Annex E. Toxicological Studies 

Table E-1. Human and animal studies. 

Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Acevedo and Ahmed 

(1998, 016003) 

Human pregnant 

myometrium 

HO-1 and HO-2 (mRNA and protein) were upregulated in 

pregnant myometrium when compared to nonpregnant 

myometrium. The HO activator hemin inhibited spontaneous and 

oxytocin-induced contractility of the myometrium. Progesterone 

induced HO-1 and HO-2 mRNA expression. 

Achouha et al. (2008, 

179918) 

Human arteries Until equilibrium Approximately 30 μM CO induced endothelium- and NO-independent relaxation of 

precontracted human ITA and RA graft by partially stimulating 

cGMP production. The mechanism and extent of relaxation 

depended upon the tissue. 

Ahmed et al. (2000, 

193863) 

Human placenta Placental HO-1 was significantly higher at term. HO-1 

significantly attenuated TNFα-dependent cellular damage in 

placental explants. HO-1 was significantly attenuated in preeclampsia pregnancies vs non-pre-eclamptic pregnancies. 

Placental arteries exposed to the HO activator hemin 

demonstrated reduced vascular tension (i.e., placental blood 

vessel relaxation). 

Ahmed et al. (2005, 

193865) 

Human placental 

cotyledons 

The source of CO in term human placental chorionic villi was 

found to be the catalysis of heme by HO and not endogenous 

lipid peroxidation. 

Alexander et al. (2007, 

193869) 

Rat 

Sprague Dawley 

Adult female 

. Modulation of the HO/CO system in the anterior pituitary of the 

female rat led to altered secretion of gonadotropins and prolactin. 

Alexandreanu et al. 

(2002, 192373) 

Rat 

Sprague Dawley 

Female 

The role of the HO/CO system in estrous cyclicity, pregnancy and 

lactation was evaluated using HO inhibitors and substrates. The 

HO inhibitor CrMP decreased time in estrous. Administering HOinhibitors to pregnant rodents induced total litter loss. CrMP 

induced decreased litter weight gain during lactation, which the 

authors attribute to maternal milk production or ejection problems 

as cross-fostered pups regained weight lost during nursing on 

CrMP dams. 

Alexandreanu and 

Lawson ((2003, 

193871) 

Rat 

Sprague Dawley 

Adult female 

Modulation of the HO/CO system in the anterior pituitary of the 

female rat led to altered secretion of gonadotropins and prolactin. 

Alexandreanu and 

Lawson (2003, 

193876) 

Rat 

Sprague Dawley 

Adult female ovary 

HO-1 and HO-2 were localized in the ovaries in rats, and 

treatment of rat ovaries in vitro with CrMP, an inhibitor of HO, or 

with hemin, a substrate for HO induced steroidogenic changes in 

the ovaries. 

Alonso et al. (2003, 

193882) 

Human muscle tissue 

mitochondria 

5 min 50-500 ppm CO significantly reduced muscle mitochondrial cytochrome c 

oxidase activity by 20%, 42%, and 55% after treatment with 50, 

100, and 500 ppm CO respectively but did not change the activity 

of 3 other electron transport proteins. 

Andersen et al. (2006, 

180449) 

Rat 

Long Evans 

Male 

Mouse 

C57BL/6J 

Male 

Cerebral vessels 

1-100 μM CO did not dilate rat or mouse cerebral arteries until 100 μM, 

which is not a physiological concentration. Also, the HO inhibitors 

constricted vessels in a nonspecific manner. 

 

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 E-1 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Antonelli et al. (2006, 

194960) 

Rat 

Wistar 

GD5-GD20 75 ppm Pups exposed to CO in utero had significant impairment of 

cortical neuronal glutamanergic transmission at PND1 in both 

neurons at rest and in neurons stimulated with depolarization. 

Appleton and Marks 

(2002, 193935) 

Human placenta Endogenous CO production by HO in the human placenta was 

regulated by O2 availability. Placental HO activity was directly 

dependent on O2 availability; this does not vary between preeclamptic and normotensive placentas. 

Ashfaq et al. (2003, 

194002) 

Human placenta Placentas were collected from smokers and nonsmokers who 

gave birth to male infants. Premature aging and a statistically 

significant increase in apoptotic cells were seen in placentas from 

smokers vs nonsmokers. 

Astrup et al. (1972, 

011121) 

Rabbit 

(strain not identified) 

Continuous CO 

exposure over 

gestation 

90 or 180 ppm Skeletal abnormalities: Three pups (from n = 123) in the 180 ppm 

CO group had deformities in their extremities at birth, whereas no 

control and no 90 ppm CO-exposed animals manifested with this 

malformation. 

Bainbridge et al. 

(2002, 043161) 

Human placenta 72–3369 nM Isolated human placenta exposed to solutions containing CO 

demonstrated a concentration-dependent decrease in perfusion 

pressure further demonstrating the role of CO in maintaining 

basal vasculature tone. 

Bainbridge et al. 

(2006, 193949) 

Human placenta 6 h Starting concentrations of 

CO: 3.9 μM CO in cell 

culture media (control) 

and CO-exposed groups: 

116 μM, 145 μM, 

181 μM. 

After 3 h, the CO in the 

culture media was 

3.7 μM (control), and 

CO-exposed cells 

10.2, 12, and 15.9 μM. 

C-section placentas were collected from healthy term 

pregnancies. Villous explants of placentas were cultured under 

hypoxia followed by reoxygenation (H/R). H/R- and CO-exposed 

placental tissue had decreased apoptosis and decreased PARP 

(a protein marker of apoptosis) vs control H/R-exposed cells. 

Secondary necrosis of the placental tissue post H/R was inhibited 

by CO treatment. 

Bainbridge and Smith 

(2005, 193946) 

Human placenta The role of HO in the placenta and during pregnancy is reviewed 

in this article. The conflicting data on the activity, localization and 

expression of HO in the placentas of pre-eclamptic women are 

presented. 

Bamberger et al. 

(2001, 016271) 

Human placenta Expression and tissue localization of soluble guanylyl cyclase in 

human placenta using antibody localization were characterized. 

These tools can be used in future studies to elucidate the 

NO/CO/cGMP pathway. 

Barber et al. (1999, 

193953) 

Human myometrium HO and NOS did not maintain human uterine quiescence during 

pregnancy. 

Barber et al. (2001, 

193891) 

Human placenta Women who had pregnancies with fetal growth restrictions (FGR) 

produced term placenta with significant decreases in HO-2 vs 

healthy pregnancies. 

Baum et al. (2000, 

016435) 

Human End-tidal CO measurements in women with pregnancy-induced 

hypertension and pre-eclampsia were significantly lower than in 

normotensive pregnant women. 

Benagiano et al. 

(2005, 180445) 

Rat 

Wistar 

Female 

GD0-GD20 75 ppm CO caused a significant reduction in glutamic acid decarboxylase 

and GABA immunoreactivities in the cerebellar cortex of adult 

rats prenatally exposed to CO (number of positive neuronal 

bodies and axon terminals and the area they covered). No 

difference was found in the microscopic structure of the 

cerebellar cortex or distribution patterns of GAD or GABA. 

Benagiano (2007, 

193892) 

Rat 

Wistar 

Female 

GD5-GD20 75 ppm Prenatal CO reduced GAD and GABA immunoreactivities. There 

were no structural alterations of the cerebellar cortex. 

Bergeron et al. (1998, 

193967) 

Rat 

Brain 

To address the developmental changes of HO staining in the 

brain, immunohistochemical staining for HO-1 was performed on 

the developing rat brain at PND7, PND14, and PND21. HO-1 

staining was most intense at PND7, and by PND21 reached its 

adult pattern of staining localizing to the hippocampus, thalamic 

and hypothalamic nuclei, with virtually no staining of endothelium, 

white matter and cortex. HO-2 is the dominant HO isoform in the 

brain. 

January 2010 E-2 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Bing et al. (1995, 

079418) 

Rodent . Spatial learning in the Morris water maze was enhanced in 

rodents exposed to the HO inhibitor tin protoporphyrin (Sn-PP). 

Burmester et al. 

(2000, 099998) 

Human 

Mouse 

Nb had a high oxygen affinity similar to Mb, and thus may 

increase the availability of O2 to brain tissue. 

Bye et al. (2008, 

193777) 

Rat 

Wistar 

Female 

100 h/wk for 

18 mo 

200 ppm CO-exposed (11-14.7% COHb) rats experienced a 24% decrease 

in aerobic capacity evidenced by VO2 max deficits. Left 

ventricular cardiomyocytes were longer and wider, had increased 

expression of growth-related proteins, and had impaired 

contraction-relaxation cycles. CO increased cGMP and impaired 

cardiomyocyte Ca2+ handling. No change in BP was observed. 

Cagiano et al. (1998, 

087170) 

Rat 

Wistar 

Female 

GD0-GD20 75 or 150 ppm At 5 mo of age, CO-exposed male offspring showed decrements 

in sexual behavior, including an increase in mount- tointromission latency, a decrease in mount-to-intromission 

frequency, and a decrease in ejaculation 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 is absent in CO-exposed rats. 

Carmines and 

Rajendran (2008, 

188440) 

Rat 

Sprague Dawley 

GD6-GD19 of 

gestation for 

2 h/day 

600 ppm Significant decreases in birth weight were reported after CO 

exposure. Maternal body weight was unchanged during 

gestation, but corrected terminal body weight (body weight minus 

uterine weight) was significantly elevated in CO-exposed dams at 

term. 

Carratu et al. (1993, 

013812) 

Rat 

Wistar 

Male pups 

GD0-GD20 75 or 150 ppm Prenatal CO exposure slowed the inactivation kinetics of 

transient sodium current in the sciatic nerve fibers of 40-day-old 

male rats. The maximum number of activatable Na channels at 

normal resting potential was increased in CO exposed rats, and 

the voltage-current relationship showed a negative shift of 

sodium equilibrium potential. 

Carratu et al. (1995, 

079427) 

Rat 

Wistar 

150 ppm Sphingolipid homeostasis was disrupted in male offspring of 

prenatally exposed rats, without a disruption in motor function. 

Carratu et al. (2000, 

015935) 

Rat 

Wistar 

GD0-GD20 150 ppm Maternal COHb (mean % ± SEM) was 1.9 ± 0.04 and 16.02 ± 

0.98 in control and 150 ppm CO-exposed animals, respectively. 

Prenatal CO exposure had no effect on brain sphinganine (SA) or 

sphingosine (SO) levels in male offspring at 90 days of age. 

However, the sciatic nerve had significant increases in SO after 

CO exposure, and no changes in SA at 90 days of age. Motor 

activity, which could be affected by changes in myelination, 

showed no differences between CO and control animals at 

90 days of age. 

Carratu et al. (2000, 

015839) 

Rat 

Wistar 

GD0-GD20 75 or 100 ppm The myelin sheath thickness of the nerve fibers was significantly 

decreased in CO-exposed animals (75 and 150 ppm). Axon 

diameter was not affected by CO exposure. Even though CO 

affected myelination, it did not significantly affect motor activity of 

CO-exposed rats at 40 and 90 days. 

