Review of Submarine Escape Action Levels for Selected Chemicals (2002)

This chapter reviews physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on carbon monoxide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine from exposure to carbon monoxide and to evaluate the Navy’s proposed submarine escape action levels (SEALs), proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to carbon monoxide exposure.

Carbon monoxide is a colorless, odorless, tasteless gas (Budavari 1989). It is very flammable and burns in air with a bright blue flame. It is highly poisonous to humans. The chemical and physical properties of carbon monoxide are summarized in Table 3–1.

Trace quantities of carbon monoxide in the environment are considered normal (WHO 1999). Plants can both metabolize and produce this gas. Carbon monoxide is also produced by incomplete combustion of carbon-containing materials (ACGIH 1996), and automobile exhaust is a major source of carbon

monoxide in the environment (NRC 1994). Another common environmental source is cigarette smoke. Indoor sources include gas stoves, furnaces, and fires. Carbon monoxide is produced inside the body by hemoglobin metabolism (NRC 1994).

Carbon monoxide is absorbed through the lungs at an approximate rate of 25.8±8 mL/min-mm Hg (Jones et al. 1982). It is then absorbed into the bloodstream from the lungs. There is competitive binding between carbon monoxide and oxygen to hemoglobin in the red blood cell, forming carboxyhemoglobin (COHb) and oxyhemoglobin, respectively (WHO 1999). The rate of formation of COHb can be predicted by a model described by Coburn et al. (1965). The affinity of hemoglobin for carbon monoxide is approximately 200–250 times its affinity for oxygen (NRC 1985). The amount of COHb depends mainly on the concentration and duration of carbon monoxide exposure, and the barometric pressure. To a lesser extent, it is also dependent on minute volume, blood volume in lung capillaries, body temperature, rate of endogenous carbon monoxide production, average partial pressure of oxygen in the lung capillaries, and the exact ratio of the affinity of blood for carbon monoxide and oxygen. Figure 3–1 shows the relationship of carbon monoxide concentration in ambient air and the COHb concentration formed at various exposure times in human volunteers

(Spencer and Schaumburg 2000). Although the primary reaction of carbon monoxide is with hemoglobin, it also interacts with myoglobin, cytochromes, and metalloenzymes (e.g., cytochrome c oxidase and cytochrome P450) (WHO 1999). The health importance of these secondary reactions is not well understood.

COHb cannot carry oxygen, and the effect of binding is a reduction of tissue partial pressure of oxygen (pO₂) (NRC 1985). When carbon monoxide binds to hemoglobin, the affinity of the remaining hemoglobin for oxygen is increased. Therefore, the presence of COHb in the blood shifts the oxyhemoglobin dissociation curve to the left, and tissue pO₂ must decrease to much lower values for the oxyhemoglobin to release its oxygen. The combination of the decrease in oxygen-carrying capacity of the blood and the impaired release of oxygen to the tissues results in a greater tissue oxygen, deficiency than is produced by an equivalent reduction in ambient pO₂ (as at high altitude) or by an equivalent reduction in hemoglobin (as in anemia).

An additional hypothesis about the mechanism of carbon monoxide-mediated toxicity invokes reoxygenation injury subsequent to the hypoxic episode. Hyperoxygenation facilitates the production of reactive oxygen species, which, in turn, lead to the formation of oxidized proteins and nucleic acids (Zhang and Piantadosi 1992). Carbon monoxide exposure also has been shown to result in lipid peroxygenation (Thom 1990). Reoxygenation after exposure to carbon monoxide is also associated with oxidative stress and the ensuing production of oxygen radicals as a result of the conversion of xanthine dehydrogenase to xanthine oxidase (reperfusion injury; Thom 1992).

The lung eliminates carbon monoxide. More than 99% of this gas is eliminated unchanged, and less than 1% is converted to carbon dioxide (Stewart 1975). The time required for absorption or elimination of half the final volume of COHb in healthy, sedentary adults at sea level is 4 h (breathing air) or 1.5 h (breathing oxygen) (Stender et al. 1977).

Carbon monoxide causes toxicity by binding reversibly to the hemoglobin molecule, forming COHb, which decreases the oxygen-carrying capacity of the blood. This capacity is further reduced because the presence of COHb alters the dissociation of oxyhemoglobin in the tissues.

