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8 Carbon Monoxide Noreen N. Khan-Mayberry, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas Spacecraft maximum allowable concentrations (SMACs) for carbon mon- oxide (CO) were initially published in Volume 1 of Spacecraft Maximum Al- lowable Concentrations for 1-h, 24-h, 7-d, 30-d, and 180-d exposures (Wong 1994). As NASA will be conducting longer missions, extended duration SMACs are required. This document will establish a CO SMAC value for 1,000-d ex- tended duration exposure; it will also reassess original SMACs and propose new values for 1-h, 24-h, 7-d, 30-d, and 180-d exposures. OCCURRENCE AND USE CO is a colorless, odorless, and tasteless gas that is produced by incom- plete combustion of carbon-containing materials (Penney 2000a). It is produced in the human biological system through hemoglobin (Hb) metabolism at a rate of 0.4 milliliter (mL)/h, which results in a carboxyhemoglobin (COHb) concen- tration of 0.4% (Coburn et al. 1965). However, Doherty reported in 2000, that CO is produced endogenously during heme metabolism, accounting for a normal COHb concentration of approximately 1%. Doherty also reported that smoke, especially from the tips of cigarettes, is a source of CO that may lead to COHb concentrations as high as 10% to 15% in heavy smokers. In a study with 80 Boston police officers working in city street conditions, McFarland reported in 1973 that almost all the nonsmokers had COHb concen- trations below 4%; for most of the smokers, it was below 6%, indicating much higher endogenous COHb concentrations in outdoor workers. CO interferes with the oxygenation of blood and the delivery of oxygen to tissues because it has approximately 245 times greater affinity for Hb than oxy- gen (Roughton 1970, as cited by NRC 2007). COHb reduces the oxygen- carrying capacity of blood thereby shifting the oxygen dissociation curve and 125

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126 SMACs for Selected Airborne Contaminants reducing oxygen delivery to tissues. Hypoxemia and resulting tissue hypoxia are the best understood mechanisms of CO toxicity. A log-log plot of estimated per- centage of COHb saturation and exposure duration for different CO concentra- tions computed from the Coburn-Foster-Kane (CFK) equation is shown in Fig- ure 8-1 (Peterson and Stewart 1975, Penney 1999). Details of the CFK equation are presented in Appendix A. The central nervous system (CNS) and cardiovascular (CV) system are the primary targets of CO toxicity. Adverse effects resulting from CO exposure vary widely from subtle vascular and neurologic changes to loss of consciousness and death (NRC 2007). There is no known use of CO in spacecraft; however, it is predicted to be an off-gas product (Leban and Wagner 1989, as cited by Wong 1994). CO is also a by-product of a fire event occurring aboard spacecraft. Such an event occurred aboard the Mir Spacestation since publication of the 1994 CO SMAC (Wong 1994). CO and COHb concentrations as well as resulting health effects were documented and provide direct evidence of CO toxicity to space- craft crews (James and Garcia 1994, James 2008). FIGURE 8-1 Prediction of CO uptake and COHb saturation using CFK equation. Log- log plot of CO uptake by humans from very low ambient CO concentrations as computed from the CFK equation. Abbreviations: DL, diffusing capacity of lungs, [COHb]0, value before CO exposure; M, equilibrium constant; PB, barometric pressure; P CO2, mean par- tial pressure of O2 in lung capillaries; ppm, parts per million; VA, alveolar ventilation rate; Vb, blood volume; VCO, rate of endogenous CO production. Source: Peterson and Stewart 1975, as cited by Penney 1999. Reprinted with permission; copyright 1975, Ap- plied Physiology.

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127 Carbon Monoxide SUMMARY OF ORIGINAL APPROACH The SMAC values that were set in 1994 were targeted to protect crew from CNS and CV toxicity. Wong used the CFK equation as tested by Peterson and Stewart (1975) to calculate COHb concentrations (see Figure 8-1). The CFK equation is a prediction based on a fitted model and has been used by all regula- tory agencies throughout the United States for setting CO exposure limits. These values are based on National Ambient Air Quality Standards (NAAQS), with an additional 2% safety margin. The longer-term SMACs—7, 30, and 180 d—were set at concentrations lower than the typical COHb levels of 1.6% in smokers (Wong 1994). 1-h SMAC, 1994 The 1-h SMAC used the studies of Ramsey (1972) and Putz et al. (1979), in which 5% COHb was found to increase reaction time and impair hand-eye coordination (Wong 1994). Even though there were several conflicting reports on COHb concentrations higher than 5% affecting reaction time and hand-eye coordination, the lowest concentration was selected, because the author believed these impairments would interfere with the crew’s ability to deal with a contin- gency event. Nevertheless, Benignus et al. (1987) (Table 8-1) repeated the Putz et al. (1976, 1979) studies and found no statistically significant change in reac- tion time at a COHb concentration of 8.24%. Benignus and others went on to show no effect on visual detection at 17% COHb (Hudnell and Benignus 1989) and no decrease in human vigilance (numerical monitoring) (Benignus et al. 1977) at 12.62% COHb. Wong (1994) selected 3% COHb as the target concentration for the 1-h SMAC to account for a 2% safety margin against the NAAQS value at that time. It also protected against cardiotoxicity, because 4% COHb for more than 1 h failed to increase the frequency of ventricular premature depolarization in car- diac patients (Sheps et al. 1990, as cited by Wong 1994). A minute volume of 20 L/min, corresponding to light activity of an adult (NRC 1992), was used to cal- culate the CO concentration. In addition, the COHb concentration of 0.6% and the in-flight Hb concentration measured in Skylab were used (Kimzey 1977, as cited by Wong 1994), which resulted in 55 parts per million (ppm) yielding 3% COHb an hour. The 1-h SMAC was set at 55 ppm. 24-h SMAC, 1994 The 24-h SMAC was based on research conducted by Putz et al. (1979). A COHb concentration of 5% impaired hand-eye coordination in 4 h (Putz et al. 1979, as cited by Wong 1994) and was assumed also to impair hand-eye coordi- nation in 24 h. The same target of 3% COHb was then used to set the SMAC.