Carraway et al. (2002, 

026018) 

Rat model of hypoxic 

pulmonary vascular 

remodeling 

(Strain of rat not stated) 

3 wk Hypobaric hypoxia ± 

50 ppm 

CO promoted remodeling and increased pulmonary vascular 

resistance in response to HH. The number of small muscular 

vessels was increased compared with HH alone. Changes in cell 

proliferation, apoptosis, actin and HO-1 gene and protein 

expression correlated with structural changes. COHb levels were 

<0.5% in controls, 1.5-2.8% in the HH treatment group, and 

3.5-3.9% in the HH + CO treatment group. 

Cella et al. (2006, 

193240) 

Rat 

Sprague Dawley 

HO-1 production and HO concentration were shown to be 

regulated by estrogen in the rat uterus. 

Chen (2001, 193985) Rat 

Long Evans 

Male 

2 mo 

3.5 h 1201 ± 18 ppm CO potentiates-noise induced hearing loss. The NMDA inhibitor 

(+)-MK-801 did not block the potentiation of the NIHL by CO. 

Cheng et al. (2009, 

193775) 

Human atherectomy 

biopsy (clinical carotid 

artery disease) 

Mouse model of 

vulnerable plaque 

ApoE-/- mouse 

HO-1 expression correlated with features of vulnerable human 

atheromatous plaque.HO-1 expression was upregulated in 

vulnerable lesions in the mouse model. Induction of HO-1 in the 

mouse impeded lesion progression into vulnerable plaques. 

Inhibition of HO-1 augmented plaque vulnerability. 

Overexpression of HO-1 resulted in plaque stabilization. It was 

concluded that HO-1 induction was atheroprotective. 

January 2010 E-3 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Chung et al. (2006, 

193987) 

Rat 

Sprague Dawley 

Male 

3-6% CO inactivation of Mb did not induce any change in the 

respiration rate, contractile function or high-energy phosphate 

levels in perfused rat hearts. 

Cronje et al. (2004, 

180440) 

Rat 

Sprague Dawley 

Male 

240-325 g 

45 min 2,500 ppm Results indicate that tissue and blood (CO) (66-72% COHb) 

dissociate during CO inhalation, but tissue (CO) does not follow 

blood (CO) or 1/pO2 as in the Warburg theory during intake or 

elimination. Tissue (CO) increases later during the resolution 

period and varies significantly among animals and tissues. The 

deviation from the predicted values in the brain is likely due to the 

release of heme and increase in NADPH stimulating endogenous 

CO production by HO. Immediately following exposure, tissue 

CO concentrations were found to be: 

Blood: 27,500 (800) pmol/mg 

Heart: 800 (300) pmol/mg 

Muscle: 90 (80) pmol/mg 

Brain: 60 (40) pmol/mg 

These values are estimates taken from a graph, with control 

levels in parentheses 

A later report stated that these tissue CO values were too high 

due to a computational error (Piantadosi et al., 2006, 180424) 

Cudmore et al. (2007, 

193991) 

Human placenta 

Human (HUVEC) 

Mouse 

(HO-1 deficient mouse on 

129/SV × C57BL/6 

background) 

Pig 

(Porcine aortic endothelial 

cells) 

HUVEC cells, porcine aortic endothelial cells, HO-1 null mice and 

placental villous explants (normotensive and pre-eclamptic 

pregnancies) were used in this study. The HO-1/CO system 

inhibited sFlt-1 and sEng release, two factors upregulated in preeclampsia. 

D'Amico et al. (2006, 

193992) 

Human embryonic kidney 

(HEK293) cells 

0-30 min 20 μM Exogenous CO inhibited respiration in HEK293 cells under 

ambient O2 concentration (21%). Inhibition was enhanced under 

hypoxic conditions. Increased endogenous CO resulting from 

HO-1 overexpression inhibited respiration by 12% and 

cytochrome c oxidase activity by 23%. This effect was enhanced 

under hypoxic conditions. 

Dani et al. (2007, 

193994) 

Human 

(neonatal blood) 

CO was lower at birth and 48-72 h postpartum in infants born by 

elective C-section and higher in vaginally born infants. 

De Luca et al. (1996, 

080911) 

Rat 

Wistar 

Female 

Male pups 

GD0-GD20 75 or 150 ppm Prenatal CO (150 ppm) delayed development of the ion channels 

responsible for passive and active membrane electrical 

properties of skeletal muscle. CO-induced lower values of resting 

chloride conductance was reversed at PND80. CO-induced 

delayed developmental reduction of resting potassium 

conductance was reversed at PND60. 

De Salvia et al. (1995, 

079441) 

Rat 

Wistar 

 GD0-GD20 75 or 150 ppm Animals exposed to the higher dose of CO (150 ppm) in utero 

had significantly impaired acquisition (at 3 and 18 mo) and 

reacquisition (at 18 mo) of conditioned avoidance behavior. 

Denschlag et al. 

(2004, 193894) 

Human Genetic polymorphisms in human HO-1 are linked to idiopathic 

recurrent miscarriages. 

Dewilde et al. (2001, 

019318) 

Nb exists as a reversibly hexacoordinated Hb type with a HisFe2+-His binding scheme. Dissociation of the internal ligand by O2

or CO is the rate limiting step. 

Di Giovanni et al. 

(1993, 013822) 

Rat 

Wistar 

Female 

GD0-GD20 75 and 150 ppm 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. 

Dubois et al. (2002, 

193911) 

Rat 

Wistar 

Adult female 

250 g 

3 wk 530 ppm Intrapulmonary resistance artery smooth muscle cells were 

isolated from control and exposed rats. Electrophysiological recordings provided evidence of increased Ca2+-activated K+

current consequent to chronic CO exposure. The authors speculated that this could in part explain the vasodilatory effect of CO 

in the pulmonary circulation. 

January 2010 E-4 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Dubois et al. (2005, 

180435) 

Rat 

Wistar 

Male 

21 days 50 ppm CO attenuated PAHT by activating BKca channels in PA myocytes 

and reduced hemodynamic changes of PAHT. 

Dubois et al. (2003, 

180439) 

Rat 

Wistar 

Male 

21 days 50 ppm CO induced relaxation of pulmonary artery rings in normoxic, 

hypoxic, and hypoxic-CO rats, and it was not endothelium 

dependent. Chronic hypoxia decreased acute CO sensitivity, 

while CO-hypoxia increased it. K+ channel blocker reduced this 

effect while sGC blocker did not. 

Durante et al. (2006, 

193778) 

Reviews the role of CO in cardiovascular function. 

Favory et al. (2006, 

184462) 

Rat 

250-300 g 

(Strain not stated) 

90 min 250 ppm CO inhibited myocardial permeabilized fiber respiration (complex 

IV), increased coronary perfusion pressure and left ventricular 

developed pressure (LVDP) first derivative and decreased the 

cGMP/cAMP ratio in the heart. These changes were maintained 

over 24-48 h of recovery in air. Cardiac function and vasodilatory 

responses were evaluated at 3-h recovery in air. β-adrenergic 

blockade had no effect on coronary perfusion pressure or LVDP 

first derivative. Total inhibition of vasodilator response to 

acetylcholine and partial inhibition of vasodilator response to 

nitroprusside were observed. An increase in myofilament calcium 

sensitivity was also observed. Thus CO promotes abnormalities 

in mitochondrial respiration, coronary vascular relaxation and 

myocardial contractility. The authors speculated that CO may 

have a detrimental effect on heart O2 supply-to-utilization which 

could potentially lead to myocardial hypoxia because of the 

increased O2 demand resulting from increased contractility, the 

inhibited mitochondrial respiration and the reduced coronary 

blood-flow reserve resulting from the decreased vasodilatory 

capacity. 

COHb was found to be 11% immediately after exposure. COHb 

levels gradually returned to baseline (1.5%) over the next 96 h. 

Fechter and Annau 

(1977, 010688) 

Rat 

Long Evans 

Continuous CO 

exposure 

throughout 

pregnancy 

150 ppm CO The authors found a 5% significantly decreased birth weights at 

PND1 in gestationally CO-exposed pups vs control animals with 

weight decrements persisting to weaning; lactational cross 

fostering did not ameliorate the CO-dependent reduced growth 

rates. Dams exposed to CO during gestation had COHb over 

gestation of 15% with control dams having less than 1%. 

Decreased birth weight and pre-weaning weight were seen in 

CO-exposed pups despite a lack of weight decrement in 

CO-exposed dams vs air-exposed control dams. 

Fechter et al. (1980, 

011294) 

Rat 

Long Evans 

Continuous CO 

exposure 

throughout 

pregnancy 

150 ppm CO-exposed animals had cardiomegaly at birth (wet heart 

weight) that dissipated by PND4. 

Fechter and Annau 

(1980, 011295) 

Rat 

Long Evans 

Continuous CO 

exposure 

throughout 

pregnancy 

150 ppm CO-exposed animals had decreased birth weight, impaired 

righting reflexes, impaired negative geotaxis, and delayed 

homing behavior. 

Fechter et al. (1987, 

012194) 

Rat 

Long-Evans 

Male 

1-4 mL/100 g BW (ip) High-dose CO led to dose-dependent, reversible loss of the 

compound action potential sensitivity for high frequency tone 

bursts. Also, CO produced a dose-dependent elevation in the 

cochlear blood flow. 

Fechter et al.(1987, 

012259) 

Rat 

Long Evans

Male 

Continuous CO 

exposure 

throughout 

pregnancy or from 

GD0 to PND10 

75, 150, or 300 ppm The neostriatum of each PND21 rat brains was collected and 

showed disrupted development following CO exposure (GD0-

PND10 group, 300 ppm CO). Dopamine levels were also 

significantly elevated in CO-exposed animals (GD0-PND10, 150 

and 300 ppm CO). 

Fechter et al. (1997, 

081322) 

Guinea pigs 35 ml/kg gas (ip) 

40% COHb 

CO impairs high-frequency auditory sensitivity, shown by 

increased compound action potential threshold at higher test 

frequencies. Free radical inhibitors blocked this response. 

Fechter et al. (1986, 

012030) 

Reviews the effects of carbon monoxide on brain development. 

January 2010 E-5 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Garofolo et al. (2002, 

193930) 

Human infants 

Rat Rat: PND2-PND5 

Human infants who die from SIDS showed decreased brainstem 

muscarinic receptor binding vs infants dying from other causes. 

ß-adrenergic modulation of muscarinic receptors in developing 

heart was observed. 

Rodent ß-adrenergic agonists at PND2-PND5 induced 

muscarinic receptor decrement in adenylyl cyclase. 

Gautier et al. (2007, 

096471) 

Rat 

Wistar 

Adult male 

Model of right ventricular 

hypertrophy secondary to 

chronic hypoxia 

3 wk of HH ± CO 

in final wk 

Or 1 wk of CO 

50 ppm CO altered the right ventricular adaptive response to pulmonary 

hypertension which occurs secondarily to chronic hypoxia. Right 

ventricular end-systolic pressure (RVESP) and right ventricular 

shortening fraction (RVSF) were smaller in rats treated with 

CO+HH compared with rats treated with HH alone. CO alone had 

no effect on these measures. Hypobaric hypoxia had no effect on 

left ventricular function while CO+ HH led to an increased left 

ventricular shortening fraction (LVSF). CO alone led to a 

decrease in LVSF and the mitral E-to-A ratio, indicative of an LVfilling impairment. Hypobaric hypoxia decreased the relative RV 

perfusion and increased the relative LV perfusion. These effects 

were prevented with concomitant exposure to CO, although 

exposure to CO alone had no effects on myocardial perfusion. 

