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Summary of the Effects of Combined Exposure to Carbon Monoxide and Hydrogen Cyanide and Recommendation for Combined-Exposure Risk Assessment

As discussed previously, certain Army operations such as firing ammunition generate toxic gases. In a confined environment, exposure of Army personnel to these gases could pose a health concern. CO and HCN are the toxic gases of major concern, but analyses show that the time-weight-average concentrations of these two gases are low and generally do not exceed OSHA’s permissible exposure limit or ACGIH’s Threshold Limit Value for these two gases (Bazar 2006). However, since both compounds can induce hypoxia in tissue and the primary targets are the brain and the heart (Pitt et al. 1979), the U.S. Army is concerned about the potential for the combined effects of exposures to low concentrations of these gases to produce performance decrements. The present assessment of the toxicity of CO + HCN co-exposures could provide a guideline to the Army for evaluating the hazard of exposures in a confined environment and implementing mitigation procedures.

CO and HCN are two of the toxic gases of major concern produced in fires and other combustion events (Esposito and Alarie 1988, Sanders et al. 1994). Smoke can kill victims outright or produce physical incapacitation. Postmortem analyses of blood samples collected from victims revealed that in some victims, inhalation of either CO or HCN could not have been the sole cause of death (Esposito and Alarie 1988). The effects of combined exposure to CO and HCN have been subjected to intensive investigation. Investigations have centered on lethality or incapacitation, and these were assessed by exposing animals simultaneously to both gases at concentrations below their individual effect levels (at concentrations of CO and HCN, which produce no effects), or by studying the shortening of time to death (Td) or incapacitation (Ti) when animals were exposed to the effect levels of both gases. The biological interaction of combined exposure to CO and HCN can be studied by investigating the fractional effective concentrations (FECs) of the two compounds (Crane et al. 1989). If the sum (ΣFEC) is equal or close to 1, the combined effects are said to be additive; if the sum is greater than 1, the effects are said to be synergistic; if the sum is less than 1, the effects are said to be antagonistic or less than additive, or to have no interaction (Crane et al. 1989).

The results of examining the CO + HCN interaction in a very large rodent study conducted by the National Bureau of Standards (NBS) under the sponsorship of the U.S. Army Medical Research Institute led the investigators to conclude that the lethal effects of combined exposure were additive (Levin et al. 1987, 1988). These results were consistent with the conclusions of earlier NBS studies (Levin et al. 1988). In a study similar to the NBS investigations, Esposito and Alarie (1988) also demonstrated that the combined lethal effects of CO + HCN were additive. Additive effects were also observed by Lynch (1975) and Kaplan (1988) in animals exposed to CO + HCN. Instead of testing the combined effects by exposing animals to predetermined durations (T) and gaseous concentrations (C), Yamamoto and



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4 Summary of the Effects of Combined Exposure to Carbon Monoxide and Hydrogen Cyanide and Recommendation for Combined-Exposure Risk Assessment As discussed previously, certain Army operations such as firing ammunition generate toxic gases. In a confined environment, exposure of Army personnel to these gases could pose a health concern. CO and HCN are the toxic gases of major concern, but analyses show that the time-weight-average concentrations of these two gases are low and generally do not exceed OSHA’s permissible exposure limit or ACGIH’s Threshold Limit Value for these two gases (Bazar 2006). However, since both compounds can induce hypoxia in tissue and the primary targets are the brain and the heart (Pitt et al. 1979), the U.S. Army is concerned about the potential for the combined effects of exposures to low concentrations of these gases to produce performance decrements. The present assessment of the toxicity of CO + HCN co-exposures could provide a guideline to the Army for evaluating the hazard of exposures in a confined environment and implementing mitigation procedures. CO and HCN are two of the toxic gases of major concern produced in fires and other combustion events (Esposito and Alarie 1988, Sanders et al. 1994). Smoke can kill victims outright or produce physical incapacitation. Postmortem analyses of blood samples collected from victims revealed that in some victims, inhalation of either CO or HCN could not have been the sole cause of death (Esposito and Alarie 1988). The effects of combined exposure to CO and HCN have been subjected to intensive investigation. Investigations have centered on lethality or incapacitation, and these were assessed by exposing animals simultaneously to both gases at concentrations below their individual effect levels (at concentrations of CO and HCN, which produce no effects), or by studying the shortening of time to death (Td) or incapacitation (Ti) when animals were exposed to the effect levels of both gases. The biological interaction of combined exposure to CO and HCN can be studied by investigating the fractional effective concentrations (FECs) of the two compounds (Crane et al. 1989). If the sum (∑FEC) is equal or close to 1, the combined effects are said to be additive; if the sum is greater than 1, the effects are said to be synergistic; if the sum is less than 1, the effects are said to be antagonistic or less than additive, or to have no interaction (Crane et al. 1989). The results of examining the CO + HCN interaction in a very large rodent study conducted by the National Bureau of Standards (NBS) under the sponsorship of the U.S. Army Medical Research Institute led the investigators to conclude that the lethal effects of combined exposure were additive (Levin et al. 1987, 1988). These results were consistent with the conclusions of earlier NBS studies (Levin et al. 1988). In a study similar to the NBS investigations, Esposito and Alarie (1988) also demonstrated that the combined lethal effects of CO + HCN were additive. Additive effects were also observed by Lynch (1975) and Kaplan (1988) in animals exposed to CO + HCN. Instead of testing the combined effects by exposing animals to predetermined durations (T) and gaseous concentrations (C), Yamamoto and 11