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TABLE 8-1 COHb Effect Level (2% to 24%) 128 Time Period (CO Concentration) COHb, % Effects Type of Individual n Reference 3-24 1 h (intermittent) Increase in muscle sympathetic nerve activity. Adult males 15 Hanada et al. (2003) No increase in heart rate or ventilation. 5, 10, 15, 1-2 h (27, 55, 83, No effect on upper and lower submaximal Adult males 16 Kizakevich et al. (2000) and 20 and 100 ppm, exercise, no overt CV injury. respectively) >15-20 2.5 h (1,000 ppm CO intoxication evidenced by severe headache Adult males 2 Stewart et al. (1970) continuous to peak and delayed response, EEG and clinical concentration) chemistry normal. 17 2 h (continuous) No effect (visual detection). Adult males 11 Hudnell and Benignus (1989) 17 1+ h (700 ppm Minimal effect on dark adaptation (driving Adult males 27 McFarland (1973) CO continuous) skills). Effect on peripheral light psychomotor response. 8 24 h (50 ppm No effect on performance (time estimation, Adult males 3 Stewart et al. (1970) continuous) reaction time, manual dexterity, steadiness, EEG, and evoked response in driving simulator). 11-13 8 h (100 ppm No effect on performance (time estimation, Adult males 24 Stewart et al. (1970) continuous) reaction time, manual dexterity, steadiness, EEG, and evoked response in driving simulator). 16 4 h (200 ppm Mild headache in 3 of 3, subsided in 30 min for Adult males 3 Stewart et al. (1970) continuous) 2 subjects and in 2 h for 1 subject. No effect on performance (time estimation, reaction time, manual dexterity, steadiness, EEG, and evoked response in driving simulator). 12.62 2 h (200 ppm) No effect on vigilance (numerical monitoring). Adult males 19 Benignus et al. (1977)

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11.22 45 min (950 ppm) No effect on depth perception visual Adult males 20 Ramsey (1973) discrimination for brightness and flicker fusion discrimination. Decrease in reaction time to visual stimulus, but improvement in reaction time in 5 of 20 subjects. 11 1+ h (700 ppm CO Minimal effect on dark adaptation (driving Adult males 27 McFarland (1973) continuous) skills), slight effect on peripheral light psychomotor response. 8.3 1 h (1,000 ppm for Effects of CO on muscle sympathetic nerve Adult males 12 Hausberg and Somers (1997) 30 min + 100 ppm for activity, forearm blood flow, blood pressure, 30 min continuous) heart rate, minute ventilation, and forearm vascular resistance not statistically significant. 8.24 4 h (100 ppm Effect noted not statistically significant (event Adult females Adult 22 Benignus et al. (1987) continuous) monitoring and visual tracking of light). males (1 adult per (repeat of Putz et al. 1976, 1979) chamber) 7.61 45 min (650 ppm) No effect on depth perception visual Adult males 20 Ramsey (1973) discrimination for brightness, flicker fusion discrimination. Decrease in reaction time to visual stimulus. 7 8 d (50 ppm P-wave changes in 6 of 15 subjects. Adult males 9 Davies and Smith (1980) continuous) 5 4 h (70 ppm Decreased ability to keep cathode ray tube on a Adult males Adult 6 Putz et al. (1976, 1979) continuous) moving spot while simultaneously detecting females (2 subjects in bright light flashes interspersed with dimmer same chamber) flashes. 2.4 8 d (15 ppm P-wave changes in 3 of 16 subjects. Adult males 9 Davies and Smith (1980) continuous) Abbreviation: EEG, electroencephalogram. 129