Carbon monoxide toxicity has been studied well in humans. If sufficiently prolonged, exposure at concentrations of 200–1,200 ppm can result in a progression of such hypoxic symptoms as headache, decreased night vision, abnormal visual evoked response, nausea, abnormal fine manual dexterity, vomiting,

FIGURE 3–1 Carbon monoxide concentrations reached in blood (% saturation at various durations of exposure) in a normal human subject as a function of inspired CO. Abbreviations: P_B, barometric pressure; P_CO2, average partial pressure of carbon dioxide in lung capillaries; V_A, alveolar ventilation rate; V_b, blood volume; M, equilibrium constant; D_L, diffusing capacity of the lungs; [COHb]_o, control value prior to carbon monoxide exposure; V_CO, rate of endogenous carbon monoxide production. Source: Peterson and Stewart (1970). Reprinted with permission from Experimental and Clinical Neurotoxicology, 2nd Edition; copyright 2000, Oxford University Press.

convulsions, and if no treatment is administered, death (NRC 1985). At 35% COHb, manual dexterity is impaired; at 40%, mental confusion is observed. Death can occur at 67% COHb. After treatment to increase pO₂, a complete recovery can be expected if tissue anoxia has not been too severe. The primary target organs of carbon monoxide are the heart and the brain, both of which have a critical need for oxygen (NRC 1994). The remainder of this section reviews the available human toxicity data on cardiovascular and central nervous system (CNS) effects after exposure to carbon monoxide; those data are summarized in Table 3–2.

The myocardium is more sensitive than any other muscle tissue to the decrease in available blood oxygen caused by formation of COHb. Cardiac dysfunction attributable to the effects of carbon monoxide binding to cardiac myoglobin also could contribute to decreased perfusion of the heart and the CNS (Cobb and Etzel 1991). As COHb concentrations increase, there is a gradient of symptoms that reflects increasing cardiovascular dysfunction (Table 3–2). Some factors have been shown to modulate the clinical effects of carbon monoxide exposure. Greater oxygen demand in actively exercising (versus sleeping) patients enhances susceptibility to carbon monoxide intoxication (Meredith and Vale 1988). The degree and duration of hypotension, the presence of cardiac or pulmonary disease or anemia, as well as cardiac dysfunction (arrhythmias or other conditions) induced by carbon monoxide exposure also influence clinical outcome (Ehrich et al. 1944; Stewart 1976).

Cardiac function in healthy persons could be affected by low to moderate carbon monoxide exposures (Davies and Smith 1980). Six matched groups of young healthy subjects lived in a closed environmental chamber for 18 d and were exposed continuously to carbon monoxide at concentrations of 15 or 50 ppm in air during the middle 8 d. Unequivocal P-wave electrocardiogram (ECG) changes were observed during exposure in 3 of the 15 subjects exposed at 15 ppm (2.4% COHb) and in 6 of 15 subjects exposed at 50 ppm (7.1% COHb), compared with none of the 14 exposed at 0 ppm (0.5% COHb).

The ability to perform physical work is drastically reduced when COHb concentrations reach 40%. Chiodi et al. (1941) observed that subjects with 40– 45% COHb were unable to perform tasks requiring only slight physical exertion. COHb concentrations of 15–20% do not appear to affect the ability to do physical work (submaximal exercise for short durations) (Chevalier et al. 1966; Ekblom and Huot 1972; Pirnay et al. 1971; Vogel and Gleser 1972; Vogel et al. 1972). In those studies, a slight increase in heart rate was observed. Gliner et al. (1975) exposed smokers and nonsmokers aged 22–55 to carbon monoxide (13.2 and 10.7% COHb, respectively) during long periods of activity (3.5 h within a 4-h period) at 35% of maximal aerobic capacity. The subjects showed only minimal changes in physiologic response.

The critical concentration at which COHb reduces maximum oxygen uptake (VO_2MAX) is 4.3%, according to Horvath et al. (1975). The same investigators also reported decreases of 4.9% and 7% in work time to exhaustion at COHb of 3.3% and 4.3%, respectively. Those findings were confirmed in a double-blind study of 6 healthy male firefighters exposed to carbon monoxide (5.0–5.5% COHb for 4 h) (Klein et al. 1980). The firefighters showed a decrease in time to exhaustion.

