home-air pollutants were measured over 9 days before each blood draw. There was 

evidence for an association of CO with IL-6, P-selectin, TNF-RII and CRP, but not for TNF- α, 

Cu,Zn-SOD, or GPx-1. Many positive associations were found for IL-6, sP-selectin, sTNF-RII, 

TNF- α, and CRP with markers of traffic-related air pollution (EC, OC, BC, NOX, and CO), 

confirming the earlier finding that traffic related pollutants may lead to increases in systemic 

inflammation and platelet activation in elderly people with a history of CAD. 

Circulating levels of BNP are directly associated with cardiac hemodynamics and symptom 

severity in patients with heart failure and serve as a marker of functional status. Wellenius et al. 

(2007, 092830) examined the association between BNP levels and short-term changes in ambient air 

pollution levels among 28 patients with chronic stable heart failure and impaired systolic function. 

The authors reported no association between CO along with the other pollutants examined and 

measures of BNP at any lag. 

Pekkanen et al. (2000, 013250) examined the association between daily concentrations of air 

pollution and concentrations of plasma fibrinogen measured among 4,982 male and 2,223 female 

office workers in Whitehall, London, U.K., between September 1991 and May 1993. Plasma 

fibrinogen data were linked to ambient exposure to BS, PM10, O3, NO2, SO2, and CO, where the 

exposures were derived from data recorded at 5 fixed sites across London. There was a high 

correlation between levels of CO and NO2 (r = 0.81) and more moderate correlations of CO with 

PM10 (r = 0.57) and SO2 (r = 0.61). The pollution data on the same day when the blood sampling was 

done (lag 0) and on the 3 previous days (lags 1-3) were analyzed. Results showed that ambient CO at 

all lags was associated with an increase in plasma fibrinogen. Results were similar for NO2, while all 

other pollutants were not associated with an increase in plasma fibrinogen. 

Liao et al. (2005, 088677) examined associations between various air pollutants and 

hemostatic and inflammatory markers (fibrinogen, factor VIII-C, von Willebrand factor, serum 

albumin, WBC) among 10,208 middle-aged males and females from the ARIC study. Exposure 

estimates for ambient PM10, NO2, SO2, O3 and CO were calculated for days 1-3 prior to the blood 

sampling. A 0.5 ppm increment in 24-h CO concentration was significantly associated with 

0.015 g/dL decrease in serum albumin among persons with a history of cardiovascular disease 

(CVD). CO was not associated with other hemostatic or inflammatory factors. 

January 2010 5-20 
In Israel, Steinvil et al. (2008, 188893) examined WBC, fibrinogen, and CRP among 3,659 

study subjects enrolled in the Tel-Aviv Sourasky Medical Center inflammation survey, in which 

subjects lived <11 km from an ambient air pollution monitor. Air pollution data in the form of PM10, NO2, SO2, O3, and CO were derived from data recorded at fixed sites. The correlation coefficients 

were high between CO and NO2 (r = 0.86) and PM10 (r = 0.75). Exposures for lag days 0-7 were 

analyzed, and ambient CO had a negative effect on fibrinogen only among males. Negative 

associations were reported for lag 0 (e.g., same day) and lags 2-5 with the decrease in fibrinogen 

ranging from -5.5 mg/dL to -9.8 mg/dL per 0.5 ppm increase in 24-h CO concentration. A similar 

negative effect for CO was observed on WBC among males only. The average CO exposure over the 

week prior to the sampling yielded the largest reduction in WBC (-263 cells/μL). 

In a German study, Rückerl and colleagues (Ruckerl et al., 2006, 088754) recruited 57 

nonsmoking male patients with CHD who were scheduled for 12 subsequent clinical visits where 

samples of blood were collected. The authors tested the primary hypothesis that CRP would increase 

in association with a rise in air pollution levels. CRP is an acute phase protein that increases during 

inflammatory processes in the body. Other markers of inflammation (serum amyloid A [SAA]), cell 

adhesion (E-selectin, von Willebrand factor antigen [vWF], ICAM-1), and coagulation (fibrinogen, 

factor VII [FVII], prothrombin fragment 1+2) were also examined. Ambient air pollution in the form 

of PM10, UFP, EC, NO2, and CO was monitored at one central site, and a 24-h avg immediately 

preceding the clinic visit (lag 0) and up to 5 days (lags 1-4) was calculated for each patient. For CRP, 

the odds of observing concentrations above the 90th percentile (8.5 mg/L) were 2.41 

(95% CI: 1.23-5.02) in association with a 0.5 ppm increase in 24-h CO concentration (lag 2). CO 

concentration during lags 1 and 2 was associated with observing ICAM-1 concentrations above the 

90th percentile (OR: 2.41 [95% CI: 1.49-4.04]; OR: 3.17 [95% CI: 1.77-6.11], respectively). CO 

concentration (lag 0-3) was associated with a decrease in FVII. 

A similar study by Rückerl and colleagues (2007, 156931) was conducted among 1,003 MI 

survivors across six European cities (Athens, Greece; Augsburg, Germany; Barcelona, Spain; 

Helsinki, Finland; Rome, Italy; Stockholm, Sweden). The study compared repeated measurements of 

interleukin-6 (IL-6), CRP and fibrinogen with concurrent ambient levels of air pollution (particle 

number count [PNC], PM10, PM2.5, NO, NO2, O3, SO2, CO) from fixed sites across each city. Lags 

0-1 and the 5-day mean prior to the blood sampling were analyzed and ambient CO was not 

associated with any of the inflammatory endpoints. 

Baccarelli et al. (2007, 090733) recruited 1,218 healthy individuals from the Lombardia region 

in Italy and assessed whether blood coagulability is associated with ambient air pollution. The main 

blood coagulability endpoints of interest were prothrombin time (PT) and activated partial 

thromboplastin time (APTT), which are measures of the quality of the coagulation pathways, 

assuming that, if shortened these measures would reflect hypercoagulability. Air pollution data 

(PM10, O3, NO2, and CO) were obtained from 53 fixed stations across the Lombardia region, which 

was divided into 9 different study areas, and a network average for each pollutant was calculated 

across the available monitors within each of the 9 study areas. The analyses examined air pollution at 

the time of the blood sampling, as well as averages for the 7 days prior and 30 days prior. Results 

showed that ambient CO at the time of blood sampling was associated with a decrease in PT 

(coefficient = -0.11 [95% CI: -0.18 to -0.05], p < 0.001), indicating hypercoagulability. However, 

PM10 and NO2 at the time of blood sampling were also associated with a decrease in PT and results 

from multipollutant models were not reported. Acute phase reactants such as fibrinogen and 

naturally occurring anticoagulants such as antithrombin, protein C and protein S were examined and 

none were associated with ambient air pollution. 

Rudez et al. (2009, 193783) collected 13 consecutive blood samples within a 1-yr period and 

measured light-transmittance platelet aggregometry, thrombin generation, fibrinogen and CRP in 

40 healthy individuals in Rotterdam, The Netherlands. In general, air pollution increased platelet 

aggregation as well as coagulation activity but had no clear effect on systemic inflammation. 

Specifically, there were notable associations between maximal aggregation and CO, NO and NO2

and between late aggregation and CO. The effects for CO were the highest in magnitude and 

persisted over most of the lag times investigated. There also was evidence of an increase in 

endogenous thrombin potential and peak thrombin generation associated with CO, NO, NO2 and O3, but no clear associations between PM10 and peak height or lag time of thrombin generation. In 

addition, there was no evidence for an effect of any of the air pollutants examined on CRP or 

fibrinogen levels. These prothrombotic effects may partly explain the relationship between air 

pollution and the risk of ischemic cardiovascular disease. 

January 2010 5-21 
Ljungman et al. (2009, 191983) investigated the effect of CO and NO2 on inflammation in 

certain genetic subpopulations of MI survivors. Specifically, they examined whether IL-6 and 

fibrinogen gene variants could affect plasma IL-6 response to CO or NO2. The study included 

955 MI survivors from 6 European cities. This study provides evidence of gene-environment 

interaction where IL-6 and fibrinogen gene polymorphisms modified the effects of CO and NO2 on 

IL-6 levels in this panel of subjects with existing cardiovascular disease. Subjects with the 

homozygous major allele genotypes for all 3 IL-6 polymorphisms examined showed larger IL-6 

responses to increased CO, and there was evidence of a genetic interaction with NO2 for one of the 

polymorphisms. Subjects with the homozygote minor allele genotype for one fibrinogen 

polymorphism showed both a larger and clearer effect modification for the IL-6 response to 

increased CO compared to the IL-6 polymorphisms. Similar magnitudes of effect modification were 

seen for NO2, but the effect modification pattern was not statistically significant. A second fibrinogen 

polymorphism did not modify the response to air pollution. Overall, this study provides evidence for 

the influence of CO on IL-6 levels in subjects with genetic polymorphisms of the IL-6 and 

fibrinogen genes. In this study, 16% of the subjects had a polymorphism combination that resulted in 

a statistically significant gene-gene-environment interaction potentially implicating a higher risk of 

health effects from air pollution in these patients with ischemic heart disease. 

In summary, a growing number of studies provide some evidence of a link between CO 

exposure and blood markers of coagulation and inflammation. Further studies are required to 

determine whether the prothrombotic effects characterized by many of the blood markers may partly 

explain the relationship between CO and the risk of ischemic cardiovascular disease. The results of a 

recent gene-gene-environment interaction study are particularly interesting. Table 5-6 summarizes 

the reviewed studies. Due to the heterogeneity of endpoints (see column “cardiac endpoint” in Table 

5-6), these studies do not lend themselves to a quantitative meta-analysis or inclusion in a summary 

figure. 

January 2010 5-22 
Table 5-6. Summary of studies investigating the effect of CO exposure on blood markers of 

coagulation and inflammation. 

Study Location, 

Sample Size Cardiac Endpoint 

Upper CO 

Concentrations 

from AQSa

 in 

ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

Copollutants 

Delfino et al. (2008, 156390) Los Angeles, CA 

(n=29) 

CRP, fibrinogen, TNFα, IL-6, fibrin D-dimer, 

sP-selectin, sVCAM-1, 

sICAM-1, MPO 

98th%: 2.9 

99th%: 3.1 

(1 h) 

Outdoor Mean: 0.71 (1 h) 

Indoor Mean: 0.78 (1 h) 

O3, NO2, EC, OC, BC, 

PM0.25, PM0.25-2.5, 

PM2.5-10

Delfino et al. (2009, 200844) Los Angeles, CA 

(n=60) 

CRP, TNF-α, IL-6, sPselectin, sTNF-RII, 

Cu,Zn-SOD, GPx-1 

NA Outdoor mean: 0.50-0.58 (1h) 

O3, NO2,NOX, EC, OC, BC, 

SOC, PN, PM0.25, PM0.25-2.5, 

PM2.5-10

Wellenius et al. (2007, 

092830) 

Boston, MA 

(n=28) 

BNP 

98th%: 0.75-2.22 

99th%: 0.92-2.48 

(24 h) 

Mean: 0.44 (24 h) PM2.5, SO2, NO2, O3, BC 

Pekkanen et al (2000, 013250) 

London, U.K. 

(n = 7205) Plasma fibrinogen NA 

Mean: 1.22 (24 h) 

10th, 50th, 90th, Max: 

0.61, 1.04, 2.0, 8.61 

PM10, BS, O3, NO2, SO2

Liao et al (2005, 088677) 

US 

(n = 10.208) 

Fibrinogen, VII-C, 

WBC, albumin, vWF 

98th%: 0.39-2.29 

99th%: 0.43-2.66 

(24 h) 

Mean: 1.4 (24 h) PM10, O3, NO2, SO2

Steinvil et al (2008, 188893) 

Tel-Aviv, Israel 

(n = 3659) 

CRP, fibrinogen, 

WBC 

NA 

Mean: 0.8 

25th, 50th, 75th percentiles: 

0.7, 0.8, 1.0 

PM10, O3, NO2, SO2

Rückerl et al (2006, 088754) Erfurt, Germany 

(n = 57) 

CRP, SAA, cell 

adhesions and 

coagulation 

NA Mean: 0.45 (24 h) 

Range: 0.10, 1.68 

PM10, PM2.5, UFP, EC, NO2

Rückerl et al (2007, 156931) Six European cities 

(n = 1003) IL-6, CRP, fibrinogen NA Mean: 0.29-1.48 (24 h) PM10, PM2.5, O3, NO2, SO2

Baccarelli et al (2007, 090733) 

Lombardia Region, 

Italy 

(n = 1218) 

PT, APTT, fibrinogen, 

anticoagulants NA 

Mean: 1.14-3.11 

Max: 5.52-11.43 

PM10, O3, NO2, SO2

Rudez et al. (2009, 193783) 

Rotterdam, The 

Netherlands 

(n=40) 

Platelet aggregation, 

thrombin generation, 

fibrinogen, CRP 

NA Median: 0.29 (24 h) PM10, NO, NO2, O3

Ljungman et al. (2009, 

191983) 

Six European cities 

(n=955) 

IL-6 and fibrinogen 

polymorphisms NA Mean: 0.25-1.29 (24 h) NO2, PM10, PM2.5

NA: Not Available 

a

 Includes range across individual monitors in study site; AQS data available for U.S. studies only. 

5.2.1.9. Hospital Admissions and Emergency Department Visits 

Since the 2000 CO AQCD (U.S. EPA, 2000, 000907) there have been a number of studies that 

investigated the effect of ambient CO on hospital admissions and ED visits for CVD. Some of these 

studies have focused solely on one specific CVD outcome, and these studies are discussed first. The 

subsequent sections provide a discussion of the studies that investigated hospital admissions and ED 

visits for all CVD outcomes (e.g., nonspecific) or a variety of specific CVD outcomes. 

 

January 2010 5-23 
Coronary Heart Disease 

Ischemic heart disease (IHD), also known as CHD, is caused by inadequate circulation of the 

blood to the heart muscle, which is a result of the coronary arteries being blocked by cholesterol 

deposits or by vasospasm. CHD can lead to sudden episodes such as MI or death, as well as chronic 

conditions such as angina pectoris (chest pain). 

Ischemic Heart Disease 

A number of studies have focused directly on hospitalizations for IHD. There is a lot of 

variation among these studies with regard to methods employed and results reported. It should be 

noted that within these studies IHD included MI and angina pectoris (ICD-9 codes 410-414; ICD-10 

codes 120, 121-123, 124). A multicity time-series study was conducted to estimate the risk of CVD 

hospitalization associated with short-term CO exposure in 126 U.S. urban counties from 1999-2005 

for over 9 million Medicare enrollees 65 yr old and older (Bell et al., 2009, 193780). The analyses 

yielded positive associations between same-day CO concentration adjusted for NO2 concentration 

and increased risk of hospitalization for IHD 1.004 (95% PI: 1.001-1.007). Cause-specific effect 

estimates were not presented for CO alone (without adjustment for NO2). 

Mann and colleagues (2002, 036723) investigated the modifying effect of secondary diagnosis 

of arrhythmia and congestive heart failure (CHF) on the relationship between hospital admissions for 

IHD (ICD-9: 410-414) and ambient air pollutants for the period of 1988-1995 in southern California. 

There were 54,863 visits analyzed and a 0.75 ppm increase in 8-h max CO concentration was 

associated with a 2.69% (95% CI: 1.21-4.19) increase in same-day IHD admissions among persons 

with a secondary diagnosis of CHF, a 2.23% (95% CI: 1.35-3.13) increase among persons with a 

secondary diagnosis of arrhythmia, and a 1.21% (95% CI: 0.49-1.94) increase among persons 

without either secondary diagnosis. Of all the pollutants examined (PM10, NO2, O3, CO), only NO2

showed positive effects estimates similar in magnitude to CO. Although no multipollutant models 

were analyzed, a moderate to high correlation between CO and NO2 was found across the seven 

regions ranging from 0.64 to 0.86. This study indicated that people with IHD and underlying CHF 

and/or arrhythmia represent a potentially susceptible population relative to the effects of ambient air 

pollution. 

By using a time-series approach, ED visits for IHD (ICD-9: 410-414) in Montreal, Canada, 

(1997-2002) were examined in relation to ambient CO concentrations (lags 0 and 1) (Szyszkowicz, 

2007, 193793). A total of 4,979 visits were analyzed, and results showed significant positive effects 

with a 0.5 ppm increase in 24-h CO concentration (lag 0), resulting in a 14.1% (95% CI: 5.8-20.6) 

increase in daily ED visits among all patients. Stratified analyses showed that this effect was mostly 

among male patients (19.8% [95% CI: 9.2-31.6]). NO2 was the only other pollutant examined, and it 

too showed significant positive associations with ED visits for IHD for same-day exposure; however, 

no multipollutant models were examined. 

Lee and colleagues (2003, 095552) examined daily counts of hospital admissions for IHD in 

Seoul, Korea, for the period from December 1997 to December 1999. Single-day lags 0-5 were 

analyzed, and the lag period with the strongest association for each pollutant was presented by the 

authors. For CO, lag 5 showed the strongest effect, with a 1 ppm increase in 1-h maximum (max) 

CO concentration associated with a daily increase in the number of hospital admissions for IHD; 

however, this was only among patients 64+ yr of age (RR: 1.07 [95% CI: 1.01-1.13]). All other 

pollutants (PM10, O3, NO2) except SO2 showed similar significant effects and in a copollutant model 

with PM10 the CO effect was somewhat attenuated (RR 1.04 [95% CI: 0.98-1.11]). 

Other studies have examined hospital admissions for IHD while investigating a broad group of 

CVD outcomes. A study was conducted in Atlanta, GA, where over 4 million ED visits from 

31 hospitals for the period 1993-2000 were analyzed (Study of Particles and Health in Atlanta 

[SOPHIA]). Several articles have been published from this research, with two examining 

cardiovascular admissions in relation to CO concentrations. The first of these (Metzger et al., 2004, 

044222) used a time-series design and analyzed a 3-day ma over single-day lags 0-2 as the a priori 

lag structure. Although of borderline statistical significance, CO was positively associated with an 

increase in ED visits for IHD (RR 1.016 [95% CI: 0.999-1.034] per 1 ppm increase in 1-h max CO 

concentration). 

The second of these reports (Peel et al., 2007, 090442) examined the association of ambient air 

pollution levels and cardiovascular-related ED visits with and without specific secondary conditions 

January 2010 5-24 
(e.g., comorbidity). Within a time-stratified case-crossover design using the same lag structure 

previously mentioned, the main results showed that a 1 ppm increase in 1-h max CO concentration 

was associated with an increase in IHD among those without diabetes (OR: 1.023 

[95% CI: 1.004-1.042]), and without CHF (OR: 1.024 [95% CI: 1.006-1.042]). 

Two Australian studies have also examined associations between ambient CO concentrations 

and increased hospital admissions for various CVD outcomes. The first of these studies (Barnett et 

al., 2006, 089770) analyzed data from five of the largest cities in Australia (Brisbane, Canberra, 

Melbourne, Perth, Sydney) and two New Zealand cities (Auckland, Christchurch) for the period 

1998-2001. A time-stratified case-crossover design was employed, and the age groups of 15-64 yr 

and ≥ 65 yr were analyzed for the 0-1 lag period. The pooled estimates across all cities showed that a 

0.75 ppm increase in 8-h max CO concentration was associated with a 1.9% (95% CI: 0.7-3.2) 

increase in admissions for IHD among the elderly group (≥ 65 yr). No association was observed for 

the younger age group. 

The second of the Australian studies (Jalaludin et al., 2006, 189416) examined ED visits for 

CVD outcomes in the elderly (65+ yr) in Sydney for the period 1997-2001. Using a time-series 

approach, single-day lags of 0, 1, 2, 3, and an average over lags 0 and 1 were examined. A 0.75 ppm 

increase in 8-h max CO concentration (lag 0) was associated with increases in IHD emergency 

department visits of 3.1% (95% CI: 1.3-4.9). 

Angina Pectoris 

 In the current literature, only one study was identified that focused solely on angina pectoris 

as an endpoint. Admissions data for angina pectoris were collected from 25 academic hospitals in 

Tehran, Iran, and linked to ambient air pollution for the period of 1996-2001 (Hosseinpoor et al., 

2005, 087413). Using a time-series approach, single-day lags of 0-3 were analyzed and a 0.5 ppm 

increase in 24-h avg CO concentration at lag 1 was associated with increased hospital admissions for 

angina (OR: 1.005 [95% CI: 1.003-1.007]). This result persisted in a multipollutant model that also 

included NO2, PM10, and O3 (OR: 1.005 [95% CI: 1.001-1.008]). 

Myocardial Infarction 

Linn et al. (2000, 002839) examined the association between ambient air pollution and 

hospital admissions for cardiopulmonary illnesses in metropolitan Los Angeles for the years 

1992-1995. Using a time-series approach, a 0.5 ppm increase in same-day 24-h avg CO 

concentration was associated with a 2.0% increase in MI hospital admissions among people aged 

>30 yr. When the analyses were stratified by season, no significant effects were observed (no 

quantitative seasonal effects reported). 

A time-series study in Denver, Colorado, investigated daily hospital admissions for various 

CVD outcomes among older adults (>65 yr) across 11 hospitals (Koken et al., 2003, 049466). Data 

between July and August for the period 1993-1997 were analyzed. Single-day lags 0-4 were 

examined and CO showed no association with hospital admissions for MI (quantitative results were 

not reported). 

As part of the Health Effects of Air Pollution among Susceptible Subpopulations (HEAPSS) 

study, Lanki et al. (2006, 089788) investigated the association between traffic-related exposure to air 

pollutants and hospitalization for first acute myocardial infarction (AMI). Data were collected from 

five European cities with either AMI registers (Augsburg, Barcelona) or hospital discharge registers 

(Helsinki, Rome, Stockholm). Correlation coefficients between CO and NO2 ranged from 0.43 to 

0.75 across the five cities, and between CO and PM10 the range was 0.21 to 0.56. A total of 26,854 

hospital admissions were analyzed, and pooled estimates from all five cities showed that there was a 

weak positive association with AMI hospital admissions and 24-h avg CO concentrations at lag 0 

(RR: 1.014 [95% CI: 1.000-1.029] per 0.5 ppm increase), but more so when only using data from the 

three cities (Helsinki, Rome, Stockholm) with hospital discharge registers (RR: 1.020 

[95% CI: 1.003-1.035] per 0.5 ppm increase). When analyses were stratified by fatality and age, 

results showed that the CO effect was significantly associated with fatal AMI among the <75-yr age 

group (RR: 1.080 [95% CI: 1.017-1.144]) and with non-fatal AMI in the ≥ 75-yr age group (RR: 

1.044 [95% CI: 1.011-1.076]). 

Further analyses within the HEAPSS cohort were conducted using the event of cardiac 

readmission among the first MI survivors (n = 22, 006) (Von Klot et al., 2005, 088070). The 

readmissions of interest were those with primary diagnosis of AMI, angina pectoris, dysrhythmia, 

January 2010 5-25 
and heart failure that occurred at least 29 days after the index event. Single-day lags 0-3 were 

examined, and pooled estimates from all 5 cities showed that a 0.5 ppm increase in same-day (lag 0) 

CO was associated with an increase in cardiac (e.g., any of the diagnoses) readmissions (RR: 1.041 

[95% CI: 1.003-1.076]); this persisted in two-pollutant models that included either PM10 or O3. Correlation coefficients with CO ranged from 0.21 to 0.57 for PM10 and 0.44 to 0.75 for NO2. 

A study in Rome, Italy, also found an association between ambient CO and hospitalizations for 

first-episode MI among 6,531 subjects (January 1995-June 1997) (D'Ippoliti et al., 2003, 074311). A 

case-crossover design with stratification of time into separate months was used to select referent 

days as the days falling on the same day of the week within the same month as the index day. CO 

concentration was positively associated with lag 2 (OR: 1.019 [95% CI: 1.001-1.037]). The other 

pollutants analyzed were NO2 and TSP, both of which exhibited a significant positive effect at lag 0. 

TSP also showed a significant positive effect at lag 0-2 and, when entered into a model with CO, the 

CO effect did not persist. 

The previously mentioned Australian and New Zealand study that analyzed data from seven 

cities (Brisbane, Canberra, Melbourne, Perth, Sydney, Auckland, and Christchurch) for the period 

1998-2001 also reported an association between CO and MI hospital admissions (Barnett et al., 

2006, 089770). The pooled estimates across all cities showed that a 0.75 ppm increase in 8-h max 

CO concentration was associated with a 2.4% (95% CI: 0.6-4.1) increase in admissions for MI, but 

only among older adults (≥ 65 yr). Table 5-7 shows a summary of the CHD hospital admission 

studies that examined CO exposures. 

In summary, the majority of studies reported significant increases in the daily number of 

admissions for IHD, angina and MI in relation to CO exposures. In studies that stratified by age 

groups and/or sex, the effects were larger among the elderly and males. Among the different lag 

periods being examined, the associations were more commonly observed with same day CO (lag 0) 

or an average over the same day and previous day (lag 0-1). Figure 5-2 shows the effect estimates 

associated with daily admissions for various forms of CHD from selected studies. 

January 2010 5-26 
Study Location Lag Age Group/Outcome Effect Estimate (95% CI) 

Metzger et al. (2004, 044222) Atlanta, GA 0-2 IHD

Peel et al. (2007, 090442) Atlanta, GA 0-2 

California, US 0-3 

California, US 0-3 sCHF 

Mann et al.(2002, 036723) 

California, US 0-3 sARR 

Barnett et al. (2006, 089770) Australia, New Zealand 0-1 15-64 yr 

Australia, New Zealand 0-1 65+ yr 

Jalaludin et al. (2006, 189416) Sydney, Australia 0-1 65+ yr 

Montreal, Canada 0 All ages 

Montreal, Canada 0 All ages Males 

Montreal, Canada 0 All ages Females 

Montreal, Canada 0 65+ yr Males and Females 

Montreal, Canada 0 65+ yr Males 

Szyszkowicz (2007, 193793) 

Montreal, Canada 0 65+ yr Females 

Lee et al. (2003, 095552) Seoul, Korea 5 All ages 

Seoul, Korea 5 64+ yr 

von Klot et al. (2005, 088070) Multicity, Europe 0 35+ yr Angina

Hosseinpoor et al. (2005, 087413) Tehran, Iran 1 All ages 

Linn et al. (Linn et al., 2000, 002839) Los Angeles, CA 0 All year MI

Barnett et al. (2006, 089770) Australia, New Zealand 0-1 15-64 yr 

Australia, New Zealand 0-1 65+ yr 

Multicity, Europe 0 35+ yr All cities 

Multicity, Europe 0 <75 yr Nonfatal 

Multicity, Europe 0 <75 yr Fatal 

Multicity, Europe 0 75+ yr Nonfatal 

Lanki et al. (2006, 089788) 

Multicity, Europe 0 75+ yr Fatal 

von Klot et al. (2005, 088070) Multicity, Europe 0 35+ yr 

Rome, Italy 0-2 18+ yr 

Rome, Italy 0-2 18-64 yr 

Rome, Italy 0-2 65-74 yr 

D'Ippoliti et al. (2003, 074311) 

Rome, Italy 0-2 75+ yr 

Relative Risk 

Figure 5-2. Summary of effect estimates (95% confidence intervals) associated with hospital 

admissions for various forms of CHD. Effect estimates have been standardized to 

a 1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-27 
Table 5-7. Summary of CHD hospital admission studies.a 

Study Location Endpoints 

Examined Copollutants Lags Examined 

Upper CO 

Concentrations from 

AQSc in ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

STUDIES THAT FOCUSED SOLELY ON CHD 

Mann et al. (2002, 036723) 

Southern 

California 

(1988-1995) 

IHD PM10, NO2, O3 0,1,2, 2-4ma 

98th%: 1.0-13.8 

99th%: 1.3-15.9 (8 h) Mean: 2.07 (8h) 

Szyszkowicz (2007, 

193793) 

Montreal, Can 

(1997-2002) 

IHD NO2 0,1 NA Mean: 0.5 (24 h) 

Lee et al.(2003, 095552) 

Seoul, Korea 

(1997-1999) 

IHD PM10, NO2, SO2, 

O3 0,1,2,3,4,5 NA Mean: 1.8 

Lanki et al. (2006, 089788)

b 5 European cities 

(1992-2000) 

MI (first 

acute) 

PM10, NO2, O3, 

PNC 0,1,2,3 NA 

Highest city was Rome. 

25th = 1.5 

75th = 2.6 

von Klot et al. (2005, 

088070)

b

 

5 European cities 

(1992-2001) 

MI, Angina, 

Cardiaca PM10, NO2, O3, 

PNC 0,1,2,3 NA Mean: highest city was Rome: 1.9 (24 h) 

D’Ippoliti et al. (2003, 

074311)

b

Rome, Italy 

(1995-1997) 

MI TSP, NO2, SO2 0,1,2,3,4, 0-2 NA Mean: 3.8 (24 h) 

Hosseinpoor et al. (2005, 

087413)

b

Tehran, Iran 

(1996-2001) Angina PM10, NO2, SO2, 

O3

0,1,2,3 NA Mean: 9.4 (24 h) 

STUDIES THAT EXAMINED CHD AMONG OTHER CVDS 

Metzger et al.(2004, 

044222) 

Atlanta, GA 

(1993-2000) 

IHD, All 

CVD, CD, 

CHF, PVCD 

PM10, NO2, SO2, 

O3 0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean: 1.8 (1 h) 

Peel et al. (2007, 090442) 

Atlanta, GA 

(1993-2000) 

IHD, All 

CVD, CD, 

CHF, PVCD 

PM10, NO2, SO2, 

O3 0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean: 1.8 (1 h) 

Barnett et al. (2006, 

089770) 

Australia and 

New Zealand 

(1998-2001) 

IHD, MI, All 

CVD, CA, 

Stroke 

PM10, NO2, O3 Lag 0-1 NA Mean: (8 h) 

0.5- 2.1 

Jalaludin et al. (2006, 

189416) 

Sydney, 

Australia 

(1997-2001) 

IHD, All 

CVD, Stroke, 

Cardiac 

PM10, NO2, SO2, 

O3 0,1,2,3, 0-1 NA Mean: 0.82 (8 h) 

Linn et al. (2000, 002839) 

Los Angeles, 

CA 

(1992-1995) 

MI, All CVD, 

CHF, CA, OS PM10, NO2, O3 0 

98th%: 1.0-7.8 

99th%: 1.1-8.3 (24 h) 

Mean: (24 h) 

Winter 1.7, Spring 1.0, 

Summer 1.2, Fall 2.1 

Koken et al.(2003, 

049466) 

Denver, CO 

(1993-1997) 

MI, CAth, 

PHD, CD, 

CHF 

PM10, NO2, SO2, 

O3

0,1,2,3,4 

98th%: 1.2-2.0 

99th%: 1.3-2.0 (24 h) Mean: 0.9 ppm (24 h) 

a Cardiac = AMI, angina, dysrhythmia, or HF; CA = Cardiac arrhythmia; CAth = Cardiac atherosclerosis; CD = cardiac dysrhythmias; CHF = Congestive heart failure; PHD = Pulmonary heart disease; 

OS = Occlusive stroke; PVCD = peripheral vascular and cerebrovascular disease, ma = moving average. 

b

These studies presented CO concentrations in the units mg/m3. The concentrations were converted to ppm using the conversion factor 1 ppm = 1.15 mg/m3, which assumes standard atmosphere 

and temperature. 

c Includes range across individual monitors in study site; AQS data available for U.S. studies only. 

NA: Not Available 

January 2010 5-28 
Stroke 

A stroke is the result of either the blood supply to the brain being blocked (e.g., embolism), 

which refers to an ischemic stroke (80% of strokes), or the occurrence of a burst blood vessel or 

hemorrhaging, referred to as a hemorrhagic stroke. Hemorrhagic stroke has two main groupings; 

intracerebral hemorrhagic stroke (10% of strokes), which is when a blood vessel in the brain leaks, 

and subarachnoid hemorrhage (3% of strokes), which is bleeding under the outer membranes of the 

brain. The third type of stroke is a transient ischemic attack (TIA) or ministroke, which has the same 

early symptoms as a normal stroke but the symptoms disappear within 24 h, leaving no apparent 

deficits. A limited number of air pollution studies have investigated hospital admissions for the three 

main forms of stroke and generally report small, positive associations or no association with ambient 

CO concentrations measured during lag periods between 0 and 3 days. 

In the multicity time-series study conducted by Bell et al. (2009, 193780), the analyses yielded 

small, positive associations between same-day CO concentration adjusted for NO2 concentration and 

increased risk of hospitalization for cerebrovascular outcomes 1.005 (95% PI: 1.002-1.009). Causespecific effect estimates were not presented for CO alone (without adjustment for NO2). 

A U.S. study across 9 cities investigated hospital admissions for ischemic and hemorrhagic 

stroke among Medicare beneficiaries aged 65+ yr of age (155,503 ischemic and 19,314 hemorrhagic 

admissions from the ED) (Wellenius et al., 2005, 088685). Single-day lags 0-2 were examined and 

based on a pooled estimate, same-day CO (lag 0) was associated with an increase in ischemic stroke 

admissions of 1.98% (95% CI: 0.86-3.12) per 0.5 ppm increase in 24-h CO concentration), but not 

hemorrhagic stroke admissions (-1.14%, 95% CI: -3.40 to 1.18). All other pollutants examined 

(PM10, NO2, SO2) were also associated with an increase in ischemic stroke admissions but not 

hemorrhagic stroke admissions. 

Villeneuve and colleagues (2006, 090191) studied ED visits for hemorrhagic strokes, acute 

ischemic strokes and transient ischemic attacks among individuals 65+ yr of age at 5 hospitals within 

the Edmonton, Canada, area between April 1992 and March 2002 (12,422 visits). Within a timestratified case-crossover design, the analyses were stratified by two seasonal groups (October-March 

and April-September). CO was found to only have an effect on ischemic stroke during AprilSeptember (OR: 1.32 [95% CI 1.09-1.60] per a 0.5 ppm increase in 24-h CO concentration) for a 

3-day avg across lags 0-2. CO had no effect on any other stroke subtype. In two-pollutant models the 

CO effect on ischemic stroke persisted after controlling for PM10, PM2.5, SO2, and O3. 

In Kaohsiung City, Taiwan, CO averaged over lags 0-2 was associated with increased 

admissions for stroke across 63 hospitals (Tsai et al., 2003, 080133). From 1997 through 2000 a total 

of 23,179 admissions were analyzed, and on warm days (≥ 20°C) the odds ratios for primary 

intracerebral hemorrhage and ischemic stroke were 1.39 (95% CI: 1.16-1.66) and 1.39 

(95% CI: 1.25-1.53) respectively for a 0.5 ppm increase in 24-h CO concentration. For the same 

increase in CO on cool days (<20°C) the odds ratios were 1.33 (95% CI: 0.38-2.55) for intracerebral 

hemorrhage and 2.68 (95% CI: 1.59-4.49) for ischemic stroke. These results persisted in twopollutant models that included PM10, SO2, and O3 but did not persist when controlling for NO2. 

Earlier research conducted in metropolitan Los Angeles examined hospital admissions for 

cardiopulmonary illnesses from 1992-1995 (Linn et al., 2000, 002839). Using a time-series 

approach, a 0.5 ppm increase in 24-h CO concentration (lag 0) was associated with a 2.18% 

(95% CI: 1.73-2.62) increase in occlusive (ischemic) stroke hospital admissions among people aged 

>30 yr. When the analyses were stratified by season, there was a 1.8% (p=0.017) increase during 

winter, a 4.55% (p=0.039) increase during summer, and a 1.6% (p=0.015) increase during fall 

(results for spring were not reported). 

A study in Taipei, Taiwan, analyzed 8,582 emergency admissions for cerebrovascular diseases, 

hemorrhagic stroke, ischemic stroke, and all strokes during 1997-2002 (Chan et al., 2006, 090193). 

Single-day lags 0-3 were analyzed, and a 0.75 ppm increase in 8-h max CO concentration (lag 2) 

was associated with an increase in cerebrovascular diseases (OR: 1.03 [95% CI: 1.01-1.05]) and all 

strokes (OR: 1.03 [95% CI: 1.01-1.05]). These results persisted in two- and three-pollutant models 

that included O3 and PM10. There was no association with individual ischemic or hemorrhagic 

stroke. CO was moderately correlated with PM10 (r = 0.47) and PM2.5 (r = 0.44), and the correlation 

was higher with NO2 (r = 0.77). 

A time-series study that focused specifically on stroke hospital admissions conducted in Dijon, 

France, did not report a significant association with ambient CO (Henrotin et al., 2007, 093270). 

Hospital admissions for different types of first-ever stroke (e.g., ischemic, hemorrhagic) among 

January 2010 5-29 
subjects >40 yr were analyzed for the period 1994-2004. A bidirectional case-crossover study design 

was employed where single-day lags between 0-3 days were examined and CO had no significant 

association for any lag. This was also the case when the analyses were stratified by gender and types 

of ischemic stroke (large arteries, lacunar, cardioembolic, transient). Of all pollutants examined 

(PM10, NOX, O3, SO2, CO), only O3 showed a significant effect. 

Two Australian studies examined associations between ambient CO and hospital admissions 

for various CVDs. The first of these studies analyzed data from five of the largest cities in Australia 

(Brisbane, Canberra, Melbourne, Perth, Sydney) and two New Zealand cities (Auckland, 

Christchurch) for the period 1998-2001 (Barnett et al., 2006, 089770). A time-stratified casecrossover design was employed and the age groups of 15-64 yr and ≥ 65 yr were analyzed for the 

0-1 lag period (average over lag 0 and 1). The pooled estimates across all cities showed that CO had 

no effect on stroke admissions (quantitative results not reported). 

The second of the Australian studies examined ED visits for CVDs in older adults (65+ yr) in 

Sydney for the period 1997-2001 (Jalaludin et al., 2006, 189416). Using a time-series approach, 

single-day lags of 0-3 and an average over lags 0 and 1 (e.g., lag 0-1) were examined, and CO 

showed no effect on stroke ED visits. When the analyses were stratified by cool and warm periods, a 

0.75 ppm increase in 8-h max CO concentration during the cool period was associated with a 3.8% 

(95% CI: 0.76-6.94) increase in stroke ED visits. 

In summary, there was limited evidence that increased ambient CO concentrations might be 

associated with hospital admissions for stroke. The largest positive effects came from the Taiwan 

study in Kaohsiung (Tsai et al., 2003, 080133), with slightly larger effects during the warmer period 

(>20°C). Similarly, in the Canadian study by Villeneuve and colleagues (2006, 090191), there was a 

stronger effect during the warmer period (April-September). Studies in France and Australia reported 

no association between ambient CO concentrations and increased hospital admissions or ED visits 

for stroke. Figure 5-3 shows the effect estimates associated with daily admissions for stroke from 

selected studies; Table 5-8 shows a summary of the stroke hospital admission studies that examined 

CO exposures. 

Study Location Lag Outcome/Group Effect Estimate (95% CI) 

Wellenius et al. (2005, 088685) Multicity, US 0-2 65+ yr Ischemic Stroke

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 IS, 65+ yr, All Seasons 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 IS, 65+ yr, Apr-Sep 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 IS. 65+ yr, Oct-Mar 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 CIS, 65+ yr, All Seasons 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 CIS, 65+ yr, Apr-Sep 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 CIS. 65+ yr, Oct-Mar 

Tsai et al. (2003, 080133) Kaohsiung, Taiwan 0-2 <20°C Temp 

Tsai et al. (2003, 080133) Kaohsiung, Taiwan 0-2 >20°C Temp 

Linn et al. (2000, 002839) Los Angeles, CA 0 

Chan et al. (2006, 090193) Taipei, Taiwan 1 

Henrotin et al. (2007, 093270) Dijon, France 3 

Wellenius et al. (2005, 088685) Multicity, US 0-2 65+ yr Hemorrhagic Stroke

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 65+ yr, All Seasons 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 65+ yr, Apr-Sep 

Villeneuve et al. (2006, 090191) Edmonton, Can 0-2 65+ yr Oct-Mar 

Tsai et al. (2003, 080133) Kaohsiung, Taiwan 0-2 <20°C Temp 

Tsai et al. (2003, 080133) Kaohsiung, Taiwan 0-2 >20°C Temp 

Chan et al. (2006, 090193) Taipei, Taiwan 1 

Henrotin et al. (2007, 093270) Dijon, France 1 

Chan et al. (2006, 090193) Taipei, Taiwan 2 Stroke (nonspecific)

Jalaludin et al. (2006, 189416) Sydney, Australia 0-1 

 Relative Risk 

Figure 5-3. Summary of effect estimates (95% confidence intervals) associated with ED visits 

and hospital admissions for stroke. Effect estimates have been standardized to a 

1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

IS=ischemic stroke, CIS=cerebral ischemic stroke. 

January 2010 5-30 
Table 5-8. Summary of stroke hospital admission studies.a 

Study Location 

Type Of 

Stroke 

Examined 

Copollutants Lags 

Examined

Upper CO 

Concentrations 

from AQSc in ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

STUDIES THAT FOCUSED SOLELY ON STROKE 

Wellenius et al. (2005, 088685) 

9 US cities 

(1993-1999) 

Isch, Hem PM10, NO2, SO2 0,1, 2 

98th%: 0.9-5.9 

99th%: 1.2-7.1 (24 h) 

25th, 50th, 75th 

percentiles: 

0.73, 1.02, 1.44 

Villeneuve et al. (2006, 090191) Edmonton, Can 

(1992-2002) Isch, Hem, TIA NO2, SO2, O3 0,1, 0-2 NA Mean: 0.8 (24 h) 

Tsai et al. (2003, 080133) Kaohsiung, Taiwan 

(1997-2000) 

Isch, Hem PM10, NO2, SO2, 

O3 0-2 NA Mean: 0.79 (24 h) 

Chan et al. (2006, 090193) Taipei, Taiwan 

(1997-2002) 

All, Isch, Hem PM10, NO2, SO2, 

O3 0,1,2,3 NA Mean: 1.7 (8h) 

Henrotin et al. (2007, 093270)

b Dijon, France 

(1994-2004) 

Isch, Hem PM10, NOX, SO2, 

O3 0,1,2,3 NA Mean: 0.59 (24 h) 

STUDIES THAT EXAMINED STROKE AMONG OTHER CVDS 

Linn et al. (2000, 002839) Los Angeles, CA 

(1992-1995) 

Isch PM10, NO2, O3 Lag 0 

98th%: 1.0-7.8 

99th%: 1.1-8.3 (24 h) 

Mean: (24 h) 

Winter 1.7, Spring 1.0, 

Summer 1.2, Fall 2.1 

Barnett et al. (2006, 089770) 

Australia and New 

Zealand 

(1998-2001) 

All PM10, NO2, O3 Lag 0-1 NA Mean: (8h) 

0.5-2.1 

Jalaludin et al. (2006, 189416) Sydney, Australia 

(1997-2001) 

All PM10, NO2, SO2, 

O3 0,1,2,3, 0-1 NA Mean: 0.82 (8h) 

a Isch = Ischemic; Hem = Hemorrhagic; TIA = transient ischemic attack 

b

These studies presented CO concentrations in the units mg/m3. The concentrations were converted to ppm using the conversion factor 1 ppm = 1.15 mg/m3, which assumes standard atmosphere and 

temperature. 

c

 Includes range across individual monitors in study site; AQS data available for U.S. studies only. 

NA: Not Available 

Congestive Heart Failure 

Heart failure (HF) is a condition in which the heart is unable to adequately pump blood to the 

rest of the body. It does not refer to the cessation of the heart but more to the inability of the heart to 

operate at an optimal capacity. HF is often called congestive heart failure (CHF), which refers to 

when the inadequate pumping leads to a buildup of fluid in the tissues. The underlying causes of 

CHF are hypertension, CAD, MI, and diabetes. 

In the multicity time-series study conducted by Bell et al. (2009, 193780), the analyses yielded 

positive associations between same-day CO concentration adjusted for NO2 concentration and 

increased risk of hospitalization for HF (1.009 [95% PI: 1.005-1.012]). Cause-specific effect 

estimates were not presented for CO alone (without adjustment for NO2). 

Wellenius and colleagues (2005, 087483) examined the rate of hospitalization for CHF among 

55,019 Medicare recipients (≥ 65 yr) residing in Allegheny County, PA, during 1987-1999. A timestratified case-crossover design was employed and single-day lags of 0-3 were analyzed. A 0.5 ppm 

increase in 24-h avg CO concentration on the same-day (lag 0) was associated with a 4.1% 

(95% CI: 3.0-5.3) increase in the rate of hospitalization for CHF. This result persisted in copollutant 

models that included PM10, NO2, O3, and SO2. CO was moderately correlated with SO2 (r = 0.54) 

and PM10 (r = 0.57) and more highly correlated with NO2 (r = 0.70). 

Another U.S. study recruited 125 patients diagnosed with CHF who were admitted to Johns 

Hopkins Bayview Medical Center in Baltimore, MD (Symons et al., 2006, 091258). The patients 

were interviewed after admission through the ED during their stays in overnight wards. The 

January 2010 5-31 
interview was designed to collect information about symptom onset, health conditions, and factors 

related to air pollution exposure. Various lag periods (single day and cumulative days 0-3) prior to 

the onset of symptoms were analyzed and although the focus of this study was exposure to PM2.5, of 

all the pollutants examined (PM2.5, CO, NO2, O3) only 8-h max CO concentration at lag 2 was 

significantly associated with the onset of CHF symptoms (OR: 1.68 [95% CI: 1.28-2.80]). 

Earlier research conducted in metropolitan Los Angeles, CA examined hospital admissions for 

cardiopulmonary illnesses (1992-1995) (Linn et al., 2000, 002839). Using a time-series approach, a 

0.5 ppm increase in same-day 24-h avg CO concentration was associated with a 1.25% increase in 

CHF hospital admissions among people >30 yr. When the analyses were stratified by seasons, only 

summer showed a significant increase (3.7%); however, the study did not report the results for the 

other seasons. 

A time-series study in Denver, CO, investigated daily admissions for various CVDs among 

older adults (>65 yr) across 11 hospitals (Koken et al., 2003, 049466). Single-day lags 0-4 were 

examined, and an increase of 0.5 ppm in 24-h avg CO concentration for lag 3 was associated with an 

18% (95% CI: 0.2-39.3) increase in risk of hospitalization for CHF. 

As stated earlier, a study was conducted in Atlanta, GA, where over 4 million ED visits from 

31 hospitals for the period 1993-2000 were analyzed (Metzger et al., 2004, 044222). A time-series 

design was used and a 3-day ma over single-day lags 0-2 as the a priori lag structure was analyzed. 

Results showed that 1-h max CO concentration was not associated with an increase in ED visits for 

CHF (RR: 1.010 [95% CI: 0.988-1.032] per 1 ppm increase). Peel et al. (2007, 090442) examined 

the same cardiovascular-related effects among those with and without specific secondary conditions 

(e.g., comorbidity) and found that 1-h max CO concentration was associated with an increase in ED 

visits for CHF only among those with COPD (OR: 1.058 [95% CI: 1.003-1.115] per 1 ppm increase). 

In Kaohsiung city, Taiwan, a study analyzed 13,475 admissions for CHF across 63 hospitals 

for the period 1996 through 2004 (Lee et al., 2007, 090707). A 0.5 ppm increase in 24-h avg CO 

concentration averaged over lag days 0-2 was positively associated with CHF hospital admissions on 

cool days (<25°C) (OR: 1.70 [95% CI: 1.43-2.01]), with a slightly weaker effect on warm days 

(>25 ̊ C) (OR: 1.32 [95% CI: 1.15-1.55]). These results persisted in two-pollutant models that 

included PM10, SO2, O3, and models with NO2 only on warmer days, not with NO2 on cooler days. 

Study Location Lag Group Effect Estimate (95% CI) 

Metzger et al. (2004, 044222) Atlanta, GA 0-2 

Peel et al. (2007, 090442) Atlanta, GA 0-2 

Wellenius et al.(2005, 087483) Pittsburgh, PA 0 65+ yr 

Linn et al. (2000, 002839) Los Angeles, CA 0 

Koken et al. (2003, 049466) Denver, CO 3 65+ yr 

Symons et al. (2006, 091258) Baltimore, MD 0-3 

Lee et al. (2007, 090707) Kaohsiung, Taiwan 0-2 <25°C Temp 

Lee et al. (2007, 090707) Kaohsiung, Taiwan 0-2 >25°C Temp 

Yang (2008, 157160) Taipei, Taiwan 0-2 <20°C Temp 

Yang (2008, 157160) Taipei, Taiwan 0-2 >20°C Temp 

 Relative Risk 

Figure 5-4. Summary of effect estimates (95% confidence intervals) associated with hospital 

admissions for CHF. Effect estimates have been standardized to a 1 ppm 

increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h max CO 

concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

A case-crossover analysis was undertaken to examine the association between levels of 

ambient air pollutants and hospital admissions for CHF among individuals residing in Taipei, 

Taiwan, from 1996 through 2004 (Yang, 2008, 157160). During the 9 yr of the study, there were 

24,240 CHF hospital admissions for the 47 hospitals in Taipei. The analyses were stratified by 

temperature, either warm days (>20°C; n = 2325 days) or cool days (<20°C; n = 963 days). The 

number of CHF admissions was associated with concentrations of PM10, NO2, CO and O3 on warm 

days, however on cool days, the positive effects on increased CHF admissions remained positive, 

although the effects were diminished for NO2 and CO, and disappeared completely for PM10 and O3

concentrations. In two-pollutant models, CO remained statistically significant after the inclusion of 

PM10, SO2 or O3 on warm days. On cool days, the effects associated with CO remained positive, but 

January 2010 5-32 
were no longer statistically significant after the inclusion of PM10, SO2, or NO2, but became 

statistically significant and negative after the inclusion of O3 in the model (Figure 5-6). 

Figure 5-4 shows the effect estimates for associations between CO and daily admissions for 

CHF from selected studies; Table 5-9 summarizes the CHF hospital admission studies that examined 

CO exposures. 

In summary, many of the studies that examined associations between ambient CO 

concentrations and daily hospital admissions for CHF reported positive associations at lags of 

0-3 days. 

Table 5-9. Summary of CHF hospital admission studies. 

Study Location Endpoints 

Examined Copollutants Lags Examined

Upper CO 

Concentrations 

from AQSa in ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

STUDIES THAT FOCUSED SOLELY ON HF 

Wellenius et al. (2005, 

087483) 

Pittsburgh, PA 

(1987-1999) CHF PM10, NO2, SO2, 

O3

0,1,2,3 

98th%: 1.4-3.4 

99th%: 1.6-3.9 (24 h) Mean: 1.03 (24 h) 

Symons et al.(2006, 

091258) 

Baltimore, MD 

(2002) CHF PM2.5, NO2, O3 0,1,2,3 

98th%: 1.9-2.1 

99th%: 2.3 (8 h) Mean: 0.4 (8 h) 

Lee et al. (2007, 

090707) 

Kaohsiung, 

Taiwan 

(1996-2004) 

CHF PM10, NO2, SO2, 

O3

0-2 NA Mean: 0.76 (24 h) 

Yang (2008, 157160) Taipei, Taiwan 

(1996-2004) 

CHF PM10, NO2, SO2, 

O3 0-2 NA Mean: 1.26 (24 h) 

STUDIES THAT EXAMINED HF AMONG OTHER CVDS 

Linn et al. (2000, 

002839) 

Los Angeles, CA 

(1992-1995) 

CHF, MI, All 

CVD, CA, OS PM10, NO2, O3 0 

98th%: 1.0-7.8 

99th%: 1.1-8.3 (24 h) 

Mean: (24 h) 

Winter 1.7; Spring 1.0 

Summer 1.2; Fall 2.1 

Koken et al. (2003, 

049466) 

Denver, CO 

(1993-1997) 

CHF, MI, CAth, 

PHD, CD 

PM10, NO2, SO2, 

O3

0,1,2,3 

98th%: 1.2-2.0 

99th%: 1.3-2.0 (24 h) Mean: 0.9 (24 h) 

Metzger et al. (2004, 

044222) 

Atlanta, GA 

(1993-2000) 

CHF, IHD, All 

CVD, CD, 

PVCD 

PM10, NO2, SO2, 

O3

0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean 1.8 (1 h) 

Peel et al. (2007, 

090442) 

Atlanta, GA 

(1993-2000) 

CHF, IHD, All 

CVD, CD, 

PVCD 

PM10, NO2, SO2, 

O3 0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean 1.8 (1 h) 

Cardiac = AMI, angina, dysrhythmia, or HF; CA = Cardiac arrhythmia; CAth = Cardiac atherosclerosis; CD = cardiac dysrhythmias; CHF = Congestive heart failure; PHD = Pulmonary heart disease; 

OS = Occlusive stroke; PVCD = peripheral vascular and cerebrovascular disease, ma = moving average. 

NA: Not Available 

a

 Includes range across individual monitors in study site; AQS data available for U.S. studies only. 

Cardiovascular Diseases 

The following section reviews studies that have investigated the effect of CO on ED visits and 

hospital admissions for all CVD outcomes (e.g., nonspecific). Several of these studies also examined 

specific CVDs and were briefly discussed in previous sections. 

A multicity time-series study was conducted to estimate the risk of CVD hospitalization 

associated with short-term CO exposure in 126 U.S. urban counties from 1999-2005 for over 

9 million Medicare enrollees 65 yr old and older (Bell et al., 2009, 193780). The analyses yielded 

positive associations between same-day CO concentration and increased risk of hospitalization for 

total CVD outcomes, which remained positive and statistically significant but were attenuated with 

copollutant adjustment, especially with NO2 (Figure 5-6). Overall, a 1 ppm increase in same-day 1-h 

max CO was associated with a 1.010 (95% PI: 1.008-1.011) increase in risk of CVD admissions. 

January 2010 5-33 
After adjustment for NO2, the estimate was attenuated to 1.005 (95% PI: 1.004-1.007). For most 

cause-specific CVD hospitalizations, associations were positive and statistically significant for same 

day CO concentration adjusted for same-day NO2 (IHD 1.004 [95% PI: 1.001-1.007], heart rhythm 

1.006 [95% PI: 1.001-1.011], HF 1.009 [95% PI: 1.005-1.012], and cerebrovascular 1.005 [95% PI: 

1.002-1.009]). Cause-specific effect estimates were not presented for CO alone (without adjustment 

for NO2). 

As discussed earlier, a study was conducted in Atlanta, GA where over 4 million ED visits 

from 31 hospitals for the period 1993-2000 were analyzed (SOPHIA). Several articles have been 

published from this research, with three examining cardiovascular admissions in relation to CO 

exposures. The first of these used a time-series design and analyzed a 3-day ma over single-day lags 

0-2 as the a priori lag structure (Metzger et al., 2004, 044222). Results showed that a 1 ppm increase 

in 1-h max CO concentration was associated with an increase in daily ED visits for all CVDs (RR: 

1.017 [95% CI: 1.008-1.027]). This persisted in two-pollutant models that included NO2 and PM2.5. The second of these publications examined the association of ambient air pollution levels and 

cardiovascular morbidity in visits with and without specific secondary conditions (Peel et al., 2007, 

090442). Within a time-stratified case-crossover design, a 3-day ma over single-day lags 0-2 was 

used as the a priori lag structure. Results from the case-crossover analyses on all cardiovascular and 

peripheral vascular and cerebrovascular disease were similar to the time-series results presented 

earlier. Results from the various comorbidity analyses are presented in Table 5-10. Similar to the 

results from the earlier publication, CO was mostly associated with peripheral vascular and 

cerebrovascular disease (PVCD) among those with and without comorbidities, except among those 

with CHF. Overall, there is limited, if any, evidence of susceptibility to the effects of CO 

concentration for those with comorbid conditions. 

Table 5-10. Association of ambient air pollution levels and cardiovascular morbidity in visits with 

and without specific secondary conditions. 

Co-morbidity IHD Dysrhythmias PVCD CHF 

HYPERTENSION 

- With 1.007 (0.978-1.037) 1.065 (1.015-1.118) 1.038 (1.004-1.074) 1.037 (0.997-1.079) 

- Without 1.022 (1.000-1.043) 1.008 (0.988-1.029) 1.027 (1.002-1.054) 1.010 (0.985-1.037) 

DIABETES 

- With 0.985 (0.945-1.027) 1.058 (0.976-1.146) 1.065 (1.012-1.121) 1.020 (0.975-1.067) 

- Without 1.023 (1.004-1.042) 1.014 (0.995-1.034) 1.025 (1.003-1.048) 1.018 (0.993-1.044) 

COPD 

- With 0.996 (0.938-1.057) 0.972 (0.878-1.077) 1.113 (1.027-1.205) 1.058 (1.003-1.115) 

- Without 1.018 (1.000-1.036) 1.018 (0.999-1.038) 1.026 (1.004-1.047) 1.011 (0.987-1.036) 

CHF 

- With 0.956 (0.907-1.007) 1.065 (0.968-1.173) 1.072 (0.981-1.172) - 

- Without 1.024 (1.006-1.042) 1.015 (0.996-1.034) 1.029 (1.008-1.051) - 

DYSRHYTHMIAS 

- With 1.028 (0.985-1.072) - 1.072 (1.011-1.138) 1.004 (0.960-1.051) 

- Without 1.014 (0.995-1.033) - 1.026 (1.004-1.048) 1.023 (0.998-1.049) 

PVCD - peripheral vascular and cerebrovascular disease, IHD = ischemic heart disease, CHF = congestive heart failure. 

Source: Reprinted with Permission of Oxford Journals from Peel et al. (2007, 090442)

The third study utilizing the SOPHIA data extended the time period to include 1993 through 

2004 (Tolbert et al., 2007, 090316) and focused on two large outcome groups: a respiratory diseases 

group and a cardiovascular diseases group. The combined cardiovascular case group included the 

January 2010 5-34 
following groups of primary ICD-9 diagnostic codes: IHD (410-414), cardiac dysrhythmias (427), 

CHF (428), and peripheral vascular and cerebrovascular disease (433-437, 440, 443-445, 451-453). 

Results showed that a 1 ppm increase in 1-h max CO concentration was associated with an increase 

in daily ED visits for all CVDs (RR: 1.016 [95% CI: 1.008-1.024]). CO was the strongest predictor 

of CVD effects in models with two-pollutant combinations of NO2, CO and total carbon, as well as 

in a model including all three pollutants. 

Earlier research conducted in Los Angeles, CA, showed that a 0.5 ppm increase in same-day 

24-h avg CO concentration was associated with a 1.6% increase in CVD hospital admissions among 

people >30 yr (Linn et al., 2000, 002839). When the analyses were stratified by season, the strongest 

CO effect occurred during the winter (1.9% increase) followed by the summer (1.8%) and fall 

(1.4%) with no effect in spring. 

In contrast to other North American studies, a study in Spokane, WA, did not find an 

association between CO (lags of 1-3 days) and an increase in the number of daily cardiac hospital 

admissions (quantitative results not reported) (Slaughter et al., 2005, 073854). Similarly, a timeseries study in Windsor, Ontario, did not find an association between ambient CO and daily hospital 

admissions for CVDs (defined as HF, IHD, or dysrhythmias) (Fung et al., 2005, 074322). A total of 

11,632 cardiac admissions were analyzed for the period 1995-2000. The lag periods analyzed in this 

study were lag 0 (same-day), a 2-day avg (lag 0-1), and a 3-day avg (lag 0-2). For a 1 ppm increase 

in 1-h max CO concentration the mean percent change in daily admissions for the <65-yr age group 

(lag 0) was -2.6 (95% CI: -6.2 to 3.3); and for the 65+ yr age group, 0.4 (95% CI: -1.9 to 2.7). The 

authors reported moderate to low correlations with NO2 (r = 0.38), PM10 (r = 0.21) and SO2

(r = 0.16). 

Two case-crossover studies in Taiwan reported an association between ambient CO and 

hospital admissions for CVDs. In Taipei, a total of 74,509 CVD admissions from 47 hospitals for the 

period 1997-2001 were analyzed (Chang et al., 2005, 080086). An increase of 0.5 ppm in 24-h avg 

CO concentration (average over lags 0-2) during warmer periods (≥ 20°C) was associated with an 

increase in daily hospital admissions (OR: 1.09 [95% CI: 1.065-1.121]) but not cooler periods 

(<20°C) (OR: 0.98 [95% CI: 0.93-1.004]). These results persisted after controlling for PM10, SO2, or 

O3 in two-pollutant models. An identical study in Kaohsiung analyzed 29,661 CVD admissions for 

the period 1997-2000 (Yang et al., 2004, 094376). Results showed that a 0.5 ppm increase in 24-h 

avg CO concentration was associated with an increase in CVD hospital admissions during both the 

warmer periods (OR: 1.50 [95% CI: 1.38-1.63]) and cooler periods (OR: 1.89 [95% CI: 1.69-2.12]). 

Similarly, two Australian studies also reported associations between ambient CO 

concentrations and increased CVD hospital admissions among older adults. The first of these studies 

analyzed data from five of the largest cities in Australia (Brisbane, Canberra, Melbourne, Perth, 

Sydney) and two New Zealand cities (Auckland, Christchurch) for the period 1998-2001 (Barnett et 

al., 2006, 089770). The combined estimates showed that an increase of 0.75 ppm in the average 8-h 

max CO concentration over the current and previous day (lag 0-1) was associated with a 1.8% 

(95% CI: 0.7-2.8) increase in all CVD admissions among those aged 65+ yr. Among those aged 

15-64 yr there was a smaller increase in CVD admissions (1.0% [95% CI: 0.2-1.7]). The second of 

the Australian studies examined ED visits for CVDs in older adults (65+ yr) in Sydney for the period 

1997-2001 (Jalaludin et al., 2006, 189416). A 0.75 ppm increase in 8-h max CO concentration for 

single-day lags 0 and 1 was associated with increases in admissions of 2.5% (95% CI: 1.6-3.5) and 

1.4% (95% CI: 0.5-2.4), respectively. Based on an average over lags 0 and 1 (e.g., lag 0-1), there was 

an increase of 2.6% (95% CI: 1.5-3.6). There were positive increases of approximately 3% in CVD 

ED visits during the cool (May-October) period but not the warm period (November-April). 

Very few studies investigating the association between CO and cardiovascular hospital 

admissions have been conducted in European cities. Ballester et al. (2001, 013257) analyzed 

emergency hospital admissions in Valencia, Spain, for the period 1994-1996. The mean daily number 

of CVD admissions was 7, and there was no association between CO and admissions for all CVDs 

(RR: 1.009 [95% CI: 0.99-1.016] per 1 ppm increase in 1-h max CO concentration), heart diseases 

(RR: 1.010 [95% CI: 0.993-1.028] per 1 ppm increase), and cerebrovascular diseases (RR: 0.985 

[95% CI: 0.959-1.012] per 1 ppm increase). When the analyses were stratified by hot and cold 

seasons, only CO concentrations during the hot season were associated with an increase in all 

cardiovascular admissions (RR: 1.033 [95% CI: 1.006-1.064] per 1 ppm increase), heart disease 

admissions (RR: 1.033 [95% CI: 1.000-1.067] per 1 ppm increase), and cerebrovascular admissions 

(RR: 1.074 [95% CI: 1.007-1.113] per 1 ppm increase). 

January 2010 5-35 
Ballester et al. (2006, 088746) extended this research to include data from 14 Spanish cities 

for the period 1995-1999. An average exposure period over lags 0-1 was analyzed and for the 

combined estimates a 0.75 ppm increase in 8-h max CO concentration was associated with a 1.77% 

(95% CI: 0.56-2.99) increase in all cardiovascular hospital admissions and a larger increase of 3.57% 

(95% CI: 1.12-6.08) for heart disease admissions. These results persisted in two-pollutant models 

that included NO2, O3 and SO2. A study was carried out to evaluate the association between air pollution cardiovascular ED 

visits in subjects with and without diabetes in Sao Paulo, Brazil (Pereira Filho et al., 2008, 190260). 

From January 2001 to July 2003, 45,000 ED visits were registered due to CVDs, of which 700 were 

registered due to CVDs in diabetic patients. SO2 and NO2 were positively and statistically 

significantly associated with CVD ED visits among diabetics and nondiabetics, while CO was only 

positive and statistically significant among non-diabetic patients. PM10 and O3 were not positively 

associated with ED admissions among either group. 

Table 5-11 summarizes the non-specific CVD hospital admission studies that examined CO 

exposures. Due to the heterogeneity of endpoints, these studies do not lend themselves to a 

quantitative meta-analysis, and a forest plot was used to summarize the results of the studies on all 

CVD outcomes. Figure 5-5 shows the effect estimates associated with daily admissions for 

nonspecific CVD hospital admissions from selected studies. 

In summary, many of the studies that examined associations between ambient CO 

concentrations and ED visits and daily hospital admissions for CVD reported small yet precise 

positive associations at short (0-1 day) lags. Among studies that conducted stratified analyses, there 

were slightly stronger effects among older adults and possibly during warmer periods. 