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130 SMACs for Selected Airborne Contaminants With a breathing rate of 20 cubic meters (m3)/d used by the National Research Council (NRC) in 1992 and in-flight Hb concentrations from Skylab, 20 ppm was calculated to yield 3% COHb in 24 h. The 24-h SMAC was set at 20 ppm. 7-d SMAC, 1994 Only one study was found in humans for continuous exposure lasting 7 d or longer (Davies and Smith 1980, as cited by Wong 1994). In this study, P- wave changes were detected at 15 ppm (2.4% COHb) in 3 of 16 subjects and at 50 ppm (7.1% COHb) in 6 of 15 subjects during an 8-d exposure. Wong (1994) targeted a COHb below 2.4% and set the 7-d SMAC based on the U.S. Envi- ronmental Protection Agency’s NAAQS of 9 ppm for 8 h, yielding 1.6% COHb in an exercising individual. Using the CFK equation and a minute volume of 20 m3/d and in-flight levels in Skylab, a 7-d SMAC was set at 10 ppm. 30-d and 180-d SMAC, 1994 The 7-d SMAC target of 1.6% was used for the 30- and 180-d SMACs. The same rationale for the 7-d exposure was applied to the 30- and 180-d SMACs (Wong 1994); with 1.6% being lower than the COHb concentrations commonly detected in smokers, it was thought that this value would be protec- tive against neurologic and CV effects in a continuous 30- or 180-d exposure. SMACs for 30 and 180 d were set at 10 ppm. The NAAQS value, selected to protect the most sensitive individuals in the population, was used as a basis for setting NASA SMACs in 1994. (The NAAQS values are presented in Table 8-2, along with recommended exposure levels from other organizations.) NASA accepts a much higher risk for astronaut crews, because they are in top physical condition; therefore, the ultraconserva- tive values for sensitive individuals are not necessarily appropriate for setting SMACs. CARDIOVASCULAR RISKS OF SPACEFLIGHT NASA has reviewed its position on the CV risks of spaceflight (Con- vertino and Cooke 2005) and has determined that, based on data from astronauts with spaceflight experience, there is no conclusive experimental evidence of cardiac dysrhythmias, manifestation of asymptomatic CV disease, or reduction in myocardial contractile function. The primary CV risks of spaceflight are compromised hemodynamic responses to central hypovolemia resulting in re- duced orthostatic tolerance and exercise capacity. NASA performs a rigorous health screening process and selects astronauts who are in excellent physical condition. The NASA process includes health screening for anemia and CV disease.

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131 Carbon Monoxide TABLE 8-2 Other Organizations’ Recommendations for CO Exposure Recommended Exposure, ppm Organization, Standard Reference OSHA 29 CFR 1910.1000 PEL 8 h TWA 50 ACGIH ACGIH 2002 TLV TWA 25 NIOSH NIOSH 2004 REL TWA 35 Ceiling 200 IDLH 1,200 AIHA AIHA 1999 ERPG-1 200 ERPG-2 350 ERPG-3 500 IPCS WHO, CO in ambient air WHO 1999 15 min 87 30 min 52 1h 26 8h 9 NAAQS, CO in ambient air EPA 2008 1h 37 8h 9 NAC, general public EPA 2001 AEGL-2, 8 h (proposed) 27 AEGL-3, 8 h (proposed) 130 NRC, Submarine NRC 2007 EEGL 1 h 180 EEGL 24 h 45 CEGL 90 d 9 NRC, Navy SEAL NRC 2002 SEAL-1 (10 d) 125 SEAL-2 (24 h) 150 Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; AIHA, American Industrial Hygiene Association; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; EPA, U.S. Environmental Protection Agency; ERPG, emergency response planning guidelines; IDLH, immediately dangerous to life and health; IPCS, International Pro- gramme on Chemical Safety; NAAQS, National Ambient Air Quality Standard; NIOSH, NAC, National Advisory Committee; National Institute for Occupational Safety and Health; ; NRC, National Research Council; OSHA, Occupational Safety and Health Ad- ministration; PEL, permissible exposure limit; REL, recommended exposure limit; SEAL, submarine escape action level; TLV, threshold limit value; TWA, time weighted average; WHO, World Health Organization.

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132 SMACs for Selected Airborne Contaminants NASA IN-FLIGHT EXPOSURE DATA SINCE ORIGINAL SMAC PUBLICATION: PREVIOUS EXPOSURE OF ASTRONAUT CREWS TO ELEVATED CO DURING SPACEFLIGHT In 1994, a fire occurred aboard the Mir Spacestation (see Figure 8-2 and Table 8-3). This event resulted in direct increased CO and COHb exposures to the crew. NASA recorded CO concentrations ranging from 570 ppm (15% COHb) at 1 h (see Table 8-3) post-fire event (pfe) to 4 ppm (9% COHb) at 90 h pfe; the CO measured decreased continuously over this time period. The sus- tained exposure to CO resulted in a peak COHb of 37% at 5 h pfe, which pro- duced the most severe toxic effects noted—headache and nausea, as reported by only one crew member. At 1-h pfe (15% COHb) at 570 ppm CO, there were no reported effects (James and Garcia 1994, James 2008). NEW RESEARCH DATA SINCE 1994 Hausberg and Somers (1997) studied the contribution of CO to the acute CV effects of smoking. This protocol examined the effects of CO on sympa- thetic and hemodynamic measurements in healthy humans. The test pool con- sisted of 10 healthy normotensive subjects (8 men and 2 women) aged 27 ± 5 years. Only one subject smoked (10 cigarettes per week). Subjects were exposed to either room air (control) or 1,000 ppm of CO for 30 min followed by the con- tinuation of room air inhalation or 100 ppm of CO for 30 min. During the expo- sure to either CO or control (vehicle), measurements were obtained for 5 of every 10 min, and COHb was measured every 10 min. While COHb concentra- tions did not change in control subjects, baseline COHb concentrations of 0.2% ± 0.1% increased to 8.3% ± 0.5% after 30 min of inhalation of 1,000 ppm of CO (P < 0.05) and were maintained at about this concentration during the 30 min of inhalation of 100-ppm of CO. Baseline minute ventilation, end-tidal partial pres- sure of O2 in lung capillaries, muscle sympathetic nerve activity (MSNA), fore- arm blood flow (FBF), blood pressure (BP), and heart rate (HR) did not change in CO-exposed or control subjects. Forearm vascular resistance (FVR) increased slightly during control inhalation exposure but did not change during CO inhala- tion. The authors concluded that CO is not a contributing factor to the reduction in central sympathetic outflow or to other hemodynamic changes observed with smoking in humans (Hausberg and Somers 1997). They further postulated that modest increases in COHb concentrations, equivalent to that resulting from ciga- rette smoking, do not have appreciable acute effects on MSNA, BP, HR, or FBF and thus are unlikely to contribute to the acute sympathetic and hemodynamic effects of smoking in healthy humans. The unchanged FVR with CO as opposed to a slight increase in FVR with vehicle may indicate a peripheral vasodilator action of even modest CO concentrations (Hausberg and Somers 1997).