Morphologic and histologic analysis demonstrated RV hypertrophy in both the HH group and the CO+HH group and fibrotic 

lesions in the CO+HH group. The authors concluded that the 

1-wk exposure to 50 ppm CO had a deleterious effect on RV 

myocardial perfusion adaptation to chronic hypoxia and pressure 

overload. Although the reduced RV pressure overload was 

beneficial, it was counterbalanced by impaired RV perfusion and 

redistribution of perfusion toward the LV. 

Gaworski et al. (2004, 

193933) 

Rat 

Sprague Dawley 

2 h/day, 7 days/wk 

by nose-only 

inhalation 

Males: 4 wk prior 

to and during 

mating; and 

Females: 2 wk 

prior to mating; 

during mating; 

and through 

weaning to 

PND21 

Cigarette smoke: 

150, 300, or 600 mg/m3 

Total Particulate Matter 

(TPM) 

Maternal exposure to high concentrations of cigarette smoke 

during gestation and lactation reduced pup birth weight and 

retarded neonatal pup growth. Developmental and 

neurobehavioral testing of neonates did not show any behavioral 

effects following parental smoke exposure. 

Rat 

Sprague Dawley 

Adult male 

24 h 50 ppm Mild neutrophil accumulation was observed in BALF, 

accompanied by increases in BALF MIP-2, protein and LDH. Iron 

status was altered since CO exposure led to an increase in BALF 

iron and ferritin, a decrease in lung non-heme iron and an 

increase in liver non-heme iron. 

Ghio et al. (2008, 

096321) 

Human bronchial 

epithelial cells 

(BEAS-2B) 

2-24 h 10-100 ppm CO exposure for 24 h led to a dose-dependent decrease in 

cellular non-heme iron, with the effect at 10 ppm statistically 

significant and the effect at 50 ppm maximal. This effect was 

reversible since removing the cells after 2 h of CO and incubating 

them in air restored non-heme iron concentrations at 24 h. A 

dose-dependent decrease in cellular ferritin was observed 

following exposure for 24 h to 50-500 ppm CO. In addition, 

exposure to 50 ppm CO for 20 h blocked iron uptake by cells, 

while exposure to 50 ppm CO for 2 h increased iron release from 

cells. Increased protein expression of the iron transporter DMT-1 

was also noted after 24 h exposure to 50 ppm CO. Oxidative 

stress, mediator release and cell proliferation were also 

decreased by exposure to 50 ppm for 24 h. This effect was also 

reversible upon removal to air. Effects of CO on cell proliferation 

indices were mimicked by with the iron-depleting agent 

deferoxamine. The authors concluded that CO exposure altered 

lung iron homeostasis possibly by initially causing heme release 

from proteins. 

Giustino et al. (1999, 

011538) 

Rat 

Wistar 

Male and pregnant female 

GD0-GD20 75 or 150 ppm This study showed that CO- exposed (75 and 150 ppm) male 

animals at 40 days of age had a significantly decreased time of 

exploration of novel objects. The 150 ppm CO group showed a 

lack of habituation after the second exposure to a previously 

viewed object. 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). 

January 2010 E-6 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Giustino et al. (1993, 

013833) 

Rat 

Wistar 

GD0-GD20 75 or 150 ppm CO exposure in utero led to a reversible and dose-dependent 

loss of function of splenic macrophages, with decreased killing 

ability, decreased phagocytosis, and decreased ROS production 

during the macrophage respiratory burst. 

Giustino et al. (1994, 

076343) 

Rat 

Wistar 

Male pups 

GD0-GD20 75 or 150 ppm CO (150 ppm) decreased the number of leukocyte common 

antigen (LCA+) cells at PND21. This was reversed by PND540. 

CO (75 ppm), and other measures of immunological changes 

showed trends toward reduction (macrophages, T cells, B cells, 

and MHC II cells). 

Glabe et al. (1998, 

086704) 

Rat 

Sprague Dawley 

Male, 

Myocardium 

pCO = 0-107 Torr Increased pCO and increased COMb saturation did not alter 

high-energy phosphate signals (ATP, phosphocreatine, Pi). MVO2

began to decline at 87.6% COMb and is likely not due to 

cytochrome c oxidase inhibition. 

Grover et al. (2000, 

010465) 

Fetal lamb 

(mixed breed) 

10 min 500 ppm Fetal methoxyhemoglobin (COHb%) ranged from 3.8 ± 0.2 to 8.1 

± 2.0 at 0 and 500 ppm CO, respectively. Inhaled 0-500 ppm CO 

administered to near-term fetal lambs did not induce pulmonary 

vasodilation (main pulmonary artery, left pulmonary artery, aorta 

and left atrium), and the HO inhibitor zinc protoporphyrin IX failed 

to affect baseline vascular tone. 

Hara et al. (2002, 

037497) 

Rat 

Sprague Dawley 

Male 

40 min 1,000-3,000 ppm CO exposure increased extracellular dopamine levels and 

decreased its major metabolites in a Na+-dependent pathway. CO 

withdrawal and reoxygenation caused levels to return to control 

or overshoot, which may suggest an increase in oxidative 

metabolism of CO, mediated by MAO-A. 

Harada et al. (2004, 

193920) 

Pig 

Granulosa cells 

In this porcine model, HO was able to augment granulosa cell 

apoptosis allowing for proper follicular maturation. 

Hendler and Baum 

(2004, 193925) 

Human End-tidal breath CO measurements in pregnant women with 

contractions (term and pre-term) were lower than those 

measurements in noncontracting women. 

Hofmann and Brittain 

(1998, 052019) 

Human Partitioning of O2 and CO in the human embryonic Hb is 

discussed. 

Iheagwara et al. 

(2007, 193861) 

Mouse 

C57BL/6 

Male 

3 h 1,000 ppm CO significantly reduced cytochrome c oxidase activity and Vmax

but not Km in myocardial mitochondria. Cytochrome c oxidase 

protein levels and heme content were significantly decreased. 

The average COHb level was 61%, but no tissue hypoxia was 

observed in the heart. 

Imai et al. (2001, 

193864) 

HO-1 transgenic mice 

which specifically overexpress HO-1 in smooth 

muscle 

Transgenic mice had a significant increase in arterial pressure 

and impaired nitrovasodilatory aortic responses. The mice had 

enhanced NO production and impaired sGC activity. The authors 

speculated that the effect of HO-1 overexpression was to 

suppress vasodilatory responses to NO in vascular smooth 

muscle. 

Ischiropoulos et al. 

(1996, 079491) 

Rat 

Wistar 

Male 

200-290 g 

60 min 

40-60 min 

1,000-3,000 ppm 

1,000 ppm 

CO poisoning resulted in free NO in brains as measured by 

electron paramagnetic resonance spectroscopy and in a 10-fold 

increase in nitrotyrosine as measured by immunohistochemical 

staining. These responses were blocked by pretreatment with a 

NOS inhibitor but not by neutrophil depletion. 

Brain nitrotyrosine formation was blocked by platelet depletion 

following 40-min but not 60-min exposure to 1,000 ppm CO. 

Following CO poisoning, myeloperoxidase activity, a measure of 

leukocyte sequestration, was increased in brain microvessels. 

This response was blocked by NOS inhibition but not by platelet 

depletion. Similar effects were noted for xanthine oxidase 

activation. 

The authors concluded that perivascular reactions mediated by 

peroxynitrite are key to CO poisoning effects in brain. 

Johnson and Johnson 

(2003, 053611) 

Rat 

Sprague Dawley 

Male 

250-300 g 

0-100 μM CO produced a concentration-dependent, endotheliumdependent vasoconstriction in isolated gracilis muscle arterioles, 

evident at 1 μM CO. Pretreatment with a NOS substrate 

prevented this response, while pretreatment with a NOS inhibitor 

converted this response to a vasodilation. The authors concluded 

that exogenous CO was acting through NOS inhibition. 

January 2010 E-7 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Johnson et al. (2003, 

193868) 

Rat 

Dahl/Rapp salt-resistant 

and salt-sensitive model 

Male 

 High-salt diet increased COHb, BP, and aortic HO-1 protein 

levels in salt-sensitive Dahl rats. Enhanced immunostaining was 

observed for HO-1 but not HO-2 in isolated gracilis muscle 

arterioles. Compared with the low-salt diet, the high-salt diet 

resulted in a smaller vasoconstrictor response when NOS was 

inhibited. Vasoconstriction was exacerbated in arterioles from 

both low-salt- and high-salt-treated rats using both NOS and HO 

inhibitors. Acetylcholine-induced vasodilation was diminished in 

the high-salt diet group compared with the low-salt diet group. 

This effect was not seen using the HO inhibitor. The high-salt diet 

did not alter endothelium-independent vasodilation. The authors 

concluded that HO-derived CO caused dysfunction of the NO•

system in salt-sensitive rats treated with a high-salt diet. 

Johnson et al. (2004, 

193870) 

Rat 

Sprague Dawley 

Male 

Deoxycorticosterone 

acetate (DOCA)-salt 

hypertension model 

Rats

WKY 

Rats 

Spontaneously 

hypertensive (SHR) 

 Salt-sensitive DOCA rats, but not SHR, had elevated aortic HO-1 

expression and blood COHb levels. Both had elevated mean 

arterial BP compared with controls. Acetylcholine-mediated 

vasodilation of isolated gracilis muscle arterioles was attenuated 

in DOCA rats but not SHR. Pretreatment with an HO inhibitor 

restored the response in DOCA rats. The authors concluded that 

HO-1-derived CO contributes to endothelial dysfunction in DOCA 

but not SHR. 

Johnson et al. (2006, 

193874) 

Rat 

Zucker 

Lean and obese 

Male 

 100 μM CO The obese rats had increased CO expiration and mean arterial 

pressure, which was decreased by pretreatment with a HO 

inhibitor. No difference was observed in HO-1 protein between 

lean and obese rats. Acetylcholine- and flow-mediated vasodilation of isolated gracilis muscle arterioles was attenuated in obese 

but not lean rats. Pretreatment with a HO inhibitor restored the 

response in obese rats. Exogenous CO prevented the restoration 

of flow-induced dilation by the HO inhibitor. The authors 

concluded that HO-derived CO contributes to endothelial 

dysfunction in this model of metabolic syndrome. 

Katoue et al. (2005, 

193896) 

Rat 

Wistar 

HO activity in the aorta is significantly increased during 

pregnancy, but aortic AVP-dependent vasoconstriction appears to 

be HO/CO independent. 

Katoue et al. (2006, 

193954) 

Rat 

Wistar 

Pregnancy-induced modulation of calcium mobilization and 

downregulation of Rho-kinase expression contributed to 

attenuated vasopressin-induced contraction of the rat aorta. 

Khan et al. (2006, 

193955) 

Nb overexpressing BDF × 

CD1 mice 

Cerebral and myocardial infarcts were decreased in neuroglobin 

overexpressing mice, decreasing ischemic injury. 