Study Location Lag Group Effect Estimate (95% CI) 

Bell et al. (2009, 193780) 126 US counties 0 65+ yr 

Tolbert et al. (2007, 090316) Atlanta, GA 0-2 

Linn et al. (2000, 002839) Los Angeles, CA 0 All Year 

Linn et al. (2000, 002839) Los Angeles, CA 0 Spring 

Linn et al. (2000, 002839) Los Angeles, CA 0 Summer 

Linn et al. (2000, 002839) Los Angeles, CA 0 Fall 

Linn et al. (2000, 002839) Los Angeles, CA 0 Winter 

Fung et al. (2005, 074322) Windsor, Can 0-2 <65 yr 

Fung et al. (2005, 074322) Windsor, Can 0-2 65+ yr 

Barnett et al. (2006, 089770) Australia, New Zealand 0-1 15-64 yr 

Barnett et al. (2006, 089770) Australia, New Zealand 0-1 65+ yr 

Jalaludin et al. (2006, 189416) Sydney, Australia 0-1 65+ yr 

Ballester et al. (2006, 088746) Multicity, Spain 0-1 

Pereira Filho et al. (2008, 190260) Sao Paulo, Brazil 0 Diabetic 

Pereira Filho et al. (2008, 190260) Sao Paulo, Brazil 0 Nondiabetic 

Chang et al. (2005, 080086) Taipei, Taiwan 0-2 >20°C Temp 

Chang et al. (2005, 080086) Taipei, Taiwan 0-2 <20°C Temp 

Yang et al. (2004, 094376) Kaohsiung, Taiwan 0-2 <20°C Temp 

Yang et al. (2004, 094376) Kaohsiung, Taiwan 0-2 >20°C Temp 

Relative Risk 

Figure 5-5. Summary of effect estimates (95% confidence intervals) associated with hospital 

admissions for CVD. Effect estimates have been standardized to a 1 ppm 

increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h max CO 

concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-36 
Table 5-11. Summary of nonspecific CVD hospital admission studies. 

Study Location CVD Codes Copollutants Lags 

Examined 

Upper CO 

Concentrations from 

AQSb in ppm 

CO Concentrations 

Reported by Study 

Authors in ppm 

Bell et al. (2009, 193780) 

126 urban US 

counties 

(1999-2005) 

Total CVD PM2.5, NO2, EC 0, 1, 2 

98th%: 1.1-19.1 

99th%: 1.2-22.1 (1 h) 

Median: 1.3 (1 h) 

Median: 0.5 (24 h) 

Metzger et al. (2004, 044222) 

Atlanta, GA 

(1993-2000) 

All CVD PM10, NO2, SO2, O3 0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean: 1.8 (1 h) 

Peel et al. (2007, 090442) 

Atlanta, GA 

(1993-2000) 

All CVD PM10, NO2, 

SO2, O3 0-2ma 

98th%: 5.0-5.1 

99th%: 5.5-5.9 (1 h) Mean 1.8 (1 h) 

Tolbert et al. (2007, 090316) 

Atlanta, GA 

(1993-2004) 

All CVD PM10, NO2, 

SO2, O3 0-2ma 

98th%: 4.7-4.9 

99th%: 5.3-5.4 (1 h) Mean 1.6 (1 h) 

Linn et al. (2000, 002839) Los Angeles, CA 

(1992-1995) 

All CVD PM10, NO2, O3 0 

98th%: 1.0-7.8 

99th%: 1.1-8.3 (24 h) 

Mean: (24 h) 

Winter 1.7; Spring 1.0;

Summer 1.2; Fall 2.1 

Slaughter et al. (2005, 073854) Spokane, WA 

(1995-2001) 

All CVD 

(ICD9: 390-

459) 

PM10, PM2.5, 

CO 1,2,3 

98th%: 1.5-4.6 

99th%: 1.7-5.0 (24 h) 

Mean: range across 5 

monitors 0.42-1.82 

(24 h) 

Fung et al. (2005, 074322) 

Windsor, Can 

(1995-2000) 

All CVD (HF, 

IHF, or 

Dysrhythmia) 

PM10, NO2, 

SO2, O3

0, 0-1, 0-2 NA Mean: 1.3 (1 h) 

Chang et al. (2005, 080086) Taipei, Taiwan 

(1997-2001) 

All CVD 

(ICD9: 410-

429) 

PM10, NO2, 

SO2, O3 0-2 NA Mean: 1.37 (24 h) 

Yang et al. (2004, 094376) Kaohsiung, Taiwan 

(1997-2000) 

All CVD 

(ICD9: 410-

429) 

PM10, NO2, 

SO2, O3 0-2 NA Mean: 0.79 (24 h) 

Barnett et al. (2006, 089770) 

Australia and New 

Zealand 

(1998-2001) 

All CVD 

(ICD9: 390-

459) 

PM10, NO2, O3 0-1 NA Mean: (8h) 

0.5-2.1 

Jalaludin et al. (2006, 189416) Sydney, Australia 

(1997-2001) 

All CVD 

(ICD9: 390-

459) 

PM10, NO2, 

SO2, O3 0,1,2,3, 0-1 NA Mean: 0.82 (8h) 

Ballester et al. (2001, 013257)

a Valencia, Spain 

(1994-1996) 

All CVD 

(ICD9: 390-

459) 

BS, NO2, SO2, 

O3 1,2,3,4,5 NA Mean: 0.54 (24 h) 

Ballester et al. (2006, 088746)

a Multicity, Spain 

(1995-1999) 

All CVD 

(ICD9: 390-

459) 

BS, PM10, TSP, 

NO2, SO2, O3

0-1 NA 

Mean: range across 14 

cities 

0.12-0.24 (8h) 

Pereira Filho et al. (2008, 

190260) 

Sao Paulo, Brazil 

(2001-2003) 

All CVD PM10, NO2, 

SO2, O3

0, 1, 2, 0-1, 

0-2, 0-3 NA Mean: 2.7 (8 h) 

a

These studies presented CO concentrations in the units mg/m3. The concentrations were converted to ppm using the conversion factor 1 ppm = 1.15 mg/m3, which assumes standard atmosphere and 

temperature. 

b

 Includes range across individual monitors in study site; AQS data available for U.S. studies only.

January 2010 5-37 
Figure 5-6 and Figure 5-7 summarize the effects of CO concentration on ED visits and 

hospital admissions for all CVD outcomes other than stroke from studies that presented the results 

from two-pollutant models. Generally, the CO effect estimates from these studies are robust to the 

inclusion of copollutants, including PM10, PM2.5, NO2, SO2, and O3. In all but two instances – Lee et 

al. (2007, 090707) (<25°C adjusted for NO2) and Yang (2008, 157160) (<20°C adjusted for O3) – 

when the single pollutant effect estimate was positive for CO, it remained positive after the addition 

of any of the copollutants investigated. 

Study Outcome Lag Pollutant Group Effect Estimate (95% CI) 

Wellenius et al. (2005, 087483) CHF 0 CO Alone PM10

Wellenius et al. (2005, 087483) CHF 0 CO + PM10

Chan et al. (2006, 090193) CD 2 CO Alone 

Chan et al. (2006, 090193) CD 2 CO + PM10

Lee et al. (2007, 090707) CHF 0 CO Alone >25°C 

Lee et al. (2007, 090707) CHF 0 CO + PM10

D’Ippoliti et al. (2003, 074311) IHD 0-2 CO Alone 

D’Ippoliti et al. (2003, 074311) IHD 0-2 CO + TSP 

Chang et al. (2005, 080086) CVD 0 CO Alone >20°C 

Chang et al. (2005, 080086) CVD 0 CO + PM10

Chang et al. (2005, 080086) CVD 0 CO Alone <20°C 

Chang et al. (2005, 080086) CVD 1 CO + PM10

Lee et al. (2003, 095552) IHD 0 CO Alone 64+ yr 

Lee et al. (2003, 095552) IHD 0 CO + PM10

Ballester et al. (2006, 088746) CVD 0-1 CO Alone 

Ballester et al. (2006, 088746) CVD 0-1 CO + PM10

von Klot et al. (2005, 088070) CVD 0 CO Alone 

von Klot et al. (2005, 088070) CVD 0 CO + PM10

Lee et al. (2007, 090707) CHF 0 CO Alone <25°C 

Lee et al. (2007, 090707) CHF 0 CO + PM10

Yang (2008, 157160) CHF 0-2 CO Alone >20°C 

Yang (2008, 157160) CHF 0-2 CO + PM10

Yang (2008, 157160) CHF 0-2 CO Alone <20°C 

Yang (2008, 157160) CHF 0-2 CO + PM10

Bell et al. (2009, 193780) CVD 0 CO Alone PM2.5

Bell et al. (2009, 193780) CVD 0 CO + PM2.5

Tolbert et al. (2007, 090316) CVD 0-2 CO Alone 

Tolbert et al. (2007, 090316) CVD 0-2 CO + PM2.5

Chan et al. (2006, 090193) CD 2 CO Alone 

Chan et al. (2006, 090193) CD 2 CO + PM2.5

 Relative Risk 

Figure 5-6. Effect estimates from studies of ED visits and hospital admissions for CVD 

outcomes other than stroke from single pollutant (CO only: black circles) and 

particulate copollutant (CO + PM2.5: red triangles; CO + PM10 or TSP: purple 

triangles) models. Effect estimates have been standardized to a 1 ppm increase 

in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h max CO 

concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-38 
Study Outcome Lag Pollutant Label Effect Estimate (95% CI) 

Bell et al. (2009, 193780) CVD 0 CO Alone NO2

Bell et al. (2009, 193780) CVD 0 CO + NO2

Wellenius et al. (2005, 087483) CHF 0 CO Alone 

Wellenius et al. (2005, 087483) CHF 0 CO + NO2

Tolbert et al. (2007, 090316) CVD 0-2 CO Alone 

Tolbert et al. (2007, 090316) CVD 0-2 CO + NO2

Ballester et al. (2006, 088746) CVD 0-1 CO Alone 

Ballester et al. (2006, 088746) CVD 0-1 CO + NO2

Chang et al. (2005, 080086) CVD 0 CO Alone >20°C 

Chang et al. (2005, 080086) CVD 0 CO + NO2

Chang et al. (2005, 080086) CVD 0 CO Alone <20°C 

Chang et al. (2005, 080086) CVD 3 CO + NO2

Lee et al. (2007, 090707) CHF 0 CO Alone >25°C 

Lee et al. (2007, 090707) CHF 0 CO + NO2

Lee et al. (2007, 090707) CHF 0 CO Alone <25°C 

Lee et al. (2007, 090707) CHF 0 CO + NO2

Yang (2008, 157160) CHF 0-2 CO Alone >20°C 

Yang (2008, 157160) CHF 0-2 CO + NO2

Yang (2008, 157160) CHF 0-2 CO Alone <20°C 

Yang (2008, 157160) CHF 0-2 CO + NO2

Wellenius et al. (2005, 087483) CHF 0 CO Alone SO2

Wellenius et al. (2005, 087483) CHF 0 CO + SO2

Ballester et al. (2006, 088746) CVD 0-1 CO Alone 

Ballester et al. (2006, 088746) CVD 0-1 CO + SO2

Chang et al. (2005, 080086) CVD 0 CO Alone >20°C 

Chang et al. (2005, 080086) CVD 0 CO + SO2

Chang et al. (2005, 080086) CVD 0 CO Alone <20°C 

Chang et al. (2005, 080086) CVD 2 CO + SO2

Lee et al. (2007, 090707) CHF 0 CO Alone >25°C 

Lee et al. (2007, 090707) CHF 0 CO + SO2

Lee et al. (2007, 090707) CHF 0 CO Alone <25°C 

Lee et al. (2007, 090707) CHF 0 CO + SO2

Yang (2008, 157160) CHF 0-2 CO Alone >20°C 

Yang (2008, 157160) CHF 0-2 CO + SO2

Yang (2008, 157160) CHF 0-2 CO Alone <20°C 

Yang (2008, 157160) CHF 0-2 CO + SO2

Wellenius et al. (2005, 087483) CHF 0 CO Alone O3

Wellenius et al. (2005, 087483) CHF 0 CO + O3

Chan et al. (2006, 090193) CD 2 CO Alone 

Chan et al. (2006, 090193) CD 2 CO + O3

Ballester et al. (2006, 088746) CVD 0-1 CO Alone 

Ballester et al. (2006, 088746) CVD 0-1 CO + O3

Chang et al. (2005, 080086) CVD 0 CO Alone >20°C 

Chang et al. (2005, 080086) CVD 0 CO + O3

Chang et al. (2005, 080086) CVD 0 CO Alone <20°C 

Chang et al. (2005, 080086) CVD 4 CO + O3

von Klot et al. (2005, 088070) Cardiac 0 CO Alone 

von Klot et al. (2005, 088070) Cardiac 0 CO + O3

Lee et al. (2007, 090707) CHF 0 CO Alone >25°C 

Lee et al. (2007, 090707) CHF 0 CO + O3

Lee et al. (2007, 090707) CHF 0 CO Alone <25°C 

Lee et al. (2007, 090707) CHF 0 CO + O3

Yang (2008, 157160) CHF 0-2 CO Alone >20°C 

Yang (2008, 157160) CHF 0-2 CO + O3

Yang (2008, 157160) CHF 0-2 CO Alone <20°C 

Yang (2008, 157160) CHF 0-2 CO + O3

 Relative Risk 

Figure 5-7. Effect estimates from studies of ED visits and HAs for CVD outcomes other than 

stroke from single pollutant (CO only: black circles) and gaseous copollutant 

models (CO + NO2, SO2 and O3= green, blue, and orange triangles, respectively). 

Effect estimates have been standardized to a 1 ppm increase in ambient CO for 

1-h max CO concentrations, 0.75 ppm for 8-h max CO concentrations, and 

0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-39 
5.2.2. Epidemiologic Studies with Long-Term Exposure 

Two studies examined CVD outcomes in association with long-term exposure to CO. 

Rosenlund et al. (2006, 089796) investigated long-term exposure (30 yr) to urban air pollution and 

the risk of MI in Sweden. The study included 2,246 cases and 3,206 controls aged 45-70 yr and 

residing in Stockholm County during 1992-1993. A detailed postal questionnaire was completed by 

4,067 subjects, and all addresses inhabited during more than 2 yr since 1960 were geocoded. The 

exposures were then derived from dispersion calculations based on emissions data for each decade 

since 1960. These calculations were estimates of annual mean levels of traffic-generated NOX, NO2, CO, PM10, and PM2.5, with the addition of SO2 from heating sources. The analyses were stratified by 

all cases, nonfatal cases, fatal cases, in-hospital death, and out-of-hospital death. Based on a 30-yr 

avg exposure all pollutants were not associated with overall MI incidence. However, increased CO 

was associated with out-of-hospital death from MI (OR: 1.81 [95% CI: 1.02-3.23] per 0.5 ppm 

increase in 30-yr avg CO concentration). Similar results were reported for NO2. The correlation 

between the 30-yr NO2 and CO exposures was reasonably strong (r = 0.74) and multipollutant 

models with both these pollutants included (NO2, CO) were not examined. No other pollutants were 

significantly associated with all other MI outcomes. The study period was extended to include 

43,275 cases of MI during 1985-1996 and 507,000 controls (Rosenlund et al., 2009, 190309). Fiveyear average exposures to NO2, PM10 and CO were associated with incidence of MI, especially with 

fatal disease; when examining only nonfatal disease, no association was observed. The effect 

estimate for CO (OR: 1.03 [95%C CI: 1.02-1.04] per 0.5 ppm increase in 5-yr avg) was similar in 

magnitude to those for NO2 and PM10. When the analysis was restricted to the group that did not 

move between population censuses (the least expected misclassification of true individual exposure), 

the effect estimate for CO increased to 1.17 (95% CI: 1.11-1.24) per 0.5 ppm increase in 5-yr avg, 

and although the effect estimates for NO2 and PM10 remained similar to the estimate for CO, in this 

analysis the effect estimate for CO was slightly greater in magnitude than the effect estimate for 

PM10. 

A small-area ecologic study analyzed mortality and hospital admissions for stroke across 1,030 

census districts in Sheffield, U.K. (Maheswaran et al., 2005, 088683). Stroke counts within each 

census district were linked to modeled air pollution data which was then grouped into quintiles of 

exposure. For stroke hospital admissions, when the analyses were adjusted for only sex and age 

demographics, there was an exposure-response pattern exhibited across the quintiles of CO exposure 

with all levels reaching significance (RR: 1.37 [95% CI: 1.24-1.52] for the highest exposure group 

compared to the lowest group). However, this result did not persist when also adjusting for a 

deprivation index and smoking rates across the districts (RR: 1.11 [95% CI: 0.99-1.25]). 

5.2.3. Summary of Epidemiologic Studies of Exposure to CO and 

Cardiovascular Effects 

A substantial number of epidemiologic studies have examined the potential association 

between exposure to CO and various relevant cardiac endpoints or biomarkers. Overall, despite some 

mixed results reported among panel and retrospective cohort studies, there was evidence that 

exposure to CO has an effect on HR, various HRV parameters, and blood markers of coagulation and 

inflammation. Conversely, based on results from panel studies, there was little evidence of a link 

between CO and cardiac arrhythmia, cardiac arrest, the occurrence of MI, and increased BP. 

Studies of ED visits and hospital admissions provide evidence that CO is associated with 

various forms of CVD, with lag periods ranging from 0 to 3 days. Nearly all of the studies include 

same day (lag 0) or next day (lag1) lag periods, which are consistent with the proposed mechanism 

and biological plausibility of these CVD outcomes. When categorized by specific cardiovascular 

outcome, the evidence is consistent. Studies of hospital admissions and ED visits for IHD provide 

the strongest evidence of ambient CO being associated with adverse CVD outcomes. The effect 

estimates for this outcome are nearly all positive, many are statistically significant, and the 

magnitude of effect is similar among the studies. Though not as consistent as the IHD effects, the 

effects for all CVD hospital admissions (which include IHD admissions) and CHF hospital 

admissions also provide evidence for an association with ambient CO concentrations. There is very 

limited evidence that ambient CO is associated with ischemic stroke. It is difficult to determine from 

this group of studies the extent to which CO is independently associated with CVD outcomes or if 

January 2010 5-40 
CO is a marker for the effects of another traffic-related pollutant or mix of pollutants. On-road 

vehicle exhaust emissions are a nearly ubiquitous source of combustion pollutant mixtures that 

include CO and can be an important contributor to CO in near-road locations. Although this 

complicates the efforts to disentangle specific CO-related health effects, the evidence indicates that 

CO associations generally remain robust in copollutant models and supports a direct effect of shortterm ambient CO exposure on CVD morbidity. 

5.2.4. Controlled Human Exposure Studies 

Controlled human exposure studies provide valuable information related to the health effects 

of short-term exposure to air pollutants. Results of controlled human exposure studies can be used to 

provide coherence with the evidence from epidemiologic studies by expanding the understanding of 

potential mechanisms for the observed health outcomes. However, they may also provide 

information that can be used directly in quantitatively characterizing the exposure concentrationhealth response relationships at ambient or near-ambient concentrations. 

Several human clinical studies cited in the 2000 CO AQCD (U.S. EPA, 2000, 000907) 

observed changes in measures of cardiovascular function among individuals with CAD, following 

short-term exposures to CO. Principal among these is a large multilaboratory study of men with 

stable angina (n = 63), designed to evaluate the effect of CO exposure resulting in COHb 

concentrations of 2% and 4% on exercise-induced angina and ST-segment changes indicative of 

myocardial ischemia (Allred et al., 1989, 013018; Allred et al., 1989, 012697; Allred et al., 1991, 

011871). The majority of subjects were following an anti-ischemic medication regimen (e.g., beta 

blockers, nitrates, or calcium channel antagonists) which was maintained throughout the study. On 

three separate occasions, subjects underwent an initial graded exercise treadmill test, followed by 50- 

to 70-min exposures under resting conditions to average CO concentrations of 0.7 ppm (room air 

concentration range 0-2 ppm), 117 ppm (range 42-202 ppm) and 253 ppm (range 143-357 ppm). 

After the 50- to 70-min exposures, subjects underwent a second graded exercise treadmill test, and 

the percent change in time to onset of angina and time to ST endpoint between the first and second 

exercise tests was determined. The investigators conducted two exercise tests on exposure days (preversus postexposure) to control for day-to-day variability in the endpoints of interest. The effect of 

CO was evaluated by comparing the percent change in time to onset of angina or ST-segment change 

between the CO and clean air exposure days. The order of the three exposures was randomly 

determined and counterbalanced across subjects. For the CO exposure sessions, postexposure target 

COHb concentrations were set at values 10% greater than the post-exercise targets (i.e., 2.2% and 

4.4%) to compensate for the elimination of CO during exercise testing in clean air following 

exposure. CO uptake constants were determined for each subject individually during a qualifying 

visit and were used to compute the inhaled concentration required to attain the target COHb 

concentrations. Although CO-oximetry was used at each center to rapidly provide approximate 

concentrations of COHb during the actual exposure, COHb concentrations determined by a gas 

chromatographic technique were used in the statistical analyses as this method is known to be more 

accurate than CO-oximetry and other spectrophotometric methods, particularly for samples 

containing COHb concentrations <5%. For the two CO exposures, the average postexposure COHb 

concentrations were reported as 2.4% and 4.7% (3.2% and 5.6% using CO-oximetry), and the 

average post-exercise COHb concentrations were reported as 2.0% and 3.9% (2.7% and 4.7% using 

CO-oximetry). While the average COHb concentrations during the exercise tests were clearly 

between the concentrations measured in postexposure and post-exercise blood samples, the study 

authors noted that the samples at the end of the exercise test represented the COHb concentrations at 

the approximate time of onset of myocardial ischemia as indicated by angina and ST segment 

changes. Relative to clean air exposure (COHb ≈ 0.6-0.7%), exposures to CO resulting in postexercise COHb concentrations of 2.0% and 3.9% were shown to decrease the time required to induce 

ST-segment changes by 5.1% (p = 0.01) and 12.1% (p < 0.001), respectively. These changes were 

well correlated with the onset of exercise-induced angina. 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 post-exercise 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 significant decreases in time to angina and ST-segment change of approximately 1.9% 

and 3.9%, respectively, per 1% increase in COHb concentration, with no evidence of a measurable 

January 2010 5-41 
threshold. The relationship between percent change in time to ST-segment endpoint and postexercise COHb concentration is illustrated in Figure 5-8. 

Source: Reprinted with Permission of HEI from Allred et al. (1989, 012697) 

Figure 5-8. Regression of the percent change in time to ST endpoint between the pre- and 

postexposure exercise tests ([postexposure–pre-exposure]/pre-exposure) and 

the measured blood COHb levels at the end of exercise for the 63 subjects 

combined. The line represents the average of individual regressions. 

In addition to the work of Allred et al. (1989, 013018; 1989, 012697; 1991, 011871) a number 

of other studies involving individuals with stable angina have also demonstrated a CO-induced 

decrease in time to onset of angina, as well as reduction in duration of exercise at COHb 

concentrations between 3 and 6%, measured using spectrophotometric methods (Adams et al., 1988, 

012692; Anderson et al., 1973, 023134; Kleinman et al., 1989, 012696; Kleinman et al., 1998, 

047186). However, Sheps et al. (1987, 012212) observed no change in time to onset of angina or 

maximal exercise time following a 1-h exposure to 100 ppm CO (targeted COHb of 4%) among a 

group of 30 patients with CAD. In a subsequent study conducted by the same laboratory, a 

significant increase in number of ventricular arrhythmias during exercise was observed relative to 

room air among individuals with CAD following a 1-h exposure to 200 ppm CO (targeted COHb of 

6%) but not following a 1-h exposure to 100 ppm CO (targeted COHb of 4%) (Sheps et al., 1990, 

013286). 

While cardiovascular effects of CO have consistently been observed in studies of controlled 

human exposure among individuals with CAD at COHb concentrations between 2 and 6%, a 

quantitative meta-analysis of these studies is of limited value considering differences in the methods 

used. For example, variation in exercise protocols resulted in substantial differences between studies 

in total exercise time. More importantly, only Allred et al. (1989, 013018; 1989, 012697; 1991, 

January 2010 5-42 
011871) analyzed COHb concentration using gas chromatography. Although all studies measured 

COHb using spectrophotometric methods, these methods are only accurate within approximately 1% 

COHb of the true value at COHb concentrations < 5% (U.S. EPA, 1991, 017643). Therefore, a 

quantitative evaluation of changes in cardiovascular response with small increases in COHb 

concentration (< 1%) as measured using CO-oximetry is neither appropriate nor informative, 

particularly at low COHb concentrations. 

It should be noted that although the subjects evaluated in the studies described above are not 

necessarily representative of the most sensitive population, the level of disease in these individuals 

was moderate to severe, with the majority either having a history of MI or having ≥ 70% occlusion 

of one or more of the coronary arteries. The 2000 CO AQCD (U.S. EPA, 2000, 000907) presented 

very little evidence of CO-induced changes in cardiovascular function in healthy adults. Davies and 

Smith (1980, 011288) exposed healthy young adults continuously for 7 days to CO concentrations of 

0, 15, or 50 ppm. In this study, a marked ST-segment depression was demonstrated in only 1 out of 

16 subjects following exposure to 15 ppm CO (2.4% COHb) or 50 ppm CO (7.2% COHb). 

Since the publication of the 2000 CO AQCD (U.S. EPA, 2000, 000907), no new human 

clinical studies have been published involving controlled CO exposures among subjects with CAD. 

However, a number of new studies have evaluated changes in various measures of cardiovascular 

and systemic responses following controlled exposures to CO in healthy adults. Adir et al. (1999, 

001026) exposed 15 young healthy adult males to room air or CO for approximately 4 min, using a 

CO exposure concentration which had been shown to produce the targeted COHb level of 4-6%. 

Following each exposure, subjects performed an exercise treadmill test at their maximal capacity. 

Exposure to CO was not observed to cause arrhythmias, ST-segment changes, or changes in 

myocardial perfusion (thallium scintigraphy) during postexposure exercise. However, CO was 

demonstrated to decrease the postexposure duration of exercise by approximately 10% (p = 0.0012). 

In addition, the authors reported significant CO-induced decreases in metabolic equivalent units (p < 

0.001), which is a relative measure of O2 consumption. These results support the findings of several 

studies cited in the 2000 CO AQCD (U.S. EPA, 2000, 000907) which observed decreases in exercise 

duration and maximal aerobic capacity among healthy adults at COHb levels ≥ 3% (Drinkwater et 

al., 1974, 041332; Ekblom and Huot, 1972, 010886; Horvath et al., 1975, 010887; Raven et al., 

1974, 041340). While these decreases in exercise duration were relatively small and only likely to be 

noticed by competing athletes, the findings are nonetheless important in providing coherence with 

the observed effects of CO on exercise-induced myocardial ischemia among patients with CAD. 

Kizakevich et al.(2000, 052691) evaluated the cardiovascular effects of increasing CO 

concentration in healthy adults engaged in upper and lower body exercise. Subjects were initially 

exposed for 4-6 min to CO concentrations between 1,000 and 3,000 ppm, followed by continued 

exposure to 27, 55, 83, and 100 ppm to maintain COHb levels of 5, 10, 15, and 20%, respectively. 

Relative to room air control, CO exposure was not observed to cause ST-segment changes or affect 

cardiac rhythm at any concentration during either upper or lower body exercise. Compensation 

mechanisms for reduced O2 carrying capacity during CO exposure were demonstrated, with 

statistically significant increases in heart rate occurring at COHb levels ≥ 5%, and statistically 

significant increases in cardiac output and cardiac contractility observed at COHb levels ≥ 10%. In a 

human clinical study designed to evaluate the contribution of CO to cardiovascular morbidity 

associated with cigarette smoking, Zevin et al. (2001, 021120) exposed 12 healthy male smokers for 

7 consecutive days to clean air, CO, or cigarette smoke, with each subject serving as his own control. 

The COHb levels were similar between the exposures to cigarette smoke and CO, with average 

concentrations of 6% and 5%, respectively. Cigarette smoke, but not CO, was observed to 

significantly increase plasma levels of CRP and plasma platelet factor 4 relative to the air control 

arm of the study. Neither cigarette smoke nor CO was shown to affect BP. Hanada et al. (2003, 

193915) observed an increase in leg muscle sympathetic nerve activity (MSNA) following 

controlled exposures to CO (COHb ≈ 20%) under normoxic or hyperoxic conditions. Although an 

increase in the magnitude of sympathetic activation is typically associated with regional 

vasoconstriction, no CO-induced changes in femoral venous blood flow were observed in this study. 

These findings are in agreement with those of Hausberg and Somers (1997, 083450) who observed 

no change in forearm blood flow or BP in a study of 10 healthy men and women following a 

controlled exposure to CO (COHb ≈ 8%). Interestingly, one recent study did observe an increase in 

retinal blood flow, retinal vessel diameter, and choroidal blood flow following controlled exposures 

to CO at a concentration of 500 ppm (Resch et al., 2005, 193853). This protocol resulted in COHb 

concentrations of 5.6% and 9.4% following exposures of 30 and 60 min, respectively, with 

January 2010 5-43 
statistically significant increases in retinal and choroidal blood flow observed at both time points 

relative to synthetic air control. This CO-induced change in ocular hemodynamics may have been 

due to local tissue hypoxia; however, the clinical significance of this finding is unclear. Exposures to 

CO have also been shown to affect skeletal muscle function, with one recent human clinical study 

reporting a decrease in muscle fatigue resistance in healthy adult males, using both voluntary and 

electrically-induced contraction protocols following controlled exposures to CO resulting in an 

average COHb level of 6% (Morse et al., 2008, 097980). 

In summary, controlled human exposures to CO among individuals with CAD have been 

shown to consistently increase markers of myocardial ischemia at COHb concentrations between 2 

and 6%. No such effects have been observed in healthy adults following controlled exposures to CO. 

Although some studies have reported CO-induced hemodynamic changes among healthy adults at 

COHb concentrations as low as 5%, this effect has not been observed consistently across studies. 

5.2.5. Toxicological Studies 

While there was no toxicological research reported in the 2000 CO AQCD (U.S. EPA, 2000, 

000907) that involved CO exposures at or below the NAAQS levels, adverse cardiovascular effects 

were reported for higher CO concentrations. The lowest observed effect levels for cardiovascular 

effects in experimental animals included 50 ppm (6-wk exposure, 2.6% COHb) for cardiac rhythm 

effects, 100 ppm (46 days, 9.3% COHb) for hematology effects, 150 ppm (30 min, 7.5% COHb) for 

hemodynamic effects, 200 ppm (30 days, 15.8% COHb) for cardiomegaly, and 250 ppm (10 wk, 

20% COHb) for atherosclerosis and thrombosis (Table 6-11 in the 2000 CO AQCD) (U.S. EPA, 

2000, 000907). Conflicting experimental data relating to the role of CO in promoting atherosclerotic 

vessel disease were discussed. While some animal studies have linked chronic CO exposure with 

atherosclerosis development resulting from increased fatty streaking and cellular lipid loading 

(Davies et al., 1976, 010660; Thomsen, 1974, 010704; Turner et al., 1979, 012328), other studies 

have failed to see this association (Penn et al., 1992, 013728; Stupfel and Bouley, 1970, 010557). 

Vascular insults due to acute exposure to CO concentrations of 50 ppm and higher were also reported 

(Ischiropoulos et al., 1996, 079491; Thom, 1993, 013895; Thom et al., 1998, 016750; Thom et al., 

1999, 016757; Thom et al., 1999, 016753). In addition, chronic CO exposure has been shown to 

result in ventricular hypertrophy (Penney et al., 1984, 011567; Penney et al., 1988, 012521). 

The following sections describe recent studies dealing with toxicity of low to moderate 

concentrations (35-250 ppm) of CO. There has been little new research with the overt purpose of 

examining environmentally-relevant levels of CO. For the most part, studies were designed to mimic 

exposures related to cigarette smoke, either side-stream or mainstream, accidental CO poisoning, or 

for the purposes of therapeutic application. Thus, few studies examined levels of CO within the 

current 1-h (35 ppm) or 8-h (9 ppm) NAAQS levels, and fewer still examined concentration 

response curves to delineate no-effects levels. However, it is apparent that CO, at low to moderate 

concentrations, has pathophysiologic effects on the cardiovascular system and on relatively 

ubiquitous cellular pathways. In evaluating these studies, it should be kept in mind that the 

traditional concept of CO pathophysiology resulting from reduced O2 delivery is likely to be more 

relevant for higher concentrations of CO than are currently found in the ambient environment. 

CO exposure at environmentally-relevant levels is unlikely to cause overt toxicity in a healthy 

cell; however, susceptibility may be rendered by disease or developmental stage. A common theme 

appears to be the vulnerability of vascular cells, especially the endothelium, which could be 

considered the first organ of contact once CO is taken up into the circulation. While relatively little 

research has been conducted since the 2000 CO AQCD (U.S. EPA, 2000, 000907), several key 

studies conducted at environmentally-relevant CO levels provide important clues to the potential 

public health implications of ambient CO exposure. 

5.2.5.1. Endothelial Dysfunction 

While the preferential binding to heme and effective displacement of O2 by CO has been well 

established for over a century, new information from various fields of study are beginning to 

elucidate nonhypoxic mechanisms that may lead to cardiovascular abnormalities associated with CO 

exposure. Research by Thom, Ischiropoulos, and colleagues (Ischiropoulos et al., 1996, 079491; 

Thom and Ischiropoulos, 1997, 085644; Thom et al., 1994, 076459; Thom et al., 1997, 084337; 

January 2010 5-44 
Thom et al., 1999, 016753; Thom et al., 1999, 016757), some of which was reported in the 2000 CO 

AQCD (U.S. EPA, 2000, 000907), has focused on CO-mediated displacement of NO from hemebinding sites. Some of this work demonstrates a specific pathway by which severe CO poisoning can 

lead to the release of NO from platelets with subsequent neutrophil activation and vascular injury 

(Ischiropoulos et al., 1996, 079491; Thom et al., 2006, 098418). The steps include: (1) peroxynitrite 

generation from the reaction of NO from platelets with neutrophil-derived superoxide; followed by 

(2) stimulation of intravascular neutrophil degranulation; that can result in (3) myeloperoxidase 

deposition along the vascular lining. Products from myeloperoxidase-mediated reactions can cause 

endothelial cell activation (Thom et al., 2006, 098418) and can lead to endothelial dysfunction. The 

concentrations used in these studies are greatly in excess of the NAAQS levels but certainly within 

the range of accidental or occupational exposures. Research by these same investigators at more 

environmentally-relevant CO levels was partially reviewed in the 2000 CO AQCD (U.S. EPA, 2000, 

000907). The release of free NO was noted in isolated rat platelets exposed to 10-20 ppm CO (Thom 

and Ischiropoulos, 1997, 085644). Increased nitrotyrosine content of the aorta was observed in rats 

exposed to 50 ppm CO for 1 h (Thom et al., 1999, 016757; Thom et al., 1999, 016753). Furthermore, 

in this same study, a 1-h exposure to 100 ppm CO led to albumin efflux from skeletal muscle 

microvasculature at 3 h and leukocyte sequestration in the aorta at 18 h; LDL oxidation was also 

reported. These effects were dependent on NOS but not on neutrophils or platelets. A second study 

demonstrated NO-dependent effects of 50-100 ppm CO in lungs and is described in Section 5.5.4

(Thom et al., 1999, 016757). Studies in cultured endothelial cells were also conducted using buffer 

saturated with 10-100 ppm CO (Thom et al., 1997, 084337). These experiments were designed to 

mimic conditions where blood COHb levels were between 3.8 and 28%, resulting in exposure of 

endothelial cells to 11-110 nM CO. CO stimulated the release of NO from endothelial cells along 

with formation of peroxynitrite; delayed cell death was observed at CO concentrations of 22 nM and 

higher (Thom et al., 1997, 084337). A more recent study demonstrated adaptive responses in 

endothelial cells exposed to this same range of CO concentrations (Thom et al., 2000, 011574). 

Specifically, 1-h exposure to 11 nM CO resulted in MnSOD and HO-1 induction and resistance to 

the apoptotic effects of 110 nM CO. These protective effects of CO were mediated by NO, as 

demonstrated using an inhibitor of NOS and a scavenger of peroxynitrite. Collectively, these 

experiments demonstrated oxidative and nitrosative stress, the initiation of inflammation, increased 

microvascular permeability and altered cell signaling in animals and isolated cells following 

exposure to 10-100 ppm CO. 

CO is an endogenous regulator of vasomotor tone through vasodilatory effects, mediated by 

activation of soluble guanylate cyclase and activation of large conductance Ca2+-activated K+

channels. However, CO does not cause vasodilation in every vascular bed. For example, 5, 100, 500 

and 2,500 ppm CO administered by inhalation to near-term fetal lambs did not induce pulmonary 

vasodilation, and the HO-inhibitor zinc protoporphyrin IX failed to affect baseline vascular tone 

(Grover et al., 2000, 097088). In some cases CO promotes vasoconstriction, which is thought to be 

mediated by inhibition of endothelial NOS (Johnson and Johnson, 2003, 053611; Thorup et al., 1999, 

193782) or decreased NO bioavailability. An interesting series of studies has also suggested that 

endogenous CO derived from HO-1 which is induced in a variety of disease models (salt-sensitive 

forms of hypertension, metabolic syndrome in obese rats) is responsible for skeletal muscle arterial 

endothelial dysfunction (Johnson and Johnson, 2003, 053611; Johnson et al., 2006, 193874; Teran et 

al., 2005, 193770). Additional studies will be useful in determining whether environmentallyrelevant concentrations of CO have detrimental effects on preexisting conditions such as 

hypertension, metabolic syndrome or pregnancy. 

Several recent animal studies examined the vascular effects of controlled exposures to 

complex combustion mixtures containing CO. Vascular dilatation was decreased following exposure 

to diesel (4 h at 4 ppm) (Knuckles et al., 2008, 191987) and gasoline engine emissions (6 h/day for 1, 

3, and 7 days at 80 ppm) (Lund et al., 2009, 180257). Furthermore, evidence of vascular ROS 

following gasoline emissions has been shown in certain animal models (6 h/day for 50 days at 

8-80 ppm) (Lund et al., 2007, 125741). While none of these studies examined the potential 

independent role of CO, it is clearly a common factor in the various combustion atmospheres, and 

future work will be needed to reveal its importance on vascular health. 

January 2010 5-45 
5.2.5.2. Cardiac Remodeling Effects 

Cardiomyopathy, or abnormal growth of the cardiac muscle, can manifest in different ways, 

depending on the nature of the insult. The adverse effects of cardiac hypertrophy are due to reduction 

of ventricular chamber volume and a diminishing efficiency of the heart. Such concentric 

hypertrophy typically occurs in response to chronic increases in load, as occurs with hypertension. 

Ischemia of the cardiac tissue can also lead to cardiac remodeling and myopathy. During and after an 

acute infarction or obstruction of major coronary vessels, downstream tissues can suffer severe 

regional ischemia that leads to significant necrosis. Such regions will lose the ability to contract, and 

surrounding tissue will show deficits in contractility. Decreased contractility is often a result of 

structural thinning of the ventricular wall, as well as metabolic impairments. Chronic ischemia, such 

as may result from CAD, may similarly impair cardiomyocyte function and cause decreased 

contractility and remodeling. However, ultimately cardiomyopathies are of a complex origin 

involving mismanagement of fluid balance, abnormal hormonal influences (epinephrine, 

angiotensin), and insufficient perfusion/nutrition. Assessing the role of exogenous CO in altering 

pathways leading to cardiomyopathy is a relatively new endeavor, and several new findings are of 

great interest. 

The heart is a known target for CO toxicity, potentially due to its high rate of O2 consumption. 

Effects of CO on the healthy heart have only been observed at relatively high concentrations. For 

example, a recent study by Sorhaug et al. (2006, 180414) demonstrated cardiac hypertrophy in rats 

exposed for 72 wk to 200 ppm CO. COHb levels were reported to be 14.7%. Neither structural signs 

of hypertension in the pulmonary arteries nor atherosclerotic lesions in the systemic arteries were 

observed. A follow-up study by the same investigators (Bye et al., 2008, 193777) found reduced 

aerobic capacity and contractile function leading to pathologic cardiac hypertrophy in rats exposed 

for 18 mo to 200 ppm CO. Cardiac hypertrophy was also demonstrated in rats exposed to 

100-200 ppm CO for 1-2 wk (Loennechen et al., 1999, 011549). This response was accompanied by 

an increase in endothelin-1 expression. COHb levels were reported to be 12-23% in this latter study. 

Effects of CO on the healthy heart have also been demonstrated following short-term 

exposures. In a study by Favory et al. (2006, 184462) rats were exposed to 90 min of 250 ppm CO, 

which led to peak COHb values of roughly 11%; recovery of 96 h was needed for COHb levels to 

return to baseline. The authors noted that within the first 24 h of recovery, while COHb values 

decreased from 11% to 5%, the coronary vascular perfusion pressure and the left ventricular 

developed pressure were significantly increased compared to baseline. Concomitantly, the ratio of 

cGMP to cAMP decreased, and the sensitivity of the coronary vascular bed to both acetylcholine and 

a NO donor was reduced by CO exposure. The authors concluded that the discordant alterations in 

contractility (increased) and perfusion (decreased) may place the heart at risk of O2 limitations 

following this exposure to CO. 

Several studies examined the impact of lower levels (50 ppm) on preexisting or concurrent 

cardiac pathologies. In one such study, CO exacerbated the effects of a hypoxia-based model of right 

ventricular remodeling and failure (Gautier et al., 2007, 096471). In controlled laboratory settings, 

chronic hypobaric hypoxia (HH) caused right ventricular hypertrophy as a result of pulmonary 

arterial vasoconstriction and increased pulmonary resistance. Using such a model (Wistar rats 

exposed for 3 wk to hypoxia), CO (50 ppm during the last week of hypoxia, continuous) only 

increased COHb from 0.5% to 2.4% in the hypoxia model, yet had significant effects on blocking 

compensatory functional responses to hypoxia, such as increased fractional shortening and 

contractility. Also, while right ventricular weight was increased by hypoxia alone, significant 

pathology related to necrosis was observed in the hypoxia + CO-exposed rats. The reduced coronary 

perfusion of the right ventricle in hypoxia + CO-exposed rats may help explain the histopathologic 

findings. The authors cited previous work demonstrating that exogenous CO can inhibit NOS 

(Thorup et al., 1999, 193782), which is essential for coronary dilation and angiogenesis. Thus, this 

study provided evidence that exogenous CO may interrupt or downregulate pathways that 

endogenous CO may activate. 

In two studies by Melin et al. (2002, 037502; 2005, 193833), Dark Agouti rats were exposed 

for 10 wk to either HH, 50 ppm CO or HH plus 50 ppm CO. CO exposure amplified the right 

ventricular cardiac hypertrophy and decreased the right ventricular diastolic function which occurred 

in response to HH. In addition, the combined exposure led to effects on left ventricular morphology 

and function which were not seen with either exposure alone. Changes in HRV were also reported. 

Results from both of these studies combined with results of Gautier and colleagues (Gautier et al., 

2007, 096471) indicated that CO may interfere with normal homeostatic responses to hypoxia. This 

January 2010 5-46 
could occur by blocking HIF-1α-responsive elements (vascular endothelial growth factor, 

erythropoietin) or other cell signaling pathways. 

In a similar study, Carraway et al. (2002, 026018) exposed rats to HH (380 torr) with or 

without co-exposure to CO (50 ppm). These exposures were continuous for up to 21 days and 

focused on pulmonary vascular remodeling. While the addition of CO to HH did not alter the 

thickness or diameter of vessels in the lung, there was a significant increase in the number of small 

(<50 μm) diameter vessels compared to control, HH-only, and CO-only exposures. Despite the 

greater number of vessels, the overall pulmonary vascular resistance was increased in the combined 

CO + hypoxic exposure, which the authors attributed to enhancement of muscular arterioles and 

β-actin. Results of this study, taken together with results from the studies of Gautier et al. (2007, 

096471) and Melin et al. (2002, 037502; 2005, 193833), suggested that the combined effect of low 

levels of CO with hypoxia is an enhanced right ventricle workload and an exacerbated 

cardiomyopathy related to pulmonary hypertension. The population at risk of primary pulmonary 

hypertension is low, but secondary pulmonary hypertension is a frequent complication of COPD and 

certain forms of heart failure. 

5.2.5.3. Electrocardiographic Effects 

In two related studies, Wellenius et al. (2004, 087874; 2006, 156152) examined the effects of 

CO in an animal model of post-infarction myocardial sensitivity (Wellenius et al., 2002, 025405). In 

a previous study, ECG changes were observed during exposure to residual oil fly ash (ROFA) 

particles in anesthetized post-MI Sprague Dawley rats (Wellenius et al., 2002, 025405). Using this 

model, Wellenius and colleagues tested the effects of 35 ppm CO (1-h exposure) on the induction of 

spontaneous arrhythmias (Wellenius et al., 2004, 087874). CO exposure caused a statistically 

significant decrease (60.4%) in ventricular premature beat (VPB) frequency during the exposure 

period in rats with a high number of pre-exposure VPB. No interaction was observed with coexposure to carbon concentrated particles, which independently reduced VPB frequency during the 

postexposure period when administered alone. In a follow-up publication, results from the analysis 

of supraventricular ectopic beats (SVEB) were provided (Wellenius et al., 2006, 156152). A decrease 

in the number of SVEB was observed with CO (average concentration 37.9 ppm) compared to 

filtered air. While the authors concluded that CO exposure did not increase risk of SVEB in this 

particular rodent model of coronary occlusion, the fact that cardiac electrophysiological dynamics 

are significantly altered by short-term exposure to low-level CO may be of concern for other models 

of susceptibility. 

5.2.5.4.

5.2.6. 

5.2.6.1.

Summary of Cardiovascular Toxicology 

Experimental studies demonstrated that short-term exposure to 50-100 ppm CO resulted in 

aortic injury as measured by increased nitrotyrosine and the sequestration of activated leukocytes in 

healthy rats. In addition, skeletal muscle microvascular permeability was increased. Short-term 

exposure to 35 ppm CO altered cardiac electrophysiology in a rat model of arrhythmia. Furthermore, 

short-term exposure to 50 ppm CO exacerbated cardiac pathology and impaired function in an 

animal model of hypertrophic cardiomyopathy and enhanced vascular remodeling and increased 

pulmonary vascular resistance in an animal model of pulmonary hypertension. Ventricular 

hypertrophy was observed in healthy rats in response to chronic exposures of 100-200 ppm CO. 

These studies provide some support for the development of adverse health effects resulting from 

exposures to CO at environmentally-relevant concentrations. 

Summary of Cardiovascular Effects 

Short-Term Exposure to CO 

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 CAD. These studies, described in the 1991 (U.S. EPA, 1991, 017643) and 

January 2010 5-47 
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 (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 COHb concentrations 

lower than those evaluated in studies of controlled human exposures. 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 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 ED visits and hospital admissions for 

IHD, CHF and cardiovascular disease 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 results 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. 

5.2.6.2. Long-Term Exposure to CO 

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. 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.

January 2010 5-48 
5.3. Central Nervous System Effects 

5.3.1. Controlled Human Exposure Studies 

The behavioral effects of controlled human exposures to CO have been examined by several 

laboratories, and these studies were summarized in the 2000 CO AQCD (U.S. EPA, 2000, 000907). 

Briefly, decreases in visual tracking as well as visual and auditory vigilance were observed following 

exposures to CO resulting in COHb levels between 5% and 20% (Benignus et al., 1987, 012250; 

Fodor and Winneke, 1972, 011041; Horvath et al., 1971, 011075; Putz et al., 1979, 023137). One 

study reported similar behavioral effects (time discrimination) among a group of healthy volunteers 

with COHb levels <3% (Beard and Wertheim, 1967, 011015), though subsequent studies were 

unable to replicate these findings at such low exposure concentrations (Otto et al., 1979, 010863; 

Stewart et al., 1973, 093412). These outcomes represent a potentially important adverse effect of CO 

exposure resulting in COHb levels ≥ 5%, although it is important to note that these findings have not 

been consistent across studies. Similarly, some studies demonstrated decreases in reaction time as 

well as decrements in cognitive function and fine motor skills following controlled exposures to CO; 

however, these studies were not typically conducted using double-blind procedures, which may 

significantly affect the outcome of behavioral studies (Benignus, 1993, 013645). It should be noted 

that all behavioral studies of controlled CO exposure were conducted in normal, healthy adults. No 

new human clinical studies have evaluated CNS or behavioral effects of exposure to CO. 

5.3.2. Toxicological Studies 

The evidence for toxicological effects of CO exposure in laboratory animal models comes 

from in utero or perinatal exposure involving relatively low to relatively high concentrations of CO 

(12.5-750 ppm). Affected endpoints from this early, developmental CO exposure include behavior, 

memory, learning, locomotor ability, peripheral nervous system myelination, auditory decrements, 

and neurotransmitter changes. These data are addressed in detail in the Birth Outcomes and 

Developmental Effects section of the ISA (Section 5.4.2). Further, a group of studies have found that 

exposure to high concentrations of CO (500-1,200 ppm) can result in CO-dependent ototoxicity, 

specifically loss of threshold of cochlear compound action potentials (CAP) and potentiation of 

noise-induced hearing loss (NIHL) (Chen et al., 2001, 193985; Fechter et al., 1997, 081322; Fechter 

et al., 2002, 193926; Liu and Fechter, 1995, 076524). Proposed mechanisms for these effects include 

ROS generation and glutamate release. 

5.3.3. Summary of Central Nervous System Effects 

Exposure to high levels of CO has long been known to adversely affect CNS function, with 

symptoms following acute CO poisoning including headache, dizziness, 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 levels 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 low to moderate 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 5.4). In utero CO 

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

behavioral outcomes in offspring including active avoidance behavior (150 ppm CO), nonspatial 

memory (75 and 150 ppm CO), spatial learning (endogenous CO inhibition), homing behavior 

January 2010 5-49 
(150 ppm CO), locomotor movement (150 ppm CO), and negative geotaxis (125 and 150 ppm). In 

two separate studies, in utero CO exposure (75 and 150 ppm) was associated with significant 

myelination decrements without associated changes in motor activity in adult animals. Multiple 

studies demonstrated that in utero CO exposure affected glutamatergic, cholinergic, 

catecholaminergic, and dopaminergic neurotransmitter levels or transmission. Possible or 

demonstrated adverse outcomes from the CO-mediated aberrant neurotransmitter levels or 

transmission include respiratory dysfunction (200 ppm CO), impaired sexual behavior (150 ppm 

CO), and an adverse response to hyperthermic insults resulting in neuronal damage (200 ppm). 

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

inducing permanent changes into adulthood. This is manifested by atrophy of cochlear cells 

innervating the inner hair cells (25 ppm CO), decreased immunostaining associated with impaired 

neuronal activation (12.5 ppm CO), impaired myelination of auditory associated nerves (25 ppm 

CO), decreased energy production in the sensory cell organ of the inner ear or the organ of corti 

(25 ppm CO). Some of these changes have been proposed to be mediated by ROS. Functional tests 

of the auditory system of rodents exposed neonatally to CO using OAE testing (50 ppm) and action 

potential amplitude measurements of the 8th cranial nerve (12, 25, 50, 100 ppm), revealed 

decrements in auditory function at PND22 and permanent changes into adulthood using action 

potential (AP) testing (50 ppm). Additionally, exposure to high concentrations of CO has been 

shown to result in CO-dependent ototoxicity in adult animals, possibly through glutamate and ROSdependent mechanisms. Together, these animal studies demonstrated that in utero or perinatal 

exposure to CO can adversely affect adult behavior, neuronal myelination, neurotransmission, and 

the auditory system in adult rodents. 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. 

5.4. Birth Outcomes and Developmental Effects 

5.4.1. Epidemiologic Studies 

Although the body of literature is growing, the research focusing on adverse birth outcomes is 

limited when compared to the numerous studies that have examined the more well-established health 

effects of air pollution. Among this small number of studies, various dichotomized measures of birth 

weight, such as low birth weight (LBW), small for gestational age (SGA), and intrauterine growth 

restriction (IUGR), have received more attention in air pollution research while preterm birth 

(<37 wk gestation; [PTB]), congenital malformations, and infant mortality are less studied. 

In the 2000 CO AQCD (U.S. EPA, 2000, 000907), only two studies were cited that examined 

the effect of ambient air pollution on adverse birth outcomes, and both of these studies investigated 

LBW as an endpoint (Alderman et al., 1987, 012243; Ritz and Yu, 1999, 086976). At that time this 

area of research was in its infancy; however, there has since been increasing interest. 

5.4.1.1. Preterm Birth 

A small number of air pollution-birth outcome studies have investigated the possible 

association between PTB and maternal exposure to CO, with the majority of U.S. studies conducted 

in southern California. The earliest of these studies examined exposures to ambient CO during the 

first month of pregnancy and the last 6 wk prior to birth among a cohort of 97,158 births in southern 

California between 1989 and 1993 (Ritz et al., 2000, 012068). The exposure assessment within this 

study was based on data from fixed-site monitors that fell within a 2-mi radius of the mother’s ZIP 

code area. The crude relative risks for PTB associated with a 1 ppm increase in 3-h avg CO 

concentration (6:00-9:00 a.m.) during the last 6 wk prior to birth and the first month of pregnancy 

were 1.04 (95% CI: 1.03-1.5) and 1.01 (95% CI: 1.00-1.03), respectively. However, when the 

authors controlled for other risk factors, only the effect associated with CO during the last 6 wk prior 

to birth persisted (RR: 1.02 [95% CI: 1.01-1.03]). Furthermore, when the analyses included variables 

January 2010 5-50 
for either season or other pollutants, the CO effect estimates generally were reduced such that they 

remained positive but were no longer statistically significant. 

Expanding on this research, Wilhelm and Ritz (2005, 088668) examined PTB among a cohort 

of 106,483 births in Los Angeles County, CA, between 1994 and 2000. Based on data recorded at 

monitoring stations of varying proximities to the mother’s residence, the main exposure windows 

examined were the first trimester and the last 6 wk prior to birth. Among women living within a 1-mi 

radius of a CO monitoring station, a 0.5 ppm increase in 24-h avg CO concentration during the first 

trimester was associated with a 3% (RR: 1.03 [95% CI: 1.00-1.06]) increased risk of PTB. This 

result persisted after simultaneously adjusting for NO2 and O3 (RR: 1.05 [95% CI: 1.00-1.10]) but 

not with the inclusion of PM10 into the regression model (RR: 0.99 [95% CI: 0.91-1.09]). The result 

from the single pollutant model for CO exposures averaged over the 6 wk prior to birth was similar 

in magnitude but failed to reach statistical significance (RR: 1.02 [95% CI: 0.99-1.04]). 

A limitation of many air pollution-birth outcome studies is the limited availability of detailed 

information on maternal lifestyle factors and time-activity patterns during pregnancy. To assess 

possible residual confounding due to these factors, Ritz and colleagues (2007, 096146) were able to 

analyze detailed maternal information from a survey of 2,543 from a cohort of 58,316 eligible births 

in 2003 in Los Angeles County. Based on data from the closest monitor to the mother’s ZIP code 

area, exposures to CO, NO2, O3, and PM2.5 during the first trimester and last 6 wk prior to delivery 

were examined, and results from the overall cohort (n = 58,316) with limited maternal information 

were compared to the more detailed nested case-control cohort (n = 2,543). Within the overall 

cohort, 24-h avg CO during the first trimester was associated with an increased risk of 25% (OR: 

1.25 [95% CI: 1.12-1.38]; highest exposure group >1.25 ppm versus lowest ≤ 0.58 ppm). This result 

persisted within the nested case-control cohort (OR: 1.21 [95% CI: 0.88-1.65]) where factors such as 

passive smoking and alcohol use during pregnancy were included in the model; however, the 

confidence intervals were wider due to the smaller sample. Any possible association between CO 

and PTB was less evident during the last 6 wk prior to birth. A strength of this study was that it also 

highlighted how there was little change in the air pollution effect estimates when controlling for 

more detailed maternal information (e.g., smoking, alcohol use), as opposed to only controlling for 

more limited maternal information that is routinely collected on birth registry forms. 

In contrast to the Los Angeles studies, a case-control study of PTB across California for the 

period 1999 through 2000 found a positive association with 24-h CO concentration during the entire 

pregnancy (OR: 1.03 [95% CI: 0.98-1.09] per 0.5 ppm increase) and the first month of gestation 

(OR: 1.05 [95% CI: 0.99-1.10] per 0.5 ppm increase), but no association during the last 2 wk of 

gestation (OR: 1.00 [95% CI: 0.96-1.04] per 0.5 ppm increase) (Huynh et al., 2006, 091240). 

Although there was an indication of an effect during early pregnancy, the small sample size (when 

compared to other studies) may not have provided sufficient power to detect statistical significance. 

Furthermore, exposures within this study were assigned based on a county-level average which may 

explain the lack of effect, given the poor level of exposure assessment. 

Studies outside of the U.S. have been conducted in Canada, Australia, and Korea, with mixed 

results reported. In Vancouver, Canada, based on a city-wide average across available monitoring 

sites, 24-h avg CO concentration during the last month of pregnancy was associated with a 4% (OR: 

1.04 [95% CI: 1.00-1.07]) increased risk of PTB per 0.5 ppm increase, while there was no 

association found during the first month of pregnancy (OR: 0.98 [95% CI: 0.94-1.00]) (Liu et al., 

2003, 089548). This study investigated maternal exposures to ambient gaseous pollutants (CO, NO2, 

SO2, O3) averaged over the first and last month of pregnancy among a cohort of 229,085 births 

between 1985 and 1998. 

In a cohort of 52,113 births in Incheon, Korea, between 2001 and 2002, a kriging technique 

was used to assign the maternal exposures to CO. Kriging is a statistical mapping technique that 

allows the prediction of an average concentration over a spatial region from data collected at specific 

points. The spatial average CO concentrations were then linked to each study subject’s residential 

address. CO concentrations during the first trimester were associated with a 26% (RR: 1.26 

[95% CI: 1.11-1.44]) increased risk of PTB for the highest quartile of exposure when compared to 

the lowest quartile (Leem et al., 2006, 089828). There was also a strong significant trend exhibited 

across the quartiles. A similar result was found for 24-h avg CO concentration during the last 

trimester, although the effect was less pronounced (RR: 1.16 [95% CI: 1.01-1.24]). 

Conversely, a study in Sydney, Australia, examined maternal exposure to ambient air pollution 

during the first and last month and the first and last trimester of pregnancy among a cohort of 

123,840 births between 1998 and 2000 and found no association between PTB and CO (Jalaludin et 

January 2010 5-51 
al., 2007, 156601). Maternal exposure estimates in this study were based on a city-wide average of 

available monitoring sites and also based on data from fixed sites within 5 km of the mother’s 

postcode area. The odds ratios for PTB associated with 8-h avg CO concentrations during the first 

trimester and last 3 mo of gestation were 1.18 (95% CI: 0.85-1.63) and 1.08 (95% CI: 0.95-1.22), 

respectively, when including births within 5 km of a monitor. Interestingly, when all births were 

included in the analyses and the exposure was based on a city-wide average, these effects had 

become protective for the first trimester (OR: 0.82 [95% CI: 0.77-0.87]) and null for the last 3 mo of 

gestation (OR: 0.99 [95% CI: 0.92-1.07]). This suggests that exposures based on data from fixed 

sites closer to the mother’s address are more likely to detect an effect than a city-wide average. 

Figure 5-9 shows the odds for the risk of delivering a preterm infant from the reviewed 

studies; Table 5-12 provides a brief overview of the PTB studies. In summary, there are mixed 

results across the studies. Although these studies are difficult to compare directly due to the different 

exposure assessment methods employed, there is some evidence that CO during early pregnancy 

(e.g., first month and trimester) is associated with an increased risk of PTB. The most consistency is 

exhibited within the studies conducted around Los Angeles, CA, and surrounding areas, whereby all 

studies reported a significant association with CO exposure during early pregnancy, and exposures 

were assigned from monitors within close proximity of the mother’s residential address (Ritz et al., 

2000, 012068; Ritz et al., 2007, 096146; Wilhelm and Ritz, 2005, 088668). It should also be noted 

that the mixed results when analyzing different cohorts that resided within varying proximities to a 

monitor may be attributable to analyzing different populations. 

Study Location Exposure Period Exposure 

Indicator Effect Estimate (95% CI) 

Ritz et al. (2000, 012068) California, US First month <2 mi of monitor 

Ritz et al. (2000, 012068) California, US Last 6 weeks <2 mi of monitor 

Wilhelm & Ritz (2005, 088668) Los Angeles, CA First trimester ZIP code level 

Wilhelm & Ritz (2005, 088668) Los Angeles, CA Last 6 weeks ZIP code level 

Huynh et al. (2006, 091240) California, US First month County level 

Huynh et al. (2006, 091240) California, US Last 2 weeks County level 

Huynh et al. (2006, 091240) California, US Entire pregnancy County level 

Liu et al. (2003, 089548) Vancouver, Can First month City wide 

Liu et al. (2003, 089548) Vancouver, Can Last month City wide 

Jalaludin et al. (2007, 156601) Sydney, Australia First month City wide 

Jalaludin et al. (2007, 156601) Sydney, Australia First trimester City wide 

Jalaludin et al. (2007, 156601) Sydney, Australia Last month City wide 

 Odds Ratio 

Figure 5-9. Summary of effect estimates (95% confidence intervals) for PTB associated with 

maternal exposure to ambient CO. Effect estimates have been standardized to a 

1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-52 
Table 5-12. Brief summary of PTB studies. 

Study Location 

Sample Size 

Mean CO 

(ppm) Exposure Assessment Exposure Window 

Ritz et al. (2000, 012068) California, US 

(n = 97,158) 2.7 (6-9 a.m.) <2 mi of monitor First mo 

Last 6 wk 

Wilhelm and Ritz (2005, 088668) Los Angeles, CA 

(n = 106,483) 1.4 (24 h) Varying distances to monitor Last 6 wk 

Ritz et al.(2007, 096146) Los Angeles, CA 

(n = 58,316) 0.87 (24 h) Nearest monitor to ZIP code 

Entire pregnancy 

First Trimester

Last 6 wk 

Huynh et al. (2006, 091240) California, US 

(n = 42,692) 0.8 (24 h) County level 

Entire pregnancy 

First mo 

Last 2 wk 

Liu et al. (2003, 089548) Vancouver, Can 

(n = 229,085) 1.0 (24 h) City-wide avg First mo 

Last mo 

Leem et al. (2006, 089828) Incheon, Korea 

(n = 52,113) 0.9 (24 h) Residential address within Dong-based on kriging 

First trimester 

Last trimester 

Jalaludin et al. (2007, 156601) Sydney, Australia 

(n = 123,840) 0.9 (8 h) City-wide avg and 

<5 km from monitor 

First mo 

First trimester 

Last trimester 

Last mo 

5.4.1.2. Birth Weight, Low Birth Weight, and Intrauterine Growth Restriction/Small for 

Gestational Age 

With birth weight routinely collected in vital statistics and being a powerful predictor of infant 

mortality, it is the most studied outcome within air pollution-birth outcome research. Air pollution 

researchers have analyzed birth weight as a continuous variable and/or as a dichotomized variable in 

the forms of LBW (<2,500 g [5 lbs, 8 oz]) and SGA. 

It should be noted that the terms SGA, which is defined as a birth weight <10th percentile for 

gestational age (and often sex), and IUGR are used interchangeably. However, this definition of SGA 

does have limitations. For example, using it for IUGR may overestimate the percentage of “growthrestricted” neonates as it is unlikely that 10% of neonates have growth restriction (Wollmann, 1998, 

193812). On the other hand, when the 10th percentile is based on the distribution of live births at a 

population level, the percentage of SGA among preterm births is most likely underestimated 

(Hutcheon and Platt, 2008, 193795). Nevertheless, it should be noted that SGA represents a 

statistical description of a small neonate, whereas the term IUGR is reserved for those with clinical 

evidence of abnormal growth. Thus, all IUGR neonates will be SGA, but not all SGA neonates will 

be IUGR (Wollmann, 1998, 193812). In the following sections the terms SGA and IUGR are referred 

to as each cited study used the terms. 

Over the past decade a number of studies examined various metrics of birth weight in relation 

to maternal exposure to CO with the majority conducted in the U.S. Given that most studies 

examined multiple birth weight metrics, the following section focuses on each study only once and 

presents results for each metric within that study. 