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133 Carbon Monoxide FIGURE 8-2 CO and COHb concentrations and toxic health effects observed on space- station. (Expected effects are noted in boxes on graph and do not reflect actual observed effects in astronauts.) Abbreviations: CPA, Combustion Products Analyzer; LTCO, Low Temperature Catalytic Oxidizer. Source: James and Garcia 1994. In 2000, Kizakevich et al. exposed healthy young men to 1-2 h of CO at COHb concentrations of up to 20%. Sixteen healthy nonsmoking men ranging in age from 18 to 29 years were the test subjects. Kizakevich et al. (2000) used a combination of exposures to CO by breathing from a bag or in an environmental chamber. Test subjects performed a randomized sequence of 5-min multilevel treadmill and hand-crank exercises on different days at less than 2% COHb and after attaining target levels of 5%, 10%, 15%, and 20% COHb. The team meas- ured cardiac output, stroke volume, HR, cardiac contractility, and time to peak ejection time. They assessed myocardial irritability and ischemia and changes in cardiac rhythm. Their results established that the CV system compensated for the reduced O2-carrying capacity of the blood by augmenting HR, cardiac con- tractility, and cardiac output for upper-body and lower-body exercise. They con- cluded that young, apparently healthy men can perform submaximal upper- and lower-body exercise without overt impairment of CV function after CO expo- sures attaining 20% COHb. They demonstrated that these subjects can perform submaximal upper- and lower-body exercise without blatant CV injury at up to 20% COHb (Kizakevich et al. 2000).

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134 SMACs for Selected Airborne Contaminants TABLE 8-3 Calculated COHb and Recorded CO Aboard Mir Spacestation Post-Fire Event Time, h CoHb, % Time, h CO, ppm 1 15 1.17 570 2 25 1.5 546 4 36 1.83 489 a 5 37 2.2 467 6 36 3.13 413 8 27.52 3.48 402 10 25.88 3.83 398 12 24.16 4.83 377 14 22.72 5.83 357 16 21.61 6.83 326 18 19.68 17.83 200 20 18.07 22.75 163 22 17.24 23.83 153 24 15.96 27.42 124 26 14.64 27.83 129 28 13.74 41.83 68 30 12.82 45.85 52 32 11.87 65.83 18 34 10.91 78.00 10 36 9.93 89.83 4 38 8.93 40 7.9 42 7.38 44 6.85 46 5.77 48 5.22 50 4.89 52 4.67 54 4.45 56 4.22 58 3.89 60 3.54 a Peak COHb at 37%; one of three crew members reported headache and nausea symp- toms (James and Garcia 1994).

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135 Carbon Monoxide Hanada et al. (2003) measured the role of arterial free oxygen partial pres- sure (Pa,O2) on increases in MSNA, HR, ventilation, and leg hemodynamics at rest and during rhythmic handgrip exercise. Twenty healthy male subjects aged 26 ± 1 years were studied in the supine position. CO was used to mimic the ef- fect of systemic hypoxia on arterial oxyhemoglobin (about 20% lower arterial oxyhemoglobin), while normalizing or increasing Pa,O2 (40-620 mmHg). Four experimental conditions were used: (1) normoxia, ~110 mmHg Pa,O2 and ~2% COHb; (2) hypoxia, ~40 mmHg Pa,O2 and ~2% COHb; (3) CO + normoxia, ~110 mmHg Pa,O2 and ~23% COHb; (4) CO + hyperoxia, ~620 mmHg Pa,O2 and ~24% COHb. Conditions (3) and (4) caused an increase in MSNA compared with con- dition (1) but did not increase HR or ventilation. In spite of the 4-fold elevation in MSNA in conditions (3) and (4), with hypoxemia and exercise no change was noted in O2 uptake, resting leg blood flow, and vascular conductance. This re- search also noted that, despite normal or elevated Pa,O2 , conditions (3) and (4) increased MSNA at rest and during exercise similarly to acute systemic hypoxia (Hanada et al. 2003). This study is the first to provide direct evidence for a CO- induced increase in MSNA. It also demonstrated that COHb concentrations of 24% do not increase HR and ventilation during normoxic and hyperoxic condi- tions. PROPOSED SMAC VALUES 2006 A review of available guidance levels, including NASA’s original CO SMACs, has found that most levels set by various organizations do not align with NASA’s mission objectives for protection of crew health. The bulk of these values are set to protect the most sensitive individuals. NASA accepts a much higher risk for spaceflight crews, who are expected to be in prime physical con- dition. The revised SMACs being proposed by NASA are presented in Table 8-4. TABLE 8-4 Spacecraft Maximum Allowable Concentrations Target mg/m3 Duration ppm COHb, % Target toxicity 1h 425 485 15 CNS/CV 24 h 100 114 15 CNS/CV 7d 55 63 8 CNS/CV 30 d 15 17 2 CNS/CV 180 d 15 17 2 CNS/CV 1,000 d 15 17 2 CNS/CV Conversion factor: 1 ppm = 1.14 mg/m3.

