Chapter 4. Dosimetry and 

Pharmacokinetics of Carbon Monoxide 

4.1. Introduction 

Inhaled ambient CO elicits various health effects by binding with and altering the function of a 

number of heme-containing molecules, mainly Hb. Traditional concepts for CO pathophysiology 

have been based on the high affinity of CO for hemoglobin, resulting in COHb formation and 

consequent reduction in O2-carrying capacity of blood and impaired O2 delivery to tissues. Research 

on CO pharmacokinetics dates back to the 1890s, but since the late 1970s has become limited. 

Current literature primarily focuses on endogenous CO produced by the metabolic degradation of 

heme by heme oxygenase (HO) and its role as a gaseous messenger. This chapter reviews the 

physiology and pharmacokinetics of CO. The chapter draws heavily from Chapter 5 of the previous 

AQCD (U.S. EPA, 2000, 000907). Relevant new data are included when available. Recent models of 

Hb binding are characterized, as well as measurements of tissue CO concentrations using new 

methods of extraction. 

CO binds with a number of heme-containing molecules including Mb and cytochromes, but 

none have been studied as extensively as Hb. The primary focus of this chapter is placed on the 

models and kinetics of such binding and the factors influencing this event. The chapter discusses 

effects at ambient or near ambient levels of CO leading to low COHb levels (≤ 5%); however few 

studies are available at ambient CO concentrations. Both human and animal studies using higher CO 

exposure concentrations, resulting in moderate to high COHb levels (<20%), are discussed where 

needed to understand CO kinetics, pathophysiologic processes, and mechanisms of cytotoxicity. 

Where human studies could not experimentally test certain hypotheses or were unavailable, animal 

experiments were used as surrogates. CO uptake and elimination has been shown to be inversely 

proportional to body mass over environmentally relevant exposure levels, meaning the smaller the 

animal, the faster the rate of absorption and elimination (Klimisch et al., 1975, 010762; Tyuma et al., 

1981, 011226). However, the basic mechanisms of CO toxicity between experimental animals and 

humans are similar and are thus extrapolated from animals to humans in this chapter, keeping in 

mind a number of interspecies differences. 

4.2. Carboxyhemoglobin Modeling 

4.2.1. The Coburn-Forster-Kane and Other Models 

Investigators have modeled the effect of CO binding to Hb in a number of ways. Empirical 

and mechanistic models are two distinct approaches that have been taken to model in vivo COHb 

formation after CO exposure. First, empirical models were used to predict COHb by regressing 

concentration and duration of exogenous CO exposure with observed COHb, with or without the 

inclusion of physiological predictors such as initial COHb levels and alveolar ventilation (VA). These 

methods were reviewed in depth in the previous AQCD (U.S. EPA, 2000, 000907). It is important to 

note that CO empirical regression models are limited to estimating COHb in the exact conditions on 

which the models were based. These simple models include those by Peterson and Stewart (1970, 

 

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 4-1 
012416) and Ott and Mage (1978, 011124), as well as various others (Chung, 1988, 012749; Forbes 

et al., 1945, 012850; Selvakumar et al., 1992, 013750; Sharan et al., 1990, 003798; Singh et al., 

1991, 013583). Using a linear differential equation where ambient CO concentrations varied, it was 

shown that the presence of brief ambient CO concentration spikes averaged over hourly intervals 

may lead to underestimating the COHb concentration by as much as 21% of the true value. To avoid 

this problem, it was suggested that ambient CO measurements be monitored and averaged over 10- 

to 15-min periods (Ott and Mage, 1978, 011124). Other empirical models predict COHb as a 

function of exposure time (Sharan et al., 1990, 003798; Singh et al., 1991, 013583) or exposure time 

and altitude (Selvakumar et al., 1992, 013750). A comparison of empirical model predictions showed 

a wide disparity in predicted COHb values, highlighting the inaccuracy of these models outside of 

the conditions on which they were presented (Tikuisis, 1996, 080960). 

Secondly, mechanistic models use physical and physiological processes and an understanding 

of biological processes to predict COHb production. The most commonly used mechanistic method 

for predicting levels of blood COHb after CO inhalation is the Coburn-Forster-Kane equation or 

CFK model developed in 1965 (Coburn et al., 1965, 011145). This differential equation was 

developed to examine endogenous CO production, using the major physiological and physical 

variables influencing this value. Since then, it has been shown to provide a good approximation to 

the COHb level at a steady level of inhaled exogenous CO (Peterson and Stewart, 1975, 010696; 

Stewart et al., 1973, 012428). The CFK model describes a four-element, physical system containing 

an exogenous CO source, a transfer interface, an endogenous CO source, and a storage compartment. 

The linear CFK model assumes O2Hb concentration is constant and is as follows in Equation 4-1: 

[ ] [ ]

[ ]

⎟

⎟

⎟

⎟

⎟

⎠

⎞

⎜

⎜

⎜

⎜

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⎝

⎛

− +

+

⎟

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⎠

⎞

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⎜

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− +

−=

• •

•

A

O2HB

L

I

A

O2HB

L

2

0 C 2

CO t

b

V

PP

COD

1

COP

V

PP

COD

1

1

MHbO

OPCOHb

V

dt

COHbd V

Equation 4-1 

Vb blood volume in milliliters (mL) 

[COHb]t COHb concentration at time t in mL CO/mL blood, at standard temperature and pressure, dry (STPD) 

VCO endogenous CO production rate in mL/min, STPD 

[COHb]0 COHb concentration at time zero in mL CO/mL blood, STPD 

[O2Hb] O2Hb concentration in mL O2/mL blood, STPD 

PCO2 average partial pressure of O2 in lung capillaries in mmHg 

M Haldane coefficient representing the CO chemical affinity for Hb 

DLCO lung diffusing capacity of CO in mL/min/mmHg, STPD 

PB barometric pressure in mmHg 

PH2O saturation pressure of water vapor at body temperature in mmHg (47 mmHg) 

VA alveolar ventilation in mL/min, STPD 

PICO CO partial pressure in inhaled air in mmHg 

The linear CFK model assumes instant equilibration of COHb concentration between venous 

and arterial blood, gases in the lung, and COHb concentrations between blood and extravascular 

tissues, which is not physiologically representative. The nonlinear CFK equation extends the linear 

CFK equation to incorporate the interdependence of COHb and O2Hb levels since they are derived 

from the same pool of blood Hb. This interdependence can be modeled by substituting (1.38 Hb 

[COHb]) for O2Hb, where THb refers to the number of grams of Hb per mililiter of blood (Peterson 

and Stewart, 1975, 010696). The nonlinear CFK differential equation is as follows in Equation 4-2: 

January 2010 4-2 
⎟

⎟

⎟

⎟

⎟

⎠

⎞

⎜

⎜

⎜

⎜

⎜

⎝

⎛

− +

+

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− + − −=

• •

•

A

O2HB

L A

O2HB

L

b t

0 C 2 CO t

b

V

PP

COD

1

1

V

PP

COD

1

1

M)]COHb[]TH[38.1(

OP]COHb[ V

dt

]COHb[d V

Equation 4-2 

The nonlinear equation is more physiologically accurate; however the linear CFK equation 

gives a good approximation to the nonlinear solution over a large range of values during CO uptake 

and during low levels of CO elimination (Smith, 1990, 013164). The linear equation prediction of 

COHb concentration at or below 6% will deviate by no more than ± 0.5% COHb from the nonlinear 

equation prediction. Sensitivity analysis of the CFK equations has shown that alterations in each 

variable of the equation will affect the outcome variably at different times of exposure, so that the 

relative importance of the CFK variables will change with the experimental conditions (McCartney, 

1990, 013162). Figure 4-1 illustrates the temporal changes in fractional sensitivities of the principal 

physiological determinants of CO uptake for the linear form of the CFK equation, where THb is the 

total blood concentration of Hb in g Hb/mL blood and FICO is the fractional concentration of CO in 

ambient air in ppm. The fractional sensitivity of unity means that, for example, a 5% error in the 

selected variable induces a 5% error in the predicted COHb value by the nonlinear model. As Figure 

4-1 demonstrates, a constant or given percent error in one variable of the model does not generally 

produce the same error in the calculated blood COHb, and the error is time dependent. Thus, each 

variable influencing CO uptake and elimination will exert its maximal influence at different times of 

exposure. This analysis found that only FICO (shown in Figure 4-1) and VCO will not affect the rate 

at which equilibrium is reached (McCartney, 1990, 013162). 

January 2010 4-3 
Source: Adapted with Permission of the American Industrial Hygiene Association from McCartney (1990, 013162) 

Figure 4-1. Plot of fractional sensitivities of selected variables versus time of exposure. 

The mechanistic CFK model contains a number of assumptions under which the model is 

solely applicable, including: (1) ventilation is a continuous process; (2) equilibrium between plasma 

CO concentration and COHb concentration is obtained in the pulmonary system; (3) percent COHb 

can exceed 100% saturation in the linear model; and (4) it does not account for the shape of the O2 or 

CO saturation versus pO2 or pCO relation (McCartney, 1990, 013162). Estimations outside of these 

assumptions have been attempted but with less predictive agreement. For example, transient 

exposures such as those that would simulate everyday conditions would violate the assumption of a 

single, well-mixed vascular compartment. COHb levels during exposure of subjects exposed to 

frequent but brief high CO exposures (667-7,500 ppm for 75 s to 5 min) were not accurately 

predicted by CFK modeling (Benignus et al., 1994, 013908; Tikuisis et al., 1987, 012219; Tikuisis et 

al., 1987, 012138). Consistently, the COHb value predicted by the nonlinear CFK overpredicted 

observed venous COHb (0.8-6%) and underpredicted arterial COHb (1.5-6.1%) and this disparity 

increased after exercise. Individual differences between arterial and venous COHb varied from 

2.3-12.1% COHb (mean, 6.2 ± 2.7% COHb), where the observed steady state COHb averaged ~14% 

and the observed arterial peak COHb averaged ~17.5% (Smith et al., 1994, 076564)(Benignus et al., 

1994, 013908). These inaccuracies between measured and predicted COHb values disappeared after 

simulated mixing of arterial and venous blood and thus are likely due to delays in mixing of arterial 

and venous blood and differences in cardiac output and lung wash-in. This discrepancy in predicted 

and observed COHb suggests that over a short period (<10 min) the arterial COHb levels that are 

delivered to tissues could be higher than what is predicted by the CFK equation. A modified CFK 

was created to adjust for these issues and produce a more accurate COHb prediction (Smith et al., 

1994, 076564). This expanded CFK model used multiple compartments to model the lung, arm 

circulation, and the rest of the body (quickly and slowly perfused tissues). This model was more 

January 2010 4-4 
accurate than the nonlinear CFK in predicting the individual peak or maximal values of arterial and 

venous COHb during CO uptake in the first 10 min after exposure. However, both the nonlinear 

CFK and this expansion produced accurate predictions several minutes after the 5-min exposure 

ended. The expanded model required the use of two parameters, VA and Vb, that were not measured 

individually or derived from the literature, and instead were estimated by adjustments between the 

simulations and experimental subject data. 