Kim et al. (2005, 

193959) 

Primary rat pulmonary 

artery smooth muscle 

cells 

Rat 

Inbred LEW 

Sprague Dawley 

200-250 g 

 24 h or 

pretreatment for 

1-2 h followed by 

24 h posttreatment 

250 ppm Exposure of cells in culture to 250 ppm CO for 24 h inhibited 

serum-stimulated cell proliferation, increased expression of 

p21Waf1/Cip1, and decreased expression of cyclin A. CO also 

inhibited PDGF-stimulated cell proliferation and reversed the 

inhibitory effect of PDGF on caveolin-1 expression. Genetic 

silencing of caveolin-1 using siRNA, prevented the 

antiproliferative effect of CO. Endogenous CO, derived from HO1 in an overexpression system, was found to upregulate 

caveolin-1 expression. Effects of CO on caveolin-1 were found to 

be mediated by p38 MAPK and cGMP. Experiments in fibroblasts 

deficient in p38 confirmed a role for p38 in CO-mediated 

inhibition of cellular proliferation via effects on p21Waf1/Cip1, 

cyclin A and caveolin-1. Experiments in fibroblasts deficient in 

caveolin-1 confirmed the role of caveolin-1 in the anti-proliferative 

effects of CO. 

In a model of neointimal injuries induced by balloon injuries in 

intact animals, exposure to CO inhibited neointimal formation and 

increased caveolin-1 expression in the intima and media. 

January 2010 E-8 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Kim et al. (2008, 

193961) 

Primary rat hepatocytes 

Primary mouse 

hepatocytes 

Respiration-deficient 

human Hep3B cells 

10-60 min 250 ppm Exposure of cells in culture to 250 CO for 1 h twice a day 

prevented spontaneous hepatocyte death over 6 days in culture. 

CO also decreased caspase-3 activity. Cell death was determined to be partly due to apoptosis. CO also increased ROS as 

measured by dichlorofluorescein fluorescence in rat hepatocytes, 

mouse hepatocytes, and Hep3B cells but not in respirationdeficient Hep3B cells, indicating that ROS were mitochondrial in 

origin. An increase in mitochondrial oxidized glutathione was 

noted in rat hepatocytes treated with CO for 30 min. Increased 

Akt phosphorylation occurred following 10-30 min CO and was 

diminished by treatment with antioxidants. CO was found to 

activate NFκB through a PI3K and oxidant-dependent pathway. 

CO mediated spontaneous cell death was found to be dependent 

on ROS and Akt phosphorylation. The authors concluded that CO 

prevents hepatocyte apoptosis through redox mechanisms, 

leading to cytoprotection. 

Kinobe et al. (2006, 

188447) 

Sheep 

Gravid and nongravid 

sheep and their near-term 

fetuses 

There were no significant differences in hypoxic adult and 

hypoxic fetal sheep when compared to their normoxic controls. 

Knuckles et al. (2008, 

191987) 

Mouse 4 h Diesel emissions: 

350 μg/m3 Diesel exhaust enhanced vasoconstriction in veins but not arteries. It were suggested that this is through the uncoupling of 

eNOS. 

Korres et al. (2007, 

190908) 

Human Transient evoked otoacoustic emissions response and amplitude 

at 4,000 Hz was lower in neonates with prenatal exposure to 

cigarette smoke. There was no dose-dependent change in 

response depending on the amount cigarettes per day that was 

smoked. 

Kreiser et al. (2004, 

193948) 

Human End-tidal CO concentrations were lower in pregnant women with 

gestational hypertension and pre-eclampsia than normotensive 

women. 

Lash et al. (2003, 

193849) 

Human 

Term placental chroionic 

villi from healthy or preeclamptic placentas 

Infarcted areas of placenta had decreased HO expression (in 

pre-eclamptic placenta only). 

Li et al. (2008, 

187003) 

Mouse 

ICR (CD-1) 

Pregnant 

The effect of maternal LPS exposure on fetal liver HO was 

measured. HO-1 was upregulated in fetal livers post-LPS 

exposure, and this HO-1 upregulation was attenuated with the 

spin trap agent PBN, pointing to a ROS-dependent HO-1 

upregulation post-maternal LPS treatment. 

Liu and Fechter (1995, 

076524) 

Guinea pig 

Male 

35 mL/kg (ip) CO increased the compound action potential threshold at high 

frequencies. This could be blocked by inhibition of the glutamate 

receptor. 

Loennechen et al. 

(1999, 011549) 

Rat 

Sprague Dawley 

Female 

220-240g 

1 wk 

1 wk 100 ppm and 

1 wk 200 pm 

100 ppm 

100-200 ppm 

Endothelin-1 expression increased by 53% and 54% in the left 

and right ventricle, respectively, during the 2-wk exposure, and by 

43% and 12% in the left and right ventricle, respectively, during 

the 1-wk exposure. Right ventricular to body weight ratio was 

increased by 18% and 16% in the 2-wk and 1-wk exposure 

groups, respectively. COHb levels were 23% and 12% in the 

2-wk and 1-wk exposure groups, respectively. 

Longo et al. (1999, 

011548) 

Rat uterine tissue and tail 

artery rings 

Sprague Dawley 

Human uterine biopsies 

10-4 M The addition of exogenous CO to isolated human and rat uterine 

tissue failed to induce relaxation of uterine tissue. Isolated rat 

aortic rings and tail artery rings from pregnant dams can be 

relaxed by submersion in exogenous CO solutions. 

January 2010 E-9 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Lopez et al. (2008, 

097343) 

Rat 

Sprague Dawley 

Pregnant rats 

exposed to CO 

GD5-GD20 

(Group A) or 

GD5-GD20 plus 

PND5-PND20 

(Group B); 

Group C (control 

air exposure). 

10-18 h/day 

25 ppm CO exposure induced damage to the spiral ganglia neurons and 

inner hair cells, with oxidative stress seen in cochlear blood 

vessels. At PND20 groups A and B showed vacuolization of 

afferent terminals at the base of the cochlea. At PND3, group A 

showed decreased synapsin-1 staining of the efferent nerve 

terminals. At PND20, groups A and B showed decreased 

neurofilament-IR (staining) in type I spiral ganglia neurons and 

afferent nerve fibers. At PND12 and PND20, group B showed increased HO-1 and SOD-1-IR in blood vessels of the stria 

vasularis; group A was similar to controls. From PND3-PND20, 

there was increased iNOS and increased nitrotyrosine-IR in 

blood vessels of the cochlea. 

Lopez et al. (2003, 

193901) 

Rat 

Sprague Dawley 

PND6 to weaning 

(PND19-PND20) 

12 or 25 ppm In the cochlea, atrophy or vacuolization of the nerve cells that 

innervate the inner (not outer) hair cells was seen. Fibers of the 

8th cranial nerve (internal auditory canal of the ARCO animals, 

25 ppm) had distorted myelination and vacuolization of the 

axoplasm. In the organ of corti and spiral ganglion neurons, 

cytochrome c oxidase and NADH-TR were significantly 

decreased in 25 ppm exposure group vs control. Expression of 

the calcium-mediated myosin ATPase in the organ of corti and 

spiral ganglion neurons was significantly decreased in the 

25 ppm CO exposure group vs controls. 

Lund et al. (2007, 

125741) 

Mouse 

ApoE-/-

Male 

High-fat diet 

6 h/day, 7days/wk, 

7 wk 

8, 40, or 60 μg/m3

 PM 

whole-gasoline exhaust; 

or filtered exhaust with 

gases matching the 60 

μg/m3

 concentration. CO 

concentrations were 9, 

50, and 80 ppm, 

corresponding to the 8, 

40, and 60 μg/m3

 PM 

whole-exhaust exposures

Both whole-gasoline and filtered-gasoline exhaust increased 

aortic mRNA expression of matrix metalloproteinase-3 (MMP-3), 

MMP-7, and MMP-9, tissue inhibitor of metalloproteinases-2, 

endothelin-1 and HO-1 at 60 μg/m3

. Aortas also showed 

increased immunostaining for MMP-9 and nitrotyrosine in 60 

μg/m3 PM whole exhaust and PM-filtered exhaust exposed 

groups. Aortic TBARS, a measure of lipid peroxidation, was also 

increased in all treatment groups. 

Lund et al. (2009, 

180257) 

Mouse 

ApoE-/-

Male 

High-fat diet 

6 h/day, 1 or 

7 days 

Gasoline engine exhaust 

containing 60 μg/m3

 PM 

and 80 ppm CO 

Gasoline exhaust exposure increased aortic MMP-2/9 activity at 

1 and 7 days. Protein levels of aortic MMP-9, MMP-2, TMP-2 and 

plasma MMP-9 were also increased after 7 days. Lipid 

peroxidation in aorta, resulting from gasoline exhaust exposure, 

was inhibited by treatment with the antioxidant Tempol, while 

increases in mRNA for ET-1 and MMP-9 in aortas were inhibited 

by treatment with BQ-123, an antagonist of ETA receptor. 

Treatment with BQ-123 also reduced aortic MMP-2/9 activity in 

aortas following gasoline exhaust exposure. The authors 

concluded that ETA receptor pathway is a key mediator of 

gasoline engine exhaust effects in the vasculature. 

Lyall and Myatt (2002, 

193971) 

Human Women with pre-eclampsia produced term placenta with 

significant decreases in HO-2 vs women with healthy 

pregnancies. 

Lyall et al. (2000, 

193902) 

Human 

(placentas from 8-to19- 

wk pregnancy and term 

placentas) 

The use of a HO inhibitor ZnPP increased placental perfusion 

pressure. HO-1 and HO-2 were expressed in the placenta and 

placental bed and vary in expression over the course of 

pregnancy. HO may thus be involved in trophoblast invasion, 

placental function, and perfusion pressure. 

Mactutus and Fechter 

(1984, 011355) 

Rat 

Long Evans 

Continuous 

exposure 

to CO over 

gestation 

150 ppm Acquisition as measured in a two-way conditioned avoidance 

(flashing light warnings followed by mild footshock) test failed to 

improve with age of in utero CO-exposed (150 ppm, dam COHb 

15%) 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. The authors also found 

impairments in reacquisition performance, an index of retention, 

in PND31 rats that had received continuous in utero CO 

exposure. Prenatal CO exposure induced learning and memory 

deficits in male and female offspring. 

McGregor et al. (1998, 

085342) 

Guinea pig GD23-GD25 until 

term 

(approximately 

68 days) 

10 h/day 

200 ppm Aberrant respiratory responses (to asphyxia and CO2) of 

offspring with prenatal CO exposure. The authors hypothesized 

that this may be related to changes in the brainstem. COHb was 

measuerd in maternal (8.53 ± 0.6% vs 0.25 ± 0.1%) and fetal 

blood (13.0 ± 0.4% vs 1.6 ± 0.1%) from CO-treated vs controls. 

January 2010 E-10 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

McLaughlin et al. 

(2001, 193823) 

Human placenta Various pathologies of pregnancy including IUGR and preeclampsia are associated with significant decreases in placental 

HO activity. The endogenous generation of CO in the placenta 

has been demonstrated in chroionic villi of term placenta. 

McLaughlin et al. 

(2000, 015815) 

Human placenta Placental regional localization of HO was explored. The chorionic 

plate, chorionic villi, basal plate, and choorio-decidua had 

significantly higher HO activity than the amnion. 

McLaughlin et al. 

(2003, 193827) 

Human placenta HO expression in various regions of term placentas was 

explored. Microsomal HO-2 protein content was not different 

between normotensive and milk pre-eclamptic pregnancies. 

There was increased expression of microsomal HO-1 protein in 

chorionic villi and fetal membranes from pre-eclamptic 

pregnancies vs normotensive pregnancies. 

McLean et al. (2000, 

016269) 

Human placenta HO activity was highest in the placenta near term. 