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136 SMACs for Selected Airborne Contaminants For 1- and 24-h SMACs, NASA defines acceptable risk as a concentration of a substance in air that may be acceptable for the performance of specific tasks during emergency conditions lasting for less than 1 h or less than 24 h (NRC 1992). The 1- and 24-h SMACs could include reversible effects that do not im- pair judgment and do not interfere with proper responses to the emergency, such as shutting a valve, closing a hatch, removing a source of heat or ignition, or using a fire extinguisher (NRC 1992). Exposure at the 1- and 24-h levels may produce effects such as increased respiratory rate from increased CO2, headache or mild CNS effects from CO, and respiratory tract and eye irritation from am- monia or sulfur dioxide (NRC 1992). SMACs for up to 180 d are concentrations designed to avoid adverse health effects, immediate or delayed, as well as to avoid degradation in performance of crew after a continuous exposure. In contrast to 1- and 24-h SMACs, which are intended to guide exposures during emergencies, SMACs lasting up to 180 d, and now 1,000 d, are intended to provide guidance for operations during those time periods (180 d in an envi- ronment like the Spacestation and 1,000 d for extended stays on the lunar, Mar- tian, or other planetary surfaces). Accounting for accumulation, detoxification, excretion, and repair of toxic injuries is important in determining long-term SMACs (NRC 1992). Whether a material has a cumulative effect must be taken into account for long-duration SMACs. Neuropathologic regeneration or repair of toxic injuries occurs more readily in intermittent than in continuous expo- sures, making repair important in setting long-term SMACs (NRC 1992). The emergency exposure guidance level (EEGL) values set by the NRC in 2007 for submariner protection most closely resemble the closed environment experienced during spaceflight, with the exceptions of the lack of microgravity and the allowance of smoking aboard their vessels. Research conducted after original publication of the CO SMAC, along with a review of older research, provides evidence for raising the current SMACs. Anecdotal support is also pro- vided by observed effects in crewmembers on NASA’s Spacestation fire event. SMACs proposed here are all below a COHb threshold of 15%. In all SMAC calculations, the use of Peterson and Stewart’s (1975) CFK calculation with a minute volume of 20 L/min, corresponding to light activity of an adult (NRC 1992), was used to calculate CO concentration. In addition, the initial COHb concentration of 1.0% was used based on a report from Doherty (2000) and the in-flight Hb concentration measured in Skylab was used (Kimzey 1977, as cited by Wong 1994). 1-h SMAC In 2007, the NRC proposed a 1-h EEGL to remain below a 20% COHb threshold based on the research of Kizakevich et al. (2000), in which healthy young men were exposed to 1-2 h of CO at COHb concentrations of up to 20% and identified no decrement to the CV system during submaximal and lower- body exercise. NRC began with a value of 200 ppm, which is a 5% COHb con-

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137 Carbon Monoxide centration on the basis of the calculations by Peterson and Stewart (1975) in Figure 8-1. The EEGL was adjusted to 180 ppm to be protective against severe headaches and was adjusted for low oxygen atmosphere to account for the dif- ferences between smokers and nonsmokers, making it tolerable to both groups of individuals and causing no neurobehavioral performance impairments (based on guidance from Stewart et al. 1970, as cited by NRC 2002). No additional factors were applied because the NRC considered this a no-observed-adverse- effect level (NOAEL). For CV protection, NASA proposes a 1-h SMAC that remains below the 20% COHb threshold. Mayr et al. (2005) exposed healthy young individuals (mean age 25 years) to 500 ppm of CO for 1 h via inhalation (full face masks), yielding a peak of 7% COHb. The exposures did not have a significant effect on vital parameters, leu- kocyte and neutrophil counts, and cytokine levels. While the focus of this study was to determine whether CO had an anti-inflammatory effect on humans at 250 ppm as had been reported in rodents, it did show a NOAEL of 500 ppm at 1 h (Mayr et al. 2005). NASA selects a value of 15% COHb to be protective against CNS and CV effects. The Committee on Spacecraft Exposure Guidelines (SEGs) recom- mended 15% COHb. This recommendation was based on the Kizakevich et al. (2000) study and the Mir Spacestation pfe. The NOAEL of 20% COHb was reported for CV effects in the Kizakevich et al. (2000) study. While NASA’s in- flight experience is not a conclusive scientific study, NASA has previously ob- served this COHb level (15%) as a no-reported-effect level in three crewmem- bers at 1 h pfe on Mir Spacestation. The NASA information from the pfe on the Mir Spacestation was recommended by the SEGs committee because the report of no effects at 15% COHb in crewmembers was assumed to cover all effects (CNS and CV). NASA selects a SMAC of 425 ppm for a 1-h exposure, which should result in a COHb value of 15% on the basis of the calculations of Peter- son and Stewart (1975) as indicated in Figure 8-1. No additional safety factors are applied, because this value is considered a NOAEL by Kizakevich et al. (2000). NASA’s 1-h SMAC is set at 425 ppm. 24-h SMAC Wong cited the only 24-h human exposure study (Stewart et al. 1970), which showed a NOAEL for CNS effects of 50 ppm, yielding 8% COHb. NASA’s experience during the Mir Spacestation fire showed no adverse re- sponses in all three crewmembers at 24 h at 15% COHb. While Wong did not base the 24-h SMAC on this study, the NRC (2004) did use this research value. NRC reduced the value to 45 ppm for a low-oxygen environment and applied no further safety factors. The NRC (2002) proposed the Navy submarine escape action level 2 (SEAL-2) for a 24-h exposure, to be 150 ppm. This would not result in a COHb concentration higher than 20% COHb. They expect some

