Annex B. Dosimetry Studies 

Table B-1. Recent studies related to CO dosimetry and pharmacokinetics. 

Reference Purpose Findings 

Aberg et al. (2009, 194082) To investigate CO concentrations in blood donors in 

Sweden. 

The mean CO concentration in blood donors was 84.5 μmol/L. 

Concentrations over 130 μmol/L were found in 6% of blood, and the 

highest concentration was 561 μmol/L . By using a calculation, 23% of 

banked blood bags could exceed 1.5% COHb, with a highest fraction of 

7.2% COHb. 

Abram et al. (2007, 193859) To present the Quantitative Circulatory Physiology 

(QCP) model as a teaching module in the practice of 

medicine. 

QCP is a dynamic mathematical model based on published models and 

parameters of biological interactions. 

Alcantara et al. (2007, 193867) 

To use a quantum mechanics/molecular mechanics 

approach to understand the cooperativity of Hb ligand 

binding and differences in energy between T and R Hb 

functional states. 

The ligand binding energies between R and T states differ due to strain 

induced in the heme and its ligands and in protein contacts in the α and 

β chains. 

Adir et al. (1999, 001026) 

To determine if low concentrations of CO would affect 

exercise performance and myocardial perfusion in 

young healthy men. 

Men with COHb levels between 4 and 6% had decreased exercise 

performance measured by decreased mean duration of exercise 

(1.52 min) and maximal effort described by metabolic equivalent units 

(2.04). No changes were seen in lactate/pyruvate ratio, arrhythmias, or 

myocardial perfusion. 

Anderson et al. (2000, 011836) To investigate if CO could be endogenously produced 

in the nose and paranasal sinuses. 

Both nose and paranasal sinuses contained HO-like immunoreactivity, 

mostly in the respiratory epithelium, indicating local CO production in 

the upper respiratory airways. 

Arora et al. (2001, 186713) To evaluate the effect of multiple transfusion recipient 

thalassemics on pulmonary function. 

DLCO was decreased in all the patients with restrictive lung disease and 

fall in DLCO showed a good correlation with the severity of restrictive 

disease. Thalassemics had a decrease in lung volume and a 

proportional decrease in flow rate. 

Benignus et al. (2006, 151344) To adapt and use a human model for toluene uptake 

and elimination including a brain compartment. 

The QCP 2004 model was used to construct simulations of scenarios of 

toxicant exposure and human activities. QCP accurately predicted 

toluene blood concentrations from inhaled exposure. 

Bos et al. (2006, 194084) To use a PBPK model to set AEGL for methylene 

chloride. 

This model adequately predicted COHb levels formed by various 

methylene chloride concentrations, specifically in nonconjugators 

lacking the GSTT-1 enzyme, and proposed AEGL values. 

Bruce and Bruce (2003, 193975) 

To create a mathematical model to predict uptake and 

distribution of CO in both vascular and tissue 

compartments during constant or variable inhalation 

levels of CO. 

This model contains 5 compartments: lung, arterial blood, venous blood, 

muscle tissue, and nonmuscle tissue. It was constructed to include 

tissue compartment flux and difference between venous and arterial 

COHb for short exposures which is not possible with the CFK model. 

Bruce and Bruce (2006, 193980) 

To use their mathematical multicompartment model 

along with experimental data to predict the factors that 

influence the washout rates of CO, along with 

predicting the rates of CO uptake, distribution in 

vascular and extravascular (muscle and nonmuscle 

tissue) compartments, and washout over a range of 

exposure and conditions. 

Rates of CO washout follow a biphasic elimination where washout was 

faster immediately post exposure. The difference in rates is likely due to 

slow equilibration between vascular and extravascular compartments. 

Important factors contributing to washout kinetics include: peak COHb 

level, exposure duration and concentration, time after exposure samples 

were obtained, and individual variability. 

Bruce and Bruce (2008, 193977) 

To develop a mathematical model able to integrate a 

large body of indirect experimental findings on the 

uptake and distribution of CO by accounting for 

arteriole to venule shunting via intratissue pathways 

and diffusion of blood gases into tissues from precapillary vessels like arterioles. 

The former model of Bruce and Bruce (2006, 193980) was altered by 

adding a mass balance equation for O2 so pO2 is directly calculated in 

the compartments, and the muscle compartment is divided into two subcompartments of muscle and nonmuscle tissue. CO uptake from blood 

by muscle is much slower than O2, thus COHb% will fall rapidly while 

COMb% could remain high. 

 

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 B-1 
Reference Purpose Findings 

Carraway et al. (2000, 021096) To test the hypothesis that HO-1 gene expression and 

protein are upregulated in the lungs of rats during 

chronic hypoxia. 

Rats were exposed to HH (17,000 ft) for 1-21 days. COHb increased 

after 1 day and progressively after 14 days. HO-1 protein and activity 

were upregulated during early chronic hypoxia. This HO-1 was localized 

to inflammatory cells and then to newly muscularized arterioles. 

Castillo et al. (2006, 193234) 

To describe a new method for measurement of CO 

DLCO and VA in sleeping infants (6-22 mo old), using a 

single 4-s breath-hold technique. 