In addition to the limitations discussed above, the CFK model does not account for 

extravascular storage sites for CO, such as muscle Mb. CO will undergo reversible muscle Mb 

binding, similar to Hb, as well as uptake into other extravascular tissues (Vreman et al., 2006, 

098272). The most recent adaptation to the CFK equation incorporates alveoli-blood and bloodtissue CO exchanges and mass conservation of CO at all times (Gosselin et al., 2009, 190946). This 

model has a single free parameter whose value is estimated from one data set; however, it better 

predicted COHb formation over a wide range of CO levels and several temporal scenarios (Stewart 

et al., 1970, 013972; Tikuisis et al., 1987, 012138; Tikuisis et al., 1987, 012219; Tikuisis et al., 1992, 

013592) compared to the linear CFK model. Like the linear CFK model, this modified model 

assumes a constant level of oxyhemoglobin. Sensitivity analysis of the model showed that the most 

important parameter influencing the level of COHb in this model is M, followed by PCO2 and VA. 

Ambient exposure scenarios were simulated with this model to determine the CO concentrations 

needed to reach certain COHb levels in humans from 3 months of age to 40-yr-old adults (Gosselin 

et al., 2009, 190946). The CO concentrations needed to achieve 2% COHb vary from 24.4-48.1 ppm 

for a 1-h exposure, from 11.1-13.1 ppm for an 8-h exposure, and from 9.8-10.1 ppm for a daily 

exposure. Infants (1 yr old) were most sensitive to CO concentrations, whereas newborns (3 mo old) 

required the highest CO concentration to reach 2% COHb. Newborns required a higher CO exposure 

partially because the values used in the model for the newborn blood Hb concentration (170 gHb/ 

Lblood) is higher than at infancy (115 gHb/Lblood) or adulthood (150 gHb/Lblood). The model was also 

used to simulate time profiles of COHb formation for two work week exposure scenarios in a 

healthy 40-yr-old man. Figure 4-2A represents a high exposure scenario where the work period is 

spent at 35 ppm and the rest of the time at 3 ppm. Figure 4-2B represents a lower exposure scenario 

where there is a constant 3 ppm exposure. Both figures consist of 5 days where 24 h are broken up 

into 3 consecutive 8-h periods: sleeping from 12 a.m. to 8 a.m.; working with light exercise from 8 

a.m. to 4 p.m.; and sitting from 4 p.m. to 12 a.m.. 

January 2010 4-5 
Source: Reprinted with Permission of Informa Healthcare from Gosselin et al. (2009, 190946) 

Figure 4-2. Simulated COHb formation for two 5-day workweeks. “The 24-h day consists of 3 

consecutive 8-h periods: sleeping from 12 a.m. to 8 a.m.; working (light exercise) 

from 8 a.m. to 4 p.m.; and sitting from 4 p.m. to 12 a.m. (A) High exposure: work 

period at 35 ppm and the rest of the time at 3 ppm. (B) Low daily exposure at 

3 ppm. The CO exposure periods are represented by dotted lines 

(----) and the COHb simulations by solid lines (—).” 

4.2.2. Multicompartment Models 

A third approach applied more recently to model COHb formation is the use of 

multicompartment or physiologically-based pharmacokinetic (PBPK) models. Cronenberger et al. 

(2008, 194085) described a two-compartment population-based model to describe and predict COHb 

pharmacokinetics from smoking. This model required a compartment for extravascular binding of 

January 2010 4-6 
CO to accurately predict COHb formation during multiple short and rapid inhalations followed by a 

period of no exposure, as occurs in smoking. 

A five-compartment PBPK model has been proposed to predict CO uptake and distribution 

from acute inhalation exposure and contains components for lung, arterial blood, venous blood, 

muscle tissue, and nonmuscle tissue (Bruce and Bruce, 2003, 193975; Bruce and Bruce, 2006, 

193980; Bruce et al., 2008, 193977). This model structure is illustrated in Figure 4-3 and includes 

the dynamics of CO storage in the lung and its dependence on ventilation and CO pressure of mixed 

venous blood, relaxes the assumption that Hb is saturated by including the role of CO in altering the 

O2 dissociation curve, includes a subcompartmentalized muscle tissue compartment, accounts for 

dissolved CO in blood and tissue, and predicts COHb based on age and body dimensions. This 

multicompartment model is limited by its exclusion of cellular metabolism or Mb diffusion, 

simplification of within tissue bed spatial variability, and assumption that ventilation and average 

partial pressure of alveolar O2 (PAO2) are constant. Another limitation of this model is that some of 

the physiological parameters used in simulations are estimated through visual fits to the COHb 

profile and not from experimental or published data. This model better predicts COHb levels when 

inspired CO levels change rapidly or when incomplete blood mixing has occurred, and better 

predicts the CO washout time course compared to the CFK equation. Bruce and Bruce (2003, 

193975) compared the two models and found similar results for long-duration exposure settings 

(1,000 min); however, the multicompartment model predicted somewhat lower COHb levels 

compared to the CFK model during transient CO uptake conditions when using data taken from 

Peterson and Stewart (1970, 012416). 

Source: Adapted with Permission of Elsevier Science from Bruce and Bruce (2008, 193977) 

Figure 4-3. Overall structure of the Bruce and Bruce (2008, 193977) multicompartment model 

of storage and transport of CO. Includes compartments for lung, arterial blood, 

venous blood, muscle tissue, and nonmuscle tissue. The muscle compartment is 

divided into two subcompartments for diffusion of gases within the tissue. 

January 2010 4-7 
A multicompartment model of the human respiratory system was developed using 

characteristics of the tissue representation of Bruce and Bruce (2003, 193975), and the lung 

representation described in Selvakumar et al. (1992, 013750) and Sharan (1999, 194673), which 

considered the exchanges of CO, O2, and CO2 (Neto et al., 2008, 194672). The model contains six 

compartments including: alveolar, pulmonary capillaries, arterial, venous, tissue capillary, and 

tissues (muscular and non-muscular). The model was applied to four simulated physical activity 

levels, resting, sitting, standing, and walking, in a healthy subject exposed to the urban atmosphere 

of a metropolitan area of Brazil. The highest and lowest COHb levels were simulated in the walking 

individual, suggesting that greater variability in COHb occurs at higher physical activity levels. 

4.2.3. Model Comparison 

A number of models have been presented which predict COHb formation over numerous 

exposure scenarios. These models are often compared to the CFK equation to determine the most 

accurate predictive model under certain exposure conditions. As was mentioned in Section 4.2.1, 

Tikuisis (1996, 080960) conducted a comparison of empirical model predictions that showed a wide 

disparity in predicted COHb values, highlighting the inaccuracy of these models outside of the 

conditions on which they were presented. Smith et al. (1990, 013164) compared the linear and 

nonlinear CFK equations and concluded that the linear CFK equation gives a good approximation 

(within 1%) to the nonlinear solution over a large range of values during CO uptake and over a 

somewhat smaller range during CO elimination. The linear equation prediction of COHb 

concentration at or below 6% will only differ ± 0.5% COHb from the nonlinear equation prediction. 

Additionally, the most recently modified CFK model (Gosselin et al., 2009, 190946) better predicted 

COHb formation over a wide range of CO levels (50-4,000 ppm) and several temporal scenarios 

(Stewart et al., 1970, 013972; Tikuisis et al., 1987, 012138; Tikuisis et al., 1987, 012219; Tikuisis et 

al., 1992, 013592) compared to the linear CFK model. Linear regression slopes between the 

simulated COHb values from Gosselin et al. (2009, 190946) and the observed experimental values 

were closer to 1 in all experimental scenarios, indicating a better fit to the observed data. When 

evaluating all validation studies the modified model had an estimated slope of 0.996 (95% CI: 

0.986-1.001) compared to 0.917 (95% CI: 0.906-0.927) using the linear CFK model. Bruce and 

Bruce (2003, 193975) compared their model to the CFK and found similar results for long-duration 

exposure settings (1,000 min [16.5 h]), however, their multicompartment model predicted somewhat 

lower COHb levels over transient CO uptake conditions when using data taken from Peterson and 

Stewart (1970, 012416). The Bruce and Bruce model better predicts However, there has not been a 

quantitative comparison of the recent multicompartment models (Bruce and Bruce, 2003, 193975; 

Neto et al., 2008, 194672) and the improved CFK equation models (Gosselin et al., 2009, 190946; 

Smith et al., 1994, 076564) to determine which is most accurate in predicting COHb levels under 

exposure scenarios that include occasional peak concentrations. The nonlinear and linear CFK 

equations remain the most extensively validated and applied models for COHb prediction. COHb 

levels when inspired CO levels change rapidly or when incomplete blood mixing has occurred, and 

better predicts the CO washout time course compared to the CFK equation. However, there has not 

been a quantitative comparison of the recent multicompartment models (Bruce and Bruce, 2003, 

193975)(Neto et al., 2008, 194672) and the improved CFK equation models (Smith et al., 1994, 

076564)(Gosselin et al., 2009, 190946) to determine which is most accurate in predicting COHb 

levels under exposure scenarios that include occasional peak concentrations. The nonlinear and 

linear CFK equations remain the most extensively validated and applied models for COHb 

prediction. 