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138 SMACs for Selected Airborne Contaminants submariners to experience slight headache and some cognitive function decre- ment; however, it would not impair the crew from escaping a disabled subma- rine. Their value was also supported by research of Theodore et al. (1971) as cited by Wong (1994), in which monkeys were exposed continuously to 380 ppm for 99 d, yielding 31% COHb; no adverse health effects were observed. NASA selects a 24-h SMAC value of 100 ppm, yielding a COHb of no more than 15%. The calculation of a 24-h exposure to 100 ppm results in a COHb concentration of 13.55%. No additional safety factors are applied because this is a NOAEL. NASA’s 24-h SMAC is set at 100 ppm. 7-d SMAC The Navy SEAL-1 for 10-d exposure to CO in submarines is proposed to be 125 ppm, which would yield a COHb value of 15%, based on the studies by Stewart et al. (1973) and Hudnell and Benignus (1989) (as cited by NRC 2002). This SEAL-1 value showed no perceptual function or cognitive effects in healthy individuals. It is noted that this value was for oxygen values of 20.95% and the SEAL should be lowered if O2 concentrations fall below this value, which is the case with NASA, who maintains a 20% O2 atmospheric value on its spacecraft. Davies and Smith (1980) noted that a determination of the end point of effect (P-wave changes) was to be evaluated as to whether it was an adverse effect. If these p-wave changes are not considered adverse, the Davies and Smith (1980) paper supports a 7-d SMAC for CO of 55 ppm, 7% COHb. NASA con- siders the target of 7% COHb as appropriate for the 7-d SMAC, because it is expected to be a NOAEL. NASA’s 7-d SMAC is set at 55 ppm. 30-d and 180-d SMAC The NRC proposed a 10-ppm SMAC for CO in 1994 based on a study by DeBias et al. (1973) (as cited by NRC 2007). This study exposed normal and infarcted monkeys to CO at 100 ppm for 23 h/d for 24 wk. The test subjects ex- perienced a higher incidence of T-wave inversions. Both normal and infarcted monkeys presented higher P-wave changes after 2 d of exposure. The 100-ppm value was thought to be a lowest-observed-adverse-effect level (LOAEL). They adjusted the value for a low-oxygen atmosphere to 90 ppm, applied an interspe- cies factor, and applied a LOAEL to NOAEL factor to set a value of 10 ppm. A 99-d continuous exposure to CO at 380 ppm (31% COHb) caused no reduction in operant behavior in monkeys (Theodore et al. 1971, as cited by Wong 1994). However, Wong did not apply an interspecies factor and he did not use this study as a basis for setting the 30- and 180-d SMACs. Instead, he tar- geted 1.6% COHb to calculate a value of 10 ppm, which is lower than the back- ground concentrations of COHb typically detected in smokers. Wong also noted

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139 Carbon Monoxide that this concentration would not be expected to cause tissue degradation based on the studies of Eckardt et al. (1972) (2 years of continuous exposure to 3.4% COHb) and Theodore et al. (1971) (32% to 33% COHb for 168 d), which pro- duced no histological morphology changes (as cited by Wong 1994). NASA selects a threshold of 2% COHb for 30- and 180-d SMACs, which is calculated to be 15 ppm. Hanada et al. (2003) used this amount as the control COHb value in normoxic and hypoxic exposure. This amount of COHb showed no decrement to CNS activities. This concentration is also below the threshold limit value time weighted average for working lifetime exposure of occupational workers, currently set at 25 ppm (ACGIH 2002). NASA’s 30- and 180-d SMAC is set at 15 ppm. 1,000-d SMAC Because there are no long-term (1,000 d) human exposure studies on CO exposure, it may be considered prudent to set a SMAC that is close to the ambi- ent CO concentrations that are experienced on Earth, because humans do not appear to experience any adverse health effects at these concentrations. How- ever, no conclusive research has been conducted on long-term health effects resulting from exposure to ambient CO concentrations, which change over the years. Background concentrations on submarines have been reported to average 5 ppm and range from 0 to 14 ppm (NRC 2007). Ambient air CO levels in large European cities generally average 17 ppm, with peaks at 53 ppm (WHO 1999). NAAQS accepts an 8-h average of 9 ppm, which is often exceeded throughout the United States (HSDB 2005, EPA 2008). NASA will therefore set its 1,000-d SMAC at the same level of 2% COHb as the 30- and 180-d SMACs. NASA’s 1,000-d SMAC is set at 15 ppm. RECOMMENDATIONS AND CONCLUSIONS Further research is needed for long-term exposures to CO. We are confi- dent in the continued use of Peterson and Stewart’s (1975) CFK calculations to set CO SMACs. Whereas the formula provides point estimates, our calculations include spaceflight variables from actual COHb concentrations attained during long-term (6 month) missions, which preclude the use of any additional space- flight factors. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2002. Carbon Monoxide. Pp. 20 in Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs) for 2002. American Con- ference of Governmental Industrial Hygienists, Cincinnati, OH.