VA30 and DLCO increased with increasing body length, and the method 

could be used as a measurement of lung development and growth. 

Chakraborty et al. (2004, 193759) 

To present an analytical expression for diffusing 

capacity of CO, NO, CO2, and O2 to the red blood cell 

in terms of optimum size and shape of the RBC, 

thickness of the unstirred plasma layer surrounding the 

RBC, diffusivities and solubilities of the gas in RBC and 

boundary layer, hematocrit, and the slope of the 

dissociation curve. 

Results indicate the discoidal shape of the RBC is optimal for O2 uptake 

and reaction velocity is limited by mass transfer resistance in 

surrounding stagnant plasma layer. The paper overviews rate constants 

and reaction kinetics for CO binding to Hb. CO diffusing capacity is 

shown to be reaction-rate limited at low pCO under normoxic and 

hyperoxic conditions, but diffusion-rate limited under hypoxic and high 

pCO conditions. 

Cronenberger et al. (2008, 

194085) 

To develop a population-based model to describe and 

predict the pharmacokinetics of COHb in adult 

smokers. 

This two-compartment model included zero-order input and first-order 

elimination and required a compartment for extravascular binding of CO 

to accurately predict COHb formation during multiple short and rapid 

inhalations, followed by a period of no exposure, as occurs in smoking. 

Smokers' COHb ranged from 0.8 to 11.1%. 

Cronje et al. (2004, 180440) To analyze CO uptake and elimination in the brain, 

muscle, heart, and blood of rats, with the intent of 

testing the Warburg hypothesis that CO partitioning is 

directly proportional to the CO/O2 ratio. 

Results indicate that tissue and blood CO concentration dissociate 

during CO inhalation, but CO concentration does not follow blood CO 

concentration or 1/pO2 as in the Warburg theory during intake or 

elimination. Tissue CO concentration 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. 

De las Heras et al. (2003, 

194087) 

To assess production of CO (venous COHb measured 

by CO-oximeter and exhaled CO) in patients with 

cirrhosis with and without spontaneous bacterial 

peritonitis. 

Patients with SBP had higher CO production than noninfected cirrhotic 

patients and both groups of patients had higher CO production 

compared to healthy controls. CO production decreased slowly after 

resolution of the disease. 

Dutton et al. (2001, 021307) 

To monitor CO, NO2, and PAH emissions during the 

operation of unvented natural gas fireplaces in two 

residences in Boulder, CO, at various times between 

1997 and 2000. 

Results showed significant accumulation of CO, NO2, and PAH indoors 

when the fireplaces were used. CO concentrations could exceed 

100 ppm. NO2 concentrations averaged 0.36 ppm over 4 h. PAH 4-h 

time avg reached 35 ng/m3. 

Ehlers et al. (2009, 194089) To determine the level of COHb found in banked blood 

in the Albany, NY region. 

The avg COHb level was 0.78%. The highest recorded COHb level was 

12%, and 10.3% of packed red blood cell units had levels of 1.5% 

COHb or higher. 

Gosselin et al. (2009, 190946) 

To develop a variant of the CFK model that links COHb 

levels in humans to ambient CO levels under various 

environmental or occupational exposure conditions. 

The model adds alveoli-blood and blood-tissue CO exchanges and 

mass conservation of CO at all times to the CFK equation. The model 

better predicted COHb formation over a wide range of CO levels and 

scenarios with linear regression analysis of predicted vs observed 

values generating a slope of 0.996 (95% CI: 0.986-1.001) compared to 

0.917 (95% CI: 0.906-0.927) using the CFK model 

Hampson and Weaver (2007, 

190272) 

To present a case study of a man with drug-induced 

hemolytic anemia and hepatic failure. 

The man had elevated endogenous CO production resulting in levels of 

COHb as high as 9.7%. 

Hart et al. (2006, 194092) To investigate the relationship between COHb and 

smoking habit and mortality. 

COHb was related to self-reported smoking in a dose-dependent 

manner. COHb was positively associated with all causes of mortality 

analyzed including CHD, COPD, stroke, and lung cancer. Mean COHb 

levels ranged from 1.59% in never-smokers to 6.02% in the most often 

smoking group. 

Hsia (2002, 193857) 

To review the current concepts and practical relevance 

of the diffusing capacity/cardiac output interaction, in 

hopes of aiding in the interpretation of diffusing 

capacity, membrane diffusing capacity, and capillary 

blood volume. 

This review helped to understand the determinants of changes in 

diffusing capacity, including hematocrit, erythrocyte distribution, blood 

volume, lung volume, and cardiac output. 

Johnson et al. (2006, 193874) 

To test that heme-derived CO formation is increased 

and contributes to hypertension and arteriolar 

endothelial dysfunction in obese Zucker rats. 

Obese Zucker rats showed increased respiratory CO excretion that was 

lowered by HO inhibition. Skeletal muscle arterioles of obese rats had 

attenuated ACh and flow responses that were abolished by HO 

inhibition (HO inhibition enhanced dilation). 