4.2.4. Mathematical Model Usage 

As no new data have become available on the distribution of COHb levels in the U.S. 

population since large-scale nationwide surveys – e.g., National Health and Nutrition Examination 

Survey II (NCHS; et al., 1982, 011442) – and human exposure field studies – e.g., Denver, CO, and 

Washington, DC (Akland et al., 1985, 011618) – were conducted in the 1970s and 1980s, 

mathematical models are used to predict the resulting COHb levels from various CO exposure 

scenarios. Table 4-1 illustrates the predictions of venous COHb after 1, 8, or 24 h of CO exposure at 

a range of concentrations in a healthy adult human at rest (VA = 6 L/min; DLCO = 20 

January 2010 4-8 
[mL/min]/mmHg), during light exercise (VA = 15 L/min; DLCO = 34 [mL/min]/mmHg), and during 

moderate exercise (VA = 22 L/min; DLCO = 43 [mL/min]/mmHg). The Quantitative Circulatory 

Physiology (QCP) model, which integrates human physiology using over 4,000 variables and 

equations based on published biological interactions, was used to predict these values (Abram et al., 

2007, 193859; Benignus et al., 2006, 151344). This dynamic whole body model uses the nonlinear 

CFK equation with modifications presented in Smith et al. (1994, 076564). The contribution of 

alveolar ventilation and lung diffusion to the changes in COHb levels is discussed in Section 4.3.1.2. 

Increased ventilation leads to an increased rate of CO uptake, causing COHb levels to reach 

equilibrium earlier. Also, increased ventilation leads to a decrease in steady state COHb levels due to 

increased CO expiration. For example, 35 ppm CO exposure at moderate exercise (22 L/min) results 

in a lower 24-h COHb saturation (4.73%), compared to COHb saturation from 35 ppm CO at rest 

(5.03%) (Table 4-1). Whereas, after 1 h, COHb levels are still increasing following exposure at all 

levels of exercise and have not reached steady state, thus the greater uptake from increased 

ventilation leads to initially elevated COHb in higher ventilation situations. 

Endogenous CO production varies as described in Section 4.5 but generally results in <1% 

COHb, with a QCP modeled value of 0.27% at time zero. The rate of endogenous CO production 

was set at 0.007 mL/min for this simulation, whereas both higher and lower values have been 

reported (Coburn et al., 1966, 010984) (Section 4.5). Table 4-1 illustrates that 35 ppm CO for 1-h 

results in between 0.9-1.9% COHb and 9 ppm CO for 8-h results in between 1.1-1.3% COHb, 

depending upon activity level. Also, this table shows that low concentration CO exposure over 

several hours can result in equivalent COHb levels compared to higher concentration, acute 

exposure. For example, in a resting condition without additional baseline COHb, COHb resulting 

from 35 ppm for 1 h (0.89%) is approximately equivalent to 6 ppm for 8 h (0.83%) or 4 ppm for 24 h 

(0.82%). 

Table 4-1. Predicted COHb levels resulting from 1, 8, and 24 h CO exposures in a modeled human 

at rest (VA = 6 L/min; DLCO = 20 (mL/min)/mmHg; VCO = 0.007 mL/min; 

initial COHb = 0.27%; Hb = 0.15 g/mL), during light exercise (VA = 15 L/min; 

DLCO = 34 (mL/min)/mmHg), and during moderate exercise (VA = 22 L/min; DLCO = 

43 (mL/min)/mmHg). The QCP model used a dynamic nonlinear CFK with the Smith 

et al. (1994, 076564) COHb algorithm and affinity constant M = 218. 

1 h 8 h 24 h 

CO (ppm) 6 L/min 15 L/min 22 L/min 6 L/min 15 L/min 22 L/min 6 L/min 15 L/min 22 L/min 

2 0.30 0.30 0.29 0.45 0.38 0.35 0.54 0.40 0.36 

3 0.31 0.33 0.34 0.54 0.51 0.48 0.68 0.54 0.49 

4 0.33 0.36 0.62 0.64 0.64 0.62 0.82 0.69 0.63 

6 0.36 0.44 0.48 0.83 0.90 0.88 1.10 0.97 0.91 

9 0.42 0.55 0.63 1.12 1.29 1.27 1.52 1.39 1.31 

15 0.53 0.77 0.92 1.69 2.05 2.06 2.35 2.22 2.12 

24 0.70 1.10 1.35 2.55 3.19 3.22 3.57 3.45 3.31 

35 0.89 1.50 1.89 3.58 4.55 4.60 5.03 4.91 4.73 

The QCP model incorporating the Smith et al. (1994, 076564) COHb algorithm was also used 

to simulate population exposure scenarios including various commuting concentrations (Figure 4-4) 

and endogenous production rates (Figure 4-5). Commuting concentrations were modeled since the 

highest ambient CO exposure levels are generally observed during transit (Section 3.6.6.2). Figure 

4-4 presents simulated COHb levels in a healthy adult throughout the second of 5 modeled days 

containing a 60-min commute at various CO concentrations. The U.S. Census Bureau estimates that 

5% of the population commutes in automobiles for 60 or more minutes to work daily 

(U.S. Census Bureau, 2008, 194013) and exposure studies have reported in-vehicle transit 

concentrations up to 50 ppm (Abi-Esber and El-Fadel, 2008, 190939; Duci et al., 2003, 044199). 

However, U.S. studies have reported in-vehicle concentrations of <6 ppm, although peak 

January 2010 4-9 
concentrations in congested urban areas have been reported to be higher than 50 ppm (Rodes et al., 

1998, 010611)(Riediker et al., 2003, 043761). CO concentrations during commuting lead to spikes in 

COHb in this model scenario with a 1% COHb increase over the initial COHb (0.3%) after 50 ppm 

exposure. Figure 4-4 also illustrates that the COHb saturation after CO exposure from commuting is 

not fully eliminated by the next commuting period. Modeling successive days results in the same 

pattern and degree of COHb formation, indicating no accumulation of COHb over time. 

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 360 720 1080 1440

Time (min)

COHb (%)

2 ppm 10 ppm 20 ppm 50 ppm

Figure 4-4. Predicted COHb levels in healthy commuters exposed to various CO 

concentrations over a 60-min commute twice a day. Ambient CO concentration 

not during commuting time was 1 ppm. The activity pattern simulated: (1) 

sleeping for 8 h; (2) standing and light exercise for 30 min; (3) sitting during a 

60-min commute; (4) light exercise for 8.5 h; (5) sitting during a second 60-min 

commute; (6) moderate exercise for 60 min; and (7) sitting for 4 h. The graph 

illustrates the second day simulated under these conditions.1

Figure 4-5 presents simulated COHb levels in adults with various endogenous CO production 

rates throughout the second of 5 modeled days containing a 60-min commute at 20 ppm CO. The 

normal endogenous rate of CO production in young adult males with an average COHb of 0.88% 

averages 0.007 mL/min (18.7 ± 0.8 μmol/h) (Coburn et al., 1963, 013971). However, a number of 

diseases and conditions described in Section 4.5 can affect this production rate. Patients with 

 

1

 Sleeping/lying human parameters: VA- 3.8 L/min, VT- 467 mL, VD- 147 mL, VCO- 0.007 mL/min, DLCO- 17.9 mL/min/mmHg, M- 218, 

initial. COHb- 0.27%. Sitting human parameters: VA- 5.2 L/min, VT- 560 mL, VD- 155 mL, VCO- 0.007 mL/min, DLCO- 18 

mL/min/mmHg. Standing human parameters: VA- 6.4 L/min, VT- 636 mL, VD- 161 mL, VCO- 0.007 mL/min, DLCO- 19.3 mL/min/mmHg. 

Light exercise (1 MPH, 32 W) human parameters: VA- 13.4 L/min, VT- 994 mL, VD- 218 mL, VCO- 0.007 mL/min, DLCO- 30.4 

mL/min/mmHg. Heavy exercise (3 MPH, 96 W) human parameters: VA- 31.4 L/min, VT- 1642 mL, VD- 241 mL, VCO- 0.007 mL/min, 

DLCO- 49.6 mL/min/mmHg. 

January 2010 4-10 
hemolytic anemia have endogenous CO production rates ranging from 0.012 to 0.053 mL/min 

(31-143 μmol/h) (Coburn et al., 1966, 010984). The venous COHb levels in these same patients 

ranged from 0.77 to 2.62%. 

0

0.5

1

1.5

2

2.5

3

3.5

0 360 720 1080 1440

Time (min)

COHb (%)

0.007 mL/min 0.02 mL/min 0.04 mL/min 0.06 mL/min

Figure 4-5. Predicted COHb levels due to various endogenous CO production rates. The 

activity pattern presented in Figure 4-4 was used. Ambient CO concentration not 

during commuting time was 1 ppm and commuting CO concentration was 

20 ppm. The graph illustrates the second day simulated under these conditions. 

4.3. Absorption, Distribution, and Elimination 

4.3.1. Pulmonary Absorption 

Pulmonary uptake of CO accounts for all environmental CO absorption and occurs at the 

respiratory bronchioles and alveolar ducts and sacs. CO and O2 share various physico-chemical 

properties, thus allowing for the extension of the knowledge about O2 kinetics to those of CO despite 

the differences in the reactivity of the gases. The exchange of CO between the air and the body 

depends on a number of physical (e.g., mass transfer and diffusion), as well as physiological factors 

(e.g., alveolar ventilation and cardiac output), which are controlled by environmental conditions, 

physical exertion, and other processes discussed in Section 4.4. The ability of the lung to take up 

inhaled CO is measured by DLCO, and CO uptake representing the product of DLCO and the mean 

alveolar pressure (PACO). The importance of dead space volume, gas mixing and homogeneity, and 

January 2010 4-11 
ventilation/perfusion matching were discussed in depth in the 2000 CO AQCD (U.S. EPA, 2000, 

000907). 

4.3.1.1. Mass Transfer of Carbon Monoxide 

Mass transfer refers to the molecular and convective transport of CO molecules within the 

body stores, driven by random molecular motion from high to low concentrations. CO enters through 

the airway opening (mouth and nose) and transfers in a gas phase to the alveoli. CO transport is due 

to convective flow, the mechanical action of the respiratory system, and diffusion in the acinar zone 

of the lung (Engel et al., 1973, 014336). Then, CO diffuses across the air-blood interface into plasma 

and subsequently into red blood cells (RBC), binding RBC Hb. At environmental CO levels, CO 

uptake into RBC is limited by the reaction rate of binding of CO to O2Hb forming COHb. 