Most of the U.S. studies have been conducted in southern California, with inconsistent results 

reported with regard to gestational timing of the CO effects. The first of these studies was reviewed 

in the 2000 CO AQCD (U.S. EPA, 2000, 000907) and is briefly summarized here. Ritz and Yu 

(1999, 086976) examined the effect of ambient CO during the last trimester on LBW among 125,573 

births in Los Angeles between 1989 and 1993. When compared to neonates born to women in the 

lowest CO exposure group (<2.2 ppm), neonates born to women in the highest exposure group 

(5.5 ppm-95th percentile) had a 22% (OR: 1.22 [95% CI: 1.03-1.44]) increased risk of being born as 

LBW. 

Building upon this research, Wilhelm and Ritz (2005, 088668) reported similar results when 

extending this study to include 136,134 births for the period 1994–2000. Exposure to ambient CO 

January 2010 5-53 
during each trimester was based on data recorded at monitoring stations of varying proximities to the 

mother’s residence. For women residing within 1 mi of a station, there was 36% (OR: 1.36 

[95% CI: 1.04-1.76]) increased risk of having a term LBW baby for women with third-trimester 

exposure above the 75th percentile when compared to women below the 75th percentile. There was 

also an increased risk of term LBW (OR: 1.28 [95% CI: 1.12-1.47]) among women in the highest 

exposure group when the analyses included women within a 5-mi radius of a station. However, when 

the analyses included women within a 1- to 2-mi or 2- to 4-mi radius of a station, the CO effects 

failed to reach statistical significance, and there was no evidence of an exposure-response pattern 

exhibited across the varying distances to a station. Furthermore, none of the significant CO results 

persisted after controlling for other pollutants. Although standard errors were certainly increased 

after controlling for the other pollutants, leading to non-significant results, some of the effect sizes 

were similar, providing some consistency. It is interesting to note, however, that maternal exposure 

to CO during trimesters one and two was not associated with LBW (quantitative results not reported 

by authors). 

Further validation in association with exposure times was observed in an analysis using a 

subset of participants in the Children’s Health Study. Salam and colleagues (2005, 087885) found 

that CO only during the first trimester was associated with reduced fetal growth. Their research 

examined birth weight, LBW, and IUGR among a subset of participants in the Children’s Health 

Study (Peters et al., 1999, 087243) who were born in California between 1975 and 1987 (n = 3,901). 

The study examined term births with a gestational age between 37 and 44 wk. Exposures in this 

study were based on CO data from up to the 3 nearest monitoring sites within 50 km of the centroid 

of the mother’s ZIP code. Exposures for the entire pregnancy and each trimester were analyzed, and 

a 0.5 ppm increase in 24-h CO concentration during the first trimester was associated with a 7.8 g 

(95% CI: 15.1-0.4) decrease in birth weight, which also translated to a 6.7% (OR: 1.07 [95% CI: 

1.00-1.13]) increased risk of IUGR; however, there was no association with LBW (OR: 1.00 

[95% CI: 0.88-1.16]). 

In contrast to the previous studies, another California study of 18,247 singleton births born at 

40-wk gestation during 2000 found no association between ambient 24-h CO concentration and 

reduced birth weight or SGA, where the highest quartile of exposure was 0.98 ppm. Based on data 

from fixed sites within 5 mi of the mother’s residence, exposures to CO and PM2.5 during the entire 

pregnancy and each trimester were analyzed. Although CO during the entire pregnancy was 

associated with a 20 g (95% CI: 40.1-0.8) reduction in birth weight, this did not persist after 

controlling for PM2.5. PM2.5 was found to have a strong effect on birth weight within each trimester 

(Parker et al., 2005, 087462). 

Two similar studies were conducted in the northeastern U.S. with inconsistent results. A study 

of 89,557 singleton term births in Boston, MA, Hartford, CT, Philadelphia, PA, Pittsburgh, PA, and 

Washington, DC, between 1994 and 1996 found that exposure to ambient 24-h avg CO during the 

third trimester was associated with an increased risk of LBW (OR: 1.14 [95% CI: 1.03-1.27] per 

0.5 ppm increase) (Maisonet et al., 2001, 016624). When stratified by race this effect was only 

significant among African-Americans for the first and third trimesters (first OR: 1.32 

[95% CI: 1.22-1.43]; third OR: 1.20 [95% CI: 1.09-1.32]). Exposures to PM10 and SO2 were 

examined, and there was no strong evidence that these pollutants were associated with LBW. 

Exposures for this study were based on a city-wide average of monitors within the mother’s city of 

residence. The second study examined 358,504 births at 32- to 44-wk gestation between 1999 and 

2002 in Connecticut and Massachusetts (Bell et al., 2007, 091059), and 24-h CO exposures were 

estimated from fixed sites within each mother’s county of residence (e.g., county level). CO 

averaged over the entire pregnancy was associated with a reduction in birth weight of 27.0 g 

(95% CI: 21.0-32.8). This result persisted after controlling for each additional pollutant (PM10, PM2.5, NO2, and SO2) in two-pollutant models. However, this reduction in birth weight did not 

translate to an increased risk of LBW (OR: 1.05 [95% CI: 0.97-1.12] per 0.5 ppm increase in CO). 

When controlling for exposure during each trimester, the reduction in birth weight associated with a 

0.5 ppm increase in 24-h CO concentration during the first trimester ranged from 18.8 to 16.5 g, 

while the reductions associated with third trimester exposure ranged between 27.2 and 23.3 g. It is 

interesting to note that, although the exposures were based on data averaged at the county level, CO 

was associated with a reduction in birth weight. In contrast, in a previously cited California study by 

Huynh and colleagues (2006, 091240) exposures were also at the county level yet there was no 

association with PTB. This difference may be due to the counties being smaller in New England than 

in California, resulting in more precise exposure estimates. 

January 2010 5-54 
Two studies in Canada investigated the effects of ambient air pollution on fetal growth with 

exposures derived from a city-wide average across the available monitoring sites. The first of these 

studies was among a cohort of 229,085 singleton term births (37- and 42-wk gestation) in Vancouver, 

BC, with monthly and trimester exposures to CO investigated in relation to LBW and IUGR (Liu et 

al., 2003, 089548). For a 0.5 ppm increase in 24-h CO concentration during the first month of 

pregnancy, there was an increased risk of IUGR (OR: 1.03 [95% CI: 1.00-1.05]), and this was of 

borderline significance when CO was averaged over the first trimester (OR: 1.02 

[95% CI: 1.00-1.05]). This result persisted after controlling for other gaseous pollutants. Conversely, 

maternal exposure to CO was not associated with LBW. The more recent of these two studies 

examined 386,202 singleton term births (37- to 42-wk gestation) in Calgary, Edmonton, and 

Montreal, between 1986 and 2000 (Liu et al., 2007, 090429). The study examined monthly and 

trimester exposures to CO with IUGR being the only endpoint. A 0.5 ppm increase in 24-h CO 

concentration was associated with an increased risk of IUGR in the first (OR: 1.09 

[95% CI: 1.07-1.11]), second (OR: 1.07 [95% CI: 1.05-1.09]), and third trimesters (OR: 1.09 

[95% CI: 1.07-1.11]) of pregnancy. This result translated to CO exposure having a positive effect on 

IUGR within each individual month of pregnancy with the highest effect during the first and last 

months. This result persisted after controlling for concurrent NO2 and PM2.5. 

Two studies in Sao Paulo, Brazil, a city with notably high levels of air pollution (mean CO 

3.7 ppm) investigated associations between maternal exposures to CO in relation to reduced birth 

weight and LBW within two consecutive time periods and found similar results. In both studies the 

exposures were derived from a city-wide average across the available monitoring sites. The first 

study examined 179,460 singleton term births during 1997 and found that a 0.75 ppm increase in 8-h 

CO concentration averaged over the first trimester was associated with a 17.3 g (95% CI: 31.0-3.7) 

reduction in birth weight (Gouveia et al., 2004, 055613). The second of these studies examined 

311,735 singleton births (37- to 41-wk gestation) between 1998 and 2000 and reported a 6.0 g (95 % 

CI: 7.75-4.1) reduction in birth weight associated with a 0.5 ppm increase in 24-h CO concentration 

averaged over the first trimester (Medeiros and Gouveia, 2005, 089824). It is important to note that 

neither of these studies found an association between CO exposure and an increased risk of LBW. 

Therefore, despite CO during the first trimester being associated with reduced birth weight, it was 

not associated with LBW. 

Similar to the two studies in Sao Paulo, Brazil, researchers in Seoul, South Korea, conducted 

two studies using data from two consecutive time periods. Both of these studies based the exposure 

estimates on a city-wide average from all available fixed sites and as would be expected, the results 

pertaining to CO were similar for both studies. Ha and colleagues (2001, 019390) examined 

maternal exposures to CO during the first and third trimesters among 276,763 singleton term births 

in Seoul between 1996 and 1997. Exposure to CO during the first trimester was associated with a 

decrease in birth weight of 13.3 g, which also translated into an increased risk of LBW (RR: 1.10 

[95% CI: 1.05-1.14] per 0.5 ppm increase in 24-h CO concentration). When Lee and colleagues 

(2003, 043202) extended this study to include singleton term births for the period 1996-1998, with 

24-h CO concentrations averaged over each month of pregnancy and trimester, CO exposure during 

the first trimester was associated with an increased risk of LBW (OR: 1.04 [95% CI: 1.01-1.07] per 

0.5 ppm increase). No associations were found in the third trimester for any of the pollutants. 

Monthly-specific exposures showed that the risk of LBW tended to increase with CO exposure 

between months two through five of pregnancy. 

In contrast to other studies reporting that early and late pregnancy are the critical periods for 

CO exposure, a Sydney, Australia study of 138,056 singleton births between 1998 and 2000 reported 

a reduction in birth weight of 21.7 g (95% CI: 38.2-5.1) and 17.2 g (95% CI: 33.4-0.9) associated 

with a 0.75 ppm increase in maternal exposure to 8-h CO averaged over the second and third 

trimesters, respectively (Mannes et al., 2005, 087895). However, this result did not persist after 

controlling for other pollutants (PM10, NO2) and was only statistically significant when including 

births where the mother resided within 5 km of a monitor. Furthermore, this result did not translate to 

an increased risk of SGA, which was defined as a birth weight two standard deviations below the 

mean. The odds ratios for SGA for CO exposures during the first, second and third trimesters were 

0.96 (95% CI: 0.91-1.03), 0.99 (95% CI: 0.92-1.07), and 1.01 (95% CI: 0.93-1.08) per 0.75 ppm 

increase in 8-h CO, respectively. While the majority of studies restrict the analyses to term births as a 

method of controlling for gestational age, it is important to note that the Sydney study used all births 

and controlled for gestational age in the birth weight analyses and SGA was derived for each 

gestational age group. 

January 2010 5-55 
Of all studies reviewed, only two did not find an association between maternal exposure to CO 

and birth weight variables. In northern Nevada, Chen and colleagues (2002, 024945) examined CO, 

PM10, and O3 exposures among a cohort of 39,338 term births (37- to 44-wk gestation) between 1991 

and 1999 and found no association between CO exposure during the entire pregnancy (and each 

trimester) and a reduction in birth weigh or an increased risk of LBW. For a 0.75 ppm increase in 8-h 

CO concentration averaged over the entire pregnancy, there was a reduction in birth weight of 6 g; 

however it failed to reach statistical significance. Exposures for this study were based on data from 

all monitoring sites across Washoe County, Nevada. 

In a retrospective cohort study among 92,288 singleton term births (37- to 44-wk gestation) in 

Taipei and Kaoshiung, Taiwan, between 1995 and 1997, maternal exposures to CO, SO2, O3, NO2, and PM10 in each trimester of pregnancy were examined, and only SO2 during the third trimester 

showed evidence of contributing to LBW. Exposure assessment was based on data from the monitor 

closest to the centroid of the mother’s residential district, and the final analyses included only those 

mothers whose district centroid was within 3 km of a monitor. CO exposures were grouped into low 

(~1.1 ppm), medium (~1.2-15.0 ppm), and high (>15.0 ppm) and when compared to the lowest 

exposure group, the odds ratio for LBW in the highest exposure group was 0.90 (95% CI: 0.75-1.09) 

for the first trimester, 1.00 (95% CI: 0.82-1.22) for the second trimester, and 0.86 (95% CI: 0.71-

1.03) for the third trimester (Lin et al., 2004, 089827). 

Table 5-13 provides a brief overview of the birth weight studies. In summary, there is evidence 

of ambient CO during pregnancy having a negative effect on fetal growth. From the reviewed studies 

Figure 5-10 shows the change in birth weight (grams), Figure 5-11 shows the effect estimates for 

LBW, and Figure 5-12 shows the effect estimates for SGA. In general the reported reductions in 

birth weight are small (~10-20g). It is difficult to conclude whether CO is related to a small change 

in birth weight in all births across the population or a marked effect in some subset of births. 

Furthermore, there is a large degree of inconsistency across these studies. This may be due to several 

factors such as inconsistent exposure assessment and statistical methods employed, different CO 

concentrations, and/or different demographics of the birth cohorts analyzed. The main inconsistency 

among these findings is the gestational timing of the CO effect. Although the majority of studies 

reported significant effects during either the first or third trimester, other studies failed to find a 

significant effect during these periods. Several studies found an association with exposure during the 

entire pregnancy, providing evidence for a possible accumulative effect; however, these results are 

inconclusive and may be the result of correlated exposure periods. 

Several studies examined various combinations of birth weight, LBW, and SGA/IUGR, and 

inconsistent results are reported across these metrics. For example, several studies reported an 

association between maternal exposure to CO and decreased birth weight, yet no increase in risk of 

LBW or SGA. However, a measurable change, even if only a small one, at the population level is 

different than an effect observed for a subset of susceptible births which may increase 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 in some subset of births. 

January 2010 5-56 
Study Location Exposure 

 Period 

Exposure 

 Indicator Effect Estimate (95% CI) 

Bell et al. (2007, 091059) CT & MA, US Entire pregnancy County wide 

Salam et al. (2005, 087885) California, US First trimester ZIP code level 

Salam et al. (2005, 087885) California, US Second trimester ZIP code level 

Salam et al. (2005, 087885) California, US Third trimester ZIP code level 

Salam et al. (2005, 087885) California, US Entire pregnancy ZIP code level 

Chen et al. (2002, 024945) Northern NV, US First trimester County level 

Chen et al. (2002, 024945) Northern NV, US Second trimester County level 

Chen et al. (2002, 024945) Northern NV, US Third trimester County level 

Chen et al. (2002, 024945) Northern NV, US Entire pregnancy County level 

Mannes et al. (2005, 087895) Sydney, Australia First trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Second trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Third trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Last month City level 

Gouveia et al. (2004, 055613) Sao Paulo, Brazil First trimester City level 

Gouveia et al. (2004, 055613) Sao Paulo, Brazil Second trimester City level 

Gouveia et al. (2004, 055613) Sao Paulo, Brazil Third trimester City level 

Medeiros and Gouveia (2005, 089824) Sao Paulo, Brazil First trimester City level 

Medeiros and Gouveia (2005, 089824) Sao Paulo, Brazil Second trimester City level 

Medeiros and Gouveia (2005, 089824) Sao Paulo, Brazil Third trimester City level 

Change in birth weight (grams) 

Figure 5-10. Summary of change in birth weight (95% confidence intervals) associated with 

maternal exposure to ambient CO. Effect estimates have been standardized to a 

1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

Study Location Exposure 

Period 

Exposure 

Indicator 

Effect Estimate (95% CI) 

Bell et al. (2007, 091059) CT & MA, US Entire pregnancy County level 

Maisonet et al. (2001, 016624) Northeastern US First trimester City level 

Maisonet et al. (2001, 016624) Northeastern US Second trimester City level 

Maisonet et al. (2001, 016624) Northeastern US Third trimester City level 

Wilhelm & Ritz (2005, 088668) LA County, CA Third trimester ZIP code level 

Salam et al. (2005, 087885) California, US First trimester ZIP code level 

Salam et al. (2005, 087885) California, US Second trimester ZIP code level 

Salam et al. (2005, 087885) California, US Third trimester ZIP code level 

Salam et al. (2005, 087885) California, US Entire pregnancy ZIP code level 

Liu et al. (2003, 089548) Vancouver, Can First month City level 

Liu et al. (2003, 089548) Vancouver, Can Second month City level 

Ha et al. (2001, 019390) Seoul, Korea First trimester City level 

Ha et al. (2001, 019390) Seoul, Korea Third trimester City level 

Lee et al. (2003, 043202) Seoul, Korea First trimester City level 

Lee et al. (2003, 043202) Seoul, Korea Second trimester City level 

Lee et al. (2003, 043202) Seoul, Korea Third trimester City level 

Lee et al. (2003, 043202) Seoul, Korea Entire pregnancy City level 

 Odds Ratio 

Figure 5-11. Summary of effect estimates (95% confidence intervals) for LBW associated with 

maternal exposure to ambient CO. Effect estimates have been standardized to a 

1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

January 2010 5-57 
Study Location Exposure Period Exposure 

Indicator Effect Estimate (95% CI) 

Salam et al. (2005, 087885) California, US First trimester ZIP code level 

Salam et al. (2005, 087885) California, US Second trimester ZIP code level 

Salam et al. (2005, 087885) California, US Third trimester ZIP code level 

Salam et al. (2005, 087885) California, US Entire pregnancy ZIP code level 

Liu et al. (2003, 089548) Vancouver, Can First month City level 

Liu et al. (2003, 089548) Vancouver, Can First trimester City level 

Liu et al. (2003, 089548) Vancouver, Can Second trimester City level 

Liu et al. (2003, 089548) Vancouver, Can Third trimester City level 

Liu et al. (2003, 089548) Vancouver, Can Last month City level 

Liu et al. (2007, 090429) Multicity, Can First trimester City level 

Liu et al. (2007, 090429) Multicity, Can Second trimester City level 

Liu et al. (2007, 090429) Multicity, Can Third trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia First trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Second trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Third trimester City level 

Mannes et al. (2005, 087895) Sydney, Australia Last month City level 

 Odds Ratio 

Figure 5-12. Summary of effect estimates (95% confidence intervals) for SGA associated with 

maternal exposure to ambient CO. Effect estimates have been standardized to a 

1 ppm increase in ambient CO for 1-h max CO concentrations, 0.75 ppm for 8-h 

max CO concentrations, and 0.5 ppm for 24-h avg CO concentrations. 

The possibility exists that the small reductions in birth weight associated with maternal CO 

exposures are the result of residual confounding associated with other factors (e.g., other pollutants, 

temperature, and spatial/temporal variation in maternal factors) or other correlated pollutants. For 

example, in some studies the CO effect did not persist after controlling for other pollutants (Mannes 

et al., 2005, 087895; Parker et al., 2005, 087462; Wilhelm and Ritz, 2005, 088668), while in some 

studies it did persist (Bell et al., 2007, 091059; Gouveia et al., 2004, 055613; Liu et al., 2003, 

089548), and other studies did not report results from multipollutant models (Ha et al., 2001, 

019390; Lee et al., 2003, 043202; Maisonet et al., 2001, 016624; Medeiros and Gouveia, 2005, 

089824). In addition, various methods have been employed to control for seasonality and trends 

(e.g., month of birth, season of birth, year of birth, smoothed function of time), which may explain 

some of the mixed results. 

The two U.S. studies conducted in the Northeast compared results from analyses stratified by 

race. The earlier of these studies found an association between CO and LBW among AfricanAmericans but not among whites and Hispanics (Maisonet et al., 2001, 016624). In contrast, despite 

reporting an 11g reduction in birth weight among African-Americans and a 17 g reduction among 

whites, the more recent of the two studies found no significant difference between these reductions 

by race (Bell et al., 2007, 091059). Parker and colleagues (2005, 087462) also tested for interactions 

between race and found no significant association. 

January 2010 5-58 
Table 5-13. Brief summary of birth weight studies. 

Study Outcomes 

Examined 

Location 

Sample Size Mean CO (ppm) Exposure Assessment Exposure Windows 

UNITED STATES 

Ritz and Yu (1999, 086976) LBW Los Angeles, CA 

(n = 125, 573) 2.6 (6-9 a.m.) <2 mi of monitor Trimester 3 

Wilhelm and Ritz (2005, 

088668) LBW Los Angeles County, CA

(n = 136, 134) 1.4 (24 h) Varying distances from monitor Trimesters 1, 2, 3 

Salam et al. (2005, 087885) 

Birth weight 

LBW 

IUGR 

California, US 

(n = 3901) 1.8 (24 h) ZIP code level Entire pregnancy 

 Trimesters 1, 2, 3 

Parker et al. (2005, 087462) Birth weight 

SGA 

California, US 

(n = 18,247) 0.75 (8 h) <5 mi from monitor 

 Entire pregnancy 

 Trimesters 1, 2, 3 

 

Maisonet et al. (2001, 016624) LBW 

Boston, MA

Hartford, CT 

Philadelphia & 

Pittsburg, PA

Washington DC 

(n = 103,465) 

1.1 (24 h) City-wide avg Trimesters 1, 2, 3 

Bell et al. (2007, 091059) Birth weight 

LBW 

CT & MA, US 

(n = 358,504) 0.6 (24 h) County-level avg Entire pregnancy 

 Trimesters 1, 3 

Chen et al. (2002, 024945) Birth weight 

LBW 

Northern Nevada, US 

(n = 36,305) 0.9 (8 h) County level Trimesters 1, 2, 3 

CANADA 

Liu et al. (2003, 089548) 

LBW 

IUGR 

Vancouver, Can 

(n = 229,085) 1.0 (24 h) City-wide avg 

 Trimester 1 

Liu et al. (2007, 090429) IUGR 

Calgary, Edmonton, & 

Montreal, Can 

(n = 386,202) 

1.1 (24 h) City-wide avg Trimesters 1, 2, 3 

SOUTH AMERICA 

Gouveia et al. (2004, 055613) Birth weight 

LBW 

Sao Paulo, Brazil 

(n = 179,460) 3.7 (8 h) City-wide avg Trimesters 1, 2, 3 

Medeiros and Gouveia (2005, 

089824) 

Birth weight 

LBW 

Sao Paulo, Brazil 

(n = 311,735) 

3.0 (24 h) 

(Presented in 

graph) 

City-wide avg Trimesters 1, 2, 3 

AUSTRALIA/ASIA 

Ha et al. (2001, 019390) Birth weight 

LBW 

Seoul, Korea 

(n = 276,763) 1.2 (24 h) City-wide avg Trimesters 1 and 3 

Lee et al. (2003, 043202) LBW Seoul, Korea 

(n = 388,105) 1.2 (24 h) City-wide avg Entire pregnancy 

Trimesters 1, 2, 3 

Mannes et al. (2005, 087895) Birth weight 

SGA 

Sydney, Australia 

(n = 138,056) 0.8 (8 h) City-wide avg and 

<5 km from monitor 

Trimesters 1, 2, 3 

Last 30 days 

Lin et al. (2004, 089827) LBW 

Taipei, Kaoshiung, 

Taiwan 

(n = 92,288) 

Taipei 1.1, 

Kaoshiung 8.1 

<3 km of monitor Entire pregnancy 

Trimesters 1, 2, 3 

 

January 2010 5-59 
5.4.1.3. Congenital Anomalies 

Despite the growing evidence of an association between ambient air pollution and various 

adverse birth outcomes, few studies have investigated the effect of temporal variations in ambient air 

pollution on congenital anomalies. Heart defects have been the focus of the majority of these recent 

air pollution studies, given the higher prevalence than other congenital anomalies and associated 

mortality. Another study’s focus was cleft lip/palate. 

The earliest of these studies was conducted in southern California (Ritz et al., 2002, 023227). 

Exposure to ambient CO, NO2, O3 and PM10 during each of the first 3 mo of pregnancy was 

examined among births during 1987-1993. Maternal exposure estimates were based on data from the 

fixed site closest to the mother’s ZIP code area. When using a case-control design where cases were 

matched to 10 randomly selected controls, results showed that CO during the second month of 

pregnancy was associated with cardiac ventricular septal defects. The CO exposures were grouped 

by quartiles (25th = 1.14, 50th = 1.57, 75th = 2.39 ppm), and when compared to those in the lowest 

quartile exposure group (<1.14 ppm), the odds ratios for ventricular septal defects across the 3 higher 

exposure groups were 1.62 (95% CI: 1.05-2.48), 2.09 (95% CI: 1.19-3.67), and 2.95 

(95% CI: 1.44-6.05), respectively. In a multipollutant model a similar exposure-response pattern was 

exhibited across the quartiles with the highest quartile of exposure reaching statistical significance 

(OR: 2.84 [95% CI: 1.15-6.99]). The only other pollutant associated with a defect was O3 during the 

second month of pregnancy, which was associated with aortic artery and valve defects. 

Another study was conducted in Texas (Gilboa et al., 2005, 087892), where exposure to 

ambient CO, NO2, SO2, O3 and PM10 during the 3rd-8th week of gestation was examined among 

births between 1997 and 2000. Maternal exposure estimates were calculated by assigning the data 

from the closest monitor to the mother’s residential address. If data were missing on a particular day 

then data from the next closest site were used. The median distances from a monitor ranged from 8.6 

to 14.2 km, with maximum distances ranging from 35.5 to 54.5 km. The main results showed that 

CO was associated with multiple conotruncal defects and Tetralogy of Fallot. CO exposures were 

grouped into quartiles of much lower concentrations (25th = 0.4, 50th = 0.5, 75th = 0.7 ppm) than 

the California study (Ritz et al., 2002, 023227), and when compared to the lowest quartile, the odds 

ratios for conotruncal defects across the 3 CO exposure groups were 1.38 (95% CI: 0.97-1.97), 1.17 

(95% CI: 0.81-1.70), and 1.46 (1.03-2.08), respectively, without a significant test for trend (p for 

trend = 0.0870). A strong exposure-response pattern was exhibited across the quartiles of CO 

exposure for Tetralogy of Fallot (25th OR: 0.82 [95% CI: 0.52-1.62]; 50th OR: 1.27 

[95% CI: 0.75-2.14]; 75th OR: 2.04 [95% CI: 1.26-3.29]; p for trend = 0.0017). The only significant 

associations found with other pollutants were between PM10 and isolated atrial septal defects, and 

SO2 and ventricular septal defects. 

A study conducted in Atlanta, GA, investigated the associations between ambient air pollution 

concentrations during weeks 3-7 of pregnancy and risks of cardiovascular malformations among a 

cohort of pregnancies conceived during 1986-2003 (Strickland et al., 2009, 190324). The mean 24-h 

CO concentration during this period was 0.75 ppm. The authors did not report any statistically 

significant associations with ambient CO concentrations and cardiac malformations, though there 

were elevated risk ratios for ambient CO concentration and patent ductus arteriosus, Tetralogy of 

Fallot, and right ventricular outflow tract defect. These results remained consistently positive in five 

sensitivity analyses conducted and were closer to achieving statistical significance in these 

sensitivity analyses. The only statistically significant results were for the association between PM10

and patent ductus arteriosus. 

The last of these studies was a case-control study that examined maternal exposure to various 

air pollutants during the first 3 mo of pregnancy and the risk of delivering an infant with an oral 

cleft, namely cleft lip with or without palate (CL/P). Birth data from the Taiwanese birth registry 

from 2001 to 2003 was linked to air pollutant data that were spatially interpolated from all fixed 

monitoring sites across Taiwan. Based on data at the center of the townships or districts, exposure 

estimates for PM10, SO2, NOX, O3, and CO were averaged over each of the first 3 mo of pregnancy. 

The mean 8-h avg CO concentration was 0.69 ppm. Interestingly, of all the pollutants examined, 

only O3 during the first 2 mo of pregnancy was significantly associated with an increased risk of 

CL/P. In multipollutant models CO was not associated with CL/P (Hwang and Jaakkola, 2008, 

193794). 

The main results from the southern California study showed that CO was associated with an 

increased risk of ventricular septal defects, and this was exhibited by an exposure-response pattern 

across the quartiles of exposure; yet there was no indication that ambient CO concentration in Texas 

January 2010 5-60 
was associated with ventricular septal defects. Conversely, ambient CO concentration in Texas was 

associated with an increased risk of conotruncal defects; yet there was no indication that CO in 

southern California was associated with conotruncal defects. The Atlanta study (Strickland et al., 

2009, 190324) found positive, though not statistically significant associations for patent ductus 

arteriosus, Tetralogy of Fallot, and right ventricular outflow tract defect. The elevated risk ratio for 

Tetralogy of Fallot is consistent with the result observed in Texas (Gilboa et al., 2005, 087892). 

Interestingly, similar inconsistencies were also found for PM10 between these studies. For 

example, PM10 in Texas was associated with an increased risk of atrial septal defects and with patent 

ductus arteriosus in Atlanta, GA; yet there was no indication of such an effect in southern California 

where PM10 concentrations were markedly higher. 

The authors of the Texas study (Gilboa et al., 2005, 087892) provided little discussion toward 

the inconsistent results with the southern California study. One suggestion was the different CO 

concentrations across the studies with the 75th quartile in southern California being 2.39 ppm while 

in Texas it was much lower at 0.7 ppm. However, this suggests that different defects are associated 

with different concentrations of CO; yet it still does not explain why particular associations were 

reported in Texas and not southern California where concentrations were higher. Similarly, the 

authors of the Texas study (Gilboa et al., 2005, 087892) also suggested the inconsistency was due to 

different exposure periods. In Texas the exposures were averaged over the 3rd-8th wk while in 

southern California the exposures were averaged over the second month of pregnancy. However, 

there was no reason provided as to why this small difference in the examined exposure period would 

explain the inconsistent results. 

Overall, there is some evidence that maternal exposure to CO is associated with an increased 

risk of congenital anomalies, namely heart defects and cleft lip and palate. Further research is 

required to corroborate these findings. 

5.4.1.4. Neonatal and Postneonatal Mortality 

A handful of studies examined the effect of ambient air pollution on neonatal and postneonatal 

mortality, with the former the least studied. These studies varied somewhat with regard to the 

outcomes and exposure periods examined and study designs employed. 

Neonatal 

In Sao Paulo, Brazil, a time-series study examined daily counts of neonatal (up to 28 days 

after birth) deaths for the period 1998-2000 in association with concurrent-day exposure to SO2, CO, 

O3, and PM10. Moving averages from 27 days were examined. The mean city-wide CO concentration 

was 2.8 ppm, and there was no association between daily ambient CO and neonatal deaths. Despite 

CO being correlated with PM10 (r = 0.71) and SO2 (r = 0.55), only PM10 and SO2 were associated 

with an increase in the daily rate of neonatal deaths (Lin et al., 2004, 095787). 

In another study of neonatal death, Hajat et al. (2007, 093276) created a daily time-series of air 

pollution and all infant deaths between 1990 and 2000 in 10 major cities in England. The mean daily 

CO concentration across the 10 cites was 0.57 ppm. This study provided no evidence for an 

association between ambient CO concentration and neonatal deaths. 

Postneonatal 

Two studies in the U.S. examined the potential association between ambient CO and 

postneonatal (from 28 days to 1 yr after birth) mortality and inconsistent results were reported. These 

studies, however, varied somewhat in study design. 

The first of these studies employed a case-control design and examined all infant deaths 

during the first year of life among infants born alive during 1989-2000 within 16 km of a monitoring 

site within the South Coast Air Basin of California. Exposures for 2-wk, 1-mo, 2-mo, and 6-mo 

periods before death were linked to each individual death. Extensive analyses were conducted for 

all-cause infant deaths, respiratory causes of death, and sudden infant death syndrome (SIDS). Given 

the long time period of the data analyzed, in order to alleviate the confounding trends in infant 

mortality and CO levels, this study was able to match by year (Ritz et al., 2006, 089819). Ambient 

January 2010 5-61 
1-h max CO concentrations averaged over the 2 mo before death were associated with an 11% (OR: 

1.11 [95% CI: 1.06-1.16]) increase in risk of all-cause post-neonatal death (per 1 ppm increase) and 

a 19% (OR: 1.19 [95% CI: 1.10-1.28]) increase in risk of SIDS. In the multipollutant models 

(including PM10, NO2, O3) the positive CO mortality effect decreased by around 50% and was not 

statistically significant. Based on exposure from 2 wk before death, CO was associated with an 

increased risk of respiratory related postneonatal deaths occurring 28 days to 1 yr after birth (OR: 

1.14 [95% CI: 1.03-1.25] per 1 ppm increase) and 28 days to 3 mo after birth (OR: 1.20 

[95% CI: 1.02-1.40]); but no effect was observed for respiratory related deaths occurring 4-12 mo 

after birth. These results persisted in the multipollutant models, and exposure-response patterns were 

exhibited across the exposures groupings of 1.02 to <2.08, and ≥ 2.08 ppm. To control for gestational 

age and birth weight the analyses were stratified by “term/normal-weight infants” and “preterm 

and/or LBW infants.” When these two strata were analyzed, CO was associated with an increased 

risk of all-cause death and SIDS within both strata (ORs ranged from 1.12 to 1.46). However, these 

effects did not persist in multipollutant models (Ritz et al., 2006, 089819). 

Another study examined 3,583,495 births, including 6,639 postneonatal deaths occurring in 

96 counties throughout the U.S. (in counties with >250,000 residents) between 1989 and 2000 

(Woodruff et al., 2008, 098386). Only exposure during the first 2 mo of life was examined, and this 

was based on an average of CO concentrations recorded across all available monitors within the 

mother’s county of residence. In contrast to the other postnatal mortality study in California, CO 

averaged over the first 2 mo of life was not associated with all-cause death (OR: 1.01 

[95% CI: 0.94-1.09] per 0.5 ppm increase in 24-h CO concentration), or with respiratory related 

deaths (OR: 1.08 [95% CI: 0.91-1.54] per 0.5 ppm increase in 24-h CO concentration), SIDS (OR 

0.85 [95% CI: 0.70-1.04] per 0.5 ppm increase in 24-h CO concentration), or other causes of 

postneonatal mortality (OR: 1.03 [95% CI: 0.96-1.09] per 0.5 ppm increase in 24-h CO 

concentration). These null findings may be due to higher error of the exposure assessment at the 

county level as opposed to using data from monitors within close proximity to the residence. 

In a study that included 10 major cities in England, Hajat et al. (2007, 093276) created a daily 

time-series of air pollution and all infant deaths between 1990 and 2000. While there was no 

evidence for an association with neonatal deaths and ambient CO concentrations, there was a strong 

adverse effect of CO in postneonatal deaths, although the confidence intervals were wide due to a 

small sample size (RR 1.09, 95% CI: 0.94-1.25). 

The only other postnatal mortality studies have been conducted throughout Asia. Two identical 

studies in Taiwan failed to find an association between daily counts of postneonatal deaths and 

ambient air pollutants, including CO. The data analyzed were from the cities of Taipei (Yang et al., 

2006, 090760) and Kaohsiung (Tsai et al., 2006, 090709), with ambient CO concentrations being 

1.6 ppm and 0.8 ppm, respectively. Both studies examined deaths for the period 1994-2000 and 

employed a case-crossover design that compared air pollution levels 1 wk before and after each 

infant’s death. 

Similarly, another study in South Korea examined postneonatal mortality for the period 

1995-1999, using a time-series design. Same-day CO was not associated with all-cause death (RR: 

1.02 [95% CI: 0.97-1.06] per 0.5 ppm increase). However, same-day CO was associated with 

postneonatal mortality when the analyses were restricted to respiratory mortality (RR: 1.33 

[95% CI: 1.01-1.76] per 0.5 ppm increase) (Ha et al., 2003, 042552). An additional study examined 

the relationship between air pollution and postneonatal mortality for all causes in Seoul, Korea. This 

study used both case-crossover and time-series analyses for all firstborn infants during 1999-2003. 

The mean 8-h max CO concentration during this time period was 1.01 ppm. The association between 

ambient CO concentration and postneonatal mortality was the strongest in magnitude for CO when 

compared to the other criteria pollutants, though the confidence intervals were wide (RR: 1.02 

[95% CI: 0.87-1.20] for case-crossover analysis; RR: 1.23 [1.06-1.44] for time-series analysis per 

0.75 ppm increase in 8-h max CO concentration). 

In general, the inconsistent exposure periods examined among these studies restricts direct 

comparison and interpretation. Nevertheless, there is limited evidence that CO is associated with an 

increased risk of infant mortality during the postneonatal period. The exposure periods examined 

varied from the same-day CO to lag periods up to a 6-mo period prior to birth, with one study 

alternatively exploring exposures averaged over the first 2 mo of life. Furthermore, given that birth 

weight and gestational age are strong predictors of infant mortality, in all of the reviewed studies 

these factors have not been considered at either the design or analysis stage. Hence, the link between 

fetal, neonatal, and postneonatal exposures, and the possible interaction that birth weight and 

January 2010 5-62 
gestational age may have on the results yielded from these examined exposure periods needs further 

attention within this field of research. 

5.4.1.5.

5.4.2. 

5.4.2.1.

Summary of Epidemiologic Studies of Birth Outcomes and Developmental 

Effects 

There is some evidence that CO during early pregnancy (e.g., first month and first trimester) is 

associated with an increased risk of PTB. Additionally, there is evidence of ambient CO during 

pregnancy having a negative effect on fetal growth. In general, the reviewed studies (Figure 5-10

through Figure 5-12) reported small reductions in birth weight (~10-20 g). Although the majority of 

studies reported significant effects during either the first or third trimester, other studies failed to find 

a significant effect during these periods. Several studies examined various combinations of birth 

weight, LBW, and SGA/IUGR, and inconsistent results are reported across these metrics. For 

example, six studies reported an association between maternal exposure to CO and decreased birth 

weight, yet the decrease in birth weight did not translate to an increased risk of LBW or SGA. 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, which may increase 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 in some subset of births. 

Three studies examined the effects of CO on cardiac birth defects and 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). In general, there is 

limited evidence that CO is associated with an increased risk of infant mortality during the 

postneonatal period. 

Toxicological Studies of Birth Outcomes and Developmental 

Effects 

The brief overview of the reproductive and development toxicology of CO that follows is not 

limited to the past 10 yr as are other areas discussed in this document. This is because reproductive 

and developmental toxicology endpoints have not been covered in previous CO AQCDs. Effects of 

both exogenous CO exposure and endogenous production of CO are discussed since exposure to 

exogenous CO could possibly alter pathways normally regulated by endogenous CO production. 

This document details how in utero or perinatal CO exposure in pregnant dams or pups affects 

outcomes in the offspring, including postnatal mortality, skeletal development, the ability of the 

developing fetus to tolerate maternal dietary manipulation, behavioral outcomes, neurotransmitters, 

brain development, the auditory system, myocardial development, and immune system development. 

Similarly, endogenous CO is discussed in relation to pregnancy maintenance, vascular tone during 

gestation, the placenta, the ovaries, the anterior pituitary axis, and lactation. Together, this 

toxicological summary documents the importance of CO in reproductive and developmental 

toxicology in laboratory animal models. 

Birth Outcomes 

Decreased Birth Weight 

Multiple reports have been published associating CO exposure in laboratory animals and 

decrements in birth weight (90-600 ppm); some of these studies also noted reduced growth evident 

in the prenatal period (65-500 ppm CO). Significant decreases in fetal body weight at GD21 after 

21 days of continuous CO exposure (125, 250, or 500 ppm) in pregnant Wistar rats have been 

reported (Prigge and Hochrainer, 1977, 012326). This decrease was not found in rats exposed to 

60 ppm CO. Penney et al. (1983, 011385) exposed pregnant rats to CO (200 ppm) for the final 

17 days of prenatal development and also found significant decreases in near-term fetal rat weight at 

GD20-GD21; gestation in rats is ~ 22 days. Penney et al.(1982, 011387) continued to find decreased 

January 2010 5-63 
body weight to PND210 after postnatal CO exposure (500 ppm, PND1-PND32) and to a larger 

extent in male pups when compared to female pups. Singh et al. (1984, 011409; 1993, 013892) 

found significant decreases in fetal weight in gestationally CO-exposed mouse pups (65, 125, 250 or 

500 ppm) in two studies. Near-term fetal body weight was decreased at GD18 in mice exposed from 

GD7-GD18 to 125, 250, and 500 ppm CO but not 65 ppm CO (Singh and Scott, 1984, 011409). 

However, a second study found decreased fetal weight at GD18 with all CO exposures (65-500 ppm) 

from GD8-GD18 (Singh et al., 1993, 013892). 

A number of studies have found decreases in birth weight after CO exposure. A decrease in 

body weight at birth was seen in neonates of pregnant rats exposed to 157, 166, and 200 ppm CO 

over GD6-GD19 (Penney et al., 1983, 011385). Singh (2006, 190512) showed decreases in birth 

weight of mouse pups gestationally exposed for 6 h/day for the first 2 wk of pregnancy to 125 ppm 

but not 65 ppm CO. Carmines and Rajendran (2008, 188440) exposed Sprague Dawley rats to 

~600 ppm CO (dam COHb 30%) via nose-only inhalation (levels similar to those seen in cigarette 

smoke) during GD6-GD19 of gestation for 2 h/day and found significant decreases in birth weight 

(0.5 g or 13%) of exposed pups versus controls. Maternal body weight was unchanged through 

gestation, but corrected terminal body weight (body weight minus uterine weight) was significantly 

elevated in CO-exposed dams at term, indicating a decrease in uterine weight. Other studies have not 

found decreases in birth weight after gestational CO exposure (Carratu et al., 2000, 015839; Mereu 

et al., 2000, 193838). 

Other animal models have been used to examine decreased birth weight resulting from CO 

exposure. Astrup et al. (1972, 011121) found significant decreases (11 and 20%, respectively) in 

birth weight of rabbits exposed to either 90 or 180 ppm CO continuously over the duration of 

gestation. Tolcos et al. (2000, 015997) found significant decreases in body, brain, and liver weights, 

and crown-to-rump length in guinea pig fetuses after exposure to 200 ppm CO for 10h/day from 

GD23-GD25 until GD61-GD63, at which time the fetuses were collected (term ranges from GD68 to 

GD72). In other studies, there was no significant differences in birth weight of guinea pig pups after 

a similar exposure (200 ppm from GD23-GD25 to term, fetal and maternal COHb levels of 13% and 

8.5%, respectively) (McGregor et al., 1998, 085342; Tolcos et al., 2000, 010468) or in Long Evans 

rats (150 ppm CO continuous exposure over all of gestation) (Fechter and Annau, 1977, 010688). 

Fetal mouse weight was significantly greater than control in the 7 h/day exposures and significantly 

less than control animals in the 24 h/day (250 ppm CO, GD6-GD15) exposure groups, with 

corresponding significant differences in crown-to-rump length in the two groups (Schwetz et al., 

1979, 011855). However, animals that showed no decrement in birth weight were significantly 

smaller at PND4 compared to control guinea pigs (McGregor et al., 1998, 085342), with dam and 

fetal COHb levels of 13% and 8.5%, respectively, during pregnancy. 

Pregnancy Loss and Perinatal Death 

Two studies have provided evidence for CO-induced pregnancy loss and perinatal death at CO 

concentrations between 90 and 250 ppm. Schwetz et al. (1979, 011855) exposed CF-1 mice and New 

Zealand rabbits to 250 ppm CO over GD6-GD15 (mice) or GD6-GD18 (rabbits) for either 7 h/day or 

24 h/day, yielding 4 exposure paradigms. The fetuses were then collected at the termination of 

exposure, near term. Maternal COHb in the 7 h/day exposure groups was approximately 10-15% 

COHb in rabbits and mice; COHb was not followed in the 24-h exposure groups. The mice exposed 

to CO for 7 h/day but not 24 h/day had a significant increase in the number of resorbed pups. Rabbits 

were less affected by CO exposure, manifesting no significant perinatal death or pregnancy loss. 

Astrup et al. (1972, 011121) studied the effect of CO on fetal development after continuous CO 

exposure (90 or 180 ppm CO, COHb 8-9% and 16-18%, respectively) over the duration of gestation 

in rabbits. In the immediate neonatal period, 24 h postpartum, 35% (180 ppm) and 9.9% (90 ppm) of 

CO-exposed animals died. In the postpartum period after the first 24 h and extending out to PND21, 

90 ppm CO-exposed pups experienced 25% mortality versus 13% in controls; there was no 

difference from control at the 80 ppm CO exposure level. Gestation length was unchanged with CO 

exposure. Conversely, Fechter and Annau (1977, 010688) exposed Long Evans rats in utero to 

150 ppm CO continuously through gestation (dam COHb 15%) and saw no effects of CO on litter 

mortality at PND1. 

January 2010 5-64 
Effect of Maternal Diet 

As mentioned above, CO induced offspring mortality after prenatal exposure. Alterations in 

maternal dietary protein and zinc further altered offspring mortality and teratogenicity caused by CO 

(65-500 ppm). 

Maternal Protein Intake and Neonatal Mouse Mortality and Teratogenicity

Pregnant CD-1 mice were exposed intermittently (6 h/day for first 2 wk of pregnancy) to CO 

(0, 65, or 125 ppm) in combination with protein modified diets (27% [supplemental protein], 16% 

[control], 8% [low], or 4% [very low protein]) to assess the role of dietary protein in modulating CO 

effects on neonatal mortality at 1 wk of age (Singh, 2006, 190512). Litter size was not affected by 

CO exposure. Pup weight was inversely related to CO exposure and directly related to dam diet 

protein content during pregnancy. Pup mortality at birth was directly related to CO exposure in 

certain protein groups (supplemental, and 4% protein) and inversely related to the dam’s dietary 

protein content. At 1 wk of age, pup mortality was significantly increased by CO exposure as well as 

dietary protein restriction; all pups in the 4% protein diet died by 1 wk of age. CO exposure (65 ppm 

only) combined with a normal protein diet (16%) and CO exposure (65 and 125 ppm) with a 

supplemental protein diet (27%) significantly increased pup mortality at 1 wk versus control air pups 

(0 ppm CO). Contrary to other findings, low protein diet (8%) combined with CO (125 ppm) led to a 

slight yet significant decrease in pup mortality at 1 wk of age versus control (0 ppm CO). In 

summary, these data show that in utero CO exposure induced increased neonatal mouse deaths at 

1 wk in supplemental protein and normal protein diet exposure groups and increased perinatal 

mortality when combined with supplemental or restricted protein. 

The role of diet as a contributor to teratogenicity of CO (0, 65, 125, or 250 ppm CO) in CD-1 

mice given various protein diets (4, 8, 16, or 27% protein) during pregnancy was explored by Singh 

et al. (1993, 013892). Timed-pregnant CD-1 mice were exposed continuously to CO from 

GD8-GD18, at which point animals were sacrificed and fetuses collected. Work by this group has 

shown that low protein diets plus CO exposure act in an additive fashion to increase placental COHb 

in mice (Singh, 2003, 053624; Singh et al., 1992, 013759). As expected, all levels of CO and the 

lowest protein diet (4 or 8% protein) given to the dams during gestation resulted in significantly 

decreased near-term weight of normal fetuses at GD18. CO exposure did not produce maternal 

toxicity except for a significant decrease in maternal weight at GD18 with 4 and 8% protein diets 

versus control diet in non-CO-exposed animals. Dam dietary protein levels were inversely related to 

gross fetal malformations including jaw changes. All concentrations of CO exposure within each 

maternal dietary protein level significantly increased the percentage of litters with malformations in 

a dose-dependent manner. Skeletal malformations were present in offspring, with the percent of 

litters affected inversely related to dietary protein levels. CO exposure concomitant with a low 

protein diet increased the percent of skeletal malformations in offspring. The percent of dead, 

resorbed, or grossly malformed fetuses was directly related to CO concentration and inversely 

related to maternal dietary protein levels. CO and maternal dietary protein restriction had a 

synergistic effect on mouse offspring mortality and an additive effect on malformations. 

Maternal Zinc and Protein Intake and Neonatal Mortality and Teratogenicity

Singh (2003, 053624) explored how teratogenicity and fetal mortality were affected by zinc 

(Zn) modulation in CO-exposed (500 ppm from GD8-GD18) pregnant dams (CD-1 mouse) given 

protein-insufficient diets. CO exposure in low-protein conditions (9% protein) decreased the mean 

implants per litter as compared to air exposure. CO exposure also increased the near-term fetal 

mortality over all groups, and to a larger extent in the low-protein groups, both Zn normal (57% 

versus 6% mortality) and Zn deficient groups (86.6% versus 70.9% mortality). Under low-protein 

conditions, CO exposure increased the incidence of malformations (9.4% versus 0%) when Zn levels 

were normal and increased the incidence of gastroschisis (5% versus 0%) when Zn levels were low. 

Joint protein and Zn deficiency led to 60% of litters with gastroschisis. Conversely, CO exposure 

under Zn deficiency decreased the incidence of other malformations such as exencephaly, jaw, 

syndactyly, and tail malformations. 

Further studies by Neggers and Singh (2006, 193964) only partially confirmed these findings. 

As before, diets deficient in both Zn and protein had significant detrimental influence on both fetal 

malformations and mortality. Exposure to 500 ppm CO increased fetal mortality and malformation 

January 2010 5-65 
rates under deficient protein (9%) and supplemental Zn (3.3 g/kg diet) conditions; however, CO had 

a negligible effect on these endpoints under deficient protein and deficient or normal Zn conditions. 

Role of Endogenous CO 

CO is produced endogenously from heme protein catabolism by heme oxygenases, HO-1, 

HO-2, and HO-3. CO has recently been recognized as a second messenger signaling molecule, 

similar to NO, with a number of normal physiological roles in the body. Some of these roles are 

played in maintaining pregnancy, controlling vascular tone, regulating hormone balance, and 

sustaining normal ovarian follicular maturation. These areas could be potential areas of interaction of 

exogenous CO. 

Pregnancy Maintenance 

HO-1 is known to protect organs from rejection (Kotsch et al., 2006, 193899) and thus, HO 

may also protect the developing fetus from rejection by the non-self maternal immune system. 

Idiopathic spontaneous abortions are more frequent in women with HO-1 polymorphisms (GT)n 

microsatellite polymorphisms associated with altered HO-1 transcription in their genome (Denschlag 

et al., 2004, 193894). Similarly, administering HO-inhibitors to pregnant rodents induced total litter 

loss, possibly due to vasoconstriction and associated ischemia of the placental vascular bed 

(Alexandreanu and Lawson, 2002, 192373). Also, mice overexpressing HO-1 had a significantly 

decreased rate of spontaneous abortion (Zenclussen et al., 2006, 193873). Various pathologies of 

pregnancy, including IUGR and pre-eclampsia, are associated with significant decreases in placental 

HO activity (Denschlag et al., 2004, 193894; McLaughlin et al., 2003, 193827). Oxygenation is 

important in early pregnancy and triggers trophoblast invasion of the spiral arteries (Kingdom and 

Kaufmann, 1997, 193897). Women living at high altitude have an increased risk of adverse 

pregnancy outcomes versus women living at lower altitudes (Zamudio et al., 1995, 193908). Also, 

women living at high altitude, women with pre-eclampsia, or women who had pregnancies with fetal 

growth restrictions (FGR) produced term placenta with significant decreases in HO-2 versus women 

living at lower altitude with uncomplicated pregnancies (Barber et al., 2001, 193891; Lyall et al., 

2000, 193902). Thus, the HO/CO system is crucial for the developing fetus, helps in maintaining 

pregnancy, and plays a role in spontaneous abortions. 

Vascular Control 

During pregnancy, there is increased blood volume without a concurrent increase in systemic 

BP, which is accomplished by a decrease in total peripheral vascular resistance (Zhao et al., 2008, 

193883). CO through the production of soluble guanylate cyclase is able to stimulate the relaxation 

of vascular smooth muscle (Villamor et al., 2000, 015838) and relaxation of pregnant rat tail artery 

and aortic rings (Longo et al., 1999, 011548). Further, the administration of the HO inhibitor SnMP 

increased maternal BP (systolic, diastolic, and mean arterial pressure) and significantly increased 

uterine artery blood flow velocity during pregnancy in mice (Zhao et al., 2008, 193883). Zhao et al. 

also showed pregnancy induced increased total body CO exhalation and that this increased CO 

production could be significantly decreased by SnMP administration. Abdominal aortas (AA) of 

pregnant dams are significantly dilated with pregnancy, and SnMP treatment leads to AA 

vasoconstriction to levels similar to nonpregnant mice. Isolated human placenta exposed to solutions 

containing CO demonstrated a concentration-dependent decrease in perfusion pressure (Bainbridge 

et al., 2002, 043161), further demonstrating the role of CO in maintaining basal vasculature tone. 

However, the addition of exogenous CO to isolated human and rat uterine tissue during pregnancy 

failed to induce relaxation and quiet the spontaneous contractility of rat or human myometrium 

(uterine smooth muscle)(Longo et al., 1999, 011548). CO is not able to relax all types of vascular 

smooth muscle (Brian et al., 1994, 076283), and pregnancy appears to modulate the response of 

tissues to CO (Katoue et al., 2005, 193896). Thus, it appears that the increased CO production during 

pregnancy may partially account for the decreased peripheral vascular resistance seen in pregnancy 

that prevents the increased blood volume of pregnancy from affecting BP. 

January 2010 5-66 
Hormone Regulation 

Endogenous CO has been shown to regulate neuroendocrine functions. Disruption of normal 

CO signaling causes changes in the cycles of a number of hormones involved in pregnancy. HO 

inhibition in rats significantly decreased ovarian production of gonadotrophin-induced 

androstenedione and progesterone without affecting estradiol levels (Alexandreanu and Lawson, 

2002, 192373). However, treatment with the HO-inducer, hemin, caused androstenedione and 

estradiol production from rat ovaries in vitro. CO also has been shown to have a stimulatory effect 

on gonadotropin-releasing hormone (GnRH) release from rat hypothalamic explants in vitro (Lamar 

et al., 1996, 078819), while in vivo CO appears not to influence GnRH secretion (Kohsaka et al., 

1999, 191000). HO-1 induction and HO concentration have been shown to be regulated by estrogen 

in the rat uterus (Cella et al., 2006, 193240) during pregnancy and in nongravid rats. This agrees 

with work by Tschugguel et al. (2001, 193785) in which CO was generated by primary endothelial 

cells from human umbilical veins and uterine arteries after exogenous 17-β estradiol administration. 

HO inhibition by CrMP decreased time in estrous in a dose-dependent manner (Alexandreanu and 

Lawson, 2002, 192373). 

HO-1 and HO-2 are expressed in rat anterior pituitary, and the secretion of gonadotropins and 

prolactin is affected by HO-inhibitor and HO-substrate administration (Alexandreanu and Lawson, 

2003, 193871). The estrogen-induced afternoon surge of luteinizing hormone (LH) was advanced 

forward in time by HO inhibition, and this advance could be reversed by concomitant administration 

of hemin. The serum follicle stimulating hormone (FSH) surge was unaffected by HO inhibition or 

hemin, but in vitro treatment of GnRH-stimulated pituitaries with hemin led to a significant increase 

in FSH release. The estrogen-dependent afternoon prolactin surge was inhibited or delayed by HO 

inhibition and significantly decreased prolactin release. In vitro studies using pituitary explants 

showed that LH release was significantly increased by HO inhibition. HO inhibition also decreased 

litter weight gain during lactation, which the authors attributed to decreased maternal milk 

production or milk ejection problems as cross-fostered pups regained weight that was lost during 

nursing on HO-inhibited dams (Alexandreanu and Lawson, 2002, 192373). The lactational effects 

seen in this model may be explained by changes in prolactin (Alexandreanu and Lawson, 2003, 

193871). It is possible that HO inhibition by CrMP may also inhibit NO production, a mechanism 

that is distinct from CO-dependent effects. 

Ovarian Follicular Atresia 

As a part of normal follicular maturation in the ovaries, the majority of follicles undergo 

atresia via apoptosis prior to ovulation. Harada et al. (2004, 193920) harvested porcine granulosa 

cells from ovaries and found that cells naturally undergoing atresia or cell death more strongly 

expressed HO-1 than did successful follicles. Addition of the HO-substrate hemin or the HOinhibitor Zn protoporphyrin IX (ZnPP IX) significantly induced or inhibited granulosa cell apoptosis, 

respectively. In this porcine model, HO was able to augment granulosa cell apoptosis allowing for 

proper follicular maturation. 

Summary of Toxicological Studies on Birth Outcomes 

There is some evidence that CO exposure leads to altered birth outcomes, including decreased 

birth and near-term body weight, increased pregnancy loss and perinatal death, and increased 

malformations. These events occurred at levels as low as 65 ppm for fetal body weight decrements 

and 90 ppm for changes in birth weight and perinatal death. Pregnancy loss was seen after exposure 

to 250 ppm CO, whereas skeletal malformations were present after 180 ppm CO. Dietary protein and 

zinc modifications exacerbated these CO-induced effects on birth outcomes. Maternal protein 

restriction and CO had a synergistic effect on peri- and postnatal mortality and an additive effect on 

malformations. Dietary zinc alterations resulted in inconsistent changes to CO-induced 

malformations and fetal mortality. 

 Endogenous CO is recognized as a second messenger signaling molecule with normal 

physiological roles in maintaining pregnancy and for proper fetal and postnatal development. The 

endogenous HO/CO system is also involved in controlling vascular tone, follicular maturation, 

ovarian steroidogenesis, secretion of gonadotropin and prolactin by the anterior pituitary, lactation, 

January 2010 5-67 
and estrous cyclicity in rodent studies. These areas could be potential points of interaction of 

exogenous CO with endogenous HO/CO. 

5.4.2.2. Developmental Effects 

Congenital Abnormalities 

Studies by Schwetz et al. (1979, 011855) found that gestational CO exposure (250 ppm) in 

CF-1 mice for 7 or 24 h/day over GD6-GD15 resulted in minor fetal skeletal alterations in the form 

of extra lumbar ribs and spurs (dam gestational COHb 10-15% for 7h/day exposure, 24 h/day dam 

COHb not measured). Similarly exposed rabbits did not exhibit these changes. 

Astrup et al. (1972, 011121) studied the effect of CO exposure on fetal rabbit development via 

continuous CO exposure (90 or 180 ppm with gestational dam COHb of 9 and 17%, respectively) 

over the duration of gestation. Three pups in the 180 ppm CO group (n = 123) had deformities in 

their extremities at birth, whereas no control and no 90 ppm CO-exposed animals manifested with 

this malformation. 

Further skeletal malformations were seen after gestational CO exposure in mice as described 

above (“Effect of Maternal Diet”) (Singh et al., 1993, 013892). Briefly, pregnant CD-1 mice were 

exposed intermittently to CO (65-250 ppm; GD8-GD18) in combination with protein modified diets 

(27% [supplemental protein], 16% [control], 8% [low], or 4% [very low protein]) to assess the role 

of dietary protein in modulating CO effects on neonates at 1 wk of age. Maternal dietary protein 

restriction additively compounded the CO-induced skeletal malformations. Further, dietary 

restriction in Zn and protein led to increased teratogenicity, specifically increased incidence of 

gastroschisis (Singh, 2003, 053624). Conversely, Carmines and Rajendran (2008, 188440) did not 

find evidence of external malformations (teratogenicity) in rats after exposure to ~600 ppm CO from 

GD6-GD19. 

CNS Developmental Effects 

Behavioral 

Investigators have used animal models to study the effects of moderate CO exposure 

(65-150 ppm) during gestation on behavioral outcomes after birth, including active avoidance, 

learning and memory, homing, and motor activity. These studies generally found decrements in 

behavior in early life after in utero exposure to CO concentrations >125 ppm and in some cases as 

low as 65 ppm. Table 5-14 shows results of behavioral response studies with CO exposure 

≤ 150 ppm. 

January 2010 5-68 
Table 5-14. Behavioral responses. 

Study Model System CO Exposure Response Notes 

BEHAVIORAL RESPONSES 

De Salvia et al. (1995, 

079441) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

Impaired acquisition (3 and 18 mo) and reacquisition (18 mo) of 

avoidance behavior at 150 ppm, not 75 ppm 

Mactutus and Fechter 

(1985, 011536) Rats 

150 ppm 

continuous 

GD0-GD20 

Delayed acquisition of active avoidance (PND120) and disrupted 

retention (PND360) COHb 15.6 ± 1.1% 

Di Giovanni et al. 

(1993, 013822) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

CO (150 ppm) reduced the minimum frequency of ultrasonic calls as 

well as decreased responsiveness to a challenge dose of diazepam. 

There was no change in locomotion; however, CO impaired learning 

in a two-way active avoidance task. 

Mactutus and Fechter 

(1984, 011355) Rats 150 ppm Acquisition did not improve with age/maturation, failure to learn; 

impaired reacquisition (PND31), failure to retain COHb 15% 

Giustino et al. (1999, 

011538) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

Decreased exploration, habituation, nonspatial working memory 

COHb: 1.6 ± 0.1% 

(0 ppm); 7.36 ± 0.2% 

(75 ppm); 16.1 ± 0.9% 

(150 ppm) 

Zhuo et al. (1993, 

013905) 

Mouse 

hippocampal brain 

sections 

ZnPPIX (HO 

inhibitor) and 

0.1-1.0 μM CO 

HO inhibition blocked long-term potentiation and CO evoked 

synaptic potentials and long-term enhancement 

Stevens and Wang 

(1993, 188458) 

Mouse and rat 

hippocampal brain 

slices 

ZnPPIX (5-15 μM) HO inhibition blocked long-term potentiation but not long-term 

depression. 

Mereu (2000, 193838) Rat hippocampal 

brain sections 

150 ppm 

GD0-GD20 Impaired long-term potentiation maintenance 

Fechter and Annau 

(1980, 011295) Rats 

150 ppm 

continuous 

GD0-GD20 

Delayed homing behavior and poor reflexive response 

Fechter and Annau 

(1977, 010688) Rats 

150 ppm 

continuous 

GD0-GD20 

Decreased locomotor activity at PND1, PND4, and PND14, but not 

PND21 COHb 15% 

Singh (1986, 012827) Mice 

65 and 125 ppm 

continuous 

GD7-GD18 

Impaired aerial righting score at PND14 (65 and 125 ppm), impaired 

negative geotaxis at PND10 and righting reflex on PND1 (125 ppm) 

Active Avoidance Behavior. To assess behavioral changes after in utero exposure, pregnant Wistar rats 

were exposed to CO (0, 75, or 150 ppm) continuously over GD0-GD20 (De Salvia et al., 1995, 

079441). Male pups from exposed dams were evaluated for active avoidance behavior (mild shock 

avoidance) during acquisition and reacquisition. This work was designed to expand on the studies of 

Mactutus and Fechter (1985, 011536), who showed delayed acquisition (120 days of age) of an 

active avoidance task and disruption of retention at a later test date (360 days) after continuous in 

utero CO exposure (150 ppm CO, dam COHb concentrations of 15.6 ± 1.1%), and to determine if 

these behavioral changes were permanent. De Salvia et al. (1995, 079441) found there were no 

significant behavioral impairments following exposure to 75 ppm CO. However, animals exposed to 

the 150 ppm in utero had significantly impaired acquisition (at 3 and 18 mo of age) and reacquisition 

(at 18 mo of age) of conditioned avoidance behavior. This impaired learning was also seen in 

gestationally CO (150 ppm, trend seen at 75 ppm) exposed rats at PND90 (Di Giovanni et al., 1993, 

013822). The authors speculated that this CO-dependent behavioral change may be mediated 

through neurotransmitter signaling, specifically changes in dopamine in the neostriatum or nucleus 

accumbens. These studies demonstrate that moderate CO exposure in utero can lead to permanent 

behavioral changes in male offspring. 

Mactutus and Fechter (1984, 011355) also found that acquisition in a two-way conditioned 

avoidance test (flashing light warnings followed by mild footshock) failed to improve with age of in 

January 2010 5-69 
utero CO-exposed (150 ppm, dam COHb 15%) Long Evans rats (male and female offspring) in 

contrast to air-exposed controls who improved with age/maturation, indicating a failure in the 

associative process of learning. They also found impairments in reacquisition performance, an index 

of retention, in PND31 rats that had received continuous in utero CO exposure. Overall, prenatal CO 

exposure (150 ppm, not 75 ppm) induced learning and memory deficits in male and female 

offspring. 

Habituation, Memory, and Learning. Giustino et al. (1999, 011538) exposed primiparious 

pregnant Wistar rats to CO (0, 75 or 150 ppm) by inhalation from GD0-GD20. Blood COHb 

concentrations (mean % ± SEM) on GD20 were reported (0 ppm: 1.6 ± 0.1; CO 75 ppm: 7.36 ± 0.2; 

CO 150 ppm: 16.1 ± 0.9). Male offspring at age 40 days were given two habituation trials. In the 

first trial (T1), two similar objects were presented. In the second trial (T2), one object from the first 

trial was presented as well as one novel object. Results were quantified three ways. Exploration 

activity was defined as the time exploring both objects during each trial. Global habituation was 

quantified as a comparison of the time spent exploring the two objects in T1 to the time spent 

exploring objects in T2. Discrimination between new and familiar objects was measured in T2 by 

contrasting the time spent exploring the familiar object to the time spent exploring the new object. 