Lamberto et al. (2004, 193845) 

To evaluate which component, alveolar membrane 

diffusing capacity (Dm) and pulmonary capillary blood 

volume (Vc), is responsible for decreased resting DLCO 

in sarcoidosis patients and which component is the 

best predictor of gas exchange abnormalities. 

Patients with pulmonary sarcoidosis had decreased lung volumes, a 

loss in DLCO, and gas exchange abnormalities during exercise, 

including decreased PaO2 and increased alveolar-arterial oxygen 

pressure difference. Dm accounted for the majority of the decrease in 

DLCO and was predictive for gas exchange abnormalities. 

January 2010 B-2 
Reference Purpose Findings 

Levesque et al. (2000, 011886) 

To describe the results of air quality monitoring in an 

indoor ice skating rink during Monster Truck and car 

demolition exhibitions. 

Maximum time-weighted avg levels of CO were 100 ppm, with several 

peaks exceeding 200 ppm (max: 1,600 ppm). 

Lim et al. (2000, 126969) 

To investigate the expression of HO-1 and HO-2 in 

bronchial biopsies obtained from patients with mild 

asthma compared with that of subjects without asthma. 

HO-1 and HO-2 expression is widely distributed equally in healthy 

subjects and subjects with asthma and is not modulated by inhaled 

corticosteroid therapy. 

Mahoney et al. (1993, 013859) To compare CO-oximeter measurements of COHb 

against a gas chromatography reference method. 

In general, the 5 CO-oximeters that were tested underestimated COHb 

concentrations for COHb >2.5% and overestimated COHb concentration 

for COHb ≤ 2.5%, when compared to reference gas chromatography 

method. 

Marks et al. (2002, 030616) To review the analytical methods for measurement of 

endogenous formation of CO in a variety of tissues. 

A variety of methods have been used to measure endogenous CO. The 

rate of formation varies over a narrow range, from 0.029 nmol/mg 

protein/h to 0.28 nmol/mg protein/h depending on tissue. Brain and liver 

regions tend to have the highest rates of CO formation, likely due to 

high levels of HO activity in these tissues. 

Marvisi et al. (2007, 186702) 

To evaluate DLCO impairment and microalbuminuria in 

patients with active ulcerative colitis (UC) and to assess 

whether these tests correlate with intestinal 

inflammation. 

Reduced DLCO was present in 67% of patients. Microalbuminuria was 

present in 63% of patients with ulcerative colitis. 

Merx et al. (2001, 002006) 

To investigate the effect of CO inactivation of Mb in 

wild-type and myo-/- mice on hemodynamics and 

oxygen dynamics. 

Fully oxygenated Mb treated with 20% CO had no change in left 

ventricular developed pressure or coronary venous pO2. Partially 

O2-saturated Mb (87% O2Mb) exposed to 20% CO had significantly 

decreased LVDP (12%) and PvO2 (30%) in wild-type but not myo-/- 

hearts. 

Monma et al. (1999, 180426). To study whether exhaled CO levels were increased in 

seasonal allergic rhinitis. 

Exhaled CO concentrations were higher in allergic rhinitis patients 

during cedar pollen season (3.6 ppm; SD 0.3 ppm) that out (1.2 ppm; 

SD 0.1 ppm). 

Morimatsu et al. (2006, 194097) To examine exhaled CO, arterial COHb, and bilirubin 

IXα levels in critically ill patients. 

Exhaled CO concentrations were significantly higher in critically ill 

patients compared to controls. There was a significant correlation 

between exhaled CO and COHb or bilirubin. There was no correlation 

between exhaled CO and disease severity or degree of inflammation. 

There was higher exhaled CO in survivors compared to nonsurvivors. 

Muchova et al. (2007, 194098) 

To determine if long-term use of statins affects HO 

activity and blood and organ CO and bilirubin in FvB 

mice (6-8 wk). 

Rosuvastatin and atorvastatin treatment increased COHb, plasma 

bilirubin, and heart tissue CO content. Both statins caused an increase 

in HO activity in heart tissue, whereas no changes were seen in brain or 

lung. Liver HO activity was inconsistent over time and between statins. 

Both statins decreased the heart antioxidant capacity, and changes in 

HO activity and antioxidant capacity can be reversed by HO inhibitor 

treatment. 

Neto et al. (2008, 194672) 

To develop a model of the respiratory system to 

analyze CO transport in the human body submitted to 

several physical activity levels. 

The model contains 6 compartments including: alveolar, pulmonary 

capillaries, arterial, venous, tissue capillary, and tissues (muscular and 

nonmuscular). The highest and lowest COHb levels were simulated in 

the walking individual, suggesting that greater variability in COHb 

occurs in higher physical activity levels. 

Pelham et al. (2002, 025716) To review the literature on exposure and effects of 

mainly CO and NO2 in enclosed ice rinks. 

CO levels as high as 300 ppm were recorded after episodes of 

malfunctioning ice resurfacing equipment or inadequate ventilation. 

Paredi et al. (1999, 194102) To investigate the level of exhaled CO produced by 

diabetic patients. 

Diabetic patients (types 1 and 2) had higher levels of exhaled CO than 

healthy subjects. Exhaled CO levels correlated with the incidence of 

glycemia and the duration of diabetes. 