Pulmonary capillary RBC CO diffusion is rapidly achieved (Chakraborty et al., 2004, 193759; 

Gibson and Roughton, 1955, 193941; Reeves and Park, 1992, 193847; Roughton and Forster, 1957, 

193862). The formation rate and level of COHb depends upon pCO, pO2 in the air, time of exposure, 

and the ventilation rate (Roughton and Forster, 1957, 193862). Most of the body CO is bound to Hb; 

however, 10-15% of the total body CO is located in extravascular tissues primarily bound to other 

heme proteins (Coburn, 1970, 013916). Considerable concentrations of CO have been measured in 

spleen, lung, kidney, liver, muscle, and heart (Vreman et al., 2005, 193786; Vreman et al., 2006, 

098272), whereas less CO is localized to fatty tissues, such as adipose and brain. The transfer of CO 

occurs by a partitioning of CO between Hb and tissue. Less than 1% of the total body CO stores 

appear as dissolved in body fluids, due to the insolubility and small tissue partial pressure of CO 

(Coburn, 1970, 013916). Transport pathways and body stores of CO are shown in Figure 4-6. 

Source: Adapted with Permission of Wiley-Blackwell from Coburn (1967, 011144) 

Figure 4-6. Diagrammatic presentation of CO uptake and elimination pathways and CO body 

stores. 

4.3.1.2. Lung Diffusion of Carbon Monoxide 

Lung diffusion of CO is an entirely passive process of gas diffusion across the alveolocapillary membrane, through the plasma, across the RBC membrane and into the RBC stroma, where 

January 2010 4-12 
CO binding to Hb rapidly occurs. Membrane and blood phase transfer are governed by physicochemical laws, including Fick’s first law of diffusion. The diffusing capacity of the lung for CO, 

represented as DLCO, is a measurement of the partial pressure difference between inspired and 

expired CO. Due to the rapid binding of CO to Hb, a high pressure differential between air and blood 

exists when CO air levels are increased. Inhalation of CO-free air reverses the pressure differential 

(higher CO pressure on the blood side than the alveolar side), and then CO is released into the 

alveolar air. Since CO is also produced endogenously, CO release will also be affected by this 

production pressure. However, the air-blood gradient for CO is usually higher than the blood-air 

gradient; therefore, CO uptake will be a proportionately faster process than CO elimination. 

A number of factors have been found to affect DLCO including Hb concentration, cardiac 

output (Q), erythrocyte flow, COHb concentration, PACO2, body position, exercise, time of day, age, 

etc. (Forster, 1966, 180430; Hsia, 2002, 193857). DLCO consistently decreases after intense bouts of 

exercise, likely due to the redistribution of blood volume to the periphery (Hanel et al., 1997, 

193918; Manier et al., 1991, 193979). However, in going from rest to exercise, DLCO can increase 

linearly from: lung expansion leading to unfolding and distension of alveolar septa, opening and/or 

distension of capillaries as Q increases, increased capillary hematocrit, and more homogeneous 

distribution of capillary erythrocytes (Hsia, 2002, 193857). DLCO is less dependent upon lung 

volume at mid-range vital capacity, but at extreme volumes the diffusion rate is varied, higher than 

average at total lung capacity and lower at residual volume (McClean et al., 1981, 012411). 

DLCO is also altered by a number of diseases. Decreased DLCO is evident in patients with 

restrictive lung disease (i.e., decreased lung volumes) since a loss of lung tissue leads to a loss of 

functional lung units. DLCO also shows a good correlation with the severity of restrictive lung 

disease (Arora et al., 2001, 186713). Conditions affecting DLCO vary and include chronic 

obstructive pulmonary disease (Terzano et al., 2009, 108046), ulcerative colitis (Marvisi et al., 2000, 

186703; Marvisi et al., 2007, 186702), severe gastroesophageal reflux (Schachter et al., 2003, 

186707), beta thalassemia (Arora et al., 2001, 186713), thoracic or abdominal aortic aneurysm 

(Sakamaki et al., 2002, 186706), pulmonary arterial hypertension (Proudman et al., 2007, 186705), 

and chemotherapy for breast cancer (Yerushalmi et al., 2009, 186711). Diseases affecting CO 

kinetics and DLCO are also discussed in Section 4.4.4. 

4.3.2. 

4.3.2.1.

Tissue Uptake 

Respiratory Tract 

The upper respiratory tract contributes little to the overall CO uptake. The lung has nearly 

constant exposure to CO; however, relatively little CO diffuses into the tissue except at the alveolar 

region en route to the circulation. No detectable uptake of CO was observed in the human nasal 

cavity or upper airway (Guyatt et al., 1981, 011196) or in the monkey oronasal cavity after high CO 

exposure (Schoenfisch et al., 1980, 011404). 

4.3.2.2. Blood 

The blood is the largest reservoir for CO, where it reversibly binds to Hb. The chemical 

affinity of CO for adult human Hb is approximately 218 times greater than that of O2, meaning one 

part CO and 218 (210-250) parts O2 would form equal parts of O2Hb and COHb (Engel et al., 1969, 

193914; Rodkey et al., 1969, 008151; Roughton, 1970, 013931). This would happen when breathing 

air containing 21% O2 and 960 ppm CO. This concept was presented by Haldane and Smith (1895, 

010538) and later represented as the Haldane constant M (210-250) in the Haldane equation by 

Douglas, Haldane, and Haldane (1912, 013965). M is relatively unaffected by changes in 

physiological pH, CO2, temperature, or 2,3-diphosphoglycerate: 

( ) ÷ 2 = × ÷ pOpCOMHbOCOHb 2

Equation 4-3 

The Hb association rate for CO is 10% slower than O2 and occurs in a cooperative manner 

(Chakraborty et al., 2004, 193759; Sharma et al., 1976, 193766). Hb is composed of four globin 

January 2010 4-13 
chains, each containing a heme group capable of binding CO or O2. The associative reaction rates 

become faster with successive heme binding, attributed to interactions within the protein and to 

strains imposed on the heme and its ligands (Alcantara et al., 2007, 193867). More simply, the 

greater the number of heme sites bound to CO, the greater the affinity of free heme sites for O2, thus 

causing Hb to bind and retain O2 that would normally be released to tissues. Cooperativity is greatly 

reduced in CO dissociation, but the rate of dissociation of CO from Hb is orders of magnitude slower 

than O2 (kCO = 4 × 10-4 kO2), which accounts for the high affinity values (Chakraborty et al., 2004, 

193759). The half-time of dissociation reaction is about 11 s at 37°C (Holland, 1970, 193856). In 

general, CO uptake to COHb equilibrium is slower in humans and large animals, requiring 8-24 h, 

than in smaller species such as rats, which will equilibrate in 1-2 h (Penney, 1988, 012519). Also, 

COHb equilibrium within the blood stream is not instantaneous. Men exposed to brief (~5 min) 

high-dose CO had an initial delay of 1-2 min in the appearance of venous COHb after the start of CO 

inhalation (Benignus et al., 1994, 013908; Smith et al., 1994, 076564). Additionally, arterial COHb 

concentrations were considerably higher than venous concentrations during CO exposure; however, 

they converged within 2-10 min after the end of exposure, as venous and arterial blood mixed. 

CO binding to Hb also has effects on the O2 dissociation curve of the remaining Hb by shifting 

the curve progressively to the left and altering the normal S-shaped curve to become more 

hyperbolic due to increased cooperative O2 binding (Roughton, 1970, 013931). This is referred to as 

the “Haldane effect” and causes tissues to have more trouble obtaining O2 from the blood, even 

compared to the same extent of reduced Hb resulting from anemia. For example, Figure 4-7 (as 

explained in the 2000 CO AQCD) illustrates that in an acute anemia patient (50% of Hb) at a venous 

pO2 of 26 mmHg (v′1), 5 vol % of O2 (50% saturation) was extracted from the blood. In contrast, for 

a CO poisoned person with 50% COHb, the venous pO2 will have to drop to 16 mmHg (v′2) to 

release the same 5 vol % O2. This more severe effect on O2 pressure may lead to brain O2 depletion 

and loss of consciousness if any higher demand of O2 is needed (e.g., exercise). 

January 2010 4-14 
Source: U.S. EPA (1991, 017643) 

Figure 4-7. O2Hb dissociation curve of normal human blood, of blood containing 50% COHb, 

and of blood with only 50% Hb because of anemia. 

4.3.2.3. Heart and Skeletal Muscle 

Mb is a globular heme protein that facilitates O2 diffusion from the muscle sarcoplasm to 

mitochondria, acting as an O2 supply buffer to maintain adequate pO2 for mitochondria when the O2

supply changes, as in exercise. O2 has a greater affinity for Mb than Hb, which allows small changes 

in tissue pO2 to release large amounts of O2 from O2Mb (Wittenberg et al., 1975, 012436). Small 

reductions in O2 storage capacity of Mb, due to CO binding, may have a profound effect on the 

supply of O2 to the tissue. 

Like Hb, Mb will undergo reversible CO binding, however the affinity constant is 

approximately eight-times lower than Hb (M = 20-40 versus 218, respectively) (Haab, 1990, 

013359). The association rate constant of CO and Mb is approximately 27 times lower than O2; 

however, the dissociation rate constant is approximately 630 times lower than O2 (Gibson et al., 

1986, 016289), causing CO to be retained and possibly stored in the muscle. CO levels have been 

measured in human muscle and heart tissues with <2% COHb concentrations at background levels 

January 2010 4-15 
(15 and 31 picomole [pmol] CO/mg ww, respectively) (Vreman et al., 2006, 098272) (Table 4-2). 