Sievers et al. (1942) studied Holland Tunnel workers exposed for approximately 13 years at an average concentration of 70 ppm for multiple periods lasting 2 h each during an 8 h shift. No adverse health effects were observed in those workers. COHb concentrations were 5–10%. In a retrospective study of bridge and tunnel officers exposed to carbon monoxide at an average COHb concentration of less than 5%, Stern et al. (1988) reported a significant increase in mortality from arteriosclerotic heart disease. Given that continuous COHb burdens of 5% might carry a significant cardiovascular risk, it is possible that the cardiovascular effects of carbon monoxide in submariners, particularly those who smoke cigarettes, could be amplified by the imposition of a 1.5–5% COHb produced by ambient carbon monoxide in a submarine (Bondi et al. 1978; Davies 1973; Goldsmith and Landaw 1968; McIlvaine et al. 1969).

Numerous studies have assessed the effects of carbon monoxide on such CNS functions as vigilance, sensory effects, coordination and tracking, driving ability, and cognitive behavior. Despite extensive investigations, the COHb concentrations that trigger an effect on human perceptual function and cognition have not been quantified. COHb concentrations as low as 4.5% perturb ability to discriminate small differences in light intensity (McFarland et al. 1944). Transient alterations of visual thresholds are associated with 5% COHb (McFarland et al. 1944). A significant performance decrement in the ability to compare the duration of tones was reported after exposure to 50 and 100 ppm carbon monoxide for 90 and 50 min, respectively (Beard and Grandstaff 1975). Other studies have not corroborated effects on perceptual function and cognition at comparably low COHb concentrations (Table 3–2). Differences in experimental design-in particular, in task duration–have been suggested to be, at least partially responsible for the discrepant results (Beard and Grandstaff 1975; Crystal and Ginsberg 2000; Stewart 1976).

Vigilance assessment measures how well a person performs at detecting small environmental changes that take place at unpredictable intervals and, therefore, demand continuous attention (NRC 1985). Decreases in vigilance due to carbon monoxide exposure have been reported by several investigators, but the data do not show conclusively which concentration of COHb will trigger impaired vigilance. Beard and Grandstaff (1975) reported impaired vigilance in subjects with 2% COHb. Horvath et al. (1971) and O’Donnell et al. (1971) reported a decrement in performance in subjects with 6.6% COHb. However, vigilance was not affected in subjects with 0.9% and 2.3% COHb. Winneke et al. (1978) did not observe any decrements in vigilance at COHb up to 11%. Putz et al. (1976, 1979) exposed subjects to carbon monoxide and found that visual-task performance was decreased at 5% COHb. This effect was not observed at 1% or 3% COHb. Using a vigilance paradigm different from that used by Putz et al. (1976, 1979), Benignus et al. (1977) and Davies et al. (1981) found no decrement in vigilance in subjects with up to 5.7% COHb.

Several studies have tested visual function after exposure to carbon monoxide. To minimize variability, McFarland et al. (1944) studied brightness discrimination in a small group of well-trained subjects. The subjects reported decreases in visual sensitivity at approximately 4.5% COHb. Another study reported no adverse effects on visual discrimination or depth perception in subjects with 8% or 12% COHb (Ramsey 1973). Luria and McKay (1979) reported no decrement in night vision with COHb of 9%. Davies et al. (1981) reported that at 7% COHb there was no effect on visual function. The studies described above used various visual paradigms, which could account for the differences in results.

Two studies that used subjects with COHb concentrations of up to 15% reported no changes in the ability to do tasks involving coordination (Stewart et al. 1970; Wright et al. 1973). Stewart et al. (1970) used several tests of manual dexterity. In one, subjects had to pick up small pins, place them in small holes, and then put collars over the pins. No effects attributable to carbon monoxide exposure were found at COHb up to 15%. Wright et al. (1973) also observed no effects on a number of coordination tasks at COHb of 5% and 7%. One study did report a decrement in a hand-eye coordination task (5% COHb) (Putz et al. 1976).

Several investigators have assessed the effects of carbon monoxide exposure on driving performance. McFarland (1973) studied subjects with 17% COHb who drove instrumented automobiles under highway conditions. Carbon monoxide did not cause a serious decrease in driving ability, but there was a statistically significant increase in roadway viewing time. No differences were reported in steering-wheel reversals. At 10% COHb and higher, Ray and Rockwell (1970) reported a significant difference in time required to respond to a velocity change in a lead car.