Paredi et al. (1999, 118798) 

To investigate whether cystic fibrosis patients have 

higher exhaled levels of CO and if this is reduced by 

corticosteroid therapy. 

Cystic fibrosis patients had higher exhaled CO concentrations compared 

to healthy controls. Patients receiving corticosteroid therapy had lower 

exhaled CO concentrations. 

Pesola et al. (2004, 193842) 

To determine if healthy African Americans may be 

misdiagnosed as having respiratory deficient due to 

comparison using Caucasian-derived prediction 

equation estimates of DLCO. 

The lung volume of African-American individuals is 10-15% lower than 

Caucasians. The measured DLCO was consistently significantly lower in 

African-Americans than what would be predicted. Thus, the authors 

suggest a race correction reduction of the Miller PEE for diffusion of 

12%. 

Pesola et al. (2006, 193855) 

To determine if healthy Asians may be misdiagnosed as 

having respiratory deficient due to comparison using 

Caucasian-derived prediction equation estimates of 

DLCO. 

The lung volume of Asian individuals is 10-15% lower than Caucasians. 

Thus a Chinese-derived prediction for DLCO should be used. 

January 2010 B-3 
Reference Purpose Findings 

Prommer and Schmidt (2007, 

180421) 

To determine the error in total Hb mass measurements 

using the optimized CO-rebreathing method due to loss 

of CO to Mb 

Optimal blood mixing (when venous and arterial blood COHb% are 

equivalent) was determined to be after 6 min. A small volume of 

administered CO leaves the vascular space (0.32% per min). A 2.3% 

increase in total Hb mass would be found if CO diffusion was not 

included. 

Proudman et al. (2007, 186705) 

To review the signs of pulmonary arterial hypertension, 

including a drop in DLCO in patients with systemic 

sclerosis. 

Richardson et al. (2002, 037513) 

To combine invasive vascular measures of arterial and 

venous blood and muscle blood flow with noninvasive 

magnetic spectroscopy of deoxy-myoglobin and high 

energy phosphates to determine the effects of mild CO 

poisoning (20% COHb) in humans during muscular 

work. 

Five humans were analyzed under normoxia, hypoxia, normoxia + CO 

(20% COHb), and 100% O2 + CO. Maximum works rates and maximal 

oxygen uptake were reduced in H, COnorm, and COhyper. CO and H 

caused elevated blood flow. Net muscle CO uptake from blood was less 

during 20% COHb trials than during normoxia and hypoxia (1-2%) trials.

Sakamaki et al. (2002, 186706) To evaluate the association of patients with aortic 

aneurysm to the prevalence obstructive airway disease.

Patients with AA had lower FEV1 and DLCO than controls. Presence of 

AA and male gender were associated with a higher risk of airway 

obstruction. 

Scharte et al. (2000, 194112) To investigate whether exhaled CO concentrations are 

increased in critically ill patients. 

Critically ill patients had higher exhaled CO concentrations and higher 

total CO production rates compared to healthy controls. No correlation 

was found between exhaled CO concentration and venous or arterial 

COHb. 

Scharte et al. (2006, 194115) 

To investigate the relationship between the severity of 

illness and endogenous CO production in critically ill 

patients. 

CO production rates weakly correlated with the multiple organ 

dysfunction score (R=0.27). Cardiac disease patients and patients 

undergoing dialysis produced higher amounts of CO compared to 

critically ill control patients. 

Schachter et al. (2003, 186707) To evaluate the association between severe 

gastroesophageal reflux and lung function. 

Patients with severe gastroesophageal reflux had reduced DLCO, 

remaining significant after adjusting for age, gender, BMI, and smoking. 

Shimazu et al. (2000, 016420) 

To study the effects of short-term (min) or long-term 

(several h) CO exposure on COHb elimination and 

developing a mathematical model to simulate this 

event. 

COHb exhibited an initial rapid decrease followed by a slower phase 

which is compatible with a 2-compartment model and biphasic 

elimination. Both exposures fit the 2-compartment, single-central-outlet 

mathematical model. 

Shimazu (2001, 016331) To discuss the findings of Weaver et al. (2000, 016421) 

on COHb t1/2. 

The authors discuss that CO elimination is biphasic and is heavily 

affected by duration of exposure which was not taken into account in the 

Weaver et al. (2000, 016421) paper. 

Sylvester et al. (2005, 191954) To assess the usage of end tidal CO levels in children 

with sickle cell disease for measurement of hemolysis. 

Children with sickle cell disease had higher exhaled CO levels (4.9 ppm; 

SD 1.7 ppm) compared to healthy controls (1.3 ppm; SD 0.4 ppm). A 

positive correlation existed between end-tidal CO levels and COHb and 

bilirubin. 

Takeuchi et al. (2000, 005675) 

To examine the relationship between min ventilation 

and rate of COHb reduction during breathing 100% O2

and during normocapnic hyperoxic hyperpnea. 