Under conditions of CO asphyxiation, tissue concentrations increased 17-18 fold (265 and 527 pmol 

CO/mg ww muscle and heart tissue, respectively); however, heart tissue concentrations varied 

widely between individuals. Mouse muscle did not show this increase after exogenous CO exposure 

(Vreman et al., 2005, 193786). This may be due to the fact that human muscle has a 15-fold higher 

concentration of myoglobin protein than mouse muscle (Weller et al., 1986, 187298). The capacity 

for diffusion of CO into the muscle is represented by the coefficient DmCO and is generally larger in 

males than in females, likely due to the differences in muscle mass and capillary density (Bruce and 

Bruce, 2003, 193975). COMb concentrations in the heart and skeletal muscle increase with work 

load, due to a higher relative rate of CO binding to Mb relative to Hb. This causes an increase in 

COMb/COHb that is not seen at rest (Sokal et al., 1984, 011591). Subjects with 2% COHb but not 

those with 20% COHb levels showed a significant uptake of CO from the blood to the muscle with 

increasing work intensity of the quadriceps muscle (Richardson et al., 2002, 037513). 

Table 4-2. CO concentration in pmol/mg wet weight tissue and fold tissue CO concentration 

changes (normalized to background tissue concentrations) – human. 

Exposure Adipose Brain Muscle Heart Kidney Lung Spleen Blood % COHb 

Background 3 ± 1 3 ± 3 15 ± 9 31 ± 23 23 ± 18 57 ± 59 79 ± 75 165 ± 143 1.5 ± 1.2 

Fire 5 ± 4 

[1.7] 

7 ± 5 

[2.3] 

24 ± 16 

[1.6] 

54 ± 33 

[1.7] 

27 ± 11 

[1.2] 

131 ± 127 

[2.3] 

95 ± 69 

[1.2] 

286 ± 127 

[1.7] 

3.8 ± 3.2 

[2.5] 

Fire + CO 18 ± 29 

[6.0] 

17 ± 14 

[5.7] 

168 ± 172 

[11.2] 

128 ± 63 

[4.1] 

721 ± 427 

[31.3] 

1097 ± 697 

[19.2] 

2290 ± 1409 

[29.0] 

3623 ± 1975 

[22.0] 

40.7 ± 28.8 

[27.1] 

CO asphyxiation 25 ± 27 

[8.3] 

72 ± 38 

[24.0] 

265 ± 157 

[17.7] 

527 ± 249 

[17.0] 

885 ± 271 

[38.5] 

2694 ± 1730 

[47.3] 

3455 ± 1347 

[43.7] 

5196 ± 2625 

[31.5] 

56.4 ± 28.9 

[37.6] 

Source: Reprinted with Permission of Wiley-Blackwell from Vreman et al. (2006, 098272)

4.3.2.4. Other Tissues 

CO binds with other hemoproteins, such as cytochrome P450, cytochrome c oxidase, catalase, 

and peroxidase, but the possibility of this binding influencing CO-O2 kinetics has not been 

established. CO transfers between COHb and tissue, the extent of which varies between organs. 

Blood-to-tissue flux causes less CO to be expired following CO exposure than what is lost from the 

blood in terms of COHb (Roughton and Root, 1945, 180418). This value is estimated to be 0.3-0.4% 

min-1 or 0.24 mL/min (Bruce and Bruce, 2003, 193975; Prommer and Schmidt, 2007, 180421). The 

equilibration rate from blood to tissue is uncertain. Newly modeled CO trafficking kinetics shows 

that CO continues to be taken up by the muscle and extravascular tissues well beyond the end of 

exposure because of a less than instant equilibration (Bruce and Bruce, 2006, 193980). Table 4-2

contains tissue CO concentrations from humans under different CO exposure conditions. The 

distribution of CO between the different human organs was shown to follow the same pattern versus 

percent of the blood CO concentration, irrespective of the level of blood CO (Vreman et al., 2006, 

098272). Consistently, the spleen, lung, and kidney had the highest measured CO concentration and 

the most dramatic increases over basal levels; the brain and adipose had the lowest CO 

concentrations. In addition to these fatty tissues, the muscular tissues including the heart and skeletal 

muscle had similarly low increases over background CO levels. This pattern was also found in 

rodents exposed to exogenous CO; however, increased endogenous CO produced after heme 

administration did not follow this pattern of uptake (Vreman et al., 2005, 193786). Increased 

endogenous CO production led to moderately increased CO present in the lung, heart, liver, and 

spleen and no change in CO concentration in the testes, intestine, muscle, brain, and kidney. The 

spleen and liver have an abundance of HO-1 expression and are involved in the catabolism of heme, 

thus it is expected to have elevated CO concentrations in these organs after heme treatment. Also, 

elevated CO in the lung is not surprising since it is the site of CO excretion. The tissues analyzed in 

these studies were blanched before analysis; however, contamination of the tissue sonicates with 

blood from the vessels within each organ is a possible source of error. The measurements were 

presented by the authors as minimum tissue CO concentrations, due to the possibility of rapid loss of 

CO from blood and tissue exposed to the atmosphere, light, and elevated temperature (Chace et al., 

1986, 012020; Ocak et al., 1985, 011641). These results are not consistent with older papers, 

January 2010 4-16 
suggesting that negligible retention of CO occurs in the liver or brain (Sokal et al., 1984, 011591; 

Topping, 1975, 193784). 

4.3.3. Pulmonary and Tissue Elimination 

Blood COHb concentrations are generally considered to have a monotonically decreasing, 

second-order (logarithmic or exponential) elimination rate from equilibrium. However, more recent 

reports have presented evidence for a biphasic washout curve, especially after brief CO exposure 

(Figure 4-8) (Bruce and Bruce, 2006, 193980; Shimazu et al., 2000, 016420; Wagner et al., 1975, 

010989). This event is modeled by a two-compartment system where the initial rapid decrease is the 

washout rate from the blood, followed by a slower phase due to CO flux from the muscle and 

extravascular compartments back to the blood. Tissue elimination rates have been reported as slower 

than those for blood (Landaw, 1973, 010803). The biphasic curve is more obvious after shortduration CO exposure (<1 h), whereas longer CO exposure (≥ 5 h) results in a virtually 

monoexponential elimination, which could account for the historical findings. However, this 

elimination curve also follows a biphasic curve with a slightly higher rate of elimination initially 

(Shimazu et al., 2000, 016420). Differences in elimination kinetics could also be a result of the 

variation in CO exposure duration (Weaver et al., 2000, 016421). 

The elimination of COHb is affected by a number of factors, including duration of exposure, 

PaO2, minute ventilation, the time post-exposure for analysis due to extravascular stores, as well as 

inter-individual variability (Bruce and Bruce, 2006, 193980; Landaw, 1973, 010803; Shimazu, 2001, 

016331). The elimination rate does not seem to be dependent upon the CO exposure source 

(e.g., fire, non-fire CO exposure) (Levasseur et al., 1996, 080895). In addition, in a series of 

poisoning cases, the COHb elimination half-life was not influenced by gender, age, smoke 

inhalation, history of loss of consciousness, concurrent tobacco smoking, degree of initial metabolic 

acidosis (base excess), or the initial COHb level (Weaver et al., 2000, 016421). On the contrary, in 

modeling the nonlinear kinetics of CO, a subject with a higher initial COHb will detoxify and 

eliminate CO more rapidly (Gosselin et al., 2009, 190946). Similarly, it has been shown that the 

absolute elimination rates are associated positively with the initial concentration of COHb, however 

the relative rate of elimination, expressed as a percentage decline in COHb% after a measured time, 

is independent of the initial COHb concentration (Wagner et al., 1975, 010989). COHb elimination 

half-life falls as the fractional inspired O2 concentration increases. While breathing air at sea level 

pressure, the expected half-life in adult males is approximately 285 min, but may be shorter in adult 

females. With inhalation of normobaric 40% O2, the half-life falls to 75 min and further to 21 min 

when breathing 100% O2 because of greater competition for Hb by O2 (Landaw, 1973, 010803). 

Another study reports the half-life falls to 74 min (mean) after breathing 100% O2, although the 

range in this particular study was 26-148 min (Weaver et al., 2000, 016421). In addition, COHb halflife will fall further after normocapnic hyperoxic hyperpnea (i.e., hyperventilation while maintaining 

normal CO2 pressure in high O2) (Takeuchi et al., 2000, 005675). 

January 2010 4-17 
1

10

100

0 30 60 90 120 150 180

Time (min)

COHb (%)

A

B

Source: Adapted with Permission of Lippincott Williams & Wilkins from Shimazu et al. (2000, 016420) 

Figure 4-8. Changes in blood COHb after exposure to CO for a few minutes (A) or several 

hours (B), representing the biphasic nature of CO elimination. Note: y-axis is logscale. 

4.3.4. COHb Analysis Methods 

Blood COHb saturation can be analyzed using numerous methods with various benefits and 

limitations. The most popular current techniques include gas chromatography (GC) and 

spectrophotometry, specifically using CO-oximeters. CO-oximeters are commonly used because they 

require little sample preparation and simultaneously measure COHb, O2Hb, methemoglobin, and 

total hemoglobin concentration. However, at low concentrations of COHb relevant to ambient 

exposure (<5%), CO-oximeters overestimate COHb levels determined by GC (Mahoney et al., 1993, 

013859; Widdop, 2002, 030493). Conversely, at higher COHb levels (>5%), CO-oximeters will 

underestimate COHb concentrations. In addition to the inaccuracy of the CO-oximeters, some 

studies report considerable imprecision in the results. Also, numerous substances or conditions can 

interfere with CO-oximeter measurements (i.e., temperature, bilirubin, fetal hemoglobin). 

Alternatively, GC is an accurate, precise, highly specific analysis method and is generally used as the 

reference method for COHb analysis. GC requires the CO incorporated into blood or tissue samples 

to first be released using a liberating agent such as potassium ferricyanide or sulfosalicylic acid 

(Vreman et al., 2005, 193786; Vreman et al., 2006, 098272), and then measured directly or 

indirectly. This methodology is more complex and time-consuming than spectrophotometry. In either 

analysis method, it is important to remember that COHb measured at one site in the body does not 

necessarily represent whole body CO distribution. 