Melin et al. (2002, 

037502) 

Rat 

Dark Agouti 

Male 

Model of right ventricle 

hypertrophy secondary to 

chronic hypoxia (HH 

10 wk) 

10 wk 50 ppm alone 

or concomitant with HH 

Hb and hematocrit levels were increased above controls in HH 

rats, CO rats and HH+CO rats, with the increase due to the 

combined treatment significantly higher than the increase due to 

HH. COHb levels were 1.1% in controls, 1.3% in HH rats, 4.7% in 

CO rats and 9.1% in HH plus CO rats. HH treatment significantly 

increased right ventricular (RV) heart weight above controls while 

CO treatment had no effect on any postmortem heart weights. 

Combined treatment with HH+CO resulted in a significant 

increase in left ventricular plus septum (LV+S) weight and RV 

weight compared with HH treatment alone. Echocardiographic 

left ventricular morphology and mass also showed the greatest 

changes in the HH+CO group. Hemodynamic measurements of 

LV function demonstrated significant effects in the HH+CO group 

for left ventricular end diastolic pressure (LVESP), left ventricular 

maximal first derived pressure (+dP/dtLV), and left ventricular 

work (LVW) compared with controls. Hemodynamic 

measurements of RV function demonstrated significant effects in 

the HH group for right ventricular end systolic and diastolic 

pressure (RVESP, RVEDP), right ventricular maximal and 

minimal first derived pressure (+dP/dtRV, -dP/dtRV) and right 

ventricular work (RVW). CO significantly enhanced the effects of 

HH on RVEDP and significantly diminished the effects of HH on 

dP/dtRV and RVW. The authors concluded that CO intensified 

the HH-induce RV hypertrophy, increased LV weight, and 

induced severe hematological responses that could hamper 

adaptation. 

Melin et al. (2005, 

193833) 

Rat 

Dark Agouti 

Male and female 

Model of right ventricle 

hypertrophy secondary to 

chronic hypoxia (HH, 

10 wk) 

Half of the animals were 

exercise trained to induce 

LV hypertrophy 

10 wk 50 ppm alone 

or concomitant with HH 

In untrained animals, combined treatment with HH+CO led to 

increased LV+S and RV weights compared with HH treatment 

alone. HH+CO led to several changes in measured 

echocardiographic parameters, including increased anterior and 

posterior wall thickness in diastole (AWTd, PWTd), and to 

increased fraction of shortening. These effects were not seen 

with HH alone. In addition, RVEDP was enhanced in HH+CO 

compared with HH alone. HRV components were altered by 

HH+CO but not by CO alone. 

Mereu et al (2000, 

193838) 

Rat 

Wistar 

GD0-GD20 

continuous CO 

exposure 

150 ppm In utero exposure to CO disrupted hippocampal LTP with 

concomitant HO-2 and nNOS reductions. The authors surmised 

that these changes may be related to the memory deficits seen in 

animals exposed to CO in utero. 

Middendorff et al. 

(2000, 015842) 

Human 

Adult males aged 65-75 yr 

Testicular tissue from 

orchiectomy 

Zn protoporphryin (ZnPP) and Hb both significantly reduced 

seminiferous tubular cGMP generation, suggesting a role for CO 

in human testicular tissue. 

Montagnani et al. 

(1996, 080902) 

Rat 

Wistar 

Male pups 

GD0-GD20 75 or 150 ppm CO caused an increase in tetrodotoxin-induced inhibition of 

perivascular nerve stimulation PNS-evoked vasoconstriction, 

increased the time to NO-related relaxant effect by ACh, and 

decreased the contractile response evoked by ACh on resting 

tone. 

January 2010 E-11 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Naik and Walker 

(2003, 193852) 

Rat 

Sprague Dawley 

Male 

210 μL of CO/100 mL 

of physiological 

saline solution 

Endogenous CO-mediated vasorelaxation involved cGMPindependent activation of vascular smooth muscle large-conductance Ca2+-activated K+

 channels. However, exogenous CO 

vasodilation was cGMP dependent. 

Ndisang et al. (2004, 

180425) 

Review of CO and hypertension. CO is a vasorelaxant due to 

activation of the big conductance calcium-activated potassium 

channels and soluble guanylate cyclase/cGMP pathway. 

Developmental stage and tissue type will determine which of 

these pathways plays more of a role in vasorelaxation. 

Neggers and Singh 

(2006, 193964) 

Mouse 

CD-1 

GD8-GD18 500 ppm Developmental toxicitiy of CO was attenuated by protein 

supplementation, i.e., protein supplemented animals (27%) 

showed a significantly lower incidence of fetal mortality vs 8% 

and 16% protein groups. Further, dietary restriction of both 

protein and zinc with CO exposure to during gestation increased 

the incidence of pup mortality and malformations including 

gastroschisis. Zinc supplementation to a protein-deficient diet in 

CO-exposed mice decreased fetal mortality and malformation. 

Newby et al. (2005, 

193966) 

Human 

placental cells 

in culture 

Term human placental cells were grown in cell culture under 

basal and hypoxic conditions to explore changes in HO 

expression. HO-1 was unchanged in cytotrophoblasts under 

hypoxia, but HO-1 was significantly decreased in hypoxic 

syncytiotrophoblasts. HO-2 was unchanged in either cell type 

with hypoxia. These cell culture data can give insight into what 

cell types might be responsive to hypoxia through the HO/CO 

system in the human placenta. 

Odrcich et al. (1998, 

193958) 

Guinea pig Immunohistochemical localization of HO in guinea pig placentae 

showed that HO-1 staining was highest near term (PND62) and 

lesser at term or earlier in pregnancy. HO-1 was localized in the 

advential layer of fetal blood vessels. 

Ozawa et al. (2002, 

193841) 

Rat 

Wistar 

Adult male 

The role of HO-1 in spermatogenesis was explored. CdCl2 

induced testicular HO-1 and reduced HO-2 protein in rats. 

Pretreatment with ZnPPIX attenuated CdCl2-dependent 

apoptosis. Leydig cells use HO-1-derived CO to trigger apoptosis 

of pre-meiotic germ cells and modulate spermatogenesis under 

CdCl2 dependent oxidative stress. 

Patel et al. (2003, 

043155) 

Rat 

Sprague Dawley 

Male 

262 ± 30 g 

Isolated hearts 

30 min Buffer saturated with 

0.01 and 0.05% CO 

The ventricular glutathione content, both reduced and oxidized, 

decreased by 76% and 84% 90 min post-exposure to 0.01% and 

0.05% CO, respectively. Treatment with antioxidants partially 

blocked the decreases in glutathione. Increased creatine kinase 

activity was observed in heart perfusate during and after 

treatment. 

Penney et al. (1983, 

011385) 

Rat 

(strain not reported) 

GD17-GD22 157, 166 or 200 ppm In utero CO exposure induced decreased fetal body weight, 

decreased placental weight, increased wet heart weight at birth, 

and altered cardiac enzymes at birth. 

Penney et al. (1982, 

011387) 

Rat 

COBS 

GD0-GD32 350 ppm PND1-PND3, 

then 425 ppm PND4-

PND7, then 500 ppm 

PND8-PND32 

Postnatal CO exposure decreased body weight, to a greater 

extent in male pups. The heart to body weight ratio and left 

ventricle plus interventricular septum and right ventricle weight 

increased after birth in CO exposed pups. This persistent 

cardiomegaly was not explained by increasing in DNA or 

hydroxyproline. 

Piantadosi (2002, 

037463) 

Reviews the biochemical activities of CO, including various heme 

protein binding. The review stresses the importance of the CO/O2

ratio in determining the physiological effects of CO. 

Piantadosi (2008, 

180423) 

Reviews the physiologic responses to exogenous and 

endogenous CO and biochemical effects, including the binding to 

heme proteins, the generation of reactive O2 species, and 

activation-related signaling pathways. 

January 2010 E-12 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Piantadosi et al. 

(2006, 180424) 

Rat 

Sprague Dawley 

Adult male 

1, 3, or 7 days 50 ppm or HH COHb produced COHb levels of 4-5% (controls approximately 

1%) and liver CO concentration of 30-40 pmol/mg wet weight 

(controls approximately 10 pmol/mg wet weight). Both CO and 

HH led to increased expression of hypoxia-sensitive proteins 

HO-1 and HIF-1α and mitochondrial antioxidant protein SOD-2. 

CO caused a greater change in mitochondrial GSH/GSSG than 

HH. Only CO increased mitochondrial 3-nitrotyrosine and protein 

mixed disulfides. Mitochondria isolated from CO-exposed rats, 

but not from HH-exposed rats, showed an increase in the calcium 

sensitivity of the mitochondrial permeability transition (MPT). 

Exposure to CO or HH resulted in a loss of the ability of adenine 

nucleotides to protect mitochondria from MPT. This effect was 

restored in the presence of a strong reductant. The authors 

concluded that CO caused mitochondrial pore stress 

independently of its hypoxic effects 

Prigge and Hochrainer 

(1977, 012326) 

Rat 

Wistar, SPF 

GD0-GD20 60, 100, 250, 500 ppm Fetuses were collected by C-section after 21-days exposure. 

Significant increases in fetal heart weight were seen in fetuses 

exposed to CO in all dose groups. Fetal body weight was significantly decreased (NOAEL 125 ppm CO). 

(Raub and Benignus, 

2002, 041616) 

Reviews the physiology of CO and the effects on the nervous 

system. It is estimated that COHb would have to rise to 15-20% 

before a 10% reduction in any behavioral or visual measurement 

could be observed. 

Richardson et al. 

(2002, 037513) 

Human 

Male 

20% COHb 20% COHb did not influence O2Mb binding indicated by unaltered 

deoxy-myoglobin signal. Resting skeletal muscle metabolic rate 

was unaffected by 20% COHb. VO2 max was decreased. No 

decrement in intracellular PO2 was found. 20% COHb altered 

exercising bioenergetics, pH, PCr, and ATP levels. 

Ryter et al. (2006, 

193765) 

Reviews the basic science of exogenous and endogenous CO 

including HO-1 regulation. It also reviews some therapeutic 

applications for CO. 

Sartiani et al. (2004, 

190898) 

Rat 

Wistar 

In utero inhalation

exposure 

150 ppm At 4 wk of age, the action potential duration APD of isolated 

cardiac myocytes from CO-exposed animals failed to shorten or 

mature as did the APD of control animals. 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 CO 

exposure at 4 wk of age. All of these CO-dependent changes 

were no longer different from controls at 8 wk of age, showing a 

delayed maturation. 

Schwetz et al. (1979, 

011855) 

Mouse 

CF-1 

Rabbit 

New Zealand 

7 or 24-h/day 

GD6-GD15 (Mice)

GD6-GD18 

(Rabbits) 

250 ppm In mice there was a significant increase in number of skeletal 

abnormalities in CO-exposed mice. Decreased birth weight in 

mice exposed to 24 h/day CO vs control. Increased birth weight 

in mice exposed to 7 h/day CO vs controls. No similar effects 

were seen in rabbits. 

Singh et al. (1992, 

013759) 

Mouse 

CD-1 

GD8-GD18 65, 125, or 250 ppm CO exposure concomitant with a low-protein diet exacerbated 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 offspring survival and an additive effect on 

malformations. 

Singh (2006, 190512) Mouse 

CD-1 

6 h/day during 

the first 

2nd wk 

of pregnancy 

65 or 125 ppm Modulating dam protein intake during in utero CO exposure 

altered pup mortality. 