Patients were exposed to 400-1,000 ppm CO, resulting in 10-12% 

COHb. The half-time of COHb reduction was 78 ± 24 min during 100% 

O2 treatment and 31 ± 6 min during normocapnic hyperpnea with O2

treatment. 

Tarquini et al. (2009, 194117) To measure plasma CO levels in patients with liver 

cirrhosis and portal hypertension. 

Plasma CO was higher in ascetic patients than nonascitic patients and 

both were higher than healthy controls. HO activity was higher in 

cirrhotic patients than healthy subjects and highest in patients with 

ascites. 

Terzano et al. (2009, 108046) To investigate the effect of postural changes on gas 

exchange in patients with COPD and healthy subjects. 

DLCO increased in healthy individuals from upright to supine position 

and upright to prone position. DLCO did not significantly change in 

COPD patients from upright to prone position. This is explained by 

homogeneous perfusion in healthy individuals and increased rigidity of 

lung capillaries due to COPD. 

Tran et al. (2007, 194120) To assess the correlation of COHb to severity of liver 

disease. 

No correlation was found with the Model for End Stage Liver Disease 

score, Child Turcotte Pugh score, or other biochemical or clinical 

measures of disease severity, such as spleen size, bilirubin, disease 

duration, or AST/ALT. The mean COHb was 2.1%. 

Vreman et al. (2005, 193786) 

To develop a sensitive and reproducible method of CO 

quantification in rodent (mouse and rat) tissue pre- and 

postexposure in hopes of understanding endogenous 

CO production. 

Tissues were sonicated mixed with sulfosalicylic acid for 30 min at 0°C 

and then liberated CO was analyzed by gas chromatograph. Blood 

contained the highest CO concentration. Lowest concentrations were 

found in brain, testes, intestine, and lung (endogenously). 

Vreman et al. (2006, 098272) 

To test a method of CO quantification in frozen 

postmortem human tissues from 3 determined 

categories of fatalities: trauma with no suspected CO 

exposure (controls), fire-related, and CO asphyxiation. 

CO levels were analyzed in adipose, brain, muscle, heart, kidney, lung, 

spleen, and blood (ordered from approximate low to high tissue 

concentration). It was suggested that blood, muscle, brain, lung, and 

kidney are suitable for diagnosing death due to lethal CO exposure due 

to regression analysis against COHb values. 

January 2010 B-4 
Reference Purpose Findings 

Weaver et al. (2000, 016421) 

To determine in COHb half-life is influenced by CO 

poisoning vs experimental CO exposure, loss of 

consciousness, concurrent tobacco smoking, or PaO2. 

COHb t1/2 determined was 74 ± 25 min with a range from 26 to 148 min 

by a single exponential decrease function. This is shorter than most 

clinical studies and was inversely proportionate to PaO2, however, not 

influenced by age, gender, smoke inhalation, loss of consciousness, 

tobacco smoking, or method of O2 treatment. 

Whincup et al. (2006, 195129) 

To report COHb levels from a population-based study in 

men aged 60-79 yr during the 20-yr follow-up of the 

British Regional Heart Study cohort. 

Mean COHb: 0.46%; Median COHb: 0.5% 

9.2% of men had COHb levels of 2.5% or greater (93% were smokers) 

0.1% of men had COHb levels of 7.5% or greater 

Smoking is the highest influence on COHb levels; however, other 

factors independently related were season, region, gas cooking and 

central heating, and active smoking 

Widdop (2002, 030493) To review carbon monoxide analysis methods, 

including CO-oximeters and gas chromatography. 

Wu and Wang (2005, 180411) 

To review the endogenous production of CO through 

HO, as well as discuss physiological roles for CO both 

toxic and therapeutic. 

CO is produced endogenously by HO-1 and -2 and acts as a 

gasotransmitter, inducing cell signaling cascades. The review discusses 

possible roles for CO in the various organ systems and the potential 

pharmacological and therapeutic applications for CO. 

Yamaya et al. (1998, 047525) To determine whether upper respiratory tract infections 

increase exhaled CO concentrations. 

Exhaled CO increased in patients at the time of upper respiratory tract 

infection symptoms but decreased to nonsmoking healthy control levels 

during recovery. 

Yamaya et al. (2001, 180130) To determine whether the level of CO is related to the 

severity of asthma. 

Severe asthmatics exhaled more CO than nonsmoking controls. 

Exhaled CO concentrations in unstable severe asthmatics were higher 

than in stable severe asthmatics. Mild and moderate asthmatics did not 

differ from controls. Exhaled CO was correlated with FEV1 in all 

asthmatics. 

Yasuda et al. (2002, 035206) To determine whether arterial COHb is increased in 

patients with inflammatory pulmonary diseases. 

Arterial COHb concentrations are increased in patients with 

inflammatory pulmonary diseases, including exacerbated bronchial 

asthma (1.05%), pneumonia (1.08%), and idiopathic pulmonary fibrosis 

(1.03%) over controls (0.6%). 

Yasuda et al. (2004, 191955) 

To determine if COHb levels in the venous blood and 

arteriovenous COHb (a-vCOHb) differences are 

increased in patients with inflammatory pulmonary 

diseases compared to patients with extrapulmonary 

inflammation and control subjects. 