CO can also be measured directly in air or breath samples by using an electrochemical sensor 

that depends on the electrical signal generated by the oxidation of CO. There are conflicting reports 

on the correlation of exhaled CO (COex) with COHb. Multiple reports present positive correlation 

coefficients (r) ranging from 0.92 and 0.98 in smoking subjects (Jarvis et al., 1980, 011813; Jarvis et 

al., 1986, 012043; Landaw, 1973, 010803). Positive linear correlations have also been shown in 

diseased patients with increased COHb (De las Heras et al., 2003, 194087). Others have reported no 

correlation between low level COHb and COex and have suggested less correlation exists at the 

lower levels of COex relevant to ambient exposures (Horvath et al., 1998, 087191; Scharte et al., 

2000, 194112). Finally, CO is endogenously produced in the nose and paranasal sinus which may 

contribute to COex concentrations (Andersson et al., 2000, 011836). 

January 2010 4-18 
4.4. Conditions Affecting Uptake and Elimination 

4.4.1. Physical Activity 

Exercise is an important determinant of CO kinetics and toxicity due to the extensive increase 

in gas exchange. O2 consumption can increase more than 10 fold during exercise. Similarly, 

ventilation, membrane and lung diffusing capacity, pulmonary capillary blood volume, and cardiac 

output increase proportional to work load. Also, exercise will improve the ventilation/perfusion ratio 

in the lung and mobilize RBC reserves from the spleen. The majority of these changes facilitate CO 

uptake and transport, by increasing gas exchange efficiency. Likewise, the COHb elimination rate 

increases with physical activity, causing a decrease in COHb half-life (Joumard et al., 1981, 011330). 

During a transition period from rest to exercise while exposed to CO (500 ppm/10 min), the 

diffusing capacity and CO uptake were reported to rise faster than O2 consumption for each exercise 

intensity (Kinker et al., 1992, 086328). The two physiological variables that are most influential in 

the formation of COHb are alveolar ventilation and cardiac output. However, exercise did not affect 

the ability of the CFK equation to predict COHb saturation as long as appropriate variables were 

used for model analysis (Tikuisis et al., 1992, 013592). 

4.4.2. Altitude 

Increased altitude changes a number of factors that contribute to the uptake and elimination of 

CO. The relationship between altitude and CO exposure has been discussed in depth in the 2000 CO 

AQCD and other documents (U.S. EPA, 1978, 086321). In an effort to maintain proper O2 transport 

and supply, physiological changes occur as compensatory mechanisms to combat the decreased 

barometric pressure and resulting altitude induced hypobaric hypoxia (HH). HH, unlike CO hypoxia, 

causes humans to hyperventilate, which reduces arterial blood CO2 (hypocapnia) and increases 

alveolar partial pressure of O2. Hypocapnia will lead to difficulty of O2 dissociation and decreased 

blood flow, thus reducing tissue O2 supply. HH increases blood pressure (BP) and cardiac output and 

leads to redistribution of blood from skin to organs and from blood vessels to extravascular 

compartments. Generally these changes will favor increased CO uptake and COHb formation, as 

well as CO elimination. In hypoxic conditions both CO and O2 bind reduced Hb through a 

competitive-parallel reaction (Chakraborty et al., 2004, 193759). Sea level residents exposed to high 

altitude (3,658-5,800 m) for short or long visits (<1 year) experience negligible or minor changes in 

DLCO, although these changes in DLCO can be accounted for by polycythemia or increased red 

blood cell count and by the increased rate of reaction of carbon monoxide with hemoglobin due to 

hypoxia (West, 1962, 199513)(Guleria et al., 1971, 199518). Breathing CO (9 ppm) at rest at altitude 

produced higher COHb compared to sea level (McGrath et al., 1993, 013865), whereas high altitude 

exposure with exercise caused a decrease in COHb levels versus similar exposure at sea level 

(Horvath et al., 1988, 012725). This decrease could be a shift in CO storage or suppression of COHb 

formation, or both. Altitude also increases the baseline COHb levels by inducing endogenous CO 

production. Initial HH increased lung HO-1 protein and activity, whereas chronic HH induced 

endogenous CO production in nonpulmonary sites (see Section 4.5) (Carraway et al., 2000, 021096). 

As the length of stay increases at high altitude, acclimatization occurs, inducing 

hyperventilation, polycythemia, and increased tissue capillarity and Mb content in skeletal muscle, 

which could also favor increased CO uptake. The DLCO of sea level natives who are long-term 

residents at altitude (3,100 m) increases from sea level values (Cerny et al., 1973, 199736). 

Additionally, natives of high altitude (3,100-3,658 m) have increased DLCO compared to natives of 

sea level or sea level natives that stay at high altitude (DeGraff et al., 1970, 199737) (Guleria et al., 

1971, 199518). This has been attributed to high pulmonary capillary blood volume and membrane 

diffusing capacity, and altered lung structure. Most of the early adaptive changes gradually revert to 

sea level values after individuals return to sea level. However, differences in people raised at high 

altitude persist even after reacclimatization to sea level (Hsia, 2002, 193857). For example, altitude 

natives (3,658 m) staying at sea-level still have increased DLCO compared to sea level natives which 

suggests a permanent change in the lung structure resulting in a larger diffusing surface area (Guleria 

et al., 1971, 199518). 

January 2010 4-19 
4.4.3. Physical Characteristics 

Certain physical characteristics (e.g., age, sex, pregnancy) can alter the variables that influence 

the uptake, distribution, and elimination of CO. Values of CO uptake and elimination change with 

age. Young children eliminate COHb more rapidly than adults after CO exposure (Joumard et al., 

1981, 011330; Klasner et al., 1998, 087196). After infancy, the COHb half-life increases with age, 

nearly doubling between 2 and 70 yr (Joumard et al., 1981, 011330). The rate of this increase in CO 

elimination is very rapid in the growing years (2-16 yr of age), but slows beyond adolescence. 

Alveolar volume and DLCO increase with increasing body length of infants and toddlers (Castillo et 

al., 2006, 193234), suggesting a further degree of lung development and faster CO uptake. After 

infancy, increasing age decreases DLCO and increases VA/Q mismatch, causing it to take longer to 

both load and eliminate CO from the blood (Neas and Schwartz, 1996, 079363). 

COHb concentrations are generally lower in female subjects than in male subjects (Horvath et 

al., 1988, 012725), and the COHb half-life may be longer in healthy men than in women of the same 

age, which may be partially explained by differences in muscle mass or the slight correlation 

between COHb half-life and increased height (Joumard et al., 1981, 011330). However, women do 

have a higher rate of endogenous production while in the progesterone phase of the menstrual cycle 

and during pregnancy (Section 4.5). The rate of decline of DLCO with age is lower in middle-aged 

women than in men; however, it evens out towards older age (Neas and Schwartz, 1996, 079363). 

Women also tended to be more resistant to altitude hypoxia (Horvath et al., 1988, 012725). 

Ethnicity does alter physiological variables that determine CO uptake and kinetics. Lung 

volumes are 10-15% less in both Asian and African-American populations when compared to 

Caucasians. This causes a reduced alveolar surface area (20% less than estimated values) for gas 

exchange, leading to a 13% difference in DLCO (Pesola et al., 2004, 193842; Pesola et al., 2006, 

193855). Certain factors, such as socioeconomic status (SES), were not controlled for in these 

studies. SES has been shown to affect pulmonary function, including decreasing DLCO (Hegewald 

and Crapo, 2007, 193923). 

4.4.3.1. Fetal Pharmacokinetics 

Inhaled CO by pregnant animals quickly passes the placental barriers and enters the fetal 

circulation (Longo, 1977, 012599). Fetal CO pharmacokinetics do not follow the same kinetics as 

maternal CO exposure, making it difficult to estimate fetal COHb based on maternal levels. Fetal 

COHb will vary as a function of maternal exposure but will also depend upon the rate of endogenous 

fetal CO production (Section 4.5), placental diffusing capacity of CO, the relative affinity of fetal Hb 

for CO compared to O2, and the affinity of fetal blood for O2 (Longo, 1970, 013922). Human fetal 

Hb has a higher affinity for CO than adult Hb, where the ratio of fetal COHb to maternal COHb at 

steady state in humans is approximately 1.11 (Longo, 1970, 013922)(Di Cera et al., 1989, 

193998)(Hayde et al., 2000, 201602). Maternal and fetal COHb concentrations have been modeled 

as a function of time using a modified CFK equation (Hill et al., 1977, 011315). At steady-state 

conditions, the fetal COHb is up to 10-15% higher than the maternal COHb levels. For example, 

exposure to 30 ppm CO results in a maternal COHb of 5% and a fetal COHb of 5.75%. The fetal CO 

uptake lags behind the maternal for the first few hours but later may overtake the maternal values 

(Figure 4-9). Fetal COHb equilibrium may not be reached for 36-48 h after exposure. Similarly, 

during washout, the fetal COHb levels are maintained for longer, with a half-life of around 7.5 h 

versus the maternal half-life of around 4 h (Longo and Hill, 1977, 010802). 

January 2010 4-20 
Source: Reprinted with Permission of the American Physiological Society from Hill et al. (1977, 011315) 

Figure 4-9. Predicted maternal and fetal COHb during periodic exposure to CO (50 ppm for 

16 h followed by 0 ppm for 8 h ). 

4.4.4. Health Status 

Health status can influence the toxicity involved with CO exposure by influencing the severity 

of hypoxia resulting from CO exposure. Any condition that would alter the blood O2 carrying 

capacity or content will result in a greater risk from COHb induced hypoxia and decreased tissue O2

delivery. The severity of this effect depends upon the initial level of hypoxia. 

Anemias are a group of diseases that result in insufficient blood O2 or hypoxia due to Hb 

deficiency through hemolysis, hemorrhage, or reduced hematopoiesis. Anemia may result from 

pathologic conditions characterized by chronic inflammation, such as malignant tumors or chronic 

infections (Cavallin-Ståhl et al., 1976, 086306; Cavallin-Ståhl et al., 1976, 193239). The bodies of 

people with anemia compensate, causing cardiac output to increase as both heart rate and stroke 

volume increase. The endogenous production of CO, thus COHb, is increased in patients with 

hemolytic anemia due to increased heme catabolism, causing an increased baseline COHb 

concentration. One of the most prevalent anemias arises from a single-point mutation of Hb, causing 

sickle cell diseases. The Hb affinity for O2 and O2 carrying capacity is reduced causing a shift to the 

right in the O2 dissociation curve. It is well documented that African-American populations have a 

higher incidence of sickle cell anemia, which may be a risk factor for CO hypoxia. 