Singh et al. (1993, 

013892) 

Mouse 

Albino CD-1 

GD8-GD18 65, 125, 250, or 500 ppm Mice were given various protein diets (4, 8, 16, or 27% protein) 

during pregnancy, along with CO exposure. All concentrations of 

CO exposure within each maternal dietary protein level 

significantly increased the percentage of litters with 

malformations in a dose-dependent manner. CO exposure 

concomitant with a low protein diet exacerbated 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. 

January 2010 E-13 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Singh (2003, 053624) Mouse 

Albino CD-1 

GD8-GD18 500 ppm CO decreased the mean implants per litter and increased the 

incidence of fetal mortality. Under low protein conditions, CO 

exposure increased the incidence of malformations (9.4% vs 0%) 

when Zn levels were normal and increased the incidence of 

gastroschisis (5% vs 0%) when Zn levels were low. 

Singh and Scott 

(1984, 011409) 

Mouse 

Albino CD-1 

GD7-GD18 65, 125, 250, or 500 ppm All concentration of CO decreased fetal weight in mouse pups. 

Near-term fetal body weight was decreased at GD18 in mice 

exposed from GD7-GD18 to 125, 250, and 500 ppm CO but not 

at 65 ppm CO. 

Singh (1986, 012827) Mouse 

Albino CD-1 

GD7-GD18 65 or 125 ppm Impaired aerial righting score at PND14 (65 and 125 ppm), 

impaired negative geotaxis at PND10 and righting reflex on 

PND1 (125 ppm) 

Sitdikova et al. (2007, 

180417) 

Frog neuro-muscular 

junctions 

20 min 96 μM CO-induced acetylcholine release, without effects on the presynaptic action potential or functional properties of post-synaptic 

receptors in frog neuro-muscular preparations. 

Song et al. (2002, 

037531) 

Human 

Primary human airway 

smooth muscle cells 

0-48 h 10-250 ppm CO inhibited SMC proliferation at concentrations from 

50-500 ppm. The cell cycle arrest occurred at the G0/G1 phase 

of the cell cycle. CO increased expression of the cell cycle 

inhibitor p21Cip1 at 1 h and decreased expression of cyclin D1 

over 24-48 h. The antiproliferative actions of CO were found to be 

independent of sGC, but instead exerted through the inhibition of 

ERK MAPK activation since 15 min exposure to 250 ppm CO 

blocked serum-mediated ERK phosphorylation. 

Sorhaug et al. (2006, 

180414) 

Rat 

Wistar 

Female 

169 ± 4.5 g 

20 h/day, 

x 5 days/wk, 

x 72 wk 

200 ppm COHb was 14.7% in CO-exposed animals and 0.3% in controls. 

Total Hb was also increased in following CO exposure. CO 

caused no changes in lung morphology or pulmonary 

hypertenstion. No atherosclerotic lesions were found in aorta or 

femoral artery. Weight increases of 20% and 14% were observed 

in the right ventricle and left ventricle plus septum, respectively, 

indicative of ventricular hypertrophy following chronic CO 

exposure. 

Stevens and Wang 

(1993, 188458) 

Mouse 

C57/Bl-6J 

Rat 

Sprague Dawley 

Hippocampal brain slices 

HO inhibition blocked long-term potentiation but not long-term 

depression. 

Stockard-Sullivan et 

al. (2003, 190947) 

Rat 

Sprague Dawley 

22 h/day, 

PND6-PND22 

12, 25, 50, or 100 ppm Using functional OAE testing and ABR showed that with perinatal 

CO exposure (50 and 100 ppm CO) there were significant 

decrements in OAE in CO-exposed animals. ABR showed no 

functional deficits with CO exposure. Using another otoacoustic 

test revealed significant attenuation of the AP of the 8th cranial 

nerve with CO exposure (12, 25, and 50 ppm CO) vs controls at 

PND22. 

Storm and Fechter 

(1985, 011653) 

Rat 

Long Evans 

GD0-parturition 150 ppm Prenatal CO exposure increased mean and total cerebellar 

norepinephrine concentration from PND14-PND42 but not in the 

cortex. 

Storm and Fechter 

(1985, 011652) 

Rat 

Long Evans 

GD0-GD20 75, 150, and 300 ppm CO transiently decreased 5HT and NE in the pons/medulla and 

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) 

Rat 

Long Evans 

GD0-PND10 

75, 150, and 300 ppm 

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- exposed (300 ppm) 

cerebella had fewer fissures. 

Styka and Penney 

(1978, 011166) 

Rat 

Charles River 

Male 

6 wk 400 ppm or gradual 

increase from 500 to 

1,100 ppm 

CO caused increased heart weight to body weight that regressed 

within a couple of mo after CO exposure. COHb: 400 ppm – 35%; 

1,100 ppm – 58% 

January 2010 E-14 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Suliman et al. (2007, 

193768) 

Mouse 

C57BL/6 

Wild-type and eNOS 

deficient 

Male 

Rat 

Embryonic 

cardiomyocytes H9c2 

cells 

1 h 50-1,250 ppm 

Or HH 

Or 100 mM 

dichloromethane 

One-h exposure of mice to 1,250 ppm CO increased cardiac 

mitochondrial content of all 5 respiratory complexes 24 h later. 

The volume density of interfibrillar mitochondria was increased by 

30% after 24 h demonstrating that CO caused cardiac 

mitochondrial biogenesis. The CO concentration in heart 

increased from 9 pmol/mg to 50-150 pmol/mg in mice exposed to 

50-1,250 ppm CO for 1 h. These levels declined to baseline by 

6 h. Peroxisome proliferator-activated receptor gamma 

coactivator 1 alpha (PGC-1α) expression was increased 6 h 

following exposure to 50-1,250 ppm CO. Expression of DNA 

polymerase and mitochondrial transcription factor A (TFAM) was 

increased 6 and 24 h after exposure, while mitochondrial DNA 

was increased two- to threefold 24 h after exposure. CO 

activated gene expression of these proteins involved in cardiac 

mitochondrial biogenesis beginning at 2 h postexposure for PGC1α, nuclear respiratory factors 1 and 2 (NRF-1 and -2) and at 6 h 

postexposure for TFAM. These effects were independent of NOS 

and not seen with HH. CO exposure resulted in phosphorylation 

of p38 MAPK and Akt at 2 and 6 h postexposure to 1,250 ppm 

CO for 1 h. Inhibition of p38 activation failed to inhibit the 

CO-mediated increase in cardiac mitochondrial biogenesis. 

In cell culture experiments, CO derived from dichloromethane 

metabolism resulted in increased cGMP, protein levels of SOD2, 

TFAM, NRF-1, NRF-2, PGC-1,mitochondrial ROS, Akt 

phosphorylation, and mitochondrial DNA. Inhibition of GC or 

PI3K/Akt but not p38 blocked the responses to CO. A role for 

mitochondrial H2O2 in Akt regulation was demonstrated. 

Mitochondrial H2O2 and the PI3K/Akt pathway were important 

mediators of TFAM expression. 

The authors concluded that CO exposure increased 

mitochondrial ROS, which promoted mitochondrial biogenesis in 

the heart. 

Sun et al. (2001, 

026022) 

Mouse 

Neuronal cultures 

prepared from the 

cerebral hemispheres of 

16-day Charles River CD1 

mouse embryos 

Nb expression was increased by neuronal hypoxia in vitro and 

focal cerebral ischemia in vivo. Inhibiting Nb reduced neuronal 

survival after hypoxia whereas Nb overexpression enhanced 

neuronal survival. 

Tattoli et al. (1999, 

011557) 

Rat 

Wistar 

Male and pregnant female 

PND1-PND10 75 and 150 ppm Cognitive function was assessed in rats after postnatal CO 

exposure at 3 and 18 mo of age. Postnatal CO exposure did not 

affect the acquisition and reacquisition of an active avoidance 

task. This is different from previous findings by the same 

laboratory, indicating that in utero exposure to CO (75 and 

150 ppm) induced long-lasting learning and memory deficits. 

Telfer et al. (2001, 

193769) 

Human 

Myometrium tissue 

obtained from gravid (preterm [25- to 34 wk 

gestation], term not in 

labor or term in labor) and 

non-gravid women 

cGMP was monitored in various myometrial tissues. cGMP was 

significantly higher than that from nonpregnant tissue and 

decreased at term, especially in tissue from laboring women. 

Teran et al. (2005, 

193770) 

Rat 

Dahl/Rapp 

salt-sensitive rats 

Male 

 100 μM A high-salt diet for 1-4 wk resulted in increased aortic HO-1 

protein expression, an increase in mean arterial pressure, and 

time-dependent inhibition of flow- and acetylcholine-mediated 

vasodilation in isolated gracilis muscle arterioles. A smaller 

degree of inhibition of acetylcholine-mediated vasodilation was 

observed with a low-salt diet for 1-4 wk. Pretreatment with a HO 

inhibitor restored these responses, but this effect was reversed in 

the presence of exogenous CO. Mean arterial pressure was 

decreased in intact animals fed a high-salt diet for 4 wk and then 

treated with a HO inhibitor. The authors concluded that the HOderived CO contributed to the development of hypertension and 

the impairment of endothelium-dependent vasodilator responses 

in this model. 

January 2010 E-15 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Thom et al. (1994, 

076459) 

Rat 

Wistar 

Male 

Isolated blood cells 

1 h 

Or 

>1 h 

30 min 

1,000 ppm 

Or 

1,000-3,000 and 

higher ppm 

0.5 mL of pure CO 

CO poisoning inhibited B2 integrin-dependent PMN adherence in 

heparinized blood obtained from rats immediately after exposure. 

Adherence was restored when platelet number was decreased. 

Adherence was also decreased when PMN from control animals 

were incubated with platelets from poisoned animals. Adherence 

of activated PMN was reduced in the presence of SOD and 

enhanced by NOS inhibition. Platelet production of NO was 

significantly greater while platelet NOS activity was significantly 

inhibited after poisoning. 

When whole blood or platelet-rich plasma was incubated with 

CO, PMN adherence was inhibited. 

The authors concluded that PMN B2 integrin activity was inhibited 

by CO-dependent release of NO from the platelets into the blood. 

Thom and 

Ischiropoulos (1997, 

085644) 

Ra 

Wistar 

Male 

200-290 g 

Platelet-rich plasma from 

rats was used as the 

source of platelets 

Bovine pulmonary artery 

endothelial cells 

1 h 

30 min or 2 h 

1 h 

20-1,000 ppm 

10-20 ppm 

10-100 ppm 

Platelets isolated from rats exposed to 20-1,000 ppm CO for 1-h 

released NO in a dose-dependent manner. COHb levels were 

0.7% in controls and 3.2%, 7.8% and 51.0% in 20, 100 and 

1,000 ppm exposure groups, respectively. 

Isolated platelets released NO when incubated for 30 min with 

20-100 ppm CO. NOS activity was not enhanced by 100 ppm 

CO. Platelets released NO in response to 10-100 ppm CO after 

30-min pretreatment with a NOS inhibitor, suggesting that CO 

displaces NO from heme-binding sites. Longer incubations (2 h) 

with the NOS inhibitor led to a diminished response to 100 ppm 

CO. There appears to be a discrepancy in the results, depending 

on howNOwas measured (electrode vs Greiss reaction). 

Endothelial cells released NO in response to 20-100 ppm CO. 

