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Is There Dose-Related Performance Degradation Resulting from Exposure to Carbon Monoxide?

In the context of this analysis, performance can be divided into physical performance and neuropsychological and neurophysiologic performances, such as reaction times, visual changes and short-term memory.

Physical performance in humans has been studied at various concentrations of carboxyhemoglobin (COHb). There appears to be a linear reduction in maximal workload with increasing COHb concentrations up to at least 20% COHb (Ekblom and Huot 1972). These effects are accentuated by heat, altitude, and anemia (Horvath et al. 1988; Bunnell and Horvath 1989; Kapoor et al.1997; Kleinman et al. 1998). At submaximal workloads, these effects are not seen at low-to-moderate COHb concentrations (Ekblom and Huot 1972).

Aronow and Cassidy (1975) and Allred et al. (1989) studied physical performance of patients who had coronary artery disease and who breathed CO to increase their COHb levels prior to moderate exercise. The researchers found that onset of ST segment elevations (determined using electrocardiography) and angina pectoris occurred sooner when COHb levels were at about 4% saturation or greater, as compared with the control group. This effect was a function of venous blood COHb% saturation. The researchers found that a value of about 4% COHb resulted in 12% and 7% decreases in exercise times for onset of ST segment elevation and onset of angina, respectively.

Of perhaps more relevance to the military scenario are the potential effects of carbon monoxide (CO) on neuropsychological and neurophysiologic performance measures. The effects of CO on neuropsychological and neurophysiologic performance in humans have been reviewed by several authors (Benignus 1994; Wong 1994). There is clearly conflicting data in this area. Although many studies that appear to be well done do not show effects until COHb levels are in the range of 10-20% (Stewart et al. 1973; Benignus and Otto 1977; Hudnell and Benignus 1989), many other studies show effects in the 3-6% range (Beard and Wertheim 1967; Wright et al. 1973; Putz 1979; Gliner et al. 1983;). There is no clear explanation for the discrepancies in these results. Although variability is probable among individual subjects, this factor alone is unlikely to account for the substantial differences in these studies. Methodologic differences, including lack of blinding in some studies, are also probably responsible for some of the inconsistencies observed. Benignus and others (Benignus et al. 1987, 1990; Benignus 1994) have estimated from animal and human data that central-nervous-system (CNS) hypoxia, and presumably neuropsychological and neurophysiologic effects, should not occur at COHb levels below 16-23%. Because of these discordant results, there is no clear dose-response association for relevant neuropsychological effects at low-to-moderate COHb levels.

A dose-response relationship for various neurobehavioral end points is apparent in animals and humans at COHb levels above 10% (Benignus 1994). The committee is unaware of any validated models that will predict biologic effects from CO exposure under circumstances relevant to the needs of the Army



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4 Is There Dose-Related Performance Degradation Resulting from Exposure to Carbon Monoxide? In the context of this analysis, performance can be divided into physical performance and neuro- psychological and neurophysiologic performances, such as reaction times, visual changes and short-term memory. Physical performance in humans has been studied at various concentrations of carboxyhemoglo- bin (COHb). There appears to be a linear reduction in maximal workload with increasing COHb concen- trations up to at least 20% COHb (Ekblom and Huot 1972). These effects are accentuated by heat, alti- tude, and anemia (Horvath et al. 1988; Bunnell and Horvath 1989; Kapoor et al.1997; Kleinman et al. 1998). At submaximal workloads, these effects are not seen at low-to-moderate COHb concentrations (Ekblom and Huot 1972). Aronow and Cassidy (1975) and Allred et al. (1989) studied physical performance of patients who had coronary artery disease and who breathed CO to increase their COHb levels prior to moderate exercise. The researchers found that onset of ST segment elevations (determined using electrocardiogra- phy) and angina pectoris occurred sooner when COHb levels were at about 4% saturation or greater, as compared with the control group. This effect was a function of venous blood COHb% saturation. The re- searchers found that a value of about 4% COHb resulted in 12% and 7% decreases in exercise times for onset of ST segment elevation and onset of angina, respectively. Of perhaps more relevance to the military scenario are the potential effects of carbon monoxide (CO) on neuropsychological and neurophysiologic performance measures. The effects of CO on neuro- psychological and neurophysiologic performance in humans have been reviewed by several authors (Be- nignus 1994; Wong 1994). There is clearly conflicting data in this area. Although many studies that ap- pear to be well done do not show effects until COHb levels are in the range of 10-20% (Stewart et al. 1973; Benignus and Otto 1977; Hudnell and Benignus 1989), many other studies show effects in the 3- 6% range (Beard and Wertheim 1967; Wright et al. 1973; Putz 1979; Gliner et al. 1983;). There is no clear explanation for the discrepancies in these results. Although variability is probable among individual subjects, this factor alone is unlikely to account for the substantial differences in these studies. Method- ologic differences, including lack of blinding in some studies, are also probably responsible for some of the inconsistencies observed. Benignus and others (Benignus et al. 1987, 1990; Benignus 1994) have es- timated from animal and human data that central-nervous-system (CNS) hypoxia, and presumably neuro- psychological and neurophysiologic effects, should not occur at COHb levels below 16-23%. Because of these discordant results, there is no clear dose-response association for relevant neuropsychological ef- fects at low-to-moderate COHb levels. A dose-response relationship for various neurobehavioral end points is apparent in animals and humans at COHb levels above 10% (Benignus 1994). The committee is unaware of any validated models that will predict biologic effects from CO exposure under circumstances relevant to the needs of the Army 16