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140 SMACs for Selected Airborne Contaminants AIHA (American Industrial Hygiene Association). 1999. P. 25 in The AIHA 1999 Emer- gency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA. Benignus, V.A., D.A. Otto, J.D. Prah, and G. Benignus. 1977. Lack of effects of carbon monoxide on human vigilance. Percept. Mot. Skills 45(3 Pt 1):1007-1014. Benignus, V.A. K.E. Muller, C.N. Barton, and J.D. Prah. 1987. Effect of low level carbon monoxide on compensatory tracking and event monitoring. Neurotoxicol. Teratol. 9(3):227-234. Coburn, R.F., R.E. Forster, and P.B. Kane. 1965. Considerations of the physiological variables that determine the blood carboxyhemoglobin concentration in man. J. Clin. Invest. 44(11):1899-1910. Convertino, V.A., and W.H. Cooke. 2005. Evaluation of cardiovascular risks of space- flight does not support the NASA bioastronautics critical path roadmap. Aviat. Space Environ. Med. 76(9): 869-876. Davies, D.M., and D.J. Smith. 1980. Electrocardiographic changes in healthy men during continuous low-level carbon monoxide exposure. Environ. Res. 21(1):197-206. DeBias, D.A., C.M. Banerjee, N.C. Birkhead, W.V. Harrer, and L.A. Kazal. 1973. Car- bon monoxide inhalation effects following myocardial infarction in monkeys. Arch. Environ. Health 27(3):161-167 (as cited in NRC 2007). Doherty, S. 2000. History, pathophysiology, clinical presentation and role of hyperbaric oxygen in acute carbon monoxide poisoning. Emerg. Med. 12(1):55-61. Eckhart, R.E., H.N. MacFarland, Y.C. Alarie, and W.M. Busey. 1972. The biologic effect from long-term exposure of primates to carbon monoxide. Arch. Environ. Health 25(6):381-387(as cited in Wong 1994). EPA (U.S. Environmental Protection Agency). 2001. Carbon Monoxide Results. AEGL Program [online]. Available: http://www.epa.gov/oppt/aegl/results50.htm [ ac- cessed Nov. 2005]. EPA (U.S. Environmental Protection Agency). 2008. National Ambient Air Quality Standards (NAAQS). Office of Air and Radiation, U.S. Environmental Protection Agency [online]. Available: http://epa.gov/air/criteria.html [accessed Apr. 3, 2008]. Hanada, A., M. Sander, and J. Gonzalez-Alonso. 2003. Human skeletal muscle sympa- thetic nerve activity, heart rate and limb haemodynamics with reduced blood oxy- genation and exercise. J. Physiol. 551(2):635-647. Hausberg, M., and V.K. Somers. 1997. Neural circulatory responses to carbon monoxide in healthy humans. Hypertension 29(5):1114-1118. HSDB (Hazardous Substance Data Bank). 2005. Carbon Monoxide (CASRN 630-08-0). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/search [ac- cessed Nov. 2005]. Hudnell, H.K., and V.A. Benignus. 1989. Carbon monoxide exposure and human visual detection thresholds. Neurotoxicol. Teratol. 11(4):363-371. James, J.T. 2008. Health effects of atmospheric contamination. Chapter 21 in Principles of Clinical Medicine for Spaceflight, M.R. Barratt, and S.L. Pool, eds. New York: Springer. James, J.T. and H. Garcia. 1994. Space Station Fire—Report on Toxicological Event. National Aeronautics and Space Administration, Johnson Space Center, Houston, TX. Kimzey, S.L. 1977. Hematology and immunology studies. P. 249-282 in Biomedical Results from Skylab, R.S. Johnson, and L.F. Dietlein, eds. NASA SP-377. Wash-