NOS inhibition blocked the response to 100 ppm CO. CO was 

found not to affect arginine transport or NOS activity in 

endothelial cells. Exposure to 40-100 ppm CO resulted in the 

release of short-lived oxidants. This response was blocked by 

NOS inhibition. Lysates from cells exposed to 50 and 100 ppm 

CO had increased nitrotyrosine content. This response was 

blocked by NOS inhibition. Cellular reduced sulfhydryls were not 

decreased by 100 ppm CO. Dihydrorhodamine 123 oxidation, a 

measure of peroxynitrite formation, was increased by exposure to 

100 ppm CO. This effect was blocked by NOS inhibition. 

Cytotoxicity of CO was evaluated by the release of 51chromium. 

Cytotoxicity was evident 4 h following a 2-h incubation with 

100 ppm CO but not immediately after exposure. This response 

was not blocked by NOS inhibition, although NOS inhibition had 

protective effects under conditions of continuous CO exposure of 

4 h. Exposure to 20 and 100 ppm CO for 2 h led to the loss of 

membrane integrity (measured by ethidium homodimer-1 

staining) 18 h later. 

Results demonstrate that 10-20 ppm CO released NO from 

platelets and endothelial cells in vitro. Platelets from rats that inhaled 20 ppm CO also released NO in vitro. The authors 

suggested that CO-mediated NO release from platelets and 

endothelial cells resulted from disrupted intracellular scavenging 

for NO. They also suggested that peroxynitrite may have been 

generated in response to CO. 

January 2010 E-16 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Thom et al. (1997, 

084337) 

Bovine pulmonary artery 

endothelial cells 

30 min-4 h 10-100 ppm (11-110 nM) One-h exposure to 111-110 nM CO led to a dose-dependent 

increase in NO release, as measured by nitrite+nitrate. Significance was achieved at 22 nM (corresponding to an interstitial 

partial pressure of 20 ppm and a blood COHb level of 7%). NOS 

inhibition blocked the response to 110 nM CO. A dosedependent increase in cellular nitrotyrosine was also observed 

following a 2-h exposure to CO, with significance achieved at 

55 nM CO. NOS inhibition blocked the response to 110 nM. CO 

exposure failed to decrease the concentration of reduced 

sulfhydryls but did result in the extracellular release of a shortlived oxidant species, which was blocked by NOS inhibition. 

Dihydrorhodamine oxidation, a measure of peroxynitrite 

formation, occurred in response to 110 nM CO, an effect which 

was blocked by NOS inhibition. Cytotoxicity of CO was evaluated 

by the release of 51chromium. Cytotoxicity was evident 4 h 

following a 2-h incubation with 110 nM CO but not immediately 

after exposure. This response was not blocked by NOS inhibition, 

although NOS inhibition had protective effects under conditions of 

continuous CO exposure of 4 h. Exposure to 110 nM CO for 2 h 

led to the loss of membrane integrity ( measured by ethidium 

homodimer-1 staining) 18 h later. This response was blocked by 

NOS inhibition. Exposure to 110 nM CO had no effect on O2 consumption, production of intracellular H2O2 or cellular redox 

activity. Exposure to 110 nM did not alter arginine transport or 

NOS activity. NO release from cells which had been pretreated 

with a NOS inhibitor and then exposed briefly to 5% CO was 

measured using a NO-selective electrode, suggesting that CO 

competed with intracellular binding sites of NO. 

The authors concluded that endothelial cells release NO and NOderived oxidants in response to CO. A delayed cell death 

occurred following exposures to 22 nM and higher concentrations 

of CO. 

Thom et al. (1999, 

016753) 

Rat 

Wistar 

Male 

200-290 g 

Some rats were fed a high 

cholesterol diet 

1 h 50-1,000 ppm Nitrotyrosine immunoreactivity was found in aortic intima in rats 

exposed to CO for 1 h but not in controls. Nitrotyrosine content 

was quantitated and found to be increased in a dose-dependent 

manner following 1-h exposure to 50-1,000 ppm CO. The effect 

was significant at 50 ppm but the COHb content measured 

immediately after exposure was not different than controls. Platelet and neutrophil depletion did not alter nitrotyrosine content 

following CO exposure. Leukocyte adherence to the aorta 

occurred 18 h but not immediately after a 1-h exposure to 

100 ppm CO. This effect was blocked by NOS inhibition. The 

influx of albumin from the microvasculature into skeletal muscle 

increased during the 3 h after exposure to 100 ppm CO but was 

not seen 18 h later. This effect was blocked by NOS inhibition. 

Rats fed a high-cholesterol diet and exposed to 100 ppm CO for 

1 h had increased aortic nitrotyrosine content, which was not 

different than that in CO-exposed rats fed the standard diet. 

However, rats on the high-cholesterol diet had a six-fold increase 

in LDL oxidation immediately after 1-h exposure to 100 ppm CO. 

This effect was not blocked by NOS inhibition. 

The authors concluded that CO can alter vascular status by 

several mechanisms linked to NO-derived oxidants. 

January 2010 E-17 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Thom et al. (1999, 

016757) 

Rat 

Wistar 

Male 

200-290 g 

 1 h 50-1,000 ppm Leakage of albumin into lung parenchyma occurred 18 h after 

rats were exposed to 100 ppm CO for 1 h. This response was not 

observed at earlier timepoints following CO exposure. This 

response was also observed using 50 and 1,000 ppm but not 

20 ppm CO. Leakage resolved by 48 h. Furthermore, no leakage 

occurred when rats which were exposed to 100 ppm CO were 

pretreated with a NOS inhibitor. COHb levels were 0.9% in 

controls and 4.8%, 10.6% and 53.7% following 1-h exposure to 

50, 100 and 1,000 ppm CO, respectively. Elevated free NO 

(determined by EPR) was observed in lungs of rats exposed to 

100 ppm CO for 1 h. This effect was blocked when rats were 

pretreated with a NOS inhibitor. Lung H2O2 was elevated by 

exposure to 100 ppm CO for 1 h, and this effect was blocked 

when rats were pretreated with a NOS inhibitor. Elevated 

nitrotyrosine content was observed in lung homogenates 2-4 h 

following 1-h exposure of rats to 100 ppm CO. This effect was 

also blocked by pretreatment with a NOS inhibitor. No leukocyte 

sequestration was observed in lungs 18 h following exposure to 

100 ppm CO. CO-induced lung leak was not affected by 

neutrophil depletion. 

The authors concluded that CO causes lung vascular injury 

which is dependent on NO. 

Thom et al. (2000, 

011574) 

Bovine pulmonary artery 

endothelial cells 

40 min-2 h 11-110 nM 

(10-100 ppm) 

Increased uptake of ethidium homodimer-1, a measure of 

decreased membrane integrity and cell death, was observed in 

endothelial cells 18 h after exposure to 110 nM for 60-120 min. 

Exposures of 20-40 nM were ineffective in this regard. Ethidium 

uptake was also increased by 2-h exposure to 88 nM CO. 

Preincubation for 2 h with an inhibitor of eNOS, an antioxidant, 

and an inhibitor of peroxynitrite reactions blocked the 

CO-mediated cell death. Morphological changes in cells were observed 2 h following a 2-h exposure to 110 nM CO. Cell death 

induced by 110 nM CO was also blocked by inhibition of protein 

synthesis and inhibition of caspase-1 but of caspase-3. 

Caspase-1 activity was increased following 2-h exposure to 

110 nM CO; this effect was blocked by inhibiting eNOS. Preexposure of cells to 11 nM CO for 40 min followed by a 3-h 

incubation period resulted in an increased level of MnSOD and 

protection against cell death 18 h following a 2-h exposure to 

110 nM CO. 

The authors concluded that exposure to 11 nM CO led to an 

adaptive response which protected cells from injury and 

apoptosis resulting from NO-derived oxidants. 

Thom et al. (2001, 

193779) 

Rat Until lost 

consciousness 

1,000-3,000 ppm Neutrophils sequestration was observed in the brain vessels of 

rats exposed to high-dose CO. CO also led to increased 

nitrotyrosine formation in the brain vessels. These events were 

blocked by pretreatment with a peroxynitrite scavenger or a PAF 

receptor antagonist. 

Thom et al. (2006, 

098418) 

Human 

Rat 

Wistar 

Male 

Mouse 

C57B6J 

MPO-deficient 

Blood samples and brain 

tissue 

1 h Humans: 

Acute CO poisoning 

Rats and mice: 

1,000-3,000 ppm 

In humans, COHb was 20-30.5%. Increased cell surface 

expression of CD18 and PAC1 was observed in neutrophils from 

people with CO poisoning. Increased surface-bound 

myeloperoxidase (MPO, indicative of neutrophil degranulation), 

increased plasma MPO, and more numerous platelet-neutrophil 

aggregates were also observed. 

Similar changes were observed in blood of CO-poisoned rats. 

Platelet depletion, inhibition of NOS, and inhibition of platelet 

integrin-dependent adhesion blocked these responses. Brains 

from poisoned rats had significant elevations in MPO, which 

could reflect either an increase number of neutrophils or an 

increase in neutrophil degranulation. Perivascular MPO and 

nitrotyrosine were CO-localized in brain. CO poisoning also 

resulted in altered brain myelin basic protein. 

Similar changes were observed in blood of CO-poisoned mice. 

MPO deficiency blocked the CO-mediated alteration in brain 

myelin basic protein. 

The authors concluded that exposure to CO triggers intravascular 

interactions between platelets and neutrophils that lead to 

neutrophil degranulation in experimental animals and people with 

CO poisoning. 

January 2010 E-18 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Thorup et al. (1999, 

193782) 

Rat 

Sprague Dawley 

Male 

200-250 g 

0.01-10 μM Perfusion of isolated rat renal resistance arteries with 

CO-containing buffer (0.001-10 μM) led to the biphasic release of 

NO, peaking at 100 nM and declining to undetectable responses 

at 10 μM. Sequential pulses of 100 nM resulted in a blunting of 

NO release with consecutive pulses, consistent with a depletion 

of intracellular NO stores. NO release was dependent on arginine 

concentrations and was inhibited by pretreatment with a NOS 

inhibitor. Perfusion with 100 nM CO blocked carbacholdependent NO release from vessels. 

Rats were treated with a HO-1 inducer, and renal resistance 

arteries were isolated 12 h later. Carbachol-induced NO release 

was smaller in the HO-1-induced rats compared with controls, 

suggesting that endogenous CO has a similar effect as 100 nM 

exogenous CO. This effect was reversed in the presence of 

excess arginine. 

Vasodilation was measured in blood-perfused afferent arterioles 

perfused with CO in solution. A biphasic vasodilatory response 

was observed as well as a blunted muscarinic vasorelaxation. 

CO (0.1-10 μM) suppressed the release of NO from purified 

recombinant eNOS in solution. 

The authors concluded that low levels of CO may release NO 

and elicit vasorelaxation and modulate basal vascular tone, while 

higher levels of CO may inhibit eNOS and NO generation. 

Tolcos et al. (2000, 

015997) 

Guinea pig 10 h/day over the 

last 60% of 

gestation 

200 ppm Fetal nd maternal COHb were 13% and 8.5%, respectively. 

Neurotransmitter systems were affected after CO exposure. The 

catecholaminergic system of the brainstem displayed significant 

decreases in immunoreactivity for tyrosine hydroxylase (TH), 

which was likely due to decreased cell number in specific 

medullar regions. The cholinergic system was also affected by 

prenatal CO exposure with significant increases in ChAT 

immunoreactivity of the medulla and no changes in muscarinic 

acetylcholine receptor. 

