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Carbon Monoxide - Toxicokinetics

Introduction

The discussion below on the toxicokinetics and mechanisms of action of carbon monoxide are primarily from investigations in humans. The toxicokinetic assessment is summarised from authoritative reviews of extensive, relevant current published literature (EPA, 2010 and EHC, 1999).

Absorption:

Pulmonary uptake of carbon monoxide (CO) accounts for all environmental CO absorption and occurs at the respiratory bronchioles, alveolar ducts and sacs. 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. The diffusion of CO across the alveolar capillary membrane is an entirely passive process of gas diffusion.

Distribution and mode of action:

The blood is the largest reservoir for CO, where it reversibly binds to haemoglobin (Hb) to form carboxyhaemoglobin (COHb); the affinity of CO for Hb in adult blood is ~218 times greater than that of oxygen, increasing further for foetal Hb. The amount of COHb formed is dependent on the concentration and duration of carbon monoxide exposure and other factors such as exercise, ambient temperature and the health status of the individual (refer to Table 1). The affinity of CO for myoglobin is about 8 times lower than that for Hb, however, the dissociation rate constant is approximately 630 times lower than O2, causing CO to be retained and potentially stored in skeletal muscle. In addition to reducing the capacity of the blood to transport oxygen, CO causes the oxyhaemoglobin dissociation curve to shift to the left, reducing the amount of oxygen unloaded at the tissues (i. e. the greater number of haem sites bound to CO, the greater the affinity of free haem sites for oxygen, thus causing Hb to bind and retain oxygen that would normally be released). A reduction in unloading of oxygen is particularly serious in tissues such as myocardium where 60-70% of the oxygen in arterial blood is usually extracted (compared to 25% in many other tissues, refer to table 2).

The EPA (2010) reported that no new data have become available on the distribution of COHb levels in the USA population since the 1970s and 1980s. Mathematical models have been used to predict resulting COHb levels from various CO exposures. Data generated from the Quantitative Circulatory Physiology (QCP) model (data below) which integrates human physiology using over 4000 variables and equations based on published biological interactions was used predict these values. This dynamic whole body model uses the nonlinear CFK equation with modifications present in Smith et al (1994) and illustrates increasing dosing of CO over time in various situations.

The following table is reproduced from the EPA review.

 

Table 1: Predicted COHb levels resulting from 1, 8 and 24 hour CO exposures in a modelled human in a variety of situations (detailed below table). The levels are derived from the QCP.

CO (ppm)

1h

8h

24h

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

0.296

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

2.05

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

At rest (Alveolar ventilation (VA) = 6 L/min; DLCO= 20 (mL/min)/mmHg; endogenous CO production rate (VCO) = 0.007 mL/min; initial COHb = 0.27%; Hb = 0.15 g/mL)

During light exercise (VA= 15 L/min; lund diffusion capacity of CO (DLCO) = 34 (mL/min)/mmHg;)

During moderate exercise (VA= 22 L/min; DLCO= 43 (mL/min)/mmHg)

Tissue distribution data on CO in exposed rats and mice were summarised by the EPA (2010) and relevant data are reproduced in Table 2.

Table 2: Tissue concentrations of CO following inhalation exposure

Study

CO Exposure

Tissue CO conc.

COHb

Notes

Cronjeet al, (2004)

Rat

2,500 ppm (45 min)

Blood: 27,500 (800) pmol/mg

Heart: 800 (300) pmol/mg

Muscle: 90 (80) pmol/mg

Brain: 60 (40) pmol/mg

 

(Control levels in parentheses)

66-72%

CO concentration increased in the heart but not in brain or skeletal muscle after CO exposure. A later report stated that these tissue CO values were too high due to a computational error (Piantadosiet al., 2006)

Vremanet al. (2005)

Mice

500 ppm

(30 min)