Bender et al. (1972) investigated the effects of exposure that resulted in 7% COHb on the ability to learn 10 nonsense syllables. The exposure caused a decrease in ability to recite the syllables and a decrease in ability to recite a series of digits in reverse order. The exposed subjects showed no change in ability to perform other tasks involving calculation problems, analogies, shape selection, dot counting, and letter recognition.

In approximately 3% of patients recovering from acute carbon-monoxide-induced coma, a severe, sometimes fatal, neurologic condition develops (Choi 1983; Min 1986). No clinical or laboratory results predict which patients are at risk for the delayed neuropsychiatric syndrome. Age appears to be a risk factor (Ernst and Zibrak 1998). Although the syndrome is widely held as a characteristic of carbon monoxide poisoning, a similar illness also can develop upon hypoglycemia, heroin overdose, strangulation, and anesthetic accident (Plum et al. 1962). The delayed syndrome is characterized as a postanoxic encephalopathy syndrome. It commonly develops 1–4 wk after an acute episode, with carbon-monoxide-induced coma and a period of recovery and lucid state. Thereafter, irritability, confusion, or manic symptoms appear, followed by a spastic or parkinsonian gait. Masked faces and rigidity are common, and most patients become somnolent and unable to walk On occasion, patients become mute or comatose, and some die. Notably, the progress of the disease can be halted at any stage, and some patients can make partial or full recovery. The most striking change associated with the delayed syndrome is diffuse demyelination in the cerebral hemispheres. Unlike injury patterns that occur in the acute carbon mon-

oxide syndrome, the corpus callosum, fornix, and anterior commissure are commonly spared.

Numerous studies have been conducted to test carbon monoxide toxicity in experimental animals. Several are reviewed in this section and summarized in Table 3–3.

There is evidence that acute exposure (20 min to 6 h) to carbon monoxide causes cardiovascular and CNS effects in experimental animals. Dogs exposed at 100 ppm (6.5% COHb) for 2 h (Aronow et al. 1979) and monkeys exposed at 100 ppm (9.3% COHb) for 6 hours showed a decrease in ventricular fibrillation threshold (DeBias et al. 1976). No effects on unconditioned reflex and conditioned avoidance tests were observed in rats exposed to 400 ppm (27% COHb) for 4 h (Mullin and Krivanek 1982). Failure of unconditioned reflex and a decrement in conditioned avoidance were observed in rats exposed to 800 ppm (34% COHb) for 4 h (Mullin and Krivanek 1982), and increased time to traverse a maze was observed in rats exposed to 2,000 ppm (75% COHb) for 30 min (Annau 1987). Monkeys exposed to 900 ppm (25–30% COHb) for 20–30 min showed a decrement in the ability to perform behavioral tasks (Purser and Berrill 1983). After 10–15 min exposure, the monkeys also had a decrease in carbon dioxide output.

Repeated (subchronic and chronic) exposure of experimental animals to carbon monoxide increases hemoglobin concentration and hematocrit in several animal species. These effects were observed in exposures at 50 ppm for 6 mo (7.3% COHb) in dogs (Musselman et al. 1959), at 96 ppm for 90 d (7.5% COHb) in rats (Jones et al. 1971), and at 200 ppm for 90 d (16–20% COHb) in rats and monkeys (Jones et al. 1971). The effects were not observed at lower COHb concentrations, for example, in exposures at 20 ppm for 2 yr (3.4% COHb) in monkeys (Eckardt et al. 1972), at 51 ppm for 90 d (5% COHb) in monkeys and rats (Jones et al. 1971), and at 66 ppm for 2 yr (7.4% COHb) in monkeys (Eckardt et al. 1972).

Several studies have examined the morphologic effects of carbon monoxide exposure in experimental animals. Dogs exposed at 100 ppm for 5.75 h/d, 6 d/wk for 11 wk (20% COHb) exhibited histopathologic changes in the cortex, white matter of the cerebral hemispheres, globus pallidus, and brain stem 3 mo after exposure (Lewey and Drabkin 1944). These animals also showed disturbance of postural and position reflexes and of gait. No histopathologic changes were observed in exposures at 50 ppm for 6 mo (7.3% COHb) in dogs (Musselman et al. 1959), at 200 ppm for 90 d (16% COHb) in rats (Jones et at. 1971), at 66 ppm for 2 yr (7.4% COHb) in monkeys (Eckardt et al. 1972), at 200 ppm for 90 d (20% COHb) in monkeys (Jones et al. 1971), and at 400 ppm for 71 d (32% COHb) followed by 500 ppm for 97 d (33% COHb) in monkeys, dogs, rats, and mice (Theodore et al. 1971).