Tolcos et al. (2000, 

010468) 

Guinea pig 10 h/day for the 

last 60% of 

gestation 

200 ppm Brains were collected at 1 and 8 wk of age. These data showed 

that CO exposure in utero sensitized the brain to hyperthermia at 

PND4 leading to generation of necrotic lesions in the brain and 

changes in neurotransmitter levels. 

Toyada et al. (1996, 

079945) 

Tschugguel et al. 

(2001, 193785) 

Human 

HUVEC 

CO was generated by primary endothelial cells from human 

umbilical veins and uterine arteries after exogenous 17-ß estradiol administration. 

Vallone et al. (2004, 

193993) 

Mouse protein The authors presented the X-ray structure of CO-bound ferrous 

murine Nb. When CO binds, the heme group slides deeper into 

the protein crevice. 

Villamor et al. (2000, 

015838) 

Vreman et al. (2000, 

096915) 

Human 

Umbilical cord (artery and 

vein) 

Rat 

Aorta, vena cavae, liver 

and heart 

HO activity was quantified in human umbilical cord and in the rat 

vasculature (aorta and vena cavae). Human umbilical artery and 

vein HO activity were equal. The rat aorta and vena cavae 

produced equal amounts of HO activity (wet weight/g tissue) but 

generated 3 times greater HO than the heart and 0.2 times of the 

liver. HO activity in rat vasculature was 3 times that of the human 

cord tissues. Use of the HO inhibitor CrMP effectively blocked 

HO activity in the rat liver and heart but was less effective at 

blocking HO activity in the human umbilical cord or the rat 

vasculature (only 50% effective). The activity of HO in the 

umbilical vessels may provide a role for CO in control of 

vasculature tone during pregnancy. 

January 2010 E-19 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Vreman et al. (2005, 

193786) 

Mouse 

BALB/c 

30 min 500 ppm 

OR 

Heme arginate 

30 μmol/kg body weight 

i.v. 

Following CO exposure, COHb levels were 28%. Tissue 

concentrations of CO were as follows with control levels in 

parenthesis. 

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 ± 7 (4) pmol/mg 

Testes: 6 ± 3 (2) pmol/mg 

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% 

Injection of heme arginate resulted in a threefold increase in CO 

excretion, reaching a maximum at 60 min. Animals were sacrificed at 90 min. COHb levels were 0.9%. Tissue concentrations 

of CO were as follows with control levels in parenthesis: 

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 

CO concentration relative to 100% blood: 

Heart: 16% 

Spleen: 13% 

Lung: 9% 

Liver: 9% 

Kidney: 8% 

Muscle: 8% 

Intestine: 3% 

Brain: 2% 

Testes: 2% 

Weaver et al. (2007, 

193939) 

Human Acute CO poisoning Mean COHb in humans with acute CO poisoning was 35%. 

Hyperbaric O2 reduces cognitive sequelae in a randomized 

clinical trial of CO-poisoned patients. Risk factors for cognitive 

sequelae without hyperbaric O2 included older age and longer 

CO exposures. Patients with loss of consciousness or high initial 

COHb levels should also be treated with hyperbaric O2. 

Webber et al. (2003, 

190515) 

Rat 

(Strain not stated) 

 PND8-PND22 12.5, 25, or 50 ppm Immunostaining of c-Fos, a marker of neuronal activation in the 

nervous system, was followed. C-Fos immunoreactivity in the 

central IC was significantly decreased in the CO-exposed 

animals at both PND27 and PND75-PND77 over all dose groups 

of CO; immnunostaining of other subregions of the IC were not 

affected by CO. These studies show exposure to CO during 

development can lead to permanent changes in the auditory 

system of rats that persist into adulthood. 

January 2010 E-20 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Webber et al. (2005, 

190514) 

Rat 

(Strain not stated) 

PND9-PND24 25 or 100 ppm Neurofilament loss from the spiral ganglion neurons and somas 

after ARCO treatment was rescued (no detectable neurofilament 

loss) with low iron+CO (ARIDCO); ARID (Iow iron) treatment 

induced no change in neurofilaments. CuZn superoxide 

dismutase (SOD1) was significantly increased with CO exposure 

(ARCO) and rescued in ARIDCO animals; SOD1 was unchanged 

in low-iron-only animals (ARID). Low-iron treatment or CO 

exposure alone led to significant decreases in c-fos positive cell 

numbers of the central IC, but c-fos levels were unchanged after 

low-iron diet concomitant with CO exposure (ARIDCO). 

Wellenius et al. (2004, 

087874) 

Rat 

Sprague Dawley 

250 g 

Diazepam-sedated 

Model of acute MI induced 

by thermocoagulation 

1 h, 12-18 h after 

surgery 

35 ppm CO exposure decreased ventricular premature beat frequency by 

60.4% during the exposure period compared to controls. 1-h 

exposure to CAPs (318 μg/m3

) decreased ventricular premature 

beat frequency in specific subgroups. Neither CAPs nor CO had 

an effect on heart rate. There were no significant interactions 

between their effects when rats were exposed to both CO and 

CAPs. 

Wellenius et al. (2006, 

156152) 

Rat 

Sprague Dawley 

250 g 

Diazepam-sedated 

Model of acute MI induced 

by thermocoagulation 

1 h, 12-18 h after 

surgery 

35 ppm Exposure to CO failed to increase the probability of observing 

supraventricular ectopic beats (SVEB). Exposure to CAPs 

(646 μg/m3

) for 1 h decreased the frequency of SVEB. There 

were no significant effects observed when rats were exposed to 

both CO and CAPs. Among a subset of rats with one or more 

SVEB at baseline, a significant decrease in number of SVEB 

during the exposure period was observed with either CO or CAPs 

exposure compared with controls. 

Yoshiki et al.(2001, 

193790) 

Human HO localization in human endometrium and its changes in 

expression over the menstrual cycle were explored in this study. 

HO-1 was constitutively expressed throughout the menstrual 

cycle, and HO-2 was greater in the secretory than the 

proliferative phase of the menstrual cycle. HO-1 was localized to 

the epithelial cells and macrophages. HO-2 was found in 

endothelial cells and smooth muscle cells of endometrial blood 

vessels. 

Yu et al. (2008, 

192384) 

Guinea pig 

Allergic rhinitis model 

using nasal ovalbumin 

sensitization 

Indicators of allergic rhinitis were enhanced by treatment with a 

HO-1 inducer and decreased by treatment with a HO-1 inhibitor. 

Immunoreactivity for HO-1 was shown in the lamina of mucosa of 

sensitized guinea pigs. Endogenous CO may play a role in the 

inflammation process of allergic rhinitis. 

Zamudio et al. (1995, 

193908) 

Human Women living at high altitude had an increased risk of adverse 

pregnancy outcomes vs women living at lower altitudes. 

Zenclussen et al. 

(2006, 193873) 

Mouse 

CBA/J x DBA/2J 

To evaluate the role of HO-1 in spontaneous abortion, a mouse 

model that spontaneously undergoes abortion (CBA/J x DBA/2J 

mice) was used with and without HO adenovirus treatment to see 

if pregnancy outcome could be modulated by changing HO 

concentration. Pregnancy outcome was significantly better 

(abortion rate significantly decreased) in mice overexpressing HO 

due to adenovirus transfer. 

Zhang et al. (2005, 

184460) 

Rat 

Pulmonary artery 

endothelial cells 

8-28 h 15 ppm Exposure to 15 ppm CO during anoxia resulted in decreased 

phosphorylation of STAT1 and increased phosphorylation of 

STAT3 at 8-24 h. Similar responses were observed when 24-h 

anoxia was followed by a period of reoxygenation (0.5-4 h). DNA 

binding of STAT1 was decreased while that of STAT3 was 

enhanced by CO treatment during anoxia/reoxygenation. 

Exposure to 15 ppm during 8-24-h anoxia or 24 h anoxia followed 

by 0.5-4 h reoxygenation resulted in increased phosphorylation of 

Akt and p38 MAPK. Inhibitor studies demonstrated that activation 

of the PI3K pathway by CO was upstream of p38 MAPK 

activation during anoxia/reoxygenation. Similarly, the PI3K and 

p38 MAPK pathways were found to be upstream of STAT 

modulation. The anti-apoptotic effects of 15 ppm CO during 

anoxia-reoxygenation involved decreased FAS expression and 

decreased caspase 3 acvitiry. These effects were dependent on 

activation of the PI3K, p38 MAPK and STAT3 pathways. 

The authors concluded that CO blocks anoxia-reoxygenation 

mediated apoptosis through modulation of PI3K/Akt/p38 MAPK 

and STAT1 and STAT3. 

January 2010 E-21 
Reference Species / Model Exposure 

Duration 

CO Concentration Findings 

Zhang et al. (2007, 

193879) 

Mouse A single dose of LPS administered to pregnant mice induced upregulation of HO-1 but not HO-2 in the mouse placenta 12-48 h 

postLPS treatment. Pretreatment of mice with the spin trap agent 

PBN or the TNF α inhibitor pentoxifylline prevented the LPSdependent HO-1 upregulation. Thus ROS may mediate the LPSdependent upregulation of HO-1. 

Zhao et al. (2008, 

193883) 

Mouse 

FVB 

With pregnancy, there was an increased blood volume without a 

concurrent increase in systemic BP; this was accomplished by a 

decrease in total vascular resistance, to which CO contributed as 

determined by using HO inhibitors. 

Zhuo et al. (1993, 

013905) 

Guinea pig 

Adult male 

 Hippocampal LTP of brain sections is significantly affected by CO 

exposure with ZnPP IX, a HO inhibitor, blocking hippocampal 

LTP. 

Zuckerbraun et al. 

(2007, 193884) 

Macrophages 

RAW 264.7 

THP-1 cells, wild-type and 

respiration-deficient 

10 min-24 h 50-500 ppm Exposure of RAW macrophages to 250 ppm CO for 10-60 min 

increased ROS generation, measured as dichlorofluorescein 

(DCF) fluorescence. ROS generation at 1 h was dose dependent 

with significant effects observed at 50, 250 and 500 ppm CO. 

This response was not blocked with a NOS inhibitor. A 1-h 

exposure to 250 ppm resulted in decreased intracellular 

glutathione levels. CO treatment was found to block TNFα

production and to enhance p38 MAPK phosphorylation in LPSstimulated cells. These effects were diminished by pretreatment 

with antioxidants. The source of CO-derived oxidants was 

determined to be mitochondrial since respiration-deficient THP-1 

macrophages, unlike wild-type cells, failed to generate ROS in 

response to 250 ppm CO. Furthermore, treatment of RAW cells 

with the mitochondrial complex III inhibitor antimycin C, blocked 

ROS generation in response to 250 ppm CO. Exposure of RAW 

cells to 250 ppm CO for 1 h inhibited cytochrome c oxidase 

activity by 50%. Exposure to 250 ppm CO for 6 h had no effect 

on cellular ATP levels or mitochondrial membrane potential. 

Antimycin C treatment was found to reverse the effects of CO on 

LPS-mediated responses (TNFα and p38 MAPK), suggesting 

that mitochondrial-derived ROS mediated the effects of CO. 

 The authors concluded that CO increased the generation of 

mitochondrial-derived ROS. 

January 2010 E-22 
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