Chronic obstructive pulmonary disease (COPD) is often accompanied by a number of changes 

in gas exchange, including increased deadspace volume (VD) and ventilation-perfusion ratio (VA/Q) 

inequality (Marthan et al., 1985, 086334), which could slow both CO uptake and elimination. 

Patients with pulmonary sarcoidosis, a restrictive lung disease, may also have a decrease in lung 

volumes, a loss of DLCO, and gas exchange abnormalities during exercise, including decreased 

arterial oxygen pressure (PaO2) and increased alveolar-arterial oxygen pressure difference (Lamberto 

et al., 2004, 193845). 

Individuals with heart disease may be at a greater risk from CO exposure since they may 

already have compromised O2 delivery. Time to onset of angina was reduced after exposure to 

January 2010 4-21 
100 ppm CO, compared to clean air (Kleinman et al., 1998, 047186). Hyperlipidemic patients may 

have decreased CO diffusion capacity, a loss of VA/Q gradient, and a decrease in PaO2 (Enzi, 1976, 

195794) (Section 5.2). 

4.5. Endogenous CO Production and Metabolism 

Humans breathing air containing no environmental sources of CO will still have a low 

measurable level of circulating COHb due to endogenous CO production from heme protein 

catabolism. In the normal degradation of RBC Hb, the porphyrin ring of heme is broken at the 

α-methene bridge by HO. HO is co-localized with NADPH-flavoprotein reductase and biliverdin 

reductase on the endoplasmic reticulum, where it catabolizes heme in an O2 and NADPH-dependent 

manner to biliverdin, ferrous iron, and CO. Biliverdin is then further broken down by biliverdin 

reductase into bilirubin, a powerful endogenous antioxidant. HO mediated metabolism functions as 

the rate-limiting enzyme step in heme degradation and endogenous CO production (Wu and Wang, 

2005, 180411). Three isoforms of HO exist, but HO-1 is the only inducible form (Maines and 

Kappas, 1974, 193976; Maines et al., 1986, 193978; McCoubrey et al., 1997, 016715). Endogenous 

CO production can be increased by the up-regulation of HO-1 expression and activity by inducers 

such as oxidative stress, hypoxia, heavy metals, sodium arsenite, heme and heme derivatives, various 

cytokines, and also exogenous CO (Wu and Wang, 2005, 180411). 

The major site of heme catabolism, and thus the major organ of CO production, is the liver, 

followed by the spleen, brain, and erythropoietic system (Berk et al., 1976, 012603). These rates of 

CO formation may be due to higher levels of HO activity in these tissues. The whole body 

production rate of CO is approximately 18.8 μmol/h (0.42 mL/h or 0.007 mL/min) and produces 

between 400-500 μmol CO per day (Coburn et al., 1963, 013971; Coburn et al., 1964, 013956; 

Coburn et al., 1966, 010984) (Figure 4-10). The endogenous rate of production varied somewhat 

within individuals measured on multiple days (±4.5 μmol/h and ±0.35% COHb) (Coburn et al., 

1966, 010984). However, these measurements of day-to-day CO production variability were 

comparable to the equipment measurement error reported (±3.1 μmol/h). The endogenous rate of CO 

formation varies between different tissues, ranging from 0.029 nmol/mg protein/h in chorionic villi 

of term human placentas to 0.28 nmol/mg protein/h in cultured rat olfactory receptor neurons and rat 

liver perfusate (Marks et al., 2002, 030616). However, these estimations are uncertain since CO is 

quickly scavenged in the cytosol of living cells. CO is endogenously produced in the nose and 

paranasal sinus which may contribute to exhaled CO concentrations (Andersson et al., 2000, 

011836). It is also important to note that increased endogenous CO production does not universally 

lead to an increase in COHb saturation. 

January 2010 4-22 
Study Condition 

Coburn et al. (1963, 013971) Adult male 

Delivoria-Papadopoulos et al. (1974, 086316) Female - Progesterone phase 

Delivoria-Papadopoulos et al. (1974, 086316) Female - Estrogen phase 

Longo (1970, 013922) Pregnancy 

Longo (1970, 013922) Fetal 

Longo (1970, 013922) Postpartum - 24 h 

Longo (1970, 013922) Postpartum - day 4 

Coburn et al. (1966, 010984) Hemolytic anemia min 

Coburn et al. (1966, 010984) Hemolytic anemia max 

Zegdi et al. (2002, 037461) Sepsis survivors 

Scharte et al. (2006, 194115) Cardiac disease patients max 

Scharte et al. (2006, 194115) Critically ill on dialysis max 

 0 0.01 0.02 0.03 0.04 0.05 0.06

Endogenous CO production (mL/min)

Figure 4-10. Representative estimates of endogenous CO production rates resulting from 

various conditions and diseases. 

Not all endogenous CO production is derived from Hb breakdown. Other hemoproteins, such 

as Mb, cytochromes, peroxidases, and catalase, contribute 20-25% to the total amount of endogenous 

CO (Berk et al., 1976, 012603). All of these sources result in a normal blood COHb concentration 

between 0.3 and 1% (Coburn et al., 1965, 011145). The level of endogenous production can be 

changed by drugs or a number of physiological conditions that alter RBC destruction, other 

hemoprotein breakdown, or HO-1 expression and activity (Figure 4-10). Nicotinic acid (Lundh et al., 

1975, 086332), allyl-containing compounds (acetamids and barbiturates) (Mercke et al., 1975, 

086303), diphenylhydantoin (Coburn, 1970, 010625), progesterone (Delivoria-Papadopoulos et al., 

1974, 086316), contraceptives (Mercke et al., 1975, 086308), and statins (Muchova et al., 2007, 

194098) can increase CO production. Compounds such as carbon disulfide and sulfur-containing 

chemicals (parathion and phenylthiourea) will increase CO by acting on P450 system moieties 

(Landaw et al., 1970, 012605). The P450 system may also cause large increases in CO produced 

from the metabolic degradation of dihalomethanes, leading to very high (>10%) COHb levels (Bos 

et al., 2006, 194084; Manno et al., 1992, 013707) that can be further enhanced by prior exposure to 

hydrocarbons or ethanol (Pankow et al., 1991, 013551; Wirkner et al., 1997, 082642). Minor sources 

of endogenous CO include auto-oxidation of phenols, flavonoids, and halomethanes, photo-oxidation 

of organic compounds, and lipid peroxidation of cell membrane lipids (Rodgers et al., 1994, 

076440). 

Women experience fluctuating COHb levels throughout menstruation when endogenous CO 

production doubles in the progesterone phase (0.62 mL/h versus 0.32 mL/h in estrogen phase) 

(Delivoria-Papadopoulos et al., 1974, 086316; Mercke and Lundh, 1976, 086309). Similarly, 

endogenous CO production increases during pregnancy (0.92 mL/h) due to contributions from fetal 

endogenous CO production (0.036 mL/h) and altered hemoglobin metabolism (Hill et al., 1977, 

011315; Longo, 1970, 013922). 

Any disturbance in RBC hemostasis by accelerated destruction of hemoproteins will lead to an 

increased production of CO (Figure 4-11 and Figure 4-12). Pathologic conditions such as anemias, 

hematomas, thalassemia, Gilbert’s syndrome with hemolysis, and other hematological diseases and 

illness will accelerate CO production (Berk et al., 1974, 012386; Hampson and Weaver, 2007, 

190272; Meyer et al., 1998, 047530; Solanki et al., 1988, 012426; Sylvester et al., 2005, 191954). 

Patients with hemolytic anemia exhibit COHb levels at least two- to threefold higher than healthy 

individuals and CO production rates two- to eightfold higher (Coburn et al., 1966, 010984). Recent 

studies report COHb levels measured by CO-oximeter that are elevated to levels between 4.6% and 

9.7% due to drug-induced hemolytic anemia (Hampson and Weaver, 2007, 190272) and between 

3.9% and 6.7% due to an unstable hemoglobin disorder (Hb Zürich) (Zinkham et al., 1980, 011435). 

January 2010 4-23 
Endogenous CO production rate varied from 0.70 to 3.18 mL/h in anemic patients (Coburn et al., 

1966, 010984). 

Study Condition 

Hampson and Weaver (2007, 190272) Hemolytic anemia max 

Hampson and Weaver (2007, 190272) Hemolytic anemia min 

Zinkham et al. (1980, 011435) Hb Zürich min 

Zinkham et al. (1980, 011435) Hb Zürich min 

Coburn et al. (1966, 010984) Hemolytic anemia max 

Coburn et al. (1966, 010984) Hemolytic anemia min 

Tran et al. (2007, 194120) Liver transplant 

De Las Heras et al. (2003, 194087) Peritonitis (SBP) 

De Las Heras et al. (2003, 194087) Cirrhosis 

Yasuda et al. (2005, 191953) Exacerbated COPD 

Morimatsu et al. (2006, 194097) Critically ill 

De Las Heras et al. (2003, 194087) Healthy 

 02468

COHb (%)

10

Figure 4-11. Representative COHb saturation resulting from various diseases and conditions. 

Measurements of COHb taken using CO-oximeter, except in Coburn et al. (1966, 

010984), where COHb was measured using GC. SBP: Spontaneous bacterial 

peritonitis 

Critically ill patients exhale more CO and have higher endogenous CO production than 

healthy controls, likely due to both increased heme turnover as well as upregulation of the 

expression and activity of HO-1 (Morimatsu et al., 2006, 194097; Scharte et al., 2000, 194112; 

Scharte et al., 2006, 194115) (Figure 4-12). CO production weakly correlates with the multiple organ 

dysfunction score (MODS), which estimates severity of organ dysfunction; however, it did not 

correlate with the Acute Physiology and Chronic Health Evaluation II score (APACHE II) (Scharte 

et al., 2006, 194115) or the sequential organ failure assessment score (SOFA) (Morimatsu et al., 

2006, 194097). Critically ill patients that survived had a higher exhaled CO (COex) concentration 

than nonsurvivors (median 3.9 ppm versus 2.4 ppm) (Morimatsu et al., 2006, 194097). Similarly, 

patients that survived severe sepsis had a higher CO production than those that did not survive (14.7 

± 5.3 versus 8.5 ± 3.3 μl/kg/h) (Zegdi et al., 2002, 037461). 