These recognition sessions test for the preference that rats have for investigating novel objects in lieu 

of familiar objects and are a measurement of nonspatial working memory. The results of this study 

showed 40 day old animals that were gestationally exposed to CO (both 75 and 150 ppm) spent less 

time exploring novel objects when compared to control animals. Control rabbits habituated or 

learned after a second exposure to a previously explored object (T2<T1), but T2 and T1 were not 

significantly different with CO exposure (150 ppm). Results for rats exposed to 75 ppm were 

inconsistent in that significantly different exploratory times were found using one statistical method 

(Wilcoxon paired signed-rank test) and not found using another method (Kruskal-Wallis ANOVA). 

Finally, the decreased time spent with a familiar object by control rats was not seen in CO-exposed 

animals (75 or 150 ppm). The authors speculated that the mesolimbic dopaminergic system may be 

responsible for these changes, possibly involving the nucleus accumbens. The human literature 

shows a possible connection with these CO-dependent rodent effects; infants whose mothers smoked 

during pregnancy manifest with habituation defects (Fried et al., 1998, 190210; Fried et al., 2003, 

190209). Nonetheless, CO is just one of many constituents of cigarette smoke. The results from 

these animal toxicology studies showed that in utero exposure to CO affects nonspatial working 

memory in young adult male rats. 

Studies have shown that endogenous and exogenous CO may be involved in the generation of 

the hippocampal long-term potentiation (LTP), which is believed to correlate with learning and 

memory (Hawkins et al., 1994, 076503; Mereu et al., 2000, 193838; Stevens and Wang, 1993, 

188458; Zhuo et al., 1993, 013905). It is possible that CO can act as a retrograde synaptic signaling 

messenger, allowing a signal to travel from a postsynaptic to presynaptic neuron. Treatment of 

mouse or rat hippocampal brain sections with ZnPPIX, an HO-inhibitor, blocked induction of the 

LTP but not long-term depression (Stevens and Wang, 1993, 188458; Zhuo et al., 1993, 013905). 

Exogenous CO exposure (0.1-1.0 μM) also evoked long-term enhancement and evoked synaptic 

potentials (Zhuo et al., 1993, 013905). Similarly, hippocampal slices from gestationally CO-exposed 

(150 ppm from GD0-20) Wistar rats exhibited an impaired ability to maintain LTP over time and a 

modest reduction in post-tetanic potentiation (Mereu et al., 2000, 193838). Conversely, other studies 

have found no correlation between CO and LTP using step-through, step-down, and water-maze tests 

(Bing et al., 1995, 079418; Toyoda et al., 1996, 079945). Thus, distinct types of learning may be 

differentially regulated by CO exposure, and endogenous CO, as modulated by HO-inhibitors, may 

manifest with different outcomes when compared to outcomes seen for exogenous CO. 

Homing and Locomotor Effects. Fechter and Annau (1977, 010688; 1980, 011295) exposed 

Long Evans rats in utero to 150 ppm CO continuously through gestation (dam COHb 15%) and saw 

significant effects of CO on pup locomotor activity measured across 10-min intervals for a 1-h 

period. CO-exposed pups showed consistently less activity than air-exposed controls through the 

preweaning window, with significantly reduced activity seen at PND1 and PND4 (both after 

subcutaneous L-DOPA administration to induce movement) and at PND14 but not at PND21. 

However, the PND14 rats only showed decreased activity after 30 min of testing. Di Giovanni et al. 

(1993, 013822) found that prenatal CO (75 and 150 ppm) did not significantly affect locomotor 

activity or D-amphetamine induced hyperactivity at PND14 or PND21, but the rats were only 

subjected to a 30-min session. This study may have overlooked the later window of possible 

decreased activity. 

January 2010 5-70 
Under analogous exposure conditions, Fechter and Annau (1980, 011295) found that the 

development of homing behavior, orientation by the rat toward its home cage, was significantly 

delayed in rats prenatally exposed to 150 ppm CO. Also, exposed offspring manifested with poorer 

than normal performance on the negative geotaxis test, a reflexive response that results in a 

directional movement with or against gravity. Similarly, continuous prenatal CO exposure (125 ppm, 

GD7-GD18) in CD-1 mice impaired negative geotaxis at PND10 (Singh, 1986, 012827). The 

standardization and use of geotaxis as a vestibular, motor, or postural metric in infant rodents has 

been debated in the literature (Kreider and Blumberg, 2005, 193944). 

Prenatal exposure to CO (125 ppm, GD7-GD18) significantly affected the righting reflex (the 

turning of an animal from its supine position to its feet) in exposed CD-1 mice on PND1. Also, the 

aerial righting score, or turning 180° and landing on the feet when dropped from the supine position 

at a height, was significantly decreased in pups exposed to CO in utero (65 and 125 ppm) at PND14 

(Singh, 1986, 012827). The same trend of impaired righting reflex was seen in gestationally CO 

(150 ppm) exposed rats (Fechter and Annau, 1980, 011295). These behavioral tests indicated 

neuromuscular, vestibular, or postural effects in the CO-exposed neonate. 

Conversely, no gross impairment of motor activity was found as measured by infrared 

movement monitoring in Wistar rats treated in utero (GD0-GD20) with 0, 75 or 100 ppm CO 

(Carratu et al., 2000, 015839). Monitoring was done at PND40 and PND90 and may have been too 

late to detect CO-dependent changes. Earlier studies by Fechter and Annau (1977, 010688) identified 

an early window of sensitivity for CO-dependent motor activity deficits of PND1-PND14, with 

recovery by PND21. 

Emotionality. In utero CO exposure caused subtle alterations in the ontogeny of emotionality 

measured by the ultrasonic vocalization emitted by rat pups removed from their nest. Prenatal CO 

exposure (150 ppm) caused a reduction in the minimum frequency of ultrasonic calls emitted by 

PND5 pups (Di Giovanni et al., 1993, 013822). The rate of calling, maximum frequency, and 

duration and sound pressure level were not affected by prenatal CO. However, the rate of calling and 

responsiveness to a challenge dose of diazepam was decreased by prenatal CO exposure. Pup 

vocalization is mediated by the GABAergic neuron function which is altered by CO exposure (see 

below). 

Neuronal 

Since behavioral changes have been caused by CO exposure, studies have investigated 

whether CO exposure results in changes to neuronal structures and electrical excitability. Moderate 

levels of CO (75 -150 ppm) decrease peripheral nervous system (PNS) myelination due to impaired 

sphingomyelin homeostasis and can reversibly delay the rate of ion channel development after 

gestational exposure. In utero CO exposure also results in irreversible changes in sodium equilibrium 

potential. Further details of these studies are given below in Table 5-15. 

January 2010 5-71 
Table 5-15. Neuronal responses. 

Study Model 

System CO Exposure Response Notes 

NEURONAL RESPONSES 

Carratu et al. (2000, 

015839) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

Decreased peripheral nerve fiber myelin sheath thickness 

COHb: 0 ppm (GD10: 0.97 ± 

0.02; GD20: 1.62 ± 0.1.), 

75 ppm (GD10: 7.20 ± 0.12; 

GD20: 7.43 ± 0.62), and 

150 ppm (GD10: 14.42 ± 0.52; 

GD20: 16.08 ± 0.88) 

Carratu et al. (2000, 

015935) Rats 

150 ppm 

continuous 

GD0-GD20 

Impaired sphingomyelin homeostasis by increasing sphingosine 

Carratu et al. (1993, 

013812) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

Produced partly reversible changes in membrane excitability through 

delayed inward current inactivation and decreased inward current 

reversal potential 

COHb: 15% at 150 ppm 

De Luca et al. (1996, 

080911) Rats 

75 and 150 ppm 

continuous 

GD0-GD20 

Delayed development of the ion channels responsible for passive and 

active membrane electrical properties of skeletal muscle 

Montagnani et al. (1996, 

080902) Rats 75 or 150 ppm 

GD0-GD20 

CO (150 ppm) increased the tetrodotoxin-inhibition of PNS-evoked 

vasoconstriction at PND5-7. CO exposure caused the relaxant effect by 

ACh to appear earlier and the contractile response to disappear earlier 

(vasodilator effects). 

Dyer et al. (1979, 

190994) Rats 150 ppm 

GD0-GD21 

Increased early components (P1-N1 and N1-P1) of the cortical flash 

evoked potential peak-to-peak amplitudes at PND65 in female rats Maternal COHb: 15% 

Peripheral Nerve Myelination. The effect of in utero exposure (GD0-GD20) to 0, 75 or 150 ppm 

CO on sciatic nerve myelination in male offspring was studied in Wistar rats (Carratu et al., 2000, 

015839). The dam CO blood concentration, expressed as % COHb, was determined for 0 ppm 

(GD10: 0.97 ± 0.02; GD20: 1.62 ± 0.1.), 75 ppm (GD10: 7.20 ± 0.12; GD20: 7.43 ± 0.62), and 

150 ppm (GD10: 14.42 ± 0.52; GD20: 16.08 ± 0.88). The myelin sheath thickness of the peripheral 

nerve fibers was significantly decreased in CO-exposed animals (75 and 150 ppm); however, axon 

diameter was not affected. As mentioned above, even though CO affected myelination, it did not 

significantly affect motor activity of CO-exposed mice at 40 and 90 days. It is possible that these 

deficits in PNS myelination are due to impaired sphingomyelin homeostasis. In utero exposure 

(GD0-GD20) of Wistar rats to CO (150 ppm) caused a twofold increase in sphingosine (SO) but not 

sphinganine (SA) in the sciatic nerve at 90 days of age (Carratu et al., 2000, 015935). SO is an 

intermediate in sphingolipid turnover and SA is an intermediate of de novo sphingolipid 

biosynthesis. Hypoxia has been shown to induce sphingomyelin changes which could lead to 

impaired myelination and motor activity decrements (Ueda et al., 1998, 195136; Yoshimura et al., 

1999, 195135). Prenatal CO exposure had no effect on brain SA or SO levels in male offspring at 

90 days of age. These results demonstrate prenatal CO exposure could interrupt sphingolipid 

homeostasis in the PNS but not CNS, causing a decrease in nerve myelination without changes in 

motor activity. 

Electrophysiological Changes. 

Gestational exposure of Wistar rats to continuous CO (75 or 150 ppm (15% COHb at 

150 ppm) yielded electrophysiological changes in the PNS (Carratu et al., 1993, 013812). Changes 

were noticeable in voltage- and time-dependent properties of sodium channels in the sciatic nerve 

after in utero CO exposure. Changes in sodium channel inactivation kinetics were reversible (present 

at PND40 and absent at PND270) but changes in the sodium equilibrium potential were irreversible. 

In utero CO exposure (150 ppm) also delayed the development of the resting chloride conductance 

(GCl) and resting potassium conductance (GK), with levels matching the control by PND80 and 

PND60, respectively (De Luca et al., 1996, 080911). CO exposure (75 and 150 ppm) also altered the 

pharmacological properties of the chloride channel and excitability parameters of skeletal muscle 

fibers. These changes in the nerve electrophysiological properties could account for increased 

January 2010 5-72 
tetrodotoxin-inhibition of the vasoconstriction evoked by the PNS in 5- to 7-day-old prenatally 

exposed pups (Montagnani et al., 1996, 080902). Finally, gestational CO exposure increased early 

components (P1-N1 and N1-P1) of the cortical flash evoked potential peak-to-peak amplitudes at 

65 days postexposure (PND65) in female, not male, rats (Dyer et al., 1979, 190994). The early 

waves of the cortical evoked potential, an indicator of visual cortical functioning, generally indicate 

activity in the retinogeniculostriate system. These studies showed that in utero CO exposure had both 

reversible and irreversible effects on sodium and potassium channels, which are essential for proper 

electrophysiological function of the muscles and PNS. 

 Neurotransmitter Changes 

The developing nervous system is extremely sensitive to decreased oxygen availability. 

Virtually all neurotransmitter systems are present at birth but require further maturation. The studies 

listed below in Table 5-16 have shown that prenatal exposure to CO alters a number of 

neurotransmitters and their pathways at concentrations ranging from 75 to 300 ppm, both transiently 

and permanently. 

Medullar Neurotransmitters. SIDS is a complex syndrome that involves the aberrant 

development of brain stem nuclei controlling respiratory, cardiovascular, and arousal activity. To 

investigate changes in the structure and neurochemistry of the brain stem, Tolcos et al. (2000, 

015997) exposed pregnant guinea pigs to CO (200 ppm) over the last 60% of gestation. Guinea pigs 

and humans both have the majority of CNS development in utero. CO-exposed pups were found to 

have significant decrements in body, brain, and liver weights, crown-to-rump length, and medullar 

volume when compared to control pups. Neurotransmitter systems were also affected after CO 

exposure. Specifically, the brain stem displayed significant decreases in protein and 

immunoreactivity for tyrosine hydroxylase (TH), an enzyme necessary for catecholamine 

production, which is likely due to decreased cell number in specific medullar regions responsible for 

cardiorespiratory control. This was consistent with earlier work showing that prenatal CO exposure 

leads to aberrant respiratory responses to asphyxia and CO2 (McGregor et al., 1998, 085342). The 

cholinergic system was also affected by prenatal CO exposure with significant increases in choline 

acetyl-transferase (ChAT) immunoreactivity of the medulla; however, no changes in muscarinic 

acetylcholine receptor were seen. This is in contrast to human infants with SIDS who show 

decreased brain stem muscarinic receptor binding (Kinney et al., 1995, 193898). ChAT changes in 

this study (Tolcos et al., 2000, 015997) were from areas of the medulla associated with tongue 

innervation, which is crucial to swallowing, possibly in relation to breathing. 

A second risk factor for SIDS is hyperthermia. To explore the interaction of hyperthermia and 

CO-induced hypoxia, pregnant guinea pigs were exposed to CO (0 or 200 ppm) for 10 h/day for the 

last 60% of gestation (Tolcos et al., 2000, 010468). At PND4 male pups were exposed to 

hyperthermia or ambient temperature as a control. Brains were then collected at 1 and 8 wk of age. 

In utero CO exposure sensitized some areas of the brain to future hyperthermic insults. Specifically, 

CO plus hyperthermia induced significant increases in serotonin in multiple brain regions (NTS, 

DMV, and hypoglossal nucleus) at 1 wk of age; this change was no longer evident at 8 wk of age. 

Hyperthermia exposure alone induced decreased met-enkephalin neurotransmitter immunoreactivity 

at 1 wk of age that was absent at 8 wk and absent in CO-plus-hyperthermia exposed animals. Brain 

stem neurotransmitter (met-enkephalin, serotonin, TH, substance P) immunohistochemical 

differences were not apparent with CO treatment alone. At 8 wk of age, CO-plus-hyperthermia 

exposure induced glial aggregations and gliosis surrounding infarct or necrotic areas in the brain and 

the medulla lesions stained positive for glial fibrillary acidic protein (GFAP). GFAP upregulation is 

classically seen with neuronal diseases or following neurodegeneration. Gross structural 

observations revealed no differences in the medulla or cerebellum following in utero CO exposure 

alone. Together, these data showed that CO exposure in utero sensitizes the brain to future 

hyperthermic insults, lea ding to generation of necrotic lesions in the brain and changes in 

neurotransmitter levels. 

January 2010 5-73 
Table 5-16. Neurotransmitter changes. 

Study Model 

System CO Exposure Response Notes 

NEUROTRANSMITTER CHANGES 

Tolcos et al. (2000, 

015997) Guinea pigs 

200 ppm 

10h/day 

GD23-GD25 to 

GD61-GD63 

CO affected catecholaminergic system in brain stem by reducing tyrosine 

hydroxylase. Affected cholinergic system by increasing choline acetyltransferase. 

Fetal COHb: 13% 

Maternal COHb: 8.5% 

Tolcos et al. (2000, 

010468) Guinea pigs 

200 ppm 

10h/day 

GD23-GD25 to 

birth 

Hyperthermia on 

PND4 

CO sensitizes the brain to the effects of a short period of hyperthermia on 

PND4. The exposure combination resulted in lesions in the brain, as well 

as increased serotonin and glial fibrillary acidic protein. The exposure also 

caused reactive astrogliosis. 

Fetal COHb: 13% 

Maternal COHb: 8.5% 

McGregor et al. (1998, 

085342) Guinea pigs 

200 ppm 

10h/day 

GD23-GD25 to 

birth 

CO increased tidal volume during steady state hypercapnia and 

progressive asphyxia, due to increased ventilation. 

Fetal COHb: 13% 

Maternal COHb: 8.5% 

Cagiano et al. (1998, 

087170) Rats 75 and 150 ppm 

GD0-GD20 

In utero CO (150 ppm) exposure increased mount/intromission latency , 

decreased mount/intromission frequency, and induced ejaculatory 

abnormalities. CO also blunted the amphetamine-induced increase in 

dopamine. 

Maternal COHb: 

GD10: 1, 7, and 15%; 

GD20: 1.5, 7, and 16% (0, 

75, and 150 ppm CO, 

respectively) 

Hermans et al. (1993, 

190510) Rats 

Hypoxia 

(10.5% O2) 

GD15-GD21 

Hypoxia caused delayed initiation latencies of male sexual behavior and 

decreased number of ejaculations. 

Fechter et al. (1987, 

012259) Rats 

75, 150, and 

300 ppm 

GD0-GD20 or 

PND10 

Prenatal CO exposure continuing to PND10 leads to increased 

concentrations of dopamine but not dopamine metabolites in striatal tissue. 

Maternal COHb: 2.5 ± 

0.1%, 11.4 ± 0.3%, 18.5 ± 

0.5%, 26.8 ± 1.1% (0, 75, 

150, and 300 ppm, 

respectively) 

Storm and Fechter 

(1985, 011653) Rats 150 ppm 

GD0-GD20 

Prenatal CO exposure increased mean and total cerebellar norepinephrine 

concentration from PND14 to PND42, but not in the cortex. 

Storm and Fechter 

(1985, 011652) Rats 

75, 150, and 

300 ppm 

GD0-GD20 

CO transiently decreased 5HT and NE in the pons/medulla. CO increased 

NE in the cortex and hippocampus at PND42. CO dose-dependently 

reduced cerebellum wet weight. 

Maternal COHb: 2.5%, 

11.5%, 18.5%, and 26.8% 

(0, 75, 150, and 300 ppm, 

respectively) 

Storm et al. (1986, 

012136) Rats 

75, 150, and 

300 ppm 

GD0-PND10 

CO decreased cerebellar weight (150-300 ppm at PND10, 75-300 ppm at 

PND21) and decreased total cerebellar GABA (150-300 ppm at PND10 

and PND21). CO (300 ppm) exposed cerebella has fewer fissures. 

Maternal COHb: 2.5%, 

11.5%, 18.5%, and 26.8% 

(0, 75, 150, and 300 ppm, 

respectively) 

Benagiano et al. (2005, 

180445) Rats 75 ppm 

GD0-GD20 

CO reduced the number of GABA and GAD 65/67 positive neuronal bodies 

and axon terminals in the cerebellar cortex. 

Benagiano (2007, 

193892) Rats 75 ppm 

GD5-GD20 

Adult offspring exposed prenatally to CO exhibited decreased GABA and 

GAD in the molecular layer and Purkinje neuron layers of the cerebellar 

cortex 

Antonelli (2006, 194960) Rats 75 ppm 

GD5-GD20 

CO decreased cortical glutamatergic transmission both at rest and after a 

chemical depolarizing stimulus. 

Dopaminergic Effects. Dopamine is a catecholamine neurotransmitter that plays an important 

role in the regulation of male rat sexual behavior. Experiments assessing sexual behavior and 

mesolimbic dopaminergic function were conducted on adult (5 and 10 mo of age) male offspring 

gestationally exposed to CO (0, 75 or 150 ppm) (Cagiano et al., 1998, 087170). Maternal COHb at 

GD10 was 1, 7, and 15% and 1.5, 7, and 16% at GD20 (0, 75, and 150 ppm CO, respectively). At 

5 mo of age, CO-exposed male offspring showed decrements in sexual behavior, including an 

increase in mount-to-intromission latency, a decrease in mount-to-intromission frequency, and a 

decrease in ejaculation frequency. Further, administration of amphetamine, which stimulates 

copulatory activity, did not alter CO-induced changes in mount-to-intromission latency or frequency. 

Basal extracellular dopamine concentration in the nucleus accumbens was unchanged after CO 

exposure. However, when stimulated with amphetamine administration, control rats had increased 

release of dopamine that was absent with CO-exposed rats. Rats followed to 10 mo of age showed 

no significant changes in copulatory activity or neurochemical parameters after CO exposure, 

January 2010 5-74 
indicating recovery from earlier decrements. This altered male sexual behavior in CO-exposed 

offspring paralleled earlier studies of mice exposed gestationally to hypoxia (Hermans et al., 1993, 

190510). In summary, in utero exposure to CO delayed copulatory sexual behavior in male offspring 

with accompanying changes in the mesolimbic dopaminergic system. 

A second study also found no change in dopamine metabolite levels after prenatal exposure to 

CO; however, it did find an elevation in dopamine concentration in rats exposed both pre- and 

postnatally to CO. Exposure of Long Evans rat dams and pups continuously to CO (75, 150, or 

300 ppm) with maternal COHb of 11, 19, and 27%, respectively) from conception to PND10 induced 

significant elevations in dopamine in the striatum at PND21 in CO-exposed offspring versus air 

exposed controls (Fechter et al., 1987, 012259).

Noradrenergic and Serotonergic Changes. Other monoamine neurotransmitters, norepinephrine 

(NE) and serotonin (5HT), were tested for sensitivity to CO during development. Long Evans rats 

exposed to CO (75, 150, or 300 ppm) over the duration of gestation yielded a dose-dependent 

reduction in cerebellum wet weight (significant at 150 and 300 ppm) at PND21, with increases in NE 

concentration found in the cortex and hippocampus at PND42 but not PND21 (Storm and Fechter, 

1985, 011652). In a separate experiment, CO-exposed (150 ppm) animals presented with increased 

mean and total NE concentrations in the cerebellum but not cortex when monitored from PND14 to 

PND42 (Storm and Fechter, 1985, 011653). Also, NE concentration in the pons/medulla decreased 

linearly with increasing CO exposure at PND21 but not at PND42. A transitory decrease in 5HT 

concentration was also shown in the pons/medulla after gestational CO exposure (Storm and Fechter, 

1985, 011652). Thus, in these studies, it appeared that CO both transiently and permanently altered 

the pattern of postnatal neurotransmitter development in a region-specific manner and stunted 

postnatal growth of the cerebellum. 

Glutamatergic System. Glutamate is an abundant excitatory neurotransmitter that serves as a 

precursor for the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) catalyzed 

by glutamic acid decarboxylase (GAD). Primary cell cultures obtained from the cerebral cortex of 

offspring (PND1) gestationally (GD5-GD20) exposed to CO (75 ppm) had decreased extracellular 

glutamate (basal and K+

-evoked) levels versus air-exposed controls (Antonelli et al., 2006, 194960). 

Similarly, CO-exposed (300 ppm only) pups at PND21 had significant decreases in cerebellar GABA 

content, decreased uptake of exogenous radio-labeled GABA, decreased fissures in the cerebellum, 

and decreased cerebellum size (Storm et al., 1986, 012136). It is possible this decrease in GABA 

content is due to a diminished activity of GAD. Rats exposed to CO (75 ppm) in utero (GD0-GD20) 

exhibited decreased GABA and GAD in the molecular layer and Purkinje neuron layer of the 

vermian cerebellar cortex (Benagiano et al., 2005, 180445; Benagiano et al., 2007, 193892). This 

alteration may functionally impair cortical glutamatergic transmission in CO-exposed offspring, 

possibly affecting learning and memory. 

The Developing Auditory System 

 The developing auditory system of rodents has recently been investigated as a target of CO 

exposure at levels as low as 12 ppm. The rat brain and auditory system go through extensive cell 

division and multicellular organization during a major growth spurt in the postnatal period (PND7-

PND20), making it a probable target for CO-induced effects. These studies showed that exposure to 

low concentrations of CO during development can lead to permanent changes in the auditory system 

that persist into adulthood. Similarly, prenatal exposure to tobacco smoke can cause auditory system 

deficits as seen in animal tests for auditory responsiveness, habituation, and auditory arousal. Term 

human infants born to smoking mothers have impaired cochlear development, albeit mild, with 

decreased amplitudes of transient evoked otoacoustic emissions (OAE) at the highest test frequency 

(4 kHz) versus newborns born to nonsmokers (Korres et al., 2007, 190908); CO is one of many 

potential affective components of cigarette smoke. 

January 2010 5-75 
Table 5-17. Developing auditory system. 

Study Model 

System CO Exposure Response Notes 

DEVELOPING AUDITORY SYSTEM 

Stockard-Sullivan et al. 

(2003, 190947) Rats 

12-100 ppm 

22 h/day 

PND6 to PND21-PND23 

CO (50 ppm) reduced otoacoustic emissions (preneural cochlear 

function) at 7.13 and 8.01 kHz. CO persistently attenuated the 

amplitude of the action potential of the eighth cranial nerve (12-

50 ppm), persisting to PND73. No functional impairment in the Morris 

Water Maze after CO exposure. 

COHb: 10.2% 

(100 ppm); 5.5% (AR); 

4.1% (MR) 

Lopez et al. (2003, 

193901) Rats 12 and 25 ppm 

PND8-PND22 

CO (25 ppm) led to swelling and mild vacuolization of nerve terminals 

innervating inner hair cells and the fibers of the 8th cranial nerve. CO 

(25 ppm) decreased expression of neurofilament and myelin basic 

proteins, cytochrome oxidase, NADH-TR, and calcium ATPase. 

Webber et al. (2003, 

190515) Rats 12.5, 25, 50 ppm 

PND8 to PND20-PND22 

CO decreased c-Fos immunoreactivity in the central inferior colliculus 

at both PND27 and PND75-PND77 over all dose groups (12.5, 25, or 

50 ppm CO) 

Webber et al. (2005, 

190514) Rats 25 and 100 ppm 

PND9-PND24 

CO exposure (25 and 100 ppm) decreased neurofilament proteins, 

decreased c-Fos expression in the central IC, and increased CuZnSOD 

in the spiral ganglion neurons. Iron deficiency ablated these responses. 

Lopez et al. (2008, 

097343) Rats 

25 ppm 

10-18 h/day 

GD5-20 or GD5-GD20 and 

PND5-PND20 

Prenatal CO exposure led to increased oxidative stress in the cochlear 

vasculature (high HO-1, SOD-1, iNOS, and nitrotyrosine) and 

decreased neurofilament proteins and synapsin-1. CO caused 

morphological deterioration of putative afferent terminals and mild 

deterioration in the inner hair cells at the basal region of the cochlea. 

Studies on the developing auditory system have used an artificial feeding system where pups 

were removed from their respective dams and fed a milk substitute comparable to natural rat milk 

via intragastric cannulation. This allowed nursing pups to be exposed to CO without possible 

confounding by lactational and maternal CO co-exposure. However, this invasive rat model does 

cause decreased brain, cerebellum, and lung weight at PND16 in normal air controls. A summary of 

these studies and others are presented in the above table (Table 5-17). 

Using this model, Stockard-Sullivan et al. (2003, 190947) examined Sprague Dawley rat pups 

receiving low-dose CO (12, 25, or 50 ppm) to determine how perinatal CO exposure (PND6 to 

PND21-PND23) functionally affected hearing in the developing rat. Rodent pups were either 

maternally reared (MR), nutritionally supported with the artificial feeding system (AR), or received 

AR plus CO exposure (ARCO). CO (50 ppm, not 25 ppm) exposure caused significant reductions in 

distortion product otoacoustic emissions (DPOAE) levels at certain frequencies (7.13 and 8.01 kHz), 

a measure of preneural cochlear function and thus not affected by eighth cranial nerve function. 

However, the frequency range where significant CO results were seen is very narrow and low 

compared to the normal rat audiogram. The eighth cranial nerve, or vestibulocochlear nerve, is 

responsible for transmitting sound from the inner ear to the brain. This study also found significant 

attenuation of the action potential (AP) of the eighth cranial nerve with ARCO exposure (12, 25, and 

50 ppm CO) versus AR controls at PND22. This is complicated by the finding that AR control 

animals had significant attenuation of the eighth cranial nerve AP versus MR control animals, 

implying that artificial rearing contributes to AP changes before CO was introduced. Nonetheless, 

the CO-dependent attenuation of the eighth cranial nerve AP (versus AR control) was permanent, 

persisting until adulthood in the 50 ppm CO exposure group (the only CO group monitored). 

Auditory brain stem response (ABR) conduction time was not affected in CO-exposed animals (12, 

25, 50, 100 ppm).These functional tests reported that neonatal exposure to low concentrations of CO 

can induce auditory functional changes in rodents. 

Further studies have investigated physiological changes in cochlear development resulting 

from chronic CO inhalation. Sprague Dawley rats exposed to low concentrations of CO (12 or 

25 ppm, ARCO) from PND6 to PND27 had no evidence of damage to the inner or outer hair cells 

(Lopez et al., 2003, 193901). However, CO (25 ppm) caused atrophy or vacuolization of the nerve 

cells that innervate the inner (not outer) hair cells. Also, fibers of the eighth cranial nerve at the level 

of the internal auditory canal had distorted myelination and vacuolization of the axoplasm after 

25 ppm CO exposure. Energy production markers in the organ of corti and spiral ganglion neurons 

January 2010 5-76 
including cytochrome oxidase (electron transport chain complex IV) and NADH-TR (marker of 

complex I reductase activity) were significantly decreased after inhalation of 25 ppm (not 12 ppm) 

CO versus control (AR and MR). Reduced energy production likely led to the decreased expression 

of the calcium-mediated myosin ATPase and neurofilament proteins in the organ of corti and spiral 

ganglion neurons (25 ppm CO). Since no changes in body weight were found after CO exposure in 

these experiments (Stockard-Sullivan et al., 2003, 190947), it is likely that the decreased electron 

transport chain enzymes are specific to vulnerable areas such as the cochlea. 

Further analysis focused attention on CO-induced changes in the inferior colliculus (IC), an 

auditory integrative section of the midbrain. Low concentrations of CO (12.5, 25, or 50 ppm) inhaled 

over PND8-PND22 decreased c-Fos immunoreactivity in the central IC at both PND27 and 

PND75-PND77; immunostaining of other subregions of the IC were not affected by CO (Webber et 

al., 2003, 190515). c-Fos is an immediate early gene whose tonotopic expression corresponds to 

neuronal activation in the auditory system. The same decrease in c-Fos expression was seen in rats 

exposed to 25 or 100 ppm CO from PND9 to PND24 (Webber et al., 2005, 190514). These COexposed rats also exhibited decreased neurofilament proteins and increased Cu-Zn superoxide 

dismutase (SOD1) in the spiral ganglion neurons. This response could be ablated by dietary iron 

restriction, suggesting an ROS-dependent contribution to the auditory changes seen after CO 

exposure. These authors postulated that CO creates a persistent oxidative stress condition where 

ROS generated via the interaction of peroxide and iron (via the Fenton reaction or Haber Weiss 

chemistry) leads to impaired cochlear development; decreasing the available iron decreases the total 

pool available for ROS generation. Further, the attenuation of the elevated SOD levels with iron 

restriction post CO-exposure gives credence to this model. 

A recent study has found comparable auditory system responses after prenatal (GD5-GD20) 

exposure to CO with postnatal exposure (GD5-PND20,) similar to the studies described above 

(Lopez et al., 2008, 097343). Prenatal CO (25 ppm) exposure led to high levels of the oxidative 

stress markers HO-1, SOD-1, iNOS, and nitrotyrosine in cochlea vasculature and stria vascularis at 

PND12; however, unlike postnatally exposed pups, HO-1 and SOD1 levels returned to normal at 

PND20. Both groups of CO-exposed rats exhibited spiral ganglion cytoplasmic vacuolization, a 

decrease in type I spiral ganglion neuron neurofilament proteins, thinning and damage in the cells of 

the stria vascularis, and mild deterioration of the innervation of the inner hair cells. These nerve 

terminals also had a persistent decrease in synapsin-1, a regulatory neuronal phosphoprotein. These 

studies suggest that mild chronic CO exposure disrupts the developing auditory system, more often 

at the IHC innervation and the eighth cranial nerve of the spiral ganglion, possibly by creating an 

oxidative stress that may be reflected as hearing impairment. 

Summary of Toxicological Studies on Developmental Central Nervous System Effects 

Toxicological studies employing rodent models have shown that exposure to low 

concentrations of CO during the in utero or perinatal period can adversely affect adult outcomes 

including behavior, neuronal myelination, neurotransmitter levels or function, and the auditory 

system. In utero CO exposure has been shown to impair active avoidance behavior (150 ppm), 

habituation (75 and 150 ppm), nonspatial memory (75 and 150 ppm), and emotionality (150 ppm). 

These behavioral changes could be due to neuronal changes or altered neurotransmitter signaling. In 

utero CO exposure (75 and 150 ppm) was associated with PNS myelination decrements from 

impaired sphingolipid homeostasis (150 ppm CO). These neuronal changes were also accompanied 

by electrophysiological changes such as reversible delays in ion channel development and 

irreversible changes in sodium equilibrium potential (150 ppm). Also, multiple studies demonstrated 

that in utero CO exposure affected cholinergic (200 ppm), catecholaminergic (200 ppm), 

noradrenergic (150 ppm), serotonergic (75 ppm), dopaminergic (75 ppm) and glutamatergic 

(75 ppm), neurotransmitter levels or transmission in exposed rodents. Possible or demonstrated 

adverse outcomes from the CO-mediated aberrant neurotransmitter levels or transmission include 

respiratory dysfunction (150 ppm), impaired sexual behavior (150 ppm), and an adverse response to 

hyperthermic insults resulting in neuronal damage (200 ppm). Finally, perinatal CO exposure has 

been shown to affect the developing auditory system of rodents, inducing permanent changes into 

adulthood at concentrations as low as 12 ppm. Together, these animal studies demonstrate that in 

utero or perinatal exposure to CO can adversely affect adult behavior, neuronal function, 

neurotransmission, and the auditory system in rodents. 

January 2010 5-77 
Cardiovascular and Systemic Developmental Effects 

In utero exposure to moderate to high concentrations of CO (60, 125, 150, 250, or 500 ppm) is 

able to induce transient changes in cardiac morphology, cardiac action potentials, and systemic 

immunity that may make a CO-exposed animal more susceptible to other outside stressors during the 

immediate neonatal period. Studies of cardiovascular and systemic developmental responses to CO 

levels of 500 ppm and less are presented below in Table 5-18. 

Table 5-18. Cardiovascular and systemic developmental responses. 

Study Model 

System CO Exposure Response Notes 

CARDIOVASCULAR AND SYSTEMIC DEVELOPMENTAL RESPONSES 

Sartiani et al. (2004, 

190898) Rats 150 ppm 

GD0-GD20 

CO delayed action potential duration shortening, decreased the density 

of Ito channels and increased the density of ICa,L channels. 

Prigge and Hochrainer 

(1977, 012326) Rats 60, 125, 250, and 500 ppm 

GD0-GD21 

CO depressed fetal hemoglobin (250 and 500 ppm), reduced fetal 

weight (125, 250, and 500 ppm), decreased hematocrit (250 and 

500 ppm), and increased heart weight (60-500 ppm). 

Fechter et al. (1980, 

011294) Rats 150 ppm 

GD0-GD20 

CO transiently increased wet heart weight. There was no increase in 

dry heart weight. COHb: 15% 

Penney et al. (1982, 

011387) Rats 500 ppm 

PND1-PND32 

CO increased heart weight to body weight ratio, which remained high to 

PND107. Right ventricular weight was high through PND217. 

Hydroxyproline and cardiac cytochrome c was depressed but only 

during CO exposure. Neither lactate dehydrogenase nor myoglobin 

was altered by CO. 

Styka and Penney 

(1978, 011166) Rats 

400 or 500 ppm increased to 

1,100 ppm 

Adult 

6 wk 

CO caused increased heart weight to body weight that regressed within 

a couple of months after CO exposure. 

COHb: 

400 ppm-35%; 

1,100 ppm-58% 

Giustino et al. (1993, 

013833) Rats 75 and 150 ppm 

GD0-GD20 

CO decreased splenic macrophage killing (75 and 150 ppm), 

phagocytosis (150 ppm), and superoxide release (150 ppm). These 

alterations were reversible, not seen at PND60. 

Giustino et al. (1994, 

076343) Rats 75 and 150 ppm 

GD0-GD20 

CO (150 ppm) decreased the frequency of splenic leukocyte common 

antigen (LCA+) cells at PND21 but not PND15 or PND540 

COHb: 

150 ppm-15% 

Myocardial Electrophysiological Maturation 

A rat model of in utero exposure was employed to study CO effects on the development of 

cardiac myocytes. Results demonstrated that in utero CO exposure (150 ppm) alters postnatal 

cellular electrophysiological maturation in the rat heart (Sartiani et al., 2004, 190898). Specifically, 

at 4 wk of age, the action potential duration (APD) of isolated cardiac myocytes from CO-exposed 

animals failed to shorten or mature as the APD of control animals did. Further, the two ion 

conduction channels Ito (transient outward current, K+

-mediated) and ICa,L (L-type Ca2+ current), 

which largely control the rat APD, were significantly different from control animals after in utero 

CO exposure at 4 wk of age. These CO-dependent changes were resolved by 8 wk of age, reflecting 

a delayed maturation. Further, these authors postulated that a CO-dependent delay in 

electrophysiological maturation of the cardiac myocyte (lack of APD shortening) could lead to 

arrhythmias and thus could be associated with SIDS deaths. 

Heart Morphological Changes after In Utero or Perinatal CO Exposure 

Multiple authors have reported cardiomegaly following in utero exposure to low 

concentrations of CO. Prigge and Hochrainer (1977, 012326) reported increased fetal Wistar rat 

heart wet weight or cardiomegaly following continuous in utero CO (60, 125, 250, and 500 ppm) 

exposure, with no decreases in near term fetal hematocrit or Hb levels seen at exposures below 

250 ppm. Fechter et al. (1980, 011294) found that prenatal exposure to CO affected cardiac 

development in exposed offspring. Long Evans rats that were exposed to CO continuously 

January 2010 5-78 
(150 ppm) during gestation manifested with significant elevations in wet heart weight, as well as 

heart weight in relation to body weight at PND1 but not at PND4, PND14, or PND21. Dry-to-wet 

weight ratios revealed that the increased heart weight of CO-exposed pups at birth was due to edema 

or water content. Penney et al. (1982, 011387) studied CO-dependent (500 ppm) cardiomegaly in 

neonates (continuous CO exposure for 32 days starting at PND1). Other studies of adult male 

Charles River-derived rats exposed to CO for 6 wk (at 400 or 500 to 1,100 ppm CO), as adults only, 

developed CO-dependent cardiomegaly during exposure that significantly regressed within a couple 

of months after termination of CO exposure (Styka and Penney, 1978, 011166). 

Systemic Immune Toxicology after In Utero CO Exposure 

In utero exposure (GD0-GD20) of male Wistar rats to moderate CO (0, 75, or 150 ppm) 

concentrations induced reversible changes in macrophage function (Giustino et al., 1993, 013833). 

The killing of Candida albicans (yeast) by splenic macrophages was significantly decreased at 

PND15 in gestationally CO-exposed male offspring (75 and 150 ppm) but recovered function by 

PND21. Macrophage phagocytosis of C. albicans was significantly reduced at PND15 and PND21 in 

CO-exposed males (150 ppm only), and recovery was seen at PND60. Superoxide production by the 

splenic macrophage respiratory burst was significantly decreased at PND15 and PND21 after in 

utero CO exposure (150 ppm only), with recovery to control levels at PND60. In summary, CO 

exposure in utero leads to a reversible and concentration-dependent loss of function of splenic 

macrophages, with decreased killing ability, decreased phagocytosis, and decreased ROS production 

during the macrophage respiratory burst. 

Further studies by the same laboratory showed that in utero exposure of male rats to CO 

(150 ppm) induced a subtle decrease in the frequency of splenic immunocompetent cells (leukocyte 

common antigen [LCA+] cells) in a population of splenic immune cells at PND21 but not PND15 or 

PND540 (Giustino et al., 1994, 076343). Specific LCA+ cell subpopulations, including 

macrophages, Major Histocompatibility (MHC) II cells, T and B lymphocytes, showed a decreasing 

trend but were not significant with CO exposure. 

Summary of Toxicological Studies of Cardiovascular and Systemic Development 

In utero CO exposure is associated with various adverse, albeit nonpersistent, cardiac 

aberrations. Exposure to 150 ppm induced a delayed maturation of the cardiac action potential in 

CO-exposed offspring. In other studies, continuous in utero CO exposure (60-500 ppm) induced 

cardiomegaly at PND1, which was transient and regressed by PND4. CO (75 and 150 ppm) also 

affects nonspecific immunity, shown through a reversible and dose-dependent loss of function of 

splenic macrophages, with decreased killing ability, decreased phagocytosis, and decreased 

macrophage ROS production (150 ppm). Also, the distribution of splenic immunocompetent cells 

was slightly skewed because of a decrease in the number of LCA+ cells in PND21 male rats exposed 

during gestation to 150 ppm CO. In conclusion, in utero exposure to moderate doses of CO 

(60-500 ppm) is able to induce transient changes in cardiac morphology, cardiac action potentials, 

and systemic nonspecific immunity. 

5.4.3. Summary of Birth Outcomes and Developmental Effects 

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

is for 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 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. 

January 2010 5-79 
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 provided 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 Figure 5-10

through Figure 5-12, reported small reductions in birth weight (~5-20 g). Several studies examined 

various combinations of birth weight, LBW, and SGA/IUGR, and inconsistent results were 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 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 postneonatal periods. In support of this limited evidence, 

animal toxicological studies provided 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 PND22 (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. 

January 2010 5-80 
5.5. Respiratory Effects 

5.5.1. Epidemiologic Studies with Short-Term Exposure 

This section evaluates the key epidemiologic studies published since the 2000 CO AQCD 

(U.S. EPA, 2000, 000907) that further examine the association between short-term exposure to CO 

and respiratory morbidity. Although the number of studies that have specifically examined the COrespiratory health relationship have increased, there are still considerably less than that for the other 

criteria air pollutants (e.g., PM and O3). The epidemiologic studies discussed below represent those 

studies which (1) were conducted in locations with ambient CO concentrations similar to those in the 

U.S.; (2) determined to use a reasonable study design and analytical methods; and (3) adequately 

adjusted for confounding using accepted methods. If limitations in the design or analytical methods 

used in a study were identified, they were noted. It is recognized that each of the studies evaluated 

has a varying degree of exposure measurement error due to (1) the number of monitors used within 

the study, the geographic size of the study area; (2) the spatial variability of CO; and (3) differences 

in personal exposure distributions in the population; (Section 3.6.8) all of which could influence the 

associations observed. As a result, in some instances specific details of a study are mentioned to 

address any potential bias in the reported CO associations. Finally, the issue of confounding by 

measured or unmeasured copollutants was evaluated, if possible, for each study, through the 

interpretation of copollutant models. The results from copollutant models were used as an attempt to 

disentangle the effect of CO from other pollutants while recognizing the high correlation between 

CO and other combustion-related pollutants. 

5.5.1.1. Pulmonary Function, Respiratory Symptoms, and Medication Use 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) briefly discussed the potential acute 

respiratory health effects associated with short-term exposure to CO. An evaluation of the 

epidemiologic literature at the time did not find any evidence of an association between short-term 

exposure to CO and lung function, respiratory symptoms, or respiratory disease. As a result, the 2000 

CO AQCD (U.S. EPA, 2000, 000907) did not conclude that a causal association exists between 

short-term exposure to CO and respiratory health effects. Multiple uncertainties were identified in 

the epidemiologic literature that contributed to this conclusion, which are discussed in Section 5.2.1. 

The following section evaluates the current literature that examines the potential association between 

short-term exposure to CO and respiratory health effects. Table 5-19 lists the studies evaluated in this 

section along with the respiratory health outcomes examined and CO concentrations reported. 

January 2010 5-81 
Table 5-19. Range of CO concentrations reported in key respiratory morbidity studies that examined 

effects associated with short-term exposure to CO. 

Study Location

Sample Size Years Health Outcome Metric 

Mean 

Concentration 

(ppm) 

Middle/Upper Percentile 

Concentrations (ppm) 

O’Connor et al. 

(2008, 156818)

b 7 U.S. cities 8/1998-7/2001 

Pulmonary 

function; 

Respiratory 

symptoms 

8-h max 

24-h avg NR 

8-h max: 

50th: 1.2 

75th 1.8 

99th 3.8 

24-h avg: 

50th: 0.7 

75th 0.9 

99th: 1.8 

Rabinovitch et al. 

(2004, 096753) 

Denver, CO 

(Year 1: n = 41) 

(Year 2: n = 63) 

(Year 3: n = 43) 

11/1999-3/2000; 

11/2000-3/2001; 

11/2001-3/2002 

Pulmonary 

function; 

Medication use 

24-h avg 1.0 

50th: 0.9 

75th: 1.2 

Maximum: 3.5 

Silkoff et al. (2005, 

087471) 

Denver, CO 

(Year 1: n = 16) 

(Year 2: n = 18) 

1999-2000 

(winter); 

2000-2001 

(winter) 

Pulmonary 

function; 

Medication use 

24-h avg 

1999-2000: 1.2 

2000-2001: 1.1 

1999-2000 

50th: 1.10 

75th: 1.43 

Maximum: 3.79 

2000-2001 

50th: 0.975 

75th: 1.34 

Maximum: 2.81 

Fischer et al. 

(2002, 025731)

 a

The Netherlands 

(n = 68) March - Aprilc Pulmonary 

function 24-h avg 0.80 Max: 1.34 

Ranzi et al. (2004, 

089500)

 a

Emilia-Romagna 

Region, Italy 

(n = 120) 

2/1999-5/1999 

Pulmonary 

function; 

Respiratory 

symptoms; 

Medication use 

24-h avg 

Urban: 1.34 

Rural: 1.06 

NR 

Lagorio et al. 

(2006, 089800)

 a

Rome, Italy 

(n = 29) 

5/1999-6/1999; 

11/1999-12/1999 

Pulmonary 

Function 24-h avg 

Spring: 1.83

Winter: 10.7

Overall: 6.4 

Overall 

Max: 25.1 

Penttinen et al. 

(2001, 030335)

 a

Helsinki, Finland 

(n = 57) 

11/1996-4/1997 Pulmonary 

function 24-h avg NR 

50th: 0.35 

75th: 0.43 

Maximum: 0.96 

Timonen et al. 

(2002, 025653)

 a

Kuopio, Finland 

(n = 33) 

2/1994-4/1994 Pulmonary 

function 24-h avg 0.52 Maximum: 2.43 

Chen et al. (1999, 

011149) 

Taiwan 

(n = 941) 

5/1995-1/1996 Pulmonary 

function 

1-h max; 

24-h avg 

NR 

1-h max 

Maximum: 3.6 

Delfino et al. 

(2003, 050460) 

Los Angeles, CA 

(n = 22) 

11/1999-1/2000 Asthma symptoms 

1-h max; 

8-h max 

1-h max: 7.7 

8-h max: 5.0 

1-h max 

90th: 12.0 

Maximum: 17 

8-h max 

90th: 7.9 

Maximum: 10 

Slaughter et al. 

(2003, 086294) 

Seattle, WA 

(n = 133) 

12/1993-8/1995 Asthma symptoms; 

Medication use 24-h avg NR 50th: 1.47 

75th: 1.87 

Yu et al. (2000, 

013254) 

Seattle, WA 

(n = 133) 

11/1993-8/1995 Asthma symptoms 24-h avg 1.6 50th: 1.47 

Maximum: 4.18 

Schildcrout et al. 

(2006, 089812) 

8 North American 

cities 

(n = 990) 

11/1993-9/1995 Asthma symptoms; 

Medication use 24-h avg NR 

50th: 0.63-1.49 

75th: 0.77-1.90 

90th: 0.95-2.40 

von Klot et al. 

(2002, 034706)

 a

Erfurt, Germany 

(n = 53) 

10/1996-3/1997 Asthma symptoms; 

Medication use 24-h avg 0.78 

50th: 0.70 

75th: 1.04 

Maximum: 2.60 

January 2010 5-82 
Study Location

Sample Size Years Health Outcome Metric 

Mean 

Concentration 

(ppm) 

Middle/Upper Percentile 

Concentrations (ppm) 

Park et al. (2005, 

088673) 

Incheon, Korea 

(n = 64) 

3/2002-6/2002 Asthma symptoms; 

Medication use 24-h avg Control days: 0.64

Dust days: 0.65 NR 

Rodriguez et al. 

(2007, 092842) 

Perth, Australia 

(n = 263) 

6/1996-7/1998 

Symptoms 

associated with 

respiratory illness 

8-h max 1.41 Maximum: 8.03 

de Hartog et al. 

(2003, 001061)

 a

Amsterdam, The 

Netherlands 

(n = 37) 

Erfurt, Germany 

(n = 47) 

Helsinki, Finland 

(n = 47) 

1998-1999 (winter) Respiratory 

symptoms 24-h avg 

Amsterdam: 0.52 

Erfurt: 0.35 

Helsinki: 0.35 

Maximum: 

Amsterdam: 1.39 

Erfurt: 2.17 

Helsinki: 0.87 

a

These studies presented CO concentrations in the units mg/m3. The concentrations were converted to ppm using the conversion factor 1 ppm = 1.15 mg/m3, which 

assumes standard atmosphere and ambient temperature. b

This study did not present air quality statistics quantitatively, as a result, the air quality statistics presented were estimated from a figure. c

This study did not provide the year(s) in which air quality data was collected. 

Pulmonary Function 

As part of the Inner-City Asthma Study (ICAS), O’Connor et al. (2008, 156818) examined the 

effect of air pollutants (i.e., PM2.5, O3, NO2, CO, and SO2) on lung function in a population of 861 

children (5-12 yr old) with persistent asthma in 7 urban U.S. communities. Throughout the study, 

percent predicted forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) were 

examined for each subject during 2-wk periods twice daily every 6 mo for 2 yr. Lung function was 

examined in single pollutant models using both same-day (lag 0) and 5-day (lag 0-4) ma pollutant 

concentrations (Figure 5-13). CO was not found to be associated with percent predicted FEV1 at lag 

0, but there was some evidence for a reduction in percent predicted FEV1 when using the 5-day ma 

(-0.32 [95% CI: -0.75 to 0.11] per 0.5 ppm increase in 24-h avg CO concentrations). When 

examining percent predicted PEF, a small reduction was observed at lag 0 (not reported 

quantitatively), but the effect was found to be slightly larger at lag 0-4 (-0.28 [95% CI: -0.71 to 

0.15]). In this study, CO was found to be moderately correlated with other combustion related 

pollutants (e.g., PM2.5 [r = 0.44] and NO2 [r = 0.54]); however, CO was not included in the 

multipollutant models examined, limiting the interpretation of the small reductions in lung function 

observed. Although the observed reductions in lung function did not reach statistical significance, the 

results do provide some evidence for a potential effect of CO on lung function at relatively low CO 

concentrations (99th percentile max 8-h avg concentrations: ~ 3.8 ppm). 

January 2010 5-83 
 Source: Reprinted with Permission of Elsevier Ltd. from O’Connor et al. (2008, 156818) 

Figure 5-13. Estimated effect (95% confidence intervals) on pulmonary function due to a 10th 

to 90th percentile increment change in pollutant concentration in single-pollutant 

models. The estimates shown are from models that included either a 1-day or 

5-day avg of pollutant concentration. Effect estimates were adjusted for site, 

month, site-by-month interaction, temperature, and intervention group in mixed 

models. Panel A: percent predicted FEV1 as outcome variable; Panel B: percent 

predicted PEFR as outcome variable. 

The remaining U.S.-based studies evaluated consisted of single-city studies conducted in 

Denver, CO. Rabinovitch et al. (2004, 096753) examined the association between exposure to 

ambient air pollutants and asthma exacerbation in a panel of urban minority children, 6-12 yr old, 

with moderate to severe asthma over three winters. The investigators examined pulmonary function 

by measuring FEV1 and PEF in the morning on school days and also at night on weekends or other 

nonschool days. Using a 3-day ma (lag 0-2) for all pollutants, Rabinovitch et al. (2004, 096753) did 

not find an association between CO and either lung function parameter during the morning or at 

night. Silkoff et al. (2005, 087471) also examined lung function during the winter months, but in a 

panel of former smokers that were at least 40 yr old and had been diagnosed with COPD. In this 

study, CO concentrations were similar to those reported in Rabinovitch et al. (2004, 096753). The 

authors examined the association between exposure to air pollutants and lung function (i.e., FEV1

and PEF) in both the morning and the evening. Silkoff et al. (2005, 087471) found contradictory 

results when examining the effects of CO for each of the winter periods (1999-2000 and 2000-2001) 

separately. During the analysis of the first winter (i.e., 1999-2000), CO was not found to be 

associated with lung function decrements in the morning at any lag, but there was some evidence for 

lung function decrements during the evening at lag 0. Of note is the increase in FEV1 during the 

morning that was observed at lag 1 during this time period. For the second winter (i.e., 2000-2001) 

the authors found a significant negative association between CO exposure and FEV1 in the evening 

at lag 2 and a moderate negative association with PEF at lag 0 in the morning and lag 2 in the 

evening. Silkoff et al. (2005, 087471) postulated that the difference in the FEV1 results for the two 

study periods could be due to higher pollution concentrations along with somewhat lower 

temperatures and higher humidity in 2000-2001. However, mean CO levels remained relatively 

constant between the first and second winters, whereas, PM10, PM2.5, and NO2 concentrations all 

increased. The decrements in FEV1 observed in the second winter, therefore, may have been due to 

the slightly worse, although not significantly different, baseline lung function of the panel of subjects 

used during the second winter (Silkoff et al., 2005, 087471). 

In the recent literature, the majority of studies that examined the association between shortterm exposure to CO and lung function have been conducted in Europe and Asia. These studies 

provide some evidence for CO-induced changes in lung function. Negative associations between 

short-term exposure to CO and lung function were observed primarily in individuals with underlying 

respiratory conditions; however, some evidence also exists for effects in children that live in urban 

environments. Penttinen et al. (2001, 030335) examined the association between CO and lung 

function in a panel consisting of 57 nonsmoking adult asthmatics during the winter and spring in 

Helsinki, Finland. The authors observed negative associations with PEF (L/min) for a 0.5 ppm 

increase in 24-h avg CO concentrations in the morning at lag 1 (β = -0.54, SE = 0.084) and in the 

January 2010 5-84 
afternoon (β = -1.52, SE = 0.29) and evening (β = -1.81, SE = 0.27) for a 5-day avg. In two-pollutant 

models with daily mean particle number concentration (PNC), CO effects on PEF in the morning 

were attenuated at lag 1 but remained negative. In addition, negative associations with PEF persisted 

in the afternoon and evening in the two-pollutant model at lag 0. In this study, moderate correlations 

between UFPs and other traffic-generated pollutants (e.g., CO [r = 0.44], NO [r = 0.60], and NO2

[r = 0.44]) make it difficult to attribute the observed respiratory effects to a specific pollutant. 

Lagorio et al. (2006, 089800) also conducted a study that examined the association between 

CO and lung function in adults. In this study, three panels of subjects with underlying asthma, 

COPD, or IHD, who resided in Rome, Italy, were selected. The ages of the subjects varied depending 

on the panel, but overall the subjects ranged from 18-80 yr old. In single-pollutant models with CO, 

a reduction in forced vital capacity (FVC) and FEV1 was observed at most of the lags examined 

(i.e., 0, 0-1, and 0-2) for both the COPD and asthma panels. No association was observed between 

CO and FVC or FEV1 in the IHD panel. Lagorio et al. (2006, 089800) did observe a relatively high 

correlation between CO and PM2.5 but not NO2 (r = 0.05). Copollutant models were not conducted in 

this analysis to identify whether the CO associations observed are potentially confounded by other 

pollutants. 

Studies that focused on alterations in lung function in asthmatic children reported results 

consistent with those observed in adult asthmatics. Timonen et al. (2002, 025653) examined the 

effect of CO on bronchial responsiveness and pulmonary function (i.e., FVC, FEV1, MMEF, and 

AEFV) at rest and after exercise in a panel of children, 7-12 yr old with chronic respiratory 

symptoms, during the winter in Kuopio, Finland. The authors found that CO was significantly 

associated with decrements in baseline lung function (i.e., lung function measured prior to exercise) 

for FVC (mL) at lags 2 (-17.5 mL), 3 (-24.8 mL), and 4-day avg (-52.5 mL), and for FEV1 (mL) at 

lag 3 (-20.9 mL), for a 0.5 ppm increase in 24-h avg CO concentration. CO was not found to be 

associated with exercise-induced changes in lung function or bronchial responsiveness. Overall, 

Timonen et al. (2002, 025653) found that increased concentrations of combustion-related byproducts 

(i.e., BS, PM10, particle numbers, NO2, and CO) was associated with impairment in baseline lung 

function. These associations, along with the high correlation between CO and combustion-related 

pollutants (e.g., PM10 [r = 0.64]; NO2 [r = 0.88]), contributed to the inability of the authors to 

conclude that the lung function effects observed were due to biological changes in lung pathology 

specific to CO exposure. 

Chen et al. (1999, 011149) examined the effect of CO on lung function in 941 8- to 13-yr-old 

asthmatic children in Taiwan. The authors observed an association between short-term exposure to 

CO and decrements in FVC (mL) at a 2-day lag when using daytime average CO concentrations 

(from 8:00 a.m. to 6:00 p.m.) in a single-pollutant model. However, the authors found a high 

correlation between CO and NO2 concentrations (r = 0.86-0.98), and did not conduct copollutant 

analyses. 

An additional study, Fischer et al. (2002, 025731), examined the association between CO and 

respiratory health, specifically lung function in a cohort study of 68 children ages 10-11 yr who lived 

in an urban environment (Utrecht, The Netherlands). In this study, the authors examined whether 

eNO was a more sensitive measure of lung damage than the traditional pulmonary function 

measurements (i.e., FVC, FEV1, PEF, and MMEF). Fischer et al. (2002, 025731) found negative 

associations between CO and FEV1, PEF, and MMEF at both lags 1 and 2, as well as an association 

between CO and an increase in eNO at lag 1. However, the study did not provide pollutant 

correlations or examine copollutant models, limiting the interpretation of these results. 

Respiratory Symptoms in Asthmatic Individuals 

Upon evaluating the literature that examined the association between short-term exposure to 

CO and respiratory symptoms in asthmatic individuals, consistent, positive associations were 

observed across studies. The studies evaluated that included children enrolled in the Childhood 

Asthma Management Program (CAMP) study found that CO was positively associated with asthma 

symptoms. Yu et al. (2000, 013254) found a 1.14-fold increase in asthma symptoms 

([95% CI: 1.05-1.23] per 0.5 ppm increase in 24-h avg CO) at lag 1 in a population of 5- to 13-yr-old 

asthmatic children (n = 133) in Seattle, WA. Similar effects were observed at lag 0 and lag 2. These 

effects persisted when controlling for previous day’s asthma symptoms at all lags, with the largest 

effect at lag 1 (OR=1.12 [95% CI: 1.05-1.19]) and in multipollutant models with PM1.0 and SO2. 

January 2010 5-85 
Using the same population of children, Slaughter et al. (2003, 086294) found an association between 

short-term exposure to CO at lag 1 and asthma severity both with and without controlling for the 

previous day’s asthma severity, (RR = 1.04 [95% CI: 1.01-1.08] and RR = 1.03 [95% CI: 1.00-1.05] 

per 0.5 ppm increase in 24-h avg CO, respectively). However, this study only examined the effect of 

copollutant models on PM risk estimates, not CO. Schildcrout et al. (2006, 089812) examined the 

association between air pollutants and asthma symptoms in 990 children ages 5-12 yr in 8 North 

American cities. The authors found a positive association between short-term exposure to CO and 

asthma symptoms at lag 0 (OR = 1.04 [95% CI: 1.00-1.07] per 0.5 ppm increase in 24-h avg CO), 

but similar effects were also observed at lag 1, 2, and the 3-day moving sum. The CO effects 

observed persisted when NO2, PM10, and SO2 where included in joint-pollutant models. 

As previously mentioned, O’Connor et al. (2008, 156818) conducted an additional multicity 

study to examine the effect of air pollutants (i.e., PM2.5, O3, NO2, CO, and SO2) on respiratory health 

in a population of 861 children (5-12 yr) with persistent asthma in 7 U.S. urban communities. The 

authors collected information on asthma symptoms every 2 mo and examined the association 

between a 2-wk recall of the asthma symptoms and each air pollutant. O’Connor et al. (2008, 

156818) used a 19-day lag, which encompassed the 14 days of the symptom recall period and the 

5-day lag period proceeding the symptom recall period. In a single-pollutant model, CO was 

significantly associated with number of days with a wheeze-cough (14% [95% CI: 2-29]), number of 

nights with asthma symptoms (i.e., nighttime asthma) (19% [95% CI: 4-36]), and number of days a 

child slowed down or stopped play (15% [95% CI: 2-30]) per 0.5 ppm increase in 24-h avg CO 

concentrations during the 2-wk recall period. In this study, CO effects were not examined in a 

copollutant model. 

U.S.-based single-city studies also found positive associations between CO and asthma 

symptoms (Delfino et al., 2003, 050460; Rabinovitch et al., 2004, 096753). Rabinovitch et al. (2004, 

096753) found evidence for an increase in asthma exacerbations in response to 24-h avg CO 

concentrations for a 3-day ma (lag 0-2) (OR = 1.02 [95% CI: 0.89-1.16] per 0.5 ppm increase in 24-h 

avg CO) in a population of urban poor children with moderate to severe asthma in Denver, CO. 

Delfino et al. (2003, 050460) also reported evidence of a positive association between CO and 

asthma symptoms (based on symptoms that interfere with daily activities) using a population of 

Hispanic children with asthma in a Los Angeles, CA, community. However, Delfino et al. (2003, 

050460) only found positive associations at 1-day lags when using either the 1-h max (OR=1.05 

[95% CI: 0.88-1.26] per 1 ppm increase in 1-h max CO concentrations) or max 8-h avg (OR=1.09 

[95% CI: 0.80-1.50] per 0.75 ppm increase in max 8-h avg CO concentrations) CO concentration as 

the exposure metric. It should be noted that in comparison to Rabinovitch et al. (2004, 096753) and 

the other respiratory symptoms studies discussed above, the mean ambient concentrations for 1-h 

max and max 8-h avg reported by Delfino et al. (2003, 050460) were 7.7 ppm and 5.0 ppm, 

respectively, both of which are approximately 3.5 times higher than the corresponding 24-h avg 

concentrations reported in the other studies. 

 In addition to the U.S.-based studies presented above, international studies were evaluated 

that examined the association between short-term exposure to CO and asthma symptoms in study 

populations that included adults. Figure 5-14 summarizes the results from studies that provided 

comparable quantitative results and examined the association between short-term exposure to CO 

and asthma or respiratory symptoms in asthmatic individuals. A panel study consisting of 53 adults 

with asthma or asthma symptoms in Germany (Von et al., 2002, 034706) observed a marginal 

association between CO concentration and the prevalence of wheezing at lag 0 (OR = 1.03 

[95% CI: 0.97-1.08] per 0.5 ppm increase in 24-h avg CO), and a positive association for a 5-day 

mean concentration (OR = 1.12 [95% CI: 1.05-1.21] per 0.5 ppm increase in 24-h avg CO). 

However, the authors found CO to be highly correlated with UFPs (r = 0.66), complicating the 

interpretation of the associations observed. Additionally, Park et al. (2005, 088673) in a panel study 

of individuals 16-75 yr old in Incheon, Korea, with bronchial asthma, did not find an association 

between CO and nighttime asthma symptoms or cough. 