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141 Carbon Monoxide ington, DC: National Aeronautics and Space Administration [online]. Available: http://lsda.jsc.nasa.gov/books/skylab/Ch28.htm [accessed Apr. 2, 2008]. Kizakevich, P.N., M.L. McCartney, M.J. Hazucha, L.H. Sleet, W.J. Jochem, A.C. Hackney, and K. Bolick. 2000. Noninvasive ambulatory assessment of cardiac function in healthy men exposed to carbon monoxide during upper and lower body exercise. Eur. J. Appl. Physiol. 83(1):7-16. Leban, M.I., and P.A. Wagner. 1989. Space Station Freedom Gaseous Trace Contaminant Load Model Development. SAE PAPER 891513. Society of Automotive Engi- neers, Warrendale, PA (as cited in Wong 1994). Mayr, F.B., A. Spiel, J. Leitner, C. Marsik, P. Germann, R. Ullrich, O. Wagner, and B. Jilma. 2005. Effects of carbon monoxide inhalation during experimental en- dotoxemia in humans. Am. J. Respir. Crit. Care Med. 171(4):354-360. McFarland, R.A. 1973. Low level exposure to carbon monoxide and driving perform- ance. Arch. Environ. Health. 27(6):355-359. NIOSH (National Institute for Occupational Safety and Health). 2004. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) 2004-103. National Institute for Oc- cupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maxi- mum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. NRC (National Research Council). 2002. Carbon monoxide. Pp. 69-96 in Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2007. Carbon monoxide. Pp. 67-102 in Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Vol. 1. Washington, DC: The National Academies Press. Penney, D.G. 1999. Carbon Monoxide Poisoning. Carbon Monoxide Headquarters – COHQ [online]. Available: http://www.coheadquarters.com/figco08.htm [accessed April 1, 2008]. Penney, D.G. 2000a. Carbon Monoxide Toxicity. Boca Raton: CRC Press. Penney, D.G. 2000b. Carbon Monoxide. Coburn-Forster-Kane Equation. Carbon Monox- ide Headquarters-COHQ. [online]. Available: http://www.coheadquarters.com/ CFKEqu1.htm [accessed April1, 2008]. Peterson, J.E., R.D. Stewart. 1975. Predicting the carboxyhemoglobin levels resulting from carbon monoxide exposures. J. Appl. Physiol. 39(4):633-638. Putz, V.R., B.L. Johnson, and J.V. Setzer. 1976. Effects of CO on Vigilance Perform- ance: Effects of Low-Level Carbon Monoxide on Divided Attention, Pitch Dis- crimination, and the Auditory Evoked Potential. DHEW (NIOSH) 77-124. Cincin- nati, OH: U.S. Department of Health, Education, and Welfare, National Institute of Occupational Safety and Health. Putz, V.R., B.L. Johnson, and J.V. Setzer. 1979. A comparative study of the effects of carbon monoxide and methylene chloride on human performance. J. Environ. Pathol. Toxicol. 2(5):97-112. Ramsey, J.M. 1972. Carbon monoxide, tissue hypoxia, and sensory psychomotor re- sponse in hypoxaemic subjects. Clin. Sci. 42(5):619-625. Ramsey, J.M. 1973. Effects of single exposures of carbon monoxide on sensory and psy- chomotor response. Am. Ind. Hyg. Assoc. J. 34(5):212-216. Roughton, F.J. 1970. The equilibrium of carbon monoxide with human hemoglobin in whole blood. Ann. N.Y. Acad. Sci. 174(1):177-188.

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142 SMACs for Selected Airborne Contaminants Sheps, D.S., M.C. Herbst, A.L. Hinderliter, K.F. Adams, L.G. Ekelund, J.J. O'Neil, G.M. Goldstein, P.A. Bromberg, J.L. Dalton, and M.N. Ballenger. 1990. Production of arrhythmias by elevated carboxyhemoglobin in patients with coronary artery dis- ease. Ann. Intern. Med. 113(5):343-351. Stewart, R.D., J.E. Peterson, E.D. Baretta, R.T. Bachand, M.J. Hosko, and A.A. Hermann. 1970. Experimental human exposure to carbon monoxide. Arch. Envi- ron. Health 21(2):154-164. Stewart, R.D., P.E. Newton, M.J. Hosko, and J.E. Peterson. 1973. Effect of carbon mon- oxide on time perception. Arch. Environ. Health 27(3):155-160. Theodore, J., R.D. O'Donnell, and K.C. Back. 1971. Toxicological evaluation of carbon monoxide in humans and other mammalian species. J. Occup. Med. 13(5):242- 255. WHO (World Health Organization). 1999. Carbon Monoxide, 2nd Ed. Environmental Health Criteria 213. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc213.htm [accessed Apr. 2, 2008]. Wong, K.L. 1994. Carbon Monoxide Pp. 61-90 in Spacecraft Maximum Allowable Con- centrations for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press.

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143 Carbon Monoxide APPENDIX A Coburn-Forster-Kane (CFK) Equation The CFK equation is the most sophisticated approach available for model- ing CO uptake by humans and other animals. Disadvantages of its use are the large number of variables and the fact that the value of many variables must be obtained from other equations (Penney 2000b). {A[HbCO]t – (BVCO + PICO)}/{A[HbCO]0 – (BVCO + PICO)} = e-tAVbB Terms of Equation A = P CO2/M [HbO2] [HbCO]t, see below B = 1/DLCO + PL/VA VCO, see below PICO, see below [HbCO]0, see below e, see below t, see below Vb, see below where P CO2 is the average partial pressure of O2 in lung capillaries (mmHg), at sea level PIO2 (159) – 49 = 110, PIO2 = 148.304 – 0.0208 PICO, M is the ratio of the affinity of blood for CO to that for O2, approximately 218, [HbO2] is mL of O2 per mL of blood, or = 0.22 – [HbCO]t, [HbCO]t is mL of CO per mL of blood at time t, or = [COHb%]t . 0.0022 (term to be solved for), DLCO is diffusivity of the lung for CO (mL/min/mmHg), or = 35VO2 e0.33, VO2 = RMV/22.274 – 0.0309, RMV is respiratory minute volume (L/min), PL is baro- metric pressure minus vapor pressure of water (49) at body temperature (mmHg), VCO is rate of endogenous CO production (mL/min); approximately 0.007 mL/min, PICO is partial pressure of CO in inhaled air (mmHg), VA is al- veolar ventilation rate (mL/min), or = 0.933 VE – 132 f, VE is ventilation volume (mL/min), f is ventilation frequency, [HbCO]0 is mL of CO per mL of blood at beginning of exposure (approximately 0.8% COHb, or 0.0176 mL of CO per mL of blood for a nonsmoker), e is the base of the natural logarithm (2.7182), t is exposure duration (min), and Vb is blood volume (mL); assume a body weight of 74 mL/kg. Data were obtained from Penney 2000b.