January 2010 4-24 
Study Condition 

Yamaya et al. (1998, 047525), Zayasu et al. (1997, 084291) Smokers 

De Las Heras et al. (2003, 194087) Peritonitis (SBP) 

De Las Heras et al. (2003, 194087) Cirrhosis 

Sylvester et al. (2005, 191954) Sickle Cell Anemia 

Yamaya et al. (1998, 047525) URTI 

Zayasu et al. (1997, 084291) Asthma w/ steroids 

Zayasu et al. (1997, 084291) Asthma 

Paredi et al. (1999, 118798) Cystic fibrosis 

Horvath et al. (1998, 087190) Bronchiectasis 

Paredi et al. (1999, 118798) Type 2 diabetes 

Paredi et al. (1999, 118798) Type 1 diabetes 

Morimatsu et al. (2006, 194097) Critically ill 

Morimatsu et al. (2006, 194097) Healthy 

 0 3 6 9 12 15

Exhaled CO (average fold change from healthy)

Figure 4-12. Representative exhaled CO concentrations (ppm) resulting from various 

conditions plotted as fold increases over healthy human controls from each 

study. SBP: Spontaneous bacterial peritonitis; URTI: Upper respiratory tract 

infection 

Diseases involving inflammation and infection result in increased endogenous CO production. 

For example, patients with severe sepsis or septic shock have a higher COex and endogenous CO 

production compared to control patients, which was reduced with treatment of the disease (i.e., 

antibiotics, surgery) (Zegdi et al., 2002, 037461). Similarly, patients with pre-existing cardiac 

disease, as well as patients with renal failure who undergo dialysis, produced higher amounts of 

endogenous CO compared to other critically ill patients (Scharte et al., 2006, 194115). High plasma 

COHb levels measured by CO-oximeter were found in nonsmoking patients evaluated for liver 

transplantation (mean 2.1%); however, this increase was not correlated with the Model for End Stage 

Liver Disease (MELD) score or the Child Turcotte Pugh score, used to assess the degree of liver 

impairment (Tran et al., 2007, 194120). Further investigation in cirrhotic patients, with and without 

ascites, provided evidence for increased plasma CO concentrations, HO-1 activity in 

polymorphonuclear cells, exhaled CO, and blood COHb (De las Heras et al., 2003, 194087; Tarquini 

et al., 2009, 194117). COex, plasma CO, and COHb levels were correlated with the Child-Pugh 

score, and thus the severity of disease. These parameters were significantly higher in patients with 

ascites or with spontaneous bacterial peritonitis (SBP) (COHb, healthy: 0.6 ± 0.1%; cirrhosis: 1.0 ± 

0.1%; with ascites: 1.6 ± 0.2%; with SBP: 1.9 ± 0.2%; measured by CO-oximeter). Both COex and 

COHb levels decreased after resolution of the infection in patients with SBP, reaching values similar 

to noninfected patients within 1 mo (De las Heras et al., 2003, 194087). Endotoxin concentration 

was correlated with plasma CO levels, suggesting a link between systemic endotoxemia and 

increased activity or expression of the HO/CO system (Tarquini et al., 2009, 194117). COex 

concentrations are also elevated in patients with diabetes (Type 1: 4.0 ± 0.7 ppm; Type 2: 5.0 ± 

0.4 ppm; healthy: 2.9 ± 0.2 ppm), and correlated with blood glucose levels and duration of disease 

(Paredi et al., 1999, 194102). Likewise, obese Zucker rats, a model of metabolic syndrome with 

insulin resistance, have increased respiratory CO excretion and COHb levels compared to lean 

Zucker rats (3.9 ± 0.1% versus 3.0 ± 0.1% COHb), which is decreased by HO inhibition (Johnson et 

al., 2006, 193874). 

Endogenous CO is also increased in airway inflammatory diseases. Patients with upper 

respiratory tract infections exhaled higher CO concentrations than normal controls and this increase 

was attenuated after recovery (Yamaya et al., 1998, 047525). Arterial COHb levels have been related 

January 2010 4-25 
to disease severity in COPD patients (Yasuda et al., 2005, 191953). Bronchiectasis patients had 

higher COex; however, anti-inflammatory treatment did not decrease the CO levels (Horvath et al., 

1998, 087191). Patients with cystic fibrosis had higher COex than normal controls (6.7 ± 0.6 ppm 

versus 2.4 ± 0.4 ppm), and patients treated with steroids had a decrease in CO levels (8.4 ± 1.0 ppm 

versus 5.1 ± 0.5 ppm) (Paredi et al., 1999, 118798). Increased arterial COHb measured by COoximeter was reported in patients with bronchial asthma, pneumonia, idiopathic pulmonary fibrosis, 

pyelonephritis, and active rheumatoid arthritis (Yasuda et al., 2002, 035206; Yasuda et al., 2004, 

191955). Similarly, asthmatic patients exhibited an elevation of COex that decreased with 

corticosteroid therapy (nonsmoking controls: 1.5 ± 0.1 ppm; asthmatics without corticosteroids: 5.6 

± 0.6 ppm; with corticosteroids: 1.7 ± 0.1 ppm; smoking controls: 21.6 ± 2.8 ppm) (Zayasu et al., 

1997, 084291). These results were confirmed and associated with increased expression of HO-1 in 

airway macrophages (Horvath et al., 1998, 087190). Also, COex was increased in patients with 

allergic rhinitis during the pollen season; however, their COex was similar to control subject levels 

out of season (Monma et al., 1999, 180426). Similarly, endogenous CO production and HO-1 

expression in nasal mucosa was correlated with allergic rhinitis in guinea pigs as described in 

Section 5.1 (Shaoqing et al., 2008, 192384). 

Altitude is also positively associated with baseline COHb concentrations (McGrath, 1992, 

001005)(McGrath et al., 1993, 013865). This increase in COHb with altitude-induced hypoxia is 

associated in rats and cells with increases in the mRNA, protein, and activity of HO-1 leading to 

enhanced endogenous CO production (Carraway et al., 2002, 026018; Lee et al., 1997, 082641). 

Whether other variables such as an accelerated metabolism or a greater pool of Hb, transient shifts in 

body stores, or a change in the elimination rate of CO, play a role has not been explored. 

Because of the sensitivity of COHb to changes in the metabolic state, ranges of endogenous 

COHb levels in the population are uncertain. However, baseline levels of COHb, which reflect 

exposure to ambient and non-ambient CO and endogenous production of CO, have been measured in 

the population. COHb levels measured by CO-oximeter in packed red blood cell units reserved for 

use between 2004 and 2005 averaged 0.78 ± 1.48%, with 10.3% of samples having COHb levels of 

1.5% or greater and a maximum measurement of 12% (Ehlers et al., 2009, 194089). This study 

reported a decrease from a study conducted in 1982-1983 in the number of units with elevated 

COHb; at that time, 49% of units had COHb levels >1.5% (Aronow et al., 1984, 194083) versus 

10.3% in 2004-2005. Another study calculated that 23% of donated blood units had COHb levels 

exceeding 1.5%, with the highest measurement being 7.2% (Aberg et al., 2009, 194082). Smoking is 

the main factor causing increased blood concentrations of CO. A dose-response relationship was 

shown to exist between COHb concentration and the number of cigarettes smoked a day 

(nonsmoker: 1.59 ± 1.72%; 1-5 cig/day: 2.31 ± 1.94%; 6-14 cig/day: 4.39 ± 2.48%; 15-24 cig/day: 

5.68 ± 2.64%; ≥ 25 cig/day: 6.02 ± 2.86% COHb). The mean baseline COHb value for former 

smokers was higher than that of never smokers in this prospective cohort study (1.96 ± 1.87 versus 

1.59 ± 1.72%) (Hart et al., 2006, 194092). 

Endogenous CO is removed from the body mainly by expiration and oxidation. CO diffuses 

across the alveolar-capillary membrane and is exhaled. This event has been used as a noninvasive 

measurement of both endogenous and body load CO (Stevenson et al., 1979, 193767). CO can also 

be oxidized to CO2 by cytochrome c oxidase in the mitochondria (Fenn, 1970, 010821; Young and 

Caughey, 1986, 012091). However, the rates of CO metabolism are much slower than the rates of 

endogenous CO production, with the rate of consumption representing only 10% of the rate of CO 

production in dogs (Luomanmäki and Coburn, 1969, 012319). 

4.6. Summary and Conclusions 

CO elicits various health effects by binding with and altering the function of a number of 

heme-containing molecules, mainly Hb. The formation of COHb reduces the O2-carrying capacity of 

blood and impairs the release of O2 from O2Hb to the tissues. Venous COHb levels have been 

modeled mainly by the CFK equation, but more recent models have included venous and arterial 

blood mixing and Mb and extravascular storage compartments, as well as other dynamics of CO 

physiology. The CFK equation remains the most extensively validated and applied model for COHb 

prediction. Recent models have indicated that CO has a biphasic elimination curve, due to initial 

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

January 2010 4-26 
blood and alveolar air or tissues is controlled by diffusion down the pCO gradient. The uptake of CO 

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

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

exercise, age, and health. Susceptible populations, including health compromised individuals and 

developing fetuses, are at a greater risk from COHb induced health effects due to altered CO 

kinetics, compromised cardiopulmonary function, and increased baseline hypoxia levels. Altitude 

may also significantly affect the kinetics of COHb formation. Compensatory mechanisms, such as 

increased cardiac output, compensate for the decrease in barometric pressure. Altitude also increases 

the endogenous production of CO through upregulation of HO-1. CO is considered a second 

messenger and is endogenously produced from the catabolism of heme proteins by enzymes such as 

HO-1. A number of diseases and conditions affect endogenous CO production, possibly causing a 

higher endogenous COHb level. Finally, CO is removed from the body by expiration or oxidation to 

CO2. 

January 2010 4-27 
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