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2 Mechanisms of Carbon Monoxide and Hydrogen Cyanide Toxicity The mechanisms of carbon monoxide (CO) and hydrogen cyanide (HCN) toxicity are reviewed in Chance (1965); Coburn et al. (1965); Wilson et al. (1972); Coburn and Forman (1987); and Lam and Wong (2000). CO binds to reduced hemoglobin with a much higher affinity (200 times greater) than does O2. The formation of carboxyhemoglobin (COHb) results in a shift of the oxyhemoglobin (O2Hb) dissociation curve (this plots increases in O2Hb versus the partial pressure of O2 [PO2]), which inhibits delivery of O2 from peripheral capillaries into tissues thus producing a decrease in the PO2 inside cells (tissue hypoxia). Molecular O2 has numerous functions in cells, but the major function is that it binds to the mitochondrial terminal cytochrome, cytochrome C oxidase (a complex that includes cytochrome a3), and accepts electrons that flow through a series of different cytochromes (electron chain transport) coupled to oxidative phosphorylations, formation of adenosine trisphosphate (energy formation) and oxidation of reduced compounds like nicotinamide adenine dinucleotide-reduced (NADH) which control the redox state. The cytoplasmic redox state is coupled to many cellular metabolic functions including acid formation (lactic acid). A COHb-evoked decrease in mitochondrial PO2 below a threshold level limits or inhibits O2 binding to cytochrome a3 and electron chain transport. Mechanisms of CO toxicity, therefore, include decreases in energy formation and changes in the redox state which results in cellular metabolic acidosis. CO also binds to reduced cytochrome a3, but the binding affinity is so low that this does not occur in intact humans or animals. The Coburn-Forster-Kane (CFK) equation allows calculation of rates of pulmonary uptake resulting from increases in ambient PCO, and reversal when CO is removed from inspired air, as well as steady state COHb values. The major factors are alveolar ventilation, a term that defines rate of uptake from alveolar gas to pulmonary capillary blood (the pulmonary diffusing capacity). Because CO has a relatively low solubility in water and a low diffusion coefficient, uptake is limited by diffusion, a major reason for the slow uptake of inhaled CO. Following a sudden steady state increase or decrease in inhaled CO at a normal PO2 and resting ventilation, it takes 4 to 5 hours to reach a steady state COHb. For an exercising human, CO uptake is increased and steady state COHb values are achieved more rapidly. Under conditions where CO exposures are rapidly changing, such as occurs in the enclosed environment of the tank cabin during gun firing, spike changes in CO concentration are buffered both by the high lung volume compared to tidal volumes, as well as the slow uptake into pulmonary capillary blood. Under conditions where ambient CO concentrations are changing rapidly, the use of the CFK equation to calculate COHb levels needs to be verified with blood COHb measurements. There is evidence for effects of small but biologically significant increases in COHb in the range of 5 to 10% saturation on human mental functions including automobile driving reflexes and visual function. In some animal experiments time-dependent tolerance to large increases in COHb occurred and it is possible that military personnel exposed to CO over several days or weeks might develop tolerance. There is evidence for tolerance to CO toxicity, and, of course, altitude hypoxia, so it is likely tolerance to CO would develop. There are no data, human or animal studies, on tolerance to small concentrations of HCN. Whether or not 7
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Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations tolerance is important during combined exposures of CO and HCN at concentrations found in the tank cabin should be given a high priority for future research. HCN is a weak acid with a pka of 9.3; therefore at physiological pH ionization is minimal. Although HCN is a highly reactive compound and is known to form simple salts with alkali earth cations and ionic complexes of varying strengths with metal cations, the major mechanism of toxicity arises from its reversible binding to an iron containing heme group of cytochrome a3 with resulting inhibition of mitochondrial electron chain transport, decreased energy formation and changes in the cellular redox state producing metabolic acidosis. As with O2, HCN binds to heme Fe2+ in reduced cytochrome a3. However, in the presence of O2 when the iron in cytochrome a3 is rapidly oxidized, its affinity for binding of HCN increases markedly. Threshold HCN concentrations that inhibit mitochondrial electron chain transport are not known. Unlike CO, HCN does not induce tissue hypoxia defined as a decrease in tissue PO2. Indeed, under conditions of HCN-evoked inhibition of O2 consumption, tissue PO2 must increase, explaining the known decrease of O2 extraction from capillary blood during HCN poisoning. HCN is miscible with water and has a high effective “solubility” in body fluids and tissues. Thus, ambient HCN is absorbed via the skin as well as the lung. However, pulmonary uptake is most important. Pulmonary uptake is determined by ventilation and blood flow and its high effective solubility in blood. Since the kinetics of HCN uptake have not been accurately determined, our knowledge is based on a few measurements of blood HCN levels in animals and humans which suggest rapid uptake reaching steady state values in minutes rather than hours as occurs with CO. Because some HCN taken up in pulmonary capillary blood binds to methemoglobin (MetHb) forming cyanmethemoglobin, blood levels reflect the presence of MetHb as well as free HCN. Since MetHb content (usually only a few “percent” of total hemoglobin content) is variable in different humans, one can not precisely equate blood content to the partial pressure of HCN which determines peripheral tissue HCN concentrations and should most closely relate to the toxicity of this gas. HCN is rapidly metabolized via several pathways, the most important being the irreversible reaction of HCN with thiosulphate to form thiocyanate. Thiocyanate is then rapidly excreted in urine. Thiocyanate itself has tissue toxicity. The relatively small “percent” of body HCN excreted via the lungs indicates a very low partial pressure of this gas in pulmonary capillary blood and that most absorbed HCN is bound. After humans suffered from smoke inhalation, half of the peak HCN content in blood was lost over 20 to 60 minutes. Unlike the case for CO toxicity there are no reports that relate small HCN exposures, such as measured in tank cabins, to human abilities. The apparent additivity of CO and HCN toxicity is explained by CO binding to hemoglobin evoking tissue hypoxia plus HCN binding to both reduced and oxidized cytochrome a3. There are possible interactions that occur during combined CO and HCN poisoning which influence their apparent additivity: (a) Does the presence of one of the gases influence pulmonary uptake of the other gas? In animal experiments large concentrations of HCN stimulated carotid body-driven ventilation which would increase uptake of CO. There is evidence that CO, as well, may stimulate the carotid body. (b) Since HCN-evoked inhibition of mitochondrial O2 consumption results in increases in tissue and mitochondrial PO2, HCN might blunt effects of concomitant CO poisoning which operates by evoking decreases in tissue PO2. RECOMMENDATIONS Tests should be conducted to determine blood COHb and air CO concentrations before and after multiple test firings over several days; pre- and concurrent-exposure to CO from other sources such as smoking and engine exhaust, should be considered in evaluating test exposures. There is evidence for tolerance to CO toxicity, and, of course, altitude hypoxia, so it is likely tolerance to CO would develop. There are no data, human or animal studies, on tolerance to small concentrations of HCN. Whether or not tolerance is important during combined exposures of CO and HCN at concentrations found in the tank cabin should be given a high priority for future research. 8