To further examine the effect of CO on asthma and asthma symptoms, some studies also 

analyzed medication use in asthmatic individuals in response to an increase in air pollutant 

concentrations. The majority of U.S.-based studies (i.e., Rabinovitch et al., 2004, 096753; 

Schildcrout et al., 2006, 089812; Slaughter et al., 2003, 086294) focused on rescue inhaler use in 

children with ages ranging from 5 to13 yr. Rabinovitch et al. (2004, 096753) found a weak 

association (OR = 1.08 [95% CI: 1.00-1.17] per 0.5 ppm increase in 24-h avg CO) between rescue 

inhaler use in a population of 6- to 12-yr old urban minority children with moderate to severe asthma 

January 2010 5-86 
in the winter in Denver, CO. In a population of 5- to 12-yr-old children with asthma in Seattle, WA, 

Slaughter et al. (2003, 086294) found a stronger association with rescue inhaler use both with and 

without taking into consideration the previous day’s asthma severity, (RR: 1.04 [95% CI: 1.01-1.08] 

per 0.5 ppm increase in 24-h avg CO) and (RR: 1.03 [95% CI: 1.00-1.05] per 0.5 ppm increase in 

24-h avg CO), respectively. Similar results were observed in a multicity study conducted by 

Schildcrout et al. (2006, 089812) which analyzed rescue inhaler use in 990 children ages 5-13 yr 

with asthma in 8 North American cities. Schildcrout et al. (2006, 089812) found that short-term 

exposure to CO was positively associated with rescue inhaler use at lags of 0, 2, and a 3-day moving 

sum, and that the association was fairly robust to a simultaneous increase in CO and other pollutants 

(i.e., NO2, PM10, and SO2) in joint models. Overall, Slaughter et al. (2003, 086294) and Schildcrout 

et al. (2006, 089812) question the associations observed due to the lack of biological plausibility for 

CO-induced respiratory effects and the high correlation between CO and NO2 (which suggests that 

other pollutants from mobile sources are driving the associations observed), respectively. Additional 

studies (Park et al., 2005, 088673; Silkoff et al., 2005, 087471; Von et al., 2002, 034706) conducted 

in Denver, CO; Erfurt, Germany; and Incheon, Korea, respectively, found associations between CO 

and medication use that are consistent with those previously reported, but in populations with 

combined ages ranging from 16 to 77 yr. Figure 5-14 presents the risk estimates from studies that 

examined the association between short-term exposure to CO and medication use in asthmatic 

individuals. 

Study Location Lag Age Effect Estimate (95% CI) 

Schildcrout et al. (2006, 089812) 8 N Amer cities 0-2a 5-12 Asthma Symptoms Children 

O’Connor et al. (2008, 156818) 7 US cities 0-18 5-12 Wheeze-cough 

O’Connor et al. (2008, 156818) 7 US cities 0-18 5-12 Nighttime asthma 

Yu et al. (2000, 013254) Seattle, WA 1 5-13 Asthma Symptoms 

Rabinovitch et al. (2004, 096753) Denver, CO 0-2 6-12 Asthma Exacerbation 

Delfino et al. (2003, 050460) LA, CA 1 10-16 Symp Score >2 (1-h max) 

Delfino et al. (2003, 050460) LA, CA 1 10-16 Symp Score >2 (max 8-h avg) 

Respiratory 

Symptoms 

von Klot et al. (2002, 034706) Erfurt, Germany 0-5 37-77 Wheeze Adults 

Schildcrout et al. (2006, 089812) 8 N. Amer cities 0-2a 5-12 Inhaler Use Children 

Slaughter et al. (2003, 086294) Seattle, WA 1 5-13 Inhaler Useb

Slaughter et al. (2003, 086294) Seattle, WA 1 5-13 Inhaler Usec

Rabinovitch et al. (2004, 096753) Denver, CO 0-2 6-12 Inhaler Use 

Medication 

von Klot et al. (2002, 034706) Erfurt, Germany 0-5 37-77 Inhaler Use (β2-agonist) Adults

Use 

von Klot et al. (2002, 034706) Erfurt, Germany 0-5 37-77 Inhaler Use (Corticosteroid) 

a

0-2 lag represents a 3-day moving sum 

b

Estimate presented is from a model that did not control for previous day’s asthma severity. 

c

Estimate presented is from a model that controlled for previous day’s asthma severity. Odds Ratio 

Figure 5-14. Summary of associations for short-term exposure to CO and asthma symptoms, 

respiratory symptoms and medication use in asthmatic individuals.1 Effect 

estimates were standardized depending on the averaging time used in the study: 

0.5 ppm for 24-h avg, 0.75 ppm for max 8-h avg, and 1.0 ppm for 1-h max. 

Respiratory Symptoms in Nonasthmatic Individuals 

In addition to examining the association between short-term exposure to CO and respiratory 

symptoms (e.g., cough, wheeze, shortness of breath) in asthmatic populations, some studies 

examined respiratory effects in individuals classified as nonasthmatics. Rodriguez et al. (2007, 

092842) examined the effect of CO on respiratory symptoms in a panel of 263 children 0- to 5-yr old 

at high risk for developing asthma in Perth, Australia. Rodriguez et al. (2007, 092842) found CO 

concentrations to be positively associated with wheeze/rattle chest and runny/blocked nose at both a 

5-day lag and a 0-5-day lag. In this study, copollutant models were not examined, CO correlations 

with other pollutants were not presented, and additional analyses were not conducted to further 

characterize the associations observed. 

 

1

 Effect estimates from Park et al. (2005, 088673) were not included in this figure because the study did not provide the increment at 

which the effect estimates were calculated. Additionally, estimates for Silkoff et al. (2005, 087471) were not included in the figure 

because results were not presented quantitatively. 

January 2010 5-87 
In a panel of individuals ≥ 50 yr of age with CHD in three European locations (Amsterdam, 

The Netherlands; Erfurt, Germany; and Helsinki, Finland) during the winter, de Hartog et al. (2003, 

001061) observed some marginal associations, specifically between CO concentration and the 

incidence of the respiratory symptoms shortness of breath and phlegm at lag 3, OR=1.17 (95% CI: 

0.96-1.40) and OR=1.22 (95% CI: 0.93-1.57), respectively, per 0.5 ppm increase in 24-h avg CO 

concentrations. However, the authors found that the associations between air-pollution exposure and 

respiratory symptoms were stronger for PM2.5 than for gaseous air pollutants. Overall, the 

associations observed in this study should be viewed with caution because the panel consisted of 

individuals on a variety of daily medications (i.e., beta blockers, ACE inhibitor + AT blocker, 

calcium antagonist, aspirin, digitalis, inhaled beta-agonist, and nitroglycerin). 

Summary of Associations between Short-Term Exposure to CO and Pulmonary 

Function, Respiratory Symptoms, and Medication Use 

A limited body of evidence is available that examined the effect of short-term exposure to CO 

on various respiratory health endpoints. Specifically, among asthmatics, the studies reviewed 

generally found positive associations between short-term exposure to CO and respiratory-related 

health effects (i.e., decrements in lung function, respiratory symptoms, and medication use). On-road 

vehicle exhaust emissions are a nearly ubiquitous source of combustion pollutant mixtures that 

include CO and can be an important contributor to CO-related health effects in near-road locations, 

which is evident by the high correlations reported between CO and other combustion-related 

pollutants (i.e., NO2 and PM). However, the limited number of copollutant analyses among this 

group of studies complicates the efforts to disentangle the health effects attributed to CO from the 

larger traffic-related pollutant mix. Additional uncertainty exists as to a biologically plausible 

mechanism that could explain the effect of CO on respiratory health. 

5.5.1.2. Respiratory Hospital Admissions, ED Visits and Physician Visits 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) evaluated a limited amount of literature that 

examined the association between short-term exposure to CO and respiratory hospital admissions 

(HAs), ED visits, and physician visits in the U.S. (i.e., Seattle, WA; Reno, NV; and Anchorage, AK) 

and Europe (i.e., Barcelona, Spain). From these studies, the 2000 CO AQCD (U.S. EPA, 2000, 

000907) concluded that positive associations were observed for short-term exposure to CO with 

several respiratory outcomes, including asthma and COPD. However, the lack of a biologically 

plausible mechanism for CO-induced respiratory morbidity at that time brought into question 

whether the results observed could be attributed to CO independently of other pollutants in the air 

pollutant mixture. Additional uncertainties were identified in the epidemiologic literature that 

contributed to this conclusion, which were discussed in Section 5.2.1. This section evaluates those studies published since the 2000 CO AQCD (U.S. EPA, 2000, 

000907) that examined the association between short-term exposure to CO at ambient concentrations 

similar to those found in the U.S. and respiratory-related HAs (Figure 5-15), ED visits (Figure 5-16), 

and physician visits. Unlike previous sections, which also evaluated studies conducted outside of 

North America, the expansive number of studies conducted in the U.S. and Canada provide adequate 

evidence to examine the association between short-term exposure to CO and respiratory HAs and 

ED visits. Although not discussed in this section, collectively, the studies conducted outside of the 

U.S. observed associations that are consistent with those observed in the U.S.- and Canadian-based 

studies evaluated below (see Annex C for results from the international studies evaluated). 

Overall, this section focuses on respiratory-related HAs because the majority of the literature 

examines HAs as opposed to ED visits or physician visits (Table 5-20 presents the studies evaluated 

in this section along with the range of CO concentrations measured in each study). It must be noted 

that when examining the association between short-term exposure to CO and health outcomes that 

require medical attention, it is important to distinguish between HAs, ED visits, and physician visits 

for respiratory outcomes (more so than for cardiovascular outcomes). This is because it is likely that 

a small percentage of respiratory ED visits will be admitted to the hospital and, therefore, may 

represent potentially less serious but more common outcomes. To adequately distinguish between the 

results presented in HAs, ED visit, and physician visit studies, each outcome is evaluated in 

individual sections. In addition, each section presents results separately for respiratory health 

January 2010 5-88 
outcomes which include all respiratory diagnoses (ICD-9: 460-519) or selected diseases 

(e.g., asthma, COPD, pneumonia and other respiratory infections) in order to evaluate the potential 

effect of short-term exposure to CO on each outcome. 

Table 5-20. Range of CO concentrations reported in key respiratory HA and ED visit studies that 

examine effects associated with short-term exposure to CO. 

Study Location Type of Visit (ICD9) Metric Mean Concentration (ppm) Middle/Upper Percentile 

Concentrations (ppm) 

Cakmak et al. 

(2006, 093272) 

10 Canadian 

cities 

Hospital Admissions: Respiratory 

disease (i.e., Acute bronchitis and 

bronchiolitis; pneumonia; chronic and 

unspecific bronchitis; emphysema; 

asthma; bronchiectasis; chronic 

airway obstruction) 

24-h avg 0.8 Maximum: 6.5 

Linn et al. 

(2000, 002839) 

Los Angeles, 

CA 

Hospital Admissions: Pulmonary; 

asthma; COPD 24-h avg Winter: 1.7; Spring: 1.0; 

Summer: 1.2; Fall: 2.1 

Maximum: 

Winter: 5.3; Spring: 2.2; 

Summer: 2.7; Fall: 4.3; 

Slaughter et al. 

(2005, 073854) Spokane, WA 

ED Visits and Hospital Admissions: 

Respiratory; asthma; COPD; 

pneumonia; acute respiratory 

infection 

24-h avg 

Hamilton St.: 1.73 

Backdoor Tavern: 1.29 

Spokane Club: 1.41 

Third and Washington: 1.82 

Rockwood: 0.42 

95th: 3.05 

Burnett et al. 

(2001, 093439) 

Toronto, ON, 

Can 

Hospital Admissions: Respiratory 

disease (i.e., asthma; acute 

bronchitis/bronchiolitis; croup; 

pneumonia) 

1-h max 1.9 

50th: 1.8; 75th: 2.3; 

95th: 3.3; 99th: 4.0 

Maximum: 6.0 

Yang et al. 

(2003, 055621) 

Vancouver, BC, 

Can 

Hospital Admissions: Respiratory 

diseases 24-h avg 0.98 50th: 0.82; 75th: 1.16 Maximum: 4.90 

Lin et al. (2003, 

042549) 

Toronto, ON, 

Can Hospital Admissions: Asthma 24-h avg 1.18 50th: 1.10; 75th: 1.40 Maximum: 6.10 

Lin et al. (2004, 

055600) 

Vancouver, BC, 

Can Hospital Admissions: Asthma 24-h avg 0.96 50th: 0.80; 75th: 1.12 Maximum: 4.90 

Moolgavkar 

(2003, 042864) 

Cook County, 

IL; Los Angeles 

County, CA 

Hospital Admissions: COPD 24-h avg NR 

Cook: 

50th: .99; 75th: 1.25 

Maximum: 3.91 

Los Angeles: 

50th: 1.35; 75th: 2.16 

Maximum: 5.96 

Yang et al. 

(2005, 090184) 

Vancouver, BC, 

Can Hospital Admissions: COPD 24-h avg 0.71 50th: 0.64 Maximum: 2.48 

Karr et al. 

(2006, 088751) 

South Coast Air 

Basin, CA 

Hospital Admissions: Acute 

bronchiolitis 24-h avg 

Lag 1: 

Index: 1.730 

Referent: 1.750 

Lag 4: 

Index: 1.760 

Referent: 1.790 

Lag 1: 

Index: 

50th: 1.52; 75th: 2.26; 

90th: 3.16 

Maximum: 9.60 

Referent: 

50th: 1.51; 75th: 2.29; 

90th: 3.23 

Maximum: 9.60 

Lag 4: 

Index: 

50th: 1.54; 75th: 2.31; 

90th: 3.23 

Maximum: 8.71 

Referent: 

50th: 1.55; 75th: 2.35; 

90th: 3.30 

Maximum: 9.60 

January 2010 5-89 
Study Location Type of Visit (ICD9) Metric Mean Concentration (ppm) Middle/Upper Percentile 

Concentrations (ppm) 

Karr et al. 

(2007, 090719) 

South Coast Air 

Basin, CA 

Hospital Admissions: Acute 

bronchiolitis 

24-h avg; 

Monthly avg 

24-h avg: 1.720 

Monthly: 1.770 

24-h avg: 

50th: 1.61; 75th: 2.08; 

90th: 2.75 

Maximum: 5.07 

Monthly avg: 

50th: 1.63; 75th: 2.13; 

90th: 2.88 

Maximum: 8.30 

Zanobetti and 

Schwartz (2006, 

090195) 

Boston, MA Hospital Admissions: Pneumonia 24-h avg NR 50th: 0.48; 75th: 0.60; 

95th: 0.88 

Lin et al. (2005, 

087828) 

Toronto, ON, 

Canada 

Hospital Admissions: Respiratory 

infections 24-h avg 1.16 50th: 1.05; 75th: 1.37 Maximum: 2.45 

Peel et al. 

(2005, 056305) Atlanta, GA ED Visits: All respiratory; asthma; 

COPD; URI; pneumonia 1-h max 1.8 90th: 3.4 

Tolbert et al. 

(2007, 090316) Atlanta, GA 

ED Visits: Respiratory diseases 

(i.e., asthma; COPD; URI; 

pneumonia; bronchiolitis) 

1-h max 1.6 50th: 1.3; 75th: 2.0; 90th: 3.0 

Maximum: 7.7 

Ito et al. (2007, 

156594) New York, NY ED Visits: Asthma 8-h max 1.31 50th: 1.23; 75th: 1.52; 

95th: 2.11 

Villeneuve et al. 

(2006, 091179) 

Toronto, ON, 

Canada 

Physicians Visits: 

Allergic rhinitis 24-h avg 1.1 Maximum: 2.2 

Sinclair et al. 

(2004, 088696) Atlanta, GA Urgent Care Visits: 

Asthma; respiratory infections 

1-h max 1.3 NR 

Hospital Admissions 

Respiratory Disease 

The majority of studies from North America that examined the association between short-term 

exposure to CO and HAs for all respiratory diseases were conducted in Canada, and only one of 

these studies presented results from a combined analysis of multiple cities (Cakmak et al., 2006, 

093272). In a study of 10 of the largest Canadian cities, Cakmak et al. (2006, 093272) examined 

respiratory HAs (ICD-9: 466, 480-486, 490-494, 496) in relation to ambient gaseous pollutant 

concentrations for the time period 1993-2000. This study reported a 0.37% (95% CI: 0.12-0.50) 

increase in respiratory hospital admissions for all ages for a 0.5 ppm increase in 24-h avg CO (lag 

2.8 days averaged over the 10 cities1

). However, Cakmak et al. (2006, 093272) only examined the 

potential confounding effects of gaseous pollutants (i.e., NO2, SO2, and O3) on the CO risk estimate 

in a multipollutant model and did not provide correlation coefficients, limiting the interpretation of 

the effects observed in the single-pollutant model. U.S.-based studies (Los Angeles and Spokane) 

that examined HAs for all respiratory diseases reported similarly weak or null associations with CO 

(Linn et al., 2000, 002839; Slaughter et al., 2005, 073854). But two single-city studies conducted in 

Canada reported stronger associations, primarily through evidence from copollutant models, between 

short-term exposure to CO and respiratory disease HAs (Burnett et al., 2001, 093439; Yang et al., 

2003, 055621). In a study conducted in Toronto, Canada, for the time period 1980-1994, Burnett 

et al. (2001, 093439) reported a relatively strong association between 1-h max CO and respiratory 

disease HAs in children <2 yr of age for the diagnoses of asthma (493), acute bronchitis/bronchiolitis 

(466), croup (464.4), and pneumonia (480-486). The authors found a 9.7% (95% CI: 4.1-15.5) 

increase in HAs for a 2-day avg (lag 0-1) per 1 ppm increase in 1-h max CO. In the two-pollutant 

model analysis with O3, the estimate for CO remained elevated (7.29% [95% CI: 1.75-13.1]), but CO 

 

1

 To determine the lag for the combined estimate across all 10 cities, Cakmak et al. (2006, 093272) averaged the strongest associations 

from lags 0-5 days from each city. 

January 2010 5-90 
was not found to be highly correlated with O3 (r = 0.24). Yang et al. (2003, 055621) reported similar 

results (OR = 1.04 [95% CI: 1.01-1.06] at lag 1 per 0.5 ppm increase in 24-h avg CO) for pediatric 

(<3 yr of age) respiratory disease (ICD-9: 460-519) HAs in Vancouver for the time period 

1986-1998. Yang et al. (2003, 055621) also reported elevated associations with 24-h avg CO and 

respiratory HAs (ICD-9: codes 460-519) for ages 65 yr and over in Vancouver, Canada, (OR = 1.02 

[95% CI: 1.00-1.04]) at lag 1 for a 0.5 ppm increase in 24-h avg CO. The authors found that the CO 

risk estimates remained the same when O3 was included in the model, which could be attributed to 

the lack of collinearity between CO and O3 due to their negative correlation (r = -0.52). 

Asthma 

Some studies that examined the effect of short-term exposure to CO on asthma HAs conducted 

all age and age-stratified analyses, specifically to examine effects in children. In a few studies 

conducted in Canada, evidence was observed for increased pediatric (ages 6-12 yr) asthma HAs 

(ICD-9: 493) in boys but not girls (Lin et al., 2003, 042549; Lin et al., 2004, 055600); however, a 

biological explanation was not provided which could explain this difference. Lin et al. (2003, 

042549) used a bidirectional case-crossover analysis in Toronto, Canada, for the years 1981-1993. 

The authors reported an OR of 1.05 (95% CI: 1.00-1.11) per 0.5 ppm increase in 24-h avg CO for a 

1-day lag for boys, with similar results being reported when averaging CO concentrations up to 

7 days prior to an HA. Risk estimates for girls did not provide evidence of an association using the 

same lag structure that was used in the boys’ analysis (OR = 1.00 [95% CI: 0.93-1.06]); lag 1). In 

this study, CO levels were moderately correlated with NO2 (r = 0.55) and PM2.5 (r = 0.45), and 

weakly correlated with SO2 (r = 0.37). In this study, copollutant analyses were not conducted to 

examine the potential confounding effect of different PM size fractions or gaseous pollutants on CO 

risk estimates. It should be noted that this study used a bidirectional case-crossover analysis, which 

may bias the results in either direction (Levy et al., 2001, 017172). Studies that examined the various 

referent selection strategies for the case-crossover study design have concluded that the preferred 

control selection strategy is the time-stratified framework (Levy et al., 2001, 017172). Lin et al. 

(2004, 055600) also examined the association between air pollutants and asthma HAs in children, 

but using a time-series study design in Vancouver during the years 1987-1998. In this study, the 

authors stratified results by socioeconomic status (SES) and found some evidence for an association 

between CO and asthma HAs for both girls and boys, of both high and low SES at lag 1 

(RR=1.01-1.06 per 0.5 ppm increase in 24-h avg CO); but overall, the evidence was less consistent 

for a greater effect in boys versus girls compared to Lin et al. (2003, 042549). In a study that 

examined asthma HAs for all ages and genders combined, Slaughter et al. (2005, 073854) observed 

some evidence for an increase in asthma HAs (ICD-9 493) in Spokane (1995-2000) for CO at lag 2 

(RR = 1.03 [ 95% CI: 0.98-1.08]) for a 0.5 ppm increase in 24-h avg CO but not for the other two 

lags examined (lag 1 and lag 3). 

Chronic Obstructive Pulmonary Disease 

A few of the studies examined the effect of short-term exposure to CO on COPD, or 

obstructive lung disease, and HAs. Moolgavkar (2003, 042864) (a reanalysis of Moolgavkar, 2000, 

010274) examined HAs for COPD plus “allied diseases” (ICD-9 490-496) in two U.S. counties 

(Cook County, IL, and Los Angeles County, CA) for the years 1987-1995, using Poisson generalized 

linear models (GLMs) or generalized additive models (GAM), with the more stringent convergence 

criteria. Overall, the results from both models were similar. Using the GAM models, the study 

reported increases in HAs of 0.53-1.20% for all ages in Los Angeles County and 0.17-1.41% for 

ages ≥ 65 yr in Cook County, for a 0.5 ppm increase in 24-h avg CO and lags ranging from 0 to 

5 days. However, CO was found to be highly correlated with NO2 in both Cook County (r = 0.63) 

and Los Angeles County (r = 0.80), but Moolgavkar (2003, 042864) did not examine the influence of 

copollutants on CO risk estimates. Yang et al. (2005, 090184) reported similar results for COPD HAs 

(ICD-9 490-492, 494, 496) in Vancouver for ages ≥ 65 yr for the years 1994-1998 for a ma of 0- to 

6-day lags (RR = 1.14 [95% CI: 1.03-1.23] per 0.5 ppm increase in 24-h avg CO). In this study, CO 

concentrations were moderately correlated with NO2, SO2, and PM10, and moderately negatively 

correlated with O3. In copollutant models, Yang et al. (2005, 090184) found that risk estimates for 

CO and COPD HAs remained elevated with O3 (RR=1.19 [95% CI: 1.07-1.32]) or SO2 (RR=1.19 

[95% CI: 1.02-1.39]), but were attenuated when adjusting for NO2 (RR=1.07 [95% CI: 0.92-1.24]) 

or PM10 (RR=1.03 [95% CI: 0.89-1.21]). Contrary to Moolgavkar (2003, 042864) and Yang et al. 

January 2010 5-91 
(2005, 090184), Slaughter et al. (2005, 073854) found no association between short-term exposure to 

CO and COPD HAs (ICD-9 491, 492, 494, 496) in Spokane, WA, at lag 1-day (RR = 0.97 

[95% CI: 0.93-1.01] per 0.5 ppm increase in 24-h avg CO) with similar results being reported for 2- 

and 3-day lags. However, this study did not examine correlations between CO and other gaseous 

pollutants or conduct copollutant analyses. 

Acute Bronchiolitis in Infants 

Karr et al. (2006, 088751; 2007, 090719) examined both short-term (lag 0 or 1) and longer 

term levels of CO in relation to acute bronchiolitis (ICD-9: 466) HAs during the first year of life 

from 1995-2000 in the South Coast Air Basin in California. Karr et al. (2006, 088751) found no 

evidence of a short-term association between ambient CO concentrations and HAs for acute 

bronchiolitis at lag 1 day (OR= 0.99 [95% CI: 0.98-1.01] per 0.5 ppm increase in 24-h avg CO). In 

addition, Karr et al. (2007, 090719), which examined longer term exposures (average in the month 

prior to a HA and lifetime average) in a matched case-control study, did not provide any evidence of 

an association with CO. Neither of these studies examined the correlation between CO and other 

pollutants nor conducted copollutant analyses. 

Pneumonia and Other Respiratory Infections 

In addition to examining the effect of short-term exposure to CO on health outcomes that can 

limit the function of the respiratory system, some studies examined the effect of CO on individuals 

with pneumonia (ICD-9: 480-486) separately or in combination with other respiratory infections. 

Zanobetti and Schwartz (2006, 090195) examined pneumonia HAs (ICD-9 480-487) in Boston, MA, 

for the years 1995-1999 for individuals ages 65 yr and older, using a time-stratified case-crossover 

analysis. The authors reported an increase in pneumonia HAs at lag 0 of 5.4% (95% CI: 1.2-10.0) 

per 0.5 ppm increase in 24-h avg CO. While Zanobetti and Schwartz (2006, 090195) did not report 

multipollutant results, they suggested that CO was most likely acting as a marker for traffic-related 

pollutants because CO was highly correlated with both BC (r = 0.80) and NO2 (r = 0.67) and 

moderately correlated with PM2.5 (r = 0.52). Instead of examining the effect of CO on pneumonia 

HAs separately, as was done by Zanobetti and Schwartz (2006, 090195), Lin et al. (2005, 087828) 

presented results for the overall effect of CO on respiratory infection HAs (ICD-9: 464, 466, 480-

487). In this analysis, Lin et al. (2005, 087828) examined the potential increase in respiratory HAs in 

children <15 yr of age in Toronto, Canada, for 1998-2001, using a bidirectional case-crossover 

approach. The authors reported elevated estimates for boys (OR=1.17 [95% CI: 1.03-1.32] per 

0.5 ppm increase in 24-h avg CO for a 6-day ma) while the estimate for girls was weaker and with 

wider confidence intervals (OR=1.06 [95% CI: 0.91-1.23]). In multipollutant models with both PM2.5

and PM10-2.5 the CO risk estimates were slightly attenuated but remained positive (boys: OR=1.10 

[95% CI: 0.96-1.26]; girls: OR=1.03 [95% CI: 0.88-1.06]). Lin et al. (2005, 087828) did not provide 

an explanation as to why the estimates were stronger for boys than for girls. It should be noted that 

this study used a bidirectional case-crossover analysis, which, as discussed previously, may bias the 

results in either direction (Levy et al., 2001, 017172). 

January 2010 5-92 
Study Location Age Lag Effect Estimate (95% CI) 

Burnett et al. (2001, 093439) Toronto, Can <2 0-1 All Respiratory 

Yang et al. (2003, 055621) Vancouver, Can <3 1 

Linn et al. (2000, 002839) Los Angeles, CA 30+ 0 

Yang et al. (2003, 055621) Vancouver, Can 65+ 1 

Cakmak et al. (2006, 093272) 10 Canadian Cities All 2.8c 

Slaughter et al. (2005, 073854) Spokane, WA All 2 

Lin et al. (2003, 042549) Toronto, Can 6-12a 1 Asthma 

Lin et al. (2003, 042549) Toronto, Can 6-12b 1 

Slaughter et al. (2005, 073854) Spokane, WA All 2 

Slaughter et al. (2005, 073854) Spokane, WA 15+ 2 COPD 

Yang et al. (2005, 090184) Vancouver, Can 65+ 0-6 

Zanobetti & Schwartz (2006, 090195) Boston, MA 65+ 0 Pneumonia 

Karr et al. (2006, 088751) SCAB, CA <1 1 Acute Bronchiolitis 

Lin et al. (2005, 087828) Toronto, Can <15a 0-5 Respiratory Infection 

Lin et al. (2005, 087828) Toronto, Can <15b 0-5 a Boys 

b

Girls 

c

To determine the lag for the combined estimate across all 10 cities, Cakmak et al. (2006, 093272) 

averaged the strongest associations from lags 0-5 days from each city. 

 

 Relative Risk / Odds Ratio 

Figure 5-15. Summary of associations for short-term exposure to CO and respiratory hospital 

admissions.1,2 Effect estimates were standardized depending on the averaging 

time used in the study: 0.5 ppm for 24-h avg, 0.75 ppm for max 8-h avg, and 

1.0 ppm for 1-h max. 

Emergency Department Visits 

Respiratory Disease 

Peel et al. (2005, 056305) conducted a large single-city respiratory disease ED visit study in 

Atlanta, GA, which included data from 31 hospitals for the time period 1993–2000. In this study, 

results were reported for various respiratory-related visits (ICD-9 460-466, 477, 480-486, 491-493, 

496, 786.09). In an all-ages analysis, the authors found a RR=1.01 (95% CI: 1.00-1.02) for all 

respiratory disease ED visits for a 3-day avg (lag 0-2) per 1 ppm increase in 1-h max CO 

concentration. Tolbert et al. (2007, 090316) expanded the time period used in the Peel et al. (2005, 

056305) study to include ED visits through 2004 and reported similar results for all respiratory 

disease ED visits (RR=1.013 [95% CI: 1.007-1.018] per 1 ppm increase in 1-h max CO). The CO 

risk estimates from the Atlanta, GA, ED visits studies were attenuated when O3, NO2, or PM were 

added to the model (results not presented quantitatively), which could potentially be explained by the 

high correlations reported in Tolbert et al. (2007, 090316) between CO and NO2 (r = 0.70) and EC 

(r = 0.66) and the moderate correlation with PM2.5 (r = 0.51). One additional ED-visits study that 

also examined respiratory disease (Slaughter et al., 2005, 073854) presented essentially null results 

at lag 1 and 2 but found similar results to Peel et al. (2005, 056305) and Tolbert et al. (2007, 090316) 

at lag 3 (RR=1.02 [95% CI: 1.00-1.03] per 0.5 ppm increase in 24-h avg CO). Slaughter et al. (2005, 

073854) reported a weak to moderate correlation between CO and various PM size fractions but did 

not report the correlation between CO and gaseous pollutants, limiting the comparison of this study 

with Peel et al. (2005, 056305) and Tolbert et al. (2007, 090316). 

Asthma 

The association between short-term exposure to CO and asthma ED visits (ICD-9 493, 786.09) 

was also examined in Atlanta, GA, by Peel et al. (2005, 056305). In this study, the authors reported 

 

1

 Risk estimates from Moolgavkar (2003, 042864) were not included in this figure because the study presented a range of effect estimates 

using different statistical models. The results from this study were more adequately highlighted in the evaluation of the study in the 

COPD section. 

2

 Risk estimates from Lin et al. (2004, 055600) were not included in the figure because the results were stratified by SES and therefore 

could not be readily compared to effect estimates from Lin et al. (2003, 042549). 

January 2010 5-93 
results from distributed lag models including lags 0-13 in addition to a ma of lags 0, 1, and 2 (lag 

0-2) for specific respiratory outcomes (e.g., asthma). Effect estimates from the distributed lag models 

were stronger than those produced from models that used 3-day ma CO concentrations (RR = 1.01 

[95% CI: 0.99-1.02] for lags 0-2 compared to RR=1.08 [95% CI: 1.05-1.11] for an unconstrained 

distributed lag of 0-13 for a 1 ppm increase in 1-h max CO). These results demonstrated the potential 

effect of CO exposures up to 13 days prior to an asthma ED visit. Estimates were stronger for 

pediatric ED visits (ages 2-18 yr) (RR=1.02 [95% CI: 1.00-1.04] per 1 ppm increase in 1-h max CO) 

for a 3-day avg (lag 0-2) compared to all ages (Peel et al., 2005, 056305). Slaughter et al. (2005, 

073854), which also examined ED visits for Spokane (1995-2001), reported an increase in asthma 

ED visits for all ages for CO at lag 3 (RR=1.03 [95% CI: 1.00-1.05] per 0.5 ppm increase in 24-h 

avg CO) but not for the other two lags examined (lags 1 and 2). The results from Ito et al. (2007, 

156594) also provide evidence of increased ED visits for asthma (ICD-9 493) for all ages in New 

York City for 1999-2002. Using three different models that adjusted for weather variables via 

different degrees of smoothing and/or a different number of weather variables, the authors found that 

CO effect estimates remained elevated in both an all-year analysis and in analyses stratified by warm 

(i.e., April to August) and cold (i.e., November to March) months. Using Model C, which adjusted 

for temporal trends using 8 degrees of freedom (df) and included variables to adjust for weather and 

day of the week, an all-year RR of 1.03 (95% CI: 1.01-1.06) per 0.75 ppm increase in maximum 8-h 

avg CO concentrations was reported. Ito et al. (2007, 156594) also examined copollutant models 

using Model C but only during the warm season. In this model CO effect estimates were robust to 

the inclusion of PM2.5 (RR = 1.06 [95% CI: 1.00-1.11]), O3 (RR=1.10 [95% CI: 1.05-1.15]), and SO2

(RR=1.04 [95% CI: 0.99, 1.09]) in the model, but the CO risk estimate was attenuated, resulting in a 

negative effect estimate when including NO2 (RR=0.97 [95% CI: 0.92-1.03]) in the model. 

Chronic Obstructive Pulmonary Disease 

In the examination of the effect of short-term exposure to CO on COPD ED visits (ICD-9 491, 

492, 496), Peel et al. (2005, 056305) reported elevated estimates for Atlanta, GA, for 1993-2000 

(RR=1.03 [95% CI: 1.00-1.05] per 1 ppm increase in 1-h max CO for lag 0-2 ma) with similar 

results for the distributed lag model (RR=1.03 [95% CI: 0.98-1.09). However, results from Slaughter 

et al. (2005, 073854) from Spokane, WA, were consistent with a null or slightly protective 

association at lag 1 (RR=0.96 [95% CI: 0.92-1.00] per 0.5 ppm increase in 24-h avg CO at lag 1) 

with similar results for lags 2 and 3. 

Pneumonia and Other Respiratory Infections 

Similar to the HA analysis conducted by Zanobetti and Schwartz (2006, 090195) discussed 

above, Peel et al. (2005, 056305) examined the effect of CO on pneumonia separately (ICD-9: 

480-486) but also included an analysis of upper respiratory infection (ICD-9: 460-466, 477) ED 

visits for all ages in Atlanta, GA, during the years 1993-2000. The authors reported a weak estimate 

for pneumonia for the 3-day ma (lag 0-2) (RR=1.01 [95% CI: 0.996-1.021] per 1 ppm increase in 1-h 

max CO). However, when using an unconstrained distributed lag model (days 0-13), Peel et al. 

(2005, 056305) observed evidence of an association (RR=1.045 [95% CI: 1.01-1.08]). An 

examination of upper respiratory infection (URI) ED visits, the largest of the respiratory ED groups, 

found slightly increased risk estimates for both the 3-day ma (lag 0-2) (RR=1.01 [95% CI: 

1.00-1.02]) and the unconstrained distributed lag for days 0-13 (RR=1.07 [95% CI: 1.05-1.09]) per 

1 ppm increase in 1-h max CO. In copollutant models, CO risk estimates were largely attenuated 

when PM10, O3, or NO2 were included in the model (not reported quantitatively). Upon conducting 

an age-stratified analysis, Peel et al. (2005, 056305) also found that infant (<1 yr of age) and 

pediatric (ages 2-18 yr) URI ED visit CO risk estimates were substantially stronger than the all-age 

risk estimates. 

January 2010 5-94 
Study Location Age Lag Effect Estimate (95% CI) 

Slaughter et al. (2005, 073854) Spokane, WA All 3 All Respiratory

Peel et al. (2005, 056305) Atlanta, GA All 0-2 

Tolbert et al. (2007, 090316) Atlanta, GA All 0-2 

Peel et al. (2005, 056305) Atlanta, GA 2-18 0-2 Asthma

Peel et al. (2005, 056305) Atlanta, GA All 0-2 

Peel et al. (2005, 056305) Atlanta, GA All 0-13a

Slaughter et al. (2005, 073854) Spokane, WA All 3 

Ito et al. (2007, 156594) NYCity, NY All 0-1 

Slaughter et al. (2005, 073854) Spokane, WA 15+ 1 COPD 

Peel et al. (2005, 056305) Atlanta, GA All 0-2 

Peel et al. (2005, 056305) Atlanta, GA All 0-13a

Peel et al. (2005, 056305) Atlanta, GA All 0-2 Pneumonia

Peel et al. (2005, 056305) Atlanta, GA All 0-13a

Peel et al. (2005, 056305) Atlanta, GA All 0-2 Respiratory Infection

Peel et al. (2005, 056305) Atlanta, GA All 0-13a

a

Unconstrained distributed lag 

 Relative Risk 

Figure 5-16. Summary of associations for short-term exposure to CO and respiratory ED 

visits. Effect estimates were standardized depending on the averaging time used 

in the study: 0.5 ppm for 24-h avg, 0.75 ppm for max 8-h avg, and 1.0 ppm for 1-h 

max. 

Physician Visits 

Although HAs and ED visits are the two most well-studied measures of morbidity, a few 

studies also examined the effect of CO on unscheduled physician visits. In a time-series study, 

Villeneuve et al. (2006, 091179) examined the effect of CO on physician visits for allergic rhinitis in 

individuals 65 yr and older in Toronto, Canada. Although quantitative results were only presented in 

figures, upon observation it was evident that estimates were consistent with a null association for 

lags 0-6 (Villeneuve et al., 2006, 091179). In an additional study, Sinclair et al. (2004, 088696) 

reported results for urgent care visits for asthma and respiratory infections in a health maintenance 

organization in Atlanta, GA; however, the study only reported statistically significant results, of 

which none were for CO. 

Summary of Associations between Short-Term Exposure to CO and Respiratory 

Hospital Admissions, ED Visits, and Physicians Visits 

Compared to other criteria air pollutants (e.g., O3 and PM), relatively few studies evaluated the 

association between short-term exposure to ambient CO and HAs and ED visits for various 

respiratory outcomes. Although evidence for consistent positive associations (Figure 5-15 and Figure 

5-16) has been found across the studies evaluated, there remains uncertainty as to a biologically 

plausible mechanism which could explain the association between CO exposure and respiratoryrelated health effects. As observed in the preceding section, several authors suggest that the observed 

associations are due to CO acting as an indicator of combustion-related pollution (e.g., traffic). The 

interpretation of the associations observed in the studies evaluated is further complicated by the 

moderate to high correlations reported between CO and other traffic-related pollutants such as NO2, PM2.5, EC, or BC. Only a few studies examined potential confounding of CO risk estimates by 

copollutants, and these studies found that CO risk estimates were generally robust to the inclusion of 

O3, SO2, and PM in two-pollutant models. However, those studies that examined two-pollutant 

models with NO2 found that CO risk estimates, although positive, were slightly attenuated. 

January 2010 5-95 
5.5.2. Epidemiologic Studies with Long-Term Exposure 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) did not evaluate any studies that examined the 

effect of long-term exposure to CO on respiratory health. The following section discusses those 

studies that analyze the effect of long-term exposure to CO on pulmonary function, asthma/asthma 

symptoms, and allergic rhinitis. Table 5-21 lists the studies evaluated in this section along with the 

respiratory health outcomes examined and CO concentrations reported. 

Table 5-21. Range of CO concentrations reported in key respiratory morbidity studies that examined 

effects associated with long-term exposure to CO. 

Studya Location 

(Sample Size) Year(s) Health Outcome Metric 

Mean 

Concentration 

(ppm) 

Middle/Upper 

Percentile 

Concentrations (ppm)

Mortimer et al. (2008, 

122163) 

San Joaquin 

Valley, CA 

(n=232) 

1989-2000 Pulmonary 

function 

Monthly mean 

of max 8-h 

avg 

NR NR 

Meng et al. (2007, 093275) 

Los Angeles and 

San Diego 

counties, CA 

11/2000-9/2001 Asthma symptoms Annual mean 

of 1-h avg NR NR 

Wilhelm et al. (2008, 

191912) 

Los Angeles and 

San Diego 

Counties, CA 

(n=612) 

1999-2001 Asthma symptoms Annual mean 

of 1-h avg 1.0 Maximum: 1.8 

Goss et al. (2004, 055624) 

U.S. 

2000 

Pulmonary 

function; Asthma 

symptoms 

Annual mean 

of 1-h avg 0.69 

25th: 0.48 

50th: 0.59 

75th: 0.83 

Hirsch et al. (1999, 003537) Dresden, Germany 9/1995-6/1996 Respiratory 

symptoms 

Annual mean 

of 0.5-h avg 0.60 75th: 0.76 

Maximum: 1.34 

Guo et al. (1999, 010937) 

Taiwan 

1994 Asthma; Asthma 

symptoms 

Annual mean 

of monthly avg 0.85 

50th: 0.84 

75th: 1.00 

Maximum: 1.61 

Wang et al. (1999, 008105) Kaohsiung and 

Pintong, Taiwan 1996 Asthma Annual avg NR 50th: 0.80 

Hwang et al. (2005, 089454) Taiwan 2000 Asthma Annual mean 

of monthly avg 0.66 

50th: 0.65 

75th: 0.75 

Maximum: 0.96 

Hwang et al. (2006, 088971) Taiwan 2000 Allergic rhinitis Annual mean 

of monthly avg 0.66 

50th: 0.65 

75th: 0.75 

Maximum: 0.96 

Lee et al. (2003, 049201) Taiwan 1994 Allergic rhinitis Annual avg 0.85 

50th: 0.84 

75th: 1.00 

Maximum: 1.61 

Arnedo-Pena et al. (2009, 

190238) 7 Spanish cities 2000 

Asthma, allergic 

rhinitis, atopic 

eczema 

Annual avg 

50th: 0.61 

75th: 0.78 

Maximum: 1.04 

Mortimer et al. (2008, 

187280) 

Fresno, CA 

(n=170) 

11/2000-4/2005 Allergic 

sensitization 

Monthly mean 

of 24-h avg NRb NRb

 

a

The number of individuals included in the study population was only provided for those studies that included less than 1,000 participants. b

This study only presented air quality data graphically. 

5.5.2.1. Pulmonary Function 

Mortimer et al. (2008, 122163) examined the effect of prenatal and lifetime exposures to air 

pollutants on pulmonary function in 232 asthmatic children who resided in the San Joaquin Valley of 

California. The strong temporal correlation between pollutants and pollutant metrics for different 

time periods in the study area contributed to the inability to draw conclusions about the effect of 

January 2010 5-96 
individual pollutant metrics on pulmonary function (Mortimer et al., 2008, 122163). The authors 

used a newly developed Deletion/Substitution/Addition (DSA) algorithm “to identify which 

pollutant metrics were most predictive of pulmonary function” (Mortimer et al., 2008, 122163). This 

methodology uses an exploratory process to identify the best predictive model for each outcome of 

interest. Focusing specifically on the exposure durations after birth, using this approach, Mortimer 

et al. (2008, 122163) found that exposure to CO early in life, ages 0-3 yr, was negatively associated 

with FEV1/FVC, resulting in an effect size of -2.5% per IQR increase in CO.1

 Additional negative 

associations were observed between exposure to CO during the first 6 yr of life and FEF25 (-6.7%) 

and FEF25-75/FVC (-4.8%) in children diagnosed with asthma prior to 2 yr of age. Overall, Mortimer 

et al. (2008, 122163) found that these effects were limited to subgroups, including AfricanAmericans and individuals diagnosed with asthma before the age of 2 yr. It must be noted that 

research still needs to be conducted to validate the aforementioned results obtained using the DSA 

algorithm and the subsequent calculation of effect estimates using GEE because the current model 

could underestimate the uncertainty surrounding the associations reported (Mortimer et al., 2008, 

122163). Although the authors did find associations between long-term exposure to CO and 

decrements in pulmonary function, they also observed high correlations between CO and NO2, which together are markers for pollutants generated by urban combustion sources (e.g., mobile 

sources) (Mortimer et al., 2008, 122163). 

Goss et al. (2004, 055624) also examined the effect of long-term exposure to CO on 

pulmonary function in a cohort of cystic fibrosis patients >6 yr of age enrolled in the Cystic Fibrosis 

National Patient Registry in 1999 and 2000. When examined cross-sectionally in 2000 using a 

multiple linear regression model, the authors found no association between CO and a reduction in 

FEV1. However, Goss et al. (2004, 055624) recognize that the CO results could be influenced by 

measurement error and subsequently exposure misclassification. 

5.5.2.2. Asthma and Asthma Symptoms 

U.S.-based studies consistently reported no association between long-term exposure to CO and 

asthma and asthma symptoms. Wilhelm et al. (2008, 191912) and Meng et al. (2007, 093275) both 

examined the association between long-term exposure to air pollutants and asthma symptoms in 

respondents to the 2001 California Health Interview Survey (CHIS) in populations consisting of 

children (0-17 yr) and adults (≥ 18 yr), respectively, who resided in Los Angeles and San Diego 

counties. Using a cross-sectional study design, Meng et al. (2007, 093275) found no association 

between long-term exposure to CO and poorly controlled asthma in adults, while Wilhelm et al. 

(2008, 191912) reported no associations between long-term exposure CO and asthma symptoms or 

asthma HA and ED visits in children during the study period (i.e., 2000-2001). In an additional 

U.S.-based study, Goss et al. (2004, 055624) found no association (OR=1.01 [95% CI: 0.92-1.10] 

per 0.5 ppm increase in annual average CO concentrations) between long-term exposure to CO and 

pulmonary exacerbations in a national cohort of individuals with cystic fibrosis >6 yr of age. 

Among studies conducted in other countries, a study conducted in Germany (Hirsch et al., 

1999, 003537) and studies conducted in Taiwan (Guo et al., 1999, 010937; Hwang et al., 2005, 

089454; Wang et al., 1999, 008105), all found positive associations between long-term exposure to 

CO and asthma or asthma symptoms in populations ranging from 6 to 16 yr old. In these studies, the 

authors addressed the observed associations differently. Guo et al. (1999, 010937) and Hwang et al. 

(2005, 089454) both concluded that it is unlikely CO directly affects the respiratory system; Hirsch 

et al. (1999, 003537) attributed the increase in the prevalence of cough and bronchitis to exposure to 

traffic-related air pollutants (i.e., NO2, CO, and benzene); and Wang et al. (1999, 008105) did not 

interpret the association observed between long-term exposure to CO and adolescent asthma. Only 

Hwang et al. (2005, 089454) conducted a copollutant analysis and found that the asthma effects 

observed were robust to the inclusion of PM10, SO2 and O3 in the model. However, this study did not 

include NOX in a copollutant model, which is notable because NOX was found to be highly 

correlated with CO (r = 0.88). 

 

1

 The study did not present the IQR for CO; therefore, the effect estimates presented were not standardized using the approach mentioned 

previously in this ISA. 

January 2010 5-97 
5.5.2.3. Respiratory Allergy and Other Allergic Responses 

Allergy is a major contributor to asthma and upper respiratory symptoms; as a result, studies 

have examined the effect of air pollutants on allergic outcomes. The studies evaluated that examined 

the association between long-term exposure to CO and allergic outcomes were primarily conducted 

outside of the U.S. and Canada. A multicity study conducted in 7 Spanish cities found that the annual 

average concentration of CO was associated with a higher prevalence of allergic rhinitis, 

rhinoconjunctivitis, and atopic eczema in 6- to 7-yr-old children (Arnedo-Pena et al., 2009, 190238). 

NO2 was also examined and found to be positively associated with allergic rhinitis, but, unlike CO, 

was negatively associated with eczema and rhinoconjunctivitis. It should be noted that in this data 

set CO and NO2 concentrations were negatively correlated (r = -0.55). Additionally, SO2 was 

positively associated with all allergic outcomes, while TSP matter was inversely associated with 

rhinitis and rhinoconjunctivitis. Hwang et al. (2006, 088971) and Lee et al. (2003, 049201) both 

examined the effect of long-term exposure to air pollutants on the prevalence of allergic rhinitis in a 

population of schoolchildren in Taiwan. Both studies found an association between allergic rhinitis 

prevalence and CO, but they also observed an association with NOX. As a result, although Hwang 

et al. (2006, 088971) and Lee et al. (2003, 049201) observed an increase in the prevalence of allergic 

rhinitis in response to an increase in long-term CO levels, they concluded that the combination of an 

association being observed for both CO and NOX can be attributed to the complex mixture of trafficrelated pollutants and not necessarily CO alone. Although questions surround the associations 

observed between long-term exposure to CO and allergic outcomes, the results are consistent with 

those presented in a multicity study that examined the association between short-term exposure to 

CO and allergic symptoms. Moon et al. (2009, 190297) observed associations between short-term 

CO exposure and allergic symptoms in children in South Korea. However, allergic symptoms were 

also associated with other pollutants, including PM10, SO2, and NO2, and the study did not present 

correlation coefficients to allow for further analysis of the results. It should be noted that 

toxicological experiments suggest that endogenously produced CO may play an integral part in the 

pathogenesis of allergic rhinitis, resulting in an additional potential pathway for CO-induced allergic 

outcomes (Shaoqing et al., 2008, 192384). 

Allergic symptoms such as rhinitis are a direct result of allergic sensitization, which is 

commonly measured by skin prick testing or IgE antibody measurement. Hirsch et al. (1999, 

003537), in a single-city study conducted in Dresden, Germany, observed no associations between 

annual average concentrations of CO, NO2, SO2, or O3 and allergy assessed by skin prick testing or 

serum IgE measurement in schoolchildren. However, prenatal exposure to CO was associated with 

allergic sensitization in a cohort of 6- to 11-year-old asthmatic children in California (Mortimer et 

al., 2008, 187280). Skin prick tests indicated higher levels of sensitization to indoor and outdoor 

allergens with an increase in CO exposure during the prenatal period; the association with 

sensitization to outdoor allergens remained after adjustment for effect modifiers, copollutants, and 

other potential confounders. Mortimer et al. (2008, 187280) also found that PM10 exposure was 

associated with sensitization to indoor allergens but was not significant after adjustment. 

Additionally, despite strong correlations between CO and NO2, no associations were reported with 

NO2. It should be noted that these results were produced using the DSA algorithm and, as discussed 

previously, additional research is still needed to evaluate the use of this method in air pollution 

epidemiology (Mortimer et al., 2008, 122163). 

5.5.2.4. Summary of Associations between Long-Term Exposure to CO and 

Respiratory Morbidity 

To date, a limited number of studies have examined the potential association between longterm exposure to CO and respiratory morbidity. Although studies have reported positive associations 

for various respiratory outcomes, the limited evidence available, the new analytical methods 

employed, and the lack of studies that examined potential confounders of the CO-respiratory 

morbidity relationship, especially due to the high correlation between CO and other traffic-related 

pollutants, makes it difficult to attribute the associations observed to CO independent of other air 

pollutants. 

January 2010 5-98 
5.5.3. Controlled Human Exposure Studies 

Human clinical studies provide very little and inconsistent evidence of changes in pulmonary 

function following exposure to CO. In one older study, Chevalier et al. (1966, 010641) observed a 

significant decrease in total lung capacity following a short-term exposure to 5,000 ppm resulting in 

a COHb level of 4%. However, a similar study conducted at a higher CO concentration resulting in 

COHb levels of 17-19% found no CO-induced changes in lung volume or mechanics (Fisher et al., 

1969, 012381). The 2000 CO AQCD (U.S. EPA, 2000, 000907) reported no evidence of CO-induced 

changes in exercise ventilation at COHb levels <15% during submaximal exercise (Koike et al., 

1991, 013500). In two recent human clinical studies, exposure to CO (COHb ≈ 10%) was not found 

to significantly affect resting pulmonary ventilation compared with exposure to clean air under either 

hypoxic or hyperoxic exposure conditions (Ren et al., 2001, 193850; Vesely et al., 2004, 194000). 

The results of these studies demonstrate that the hypoxia- and CO2-induced increases in pulmonary 

ventilation are not affected by CO. One recent study evaluated the potential anti-inflammatory 

effects of controlled exposures to CO in the airways of 19 individuals with COPD (Bathoorn et al., 

2007, 193963). Subjects were exposed to both CO at concentrations of 100-125 ppm as well as room 

air for 2 h on each of 4 consecutive days. The authors reported a small decrease in sputum 

eosinophils, as well as a slight increase in the provocative concentration of methacholine required to 

cause a 20% reduction in FEV1 following exposure to CO. Although this study appears to 

demonstrate some evidence of an anti-inflammatory effect of CO among subjects with COPD, it 

must be noted that two of these patients experienced exacerbations of COPD during or following CO 

exposure. A similar study found no evidence of systemic anti-inflammatory effects following 

exposure to higher CO concentrations (500 ppm for 1 h) in a group of healthy adults (Mayr et al., 

2005, 193984). 

5.5.4. Toxicological Studies 

As discussed in Section 5.2.5, the work of Thom, Ischiropoulos and colleagues (Ischiropoulos 

et al., 1996, 079491; Thom and Ischiropoulos, 1997, 085644; Thom et al., 1997, 084337; Thom et 

al., 1999, 016753; Thom et al., 1999, 016757) focused on CO-mediated displacement of NO from 

heme-binding sites. Although the concentrations of CO used in many of their studies were far higher 

than ambient levels, some of this research involved more environmentally-relevant CO levels. In one 

study (Thom et al., 1999, 016757), 1-h exposure of rats to 50 ppm CO resulted in increased lung 

capillary leakage 18 h later. Increased NO was observed in the lungs by electron paramagnetic 

resonance during 1-h exposure to 100 ppm CO and was accompanied by increases in H2O2 and 

nitrotyrosine. All of these effects were blocked by inhibition of NOS. These results, which were 

partially discussed in the 2000 CO AQCD (U.S. EPA, 2000, 000907), demonstrate the potential for 

exogenous CO to interact with NO-mediated pathways and to lead to pathophysiological effects in 

the lung. 

Recent work by Ghio et al. (2008, 096321) showed a disruption of cellular iron homeostasis 

following exposure to a low level of CO (50 ppm for 24 h) in rats. In lungs of inhalation-exposed 

rats, non-heme iron was significantly reduced, while lavagable iron was increased dramatically, 

suggesting an active removal of cellular iron. Lavagable ferritin was also increased following the CO 

exposure. Concurrently, liver iron levels increased, implying that the anatomical distribution of iron 

stores may significantly shift during/after CO exposures. These investigators were able to replicate 

the effect of loss of cellular iron in an in vitro model of cultured BEAS-2B cells and reported 

statistically significant effects at 10 ppm CO and an apparent maximal effect at 50 ppm CO 

(concentrations up to 500 ppm did not significantly enhance the iron loss beyond 50 ppm). Similar 

responses were observed for cellular ferritin. Both enhancement of iron removal and diminished iron 

uptake were noted in CO-exposed cells. Furthermore, decreased oxidative stress, mediator release 

and proliferation were noted in respiratory cells. These effects were reversible with a recovery period 

in fresh air. Interestingly, the in vivo exposure to CO induced mild but significant neutrophilia in the 

lungs compared to air-exposed rats. This finding is contrary to the concept that CO acts as an antiinflammatory agent; however, with alterations in iron handling several potential pathways could be 

initiated to recruit inflammatory cells into airways. The authors pointed out that while CO derived 

from HO activity may have an important role in iron regulation, the nonspecific application of 

exogenous CO would have little capacity to discriminate between excessive and/or inappropriate 

iron which catalyzes oxidative stress and iron which may be required for normal homeostasis. 

January 2010 5-99 
A chronic inhalation study by Sorhaug et al. (2006, 180414) demonstrated no alterations in 

lung morphology in Wistar rats exposed to 200 ppm CO for 72 wk. COHb levels were reported to be 

14.7%, and morphological changes were noted in the heart as described in Section 5.2.5.2. 

A recent study by Carraway et al. (2002, 026018) involved continuous exposure of rats to HH 

(380 torr) with or without co-exposure to CO (50 ppm) for up to 21 days. The focus of this study was 

on remodeling of the pulmonary vasculature. While the addition of CO to HH did not alter the 

thickness or diameter of vessels in the lung, there was a significant increase in the number of small 

(<50 μm) diameter vessels compared to control, HH-only, and CO-only exposures. Despite the 

greater number of vessels, the overall pulmonary vascular resistance was increased in the combined 

CO + HH exposure, which the authors attribute to enhancement of muscular arterioles and β-actin. 

One new study found an association between increased endogenous CO and the development 

of allergic rhinitis (Shaoqing et al., 2008, 192384). In this model, guinea pigs which were sensitized 

and challenged with ovalbumin exhibited high immunoreactivity of HO-1 in the nasal mucosa and a 

more than doubling of blood COHb levels (measured by gas chromatography). It is not known 

whether the observed increase in endogenous CO resulting from ovalbumin-mediated 

inflammation/oxidative stress plays a role in the development of allergic rhinitis but suggests a 

potential mechanism by which exogenous CO could impact an allergic phenotype. 

In summary, one older study (Thom et al., 1999, 016757) and two new studies (Carraway et 

al., 2002, 026018; Ghio et al., 2008, 096321) demonstrated effects of 50-100 ppm CO on the lung. 

Responses included an increase in alveolar capillary permeability, disrupted iron homeostasis, mild 

pulmonary inflammation, and an exacerbation of pulmonary vascular remodeling elicited by HH. 

These results should be considered in view of the potential for inhaled CO to interact directly with 

lung epithelial cells and resident macrophages. However, a chronic study involving 200 ppm CO 

demonstrated no changes in pulmonary morphology (Sorhaug et al., 2006, 180414). 

5.5.5. 

5.5.5.1.

Summary of Respiratory Health Effects 

Short-Term Exposure to CO 

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, HAs, and ED visits. The majority of the studies evaluated did not 

conduct 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 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 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 CO-induced 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 5-100 
5.5.5.2.

5.6.1. 

Long-Term Exposure to CO 

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. 

5.6. Mortality 

Epidemiologic Studies with Short-Term Exposure to CO 

Epidemiologic studies have traditionally focused on mortality effects associated with exposure 

to PM and O3, resulting in a limited number of studies that have conducted extended analysis to 

examine the potential influence of model selection, effect modifiers, or confounders on the 

association between CO and mortality. This has contributed to the inability to formulate a clear 

understanding of the association between short-term exposure to CO and mortality. This section 

summarizes the main findings of the 2000 CO AQCD (U.S. EPA, 2000, 000907) and evaluates the 

newly available information on the relationship between short-term exposure to CO and daily 

mortality in an effort to disentangle the CO-mortality effect from those effects attributed to other 

criteria air pollutants. 

5.6.1.1. Summary of Findings from 2000 CO AQCD 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) examined the association between short-term 

exposure to CO and mortality through the analysis of primarily single-city time-series studies, with 

additional evidence from one multicity study which included 11 Canadian cities. While the results 

presented by these studies did provide suggestive evidence that an association exists between CO 

and mortality, the AQCD concluded that inadequate evidence existed to infer a causal association 

between mortality and short-term exposure to ambient concentrations of CO. Multiple uncertainties 

were identified in the epidemiologic literature that contributed to this conclusion, which were 

discussed in Section 5.2.1. 

The majority of the recent time-series mortality studies, as mentioned previously, have not 

extensively examined the CO-mortality relationship. As such, CO has usually been considered as one 

of the potential confounding copollutants in air pollution epidemiologic studies. Given the limitation 

that most of these studies were not conducted to examine CO, the goal of this review is to evaluate 

the CO-mortality association and specifically the consistency of associations across studies, along 

with evidence of confounding and effect modification. 

5.6.1.2. Multicity Studies 

The following sections evaluate the recent literature that examined the association between 

short-term exposure to CO and mortality, and, in addition, discuss newly available information with 

regard to the issues specific to CO mentioned above. This evaluation focuses primarily on multicity 

studies because they provide a more representative sample of potential CO-related mortality effects 

and especially useful information by analyzing data from multiple cities using a consistent method, 

January 2010 5-101 
and thus avoiding potential publication bias.1 Table 5-22 details the multicity studies evaluated along 

with the mean CO concentrations reported in each study. 

Table 5-22. Range of CO concentrations reported in multicity studies that examine mortality effects 

associated with short-term exposure to CO. 

Study Location Years Averaging 

Time 

Mean 

Concentration 

(ppm) 

Range of Mean 

Concentrations 

Across Cities (ppm) 

Dominici et al. (2003, 056116; 2005, 

087912); Reanalysis of Samet et al. (2000, 

156939) 

82 US citiesa

(NMMAPS) 

1987-1994 24-h avg 1.02 Baton Rouge = 0.43 

Spokane = 2.19 

Burnett et al. (2004, 086247) 12 Canadian cities 1981-1999 24-h avg 1.02 Winnipeg = 0.58 

Toronto = 1.31 

Samoli et al. (2007, 098420)

b 19 European cities 

(APHEA2) 1990-1997c 8-h max 2.12 Basel = 0.52 

Athens = 5.3 

a

The study actually consisted of 90 U.S. cities, but only 82 had CO data. 

b

This study presented CO concentrations in the units mg/m3. The concentrations were converted to ppm using the conversion factor 1 ppm = 1.15 mg/m3, which assumes 

standard atmosphere and temperature. 

c

The study period varied from city to city. These years represent the total years in which data was collected across all cities. 

National Morbidity, Mortality, and Air Pollution Study of 90 U.S. Cities 

The time-series analysis of the 90 largest U.S. cities (82 cities for CO) in the National 

Morbidity, Mortality, and Air Pollution Study (NMMAPS) (Dominici et al., 2003, 056116; Dominici 

et al., 2005, 087912; a reanalysis of Samet et al., 2000, 156939) is by far the largest multicity study 

conducted to date to investigate the mortality effects of air pollution; however, the study primarily 

focused on PM10. The range in 24-h avg CO concentrations in a subset of the largest 20 cities (by 

population size) was 0.66 ppm (Detroit, MI) to 2.04 ppm (New York City). The analysis in the 

original report used GAM with default convergence criteria. In response to the bias observed in the 

estimates generated using GAM models with default convergence criteria (Dominici et al., 2002, 

030458), Dominici et al. (2003, 056116; 2005, 087912)(reanalysis of Samet et al. (2000, 156939) 

conducted a reanalysis of the original data using GAM with stringent convergence criteria as well as 

GLM. 

Focusing on the results obtained using GLM, PM10 and O3 (in summer) appeared to be more 

strongly associated with mortality than the other gaseous pollutants. The authors stated that the 

results did not indicate associations between CO, SO2, or NO2, and total (nonaccidental) mortality. 

However, as with PM10, the gaseous pollutants CO, SO2, and NO2 each showed the strongest 

association at a 1-day lag (for O3, a 0-day lag). Figure 5-17 presents the total mortality risk estimates 

for CO from Dominici et al. (2003, 056116). The authors found a mortality risk estimate of 0.23% 

(95% PI: 0.09-0.36) per 0.5 ppm increase in 24-h avg CO for a 1-day lag in a single-pollutant model. 

The inclusion of PM10 or PM10 and O3 in the model did not reduce CO risk estimates. However, the 

confidence intervals were wider in the multipollutant models; however, this could be attributed to: 

(1) PM10 data in many of the cities being collected every 6th day as opposed to daily data for 

gaseous pollutants; and (2) O3 being collected in some cities only during warm months. The addition 

of NO2 (along with PM10) to the model resulted in a reduced CO risk estimate. Some caution is 

required when interpreting this apparent reduction because a smaller number of cities (57 cities2

) 

were available for the CO multipollutant analysis with PM10 and NO2 compared to the singlepollutant CO analysis (82 cities). However, most of the 32 cities that were excluded due to the lack 

of NO2 data were some of the least populated cities. Thus, the difference in the number of cities in 

the multi- and single-pollutant analyses is unlikely to be the underlying cause for the reduction in the 

 

1

 To compare studies in this section that used different averaging times, effects estimates were standardized to the following: 0.5 ppm for 

studies that used 24-h avg concentrations and 0.75 ppm for studies that used max 8-h avg concentrations. These standardized values 

represent the range of current mean ambient concentrations across the U.S. 

2

 One city was excluded from the multipollutant analysis because it contained NO2 data but did not contain CO data. 

January 2010 5-102 
CO risk estimate in the CO multipollutant analysis with PM10 and NO2. In comparison to the PM10

risk estimates which were not reduced in multipollutant models, the CO risk estimates from 

multipollutant models indicate less consistent associations with mortality. 

Source: Reprinted with Permission of HEI from Dominici et al.(2003, 056116) 

Figure 5-17. Posterior means and 95% posterior intervals of national average estimates for 

CO effects on total (nonaccidental) mortality at lags 0, 1, and 2 within sets of the 

90 U.S. cities with available pollutant data. Models A = CO alone; B = CO + PM10; 

C = CO + PM10 + O3; D = CO + PM10 + NO2; E = CO + PM10 + SO2. 

Canadian Multicity Studies 

Since the 2000 CO AQCD (U.S. EPA, 2000, 000907), two Canadian multicity studies have 

been published that examined the association between mortality and short-term exposure to air 

pollutants: (1) an analysis of PM10, PM2.5, PM10-2.5, and gaseous pollutants in 8 cities from 1986 to 

1996 (Burnett et al., 2000, 010273); and (2) an analysis of PM10, PM2.5, PM10-2.5, and gaseous 

pollutants in 12 cities from 1981 to 1999 (Burnett et al., 2004, 086247). The 2000 study (Burnett and 

Goldberg, 2003, 042798) utilized GAM with default convergence criteria and, upon reanalysis, only 

examined PM indices. 

Burnett et al. (2004, 086247) is the most extensive Canadian multicity study conducted to 

date, both in terms of the length of the study and the number of cities covered. This study focused 

primarily on NO2-mortality associations because it was found to be the best predictor of fluctuations 

in mortality among the air pollutants examined (NO2, O3, SO2, CO, PM2.5, and PM10-2.5); however, 

the study did present single- and copollutant results for all pollutants included in the analysis. The 

mean CO concentrations reported by Burnett et al. (2004, 086247) are similar to those reported in 

NMMAPS (Table 5-22). 