Patients with inflammatory pulmonary diseases, including bronchial 

asthma and pneumonia, had a large a-vCOHb difference. Both arterial 

and venous blood COHb increased in patients with inflammatory 

pulmonary disease, such as bronchial asthma, pneumonia, 

pyelonephritis and active rheumatoid arthritis. 

Yasuda et al. (2005, 102183) To study the relationship between COHb and disease 

severity in patients with COPD. 

COHb concentrations increased in patients with COPD at a stable 

condition over controls and patients with COPD with exacerbations were 

further increased. 

Yerushalmi et al. (2009, 186711) 

To evaluate the association of dose-dense 

chemotherapy in breast cancer patients with pulmonary 

dysfunction. 

Patients receiving dose-dense chemotherapy for breast cancer had a 

significant reduction in DLCO. 

Zegdi et al. (2002, 037461) 

To compare endogenous CO production in 

mechanically ventilated critically ill adult patients with 

and without severe sepsis. 

CO production was higher in septic patients during the first 3 days of 

treatment compared to controls. Survivors of sepsis had a significantly 

higher CO production compared to nonsurvivors. 

January 2010 B-5 
References 

Aberg AM; Sojka BN; Winsö O; Abrahamsson P; Johansson G; Larsson JE (2009). Carbon monoxide concentration in 

donated blood: Relation to cigarette smoking and other sources. Transfusion, 49: 347-353. 194082

Abram SR; Hodnett BL; Summers RL; Coleman TG; Hester RL (2007). Quantitative circulatory physiology: An 

integrative mathematical model of human physiology for medical education. Adv Physiol Educ, 31: 202-210. 

193859

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

Alcantara RE; Xu C; Spiro TG; Guallar V (2007). A quantum-chemical picture of hemoglobin affinity. PNAS, 104: 18451-

18455. 193867

Andersson JA; Uddman R; Cardell L-O (2000). Carbon monoxide is endogenously produced in the human nose and 

paranasal sinuses. J Allergy Clin Immunol, 105: 269-273. 011836

Arora M; Chandra J; Suri JC; Narayan S; Dutta AK (2001). Pulmonary function tests in beta thalassemia. Indian J Pediatr, 

68: 239-242. 186713

Benignus VA; Coleman T; Eklund CR; Kenyon EM (2006). A general physiological and toxicokinetic (GPAT) model for 

simulating complex toluene exposure scenarios in humans. Toxicol Mech Meth, 16: 27-36. 151344

Bos PM; Zeilmaker MJ; van Eijkeren JC (2006). Application of physiologically based pharmacokinetic modeling in setting 

acute exposure guideline levels for methylene chloride. Toxicol Sci, 91: 576-585. 194084

Bruce EN; Bruce MC (2003). A multicompartment model of carboxyhemoglobin and carboxymyoglobin responses to 

inhalation of carbon monoxide. J Appl Physiol, 95: 1235-1247. 193975

Bruce EN; Bruce MC; Erupaka K (2008). Prediction of the rate of uptake of carbon monoxide from blood by extravascular 

tissues. Respir Physiol Neurobiol, 161: 142-159. 193977

Bruce MC; Bruce EN (2006). Analysis of factors that influence rates of carbon monoxide uptake, distribution, and washout 

from blood and extravascular tissues using a multicompartment model. J Appl Physiol, 100: 1171-1180. 193980

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

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

Chakraborty S; Balakotaiah V; Bidani A (2004). Diffusing capacity reexamined: relative roles of diffusion and chemical 

reaction in red cell uptake of O2, CO, CO2, and NO. J Appl Physiol, 97: 2284-2302. 193759

Cronenberger C; Mould DR; Roethig HJ; Sarkar M (2008). Population pharmacokinetic analysis of carboxyhaemoglobin 

concentrations in adult cigarette smokers. Br J Clin Pharmacol, 65: 30-39. 194085

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

De las Heras D; Fernández J; Ginès P; Cárdenas A; Ortega R; Navasa M; Barberá JA; Calahorra B; Guevara M; Bataller R; 

Jiménez W; Arroyo V; Rodés J (2003). Increased carbon monoxide production in patients with cirrhosis with and 

without spontaneous bacterial peritonitis. Hepatology, 38: 452-459. 194087

Dutton SJ; Hannigan MP; Miller SL (2001). Indoor pollutant levels from the use of unvented natural gas fireplaces in 

Boulder, Colorado. J Air Waste Manag Assoc, 51: 1654-1661. 021307

 

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 B-6 
Ehlers M; Labaze G; Hanakova M; McCloskey D; Wilner G (2009). Alarming levels of carboxyhemoglobin in banked 

blood. J Cardiothorac Vasc Anesth, 23: 336-338 . 194089

Gosselin NH; Brunet RC; Carrier G (2009). Determination of carboxyhaemoglobin in humans following low-level 

exposures to carbon monoxide. Inhal Toxicol, 21: 1077-1091. 190946

Hampson NB; Weaver LK (2007). Carbon monoxide poisoning: a new incidence for an old disease. Undersea Hyperb Med, 

34: 163-168. 190272

Hart CL; Smith GD; Hole DJ; Hawthorne VM (2006). Carboxyhaemoglobin concentration, smoking habit, and mortality in 

25 years in the Renfrew/Paisley prospective cohort study. Heart, 92: 321-324. 194092

Hsia CC (2002). Recruitment of lung diffusing capacity: Update of concept and application. Chest, 122: 1774-1783. 