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Dose-Related Performance Degradation from Exposure to CO and in the presence of other CNS active gases, such as hydrogen cyanide (HCN) and carbon dioxide (CO2). In the absence of reliable definitive data at low-to-moderate CO concentrations and in order to provide a safety margin for neuropsychological and neurophysiologic effects and potential cardiovascular effects, governmental groups have generally chosen to rely on the studies reporting effects at low levels when setting standards for critical tasks (Wong 1994). Recommendation Information provided to the committee by the Army indicates that exposure sce- narios in armored vehicles deployed in battle are expected to generate COHb levels less than 10% in ve- hicle personnel (M. Bazar and T. Kluchinsky, CHPPM, personal commun., April 14, 2008). In view of the lack of reliable and relevant neuropsychological data and the inconsistencies in ex- isting data at levels in this range, the committee recommends that the Army consider controlled human experiments using scenarios and exposure concentrations of CO relevant to combat conditions. Such ex- periments should be designed to seek a dose-response relationship at CO and COHb levels at less than 10% and with neuropsychological end points, such as visual and reaction-time decrements relevant to real-life scenarios in enclosed armored vehicles. It would not be feasible to measure these same end points in a meaningful way in exposure experiments using animals (also see discussion in Chapter 3). Also, the lack of consistent neuropsychological and neurophysiologic data precludes the use of computa- tional models to estimate expected changes in human performance with increased COHb. Controlled human experiments could be done best with vehicle simulators in an atmospheric chamber (or less desirably with face-delivery systems) where scenarios, CO concentrations, temperature, and humidity could be individually controlled. The Army will also need to control for “background” CO exposure from smoking and other sources. If these studies were done under controlled conditions, the Army would need to decide whether to model a scenario of rapid CO buildup or slow CO buildup, be- cause the physiologic effects, and subsequent behavioral responses, might be different for these two sce- narios. The small number of subjects who can practically be tested will likely be a limiting factor in these experiments, but given the current state of existing data, such controlled experimentation is the only con- clusive way to assess the qualitative and quantitative risks of performance degradation resulting from in- vehicle CO release. Alternatively, experiments could be done in a test vehicle with standardized measures of performance under battlefield conditions. Such experiments, however, are unlikely to give definitive results due to multiple uncontrollable variables, such as heat, workload, and stress. Attention should be paid to assessment of armored-vehicle crews for medical conditions that might adversely affect any performance degradation from CO or other hypoxia-producing conditions (for example, high altitude). Such conditions would also include diseases affecting pulmonary efficiency (for example, asthma and chronic obstructive pulmonary disease), cardiac diseases that can increase the risk of cardiac dysrhythmias or dysfunction, and blood diseases that can affect oxygen transport (for example, anemia and hemoglobinopathies). The committee acknowledges that the Army probably currently screens for some or all of these conditions in its crews. 17