Burnett et al. (2004, 086247) examined the effect of short-term exposure to CO on total 

(nonaccidental) mortality. The authors found the strongest mortality association at lag 1-day for CO, 

SO2, PM2.5, PM10-2.5, PM10 (arithmetic addition of PM2.5 and PM10-2.5), and CoH, whereas for NO2, the strongest association was for the 3-day ma (i.e., average of 0-, 1-, and 2-day lags), and for O3, it 

was the 2-day ma. In this study, Burnett et al. (2004, 086247) used 24-h avg pollutant concentrations 

because these values showed stronger associations with mortality than the daily 1-h max values for 

all of the gaseous pollutants and CoH but not for O3. In a single-pollutant model, the CO risk 

estimate for total (nonaccidental) mortality was 0.33% (95% CI: 0.12-0.54) per 0.5 ppm increase in 

24-h avg CO at lag 1. After adjusting for NO2, the CO risk estimate was reduced to 0.04% 

(95% CI: -0.19 to 0.26), while the NO2 risk estimate was only slightly affected (increased from 2.25 

to 2.35%) when including CO in the model. In this analysis, a copollutant model including both CO 

January 2010 5-103 
and PM was not presented. The results presented in this Canadian multicity study and NMMAPS are 

similar in that the CO risk estimates appeared to be sensitive to the addition of NO2 in the regression 

model. However, interpretation of these results requires some caution because: (1) NO2 tends to have 

a more spatially uniform distribution within a city compared to CO; (2) CO and NO2 share common 

sources (e.g., traffic); and (3) CO and NO2 are often moderately to highly correlated. 

Air Pollution and Health: A European Approach 

Most of the Air Pollution and Health: A European Approach (APHEA) analyses have focused 

on the mortality effects of PM (PM10 and BS), SO2, NO2, and O3, but not CO. In addition, some of 

the analyses have not even considered CO as a potential confounder, such as the extended analysis 

(APHEA2) of PM (Katsouyanni et al., 2001, 019008) and NO2. Gryparis et al. (2004, 057276) did 

consider CO as a potential confounder in an analysis of O3 and found that the addition of CO 

increased O3 mortality risk estimates both in the summer and winter, although the number of cities 

included in the copollutant model were reduced from 21 to 19. However, the study did not present 

CO risk estimates. Unlike other APHEA studies (or the NMMAPS and Canadian multicity studies), 

the Samoli et al. (2007, 098420) analysis focused specifically on CO. 

Samoli et al. (2007, 098420) investigated the effect of short-term exposure to CO on total 

(nonaccidental) and cardiovascular mortality in 19 European cities participating in the APHEA2 

project by using a two-stage analysis to examine city-specific effects and potential sources of 

heterogeneity in CO-mortality risk estimates. The mean levels of the max 8-h avg CO concentration 

in this study ranged from 0.52 ppm (Basel, Switzerland, and The Netherlands) to 5.3 ppm (Athens, 

Greece). The max 8-h avg CO concentration across all cities in the APHEA2 study of 2.12 ppm is 

higher than the estimated max 8-h avg CO concentrations reported for the U.S. cities examined in 

Dominici et al. (2003, 056116; 2005, 087912) and the Canadian cities examined in Burnett et al. 

(2004, 086247) of 1.53 ppm.1

 In APHEA cities, the correlation between CO and BS (r = 0.67-0.82) 

was higher than the correlation between CO and PM10 (r = 0.16-0.70) or CO and 1-h max NO2

(r = 0.03-0.68). 

To examine the CO-mortality relationship, Samoli et al. (2007, 098420) conducted a timeseries analysis of individual cities following the revised APHEA2 protocol.2

 The primary results 

presented by the authors are from a sensitivity analysis that used two alternative methods to select 

the extent of adjustment for temporal confounding. These methods consisted of: (1) confining the 

extent of smoothing to 8 df/yr; and (2) selecting the appropriate extent of smoothing through 

minimization of the absolute value of the sum of partial autocorrelation functions (PACF) of the 

residuals, which resulted in the analysis using on average 5 df/yr for total (nonaccidental) mortality 

and 4 df/yr for cardiovascular mortality. The authors also conducted copollutant analyses using 

PM10, BS, SO2, NO2, or O3 (1 h). In the second stage model, Samoli et al. (2007, 098420) examined 

heterogeneity in CO risk estimates between cities by regressing risk estimates from individual cities 

on potential effect modifiers including: (1) the air pollution level and mix in each city (i.e., mean 

levels of pollutants, ratio PM10/NO2); (2) the exposure (number of CO monitors, correlation between 

monitors’ measurements); (3) variables describing the health status of the population (e.g., crude 

mortality rate);(4) the geographic area (northern, western, and central-eastern European cities); and 

(5) climatic conditions (mean temperature and relative humidity levels). 

Samoli et al. (2007, 098420) found that CO was associated with total (nonaccidental) and 

cardiovascular mortality. The primary results represent the combined random effects estimate for a 

0.75 ppm increase in max 8-h avg CO concentrations for the average of 0- and 1-day lag for total 

(nonaccidental) mortality (1.03% [95% CI: 0.55-1.53]) and for cardiovascular mortality (1.08% 

[95% CI: 0.25-1.90]). These results were obtained using PACF to choose the extent of adjustment for 

temporal trends. Although the results obtained using PACF are insightful, the use of 8 df/yr would 

have been more consistent with the NMMAPS model (7 df/yr) and would have allowed for a more 

accurate comparison of the results between APHEA2 and NMMAPS. The corresponding risk 

estimates obtained using the 8 df/yr model are 0.57% (95% CI: 0.23-0.91) for total (nonaccidental) 

mortality and 0.70% (95% CI: 0.31-1.09) for cardiovascular mortality. In the sensitivity analysis, 

 

1

 The max 8-h avg concentration for the Dominici et al. (2003, 056116) and Burnett et al. (2004, 086247) studies was calculated using the 

conversion factor of 2:3 to convert 24-h avg concentrations to max 8-h avg concentrations. 

2

 The APHEA2 protocol used a Poisson GAM model with penalized splines as implemented in the statistical package R. 

January 2010 5-104 
Samoli et al. (2007, 098420) used 8 or 12 df/yr to adjust for temporal confounding. Both approaches 

resulted in similar risk estimates, but using PACF to choose the extent of smoothing separately in 

each city generally resulted in larger CO risk estimates (by ~50-80%). This can be attributed to the 

smaller number of df/yr used in the model (on average 5 df/yr for total [nonaccidental] mortality and 

4 df/yr for cardiovascular mortality), which increases the magnitude of the effect and the amount of 

observed heterogeneity (Samoli et al., 2007, 098420). 

During the examination of the results obtained from the copollutant models, the authors noted 

that there was indication of confounding of CO risk estimates by BS and NO2 but not PM10. These 

results are consistent with CO, BS, and NO2 being part of the traffic-pollution mixture, and PM10

likely including secondary aerosols that do not correlate well with traffic-derived pollution. The risk 

estimates from the model using 8 df/yr that included NO2 were 0.26% (-0.09 to 0.61) for total 

(nonaccidental) mortality and 0.37% (-0.05 to 0.80) for cardiovascular mortality. Thus, the inclusion 

of NO2 in the model nearly halved the CO risk estimates (whereas the NO2 risk estimate was not 

sensitive to the inclusion of CO in the model). CO risk estimates were reduced by a similar 

magnitude when including BS in the model. Overall, the sensitivity of CO risk estimates to the 

inclusion of NO2 in the model is consistent with the results presented in NMMAPS (Dominici et al., 

2003, 056116) and the Canadian multicity study (Burnett et al., 2004, 086247). 

In the second-stage model, Samoli et al. (2007, 098420) found that geographic region was the 

most significant effect modifier, while the other effect modifiers (mentioned above) did not result in 

strong associations. Effects were primarily found in western and southern European cities and were 

larger in cities where the standardized mortality rate was lower. Earlier APHEA studies also reported 

a regional pattern of air pollution associations for BS and SO2 and found that western cities showed 

stronger associations than eastern cities. However, the heterogeneity in CO risk estimates by 

geographic region does not provide specific information to evaluate the CO-mortality association. 

An ancillary analysis conducted by Samoli et al. (2007, 098420) examined the possible 

presence of a CO threshold. 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 very 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., 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). 

In summary, the APHEA2 analysis of CO in 19 cities found an association between CO and 

total (nonaccidental) and cardiovascular mortality in single-pollutant models, but the associations 

were substantially reduced when NO2 or BS was included in copollutant models. The evidence for 

potential confounding of CO risk estimates by NO2 is consistent with the findings from NMMAPS 

and the Canadian 12-city study. In addition, Samoli et al. (2007, 098420) found that geographic 

region was a potential effect modifier, but such geographic heterogeneity is not specific to CO, based 

on previously conducted APHEA studies. Finally, examination of the CO concentration-response 

relationship found very weak evidence of a CO threshold, which requires further investigation. 

Other European Multicity Studies 

An additional European multicity study was conducted by Biggeri et al. (2005, 087395) in 

eight Italian cities. The authors examined the effect of short-term exposure to CO on mortality in 

single-pollutant models using a time-series approach. In this analysis, all of the pollutants showed 

positive associations with the mortality endpoints examined. However, copollutant models were not 

examined, and the correlations among the pollutants were not presented; therefore, it is unclear if the 

observed associations are shared or confounded. 

Summary of Multicity Studies 

In summary, the mortality risk estimates from single-pollutant models are comparable for the 

NMMAPS and Canadian 12-city studies, 0.23% and 0.33%, respectively, with the estimate from the 

January 2010 5-105 
APHEA2 study being slightly larger (0.57%) (Figure 5-18). In both the NMMAPS and Canadian 

studies, a 1-day lag showed the strongest association; however, the APHEA2 study used an a priori 

exposure window (i.e., average of 0- and 1-day lags), which has been found to be the exposure 

window most strongly associated with mortality in PM analyses. 

The APHEA2 risk estimates presented in Figure 5-18 are from a model that used a fixed 

amount of smoothing to adjust for temporal confounding (8 df/yr), which is similar to that used in 

the NMMAPS study (7 df/yr). However, the APHEA2 sensitivity analysis suggested an approximate 

50-80% difference in CO risk estimates between the models that used 8 or 12 df/yr and the models 

that used minimization of the absolute value of the sum of PACF of the residuals as a criterion to 

choose the smoothing parameters. Thus, some model uncertainty likely influences the range of CO 

risk estimates obtained from the studies evaluated. 

The CO risk estimates from the aforementioned studies are also consistently sensitive to the 

inclusion of NO2 in a copollutant model (0.11, 0.03, and 0.26%, for the NMMAPS, Canadian 12-city 

study, and APHEA2, respectively). Thus, these results suggest confounding by NO2. However, this 

interpretation is further complicated because as with CO, NO2 itself may be an indicator of 

combustion sources, such as traffic. 

Study Pollutant Effect Estimate (95% CI)

CO Alone 82 cities 

CO + PM10 

 82 cities 

Dominici et al. (2003, 056116; 2005, 087912) 

(reanalysis of Samet et al. (2000, 156939)) 

NMMAPS, lag 1 

CO + PM10 and NO2 

 57 cities 

CO Alone 

Burnett et al. (1998, 086427) 

12 Canadian cities, lag 1 

CO + NO2

a

CO Alone 

CO + PM10

CO + BS 

Samoli et al. (2007, 098420) 

APHEA2 (19 European cities, lag 0-1) 

CO + NO2 

a

NO2 is the average of 0-day, 1-day, and 2-day lags 

 Percent Increase 

Figure 5-18. Summary of percent increase in total (nonaccidental) mortality for short-term 

exposure to CO from multicity studies. Estimates were standardized to 0.5 ppm 

and 0.75 ppm for studies that used 24-h avg CO and max 8-h avg CO exposure 

metrics, respectively. 

5.6.1.3. Meta-Analysis of All Criteria Pollutants 

Stieb et al. (2002, 025205) reviewed the time-series mortality studies published between 1985 

and 2000 and conducted a meta-analysis to estimate combined effects for PM10, CO, NO2, O3, and 

SO2. Because many of the studies reviewed in the 2000 analysis used GAM with default 

convergence criteria, Stieb et al. (2003, 056908) updated the estimates from the meta-analysis by 

separating the GAM versus non-GAM studies. In this meta-analysis, the authors also presented 

separate combined estimates for single- and multipollutant models. Overall, there were more GAM 

estimates than non-GAM estimates for all of the pollutants except SO2. For CO, 4 single-pollutant 

model risk estimates were identified, resulting in a combined estimate of 3.18% (95% CI: 0.76-5.66) 

per 0.5 ppm increase in 24-h avg CO, and only 1 multipollutant model risk estimate (0.00% 

[95% CI: -1.71 to 1.74]) from the non-GAM studies. Thus, for CO, this study did not provide useful 

meta-estimates because the number of studies that contributed to the combined estimates for CO was 

small. 

January 2010 5-106 
5.6.1.4. Single-City Studies 

In addition to the multicity studies discussed above, there have also been several single-city 

U.S.- and Canadian-based time-series mortality studies that examined CO. The single-city studies, 

similar to the multicity studies, often focused on the PM-mortality association but also provided 

additional information that is not available in the multicity studies. Because the sample size used in 

each single-city study is small and subsequently results in wide confidence intervals, a quantitative 

comparison of the results from single- and multicity studies is difficult. In addition, some studies do 

not present CO results quantitatively, adding to the inability to adequately compare studies. Table 

5-23 lists the single-city studies evaluated along with the mean CO concentrations reported in each 

study. 

Table 5-23. Range of CO concentrations reported in single-city studies that examine mortality 

effects associated with short-term exposure to CO. 

Study Location Years Averaging 

Time 

Mean Concentration 

(ppm) 

Upper Percentile 

Concentrations 

(ppm) 

De Leon et al. (2003, 055688) New York, NY 1985-1994 24-h avg 2.45 95th: 4.04 

Klemm et al. (2004, 056585) Atlanta, GA 1998-2000 1-h max 1.31 Max: 7.40 

75th: 1.66 

Vedal et al. (2003, 039044)

a Vancouver, BC, Can 1994-1996 24-h avg 0.5 Max: 1.9 

90th: 0.9 

Villeneuve et al. (2003, 055051) Vancouver, BC, Can 1986-1999 24-h avg 1.0 Max: 4.9 

90th: 1.6 

Goldberg et al. (2003, 035202) Montreal, Quebec, Can 1984-1993 24-h avg 0.8 Max: 5.1 

75th: 1.0 

Hoek et al. (2000, 010350; 2001, 

016550); Reanalyzed by Hoek (2003, 

042818) 

The Netherlands 1986-1994 24-h avg Entire Country: 0.46 

Four Major Cities: 0.59 

Max. 

Entire Country: 2.6 

Four Major Cities: 4.6 

a

Study reported median CO concentrations. 

Single-City Studies Conducted in the United States 

De Leon et al. (2003, 055688) focused on the role of contributing respiratory diseases on the 

association between air pollution (i.e., PM10, O3, NO2, SO2, and CO) and primary nonrespiratory 

mortality (circulatory and cancer) in New York City, NY, during the period 1985-1994. This study 

only presented risk estimates graphically for each of the pollutants analyzed, except PM10. In singlepollutant models, PM10, CO, SO2, and NO2 all showed the same pattern of association with 

circulatory mortality for individuals ≥ 75 yr, indicating a larger risk of death in individuals with 

contributing respiratory diseases compared to those without. In two-pollutant models, PM10 and CO 

risk estimates were reduced but each remained significantly positive. 

Klemm et al. (2004, 056585) analyzed 15 air pollutants for their associations with mortality in 

Atlanta, GA, for a 2-yr period starting in August 1998. These pollutants included PM2.5, PM10-2.5, 

UFP surface area and counts, aerosol acidity, EC, OC, SO4

2-, O3, CO, SO2, and NO2. This study 

presented risk estimates using three levels of smoothing (quarterly, monthly, and biweekly knots) for 

temporal trend adjustment and suggested that the risk estimates were rather sensitive to the extent of 

smoothing. It should be noted that temporal smoothing using biweekly knots is a more aggressive 

modeling approach than the degrees-of-freedom approach used by most studies. In the singlepollutant models for nonaccidental mortality, the strongest association, which was also statistically 

significant, was found for PM2.5. CO, SO4

2-, and PM10-2.5 also showed positive associations with 

nonaccidental mortality (CO: Quarterly knots and Monthly Knots β = 0.00002 [SE = 0.00001]; 

Biweekly knots β = 0.00001 [SE = 0.00002]). However, CO was significantly associated with 

circulatory mortality in older adults (≥ 65 yr), and these associations remained when PM2.5 was 

included in the model (results were presented graphically). 

January 2010 5-107 
Single-City Studies Conducted in Canada 

Vedal et al. (2003, 039044) examined the association between short-term exposure to “low 

levels” of air pollution (i.e., PM10, O3, NO2, SO2, and CO) and daily mortality in Vancouver, British 

Columbia, Canada, for the years 1994-1996. In this analysis, all of the risk estimates were presented 

graphically; however, the results suggested that O3 in the summer and NO2 in the winter showed the 

strongest associations with mortality. Vedal et al. (2003, 039044) found that CO was positively but 

not significantly associated with mortality. Additionally, the association between short-term exposure 

to NO2 and mortality was found to be consistent with the results from the Canadian multicity study 

conducted by Burnett et al. (2004, 086247). 

Villeneuve et al. (2003, 055051) also conducted an analysis using data from Vancouver, 

Canada, using a cohort of 550,000 individuals whose vital status was ascertained between 1986 and 

1999. In this study, PM2.5, PM10-2.5, TSP, CoH, PM10, SO4

2-, O3, CO, SO2, and NO2 were examined 

for their associations with all-cause (nonaccidental), cardiovascular, and respiratory mortality. When 

examining the association between gaseous pollutants and all-cause (nonaccidental) mortality in this 

data set, NO2 and SO2 showed the strongest associations, while the association between CO and allcause mortality were generally weaker than those for NO2 and SO2. For cardiovascular mortality, 

SO2 risk estimates were smaller than those for NO2 or CO, while for respiratory mortality, SO2

showed the strongest associations. However, the wider confidence intervals for these categories and 

the smaller daily counts make it difficult to assess CO associations with cause-specific mortality 

outcomes. 

Goldberg et al. (2003, 035202) contrasted associations between air pollution and mortality in 

individuals with underlying CHF versus mortality in individuals who were identified as having CHF 

1 yr prior to death based on information from the universal health insurance plan in Montreal, 

Quebec, Canada, during the period 1984-1993. In this study, Goldberg et al. (2003, 035202) 

examined associations between PM2.5, CoH, SO4

2-, O3, CO, SO2, and NO2, and mortality. The 

authors found no association between any of the air pollutants and mortality with underlying CHF. 

However, Goldberg et al. (2003, 035202) found positive associations between air pollution and 

mortality in individuals diagnosed with CHF 1 yr prior to death. Of the air pollutants examined, 

CoH, NO2, and SO2 were most consistently associated with mortality for ages 65 yr and older, while 

CO showed positive but weaker associations compared to these three pollutants. 

Single-City Studies Conducted in Other Countries 

 Of the epidemiologic studies conducted in other countries that examine the association 

between short-term exposure to CO and mortality, only those studies conducted in European 

countries that have CO levels comparable to the U.S. were evaluated. However, because Samoli et 

al. (2007, 098420) conducted a multicity study of European cities that focused on short-term 

exposure to CO, there are only a few single-city studies that provide additional information, 

specifically those studies conducted in The Netherlands. The Netherland studies were evaluated 

because they provide risk estimates for multiple pollutants and cause-specific mortality and 

consisted of relatively large sample sizes (i.e., the mortality time-series of the entire country was 

analyzed). 

Hoek et al. (2000, 010350) (reanalyzed by Hoek) (2003, 042818) examined associations 

between air pollution and all-cause (nonaccidental), cardiovascular, COPD, and pneumonia deaths in 

the entire Netherlands, the four major cities combined, and the entire country minus the four major 

cities for the period 1986-1994. The air pollutants analyzed included BS, PM10, O3, NO2, SO2, CO, 

SO4

2– and NO3–

. In the single-pollutant models, all of the pollutants were significantly associated 

with nonaccidental mortality at lag 1-day and 0-6 days when using the entire Netherlands data set. In 

the two-pollutant model, CO risk estimates were reduced to null when PM10, BS, SO4

2- and NO3–

were included in the model, while the risk estimates for these copollutants remained significantly 

positive. BS, CO, and NO2 were highly correlated (r > 0.85) in this data set, and the authors noted 

“all these pollutants should be interpreted as indicators for motorized traffic emissions” (Hoek et al., 

2000, 010350). The authors found that O3 showed the most consistent and independent associations 

with mortality and that the risk estimates for all of the pollutants were substantially higher in the 

summer months than in the winter months. Pneumonia deaths showed the largest risk estimates for 

most pollutants including CO. The result from the Hoek et al. (2000, 010350) study is somewhat in 

January 2010 5-108 
contrast to the result from the Samoli et al. (2007, 098420) multicity study in that in the Hoek et al. 

(2000, 010350) analysis, CO was more sensitive to the addition of PM indices in copollutant models. 

This may be due to the high correlation between CO and PM indices in The Netherlands. 

Hoek et al. (2001, 016550) (reanalysis by Hoek) (2003, 042818) analyzed The Netherlands 

data using more specific cardiovascular causes of death: MI and other IHD, arrhythmia, heart failure, 

cerebrovascular mortality, and embolism/thrombosis. In this analysis, the authors analyzed O3, BS, 

PM10, CO, SO2, and NO2 in only single-pollutant models. For all of the pollutants, risk estimates 

were larger for arrhythmia, heart failure, and cerebrovascular mortality than for the combined 

cardiovascular mortality outcome. Thus, the results suggested larger impacts of air pollution on more 

specific cardiovascular causes; however, it is difficult to distinguish the effects of each pollutant 

from the larger air-pollution mixture. 

5.6.1.5. Summary of Mortality and Short-Term Exposure to CO 

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 (Samoli et al., 2007, 098420) 

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 (Samoli et al., 2007, 098420), and, in the process, examined: (1) model sensitivity; (2) 

the CO-mortality concentration-response (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 shortterm exposures to CO and mortality. 

5.6.2. Epidemiologic Studies with Long-Term Exposure to CO 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) did not evaluate the association between longterm exposure to CO and mortality because there were no studies at the time that examined this 

relationship. Since then there have been several new studies that examined the association between 

long-term exposure to CO and mortality. It should be noted, however, that these studies focused 

January 2010 5-109 
primarily on PM, and that CO was only considered in these studies as a potential confounder. 

Therefore, the information available from these new long-term exposure studies is somewhat 

limited, especially in comparison to that for PM. Table 5-24 lists the U.S.-based studies evaluated 

that examined the association between long-term exposure to CO and mortality, along with the mean 

CO concentrations reported in each study. 

Table 5-24. Range of CO concentrations reported in U.S.-based studies that examine mortality 

effects associated with long-term exposure to CO. 

Study Location Years Averaging 

Time 

Mean Concentration 

(ppm) 

Upper Percentile 

Concentrations 

(ppm) 

Jerrett et al. (2003, 087380) 107 US cities 1980 Annual avg 1.56 Maximum: 3.95 

Pope et al. (2002, 024689) 

1980: 113 US cities 

1982-1998: 122 US 

cities 

1980 

1982-1998 Annual avg 1980: 1.7 1982-1998: 1.1 NR 

Krewski et al. (2009, 191193) 108 US cities 1980 Annual avg 1.68 

75th: 2.13 

90th: 2.58 

95th: 3.05 

Maximum: 3.95 

Miller et al. (2007, 090130) 36 US cities 2000 Annual avg NR NR 

Lipfert et al. (2000, 004087) US 

1960-1974 

1975-1981 

1982-1988 

1989-1996 

Mean annual 95th 

percentile of 

hourly CO values 

1960-1974: 10.82 

1975-1981: 7.64 

1982-1988: 3.42 

1989-1996: 2.36 

1960-1974 

50th: 9.31 

Maximum: 35.3 

1975-1981 

50th: 7.04 

Maximum: 22.4 

1982-1988 

50th: 3.33 

Maximum: 15.20 

1989-1996 

50th: 2.30 

Maximum: 7.10 

Lipfert et al. (2006, 088756) US 1999-2001 

Mean annual 95th 

percentile of 

hourly CO values 

1.63 Maximum: 6.7 

Lipfert et al. (2006, 088218) US 

1976-1981 

1982-1988 

1989-1996 

1997-2001 

Mean annual 95th 

percentile of 

hourly CO values 

1976-1981: 7.6 

1982-1988: 3.4 

1989-1996: 2.4 

1997-2001: 1.6 

NR 

Lipfert and Morris (2002, 019217) 

1960-1969: 44 US 

counties 

1970-1974: 206 US 

counties 

1979-1981: 272 US 

counties 

1989-1991: 246 US 

counties 

1995-1997: 261 US 

counties 

1960-1969 

1970-1974 

1979-1981 

1989-1991 

1995-1997 

Mean annual 95th 

percentile of 

hourly CO values 

1960-1969: 13.8 

1970-1974: 9.64 

1979-1981: 5.90 

1989-1991: 2.69 

1995-1997: 1.72 

NR 

 

5.6.2.1. U.S. Cohort Studies 

American Cancer Society Cohort Studies 

Pope et al. (1995, 045159) investigated associations between long-term exposure to PM and 

mortality outcomes in the ACS cohort. In this study, ambient air pollution data from 151 U.S. 

metropolitan areas in 1981 were linked with individual risk factors in 552,138 adults who resided in 

these areas when enrolled in the prospective study in 1982; death outcomes were ascertained through 

1989. PM2.5 and SO4

2– were associated with total (nonaccidental), cardiopulmonary, and lung cancer 

mortality, but not with mortality for all other causes (i.e., nonaccidental minus cardiopulmonary and 

lung cancer). Gaseous pollutants were not analyzed in Pope et al. (1995, 045159). Jerrett et al. (2003, 

January 2010 5-110 
087380), using data from Krewski et al. (2000, 012281), conducted an extensive sensitivity analysis 

of the Pope et al. (1995, 045159) ACS data, augmented with additional gaseous pollutants data. Due 

to the smaller number of CO monitors available compared to SO4

2-, the number of metropolitan 

statistical areas (MSAs) included in the CO analysis were reduced (from 151 with SO4

2– to 107). The 

mean annual CO concentrations in these MSAs ranged from 0.19 to 3.95 ppm. CO was weakly 

negatively correlated with SO4

2- (r = -0.07). Among the gaseous pollutants examined (CO, NO2, O3, SO2), only SO2 showed positive associations with mortality, and, in addition, was the only 

copollutant that reduced SO4

2- risk estimates. For CO, the relative risk estimates for total 

(nonaccidental) mortality in single- and copollutant models with SO4

2- was 0.99 (95% CI: 0.96-1.01) 

and 0.98 (95% CI: 0.96-1.01), respectively, per 0.5 ppm increase in mean annual average CO 

concentrations. 

Pope et al. (2002, 024689) conducted an extended analysis of the ACS cohort with double the 

follow-up time (to 1998) and triple the number of deaths compared to the original Pope et al. (2002, 

024689) study. In addition to PM2.5, data for all of the gaseous pollutants were retrieved for the 

extended period and analyzed for their associations with mortality-specific outcomes. As in the 1995 

analysis, the air-pollution exposure estimates were based on the MSA-level averages. The authors 

found that PM2.5 and SO4

2– were both associated with all-cause, cardiopulmonary, and lung cancer 

mortality.1

 In this study, the CO analysis used two different data sets: the first data set consisted of 

1980 data and 113 MSAs; while the second data set used averages of the years 1982-1998 and 

122 MSAs. The authors found, when using the 1980 data, that CO was not associated (risk estimates 

~ 1) (Figure 5-19) with all-cause, cardiopulmonary, lung cancer, or mortality for all other causes. 

However, the analysis of the 1982-1998 data found that CO was negatively (and significantly) 

associated with all-cause, cardio-pulmonary, and lung cancer mortality. It is unclear why significant 

negative associations were observed when analyzing the 1982-1998 data, but evidence from other 

mortality studies that examined the association between long-term exposure to CO and mortality do 

not suggest that CO elicits a protective effect. 

Krewski et al. (2009, 191193) further analyzed the ACS cohort by adding two additional years 

of mortality data (total period 1982-2000). This study extended the range of the analysis to 

incorporate sophisticated adjustment for bias and confounding as well as intra-urban analyses. 

However, the CO analysis was limited to using (1) nationwide data; (2) only 1980 CO 

concentrations; and (3) the standard Cox proportional hazards model. In addition to the death 

categories examined in Pope et al. (2002, 024689), this analysis also examined IHD mortality. As 

was the case with the Pope et al. (2002, 024689) analysis, Krewski et al. (2009, 191193) found that 

1980 CO data was not associated with any of the mortality categories examined: all-cause mortality 

HR=1.00 (95%CI: 0.99-1.01); cardio-pulmonary mortality, HR=1.00 (95% CI: 0.99-1.00); and IHD 

mortality, HR=1.00 (95% CI: 0.99-1.01) per 0.5 ppm increase in CO. 

Women’s Health Initiative Cohort Study 

Miller et al. (2007, 090130) studied 65,893 postmenopausal women between the ages of 50 

and 79 yr without previous CVD in 36 U.S. metropolitan areas from 1994 to 1998. The authors 

examined the association between one or more fatal or nonfatal cardiovascular events and airpollutant concentrations. Exposures to air pollution were estimated by assigning the year 2000 mean 

concentration of air pollutants measured at the nearest monitor to the location of residence of each 

subject on the basis of its five-digit ZIP code centroid, which allowed estimation of effects due to 

both within-city and between-city variation of air pollution. The investigators excluded monitors 

whose measurement objective focused on a single point source or those with “small measurement 

scale (0-100 m).” Thus, presumably, these criteria reduced some of the exposure measurement error 

associated with monitors that are highly impacted by local sources. 

During the course of the study, a total of 1,816 women had one or more fatal or nonfatal 

cardiovascular event, including 261 cardiovascular-related deaths. Hazard ratios for the initial 

cardiovascular event were estimated. The following results are for models that included only subjects 

with nonmissing exposure data for all pollutants (n = 28,402 subjects, resulting in 879 CVD events). 

In the single-pollutant models, PM2.5 showed the strongest associations with CVD events among all 

pollutants (HR = 1.24 [95% CI: 1.04-1.48] per 10 μg/m3

 increase in annual average), followed by 

 

1

 These results were presented graphically in Pope et al. (2002, 024689) and were estimated for . Figure 5-19

January 2010 5-111 
SO2 (HR = 1.07 [95% CI: 0.95-1.20] per 5 ppb increase in the annual average). For CO the singlepollutant risk estimate was slightly (but not significantly) negative (HR = 0.96 [95% CI: 0.84-1.10]). 

In the multipollutant model, which included all pollutants (i.e., PM2.5, PM10-2.5, SO2, NO2, and O3), 

the CO risk estimate was similar to the one presented in the single-pollutant model (HR = 0.96 

[95% CI: 0.82-1.14]). In addition, CO was not associated with CVD events in a single pollutant 

model (HR = 1.00 [95% CI: 0.90-1.10] per 0.5 ppm increase in mean annual average CO 

concentration) that used all available observations. Overall this study found that PM2.5 was clearly 

the best predictor of cardiovascular events. 

The Washington University-EPRI Veterans’ Cohort Mortality Studies 

Lipfert et al. (2000, 004087) conducted an analysis of a national cohort of ~70,000 male U.S. 

military veterans who were diagnosed as hypertensive in the mid-1970s and were followed for 

approximately 21 yr (up to 1996). Demographically, 35% of the cohort consisted of AfricanAmerican men and 57% of the cohort was defined as current smokers; however, 81% of the cohort 

had been smokers at one time in their life. The study examined mortality effects in response to longterm exposure to multiple pollutants, including, PM2.5, PM10, PM10-2.5, TSP, SO4

2-, CO, O3, NO2, SO2, and Pb. Lipfert et al. (2000, 004087) estimated exposures by indentifying the county of residence at 

the time of entry to the study. Four exposure periods (1960-1974, 1975-1981, 1982-1988, and 

1989-1996) were defined, and deaths during each of the three most recent exposure periods were 

considered. The mean annual 95th percentile of hourly CO values during these periods declined from 

10.8 ppm to 2.4 ppm. The authors noted that the pollution risk estimates were sensitive to the 

regression model specification, exposure periods, and the inclusion of ecological and individual 

variables. Lipfert et al. (2000, 004087) reported that indications of concurrent mortality risks 

(i.e., associations between mortality and air quality for the same period) were found for NO2 and 

peak O3. The estimated CO mortality risks were all negative, but not significant. 

Lipfert et al. (2006, 088756) examined associations between traffic density and mortality in 

the same Veterans’ Cohort; however, in this analysis, the follow-up period was extended to 2001. As 

in their 2000 study, four exposure periods were considered, but more recent years were included in 

the 2006 analysis. The authors used the mean annual average of the 95th percentile of 24-h avg CO 

in each of the exposure periods as the averaging metric. The traffic-density variable was the most 

significant predictor of mortality in their analysis, remaining so in two- and three pollutant models 

with other air pollutants (i.e., CO, NO2, O3. PM2.5, SO4

2–, non-SO42– PM2.5, and PM10-2.5). In the 

multipollutant models, mortality-risk estimates were not statistically significant for any of the other 

pollutants, except O3. The natural log of the traffic-density variable (VKTA = vehicle-km traveled 

per yr) was not correlated with CO (r = -0.06) but moderately correlated with PM2.5 (r = 0.50) in this 

data set. For the 1989-1996 data period, the estimated mortality relative risk was 1.02 (95% CI: 

0.98-1.06) per 1 ppm increase in the mean annual 95th percentile of hourly CO concentration in a 

single-pollutant model. The two-pollutant model, which included the traffic-density variable, 

resulted in a relative risk of 1.00 (95% CI: 0.96-1.04). Lipfert et al. (2006, 088218) noted that the 

low risk estimates for CO in this study were consistent with those observed in other long-term 

exposure studies and may have been due to the localized nature of CO, which can lead to exposure 

errors when data from centralized monitors is used to represent an entire county. Interestingly, as 

Lipfert et al. (2006, 088756) pointed out, the risk estimates due to traffic density did not vary 

appreciably across these four periods, even though regulated tailpipe emissions declined during the 

study period. The authors speculated that some combination of other environmental factors such as 

road dust, psychological stress, and noise (all of which constitute the environmental effects of 

vehicular traffic), along with spatial gradients in SES, might contribute to the nonnegative effects 

observed. 

Lipfert et al. (2006, 088218) extended the analysis of the Veterans Cohort data to include the 

EPA’s Speciation Trends Network (STN) data, which collected chemical components of PM2.5. The 

authors analyzed the STN data for the year 2002 and again used county-level averages. In addition, 

they analyzed PM2.5 and gaseous pollutants data for 1999-2001. As in the other Lipfert et al. (2006, 

088218) study, traffic density was the most important predictor of mortality, but associations were 

also observed for EC, vanadium (V), nickel (Ni), and NO3

–

. Ozone, NO2, and PM10 also showed 

positive but weaker associations. The authors found no association between the mean annual 95th 

percentile of hourly CO values and mortality (RR = 0.995 [95% CI: 0.988-1.001] per 1 ppm increase 

January 2010 5-112 
in CO concentration) in a single-pollutant model. The study did not present copollutant model results 

for CO. 

Cause-specific 

Mortality Study Cohort 

Years of 

Mortality 

Data 

Year(s) 

of AQ 

Data 

Effect Estimate (95% CI)d 

Pope et al. (2002, 024689)

a ACS 1982-1998 1980 

Krewski et al. (2009, 191193) ACS 1982-2000 1980 

Pope et al. (2002, 024689)

a ACS 1982-1998 1982-98 

Lipfert et al. (2006, 088218) Veterans 1976-2001 1989-96 

Lipfert et al. (2006, 088218) Veterans 1976-2001 1989-96 + ln(VKTA)e

Lipfert et al. (2006, 088756) Veterans 1997-2001 1999-01 

Jerrett et al. (2003, 087380) ACS 1982-1998 1982c

All-cause 

Jerrett et al. (2003, 087380) ACS 1982-1998 1982c + SO4

2-

Pope et al. (2002, 024689)

a ACS 1982-1998 1980 

Cardiopulmonary Krewski et al. (2009, 191193) ACS 1982-2000 1980 

Pope et al. (2002, 024689)

a ACS 1982-1998 1982-98 

Miller et al. (2007, 090130)

b WHI 1994-1998 2000 Cardiovascular Miller et al. (2007, 090130)

b WHI 1994-1998 2000 Multipollutantf

IHD Krewski et al. (2009, 191193) ACS 1982-2000 1980 

Lung Cancer Krewski et al. (2009, 191193) ACS 1982-2000 1980 

a

The study does not present CO results quantitatively. This effect estimate and 95% confidence interval 

were estimated from Figure 5 in Pope et al. (2002, 024689). b

Effect estimate is only for subjects with non-missing exposure data for all pollutants. 

c

The study did not report the range of years of CO data used; however, it does specify that air quality data 

was obtained from pollution monitoring stations operating in 1982. d

Unless otherwise specified, all results represent single pollutant models 

e

Natural log of Vehicle-km Traveled variable. 

f

Multipollutant model consisted of CO + PM2.5, PM10-2.5, SO2, NO2, O3. 

Relative Risk / Hazard Ratio 

Figure 5-19. Summary of mortality risk estimates for long-term exposure to CO. Estimates 

were standardized to 0.5 ppm and 1.0 ppm for studies that used mean annual 

average CO and the mean annual 95th percentile of hourly CO values exposure 

metrics, respectively. 

5.6.2.2. U.S. Cross-Sectional Analysis 

An ecological cross-sectional analysis involves regressing county- (or city-) average health 

outcome values on county-average explanatory variables such as air pollution and census statistics. 

Unlike the cohort studies described above, to the extent that individual level confounders are not 

adjusted for, the cross-sectional study design is considered to be subject to ecologic confounding. 

However, all of the cohort studies described above are also semi-ecologic in that the air-pollution 

exposure variables are ecologic (Kunzli and Tager, 1997, 086180). In this sense, cross-sectional 

studies may be useful in evaluating the correlation among exposure variables. 

Lipfert and Morris (2002, 019217) conducted ecological cross-sectional regressions for U.S. 

counties (except Alaska) during five periods: 1960-1969, 1970-1974, 1979-1981, 1989-1991, and 

1995-1997. They regressed age-specific (15-44, 45-64, 65-74, 76-84, and 85+ yr) all-cause 

(excluding AIDS and trauma) mortality on air pollution, demography, climate, SES, lifestyle, and 

diet. The authors analyzed TSP, PM10, PM2.5, SO4

2-, SO2, CO, NO2, and O3. However, air pollution 

data was only available for limited periods of time depending on the pollutant: TSP up to 1991; PM10

between 1995 and 1999; and PM2.5 between 1979 and 1984 and for 1999. In response to the varying 

number of counties with valid air pollution data by pollutant and time, Lipfert and Morris (2002, 

019217) employed a staged-regression approach. In the first stage, a national model was developed 

for each dependent variable, excluding air pollution variables. In the second stage, regressions were 

performed with the residuals on concurrent and previous periods’ air pollution variables to identify 

the pollutants of interest. Many results were presented because of the large number of age groups, 

lagged-exposure time windows, and mortality study periods examined in the study; overall, the 

results were similar to those presented in the ACS cohort studies (i.e., PM2.5 and SO4

2- were found to 

be consistently and positively associated with mortality). Lipfert and Morris (2002, 019217) 

generally found the strongest associations in the earlier time periods and when mortality and air 

quality were measured in different periods (e.g., mortality data 1995-1997 and CO data 1970-1974). 

January 2010 5-113 
Also, consistent with the Lipfert et al. (2000, 012281) and the Pope et al. (2002, 024689) cohort 

studies, CO was frequently negatively (and often significantly) associated with mortality in older age 

groups, especially when mortality was matched with CO levels in more recent time periods. The 

younger age group (15-44 yr) often showed a positive association with CO, but considering the small 

number of deaths attributed to this age group (<1% of total deaths), the association was not 

informative. Overall, this study highlighted that the CO-mortality associations presented in purely 

ecologic study designs are generally consistent with those found in semi-individual cohort studies. 

5.6.2.3. Summary of Mortality and Long-Term Exposure to CO 

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 ACS data (Pope et al., 1995, 

045159) 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 (Pope et al., 2002, 

024689) when using earlier (1980) CO data; however, negative associations were found when using 

more recent (1982-1998) data. These results were further confirmed in an extended analysis of the 

ACS data (Krewski et al., 2009, 191193). The Women’s Health Initiative Study also found no 

association between CO and CVD events (including mortality) using the mortality data from recent 

years (1994-1998) (Miller et al., 2007, 090130), 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 (Lipfert et al., 2006, 088218; Lipfert et al., 2006, 088756). An additional study (Lipfert and 

Morris, 2002, 019217) was identified that used a cross-sectional study design, which reported results 

for a study of U.S. counties that were 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., postmenopausal 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. 

5.7. Susceptible Populations 

Interindividual variation in human responses indicates that some populations are at increased 

risk for the detrimental effects of ambient exposure to an air pollutant (Kleeberger and Ohtsuka, 

2005, 130489). The NAAQS are intended to provide an adequate margin of safety for both general 

populations and sensitive subgroups, or those individuals potentially at increased risk for health 

effects in response to ambient air pollution (Section 1.1). To facilitate the identification of 

populations at the greatest risk for CO-related health effects, studies have evaluated factors that 

contribute to the susceptibility and/or vulnerability of an individual to CO. The definition for both of 

these terms varies across studies, but in most instances “susceptibility” refers to biological or 

intrinsic factors (e.g., lifestage, gender) while “vulnerability” refers to nonbiological or extrinsic 

factors (e.g., visiting a high-altitude location, medication use) (Table 5-25). Additionally, in some 

cases, the terms “at-risk” and sensitive populations have been used to encompass these concepts 

more generally. However, in many cases a factor that increases an individual's risk for morbidity or 

mortality effects from exposure to an air pollutant (e.g., CO) can not be easily categorized as a 

susceptibility or vulnerability factor. For example, a population that is characterized as having low 

SES, traditionally defined as a vulnerability factor, may have less access to healthcare resulting in 

the manifestation of disease (i.e., a susceptibility factor). But they may also reside in a location that 

results in exposure to higher concentrations of an air pollutant, increasing their vulnerability. 

Therefore, the terms “susceptibility” and “vulnerability” are intertwined and at times cannot be 

distinguished from one another. 

January 2010 5-114 
As a result of the inconsistencies in the definitions of “susceptibility” and “vulnerability” 

presented in the literature as well as the inability to clearly delineate whether an identified factor 

increases an individual's susceptibility or vulnerability to an air pollutant, in this ISA, the term 

“susceptible population” will be used as a blanket term and defined as follows: 

Populations that have a greater likelihood of experiencing health effects related to 

exposure to an air pollutant (e.g., CO) due to a variety of factors including, but not limited to: 

genetic or developmental factors, race, gender, lifestage, lifestyle (e.g., smoking status and 

nutrition) orpreexisting disease, as well as population-level factors that can increase an 

individual's exposure to an air pollutant (e.g., CO) such as socioeconomic status [SES], which 

encompasses reduced access to health care, low educational attainment, residential location, 

and other factors. 

Table 5-25. Range of definitions of “susceptible” and “vulnerable” in the CO literature. 

Definition Reference 

Susceptible: predisposed to develop a noninfectious disease 

Vulnerable: capable of being hurt; susceptible to injury or disease Merriam-Webster (2009, 192146) 

Susceptible: greater likelihood of an adverse outcome given a specific exposure, in comparison with the general 

population. Includes both host and environmental factors (e.g., genetics, diet, physiologic state, age, gender, social, 

economic, and geographic attributes). 

Vulnerable: periods during an individual’s life when they are more susceptible to environmental exposures. 

American Lung Association (2001, 016626) 

Susceptible: those who are more likely to experience adverse effects of CO exposure than normal healthy adults 

(e.g., persons with cardiovascular disease, COPD, reduced or abnormal hemoglobin, older adults, neonates). U.S. EPA (2008, 193995) 

Susceptible: greater or lesser biological response to exposure. 

Vulnerable: more or less exposed. U.S. EPA (2009, 192149) 

Vulnerable: to be susceptible to harm or neglect, that is, acts of commission or omission on the part of others that 

can wound. Aday (2001, 192150) 

Susceptible: may be those who are significantly more liable than the general population to be affected by a stressor 

due to life stage (e.g., children, the elderly, or pregnant women), genetic polymorphisms (e.g., the small but 

significant percentage of the population who have genetic susceptibilities), prior immune reactions (e.g., individuals 

who have been “sensitized” to a particular chemical), disease state (e.g., asthmatics), or prior damage to cells or 

systems (e.g., individuals with damaged ear structures due to prior exposure to toluene, making them more sensitive 

to damage by high noise levels). 

Vulnerable: differential exposure and differential preparedness (e.g., immunization). 

U.S. EPA (2003, 192145) 

Susceptible: intrinsic (e.g., age, gender, preexisting disease (e.g., asthma) and genetics) and extrinsic (previous 

exposure and nutritional status) factors. Kleeberger and Ohtsuka (2005, 130489) 

To examine whether air pollutants (e.g., CO) differentially affect certain populations, 

epidemiologic studies conduct stratified analyses to identify the presence or absence of effect 

modification. A thorough evaluation of potential effect modifiers may help identify populations that 

are more susceptible to an air pollutant (e.g., CO). Although the design of toxicological and 

controlled human exposure studies does not allow for an extensive examination of effect modifiers, 

the use of animal models of disease and the study of individuals with underlying disease or genetic 

polymorphisms do allow for comparisons between subgroups. Therefore, the results from these 

studies, combined with those results obtained through stratified analyses in epidemiologic studies, 

contribute to the overall weight of evidence for the increased susceptibility of specific populations to 

an air pollutant (e.g., CO). 

The remainder of this section discusses the epidemiologic, controlled human exposure, and 

toxicological studies evaluated in previous sections of Chapter 5 that provide information on 

potentially susceptible populations. The studies highlighted include only those studies that presented 

stratified results (e.g., males versus females or <65 yr versus ≥ 65 yr). This approach allows for a 

direct comparison between populations exposed to similar CO concentrations and within the same 

study design to determine whether a factor increases the susceptibility of a population to CO-related 

health effects. In addition, numerous studies that focus on only one potentially susceptible 

population can provide supporting evidence on susceptibility and are described in Sections 5.2

January 2010 5-115 
through 5.6; however, these studies are not discussed in detail in this section. It is recognized that by 

using this approach to identify potentially susceptible populations, some individuals with underlying 

medical conditions (i.e., reduced O2-carrying capacity or elevated COHb levels) or lifestyle 

characteristics may not be identified due to the lack of studies focusing on these populations. 

Discussion of conditions affecting CO uptake and elimination as well as endogenous CO production 

is presented in Sections 4.4 and 4.5, respectively. 

5.7.1. Preexisting Disease 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) identified certain populations within the 

general population that may be more susceptible to the effects of CO exposure, including individuals 

(particularly older adults) with CHD and other vascular diseases, anemia, or COPD. As discussed in 

the 2000 CO AQCD (U.S. EPA, 2000, 000907) and reviewed in Section 4.5 of this assessment, 

diseases that cause inflammation and systemic stress are known to increase endogenous CO 

production, which could potentially increase the susceptibility of individuals with such conditions to 

health effects induced by ambient CO exposure. The level of COHb that results in the manifestation 

of health effects varies depending on health outcome and disease state of individuals. The following 

sections summarize the evidence presented in the 2000 CO AQCD (U.S. EPA, 2000, 000907) along 

with new evidence which identifies populations with various preexisting diseases that may be 

susceptible to CO-induced health effects. 

5.7.1.1. Cardiovascular Disease 

Controlled exposures to CO resulting in COHb concentrations of 2-6% have been shown to 

affect cardiovascular function among individuals with CAD. Several studies have reported 

significant decreases in the time to onset of exercise-induced angina or ST-segment changes 

following CO exposure in patients with stable angina. In the largest such study (Allred et al., 1989, 

013018; Allred et al., 1989, 012697; Allred et al., 1991, 011871), COHb concentrations as low as 

2.0-2.4% were observed to significantly decrease the time required to induce ST-segment changes 

indicating myocardial ischemia (p = 0.01) (Section 5.2.4). In addition to the effects of CO on 

myocardial ischemia, there is some evidence to suggest that CO may provoke cardiac arrhythmia in 

patients with CAD; however, this has not been observed at COHb concentrations below 6% (Sheps 

et al., 1990, 013286). While healthy adults have been shown to experience a decrease in exercise 

performance following or during exposure to CO, no changes in cardiac rhythm or ECG parameters 

have been demonstrated. 

Evidence of CO-induced health effects in individuals with CAD is coherent with results from 

epidemiologic studies that examined the effect of preexisting cardiovascular conditions, through 

either secondary diagnoses or underlying comorbidities, on associations between CO and ED visits 

and HAs. Mann et al. (2002, 036723) found increased associations between CO and IHD HAs in 

individuals with secondary diagnoses of either CHF or dysrhythmia in southern California. Peel et 

al. (2007, 090442) also examined the effect of underlying cardiovascular conditions on 

cardiovascular-related HAs in response to short-term exposure to air pollutants, including CO in 

Atlanta, GA. Individuals with underlying dysrhythmia were found to have increased HAs for IHD, 

but unlike Mann et al. (2002, 036723), underlying CHF was not found to increase IHD HAs. Peel et 

al. (2007, 090442) also examined other underlying conditions and found increased HAs for 

additional cardiovascular effects not specifically related to IHD, including: dysrhythmia, PVCD, and 

CHF in individuals with underlying hypertension; dysrhythmia and PVCD in individuals with 

underlying CHF; and PVCD in individuals with underlying dysrhythmia. Although there is no 

evidence for a clear pattern of CO-induced cardiovascular effects among individuals without CAD 

across the epidemiologic studies evaluated, the available evidence suggests that underlying 

dysrhythmia increases IHD HAs in response to short-term exposure to CO. 

Additional evidence for increased CO-induced cardiovascular effects not specifically related to 

IHD is provided by toxicological studies that used animal models of cardiovascular disease. These 

studies have demonstrated that short-term exposure to 50 ppm CO in rats exacerbates 

cardiomyopathy and vascular remodeling related to pulmonary hypertension (Carraway et al., 2002, 

026018; Gautier et al., 2007, 096471; Melin et al., 2002, 037502; 2005, 193833). Although the 

population at risk for primary pulmonary hypertension is low, secondary pulmonary hypertension is 

January 2010 5-116 
a frequent complication of COPD (Section 5.7.1.2) and certain forms of heart failure. These studies 

demonstrate the potential for short-term exposure to CO to adversely affect individuals with 

underlying cardiovascular conditions. 

The combined evidence from controlled human exposure and epidemiologic studies provides 

coherence and biological plausibility for the association between CO and cardiovascular morbidity 

in individuals with CAD, particularly those with IHD. Approximately 13.7 million people in the U.S. 

have been diagnosed with CAD (also known as CHD), some fraction of whom have IHD (Table 

5-26). These individuals, therefore, represent a large population that may be more susceptible to 

ambient CO exposure than the general population. In addition, the continuous nature of the 

progression of CAD and its close relationship with other forms of cardiovascular disease suggest that 

a larger population than just those individuals with a prior diagnosis of CAD may be susceptible to 

health effects from CO exposure. 

Table 5-26. Adult U.S. population in 2007 with respiratory diseases and cardiovascular diseases. 

Chronic Condition/ 

Disease Adults (18+) Percentage of U.S. Adult Population by Age Percentage by Region 

COPDa (Millions) All (18+) 18-44 45-64 65-74 75+ NE MW S W 

 Chronic bronchitis 7.6 3.4 2.3 4.2 5.5 4.8 2.8 3.2 4.0 2.9 

 Emphysema 3.7 1.6 0.2 2.3 4.5 5.2 1.1 1.8 1.8 1.6 

Cardiovascular Diseasesb (Millions) All (18+) 18-44 45-64 65-74 75+ NE MW S W 

 All heart diseasec 25.1 11.2 4.1 12.2 27.1 35.8 10.6 12.3 11.3 10.2 

 Coronary heart diseased 13.7 6.1 0.9 6.7 18.6 23.6 5.3 6.7 6.4 5.5 

 Hypertension 52.9 23.2 8.2 32.1 50.9 57.4 21.3 23.4 25.1 21.0 

 Stroke 5.4 2.4 0.3 2.8 6.3 10.6 2.2 2.3 2.7 2.2 

a Respondents were asked if they had ever been told by a doctor or other health professional that they had emphysema. In a separate question, respondents were asked if they had been told by a doctor or 

other health professional in the last 12 mo that they had bronchitis. A person may be represented in more than one row. 

b

 In separate questions, respondents were asked if they had ever been told by a doctor or other health professional that they had: hypertension (or high blood pressure), coronary heart disease, angina (or 

angina pectoris), heart attack (or myocardial infarction), any other heart condition or disease not already mentioned, or a stroke. A person may be represented in more than one row. c

 Heart disease includes coronary heart disease, angina pectoris, heart attack, or any other heart condition or disease. d

 Coronary heart disease includes coronary heart disease, angina pectoris, or heart attack. 

Source: National Health Interview Survey, 2007, Tables 1-4 (Pleis and Lucas, 2009, 202833).

5.7.1.2. Obstructive Lung Disease 

COPD is a progressive disease resulting in decreased air flow to the lungs and which is 

especially prevalent among smokers. O2 limitation resulting from this reduction in air flow may 

exacerbate CO-related O2 limitation and subsequent cardiovascular or respiratory effects in 

individuals with COPD. The national prevalence of chronic bronchitis and emphysema, the two main 

forms of COPD, was estimated to be 7.6 million and 3.7 million people in 2007, respectively (Table 

5-26), although there could be overlap among these two populations. The 2000 CO AQCD 

(U.S. EPA, 2000, 000907) identified individuals with obstructive lung diseases, such as COPD, as a 

susceptible population due to a majority of COPD patients having exercise limitations as 

demonstrated by a decrease in O2 saturation during mild to moderate exercise. This may heighten the 

sensitivity of these individuals to CO during submaximal exercise typical of normal daily activity. In 

addition, COPD patients who are smokers may have elevated baseline COHb levels of 4-8% 

(U.S. EPA, 2000, 000907). COPD is often accompanied by a number of changes in gas exchange, 

including increased VD and VA/Q inequality (Marthan et al., 1985, 086334), which could slow both 

CO uptake and elimination. 

The few epidemiologic studies of cardiovascular effects in individuals with underlying COPD 

show weak positive associations between ambient CO and increased CVD HAs or ED visits. For 

example, Peel et al. (2007, 090442) found that associations between short-term CO exposure and 

HAs for PVCD or CHF were increased in individuals with a secondary diagnosis of COPD. 

However, underlying COPD was not associated with increased IHD or dysrhythmia HAs. As 

January 2010 5-117 
described in Section 5.7.1.1, animal toxicological studies demonstrate CO-induced exacerbation of 

vascular remodeling related to pulmonary hypertension, a form of which is a frequent complication 

of COPD. 

A controlled human exposure study of respiratory effects in individuals with COPD (Bathoorn 

et al., 2007, 193963), found that two of the patients experienced COPD exacerbation during or 

following CO exposure at 100-125 ppm for 2 h, although a slight anti-inflammatory effect was also 

observed. Although the majority of the evidence for CO-induced effects comes from studies that 

focus on individuals with COPD, epidemiologic studies also report weak positive associations for 

asthmatics (Section 5.5.2.2) who can also experience exercise-induced airflow limitation. In 

addition, preliminary evidence from a recent animal toxicological study indicates mild pulmonary 

inflammation in response to 50 ppm CO (Ghio et al., 2008, 096321). Since pulmonary inflammation 

plays an important role in the exacerbation of COPD and asthma, it may serve as a mechanism 

underlying CO-induced respiratory effects; however, additional research is needed to confirm these 

results. Taken together, the limited evidence from epidemiologic and controlled human exposure 

studies and some preliminary evidence from toxicological studies suggests 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. 

5.7.1.3. Diabetes 

Exhaled CO concentrations are elevated in individuals with diabetes and are correlated with 

blood glucose levels and duration of disease, indicating increased endogenous CO production 

(Section 4.5). As a result, it has been speculated that elevated baseline COHb levels in diabetic 

individuals could increase the susceptibility of diabetics to CO-induced health effects in response to 

ambient CO exposures. Epidemiologic studies provide evidence which suggests that diabetics are at 

increased risk for cardiovascular ED visits and HAs compared to nondiabetics in response to shortterm exposure to CO (Pereira Filho et al., 2008, 190260; Zanobetti and Schwartz, 2001, 016710). 

This is consistent with results reported by Peel et al. (2007, 090442), who observed an increase in 

cardiovascular-related ED visits for dysrhythmias and PVCD in individuals with diabetes but not for 

IHD or CHF ED visits. The results from Peel et al. (2007, 090442) that indicate an increase in 

dysrhythmia ED visits for individuals with diabetes are consistent with results from a panel study 

conducted by Min et al. (2009, 199514) to investigate the relationship between CO and HRV in 

individuals with metabolic syndrome. Metabolic syndrome is characterized by risk factors for both 

diabetes and CVD, including elevations in blood pressure, fasting blood glucose, triglycerides, and 

waist circumference, as well as low levels of HDL cholesterol. Min et al. (2009, 199514) observed 

associations between short-term exposure to CO and changes in HRV parameters among subjects 

with metabolic syndrome but not among healthy subjects. In addition, the observed associations 

were robust in copollutant models with either PM10 or NO2. In an analysis of individual risk factors, 

the CO effects were stronger among subjects with higher levels of fasting blood glucose or 

triglycerides. Although no evidence was identified from controlled human exposure or toxicological 

studies regarding CO exposure and diabetes, vascular dysfunction was demonstrated in an animal 

model of metabolic syndrome and was attributed to increased endogenous CO production (Johnson 

et al., 2006, 193874). Thus, increased endogenous CO production and the potential for higher 

baseline COHb concentrations, combined with the limited epidemiologic evidence showing 

cardiovascular effects, suggests that diabetics are potentially susceptible to short-term exposure to 

CO. 

5.7.1.4. Anemia 

Although no controlled human exposure or epidemiologic studies were identified that 

specifically examined CO-related health effects in individuals with anemia, the 2000 CO AQCD 

(U.S. EPA, 2000, 000907) suggested that conditions such as anemia that produce tissue hypoxia by 

lowering the blood O2 carrying capacity or content will result in a greater risk of effects from COHbinduced hypoxia due to the combined effects of both sources of hypoxia. As discussed in Section 

4.4.4 of this ISA, anemias are a group of diseases that lower hematocrit and result in reduced arterial 

O2 content due to Hb deficiency through hemolysis, hemorrhage, or reduced hematopoiesis. 

Hereditary hemoglobinopathies such as sickle cell anemia and thalassemia also reduce the O2-

carrying capacity of the blood. Anemia may also result from pathologic conditions characterized by 

January 2010 5-118 
chronic inflammation such as malignant tumors or chronic infections (Cavallin-Ståhl et al., 1976, 

086306; Cavallin-Ståhl et al., 1976, 193239). The cardiovascular system of people with anemia 

compensates for the reduction in O2 carrying capacity by increasing cardiac output as both heart rate 

and stroke volume increase. One of the most prevalent forms of anemia arises from a single-point 

mutation in the Hb gene, resulting in sickle cell diseases. The affinity of Hb for O2 and its O2

carrying capacity is reduced, causing a shift to the right in the O2 dissociation curve. It is well 

documented that African-American populations have a higher incidence of sickle cell anemia, which 

may be a risk factor for effects due to CO-mediated hypoxia. Other hereditary hemoglobinopathies, 

such as thalassemia, also reduce the O2-carrying capacity of the blood due to the production of an 

abnormal form of hemoglobin. Overall, lowered hematocrit due to anemia may result in increased 

susceptibility and a greater response to inhalation of ambient CO. 

Anemia may also increase the susceptibility of an individual to CO exposure in a different 

manner through the increased production of endogenous CO as a result of the disturbance of RBC 

hemostasis by accelerated destruction of hemoproteins (Section 4.5). Pathologic conditions such as 

hemolytic anemias, hematomas, thalassemia, Gilbert’s syndrome with hemolysis, and other 

hematological diseases and illness will accelerate endogenous CO production (Berk et al., 1974, 

012386; Hampson and Weaver, 2007, 190272; Meyer et al., 1998, 047530; Solanki et al., 1988, 

012426; Sylvester et al., 2005, 191954). Patients with hemolytic anemia exhibit COHb levels at least 

two- to threefold higher than healthy individuals and CO production rates two- to eightfold higher 

(Coburn et al., 1966, 010984). Recent studies report elevated COHb levels of 4.6-9.7% due to druginduced hemolytic anemia (Hampson and Weaver, 2007, 190272) and between 3.9% and 6.7% due 

to an unstable hemoglobin disorder (Hb Zürich) (Zinkham et al., 1980, 011435). Taken together, this 

evidence 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. 

5.7.2. Lifestage 

Age alters the variables that influence the uptake, distribution, and elimination of CO 

(Section 4.4.3). COHb levels decline more rapidly in young children compared to adults after CO 

exposure (Joumard et al., 1981, 011330; Klasner et al., 1998, 087196). After infancy, the COHb halflife increases with age, practically doubling between the ages of 2 and 70 yr (Joumard et al., 1981, 

011330). However, it should be noted that the rate of this reduction in CO elimination is very rapid 

in the growing years (2-16 yr of age) but slows beyond adolescence. An increase in alveolar volume 

and DLCO were observed with increasing body length of infants and toddlers (Castillo et al., 2006, 

193234); these changes suggest faster CO uptake due to more advanced lung development. After 

infancy, increasing age decreases DLCO and increases VA/Q mismatch, resulting in a longer duration 

for both loading and elimination of CO from the blood (Neas and Schwartz, 1996, 079363). 

5.7.2.1. Older Adults 

The 2000 CO AQCD (U.S. EPA, 2000, 000907) noted that 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. Several epidemiologic studies 

compared cardiovascular outcomes in older and younger adults, although no such studies were 

conducted in the U.S. In a study in Australia and New Zealand, Barnett et al. (2006, 089770) found 

an increase in IHD and MI HAs among individuals ≥ 65 yr of age compared with individuals aged 

15-64 yr in response to short-term exposure to CO. Lee et al. (2003, 095552) also found an 

association with IHD HAs in Seoul, Korea, for individuals ≥ 65 yr of age but not when all 

individuals were included in the analysis. Lanki et al. (2006, 089788) found an association with HAs 

for nonfatal MI in a multicity European study among those aged ≥ 75 yr but not for those <75 yr old. 

In contrast, D’Ippoliti et al. (2003, 074311) observed higher associations for MI hospital admissions 

in Rome among 18- to 64-yr olds than among either 65- to 74-yr olds or those 75 yr and over. 

Szyszkowicz (2007, 193793) found slightly lower associations for IHD hospital admissions in 

Montreal, Canada among those >64 yr of age than for the all-age group. Another Canadian study 

(Fung et al., 2005, 074322) conducted in Windsor, Ontario, found some evidence of increased 

January 2010 5-119 
associations for between CO and CVDs (defined as HF, IHD, or dysrhythmia) among individuals 

≥ 65 yr of age compared with the <65-yr age group. No controlled human exposure studies or 

toxicological studies were identified that compared CO effects among older and younger adults or 

animal models of senescence, respectively. Overall, the epidemiologic studies evaluated provide 

limited evidence that older adults may be susceptible to CO exposure. 

A combination of factors may be responsible for increased susceptibility to CO-related health 

effects among older adults. One important factor which may contribute to the observed increases in 

CO-induced cardiovascular effects is the much higher prevalence of CAD and other cardiovascular 

conditions in older adults compared with the general population. As shown in Table 5-26,18.6% of 

adults aged 65-74 yr and 23.6% of adults aged 75 yr and over reported having CHD, as compared 

with 6.1% of the population as a whole. Both the higher prevalence of CAD and the gradual decline 

in physiological processes associated with aging (U.S. EPA, 2006, 192082) may contribute to 

increased health effects in response to CO in this population. Older adults represent a large and 

growing fraction of the U.S. population, from 12.4% or 35 million people in 2000 to a projected 

19.3% or 72 million people in 2030 (U.S. Census, 2000, 157064), and, as a result, are a large 

population that is potentially susceptible to CO-induced health effects. 