193857

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

Lamberto C; Nunes H; Le Toumelin P; Duperron F; Valeyre D; Clerici C (2004). Membrane and capillary blood 

components of diffusion capacity of the lung for carbon monoxide in pulmonary sarcoidosis: relation to exercise 

gas exchange. Chest, 125: 2061-2068. 193845

Levesque B; Allaire S; Prud'homme H; Dupuis K; Bellemare D (2000). Air quality monitoring during indoor monster truck 

and car demolition shows. J Expo Sci Environ Epidemiol, 10: 58-65. 011886

Lim S; Groneberg D; Fischer A; Oates T; Caramori G; Mattos W; Adcock I; Barnes PJ; Chung KF (2000). Expression of 

heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: Effect of inhaled corticosteroids. Am J 

Respir Crit Care Med, 162: 1912-1918. 126969

Mahoney JJ; Vreman HJ; Stevenson DK; Van Kessel AL (1993). Measurement of carboxyhemoglobin and total 

hemoglobin by five specialized spectrophotometers (CO-oximeters) in comparison with reference methods. Clin 

Chem, 39: 1693-1700. 013859

Marks GS; Vreman HJ; McLaughlin BE; Brien JF; Nakatsu K (2002). Measurement of endogenous carbon monoxide 

formation in biological systems. Antioxid Redox Signal, 4: 271-277. 030616

Marvisi M; Bassi E; Bonassi R; Civardi G; Delsignore R (2007). DLCO correlates with intestinal inflammation in 

ulcerative colitis, but albuminuria does not. Minerva Gastroenterol Dietol, 53: 321-7. 186702

Merx MW; Flogel U; Stumpe T; Godecke A; Decking UK; Schrader J (2001). Myoglobin facilitates oxygen diffusion. 

FASEB J, 15: 1077-1079. 002006

Monma M; Yamaya M; Sekizawa K; Ikeda K; Suzuki N; Kikuchi T; Takasaka T; Sasaki H (1999). Increased carbon 

monoxide in exhaled air of patients with seasonal allergic rhinitis. Clin Exp Allergy, 29: 1537-1541. 180426

Morimatsu H; Takahashi T; Maeshima K; Inoue K; Kawakami T; Shimizu H; Takeuchi M; Yokoyama M; Katayama H; 

Morita K (2006). Increased heme catabolism in critically ill patients: Correlation among exhaled carbon monoxide, 

arterial carboxyhemoglobin, and serum bilirubin IXalpha concentrations. Am J Physiol Lung Cell Mol Physiol, 

290: L114-L119. 194097

Muchova L; Wong RJ; Hsu M; Morioka I; Vitek L; Zelenka J; Schröder H; Stevenson DK (2007). Statin treatment 

increases formation of carbon monoxide and bilirubin in mice: A novel mechanism of in vivo antioxidant 

protection. Can J Physiol Pharmacol, 85: 800-810. 194098

Neto CA; Yanagihara JI; Turri F (2008). A carbon monoxide transport model of the human respiratory system applied to 

urban atmosphere exposure analysis. J Braz Soc Mech Sci & Eng, 30: 253-260. 194672

Paredi P; Biernacki W; Invernizzi G; Kharitonov SA; Barnes PJ (1999). Exhaled carbon monoxide levels elevated in 

diabetes and correlated with glucose concentration in blood: A new test for monitoring the disease? Chest, 116: 

1007-1011. 194102

Paredi P; Shah PL; Montuschi P; Sullivan P; Hodson ME; Kharitonov SA; Barnes PJ (1999). Increased carbon monoxide 

in exhaled air of patients with cystic fibrosis. Thorax, 54: 917-20. 118798

Pelham TW; Holt LE; Moss MA (2002). Exposure to carbon monoxide and nitrogen dioxide in enclosed ice arenas. Occup 

Environ Med, 59: 224-233. 025716

January 2010 B-7 
Pesola GR; Huggins G; Sherpa TY (2006). Abnormal predicted diffusion capacities in healthy Asians: an inequality with a 

solution. Respiration, 73: 799-807. 193855

Pesola GR; Sunmonu Y; Huggins G; Ford JG (2004). Measured diffusion capacity versus prediction equation estimates in 

blacks without lung disease. Respiration, 71: 484-492. 193842

Prommer N; Schmidt (2007). Loss of CO from the intravascular bed and its impact on the optimised CO-rebreathing 

method. Eur J Appl Physiol, 100: 383-391. 180421

Proudman SM; Stevens WM; Sahhar J; Celermajer D (2007). Pulmonary arterial hypertension in systemic sclerosis: the 

need for early detection and treatment. J Intern Med, 37: 485-94. 186705

Richardson RS; Noyszewski EA; Saltin B; Gonzalez-Alonso J (2002). Effect of mild carboxy-hemoglobin on exercising 

skeletal muscle: Intravascular and intracellular evidence. Am J Physiol, 283: R1131-R1139. 037513