The Navy has proposed a SEAL 1 set at 75 ppm and a SEAL 2 set at 85 ppm. These values are based on a model developed by Coburn et al. (1965) for estimating COHb concentrations from environmental exposures. COHb at these values would range from 8.3% to 12.4%.

Recommended exposure guidance levels for carbon monoxide from the NRC and other organizations are summarized in Table 3–4. The 24-h emergency exposure guidance level (EEGLs) (NRC 1985) is the most relevant guidance level to compare to the SEALs. EEGLs were developed for healthy military personnel in emergency situations. An important difference between EEGLs and SEALs is that EEGLs allow mild, reversible health effects, whereas SEALs allow moderate, reversible health effects. Therefore, the SEAL values are higher than the corresponding EEGL values.

On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 1 of 75 ppm for carbon monoxide is too conservative. The subcommittee rec

ommends a SEAL 1 of 125 ppm; exposure at this concentration would not result in blood COHb concentration above 15%. Studies in humans show that COHb concentrations of approximately 15% do not result in significant effects on perceptual function or cognition in healthy individuals (Stewart et al. 1973; Hudnell and Benignus 1989).

It should be noted that the SEAL 1 was recommended within the context of inspired air at sea level, where the oxygen concentration is at 20.95%. The oxygen concentration in a disabled submarine may be lower. Oxygen and carbon monoxide compete for binding sites on hemoglobin. When the oxygen pressure is low in the lung capillaries, as might be found in crew members on a disabled submarine, there is more unoxygenated hemoglobin for carbon monoxide to bind to. Therefore, carbon monoxide exposure becomes more dangerous to crew members in a submarine with lower oxygen concentration than one in which the oxygen concentration is 20.95%. The partial pressure of carbon monoxide (Pco) should be proportional to the partial pressure of alveolar oxygen (PAo₂). Therefore, in a disabled submarine with 16% oxygen concentration instead of 20.95%, the inspired Po₂ would be 114 mm Hg, PAo₂=64 mm Hg (PAo₂=(P_B-47)-50 mm Hg; where P_B is barometric pressure). Because Pco/Po₂ =1/220×Po₂, in equilibrium the ratio would reduce the allowable carbon monoxide from the proposed 125 ppm carbon monoxide to 80 ppm (64/100×125).

On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 85 ppm for carbon monoxide is too conservative. The subcommittee recommends a SEAL 2 of 150 ppm, which would not result in blood COHb concentration above 20%. Human data suggest that at a COHb concentration of approximately 20%, some submariners could experience mild headache and some decrement in cognitive function (Schulte 1963; Parving 1972; Stewart et al. 1973). Such effects would not impair the ability of a crew to escape from a disabled submarine. The recommended SEAL 2 is also supported by Theodore et al. (1971) where monkeys were exposed to a carbon monoxide concentration of 380 ppm for 90 d (COHb=31%) and there were no adverse health effects.

As pointed out in the discussion on SEAL 1, the recommended value for SEAL 2 is set for oxygen concentration at sea level (20.95%). Given that the oxygen concentration in the disabled submarine will likely be lower, it is necessary to correct the SEAL 2 for this change. Applying the same assumptions and calculations, one derives a SEAL 2 of 96 ppm (64/100×150) for a submarine in which the oxygen concentration is at 16%.

The subcommittee recommends that the Navy consider conducting the following studies:

• Studies to determine whether the rates of formation and elimination of COHb will increase under hyperbaric conditions. Such studies should be conducted because carbon monoxide exerts its toxic effects by reduction of the oxygen-carrying capacity of the blood. Thus, the ratio of the pressure of carbon monoxide and the pressure of oxygen will determine the toxicity of carbon monoxide. This ratio will not be affected by absolute pressure.

• Studies on the additive effects of carbon monoxide and hydrogen cyanide, at concentrations likely to be produced in disabled submarines.

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