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Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations Kuwahara (1981) exposed rats to various combinations of CO and HCN concentrations and recorded the C x T values when animal deaths occurred; the results also led these authors to conclude that the combined effects were additive. Several studies were carried out by the Civil Aerospace Medical Institute (CAMI) of the Federal Aviation Administration (Oklahoma City, OK); Sanders et al. (1994) and Chaturvedi et al. (1995) reported that the Ti for combined CO + HCN exposure in rodents was shortened compared with the Ti for individual gas exposures; these observations led the authors to conclude that the combined effects were additive. The results of an earlier study conducted at CAMI led Smith et al. (1974) to come to the same conclusion. Higgins et al. (1971) observed no additive toxicity in animals exposed to CO followed by HCN. However, additive lethal effects might not have been detected because of the great variation in the data points; the large confidence limits may have prevented detection of the combined biological effects of CO + HCN. Moore’s group concluded that the combined lethal effects in CO-exposed mice given lethal doses of cyanide salt by intraperitoneal injection were synergistic (Norris et al. 1986). However, the fact that the two compounds were given by different routes, resulting in different toxicokinetics, coupled with the fact that the data were not rigidly analyzed. A similar study by Moore’s group examining biochemical variables in blood showed that some results were additive and others were synergistic (Moore et al. 1991). Pitt et al. (1979) studied effects of CO and cyanide on cerebral blood flow (CBF) and oxygen consumption in anesthetized and CO-exposed dogs, to which cyanide was given by slow intravenous infusion. The exposure concentrations were comparable to those that produce physical incapacitation. These authors concluded that the combined effects of co-exposure on CBF and cerebral conductance were additive. The weight of evidence on combined exposures to CO and HCN supports the conclusion that the effects of these toxic gases are additive. However, the exposure concentrations that were used to investigate the combined effects were high in efforts to observe lethality or physical incapacitation. As pointed out above, the U.S. Army is concerned about the potential for the combined effects of exposures to low concentrations of these gases to produce performance decrements. In assessing the toxicity of these two compounds, it is prudent to expect that the additive effects of combined exposure observed with high concentrations would occur in subjects exposed to low concentrations. The hazard quotient or hazard index should be used for calculating the risk of the CO+HCN combined exposures. Hazard Quotient or Hazard Index = [CO]exp + [HCN]exp . [CO]al [HCN]al where [CO]exp and [HCN]exp are exposure concentrations, and [CO]al and [HCN]al are allowable concentrations. For the blood, COHb% and the 15-min average [HCN] are the variables measured and 10% COHb and 4.7 ppm HCN are the Army’s current allowable values, and the equation becomes Hazard Quotient = COHb% + 15 min avg. HCN (ppm) . 10% 4.7 ppm The appropriateness of the Army’s current level of 10% for CoHb and 4.7 ppm for HCN will be evaluated in the committee’s final report, which is likely to be finalized in September 2008. 12