Sakamaki F; Oya H; Nagaya N; Kyotani S; Satoh T; Nakanishi N (2002). Higher prevalence of obstructive airway disease 

in patients with thoracic or abdominal aortic aneurysm. J Vasc Surg, 36: 35-40. 186706

Schachter LM; Dixon J; Pierce RJ; O'Brien P (2003). Severe gastroesophageal reflux is associated with reduced carbon 

monoxide diffusing capacity. Chest, 123: 1932-8. 186707

Scharte M; Bone HG; Van Aken H; Meyer J (2000). Increased carbon monoxide in exhaled air of critically ill patients. 

Biochem Biophys Res Commun, 267: 423-426. 194112

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

Shimazu T (2001). Half-life of blood carboxyhemoglobin. Chest, 119: 661-663. 016331

Shimazu T; Ikeuchi H; Sugimoto H; Goodwin CW; Mason AD Jr; Pruitt BA Jr (2000). Half-life of blood 

carboxyhemoglobin after short-term and long-term exposure to carbon monoxide. J Trauma, 49: 126-131. 016420

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

Takeuchi A; Vesely A; Rucker J; Sommer LZ; Tesler J; Lavine E; Slutsky AS; Maleck WA; Volgyesi G; Fedorko L; Iscoe 

S; Fisher JA (2000). A simple "new" method to accelerate clearance of carbon monoxide. Am J Respir Crit Care 

Med, 161: 1816-1819. 005675

Tarquini R; Masini E; La Villa G; Barletta G; Novelli M; Mastroianni R; Romanelli RG; Vizzutti F; Santosuosso U; Laffi G 

(2009). Increased plasma carbon monoxide in patients with viral cirrhosis and hyperdynamic circulation. Am J 

Gastroenterol, 104: 891-897. 194117

Terzano C; Conti V; Petroianni A; Ceccarelli D; De Vito C; Villari P (2009). Effect of Postural Variations on Carbon 

Monoxide Diffusing Capacity in Healthy Subjects and Patients with Chronic Obstructive Pulmonary Disease. 

Respiration, 77: 51-57. 108046

Tran TT; Martin P; Ly H; Balfe D; Mosenifar Z (2007). Carboxyhemoglobin and its correlation to disease severity in 

cirrhotics. J Clin Gastroenterol, 41: 211-215. 194120

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

Vreman HJ; Wong RJ; Stevenson DK; Smialek JE; Fowler DR; Li L; Vigorito RD; Zielke HR (2006). Concentration of 

Carbon Monoxide (CO) in Postmortem Human Tissues: Effect of Environmental CO Exposure. J Forensic Sci, 51: 

1182-1190. 098272

Weaver LK; Howe S; Hopkins R; Chan K (2000). Carboxyhemoglobin half-life in carbon monoxide-poisoned patients 

treated with 100% oxygen at atmospheric pressure. Chest, 117: 801-808. 016421

Whincup P; Papacosta O; Lennon L; Haines A (2006). Carboxyhaemoglobin levels and their determinants in older British 

men. BMC Public Health, 6: 189-197. 195129

Widdop B (2002). Analysis of carbon monoxide. Ann Clin Biochem, 39: 378-391. 030493

Wu L; Wang R (2005). Carbon monoxide: endogenous production, physiological functions, and pharmacological 

applications. Pharmacol Rev, 57: 585-630. 180411

January 2010 B-8 
Yamaya M; Hosoda M; Ishizuka S; Monma M; Matsui T; Suzuki T; Sekizawa K; Sasaki H (2001). Relation between 

exhaled carbon monoxide levels and clinical severity of asthma. Clin Exp Allergy, 31: 417-422. 180130

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

Yasuda H; Sasaki T; Yamaya M; Ebihara S; Maruyama M; Kanda A; Sasaki H (2004). Increased arteriovenous 

carboxyhemoglobin differences in patients with inflammatory pulmonary diseases. Chest, 125: 2160-2168. 191955

Yasuda H; Yamaya M; Nakayama K; Sasaki H (2005). Blood carbon monoxide will increase from a decline in pulmonary 

function alone 7. Am J Respir Crit Care Med, 172: 1231-1232. 102183

Yasuda H; Yamaya M; Yanai M; Ohrui T; Sasaki H (2002). Increased blood carboxyhaemoglobin concentrations in 

inflammatory pulmonary diseases. Thorax, 57: 779-783. 035206

Yerushalmi R; Kramer MR; Rizel S; Sulkes A; Gelmon K; Granot T; Neiman V; Stemmer SM (2009). Decline in 

pulmonary function in patients with breast cancer receiving dose-dense chemotherapy: a prospective study. Ann 

Oncol, 20: 437-440. 186711

Zegdi R; Perrin D; Burdin M; Boiteau R; Tenaillon A (2002). Increased endogenous carbon monoxide production in severe 

sepsis. Intensive Care Med, 28: 793-796. 037461

January 2010 B-9