Blood: 2648 ± 400 (45) pmol/mg

Heart: 100 ± 18 (6) pmol/mg

Muscle: 14 ± 1 (10) pmol/mg

Brain: 18 ± 4 (2) pmol/mg

Kidney: 120 ± 12 (7) pmol/mg

Spleen: 229 ± 55 (6) pmol/mg

Liver: 115 ± 31 (5) pmol/mg

Lung: 250 ± 2 (3) pmol/mg

Intestine: 9 ± (4) pmol/mg

Testes: 6 ± 3 (2) pmol/mg

 

(Control levels in parentheses)

28%

CO concentration relative to 100% blood:

Lung: 9.4%; Spleen: 8.6%; Kidney: 4.5%; Liver: 4.3%; Heart: 3.8%; Brain: 0.7%; Muscle: 0.5%; Intestine: 0.3%; Testes: 0.2%

Data expressed as pmol CO/mg tissue wet weight

The human foetus is particularly sensitive to CO because of several differences from the adult. Under steady-state conditions foetal COHb is ~10-15% greater than corresponding maternal blood. Additionally, the partial pressure of foetal blood is approximately 5 times lower than the adult value. Furthermore, the foetal oxygen-Hb dissociation curve lies to the left of the adult curve, resulting in greater tissue hypoxia at equivalent COHb concentrations. Due to CO’s increased affinity for foetal Hb, the half-life of elimination is greater than in the mother. Acute exposure to CO concentrations that are non-lethal to the mother have been associated with foetal loss.

The binding of CO to Hb to form COHb, decreasing the oxygen carrying capacity of the blood appears to be the principal mechanism of action underlying the induction of toxic effects of CO exposure. Any toxic effects are due to hypoxia, which becomes evident in organs and tissues with high oxygen consumption (such as the brain, heart, exercising skeletal muscle, developing foetus).

The diverse effects of CO are dependent upon concentration and duration of exposure as well as on the cell types and tissue involved. Responses to CO are not necessarily due to a single process and may instead be mediated by a combination of effects including COHb-mediated hypoxic stress and other mechanisms such as free radical production and the initiation of cell signalling.

Other nonhypoxic mechanisms of action underlying the biological effects of CO include alteration in nitric oxide signalling, inhibition in cytochromecoxidase (terminal enzyme in the mitochondrial electron transport chain), haem loss from proteins, disruption in iron homeostasis, alteration in cellular redox status (leading to an increase in cellular oxidative stress) and ion channel activity (in particular Ca2+activated K+channels), and modulation of protein kinase pathways. Furthermore, it is important to note that CO is a ubiquitous cell signalling molecule, with numerous physiological functions. Therefore, interference in the intracellular concentrations of CO has the potential to disrupt cellular and haem based signalling pathways.

Metabolism and Excretion:

Endogenous, indirect release of CO results from the degradation of red blood cells and other haem containing proteins via haem oxygenase-1 (HO-1) activity. Expression of HO-1 is highest in the liver and spleen. Whilst haem proteins undergo catabolism, bound CO is released back into the blood predominantly unchanged. In the absence of pathological conditions (e.g. anaemia’s, thalassemia, Gilbert’s syndrome with haemolysis), CO production resulting from such catabolism would not significantly contribute to endogenous CO levels.

CO is eliminated from tissues back into the blood (carried as COHb) and excreted predominantly via the lungs, unchanged, with a minor component undergoing oxidation to carbon dioxide. The same factors that govern CO uptake also affect CO elimination. The rate of elimination is initially high, due to the washout rate of CO from the blood, followed by a slower phase due to CO flux from muscle and other extracellular compartments back into the blood. As previously stated, due to the increased affinity of CO for foetal Hb, the rate of elimination is further increased. The elimination half –time ranges from 2 to 6.5 hours depending on the initial levels of COHb and the ventilation rate of the individual.

References:

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

EHC, 1999. Environmental Health Criteria, 213, International Programme for Chemical Safety, WHO.

EPA, 2010. Integrated Science Assessment for Carbon Monoxide. EPA/600/R-09/019F. January 2010.

Smith MV; Hazucha MJ; Benignus VA; Bromberg PA (1994). Effect of regional circulation patterns on observed HbCO levels. J Appl Physiol, 77: 1659-1665.

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.