5.7.2.2. Gestational Development 

CO inhaled by pregnant animals quickly crosses the placental barriers and enters fetal 

circulation. Effects of ambient CO may be enhanced during gestation because fetal CO 

pharmacokinetics do not follow the same kinetics as maternal CO exposure; this contributes to the 

difficulty in estimating fetal COHb based on maternal levels. It has been demonstrated that human 

fetal Hb has a higher affinity for CO than adult Hb (Di Cera et al., 1989, 193998). Maternal and fetal 

COHb concentrations have been modeled as a function of time using a modified CFK equation (Hill 

et al., 1977, 011315). At steady-state conditions, fetal COHb has been found to be 10-15% higher 

than maternal COHb levels. For example, exposure to 30 ppm CO results in a steady-state maternal 

COHb of 5% and a fetal COHb of 5.75%. Fetal CO uptake lags behind maternal uptake for the first 

few hours but later may overtake the maternal values. Similarly, during washout, fetal COHb levels 

are maintained for longer, with a half-life of around 7.5 h versus the maternal half-life of around 4 h 

(Longo and Hill, 1977, 010802). In addition, maternal endogenous CO production increases during 

pregnancy (0.92 mL/h) due to contributions from fetal endogenous CO production (0.036 mL/h) and 

altered hemoglobin metabolism (Hill et al., 1977, 011315; Longo, 1970, 013922). 

Epidemiologic studies provide limited evidence that in utero CO exposure is associated with 

changes in various birth outcomes (Section 5.4.1). CO exposure during early pregnancy was 

associated with an increased risk of PTB. In the studies that examined associations between CO and 

birth defects, maternal CO exposure was associated with an increased risk of cardiac birth defects, 

which is also coherent with evidence in Section 5.2 identifying the heart as a target organ for CO. 

There is also evidence for small reductions in birth weight (10-20 g) associated with CO exposure, 

generally in the first or third trimester, although the decrease does not generally translate to an 

increased risk of LBW or SGA. It is therefore difficult to conclude if CO is related to a small change 

in birth weight across all births or a marked effect in some subset of births. In addition, there is 

limited evidence that prenatal CO exposure is associated with an increased risk of infant mortality in 

the post-neonatal period. 

Toxicological studies lend biological plausibility to the CO-related developmental outcomes 

observed in epidemiologic studies (Section 5.4.2). Associations have been observed between CO 

exposure in laboratory animals and decrements in birth weight as well as reduced prenatal growth. 

Animal toxicological studies also provide evidence for effects on the heart, including transient 

cardiomegaly at birth after continuous in utero CO exposure and delayed myocardial 

electrophysiological maturation. 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. Furthermore, exogenous CO may interact or disrupt the normal 

physiological roles of endogenous CO in the body. There is evidence that CO plays a role in 

maintaining pregnancy, controlling vascular tone, regulating hormone balance, and sustaining 

normal follicular maturation. 

The developmental outcomes examined in the epidemiologic studies evaluated affect a 

substantial portion of the U.S. population. PTB and LBW have been established as strong predictors 

January 2010 5-120 
of infant mortality and morbidity (Barker et al., 2002, 193960; Berkowitz and Papiernik, 1993, 

055466; Li et al., 2003, 193965; McIntire et al., 1999, 015310). In 2004, 36.5% of all infant deaths 

in the U.S. were preterm-related (MacDorman et al., 2007, 193973). Vital statistics for the year 2005 

in the U.S. showed that the rate for PTB was 12.7%, which has risen 20% since 1990, and the rate 

for LBW was 8.2%, which has risen 17% since 1990 (Martin et al., 2007, 193982). Data from the 

Metropolitan Atlanta Congenital Defects Program (MACDP), which is one of the most 

comprehensive birth defect registries in the U.S., have shown that the prevalence of congenital heart 

defects increased between 1968 and 1997. During 1995-1997 the rate was 90.2 per 10,000 births 

(0.9%) and this was an increase of 58.7 per 10,000 births above the rate during 1968-1972 (Botto et 

al., 2001, 192379). Cardiovascular defects are the single largest contributor to infant mortality 

attributable to birth defects (CDC, 1998, 193243). Between 1995 and 1997, 1 in 13 infant deaths 

(7.4%) was due to a congenital heart defect (Boneva et al., 2001, 193972). The combined evidence 

from epidemiologic and toxicological studies, along with the increasing prevalence of PTB, LBW, 

and cardiac birth defects in the U.S. population, indicates that critical developmental phases may be 

characterized by enhanced sensitivity to CO exposure. 

5.7.3. Gender

COHb concentrations are generally higher in male subjects than in female subjects (Horvath et 

al., 1988, 012725). In addition, the COHb half-life is longer in healthy men than in women of the 

same age, which may be partially explained by differences in muscle mass or the slight correlation 

between COHb half-life and increased height (Joumard et al., 1981, 011330). The rate of decline of 

DLCO with age is lower in middle-aged women than in men; however, it is similar in older adults 

(Neas and Schwartz, 1996, 079363). Lower rates of decline in lung diffusing capacity are consistent 

with the observation that women tend to be more resistant than men to altitude hypoxia (Horvath et 

al., 1988, 012725). Women also experience fluctuating COHb levels through the menstrual cycle 

when endogenous CO production doubles in the progesterone phase (0.62 mL/h versus 0.32 mL/h in 

estrogen phase) (Delivoria-Papadopoulos et al., 1974, 086316; Mercke and Lundh, 1976, 086309). 

Similarly, endogenous CO production increases during pregnancy due to contributions from fetal CO 

production and altered hemoglobin metabolism as described above. In an epidemiologic study 

investigating the association between short-term CO exposure and IHD hospital admissions 

(Szyszkowicz, 2007, 193793), males had higher associations than females in both the all-ages group 

and in those >64 yr of age. However, this 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. 

5.7.4. Altitude 

Higher altitude results in changes in a number of factors that contribute to the uptake and 

elimination of CO. The relationship between altitude and CO exposure has been discussed in depth 

in the 2000 CO AQCD (U.S. EPA, 2000, 000907) and other documents (U.S. EPA, 1978, 086321) 

and is reviewed in Section 4.4.2 of this ISA. In an effort to maintain proper O2 transport and supply, 

physiological changes occur as compensatory mechanisms to combat the decreased barometric 

pressure and resulting altitude-induced hypobaric hypoxia. These changes, which include increases 

in BP and cardiac output and redistribution of blood from skin to organs and from blood to 

extravascular compartments, generally will favor increased CO uptake and COHb formation, as well 

as CO elimination. It has been demonstrated that breathing CO (9 ppm) at rest at altitude produces 

higher COHb compared to sea level (McGrath et al., 1993, 013865), whereas high-altitude exposure 

in combination with exercise causes a decrease in COHb levels versus similar exposure at sea level 

(Horvath et al., 1988, 012725). This decrease could be a shift in CO storage or suppression of COHb 

formation, or both. In a controlled human exposure study on the health effects of CO at altitude, 

Kleinman et al. (1998, 047186) observed that CO exposure and simulated high altitude reduced the 

time to onset of angina relative to clean-air exposure at sea level by 9% and 11%, respectively, 

among a group of individuals with CAD. In this study, the combined effects of altitude and CO 

exposure were observed to be additive, with subjects experiencing, on average, an 18% decrease in 

the time to onset of angina following exposure to CO and simulated altitude relative to clean air 

January 2010 5-121 
exposure at sea level. No epidemiologic studies were identified that specifically examined the effect 

of altitude on health effects due to CO exposure. 

Altitude also increases the baseline COHb levels by inducing endogenous CO production and 

has been shown to be positively associated with baseline COHb concentrations (McGrath, 1992, 

001005; McGrath et al., 1993, 013865). This increase in COHb with altitude-induced hypoxia has 

also been associated with increases in mRNA, protein, and activity of HO-1 in rats and cells leading 

to enhanced endogenous CO production (Carraway et al., 2002, 026018; Chin et al., 2007, 190601). 

Early HH has been found to increase lung HO-1 protein and activity, whereas chronic HH induced 

endogenous CO production in nonpulmonary sites (Section 4.5) (Carraway et al., 2000, 021096). 

Whether other variables (such as an accelerated metabolism or a greater pool of Hb, transient shifts 

in body stores, or a change in the elimination rate of CO) play a role in increasing COHb 

concentrations at high altitudes has not been explored. 

As the length of stay increases at high altitude, acclimatization occurs, inducing 

hyperventilation, polycythemia or increased red blood cell count, and increased tissue capillarity and 

Mb content in skeletal muscle, which could also favor increased CO uptake. Most of the initial 

adaptive changes gradually revert to sea-level values. However, these adaptive changes persist in 

people raised at high altitude even after reacclimatization to sea level (Hsia, 2002, 193857). This 

evidence indicates that visitors to high altitude locations may represent a potentially susceptible 

population for increased risk of health effects due to CO exposure. 

5.7.5. Exercise 

Exercise is an important determinant of CO kinetics and toxicity due to the extensive increase 

in gas exchange. O2 consumption can increase more than 10-fold during exercise. Similarly, 

ventilation, membrane and lung diffusing capacity, pulmonary capillary blood volume, and cardiac 

output increase proportional to work load. The majority of these changes facilitate CO uptake and 

transport by increasing gas exchange efficiency. Likewise, the COHb elimination rate increases with 

physical activity, causing a decrease in COHb half-life (Joumard et al., 1981, 011330). The potential 

effects of CO on exercising individuals was demonstrated in a controlled human exposure study 

where healthy subjects exposed to CO achieved COHb levels of approximately 5%, which resulted 

in a significant decrement in exercise duration and maximal effort capability (measured by metabolic 

equivalent units) (Adir et al., 1999, 001026). These effects could be attributed to CO lowering the 

anaerobic threshold, allowing earlier fatigue of the skeletal muscles and decreasing maximal effort 

capability during heavy exercise. Due to the counterbalancing effects of increased rates of COHb 

formation and elimination, it is unclear whether individuals engaging in light to moderate exercise 

are a potentially susceptible population for increased health effects due to ambient CO exposure. 

5.7.6. Proximity to Roadways 

Individuals that spend a substantial amount of time on or near heavily traveled roadways, such 

as commuters and those living or working near freeways, are likely to be exposed to elevated CO 

concentrations, as discussed in Chapter 3. Targeted sampling studies have found CO concentrations 

measured at the roadside to be several-fold higher than concentrations measured a few hundred 

meters downwind (Baldauf et al., 2008, 191017; Zhu et al., 2002, 041553), with the shape of the 

concentration profile dependent on wind speed and direction. AQS monitoring data aggregated 

across multiple sites with no adjustment for wind conditions show somewhat higher concentrations 

for microscale (near-road) monitors relative to middle-scale monitors, although the ratio is lower 

than that observed in the roadside studies. Elevated near-road concentrations are important for 

residents of the estimated 17.9 million occupied homes nationwide (16.1%) that are within 

approximately 90 m of a freeway, railroad, or airport, according to the 2007 American Housing 

Survey (2008, 194013). 

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 (Bruinen de Bruin et 

al., 2004, 190943; Kaur et al., 2005, 086504; Scotto Di Marco et al., 2005, 144054). In-vehicle 

concentrations have been measured to be several times higher than concentrations measured at fixedsite monitors not located adjacent to roadways (Bruinen de Bruin et al., 2004, 190943; Chang et al., 

2000, 001276; Kaur et al., 2005, 086504; Riediker et al., 2003, 043761; Scotto Di Marco et al., 2005, 

January 2010 5-122 
144054). Commuting is likely to be an important contributor to CO exposure for the 5.5 million U.S. 

worker (5%) who drive 60 min or more to work (U.S. Census Bureau, 2008, 194013). 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. 

5.7.7. Medications and Other Substances 

Endogenous CO production can be altered by medications or a number of physiological 

conditions that increase RBC destruction, the breakdown of hemoproteins other than Hb, and the 

production of bilirubin (Section 4.5). Nicotinic acid, allyl-containing compounds (acetamids and 

barbiturates), diphenylhydantoin, progesterone, contraceptives, and statins increase CO production. 

One epidemiologic study (Dales, 2004, 099036) investigated the effect of medication use on the 

relationship between ambient CO and HRV in individuals with CAD. The authors 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. 

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 leading to very high (>10%) COHb levels, which can be further enhanced by 

prior exposure to HCs or ethanol. 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. 

5.7.8. Summary of Susceptible Populations 

Individuals with CAD represent the population most susceptible to increased risk of COinduced health effects, based on evidence of significant decreases in the time to onset of exerciseinduced angina or ST-segment changes observed in controlled human exposure studies of individuals 

with CAD. This is coherent with the results from epidemiologic studies that observed associations 

between short-term CO exposure and ED visits and HAs for IHD and related outcomes. The limited 

evidence from stratified analyses in epidemiologic studies, which indicates that secondary diagnoses 

of CHF or dysrhythmia modify associations between short-term CO exposure and IHD HAs, 

provides further support that individuals with cardiovascular disease represent a potentially 

susceptible population. Additional evidence is provided by toxicological studies that demonstrated 

exacerbation of cardiomyopathy and increased vascular remodeling in animal models of 

cardiovascular disease. Although it is not clear whether the small changes in COHb associated with 

ambient CO exposures result in substantially diminished O2 delivery to tissues, the known role of 

CO in limiting O2 availability provides biological plausibility for ischemia-related health outcomes 

following CO exposure. The continuous nature of the progression of CAD and its close relationship 

with other forms of cardiovascular disease suggest that a larger population than just those individuals 

with a prior diagnosis of CAD may be susceptible to health effects from CO exposure. 

Populations potentially susceptible to CO-induced health effects also include individuals with 

other preexisting diseases, such as COPD or diabetes. Preliminary evidence available from 

controlled human exposure and epidemiologic studies suggests that individuals with obstructive lung 

disease may be susceptible to increased cardiovascular or respiratory effects due to CO exposure. 

Increased endogenous CO production and the potential 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 types of 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 individuals with anemia. 

There is also evidence that older adults and the developing young represent populations 

potentially susceptible to CO-induced health effects. Epidemiologic studies provide limited evidence 

January 2010 5-123 
from stratified analyses indicating that associations between short-term CO exposure and hospital 

admissions for CAD are higher among those ≥ 65 yr old than for those <65 yr. The older adult 

population also has a much higher prevalence of CAD than the general population as a whole, which 

may contribute to their increased susceptibility. Recent studies on birth outcomes have provided 

limited evidence of associations between in utero CO exposure and PTB, LBW and cardiac birth 

defects. Toxicological studies provide evidence of effects on birth weight and growth as well as 

development of the cardiovascular and nervous systems following prenatal exposure to CO. This 

evidence, combined with differences between fetal and maternal CO pharmacokinetics, indicates that 

critical developmental phases may be characterized by enhanced sensitivity to CO exposure. 

Visitors to high-altitude locations may represent a potentially susceptible population due to 

changes in factors which affect the uptake and elimination of CO, although acclimatization occurs as 

length of stay increases. Individuals with substantial exposure to mobile source emissions, such as 

commuters and those living near heavily traveled roadways, represent an important population 

potentially susceptible to increased risk of CO-induced health effects due to elevated on-road and 

roadside CO concentrations. 

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. 

5.8. Summary 

The evidence reviewed in this chapter describes recent findings regarding the health effects of 

ambient CO. Section 5.1 presents evidence on the mode of action of CO, including its role in 

limiting O2 availability as well as its role in altered cell signaling. Evidence is presented in 

subsequent sections on the effect of short- and long-term exposure to CO on cardiovascular 

morbidity (Section 5.2), the central nervous system (Section 5.3), birth outcomes and developmental 

effects (Section 5.4), respiratory morbidity (Section 5.5), and mortality (Section 5.6). Potentially 

susceptible populations at increased risk of CO-induced health effects are discussed in Section 5.7. 

Table 2-1 summarizes causal determinations for the health outcome categories reviewed in this 

assessment. An integrative overview of the health effects of ambient CO and uncertainties associated 

with interpretation of the evidence is provided in Chapter 2. The strongest evidence regarding COinduced health effects relates to cardiovascular morbidity, and the combined evidence from 

controlled human exposure studies and epidemiologic studies indicates that a causal relationship is 

likely to exist between relevant short-term CO exposures and cardiovascular morbidity, particularly 

in individuals with CAD. The evidence is suggestive of a causal relationship between short-term 

exposure to CO and respiratory morbidity as well as between short-term CO exposure and mortality. 

The evidence is also suggestive of a causal relationship for birth outcomes and developmental effects 

following long-term exposure to CO, and for central nervous system effects linked to short- and 

long-term exposure to CO. The evidence indicates that there is not likely to be a causal relationship 

between long-term exposure to CO and mortality. For respiratory morbidity following long-term 

exposure to CO, the evidence was inadequate to infer a causal relationship. 

January 2010 5-124 
References 

Achouh PE; Simonet S; Fabiani JN; Verbeuren TJ (2008). Carbon monoxide induces relaxation of human internal thoracic 

and radial arterial grafts. Interact Cardiovasc Thorac Surg, 7: 959-963. 179918

Adams KF; Koch G; Chatterjee B; Goldstein GM; O'Neil JJ; Bromberg PA; Sheps DS; McAllister S; Price CJ; Bissette J 

(1988). Acute elevation of blood carboxyhemoglobin to 6% impairs exercise performance and aggravates 

symptoms in patients with ischemic heart disease. J Am Coll Cardiol, 12: 900-909. 012692

Aday LA (2001). At risk in America: The health and health care needs of vulnerable populations in the United States. San 

Francisco, CA: Jossey-Bass, Inc. 192150

Adir Y; Merdler A; Haim SB; Front A; Harduf R; Bitterman H (1999). Effects of exposure to low concentrations of carbon 

monoxide on exercise performance and myocardial perfusion in young healthy men. Occup Environ Med, 56: 535-

538. 001026

Alderman BW; Baron AE; Savitz DA (1987). Maternal exposure to neighborhood carbon monoxide and risk of low infant 

birth weight. Public Health Rep, 102: 410-414. 012243

Alexandreanu IC; Lawson DM (2002). Effects of chronic administration of a heme oxygenase substrate or inhibitor on 

progression of the estrous cycle, pregnancy and lactation of Sprague-Dawley rats. Life Sci, 72: 153-162. 192373

Alexandreanu IC; Lawson DM (2003). Heme oxygenase in the rat anterior pituitary: Immunohistochemical localization 

and possible role in gonadotropin and prolactin secretion. Exp Biol Med, 228: 64-69. 193871

Allred EN; Bleecker ER; Chaitman BR; Dahms TE; Gottlieb SO; Hackney JD; Hayes D; Pagano M; Selvester RH; Walden 

SM; Warren J (1989). Acute effects of carbon monoxide exposure on individuals with coronary artery disease. 

Health Effects Institute. Boston, MA. 012697

Allred EN; Bleecker ER; Chaitman BR; Dahms TE; Gottlieb SO; Hackney JD; Pagano M; Selvester RH; Walden SM; 

Warren J (1989). Short-term effects of carbon monoxide exposure on the exercise performance of subjects with 

coronary artery disease. N Engl J Med, 321: 1426-1432. 013018

Allred EN; Bleecker ER; Chaitman BR; Dahms TE; Gottlieb SO; Hackney JD; Pagano M; Selvester RH; Walden SM; 

Warren J (1991). Effects of carbon monoxide on myocardial ischemia. Environ Health Perspect, 91: 89-132. 

011871

Alonso JR; Cardellach F; Lopez S; Casademont J; Miro O (2003). Carbon monoxide specifically inhibits cytochrome c 

oxidase of human mitochondrial respiratory chain. Pharmacol Toxicol, 93: 142-146. 193882

American Lung Association (2001). Urban air pollution and health inequities: A workshop report. Environ Health Perspect, 

3: 357-374. 016626

Anderson EW; Andelman RJ; Strauch JM; Fortuin NJ; Knelson JH (1973). Effect of low-level carbon monoxide exposure 

on onset and duration of angina pectoris: a study in ten patients with ischemic heart disease. Ann Intern Med, 79: 

46-50. 023134

Andresen JJ; Shafi NI; Durante W; Bryan RM Jr (2006). Effects of carbon monoxide and heme oxygenase inhibitors in 

cerebral vessels of rats and mice. Am J Physiol Heart Circ Physiol, 291: H223-H230. 180449

Antonelli T; Tomasini MC; Tattoli M; Cassano T; Finetti S; Mazzoni E; Trabace L; Carratu MR; Cuomo V; Tanganelli S; 

Ferraro L (2006). Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide 

reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures. Neurochem Int, 49: 568-76. 

194960

Arnedo-Pena A; Garcia-Marcos L; Carvajal Uruena I; Busquets Monge R; Morales Suarez-Varela M; Miner Canflanca I; 

Batlles Garrido J; Blanco Quiros A; Lopez-Silvarrey Varela A; Garcia Hernandez G; Aguinaga Ontoso I; Gonzalez 

Diaz C (2009). Air pollution and recent symptoms of asthma, allergic rhinitis, and atopic eczema in schoolchildren 

aged between 6 and 7 years. Arch Bronconeumol, 45: 224-229. 190238

 

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 5-125 
Astrup P; Olsen HM; Trolle D; Kjeldsen K (1972). Effect of moderate carbon-monoxide exposure on fetal development. 

Lancet, 7789: 1220-1222. 011121

Ayres SM; Giannelli S Jr; Mueller H; Criscitiello A (1973). Myocardial and systemic vascular responses to low 

concentration of carboxyhemoglobin. Ann Clin Lab Sci, 3: 440-447. 193943

Baccarelli A; Zanobetti A; Martinelli I; Grillo P; Hou L; Giacomini S; Bonzini M; Lanzani G; Mannucci PM; Bertazzi PA; 

Schwartz J (2007). Effects of exposure to air pollution on blood coagulation. J Thromb Haemost, 5: 252-260. 

090733

Bainbridge SA; Farley AE; McLaughlin BE; Graham CH; Marks GS; Nakatsu K; Brien JF; Smith GN (2002). Carbon 

monoxide decreases perfusion pressure in isolated human placenta. Placenta, 23: 563-569. 043161

Baldauf R; Thoma E; Khlystov A; Isakov V; Bowker G; Long T; Snow R (2008). Impacts of noise barriers on near-road air 

quality. Atmos Environ, 42: 7502-7507. 191017

Ballester F; Rodriguez P; Iniguez C; Saez M; Daponte A; Galan I; Taracido M; Arribas F; Bellido J; Cirarda FB; Canada A; 

Guillen JJ; Guillen-Grima F; Lopez E; Perez-Hoyos S; Lertxundi A; Toro S (2006). Air pollution and 

cardiovascular admisisons association in Spain: results within the EMECAS project. J Epidemiol Community 

Health, 60: 328-336. 088746

Ballester F; Tenias JM; Perez-Hoyos S (2001). Air pollution and emergency hospital admissions for cardiovascular diseases 

in Valencia, Spain. J Epidemiol Community Health, 55: 57-65. 013257

Barber A; Robson SC; Myatt L; Bulmer JN; Lyall F (2001). Heme oxygenase expression in human placenta and placental 

bed: reduced expression of placenta endothelial HO-2 in preeclampsia and fetal growth restriction. FASEB J, 15: 

1158-68. 193891

Barker DJ; Eriksson JG; Forsen T; Osmond C (2002). Fetal origins of adult disease: Strength of effects and biological 

basis. Int J Epidemiol, 31: 1235-1239. 193960

Barnett AG; Williams GM; Schwartz J; Best TL; Neller AH; Petroeschevsky AL; Simpson RW (2006). The effects of air 

pollution on hospitalizations for cardiovascular disease in elderly people in Australian and New Zealand cities. 

Environ Health Perspect, 114: 1018-1023. 089770

Bathoorn E; Slebos DJ; Postma DS; Koeter GH; van Oosterhout AJ; van der Toorn M; Boezen HM; Kerstjens HA (2007). 

Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: A pilot study. Eur Respir J, 30: 

1131-1137. 193963

Beard RR; Wertheim GA (1967). Behavioral impairment associated with small doses of carbon monoxide. Am J Public 

Health, 57: 2012-2022. 011015

Bell ML; Ebisu K; Belanger K (2007). Ambient air pollution and low birth weight in Connecticut and Massachusetts. 

Environ Health Perspect, 115: 1118-24. 091059

Bell ML; Peng RD; Dominici F; Samet JM (2009). Emergency admissions for cardiovascular disease and ambient levels of 

carbon monoxide: Results for 126 U.S. urban counties, 1999-2005. Circulation, 120: 949-955. 193780

Benagiano V; Lorusso L; Coluccia A; Tarullo A; Flace P; Girolamo F; Bosco L; Cagiano R; Ambrosi G (2005). Glutamic 

acid decarboxylase and GABA immunoreactivities in the cerebellar cortex of adult rat after prenatal exposure to a 

low concentration of carbon monoxide. Neuroscience, 135: 897-905. 180445

Benagiano V; Lorusso L; Flace P; Girolamo F; Rizzi A; Sabatini R; Auteri P; Bosco L; Cagiano R; Ambrosi G (2007). 

Effects of prenatal exposure to the CB-1 receptor agonist WIN 55212-2 or CO on the GABAergic neuronal systems 

of rat cerebellar cortex. Neuroscience, 149: 592-601. 193892

Benignus VA (1993). Importance of experimenter-blind procedure in neurotoxicology. Neurotoxicol Teratol, 15: 45-49. 

013645

Benignus VA; Muller KE; Barton CN; Prah JD (1987). Effect of low level carbon monoxide on compensatory tracking and 

event monitoring. Neurotoxicol Teratol, 9: 227-234. 012250

Berger A; Zareba W; Schneider A; Ruckerl R; Ibald-Mulli A; Cyrys J; Wichmann HE; Peters A (2006). Runs of ventricular 

and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. J Occup Environ 

Med, 48: 1149-58. 098702

January 2010 5-126 
Berk PD; Rodkey FL; Blaschke TF; Collison HA; Waggoner JG (1974). Comparison of plasma bilirubin turnover and 

carbon monoxide production in man. J Lab Clin Med, 83: 29-37. 012386

Berkowitz GS; Papiernik E (1993). Epidemiology of preterm birth. Epidemiol Rev, 15: 414-443. 055466

Bernard N; Saintot M; Astre C; Gerber M (1998). Personal exposure to nitrogen dioxide pollution and effect on plasma 

antioxidants. J Lab Clin Med, 53: 122-128. 086427

Biggeri A; Baccini M; Bellini P; Terracini B (2005). Meta-analysis of the Italian studies of short-term effects of air 

pollution (MISA), 1990-1999. Int J Occup Environ Health, 11: 107-122. 087395

Bing O; Grundemar L; Ny L; Moller C; Heilig M (1995). Modulation of carbon monoxide production and enhanced spatial 

learning by tin protoporphyrin. Neuroreport, 6: 1369-1372. 079418

Boneva RS; Botto LD; Moore CA; Yang QH; Correa A; Erickson JD (2001). Mortality associated with congenital heart 

defects in the United States: Trends and racial disparities, 1979-1997. Circulation, 103: 2376-2381. 193972

Botto LD; Correa A; Erickson JD (2001). Racial and temporal variations in the prevalence of heart defects. Pediatrics, 107: 

E32. 192379

Brian JE Jr; Heistad DD; Faraci FM (1994). Effect of carbon monoxide on rabbit cerebral arteries. Stroke, 25: 639-644. 

076283

Briet M; Collin C; Laurent S; Tan A; Azizi M; Agharazii M; Jeunemaitre X; Alhenc-Gelas F; Boutouyrie P (2007). 

Endothelial function and chronic exposure to air pollution in normal male subjects. Hypertension, 50: 970-976. 

093049

Brown SD; Piantadosi CA (1992). Recovery of energy metabolism in rat brain after carbon monoxide hypoxia. J Clin 

Invest, 89: 666-672. 013441

Bruinen de Bruin Y; Carrer P; Jantunen M; Hänninen O; Scotto di Marco G; Kephalopoulos S; Cavallo D; Maroni M 

(2004). Personal carbon monoxide exposure levels: Contribution of local sources to exposures and 

microenvironment concentrations in Milan. J Expo Anal Environ Epidemiol, 14: 312-322. 190943

Brüne B; Ullrich V (1987). Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate 

cyclase. Mol Pharmacol, 32: 497-504. 016535

Burnett RT; Brook J; Dann T; Delocla C; Philips O; Cakmak S; Vincent R; Goldberg MS; Krewski D (2000). Association 

between particulate- and gas-phase components of urban air pollution and daily mortality in eight Canadian cities. 

Inhal Toxicol, 12: 15-39. 010273

Burnett RT; Goldberg MS (2003). Size-fractionated particulate mass and daily mortality in eight Canadian cities. Health 

Effects Institute. Boston, MA. 042798

Burnett RT; Smith-Doiron M; Stieb D; Raizenne ME; Brook JR; Dales RE; Leech JA; Cakmak S; Krewski D (2001). 

Association between ozone and hospitalization for acute respiratory diseases in children less than 2 years of age. 

Am J Epidemiol, 153: 444-452. 093439

Burnett RT; Stieb D; Brook JR; Cakmak S; Dales R; Raizenne M; Vincent R; Dann T (2004). Associations between shortterm changes in nitrogen dioxide and mortality in Canadian cities. Arch Environ Occup Health, 59: 228-236. 

086247

Bye A; Sørhaug S; Ceci M; Høydal MA; Stølen T; Heinrich G; Tjønna AE; Najjar SM; Nilsen OG; Catalucci D; Grimaldi 

S; Contu R; Steinshamn S; Condorelli G; Smith GL; Ellingsen O; Waldum H; Wisløff U (2008). Carbon monoxide 

levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological 

hypertrophy. Inhal Toxicol, 20: 635-646. 193777

Cagiano R; Ancona D; Cassano T; Tattoli M; Trabace L; Cuomo V (1998). Effects of prenatal exposure to low 

concentrations of carbon monoxide on sexual behaviour and mesolimbic dopaminergic function in rat offspring. Br 

J Pharmacol, 125: 909-915. 087170

Cakmak S; Dales RE; Judek S (2006). Respiratory health effects of air pollution gases: modification by education and 

income. Arch Environ Occup Health, 61: 5-10. 093272

Cardell L-O; Ueki IF; Stjarne P; Agusti C; Takeyama K; Linden A; Nadel JA (1998). Bronchodilatation in vivo by carbon 

monoxide, a cyclic GMP related messenger. Br J Pharmacol, 124: 1065-1068. 086700

January 2010 5-127 
Cardell LO; Lou YP; Takeyama K; Ueki IF; Lausier J; Nadel JA (1998). Carbon monoxide, a cyclic GMP-related 

messenger, involved in hypoxic bronchodilation in vivo. Pulm Pharmacol Ther, 11: 309-315. 011534

Carmines E; Rajendran N (2008). Evidence for carbon monoxide as the major factor contributing to lower fetal weights in 

rats exposed to cigarette smoke. Toxicol Sci, 102: 383. 188440

Carratu MR; Cagiano R; Desantis S; Labate M; Tattoli M; Trabace L; Cuomo V (2000). Prenatal exposure to low levels of 

carbon monoxide alters sciatic nerve myelination in rat offspring. Life Sci, 67: 1759-1772. 015839

Carratu MR; Cagiano R; Tattoli M; Trabace L; Borracci P; Cuomo V (2000). Prenatal exposure model simulating CO 

inhalation in human cigarette smokers: sphingomyelin alterations in the rat sciatic nerve. Toxicol Lett, 117: 101-

106. 015935

Carratu MR; Renna G; Giustino A; De Salvia MA; Cuomo V (1993). Changes in peripheral nervous system activity 

produced in rats by prenatal exposure to carbon monoxide. Arch Toxicol, 67: 297-301. 013812

Carraway MS; Ghio AJ; Carter JD; Piantadosi CA (2000). Expression of heme oxygenase-1 in the lung in chronic hypoxia. 

Am J Physiol, 278: L806-L812. 021096

Carraway MS; Ghio AJ; Suliman HB; Carter JD; Whorton AR; Piantadosi CA (2002). Carbon monoxide promotes hypoxic 

pulmonary vascular remodeling. Am J Physiol, 282: L693-L702. 026018

Castillo A; Llapur CJ; Martinez T; Kisling J; Williams-Nkomo T; Coates C; Tepper RS (2006). Measurement of single 

breath-hold carbon monoxide diffusing capacity in healthy infants and toddlers. Pediatr Pulmonol, 41: 544-550 . 

193234

Cavallin-Ståhl E; Mercke C; Lundh B (1976). Carbon monoxide production in patients with breast carcinoma. Br J 

Haematol, 32: 177-182. 086306

Cavallin-Ståhl E; Mercke C; Lundh B (1976). Erythropoiesis and carbon monoxide production in Hodgkin's disease. Br J 

Haematol, 32: 167-175. 193239

CDC (1998). Trends in infant mortality attributable to birth defects--United States, 1980-1995. MMWR Morb Mortal Wkly 

Rep, 47: 773-778. 193243

Cella M; Farina MG; Sarmiento MIK; Chianelli M; Rosenstein RE; Franchi AM (2006). Heme oxygenase-carbon 

monoxide (HO-CO) system in rat uterus : Effect of sexual steroids and prostaglandins. J Steroid Biochem Mol Biol, 

99: 59-66 . 193240

Chan C-C; Chuang K-J; Chien L-C; Chen W-J; Chang W-T (2006). Urban air pollution and emergency admissions for 

cerebrovascular diseases in Taipei, Taiwan. Eur Heart J, 27: 1238-1244. 090193

Chan C-C; Chuang K-J; Su T-C; Lin L-Y (2005). Association between nitrogen dioxide and heart rate variability in a 

susceptible population. Eur J Cardiovasc Prev Rehabil, 12: 580-586. 088988

Chang C-C; Tsai S-S; Ho S-C; Yang C-Y (2005). Air pollution and hospital admissions for cardiovascular disease in Taipei, 

Taiwan. Environ Res, 98: 114-119. 080086

Chang L-T; Koutrakis P; Catalano PJ; Suh HH (2000). Hourly personal exposures to fine particles and gaseous pollutants--

results from Baltimore, Maryland. J Air Waste Manag Assoc, 50: 1223-1235. 001276

Chen GH; Kong J; Reinhard K; Fechter LD (2001). NMDA receptor blockage protects against permanent noise-induced 

hearing loss but not its potentiation by carbon monoxide . Hear Res, 154: 108-115. 193985

Chen L; Yang W; Jennison BL; Goodrich A; Omaye ST (2002). Air pollution and birth weight in northern Nevada, 1991-

1999. Inhal Toxicol, 14: 141-157. 024945

Chen P-C; Lai Y-M; Chan C-C; Hwang J-S; Yang C-Y; Wang J-D (1999). Short-term effect of ozone on the pulmonary 

function of children in primary school. Environ Health Perspect, 107: 921-925. 011149

Cheng C; Noordeloos AM; Jeney V; Soares MP; Moll F; Pasterkamp G; Serruys PW; Duckers HJ (2009). Heme oxygenase 

1 determines atherosclerotic lesion progression into a vulnerable plaque. Circulation, 119: 3017-3027. 193775

Chevalier RB; Krumholz RA; Ross JC (1966). Reaction of nonsmokers to carbon monoxide inhalation: cardiopulmonary 

responses at rest and during exercise. JAMA, 198: 1061-1064. 010641

January 2010 5-128 
Chin BY; Jiang G; Wegiel B; Wang HJ; Macdonald T; Zhang XC; Gallo D; Cszimadia E; Bach FH; Lee PJ; Otterbein LE 

(2007). Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. 

PNAS, 104: 5109-5114. 190601

Chuang KJ; Coull BA; Zanobetti A; Suh H; Schwartz J; Stone PH; Litonjua A; Speizer FE; Gold DR (2008). Particulate 

Air Pollution as a Risk Factor for ST-Segment Depression in Patients With Coronary Artery Disease. Circulation, 

118: 1314-1320. 155731

Chung Y; Huang SJ; Glabe A; Jue T (2006). Implication of CO inactivation on myoglobin function. Am J Physiol Lung 

Cell Mol Physiol, 290: 1616-1624. 193987

Coburn RF; Williams WJ; Kahn SB (1966). Endogenous carbon monoxide production in patients with hemolytic anemia. J 

Clin Invest, 45: 460-468. 010984

Coceani F; Breen CA; Lees JG; Falck JR; Olley PM (1988). Further evidence implicating a cytochrome P-450-mediated 

reaction in the contractile tension of the lamb ductus arteriosus. Circ Res, 62: 471-477. 040493

Cronje FJ; Carraway MS; Freiberger JJ; Suliman HB; Piantadosi CA (2004). Carbon monoxide actuates O2-limited heme 

degradation in the rat brain. Free Radic Biol Med, 37: 1802-1812. 180440

D'Amico G; Lam F; Hagen T; Moncada S (2006). Inhibition of cellular respiration by endogenously produced carbon 

monoxide. J Cell Sci, 119: 2291-2298. 193992

D'Ippoliti D; Forastiere F; Ancona C; Agabiti N; Fusco D; Michelozzi P; Perucci CA (2003). Air pollution and myocardial 

infarction in Rome: a case-crossover analysis. Epidemiology, 14: 528-535. 074311

Dales R (2004). Ambient carbon monoxide may influence heart rate variability in subjects with coronary artery disease. J 

Occup Environ Med, 46: 1217-1221. 099036

Davies DM; Smith DJ (1980). Electrocardiographic changes in healthy men during continuous low-level carbon monoxide 

exposure. Environ Res, 21: 197-206. 011288

Davies RF; Topping DL; Turner DM (1976). The effect of intermittent carbon monoxide exposure on experimental 

atherosclerosis in the rabbit. Atherosclerosis, 24: 527-536. 010660

Deedwania PC; Stein PK; Koren A; Mukherjee R; Pitt B (2005). Decreased heart rate variability is an independent 

predictor of sudden cardiac death in post-ML heart failure: Results of the EPHESUS arrhythmia and heart-rate 

variability analysis. In JT Dipiro (Ed.),Pharmacotherapy: A Pathophysiological Approach (pp. 3029). New York 

City: McGraw-Hill. 195134

Delfino RJ: Staimer N; Tjoa T; Gillen DL; Polidori A; Arhami M; Kleinman MT; Vaziri ND; Longhurst J; Sioutas C 

(2009). Air pollution exposures and circulating biomarkers of effect in a susceptible population: clues to potential 

causal component mixtures and mechanisms. Environ Health Perspect, 117: 1232-1238. 200844

Delfino RJ; Gone H; Linn WS; Pellizzari ED; Hu Y (2003). Asthma symptoms in Hispanic children and daily ambient 

exposures to toxic and criteria air pollutants. Environ Health Perspect, 111: 647-656. 050460

Delfino RJ; Staimer N; Tjoa T; Polidori A; Arhami M; Gillen DL; Kleinman MT; Vaziri ND; Longhurst J; Zaldivar F; 

Sioutas C (2008). Circulating biomarkers of inflammation, antioxidant activity, and platelet activation are 

associated with primary combustion aerosols in subjects with coronary artery disease. Environ Health Perspect, 

116: 898-906. 156390

Delivoria-Papadopoulos M; Coburn RF; Forster RE (1974). Cyclic variation of rate of carbon monoxide production in 

normal women. J Appl Physiol, 36: 49-51. 086316

Denschlag D; Marculescu R; Unfried G; Hefler LA; Exner M; Hashemi A; Riener EK; Keck C; Tempfer CB; Wagner O 

(2004). The size of a microsatellite polymorphism of the haem oxygenase 1 gene is associated with idiopathic 

recurrent miscarriage. Mol Hum Reprod, 10: 211-4. 193894

De Hartog JJ; Hoek G; Peters A; Timonen KL; Ibald-Mulli A; Brunekreef B; Heinrich J; Tiittanen P; Van Wijnen JH; 

Kreyling W; Kulmala M; Pekkanen J (2003). Effects of fine and ultrafine particles on cardiorespiratory symptoms 

in elderly subjects with coronary heart disease: the ULTRA study. Am J Epidemiol, 157: 613-623. 001061

De Jong MJ; Randall DC (2005). Heart rate variability analysis in the assessment of autonomic function in heart failure. J 

Cardiovasc Nurs, 20: 186-195; quiz 196-197. 193996

January 2010 5-129 
De Leon SF; Thurston GD; Ito K (2003). Contribution of respiratory disease to nonrespiratory mortality associations with 

air pollution. Am J Respir Crit Care Med, 167: 1117-1123. 055688

De Luca A; Pierno S; Tricarico D; Carratu MR; Cagiano R; Cuomo V; Camerino DC (1996). Developmental changes of 

membrane electrical properties of rat skeletal muscle fibers produced by prenatal exposure to carbon monoxide. 

Environ Toxicol Pharmacol, 2: 213-221. 080911

De Salvia MA; Cagiano R; Carratu MR; Di Giovanni V; Trabace L; Cuomo V (1995). Irreversible impairment of active 

avoidance behavior in rats prenatally exposed to mild concentrations of carbon monoxide. Psychopharmacology, 

122: 66-71. 079441

Di Cera E; Doyle ML; Morgan MS; De Cristofaro R; Landolfi R; Bizzi B; Castagnola M; Gill SJ (1989). Carbon monoxide 

and oxygen binding to human hemoglobin F0. Biochemistry, 28: 2631-2638. 193998

Di Giovanni V; Cagiano R; De Salvia MA; Giustino A; Lacomba C; Renna G; Cuomo V (1993). Neurobehavioral changes 

produced in rats by prenatal exposure to carbon monoxide. Brain Res, 616: 126-131. 013822

Dockery DW; Luttmann-Gibson H; Rich DQ; Link MS; Mittleman MA; Gold DR; Koutrakis P; Schwartz JD; Verrier RL 

(2005). Association of air pollution with increased incidence of ventricular tachyarrhythmias recorded by implanted 

cardioverter defibrillators. Environ Health Perspect, 113: 670-674. 078995

Dominici F; McDermott A; Daniels M; Zeger SL; Samet JM (2003). Mortality among residents of 90 cities. In: Revised 

analyses of time-series studies of air pollution and health. Health Effects Institute. Boston, MA. HEI Special 

Report. http://www.healtheffects.org/Pubs/TimeSeries.pdf. 056116

Dominici F; McDermott A; Daniels M; Zeger SL; Samet JM (2005). Revised analyses of the national morbidity, mortality, 

and air pollution study: mortality among residents of 90 cities. J Toxicol Environ Health A Curr Iss, 68: 1071-1092. 

087912

Dominici F; McDermott A; Zeger SL; Samet JM (2002). On the use of generalized additive models in time-series studies 

of air pollution and health. Am J Epidemiol, 156: 193-203. 030458

Drinkwater BL; Raven PB; Horvath SM; Gliner JA; Ruhling RO; Bolduan NW; Taguchi S (1974). Air pollution, exercise, 

and heat stress. Arch Environ Occup Health, 28: 177-181. 041332

Dubuis E; Gautier M; Melin A; Rebocho M; Girardin C; Bonnet P; Vandier C (2002). Chronic carbon monoxide enhanced 

IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol 

Physiol, 283: L120-L129. 193911

Dubuis E; Gautier M; Melin A; Rebocho M; Girardin C; Bonnet P; Vandier C (2003). Chronic carbon monoxide exposure 

of hypoxic rats increases in vitro sensitivity of pulmonary artery smooth muscle. Can J Physiol Pharmacol, 81: 711-

719. 180439

Durante W; Johnson FK; Johnson RA (2006). Role of carbon monoxide in cardiovascular function. J Cell Mol Med, 10: 

672-686. 193778

Dyer R; Eccles U; Swartzwelder H; Fechter L; Annau Z (1979). Prenatal carbon monoxide and adult evoked potentials in 

rats. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 13: 107-120. 190994

Ekblom B; Huot R (1972). Response to submaximal and maximal exercise at different levels of carboxyhemoglobin. Acta 

Physiol, 86: 474-482. 010886

Farrugia G; Irons WA; Rae JL; Sarr MG; Szurszewski JH (1993). Activation of whole cell currents in isolated human 

jejunal circular smooth muscle cells by carbon monoxide. Am J Physiol, 264: G1184-G1189. 013826

Favory R; Lancel S; Tissier S; Mathieu D; Decoster B; Neviere R (2006). Myocardial dysfunction and potential cardiac 

hypoxia in rats induced by carbon monoxide inhalation. Am J Respir Crit Care Med, 174: 320-325. 184462

Fechter LD; Annau Z (1977). Toxicity of mild prenatal carbon monoxide exposure. Science, 197: 680-682. 010688

Fechter LD; Annau Z (1980). Prenatal carbon monoxide exposure alters behavioral development. Neurotoxicol Teratol, 2: 

7-11. 011295

Fechter LD; Chen GD; Rao D (2002). Chemical Asphyxiants and Noise. Noise Health, 4: 49-61. 193926

Fechter LD; Karpa MD; Proctor B; Lee AG; Storm JE (1987). Disruption of neostriatal development in rats following 

perinatal exposure to mild, but chronic carbon monoxide. Neurotoxicol Teratol, 9: 277-281. 012259

January 2010 5-130 
Fechter LD; Liu Y; Pearce TA (1997). Cochlear protection from carbon monoxide exposure by free radical blockers in the 

guinea pig. Toxicol Appl Pharmacol, 142: 47-55. 081322

Fechter LD; Thakur M; Miller B; Annau Z; Srivastava U (1980). Effects of prenatal carbon monoxide exposure on cardiac 

development. Toxicol Appl Pharmacol, 56: 370-375. 011294

Fischer PH; Steerenberg PA; Snelder JD; Van Loveren H; Van Amsterdam JGC (2002). Association between exhaled nitric 

oxide, ambient air pollution and respiratory health in school children. Int Arch Occup Environ Health, 75: 348-353. 

025731

Fisher AB; Hyde RW; Baue AE; Reif JS; Kelly DF (1969). Effect of carbon monoxide on function and structure of the 

lung. J Appl Physiol, 26: 4-12. 012381

Fodor GG; Winneke G (1972). Effect of low CO concentrations on resistance to monotony and on psychomotor capacity. 

Gefahrst Reinhalt Luft, 32: 46-54. 011041

Fried PA; Watkinson B; Gray R (1998). Differential effects on cognitive functioning in 9- to 12-year olds prenatally 

exposed to cigarettes and marihuana. Neurotoxicol Teratol, 20: 293-306. 190210

Fried PA; Watkinson B; Gray R (2003). Differential effects on cognitive functioning in 13- to 16-year-olds prenatally 

exposed to cigarettes and marihuana. Neurotoxicol Teratol, 25: 427-436. 190209

Fung KY; Luginaah I; Gorey KM; Webster G (2005). Air pollution and daily hospital admissions for cardiovascular 

diseases in Windsor, Ontario. Can J Public Health, 96: 29-33. 074322

Gautier M; Antier D; Bonnet P; Le Net JL; Hanton G; Eder V (2007). Continuous inhalation of carbon monoxide induces 

right ventricle ischemia and dysfunction in rats with hypoxic pulmonary hypertension. Am J Physiol Heart Circ 

Physiol, 293: H1046-52. 096471

Ghio AJ; Stonehuerner JG; Dailey LA; Richards JH; Madden MD; Deng Z; Nguyen NB; Callaghan KD; Yang F; 

Piantadosi CA (2008). Carbon monoxide reversibly alters iron homeostasis and respiratory epithelial cell function. 

Am J Respir Cell Mol Biol, 38: 715-723. 096321

Gilboa SM; Mendola P; Olshan AF; Langlois PH; Savitz DA; Loomis D; Herring AH; Fixler DE (2005). Relation between 

ambient air quality and selected birth defects, seven county study, Texas, 1997-2000. Am J Epidemiol, 162: 238-

252. 087892

Giustino A; Cagiano R; Carratu MR; Cassano T; Tattoli M; Cuomo V (1999). Prenatal exposure to low concentrations of 

carbon monoxide alters habituation and non-spatial working memory in rat offspring. Brain Res, 844: 201-205. 

011538

Giustino A; Cagiano R; Carratu MR; De Salvia MA; Panaro MA; Jirillo E; Cuomo V (1993). Immunological changes 

produced in rats by prenatal exposure to carbon monoxide. Basic Clin Pharmacol Toxicol, 73: 274-278. 013833

Giustino A; Carratu MR; Brigiani GS; De Salvia MA; Pellegrino NM; Steardo L; Jirillo E; Cuomo V (1994). Changes in 

the frequency of splenic immunocompetent cells in rats exposed to carbon monoxide during gestation. 

Immunopharmacol Immunotoxicol, 16: 281-292. 076343

Glabe A; Chung Y; Xu D; Jue T (1998). Carbon monoxide inhibition of regulatory pathways in myocardium. Am J Physiol, 

274: H2143-2151. 086704

Gold DR; Litonjua A; Schwartz J; Lovett E; Larson A; Nearing B; Allen G; Verrier M; Cherry R; Verrier R (2000). 

Ambient pollution and heart rate variability. Chest, 101: 1267-1273. 011432

Gold DR; Litonjua AA; Zanobetti A; Coull BA; Schwartz J; MacCallum G; Verrier RL; Nearing BD; Canner MJ; Suh H; 

Stone PH (2005). Air pollution and ST-segment depression in elderly subjects. Environ Health Perspect, 113: 883-

887. 087558

Goldberg MS; Burnett RT; Valois M-F; Flegel K; Bailar JC III; Brook J; Vincent R; Radon K (2003). Associations between 

ambient air pollution and daily mortality among persons with congestive heart failure. Environ Res, 91: 8-20. 

035202

Goldberg MS; Giannetti N; Burnett RT; Mayo NE; Valois MF; Brophy JM (2008). A panel study in congestive heart failure 

to estimate the short-term effects from personal factors and environmental conditions on oxygen saturation and 

pulse rate. Occup Environ Med, 65: 659-666. 180380

January 2010 5-131 
Goss CH; Newsom SA; Schildcrout JS; Sheppard L; Kaufman JD (2004). Effect of ambient air pollution on pulmonary 

exacerbations and lung function in cystic fibrosis. Am J Respir Crit Care Med, 169: 816-821. 055624

Gouveia N; Bremner SA; Novaes HMD (2004). Association between ambient air pollution and birth weight in Sao Paulo, 

Brazil. J Epidemiol Community Health, 58: 11-17. 055613

Grover TR; Rairigh RL; Zenge JP; Abman SH; Kinsella JP (2000). Inhaled carbon monoxide does not cause pulmonary 

vasodilation in the late-gestation fetal lamb. Am J Physiol Lung Cell Mol Physiol, 278: L779-84. 097088

Gryparis A; Forsberg B; Katsouyanni K; Analitis A; Touloumi G; Schwartz J; Samoli E; Medina S; Anderson HR; Niciu 

EM; Wichmann HE; Kriz B; Kosnik M; Skorkovsky J; Vonk JM; Dortbudak Z (2004). Acute effects of ozone on 

mortality from the "Air pollution and health: a European approach" project. Am J Respir Crit Care Med, 170: 1080-

1087. 057276

Guo YL; Lin Y-C; Sung F-C; Huang S-L; Ko Y-C; Lai J-S; Su H-J; Shaw C-K; Lin R-S; Dockery DW (1999). Climate, 

traffic-related air pollutants, and asthma prevalence in middle-school children in Taiwan. Environ Health Perspect, 

107: 1001-1006. 010937

Ha E-H; Hong Y-C; Lee B-E; Woo B-H; Schwartz J; Christiani DC (2001). Is air pollution a risk factor for low birth weight 

in Seoul? Epidemiology, 12: 643-648. 019390

Ha E-H; Lee J-T; Kim H; Hong Y-C; Lee (2003). Infant susceptibility of mortality to air pollution in Seoul, South Korea. 

Pediatrics, 111: 284-290. 042552

Hajat S; Armstrong B; Wilkinson P; Busby A; Dolk H (2007). Outdoor air pollution and infant mortality: Analysis of daily 

time-series data in 10 English cities. J Epidemiol Community Health, 61: 719-722. 093276

Hampson NB; Weaver LK (2007). Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med, 

34: 163-168. 190272

Hanada A; Sander M; González-Alonso J (2003). Human skeletal muscle sympathetic nerve activity, heart rate and limb 

haemodynamics with reduced blood oxygenation and exercise. J Physiol, 551: 635-647. 193915

Harada T; Koi H; Kubota T; Aso T (2004). Haem oxygenase augments porcine granulosa cell apoptosis in vitro. J 

Endocrinol, 181: 191-205. 193920

Hausberg M; Somers VK (1997). Neural circulatory responses to carbon monoxide in healthy humans. Hypertension, 29: 

1114-1118. 083450

Hawkins RD; Zhuo M; Arancio O (1994). Nitric oxide and carbon monoxide as possible retrograde messengers in 

hippocampal long-term potentiation. Dev Neurobiol, 25: 652-665. 076503

Henrotin JB; Besancenot JP; Bejot Y; Giroud M (2007). Short-term effects of ozone air pollution on ischaemic stroke 

occurrence: A case-crossover analysis from a 10-year population-based study in Dijon, France. Occup Environ 

Med, 64: 439-445. 093270

Hermans RH; McGivern RF; Chen W; Longo LD (1993). Altered adult sexual behavior in the male rat following chronic 

prenatal hypoxia. Neurotoxicol Teratol, 15: 353-63. 190510

Hill EP; Hill JR; Power GG; Longo LD (1977). Carbon monoxide exchanges between the human fetus and mother: A 

mathematical model. Am J Physiol, 232: H311-H323. 011315

Hirsch T; Weiland SK; Von Mutius E; Safeca AF; Grafe H; Csaplovics E; Duhme H; Keil U; Leupold W (1999). Inner city 

air pollution and respiratory health and atopy in children. Eur Respir J, 14: 669-677. 003537

Hoek G (2003). Daily mortality and air pollution in The Netherlands. Health Effects Institute. Boston, MA. 042818

Hoek G; Brunekreef B; Fischer P; Van Wijnen J (2001). The association between air pollution and heart failure, arrhythmia, 

embolism, thrombosis, and other cardiovascular causes of death in a time series study. Epidemiology, 12: 355-357. 

016550

Hoek G; Brunekreef B; Verhoeff A; Van Wijnen J; Fischer P (2000). Daily mortality and air pollution in the Netherlands. J 

Air Waste Manag Assoc, 50: 1380-1389. 010350

Holguin F; Tellez-Rojo MM; Hernandez M; Cortez M; Chow JC; Watson JG; Mannino D; Romieu I (2003). Air pollution 

and heart rate variability among the elderly in Mexico City. Epidemiology, 14: 521-527. 057326

January 2010 5-132 
Horvath SM; Bedi JF; Wagner JA; Agnew JW (1988). Maximal aerobic capacity at several ambient concentrations of 

carbon monoxide at several altitudes. J Appl Physiol, 65: 2696-2708. 012725

Horvath SM; Dahms TE; O'Hanlon JF (1971). Carbon monoxide and human vigilance: A deleterious effect of present 

urban concentrations. Arch Environ Occup Health, 23: 343-347. 011075

Horvath SM; Raven PB; Dahms TE; Gray DJ (1975). Maximal aerobic capacity at different levels of carboxyhemoglobin. J 

Appl Physiol, 38: 300-303. 010887

Hosseinpoor AR; Forouzanfar MH; Yunesian M; Asghari F; Naieni KH; Farhood D (2005). Air pollution and 

hospitalization due to angina pectoris in Tehran, Iran: A time-series study. Environ Res, 99: 126-131. 087413

Hsia CC (2002). Recruitment of lung diffusing capacity: Update of concept and application. Chest, 122: 1774-1783. 

193857

Huikuri HV; Jokinen V; Syvanne M; Nieminen MS; Airaksinen KEJ; Ikaheimo MJ; Koistinen JM; Kauma H; Kesaniemi 

AY; Majahalme S; Niemela KO; Frick MH (1999). Heart rate variability and progression of coronary 

atheroscerosis. Arterioscler Thromb Vasc Biol, 19: 1979-1985. 184464

Hutcheon JA; Platt RW (2008). The missing data problem in birth weight percentiles and thresholds for "small-forgestational-age". Am J Epidemiol, 167: 786-792. 193795

Huynh M; Woodruff TJ; Parker JD; Schoendorf KC (2006). Relationships between air pollution and preterm birth in 

California. Paediatr Perinat Epidemiol, 20: 454-461. 091240

Hwang B-F; Jaakkola JJK; Lee Y-L; Lin Y-C; Guo Y-LL (2006). Relation between air pollution and allergic rhinitis in 

Taiwanese schoolchildren. Respir Res, 7: 23. 088971

Hwang B-F; Lee Y-L; Lin Y-C; Jaakkola JJK; Guo YL (2005). Traffic related air pollution as a determinant of asthma 

among Taiwanese school children. Thorax, 60: 467-473. 089454

Hwang BF; Jaakkola JJ (2008). Ozone and other air pollutants and the risk of oral clefts. Environ Health Perspect, 116: 

1411-1415. 193794

Ibald-Mulli A; Stieber J; Wichmann H-E; Koenig W; Peters A (2001). Effects of air pollution on blood pressure: A 

population-based approach. Am J Public Health, 91: 571-577. 016030

Ibald-Mulli A; Timonen KL; Peters A; Heinrich J; Wolke G; Lanki T; Buzorius G; Kreyling WG; De Hartog J; Hoek G; 

Ten Brink HM; Pekkanen J (2004). Effects of particulate air pollution on blood pressure and heart rate in subjects 

with cardiovascular disease: a multicenter approach. Environ Health Perspect, 112: 369-377. 087415

Iheagwara KN; Thom SR; Deutschman CS; Levy RJ (2007). Myocardial cytochrome oxidase activity is decreased 

following carbon monoxide exposure. Biochim Biophys Acta, 1772: 1112-1116. 193861

Imai T; Morita T; Shindo T; Nagai R; Yazaki Y; Kurihara H; Suematsu M; Katayama S (2001). Vascular smooth muscle 

cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxideinduced vasodilation in mice. Circ Res, 89: 55-62. 193864

Ischiropoulos H; Beers MF; Ohnishi ST; Fisher D; Garner SE; Thom SR (1996). Nitric oxide production and perivascular 

tyrosine nitration in brain after carbon monoxide poisoning in the rat. J Clin Invest, 97: 2260-2267. 079491

Ito K; Thurston GD; Silverman RA (2007). Characterization of PM2.5, gaseous pollutants, and meteorological interactions 

in the context of time-series health effects models. J Expo Sci Environ Epidemiol, 17 Suppl 2: S45-S60. 156594

Jalaludin B; Mannes T; Morgan G; Lincoln D; Sheppeard V; Corbett S (2007). Impact of ambient air pollution on 

gestational age is modified by season in Sydney, Australia. Environ Health, 6: 16. 156601

Jalaludin B; Morgan G; Lincoln D; Sheppeard V; Simpson R; Corbett S (2006). Associations between ambient air pollution 

and daily emergency department attendances for cardiovascular disease in the elderly (65+ years), Sydney, 

Australia. J Expo Sci Environ Epidemiol, 16: 225-237. 189416

Jerrett M; Burnett RT; Willis A; Krewski D; Goldberg MS; DeLuca P; Finkelstein N (2003). Spatial analysis of the air 

pollution-mortality relationship in the context of ecologic confounders. J Toxicol Environ Health A Curr Iss, 66: 

1735-1777. 087380

Johnson FK; Durante W; Peyton KJ; Johnson RA (2003). Heme oxygenase inhibitor restores arteriolar nitric oxide function 

in Dahl rats. Hypertension, 41: 149-155. 193868

January 2010 5-133 
Johnson FK; Durante W; Peyton KJ; Johnson RA (2004). Heme oxygenase-mediated endothelial dysfunction in DOCAsalt, but not in spontaneously hypertensive, rat arterioles. Am J Physiol Heart Circ Physiol, 286: 1681-1687. 193870

Johnson FK; Johnson RA (2003). Carbon monoxide promotes endothelium-dependent constriction of isolated gracilis 

muscle arterioles. Am J Physiol, 285: R536-R541. 053611

Johnson FK; Johnson RA; Durante W; Jackson KE; Stevenson BK; Peyton KJ (2006). Metabolic syndrome increases 

endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker 

rats. Am J Physiol Regul Integr Comp Physiol, 290: 601-608. 193874

Joumard R; Chiron M; Vidon R; Maurin M; Rouzioux J-M (1981). Mathematical models of the uptake of carbon monoxide 

on hemoglobin at low carbon monoxide levels. Environ Health Perspect, 41: 277-289. 011330

Kanten WE; Penney DG; Francisco K; Thill JE (1983). Hemodynamic responses to acute carboxyhemoglobinemia in the 

rat. Am J Physiol, 244: H320-H327. 011333

Karr C; Lumley T; Schreuder A; Davis R; Larson T; Ritz B; Kaufman J (2007). Effects of subchronic and chronic exposure 

to ambient air pollutants on infant bronchiolitis. Am J Epidemiol, 165: 553-560. 090719

Karr C; Lumley T; Shepherd K; Davis R; Larson T; Ritz B; Kaufman J (2006). A case-crossover study of wintertime 

ambient air pollution and infant bronchiolitis. Environ Health Perspect, 114: 277-281. 088751

Katoue MG; Khan I; Oriowo MA (2005). Increased expression and activity of heme oxygenase-2 in pregnant rat aorta is 

not involved in attenuated vasopressin-induced contraction. Naunyn Schmiedebergs Arch Pharmacol, 372: 220-7. 

193896

Katsouyanni K; Touloumi G; Samoli E; Gryparis A; Le Tertre A; Monopolis Y; Rossi G; Zmirou D; Ballester F; Boumghar 

A; Anderson HR; Wojtyniak B; Paldy A; Braunstein R; Pekkanen J; Schindler C; Schwartz J (2001). Confounding 

and effect modification in the short-term effects of ambient particles on total mortality: results from 29 European 

cities within the APHEA2 project. Epidemiology, 12: 521-531. 019008

Kaur S; Nieuwenhuijsen M; Colvile R (2005). Personal exposure of street canyon intersection users to PM2.5, ultrafine 

particle counts and carbon monoxide in central London, UK. Atmos Environ, 39: 3629-3641. 086504

Kim HP; Wang X; Nakao A; Kim SI; Murase N; Choi ME; Ryter SW; Choi AM (2005). Caveolin-1 expression by means 

of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide. PNAS, 102: 

11319-11324. 193959

Kim HS; Loughran PA; Rao J; Billar TR; Zuckerbraun BS (2008). Carbon monoxide activates NF-kappaB via ROS 

generation and Akt pathways to protect against cell death of hepatocytes. Am J Physiol Gastrointest Liver Physiol, 

295: G146-G152. 193961

Kingdom JC; Kaufmann P (1997). Oxygen and placental villous development: origins of fetal hypoxia. Placenta, 18: 613-

21; discussion 623-6. 193897

Kinney HC; Filiano JJ; Sleeper LA; Mandell F; Valdes-Dapena M; White WF (1995). Decreased muscarinic receptor 

binding in the arcuate nucleus in sudden infant death syndrome. Science, 269: 1446-1450. 193898

Kizakevich PN; McCartney ML; Hazucha MJ; Sleet LH; Jochem WJ; Hackney AC; Bolick K (2000). Noninvasive 

ambulatory assessment of cardiac function in healthy men exposed to carbon monoxide during upper and lower 

body exercise. Eur J Appl Physiol, 83: 7-16. 052691

Klasner AE; Smith SR; Thompson MW; Scalzo AJ (1998). Carbon monoxide mass exposure in a pediatric population. 

Acad Emerg Med, 5: 992-996. 087196

Klausen K; Rasmussen B; Gjellerod H; Madsen H; Petersen E (1968). Circulation, metabolism and ventilation during 

prolonged exposure to carbon monoxide and to high altitude. Scand J Clin Lab Invest, 103: 26-38. 193936

Kleeberger SR; Ohtsuka Y (2005). Gene-particulate matter-health interactions. Toxicol Appl Pharmacol, 207: S276-S281. 

130489

Kleinman MT; Davidson DM; Vandagriff RB; Caiozzo VJ; Whittenberger JL (1989). Effects of short-term exposure to 

carbon monoxide in subjects with coronary artery disease. Arch Environ Occup Health, 44: 361-369. 012696

Kleinman MT; Leaf DA; Kelly E; Caiozzo V; Osann K; O'Niell T (1998). Urban angina in the mountains: effects of carbon 

monoxide and mild hypoxemia on subjects with chronic stable angina. Arch Environ Occup Health, 53: 388-397. 

