Review
Carbon monoxide and the nervous system

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Abstract

Carbon monoxide (CO) is a colorless, tasteless, odorless, and non-irritating gas formed when carbon in fuel is not burned completely. It enters the bloodstream through the lungs and attaches to hemoglobin (Hb), the body's oxygen carrier, forming carboxyhemoglobin (COHb) and thereby reducing oxygen (O2) delivery to the body's organs and tissues. High COHb concentrations are poisonous. Central nervous system (CNS) effects in individuals suffering acute CO poisoning cover a wide range, depending on severity of exposure: headache, dizziness, weakness, nausea, vomiting, disorientation, confusion, collapse, and coma.

At lower concentrations, CNS effects include reduction in visual perception, manual dexterity, learning, driving performance, and attention level. Earlier work is frequently cited to justify the statement that CO exposure sufficient to produce COHb levels of ca. 5% would be sufficient to produce visual sensitivity reduction and various neurobehavioral performance deficits. In a recent literature re-evaluation, however, the best estimate was that [COHb] would have to rise to 15–20% before a 10% reduction in any behavioral or visual measurement could be observed. This conclusion was based on (1) critical review of the literature on behavioral and sensory effects, (2) review and interpretation of the physiological effects of COHb on the CNS, (3) extrapolation from the effects of hypoxic hypoxia to the effects of CO hypoxia, and (4) extrapolation from rat behavioral effects of CO to humans.

Also covered in this review article are effects of chronic CO exposure, the discovery of neuroglobin, a summary of the relatively new role for endogenous CO in neurotransmission and vascular homeostasis, groups which might be especially sensitive to CO, and recommendations on further research. The interested reader is directed to other published reviews of the literature on CO and historically seminal references that form our understanding of this ubiquitous gas.

Introduction

Carbon monoxide (CO) is a colorless, tasteless, odorless, and non-irritating gas formed when carbon in fuel is not burned completely. Outdoors, the largest source of CO is motor vehicle exhaust. Other sources include industrial processes, non-transportation fuel combustion, and natural sources such as wildfires. Indoors, CO can be found in tobacco smoke and can accumulate from inadequately vented stoves, furnaces, and other combustion sources. Carbon monoxide enters the bloodstream through the lungs and attaches to hemoglobin (Hb), the body's oxygen carrier, forming carboxyhemoglobin (COHb) and thereby reducing oxygen (O2) delivery to the body's organs and tissues. Equilibrium COHb levels estimated to result from increasing concentrations of CO are given in Table 1. At high concentrations, CO is poisonous. Symptoms in individuals suffering acute CO poisoning cover a wide range, depending on severity of exposure: headache, dizziness, weakness, nausea, vomiting, disorientation, confusion, collapse, and coma. Perhaps the most insidious effect of CO poisoning is the delayed development of central nervous system (CNS) impairment within 1–3 weeks, and the neurobehavioral consequences, especially in children. At lower concentrations, CNS effects include reduction in visual perception, manual dexterity, learning, driving performance, and attention level.

Section snippets

Review of the literature

In this section, the arguments from the recent literature about the effect of acute exposure to CO, and its behavioral effects, will be summarized. Not only will conclusions be made and defended, but the uncertainties and their possible explanations will be discussed.

Throughout this review, it will be assumed that the mechanism by which acute CO exposure produces its effects is that of hypoxia [1], [2]. This appears to be the case for all of the other effects of acute COHb elevation. For this

Chronic effects of carbon monoxide

There are many published studies on acute experimental and accidental exposures to CO (Section 6); however, there is not enough reliable information on effects of chronic exposures to low concentrations from either controlled-human studies, ambient population-exposure studies, or from occupational studies. Further work is needed, therefore, to determine the potential for long-term exposures in the population and to develop reliable dose-response relationships for at-risk groups. This

Physiologic responses to carbon monoxide exposure

One of the possible reasons why chronic exposures to low CO concentrations may not pose as much a problem as high, acute exposure is due to physiological compensation, tolerance, or adaptation. Smokers show an adaptive response to elevated COHb levels, as evidenced by increased red blood cell volumes (through increased hemopoiesis) or reduced plasma volumes. The major source of total exposure to CO for smokers comes from active tobacco smoking. Baseline COHb concentrations in smokers average 4%

Sensitive population groups

Health effects caused by CO are most likely to occur in individuals who are physiologically stressed, either by exercise or by medical conditions that can make them more susceptible to low levels of CO. Most of the known quantitative concentration–response relationships regarding the human health effects of CO come from carefully controlled studies in healthy, predominantly male, young adults and in patients with diagnosed cardiovascular diseases (e.g. coronary artery disease). It can be

Intracellular effects of carbon monoxide

Traditional concepts for CO pathophysiology have been based on the high affinity of CO for Hb and consequent reduction of O2 delivery. Recently published information suggests the possibility for biochemical mechanisms that are not necessarily related to an impairment of oxygen delivery from elevations in COHb. Most of this research was done with cells in culture and with laboratory animals. To be relevant to human exposures from environmental contamination, it is important to note what

Physiologic role of endogenous carbon monoxide

A number of endogenously produced gases have modulation functions in biological systems (Table 3). Of these, the two diatomic gases, CO and NO, have important physiological roles in neuronal signal transduction and in the maintenance of vascular tone. The intercellular roles of these two gases are often difficult to separate.

Carbon monoxide is produced endogenously by oxidation of organic molecules, but the predominant source is from the degradation of heme. The rate-limiting enzyme for heme

Specially sensitive persons

Anyone with the inability to adequately regulate O2 supply or metabolism would seem to be specially sensitive to elevation in COHb. This has been empirically demonstrated for the onset of chest pain during exercise in angina patients. There are a number of physical conditions which impair the ability of O2 to reach the brain and thus could make persons with such an affliction more sensitive to elevated COHb. Among these are atherosclerotic lesions [80], non-insulin dependent diabetes [81], and

Disclaimer

The information in this document has been funded wholly (or in part) by the US Environmental Protection Agency. It has been subjected to review by EPA's Office of Research and Development and approved for publication. Approval does not signify that the contents reflect the views of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Acknowledgements

We thank S.R. Thom of the Institute for Environmental Medicine and Department of Emergency Medicine, University of Pennsylvania, Philadelphia, PA for contributions to material used in preparation of this review. We also thank J.J. McGrath of the Department of Physiology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX and D.A. Otto and J.M. Davis of the US Environmental Protection Agency, Research Triangle Park, NC for their valuable comments. We extend our

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