047186

January 2010 5-134 
Klemm RJ; Lipfert FW; Wyzga RE; Gust C (2004). Daily mortality and air pollution in Atlanta: two years of data from 

ARIES. Inhal Toxicol, 16 Suppl 1: 131-141. 056585

Knuckles TL; Lund AK; Lucas SN; Campen MJ (2008). Diesel exhaust exposure enhances venoconstriction via uncoupling 

of eNOS. Toxicol Appl Pharmacol, 230: 346-351. 191987

Koehler RC; Jones MD Jr; Traystman RJ (1982). Cerebral circulatory response to carbon monoxide and hypoxic hypoxia 

in the lamb. Am J Physiol, 243: H27-H32. 011341

Kohsaka A; Watanobe H; Kakizaki Y; Suda T (1999). A comparative study of the effects of nitric oxide and carbon 

monoxide on the in vivo release of gonadotropin-releasing hormone and neuropeptide Y from rat hypothalamus 

during the estradiol-induced luteinizing hormone surge: estimation by push-pull perfusion. Neuroendocrinology, 

69: 245-253. 191000

Koike A; Wasserman K; Armon Y; Weiler-Ravell D (1991). The work-rate-dependent effect of carbon monoxide on 

ventilatory control during exercise. Respir Physiol Neurobiol, 85: 169-183. 013500

Koken PJM; Piver WT; Ye F; Elixhauser A; Olsen LM; Portier CJ (2003). Temperature, air pollution, and hospitalization 

for cardiovascular diseases among elderly people in Denver. Environ Health Perspect, 111: 1312-1317. 049466

Korres S; Riga M; Balatsouras D; Papadakis C; Kanellos P; Ferekidis E (2007). Influence of smoking on developing 

cochlea: Does smoking during pregnancy affect the amplitudes of transient evoked otoacoustic emissions in 

newborns? Int J Pediatr Otorhinolaryngol, 71: 781-786. 190908

Kotsch K; Francuski M; Pascher A; Klemz R; Seifert M; Mittler J; Schumacher G; Buelow R; Volk HD; Tullius SG; 

Neuhaus P; Pratschke J (2006). Improved long-term graft survival after HO-1 induction in brain-dead donors. Am J 

Transplant, 6: 477-86. 193899

Kreider JC; Blumberg MS (2005). Geotaxis and beyond: Commentary on Motz and Alberts. Neurotoxicol Teratol, 27: 529-

533. 193944

Krewski D; Burnett RT; Goldberg MS; Hoover K; Siemiatycki J; Jerrett M; Abrahamowicz M; White WH (2000). 

Reanalysis of the Harvard Six Cities study and the American Cancer Society study of particulate air pollution and 

mortality. Health Effects Institute. Cambridge, MA.http://pubs.healtheffects.org/view.php?id=6. 012281

Krewski D; Jerrett M; Burnett RT; Ma R; Hughes E; Shi Y; Turner MC; Pope AC III; Thurston G; Calle EE; Thun MJ 

(2009). Extended follow-up and spatial analysis of the American Cancer Society study linking particulate air 

pollution and mortality. Health Effects Institute. Cambridge, MA. Report Nr. 140. 191193

Kunzli N; Tager IB (1997). The semi-individual study in air pollution epidemiology: a valid design as compared to 

ecologic studies. Environ Health Perspect, 105: 1078-1083. 086180

Lagorio S; Forastiere F; Pistelli R; Iavarone I; Michelozzi P; Fano V; Marconi A; Ziemacki G; Ostro BD (2006). Air 

pollution and lung function among susceptible adult subjects: a panel study. Environ Health, 5: 11. 089800

Lamar CA; Mahesh VB; Brann DW (1996). Regulation of gonadotropin-releasing hormone (GnRH) secretion by heme 

molecules: a regulatory role for carbon monoxide? Endocrinology, 137: 790-793. 078819

Lanki T; Pekkanen J; Aalto P; Elosua R; Berglind N; D'Ippoliti D; Kulmala M; Nyberg F; Peters A; Picciotto S; Salomaa V; 

Sunyer J; Tiittanen P; Von Klot S; Forastiere F; for the HEAPSS Study Group (2006). Associations of traffic-related 

air pollutants with hospitalisation for first acute myocardial infarction: the HEAPSS study. Occup Environ Med, 63: 

844-851. 089788

Lee BE; Ha EH; Park HS; Kim YJ; Hong YC; Kim H; Lee JT (2003). Exposure to air pollution during different gestational 

phases contributes to risks of low birth weight. Hum Reprod, 18: 638-643. 043202

Lee I-M; Tsai S-S; Chang C-C; Ho C-K; Yang C-Y (2007). Air pollution and hospital admissions for chronic obstructive 

pulmonary disease in a tropical city: Kaohsiung, Taiwan. Inhal Toxicol, 19: 393-398. 090707

Lee JT; Kim H; Cho YS; Hong YC; Ha EH; Park H (2003). Air pollution and hospital admissions for ischemic heart 

diseases among individuals 64+ years of age residing in Seoul, Korea. Arch Environ Health, 58: 617-623. 095552

Lee Y-L; Shaw C-K; Su H-J; Lai J-S; Ko Y-C; Huang S-L; Sung F-C; Guo Y-L (2003). Climate, traffic-related air 

pollutants and allergic rhinitis prevalence in middle-school children in Taiwan. Eur Respir J, 21: 964-970. 049201

Leem J-H; Kaplan BM; Shim YK; Pohl HR; Gotway CA; Bullard SM; Rogers JF; Smith MM; Tylenda CA (2006). 

Exposures to air pollutants during pregnancy and preterm delivery. Environ Health Perspect, 114: 905-910. 089828

January 2010 5-135 
Levy D; Lumley T; Sheppard L; Kaufman J; Checkoway H (2001). Referent selection in case-crossover analyses of acute 

health effects of air pollution. Epidemiology, 12: 186-192. 017172

Levy D; Sheppard L; Checkoway H; Kaufman J; Lumley T; Koenig J; Siscovick D (2001). A case-crossover analysis of 

particulate matter air pollution and out-of-hospital primary cardiac arrest. Epidemiology, 12: 193-199. 017171

Li CI; Daling JR; Emanuel I (2003). Birthweight and risk of overall and cause-specific childhood mortality. Paediatr 

Perinat Epidemiol, 17: 164-170. 193965

Liao D; Duan Y; Whitsel EA; Zheng Z-J; Heiss G; Chinchilli VM; Lin H-M (2004). Association of higher levels of ambient 

criteria pollutants with impaired cardiac autonomic control: a population-based study. Am J Epidemiol, 159: 768-

777. 056590

Liao D; Heiss G; Chinchilli VM; Duan Y; Folsom AR; Lin HM; Salomaa V (2005). Association of criteria pollutants with 

plasma hemostatic/inflammatory markers: a population-based study. J Expo Sci Environ Epidemiol, 15: 319-328. 

088677

Lin C-M; Li C-Y; Mao I-F (2004). Increased risks of term low-birth-weight infants in a petrochemical industrial city with 

high air pollution levels. Arch Environ Occup Health, 59: 663-668. 089827

Lin CA; Pereira LAA; Nishioka DC; Conceicao GMS; Graga ALF; Saldiva PHN (2004). Air pollution and neonatal deaths 

in Sao Paulo, Brazil. Braz J Med Biol Res, 37: 765-770. 095787

Lin H; McGrath JJ (1988). Carbon monoxide effects on calcium levels in vascular smooth muscle. Life Sci, 43: 1813-1816. 

012773

Lin M; Chen Y; Burnett RT; Villeneuve PJ; Krewski D (2003). Effect of short-term exposure to gaseous pollution on 

asthma hospitalisation in children: a bi-directional case-crossover analysis. J Epidemiol Community Health, 57: 50-

55. 042549

Lin M; Chen Y; Villeneuve PJ; Burnett RT; Lemyre L; Hertzman C; McGrail KM; Krewski D (2004). Gaseous air 

pollutants and asthma hospitalization of children with low household income in Vancouver, British Columbia, 

Canada. Am J Epidemiol, 159: 294-303. 055600

Lin M; Stieb DM; Chen Y (2005). Coarse particulate matter and hospitalization for respiratory infections in children 

younger than 15 years in Toronto: a case-crossover analysis. Pediatrics, 116: 235-240. 087828

Linn WS; Szlachcic Y; Gong H Jr; Kinney PL; Berhane KT (2000). Air pollution and daily hospital admissions in 

metropolitan Los Angeles. Environ Health Perspect, 108: 427-434. 002839

Lipfert FW; Baty JD; Miller JP; Wyzga RE (2006). PM2.5 constituents and related air quality variables as predictors of 

survival in a cohort of U.S. military veterans. Inhal Toxicol, 18: 645-657. 088756

Lipfert FW; Morris SC (2002). Temporal and spacial relationships between age-specific mortality and ambient air quality 

in the United States: preliminary results for counties, 1960-97. Occup Environ Med, 59: 156-174. 019217

Lipfert FW; Perry HM Jr; Miller JP; Baty JD; Wyzga RE; Carmody SE (2000). The Washington University-EPRI veterans' 

cohort mortality study: preliminary results. Inhal Toxicol, 4: 41-73. 004087

Lipfert FW; Wyzga RE; Baty JD; Miller JP (2006). Traffic density as a surrogate measure of environmental exposures in 

studies of air pollution health effects: long-term mortality in a cohort of US veterans. Atmos Environ, 40: 154-169. 

088218

Liu S; Krewski D; Shi Y; Chen Y; Burnett R (2007). Association between maternal exposure to ambient air pollutants 

during pregnancy and fetal growth restriction. J Expo Sci Environ Epidemiol, 17: 426-432. 090429

Liu S; Krewski D; Shi Y; Chen Y; Burnett RT (2003). Association between gaseous ambient air pollutants and adverse 

pregnancy outcomes in Vancouver, Canada. Environ Health Perspect, 111: 1773-1778. 089548

Liu Y; Fechter LD (1995). MK-801 protects against carbon monoxide-induced hearing loss. Toxicol Appl Pharmacol, 132: 

196-202. 076524

Ljungman P; Bellander T; Schneider A; Breitner S; Forastiere F; Hampel R; Illig T; Jacquemin B; Katsouyanni K; von Klot 

S (2009). Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen 

polymorphisms. Environ Health Perspect, 117: 1373-1379. 191983

January 2010 5-136 
Loennechen JP; Beisvag V; Arbo I; Waldum HL; Sandvik AK; Knardahl S; Ellingsen O (1999). Chronic carbon monoxide 

exposure in vivo induces myocardial endothelin-1 expression and hypertrophy in rat. Pharmacol Toxicol, 85: 192-

197. 011549

Longo LD (1970). Carbon monoxide in the pregnant mother and fetus and its exchange across the placenta. Ann N Y Acad 

Sci, 174: 313-341. 013922

Longo LD; Hill EP (1977). Carbon monoxide uptake and elimination in fetal and maternal sheep. Am J Physiol, 232: 

H324-H330. 010802

Longo M; Jain V; Vedernikov YP; Saade GR; Goodrum L; Facchinetti F; Garfield RE (1999). Effect of nitric oxide and 

carbon monoxide on uterine contractility during human and rat pregnancy. Am J Obstet Gynecol, 181: 981-988. 

011548

Lopez I; Acuna D; Webber DS; Korsak RA; Edmond J (2003). Mild carbon monoxide exposure diminishes selectively the 

integrity of the cochlea of the developing rat. J Neurosci Res, 74: 666-75. 193901

Lopez IA; Acuna D; Beltran-Parrazal L; Espinosa-Jeffrey A; Edmond J (2008). Oxidative stress and the deleterious 

consequences to the rat cochlea after prenatal chronic mild exposure to carbon monoxide in air. Neuroscience, 151: 

854-867. 097343

Lund AK; Knuckles TL; Obot Akata C; Shohet R; McDonald JD; Gigliotti A; Seagrave JC; Campen MJ (2007). Gasoline 

exhaust emissions induce vascular remodeling pathways involved in atherosclerosis. Toxicol Sci, 95: 485-94. 

125741

Lund AK; Lucero J; Lucas S; Madden MC; McDonald JD; Seagrave JC; Knuckles TL; Campen MJ (2009). Vehicular 

emissions induce vascular MMP-9 expression and activity associated with endothelin-1 mediated pathways. 

Arterioscler Thromb Vasc Biol, 29: 511-517. 180257

Lyall F; Barber A; Myatt L; Bulmer JN; Robson SC (2000). Hemeoxygenase expression in human placenta and placental 

bed implies a role in regulation of trophoblast invasion and placental function. FASEB J, 14: 208-19. 193902

MacDorman MF; Callaghan WM; Mathews TJ; Hoyert DL; Kochanek KD (2007). Trends in preterm-related infant 

mortality by race and ethnicity, United States 1999-2004. Int J Health Serv, 37: 635-641. 193973

MacMillan V (1975). Regional cerebral blood flow of the rat in acute carbon monoxide intoxication. Can J Physiol 

Pharmacol, 53: 644-650. 012909

Mactutus CF; Fechter LD (1984). Prenatal exposure to carbon monoxide: learning and memory deficits. Science, 223: 409-

411. 011355

Mactutus CF; Fechter LD (1985). Moderate prenatal carbon monoxide exposure produces persistent, and apparently 

permanent, memory deficits in rats. Teratology, 31: 1-12. 011536

Maheswaran R; Haining RP; Brindley P; Law J; Pearson T; Fryers PR; Wise S; Campbell MJ (2005). Outdoor air pollution 

and stroke in Sheffield, United Kingdom: A small-area level geographical study. Stroke, 36: 239-243. 088683

Maisonet M; Bush TJ; Correa A; Jaakkola JJK (2001). Relation between ambient air pollution and low birth weight in the 

northeastern United States. Environ Health Perspect, 1093: 351-356. 016624

Mann JK; Tager IB; Lurmann F; Segal M; Quesenberry CP Jr; Lugg MM; Shan J; Van den Eeden SK (2002). Air pollution 

and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia. Environ 

Health Perspect, 110: 1247-1252. 036723

Mannes T; Jalaludin B; Morgan G; Lincoln D; Sheppeard V; Corbett S (2005). Impact of ambient air pollution on birth 

weight in Sydney, Australia. Occup Environ Med, 62: 524-530. 087895

Marthan R; Castaing Y; Manier G; Guenard H (1985). Gas exchange alterations in patients with chronic obstructive lung 

disease. Chest, 87: 470-475. 086334

Martin JA; Hamilton BE; Sutton PD; Ventura SJ; Menacker F; Kirmeyer S; Munson ML (2007). Births: Final data for 

2005. National Center for Health Statistics. Hyattsville, MD. 193982

Mayr FB; Spiel A; Leitner J; Marsik C; Germann P; Ullrich R; Wagner O; Jilma B (2005). Effects of carbon monoxide 

inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med, 171: 354-360. 193984

McGrath JJ (1992). Effects of altitude on endogenous carboxyhemoglobin levels. J Toxicol Environ Health, 35: 127-133. 

001005

January 2010 5-137 
McGrath JJ; Schreck RM; Lee PS (1993). Carboxyhemoglobin levels in humans: Effects of altitude. Inhal Toxicol, 5: 241-

249. 013865

McGregor HP; Westcott K; Walker DW (1998). The effect of prenatal exposure to carbon monoxide on breathing and 

growth of the newborn guinea pig. Pediatr Res, 43: 126-131. 085342

McIntire DD; Bloom SL; Casey BM; Leveno KJ (1999). Birth weight in relation to morbidity and mortality among 

newborn infants. N Engl J Med, 340: 1234-1238. 015310

McLaughlin BE; Lash GE; Smith GN; Marks GS; Nakatsu K; Graham CH; Brien JF (2003). Heme oxygenase expression 

in selected regions of term human placenta. Exp Biol Med, 228: 564-567. 193827

Medeiros A; Gouveia N (2005). Relacao entre baixo peso ao nascer e a poluicao do ar no Municipio de Sao Paulo 

[Relationship between low birthweight and air pollution in the city of Sao Paulo, Brazil]. Rev Saude Publica, 39: 

965-972. 089824

Meilin S; Rogatsky GG; Thom SR; Zarchin N; Guggenheimer-Furman E; Mayevsky A (1996). Effects of carbon monoxide 

on the brain may be mediated by nitric oxide. J Appl Physiol, 81: 1078-1083. 079919

Melin A; Bonnet P; Eder V; Antier D; Obert P; Fauchier L (2005). Direct implication of carbon monoxide in the 

development of heart failure in rats with cardiac hypertrophy subjected to air pollution. Cardiovasc Toxicol, 5: 311-

320. 193833

Melin A; Obert P; Rebocho M; Bonnet P (2002). Cardiac morphology and function following long-term exposure to carbon 

monoxide at high altitude in rats. J Toxicol Environ Health A Curr Iss, 65: 1981-1998. 037502

Meng YY; Wilhelm M; Rull RP; English P; Ritz B (2007). Traffic and outdoor air pollution levels near residences and 

poorly controlled asthma in adults. Ann Allergy Asthma Immunol, 98: 455-463. 093275

Mercke C; Lundh B (1976). Erythrocyte filterability and heme catabolism during the menstrual cycle. Ann Intern Med, 85: 

322-324. 086309

Mereu G; Cammalleri M; Fà M; Francesconi W; Saba P; Tattoli M; Trabace L; Vaccari A; Cuomo V (2000). Prenatal 

exposure to a low concentration of carbon monoxide disrupts hippocampal long-term potentiation in rat offspring. J 

Pharmacol Exp Ther, 294: 728-734. 193838

Merriam-Webster (2009). Merriam-Webster on-line. Retrieved 15-JUN-09, from http://www.merriamwebster.com/medical/susceptible; http://www.merriam-webster.com/medical/vulnerable. 192146

Metzger KB; Klein M; Flanders WD; Peel JL; Mulholland JA; Langberg JJ; Tolbert PE (2007). Ambient air pollution and 

cardiac arrhythmias in patients with implantable defibrillators. Epidemiology, 18: 585-592. 092856

Metzger KB; Tolbert PE; Klein M; Peel JL; Flanders WD; Todd KH; Mulholland JA; Ryan PB; Frumkin H (2004). 

Ambient air pollution and cardiovascular emergency department visits. Epidemiology, 15: 46-56. 044222

Meyer J; Prien T; Van Aken H; Bone H-G; Waurick R; Theilmeier G; Booke M (1998). Arterio-venous carboxyhemoglobin 

difference suggests carbon monoxide production by human lungs. Biochem Biophys Res Commun, 244: 230-232. 

047530

Miller KA; Siscovick DS; Sheppard L; Shepherd K; Sullivan JH; Anderson GL; Kaufman JD (2007). Long-term exposure 

to air pollution and incidence of cardiovascular events in women. N Engl J Med, 356: 447-458. 090130

Min JY; Paek D; Cho SI; Min KB (2009). Exposure to environmental carbon monoxide may have a greater negative effect 

on cardiac autonomic function in people with metabolic syndrome. Sci Total Environ, 407: 4807-4811. 199514

Montagnani M; Serio M; Potenza MA; Mansi G; De Salvia MA; Cagiano R; Cuomo V; Mitolo-Chieppa D (1996). Prenatal 

exposure to carbon monoxide and vascular responsiveness of rat resistance vessels. Life Sci, 59: 1553-1561. 

080902

Moolgavkar SH (2000). Air pollution and hospital admissions for chronic obstructive pulmonary disease in three 

metropolitan areas in the United States. Inhal Toxicol, 12: 75-90. 010274

Moolgavkar SH (2003). Air pollution and daily deaths and hospital admissions in Los Angeles and Cook counties. Health 

Effects Institute. Boston, MA. 042864

Moon JS; Kim YS; Kim JH; Son BS; Kim DS; Yang W (2009). Respiratory health effects among schoolchildren and their 

relationship to air pollutants in Korea. Int J Environ Health Res, 19: 31-48. 190297

January 2010 5-138 
Morita T; Mitsialis SA; Koike H; Liu Y; Kourembanas S (1997). Carbon monoxide controls the proliferation of hypoxic 

vascular smooth muscle cells. J Biol Chem, 272: 32,804-32,809. 085345

Morse CI; Pritchard LJ; Wust RC; Jones DA; Degens H (2008). Carbon monoxide inhalation reduces skeletal muscle 

fatigue resistance. Eur Phys J A, 192: 397-401. 097980

Mortimer K; Neugebauer R; Lurmann F; Alcorn S; Balmes J; Tager I (2008). Air pollution and pulmonary function in 

asthmatic children: Effects of prenatal and lifetime exposures. Epidemiology, 19: 550-557. 122163

Mortimer K; Neugebauer R; Lurmann F; Alcorn S; Balmes J; Tager I (2008). Early-Lifetime exposure to air pollution and 

allergic sensitization in children with asthma. J Asthma, 45: 874-881. 187280

Naik JS; Walker BR (2003). Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell 

hyperpolarization. Am J Physiol Heart Circ Physiol, 285: 220-228. 193852

Ndisang JF; Tabien HE; Wang R (2004). Carbon monoxide and hypertension. Am J Hypertens, 22: 1057-1074. 180425

Neas LM; Schwartz J (1996). The determinants of pulmonary diffusing capacity in a national sample of US adults. Am J 

Respir Crit Care Med, 153: 656-664. 079363

Neggers YH; Singh J (2006). Zinc supplementation to protein-deficient diet in CO-exposed mice decreased fetal mortality 

and malformation. Biol Trace Elem Res, 114: 269-279. 193964

O'Connor GT; Neas L; Vaughn B; Kattan M; Mitchell H; Crain EF; Evans R 3rd; Gruchalla R; Morgan W; Stout J; Adams 

GK; Lippmann M (2008). Acute respiratory health effects of air pollution on children with asthma in US inner 

cities. J Allergy Clin Immunol, 121: 1133-1139. 156818

Otto DA; Benignus VA; Prah JD (1979). Carbon monoxide and human time discrimination: Failure to replicate BeardWertheim experiments. Aviat Space Environ Med, 50: 40-43. 010863

Park JW; Lim YH; Kyung SY; An CH; Lee SP; Jeong SH; Ju S-Y (2005). Effects of ambient particulate matter on peak 

expiratory flow rates and respiratory symptoms of asthmatics during Asian dust periods in Korea. Respirology, 10: 

470-476. 088673

Park SK; O'Neill MS; Vokonas PS; Sparrow D; Schwartz J (2005). Effects of air pollution on heart rate variability: The VA 

normative aging study. Environ Health Perspect, 113: 304-309. 057331

Parker JD; Woodruff TJ; Basu R; Schoendorf KC (2005). Air pollution and birth weight among term infants in California. 

Pediatrics, 115: 121-128. 087462

Patel AP; Moody JA; Handy RD; Sneyd JR (2003). Carbon monoxide exposure in rat heart: glutathione depletion is 

prevented by antioxidants. Biochem Biophys Res Commun, 302: 392-396. 043155

Peel JL; Metzger KB; Klein M; Flanders WD; Mulholland JA; Tolbert PE (2007). Ambient air pollution and cardiovascular 

emergency department visits in potentially sensitive groups. Am J Epidemiol, 165: 625-633. 090442

Peel JL; Tolbert PE; Klein M; Metzger KB; Flanders WD; Knox T; Mulholland JA; Ryan PB; Frumkin H (2005). Ambient 

air pollution and respiratory emergency department visits. Epidemiology, 16: 164-174. 056305

Pekkanen J; Brunner EJ; Anderson HR; Tiittanen P; Atkinson RW (2000). Daily concentrations of air pollution and plasma 

fibrinogen in London. Occup Environ Med, 57: 818-822. 013250

Penn A; Currie J; Snyder C (1992). Inhalation of carbon monoxide does not accelerate arteriosclerosis in cockerels. Eur J 

Clin Pharmacol, 228: 155-164. 013728

Penney DG (1988). A review: Hemodynamic response to carbon monoxide. Environ Health Perspect, 77: 121-130. 012519

Penney DG; Baylerian MS; Thill JE; Fanning CM; Yedavally S (1982). Postnatal carbon monoxide exposure: immediate 

and lasting effects in the rat. Am J Physiol, 243: H328-H339. 011387

Penney DG; Baylerian MS; Thill JE; Yedavally S; Fanning CM (1983). Cardiac response of the fetal rat to carbon 

monoxide exposure. Am J Physiol, 244: H289-H297. 011385

Penney DG; Davidson SB; Gargulinski RB; Caldwell-Ayre TM (1988). Heart and lung hypertrophy, changes in blood 

volume, hematocrit and plasma renin activity in rats chronically exposed to increasing carbon monoxide 

concentrations. J Appl Toxicol, 8: 171-178. 012521

Penney DG; Stryker AE; Baylerian MS (1984). Persistent cardiomegaly induced by carbon monoxide and associated 

tachycardia. J Appl Physiol, 56: 1045-1052. 011567

January 2010 5-139 
Penttinen P; Timonen KL; Tiittanen P; Mirme A; Ruuskanen J; Pekkanen J (2001). Ultrafine particles in urban air and 

respiratory health among adult asthmatics. Eur Respir J, 17: 428-435. 030335

Pereira Filho MA; Pereira LAA; Arbex FF; Arbex M; Conceição GM; Santos UP; Lopes AC; Saldiva PHN; Braga ALF; 

Cendon S (2008). Effect of air pollution on diabetes and cardiovascular diseases in São Paulo, Brazil. Braz J Med 

Biol Res, 41: 526-532. 190260

Peters A; Dockery DW; Muller JE; Mittleman MA (2001). Increased particulate air pollution and the triggering of 

myocardial infarction. Circulation, 103: 2810-2815. 016546

Peters A; Liu E; Verrier RL; Schwartz J; Gold DR; Mittleman M; Baliff J; Oh JA; Allen G; Monahan K; Dockery DW 

(2000). Air pollution and incidence of cardiac arrhythmia. Epidemiology, 11: 11-17. 011347

Peters A; Perz S; Doring A; Stieber J; Koenig W; Wichmann H-E (1999). Increases in heart rate during an air pollution 

episode. Am J Epidemiol, 150: 1094-1098. 011554

Peters JM; Avol E; Navidi W; London SJ; Gauderman WJ; Lurmann F; Linn WS; Margolis H; Rappaport E; Gong H Jr; 

Thomas DC (1999). A study of twelve southern California communities with differing levels and types of air 

pollution I Prevalence of respiratory morbidity. Am J Respir Crit Care Med, 159: 760-767. 087243

Petersen LC (1977). The effect of inhibitors on the oxygen kinetics of cytochrome c oxidase. Biochim Biophys Acta, 460: 

299-307. 193764

Piantadosi CA (2002). Biological chemistry of carbon monoxide. Antioxid Redox Signal, 4: 259-270. 037463

Piantadosi CA (2008). Carbon monoxide, reactive oxygen signaling, and oxidative stress. Free Radic Biol Med, 45: 562-

569. 180423

Piantadosi CA; Carraway MS; Suliman HB (2006). Carbon monoxide, oxidative stress, and mitochondrial permeability 

pore transition. Free Radic Biol Med, 40: 1332-1339. 180424

Piantadosi CA; Zhang J; Demchenko IT (1997). Production of hydroxyl radical in the hippocampus after CO hypoxia or 

hypoxic hypoxia in the rat. Free Radic Biol Med, 22: 725-732. 081326

Pleis JR; Lucas JW (2009). Summary health statistics for US adults: National Health Interview Survey, 2007. National 

Center for Health Statistics, Centers for Disease Control and Prevention, U.S. Department of Health and Human 

Services . Hyattsville, Maryland. Series 10, Number 240; (PHS) 2009?1568. 

http://www.cdc.gov/nchs/data/series/sr_10/sr10_240.pdf. 202833

Pope CA III; Burnett RT; Thun MJ; Calle EE; Krewski D; Ito K; Thurston GD (2002). Lung cancer, cardiopulmonary 

mortality, and long-term exposure to fine particulate air pollution. JAMA, 287: 1132-1141. 024689

Pope CA III; Thun MJ; Namboodiri MM; Dockery DW; Evans JS; Speizer FE; Heath CW Jr (1995). Particulate air 

pollution as a predictor of mortality in a prospective study of US adults. Am J Respir Crit Care Med, 151: 669-674. 

045159

Prigge E; Hochrainer D (1977). Effects of carbon monoxide inhalation on erythropoiesis and cardiac hypertrophy in fetal 

rats. Toxicol Appl Pharmacol, 42: 225-228. 012326

Putz VR; Johnson BL; Setzer JV (1979). A comparative study of the effects of carbon monoxide and methylene chloride on 

human performance. J Environ Pathol Toxicol Oncol, 2: 97-112. 023137

Rabinovitch N; Zhang LN; Murphy JR; Vedal S; Dutton SJ; Gelfand EW (2004). Effects of wintertime ambient air 

pollutants on asthma exacerbations in urban minority children with moderate to severe disease. J Allergy Clin 

Immunol, 114: 1131-1137. 096753

Rajendra Acharya U; Paul Joseph K; Kannathal N; Lim CM; Suri JS (2006). Heart rate variability: A review. Med Biol Eng 

Comput, 44: 1031-1051. 193787

Ranzi A; Gambini M; Spattini A; Galassi C; Sesti D; Bedeschi M; Messori A; Baroni A; Cavagni G; Lauriola P (2004). Air 

pollution and respiratory status in asthmatic children: Hints for a locally based preventive strategy AIRE study. Eur 

J Epidemiol, 19: 567-576. 089500

Raub JA; Benignus VA (2002). Carbon monoxide and the nervous system. Neurosci Biobehav Rev, 26: 925-940. 041616

Raven PB; Drinkwater BL; Ruhling RO; Bolduan N; Taguchi S; Gliner J; Horvath SM (1974). Effect of carbon monoxide 

and peroxyacetyl nitrate on man's maximal aerobic capacity. J Appl Physiol, 36: 288-293. 041340

January 2010 5-140 
Ren X; Dorrington KL; Robbins PA (2001). Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, 

or carboxyhemoglobinemia. J Appl Physiol, 90: 1189-1195. 193850

Resch H; Zawinka C; Weigert G; Schmetterer L; Garhofer G (2005). Inhaled carbon monoxide increases retinal and 

choroidal blood flow in healthy humans. Invest Ophthalmol Vis Sci, 46: 4275-4280. 193853

Rich DQ; Kim MH; Turner JR; Mittleman MA; Schwartz J; Catalano PJ; Dockery DW (2006). Association of ventricular 

arrhythmias detected by implantable cardioverter defibrillator and ambient air pollutants in the St Louis, Missouri 

metropolitan area. Occup Environ Med, 63: 591-596. 089814

Rich DQ; Schwartz J; Mittleman MA; Link M; Luttmann-Gibson H; Catalano PJ; Speizer FE; Dockery DW (2005). 

Association of short-term ambient air pollution concentrations and ventricular arrhythmias. Am J Epidemiol, 161: 

1123-1132. 079620

Rich KE; Petkau J; Vedal S; Brauer M (2004). A case-crossover analysis of particulate air pollution and cardiac arrhythmia 

in patients with implantable cardioverter defibrillators. Inhal Toxicol, 16: 363-372. 055631

Riediker M; Williams R; Devlin R; Griggs T; Bromberg P (2003). Exposure to particulate matter, volatile organic 

compounds, and other air pollutants inside patrol cars. Environ Sci Technol, 37: 2084-2093. 043761

Riojas-Rodriguez H; Escamilla-Cejudo JA; Gonzalez-Hermosillo JA; Tellez-Rojo MM; Vallejo M; Santos-Burgoa C; 

Rojas-Bracho L (2006). Personal PM2.5 and CO exposures and heart rate variability in subjects with known 

ischemic heart disease in Mexico City. J Expo Sci Environ Epidemiol, 16: 131-137. 156913

Ritz B; Wilhelm M; Hoggatt KJ; Ghosh JK (2007). Ambient air pollution and preterm birth in the environment and 

pregnancy outcomes study at the University of California, Los Angeles. Am J Epidemiol, 166: 1045-1052. 096146

Ritz B; Wilhelm M; Zhao Y (2006). Air pollution and infant death in southern California, 1989-2000. Pediatrics, 118: 493-

502. 089819

Ritz B; Yu F (1999). The effect of ambient carbon monoxide on low birth weight among children born in southern 

California between 1989 and 1993. Environ Health Perspect, 107: 17-25. 086976

Ritz B; Yu F; Chapa G; Fruin S (2000). Effect of air pollution on preterm birth among children born in Southern California 

between 1989 and 1993. Epidemiology, 11: 502-511. 012068

Ritz B; Yu F; Fruin S; Chapa G; Shaw GM; Harris JA (2002). Ambient air pollution and risk of birth defects in Southern 

California. Am J Epidemiol, 155: 17-25. 023227

Rodriguez C; Tonkin R; Heyworth J; Kusel M; De Klerk N; Sly PD; Franklin P; Runnion T; Blockley A; Landau L; 

Hinwood AL (2007). The relationship between outdoor air quality and respiratory symptoms in young children. Int 

J Environ Health Res, 17: 351-360 . 092842

Rosenlund M; Bellander T; Nordquist T; Alfredsson L (2009). Traffic-generated air pollution and myocardial infarction. 

Epidemiology, 20: 265-71. 190309

Rosenlund M; Berglind N; Pershagen G; Hallqvist J; Jonson T; Bellander T (2006). Long-term exposure to urban air 

pollution and myocardial infarction. Epidemiology, 17: 383-390. 089796

Roth RA Jr; Rubin RJ (1976). Comparison of the effect of carbon monoxide and of hypoxic hypoxia I In vivo metabolism, 

distribution and action of hexobarbital. J Pharmacol Exp Ther, 199: 53-60. 012703

Roth RA Jr; Rubin RJ (1976). Comparison of the effect of carbon monoxide and of hypoxic hypoxia. II. Hexobarbital 

metabolism in the isolated, perfused rat liver. J Pharmacol Exp Ther, 199: 61-66. 012420

Ruckerl R; Greven S; Ljungman P; Aalto P; Antoniades C; Bellander T; Berglind N; Chrysohoou C; Forastiere F; 

Jacquemin B; von Klot S; Koenig W; Kuchenhoff H; Lanki T; Pekkanen J; Perucci CA; Schneider A; Sunyer J; 

Peters A (2007). Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial 

infarction survivors. Environ Health Perspect, 115: 1072-1080. 156931

Ruckerl R; Ibald-Mulli A; Koenig WSchneider A; Woelke G; Cyrys J; Heinrich J; Marder V; Frampton M; Wichmann HE; 

Peters A (2006). Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. 

Environ Health Perspect, 173: 432-441. 088754

Rudez G; Janssen NA; Kilinc E; Leebeek FW; Gerlofs-Nijland ME; Spronk HM; ten Cate H; Cassee FR; de Maat MP 

(2009). Effects of ambient air pollution on hemostasis and inflammation. Environ Health Perspect, 117: 995-1001. 

193783

January 2010 5-141 
Ryter SW; Alam J; Choi AMK (2006). Heme oxygenase-1/carbon monoxide: From basic science to therapeutic 

applications. Physiol Rev, 86: 583-650. 193765

Salam MT; Millstein J; Li Y-F; Lurmann FW; Margolis HG; Gilliland FD (2005). Birth outcomes and prenatal exposure to 

ozone, carbon monoxide, and particulate matter: results from the Children's Health Study. Environ Health Perspect, 

113: 1638-1644. 087885

Samet JM; Zeger SL; Dominici F; Curriero F; Coursac I; Dockery DW; Schwartz J; Zanobetti A (2000). The National 

Morbidity, Mortality, and Air Pollution Study. Part II: Morbidity and mortality from air pollution in the United 

States. 156939

Samoli E; Touloumi G; Schwartz J; Anderson HR; Schindler C; Forsberg B; Vigotti MA; Vonk J; Kosnik M; Skorkovsky J; 

Katsouyanni K (2007). Short-term effects of carbon monoxide on mortality: An analysis within the APHEA project. 

Environ Health Perspect, 115: 1578-1583. 098420

Sarnat SE; Suh HH; Coull BA; Schwartz J; Stone PH; Gold DR (2006). Ambient particulate air pollution and cardiac 

arrhythmia in a panel of older adults in Steubenville, Ohio. Occup Environ Med, 63: 700-706. 090489

Sartiani L; Cerbai E; Lonardo G; DePaoli P; Tattoli M; Cagiano R; Carratu M; Cuomo V; Mugelli A (2004). Prenatal 

exposure to carbon monoxide affects postnatal cellular electrophysiological maturation of the rat heart: a potential 

substrate for arrhythmogenesis in infancy. Circulation, 109-: 419-423. 190898

Scharte M; von Ostrowski TA; Daudel F; Freise H; Van Aken H; Bone HG (2006). Endogenous carbon monoxide 

production correlates weakly with severity of acute illness. Eur J Anaesthesiol, 23: 117-122. 194115

Schildcrout JS; Sheppard L; Lumley T; Slaughter JC; Koenig JQ; Shapiro GG (2006). Ambient air pollution and asthma 

exacerbations in children: An eight-city analysis. Am J Epidemiol, 164: 505-517. 089812

Schwartz J; Litonjua A; Suh H; Verrier M; Zanobetti A; Syring M; Nearing B; Verrier R; Stone P; MacCallum G; Speizer 

FE; Gold DR (2005). Traffic related pollution and heart rate variability in a panel of elderly subjects. Thorax, 60: 

455-461. 074317

Schwetz BA; Smith FA; Leong BKJ; Staples RE (1979). Teratogenic potential of inhaled carbon monoxide in mice and 

rabbits. Teratology, 19: 385-391. 011855

Scotto Di Marco G; Kephalopoulos S; Ruuskanen J; Jantunen M (2005). Personal carbon monoxide exposure in Helsinki, 

Finland. Atmos Environ, 39: 2697-2707. 144054

Shaoqing Y; Ruxin Z; Yinjian C; Jianqiu C; Chunsheng Z; Jiangfeng T; Genhong L (2008). Possible contribution of 

endogenous carbon monoxide to the development of allergic rhinitis in guinea pigs. J Inflamm, 5: 23. 192384

Sheps DS; Adams KF Jr; Bromberg PA; Goldstein GM; O'Neil JJ; Horstman D; Koch G (1987). Lack of effect of low 

levels of carboxyhemoglobin on cardiovascular function in patients with ischemic heart disease. Arch Environ 

Occup Health, 42: 108-116. 012212

Sheps DS; Herbst MC; Hinderliter AL; Adams KF; Ekelund LG; O'Neil JJ; Goldstein GM; Bromberg PA; Dalton JL; 

Ballenger MN; Davis SM; Koch GG (1990). Production of arrhythmias by elevated carboxyhemoglobin in patients 

with coronary artery disease. Ann Intern Med, 113: 343-351. 013286

Silkoff PE; Zhang L; Dutton S; Langmack EL; Vedal S; Murphy J; Make B (2005). Winter air pollution and disease 

parameters in advanced chronic obstructive pulmonary disease panels residing in Denver, Colorado. J Allergy Clin 

Immunol, 115: 337-344. 087471

Sinclair AH; Tolsma D (2004). Associations and lags between air pollution and acute respiratory visits in an ambulatory 

care setting: 25-month results from the aerosol research and inhalation epidemiological study. J Air Waste Manag 

Assoc, 54: 1212-1218. 088696

Singh J (1986). Early behavioral alterations in mice following prenatal carbon monoxide exposure. Neurotoxicology, 7: 

475-481. 012827

Singh J (2003). Gastroschisis is caused by the combination of carbon monoxide and protein-zinc deficiencies in mice. Birth 

Defects Res B Dev Reprod Toxicol, 68: 355-362. 053624

Singh J (2006). Interaction of maternal protein and carbon monoxide on pup mortality in mice: implications for global 

infant mortality. Birth Defects Res B Dev Reprod Toxicol, 77: 216-26. 190512

January 2010 5-142 
Singh J; Aggison L Jr; Moore-Cheatum L (1993). Teratogenicity and developmental toxicity of carbon monoxide in 

protein-deficient mice. Teratology, 48: 149-159. 013892

Singh J; Scott LH (1984). Threshold for carbon monoxide induced fetotoxicity. Teratology, 30: 253-257. 011409

Singh J; Smith CB; Moore-Cheatum L (1992). Additivity of protein deficiency and carbon monoxide on placental 

carboxyhemoglobin in mice. Am J Obstet Gynecol, 167: 843-846. 013759

Slaughter JC; Kim E; Sheppard L; Sullivan JH; Larson TV; Claiborn C (2005). Association between particulate matter and 

emergency room visits, hospital admissions and mortality in Spokane, Washington. J Expo Sci Environ Epidemiol, 

15: 153-159. 073854

Slaughter JC; Lumley T; Sheppard L; Koenig JQ; Shapiro GG (2003). Effects of ambient air pollution on symptom severity 

and medication use in children with asthma. Ann Allergy Asthma Immunol, 91: 346-353. 086294

Solanki DL; McCurdy PR; Cuttitta FF; Schechter GP (1988). Hemolysis in sickle cell disease as measured by endogenous 

carbon monoxide production: A preliminary report. Am J Clin Pathol, 89: 221-225. 012426

Song R; Mahidhara RS; Liu F; Ning W; Otterbein LE; Choi AMK (2002). Carbon monoxide inhibits human airway smooth 

muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol, 27: 603-610. 

037531

Sorhaug S; Steinshamn S; Nilsen OG; Waldum HL (2006). Chronic inhalation of carbon monoxide: Effects on the 

respiratory and cardiovascular system at doses corresponding to tobacco smoking. Toxicology, 228: 280-290. 

180414

Steinvil A; Kordova-Biezuner L; Shapira I; Berliner S; Rogowski O (2008). Short-term exposure to air pollution and 

inflammation-sensitive biomarkers. Environ Res, 106: 51-61. 188893

Stevens CF; Wang Y (1993). Reversal of long-term potentiation by inhibitors of haem oxygenase. Nature, 364: 147-149. 

188458

Stewart RD; Newton PE; Hosko MJ; Peterson JE (1973). Effect of carbon monoxide on time perception. Arch Environ 

Occup Health, 27: 155-160. 093412

Stewart RD; Peterson JE; Fisher TN; Hosko MJ; Baretta ED; Dodd HC; Herrmann AA (1973). Experimental human 

exposure to high concentrations of carbon monoxide. Arch Environ Occup Health, 26: 1-7. 012428

Stieb DM; Judek S; Burnett RT (2002). Meta-analysis of time-series studies of air pollution and mortality: effects of gases 

and particles and the influence of cause of death, age, and season. J Air Waste Manag Assoc, 52: 470-484. 025205

Stieb DM; Judek S; Burnett RT (2003). Meta-analysis of time-series studies of air pollution and mortality: Update in 

relation to the use of generalized additive models. J Air Waste Manag Assoc, 53: 258-261. 056908

Stockard-Sullivan JE; Korsak RA; Webber DS; Edmond J (2003). Mild carbon monoxide exposure and auditory function in 

the developing rat. J Neurosci Res, 74: 644-654. 190947

Stone JR; Marletta MA (1994). Soluble guanylate cyclase from bovine lung: Activation with nitric oxide and carbon 

monoxide and spectral characterization of the ferrous and ferric states. Biochemistry, 33: 5636-5640. 076455

Storm JE; Fechter LD (1985). Alteration in the postnatal ontogeny of cerebellar norepinephrine content following chronic 

prenatal carbon monoxide. J Neurochem, 45: 965-969. 011653

Storm JE; Fechter LD (1985). Prenatal carbon monoxide exposure differentially affects postnatal weight and monoamine 

concentration of rat brain regions. Toxicol Appl Pharmacol, 81: 139-146. 011652

Storm JE; Valdes JJ; Fechter LD (1986). Postnatal alterations in cerebellar GABA content, GABA uptake and morphology 

following exposure to carbon monoxide early in development. Dev Neurosci, 8: 251-261. 012136

Strickland MJ; Klein M; Correa A; Reller MD; Mahle WT; Riehle-Colarusso TJ; Botto LD; Flanders WD; Mulholland JA; 

Siffel C; Marcus M; Tolbert PE (2009). Ambient air pollution and cardiovascular malformations in Atlanta, 

Georgia, 1986-2003. Am J Epidemiol, 169: 1004-14. 190324

Stupfel M; Bouley G (1970). Physiological and biochemical effects on rats and mice exposed to small concentrations of 

carbon monoxide for long periods. Ann N Y Acad Sci, 174: 342-368. 010557

Styka PE; Penney DG (1978). Regression of carbon monoxide-induced cardiomegaly. Am J Physiol, 235: H516-H522. 

011166

January 2010 5-143 
Suliman HB; Carraway MS; Tatro LG; Piantadosi CA (2007). A new activating role for CO in cardiac mitochondrial 

biogenesis. J Cell Sci, 120: 299-308. 193768

Sullivan J; Ishikawa N; Sheppard L; Siscovick D; Checkoway H; Kaufman J (2003). Exposure to ambient fine particulate 

matter and primary cardiac arrest among persons with and without clinically recognized heart disease. Am J 

Epidemiol, 157: 501-509. 043156

Sylvester KP; Patey RA; Rafferty GF; Rees D; Thein SL; Greenough A (2005). Exhaled carbon monoxide levels in 

children with sickle cell disease. Eur J Pediatr, 164: 162-165. 191954

Symons JM; Wang L; Guallar E; Howell E; Dominici F; Schwab M; Ange BA; Samet J; Ondov J; Harrison D; Geyh A 

(2006). A case-crossover study of fine particulate matter air pollution and onset of congestive heart failure symptom 

exacerbation leading to hospitalization. Am J Epidemiol, 164: 421-433. 091258

Szyszkowicz M (2007). Air pollution and emergency department visits for ischemic heart disease in Montreal, Canada. Int 

J Occup Med Environ Health, 20: 167-173. 193793

Tarkiainen TH; Timonen KL; Vanninen EJ; Alm S; Hartikainen JEK; Pekkanen J (2003). Effect of acute carbon monoxide 

exposure on heart rate variability in patients with coronary artery disease. Clin Physiol Funct Imaging, 23: 98-102. 

053625

Teran FJ; Johnson RA; Stevenson BK; Peyton KJ; Jackson KE; Appleton SD; Durante W; Johnson FK (2005). Heme 

oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced 

hypertension in Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol, 288: 615-622. 193770

Thom SR (1993). Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated 

brain injury in rats. Toxicol Appl Pharmacol, 123: 248-256. 013895

Thom SR; Bhopale VM; Han ST; Clark JM; Hardy KR (2006). Intravascular neutrophil activation due to carbon monoxide 

poisoning. Am J Respir Crit Care Med, 174: 1239-1248. 098418

Thom SR; Fisher D; Manevich Y (2001). Roles for platelet-activating factor and NO-derived oxidants causing neutrophil 

adherence after CO poisoning. Am J Physiol Heart Circ Physiol, 281: H923-H930. 193779

Thom SR; Fisher D; Xu YA; Garner S; Ischiropoulos H (1999). Role of nitric oxide-derived oxidants in vascular injury 

from carbon monoxide in the rat. Am J Physiol, 276: H984-H992. 016753

Thom SR; Fisher D; Xu YA; Notarfrancesco K; Ischiropoulos H (2000). Adaptive responses and apoptosis in endothelial 

cells exposed to carbon monoxide. PNAS, 97: 1305-1310. 011574

Thom SR; Garner S; Fisher D; Ischiropoulos H (1998). Vascular nitrosative stress from CO exposure. Undersea Hyperb 

Med, 25: 47. 016750

Thom SR; Ischiropoulos H (1997). Mechanism of oxidative stress from low levels of carbon monoxide. Health Effects 

Institute. Boston, MA. 085644

Thom SR; Ohnishi ST; Fisher D; Xu YA; Ischiropoulos H (1999). Pulmonary vascular stress from carbon monoxide. 

Toxicol Appl Pharmacol, 154: 12-19. 016757

Thom SR; Ohnishi ST; Ischiropoulos H (1994). Nitric oxide released by platelets inhibits neutrophil B2 integrin function 

following acute carbon monoxide poisoning. Toxicol Appl Pharmacol, 128: 105-110. 076459

Thom SR; Xu YA; Ischiropoulos H (1997). Vascular endothelial cells generate peroxynitrite in response to carbon 

monoxide exposure. Chem Res Toxicol, 10: 1023-1031. 084337

Thomsen HK (1974). Carbon monoxide-induced atherosclerosis in primates: an electron-microscopic study on the 

coronary arteries of Macaca trus monkeys. Atherosclerosis, 20: 233-240. 010704

Thorup C; Jones CL; Gross SS; Moore LC; Goligorsky MS (1999). Carbon monoxide induces vasodilation and nitric oxide 

release but suppresses endothelial NOS. Am J Physiol, 277: F882-F889. 193782

Timonen KL; Pekkanen J; Tiittanen P; Salonen RO (2002). Effects of air pollution on changes in lung function induced by 

exercise in children with chronic respiratory symptoms. Occup Environ Med, 59: 129-134. 025653

Timonen KL; Vanninen E; De Hartog J; Ibald-Mulli A; Brunekreef B; Gold DR; Henrich J; Hoek G; Lanki T; Peters A; 

Tarkiainen T; Tiittanen P; Kreyling W; Pekkanen J (2006). Effects of ultrafine and fine particulate and gaseous air 

pollution on cardiac autonomic control in subjects with coronary artery disease: The ULTRA study. J Expo Sci 

Environ Epidemiol, 16: 332-341. 088747

January 2010 5-144 
Tolbert PE; Klein M; Peel JL; Sarnat SE; Sarnat JA (2007). Multipollutant modeling issues in a study of ambient air quality 

and emergency department visits in Atlanta. J Expo Sci Environ Epidemiol, 17: S29-S35. 090316

Tolcos M; Mallard C; McGregor H; Walker D; Rees S (2000). Exposure to prenatal carbon monoxide and postnatal 

hyperthermia: short and long-term effects on neurochemicals and neuroglia in the developing brain. Exp Neurol, 

162: 235-246. 010468

Tolcos M; McGregor H; Walker D; Rees S (2000). Chronic prenatal exposure to carbon monoxide results in a reduction in 

tyrosine hydroxylase-immunoreactivity and an increase in choline acetyltransferase-immunoreactivity in the fetal 

medulla: implications for sudden infant death syndrome. J Neuropathol Exp Neurol, 59: 218-228. 015997

Toyoda M; Saito H; Matsuki N (1996). Nitric oxide but not carbon monoxide is involved in spatial learning of mice. J 

Pharmacol Sci, 71: 205-211. 079945

Tsai S-S; Chen C-C; Hsieh H-J; Chang C-C; Yang C-Y (2006). Air pollution and postneonatal mortality in a tropical city: 

Kaohsiung, Taiwan. Inhal Toxicol, 18: 185-189. 090709

Tsai S-S; Goggins WB; Chiu H-F; Yang C-Y (2003). Evidence for an association between air pollution and daily stroke 

admissions in Kaohsiung, Taiwan. Stroke, 34: 2612-2616. 080133

Tschugguel W; Stonek F; Zhegu Z; Dietrich W; Schneeberger C; Stimpfl T; Waldhoer T; Vycudilik W; Huber JC (2001). 

Estrogen increases endothelial carbon monoxide, heme oxygenase 2, and carbon monoxide-derived cGMP by a 

receptor-mediated system. J Clin Endocrinol Metab, 86: 3833-3839. 193785

Turner DM; Lee PN; Roe FJ; Gough KJ (1979). Atherogenesis in the White Carneau pigeon: further studies of the role of 

carbon monoxide and dietary cholesterol. Atherosclerosis, 34: 407-417. 012328

U.S. Census Bureau (2000). Census Bureau projects doubling of nation's population by 2100. Retrieved 13-MAY-01, from 

http://www.census.gov/Press-Release/www/2000/cb00-05.html. 157064

U.S. Census Bureau (2008). American Housing Survey for the United States: 2007. U.S. Government Printing Office. 

Washington, DC. 194013

U.S. EPA (1978). Altitude as a factor in air pollution. U.S. Envrionmental Protection Agency. Research Triangle Park, NC. 

EPA-600/9-78-015. 086321

U.S. EPA (1991). Air quality criteria for carbon monoxide. U.S. Environmental Protection Agency. Research Triangle Park, 

NC. EPA/600/8-90/045F. http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=3000554R.txt. 017643

U.S. EPA (2000). Air quality criteria for carbon monoxide. National Center for Environmental Assessment, Office of 

Research and Development, U.S. Environmental Protection Agency. Research Triangle Park, NC. EPA 600/P99/001F. 000907

U.S. EPA (2003). Framework for cumulative risk assessment. National Center for Environmental Assessment, Office of 

Research and Development, U.S. Environmental Protection Agency. Washington, DC. EPA/630/P-02/001F. 192145

U.S. EPA (2006). Aging and Toxic Response: Issues Relevant to Risk Assessment (Final). U.S. Environmental Protection 

Agency. Washington, DC.http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=156648. 192082

U.S. EPA (2008). Plan for review of the National Ambient Air Quality Standards for carbon monoxide. U.S. Environmental 

Protection Agency. Research Triangle Park, NC. EPA-HQ-OAR-2008-0015; FRL-8792-1. 193995

U.S. EPA (2009). Susceptible subpopulations. Retrieved 15-MAY-09, from 

http://www.epa.gov/nerl/goals/health/populations.html. 192149

Ueda N; Kaushal GP; Hong X; Shah SV (1998). Role of enhanced ceramide generation in DNA damage and cell death in 

chemical hypoxic injury to LLC-PK1 cells. Kidney Int, 54: 399-406. 195136

Vedal S; Brauer M; White R; Petkau J (2003). Air pollution and daily mortality in a city with low levels of pollution. 

Environ Health Perspect, 111: 45-51. 039044

Vedal S; Rich K; Brauer M; White R; Petkau J (2004). Air pollution and cardiac arrhythmias in patients with implantable 

cardiovascular defibrillators. Inhal Toxicol, 16: 353-362. 055630

Verma A; Hirsch DJ; Glatt CE; Ronnett GV; Snyder SH (1993). Carbon monoxide: a putative neural messenger. Science, 

259: 381-384. 193999

January 2010 5-145 
Vesely AE; Somogyi RB; Sasano H; Sasano N; Fisher JA; Duffin J (2004). The effects of carbon monoxide on respiratory 

chemoreflexes in humans. Environ Res, 94: 227-233. 194000

Villamor E; Perez-Vizcaino F; Cogolludo AL; Conde-Oviedo J; Zaragoza-Arnaez F; Lopez-Lopez JG; Tamargo J (2000). 

Relaxant effects of carbon monoxide compared with nitric oxide in pulmonary and systemic vessels of newborn 

piglets. Pediatr Res, 48: 546-553. 015838

Villeneuve PJ; Burnett RT; Shi Y; Krewski D; Goldberg MS; Hertzman C; Chen Y; Brook J (2003). A time-series study of 

air pollution, socioeconomic status, and mortality in Vancouver, Canada. J Expo Sci Environ Epidemiol, 13: 427-

435. 055051

Villeneuve PJ; Chen L; Stieb D; Rowe BH (2006). Associations between outdoor air pollution and emergency department 

visits for stroke in Edmonton, Canada. Eur J Epidemiol, 21: 689-700. 090191

Villeneuve PJ; Doiron M-S; Stieb D; Dales R; Burnett RT; Dugandzic R (2006). Is outdoor air pollution associated with 

physician visits for allergic rhinitis among the elderly in Toronto, Canada? Allergy, 61: 750-758. 091179

Vogel JA; Gleser MA (1972). Effect of carbon monoxide on oxygen transport during exercise. J Appl Physiol, 32: 234-239. 

010898

Von Klot S; Wolke G; Tuch T; Heinrich J; Dockery DW; Schwartz J; Kreyling WG; Wichmann HE; Peters A (2002). 

Increased asthma medication use in association with ambient fine and ultrafine particles. Eur Respir J, 20: 691-702. 

034706

Von Klot S; Peters A; Aalto P; Bellander T; Berglind N; D'Ippoliti D; Elosua R; Hormann A; Kulmala M; Lanki T; Lowel 

H; Pekkanen J; Picciotto S; Sunyer J; Forastiere F; Health Effects of Particles on Susceptible Subpopulations 

(HEAPSS) Study Group (2005). Ambient air pollution is associated with increased risk of hospital cardiac 

readmissions of myocardial infarction survivors in five European cities. Circulation, 112: 3073-3079. 088070

Vreman HJ; Wong RJ; Kadotani T; Stevenson DK (2005). Determination of carbon monoxide (CO) in rodent tissue: effect 

of heme administration and environmental CO exposure. Anal Biochem, 341: 280-289. 193786

Wang R (1998). Resurgence of carbon monoxide: an endogenous gaseous vasorelaxing factor. Can J Physiol Pharmacol, 

76: 1-15. 086074

Wang R; Wu L; Wang Z (1997). The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells. 

Pflugers Arch, 434: 285-291. 084341

Wang T-N; Ko Y-C; Chao Y-Y; Huang C-C; Lin R-S (1999). Association between indoor and outdoor air pollution and 

adolescent asthma from 1995 to 1996 in Taiwan. Environ Res, 81: 239-247. 008105

Weaver LK; Valentine KJ; Hopkins RO (2007). Carbon monoxide poisoning: risk factors for cognitive sequelae and the 

role of hyperbaric oxygen. Am J Respir Crit Care Med, 176: 491 - 497. 193939

Webber D; Lopez I; Korsak R; Hirota S; Acuna D; Edmond J (2005). Limiting iron availability confers neuroprotection 

from chronic mild carbon monoxide exposure in the developing auditory system of the rat. J Neurosci Res, 80: 620-

633. 190514

Webber DS; Korsak RA; Sininger LK; Sampogna SL; Edmond J (2003). Mild carbon monoxide exposure impairs the 

developing auditory system of the rat. J Neurosci Res, 74: 655-665. 190515

Wellenius GA; Batalha JRF; Diaz EA; Lawrence J; Coull BA; Katz T; Verrier RL; Godleski JJ (2004). Cardiac effects of 

carbon monoxide and ambient particles in a rat model of myocardial infarction. Toxicol Sci, 80: 367-376. 087874

Wellenius GA; Bateson TF; Mittleman MA; Schwartz J (2005). Particulate air pollution and the rate of hospitalization for 

congestive heart failure among medicare beneficiaries in Pittsburgh, Pennsylvania. Am J Epidemiol, 161: 1030-

1036. 087483

Wellenius GA; Coull BA; Batalha JRF; Diaz EA; Lawrence J; Godleski JJ (2006). Effects of ambient particles and carbon 

monoxide on supraventricular arrhythmias in a rat model of myocardial infarction. Inhal Toxicol, 18: 1077-1082. 

156152

Wellenius GA; Saldiva PHN; Batalha JRF; Murthy GGK; Coull BA; Verrier RL; Godleski JJ (2002). Electrocardiographic 

changes during exposure to residual oil fly ash (ROFA) particles in a rat model of myocardial infarction. Toxicol 

Sci, 66: 327-335. 025405

January 2010 5-146 
Wellenius GA; Schwartz J; Mittleman MA (2005). Air pollution and hospital admissions for ischemic and hemorrhagic 

stroke among medicare beneficiaries. Stroke, 36: 2549-2553. 088685

Wellenius GA; Yeh GY; Coull BA; Suh HH; Phillips RS; Mittleman MA (2007). Effects of ambient air pollution on 

functional status in patients with chronic congestive heart failure: a repeated-measures study. Environ Health, 6: 1-

7. 092830

Wheeler A; Zanobetti A; Gold DR; Schwartz J; Stone P; Suh HH (2006). The relationship between ambient air pollution 

and heart rate variability differs for individuals with heart and pulmonary disease. Environ Health Perspect, 114: 

560-566. 088453

Wilhelm M; Meng YY; Rull RP; English P; Balmes J; Ritz B (2008). Environmental public health tracking of childhood 

asthma using California health interview survey, traffic, and outdoor air pollution data. Environ Health Perspect, 

116: 1254-1260. 191912

Wilhelm M; Ritz B (2005). Local variations in CO and particulate air pollution and adverse birth outcomes in Los Angeles 

County, California, USA. Environ Health Perspect, 113: 1212-1221. 088668

Wittenberg BA; Wittenberg JB (1993). Effects of carbon monoxide on isolated heart muscle cells. Health Effects Institute. 

Cambridge, MA. 013909

Wollmann HA (1998). Intrauterine growth restriction: definition and etiology. Horm Res, 49: 1-6. 193812

Woodruff TJ; Darrow LA; Parker JD (2008). Air pollution and postneonatal infant mortality in the United States, 1999-

2002. Environ Health Perspect, 116: 110-115. 098386

Yamaya M; Sekizawa K; Ishizuka S; Monma M; Mizuta K; Sasaki H (1998). Increased carbon monoxide in exhaled air of 

subjects with upper respiratory tract infections. Am J Respir Crit Care Med, 158: 311-314. 047525

Yang C-Y; Chen Y-S; Yang C-H; Ho S-C (2004). Relationship between ambient air pollution and hospital admissions for 

cardiovascular diseases in Kaohsiung, Taiwan. J Toxicol Environ Health A Curr Iss, 67: 483-493. 094376

Yang C-Y; Hsieh H-J; Tsai S-S; Wu T-N; Chiu H-F (2006). Correlation between air pollution and postneonatal mortality in 

a subtropical city: Taipei, Taiwan. J Toxicol Environ Health A Curr Iss, 69: 2033-2040. 090760

Yang CY (2008). Air pollution and hospital admissions for congestive heart failure in a subtropical city: Taipei, Taiwan. J 

Toxicol Environ Health A Curr Iss, 71: 1085-1090. 157160

Yang Q; Chen Y; Krewski D; Burnett RT; Shi Y; McGrail KM (2005). Effect of short-term exposure to low levels of 

gaseous pollutants on chronic obstructive pulmonary disease hospitalizations. Environ Res, 99: 99-105. 090184

Yang Q; Chen Y; Shi Y; Burnett RT; McGrail KM; Krewski D (2003). Association between ozone and respiratory 

admissions among children and the elderly in Vancouver, Canada. Inhal Toxicol, 15: 1297-1308. 055621

Yasuda H; Yamaya M; Nakayama K; Ebihara S; Sasaki T; Okinaga S; Inoue D; Asada M; Nemoto M; Sasaki H (2005). 

Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease. Am J Respir Crit 

Care Med, 171: 1246-1251. 191953

Yoshimura S; Banno Y; Nakashima S; Hayashi K; Yamakawa H; Sawada M; Sakai N; Nozawa Y (1999). Inhibition of 

neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC12 cell death. J 

Neurochem, 73: 675-683. 195135

Yu O; Sheppard L; Lumley T; Koenig JQ; S (2000). Effects of ambient air pollution on symptoms of asthma in Seattle-area 

children enrolled in the CAMP study. Environ Health Perspect, 108: 1209-1214. 013254

Zamudio S; Palmer SK; Dahms TE; Berman JC; Young DA; Moore LG (1995). Alterations in uteroplacental blood flow 

precede hypertension in preeclampsia at high altitude. J Appl Physiol, 79: 15-22. 193908

Zanobetti A; Canner MJ; Stone PH; Schwartz J; Sher D; Eagan-Bengston E; Gates KA; Hartley LH; Suh H; Gold DR 

(2004). Ambient pollution and blood pressure in cardiac rehabilitation patients. Circulation, 110: 2184-2189. 

087489

Zanobetti A; Schwartz J (2001). Are diabetics more susceptible to the health effects of airborne particles? Am J Respir Crit 

Care Med, 164: 831-833. 016710

Zanobetti A; Schwartz J (2006). Air pollution and emergency admissions in Boston, MA. J Epidemiol Community Health, 

60: 890-895. 090195

January 2010 5-147 
Zenclussen ML; Anegon I; Bertoja AZ; Chauveau C; Vogt K; Gerlof K; Sollwedel A; Volk HD; Ritter T; Zenclussen AC 

(2006). Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a 

murine model of abortion. Am J Reprod Immunol, 69: 35-52. 193873

Zevin S; Saunders S; Gourlay SG; Jacob P III; Benowitz NL (2001). Cardiovascular effects of carbon monoxide and 

cigarette smoking. J Am Coll Cardiol, 38: 1633-1638. 021120

Zhang X; Shan P; Alam J; Fu XY; Lee PJ (2005). Carbon monoxide differentially modulates STAT1 and STAT3 and 

inhibits apoptosis via a phosphatidylinositol 3-kinase/akt and p38 kinase-dependent STAT3 pathway during anoxiareoxygenation injury. J Biol Chem, 280: 8714-8721. 184460

Zhao H; Wong RJ; Doyle TC; Nayak N; Vreman HJ; Contag CH; Stevenson DK (2008). Regulation of maternal and fetal 

hemodynamics by heme oxygenase in mice. Biol Reprod, 78: 744-751. 193883

Zhu Y; Hinds WC; Kim S; Shen S; Sioutas C (2002). Study of ultrafine particles near a major highway with heavy-duty 

diesel traffic. Atmos Environ, 36: 4323-4335. 041553

Zhuo M; Small SA; Kandel ER; Hawkins RD (1993). Nitric oxide and carbon monoxide produce activity-dependent longterm synaptic enhancement in hippocampus. Science, 260: 1946-1950. 013905

Zinkham WH; Houtchens RA; Caughey WS (1980). Carboxyhemoglobin levels in an unstable hemoglobin disorder (Hb 

Zürich): effect on phenotypic expression. Science, 209: 406-408. 011435

Zuckerbraun BS; Chin BY; Bilban M; d'Avila JC; Rao J; Billiar TR; Otterbein LE (2007). Carbon monoxide signals via 

inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J, 21: 1099-

1106. 193884

January 2010 5-148