Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations: Final Report (2008)

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1 Introduction The U.S. Army’s Health Hazard Assessment (HHA) Program of the Center for Health Promotion and Preventive Medicine (CHPPM) is designed to identify and eliminate health hazards or to reduce them to some acceptable level during the life-cycle management of materiel systems. Although the Army oper- ates mechanical ventilation systems in the vehicle compartments of its armored vehicles, military person- nel within these vehicles are still exposed to low levels of combustion by-products generated from propel- lants used to fire the vehicle’s guns. Personnel may also be exposed concurrently to other substances present in the vehicle compartment, such as diesel exhaust. HHA evaluates weapons emissions, including carbon monoxide (CO), hydrogen cyanide (HCN), oxides of nitrogen (NOx), sulfur dioxide (SO2), ammo- nia (NH3), and carbon dioxide (CO2). The Army assessed the potential additive or synergistic toxic effects of these substances. Specific attention has been given to the combined effects of simultaneous low-level exposures to CO and HCN because both gases produce similar toxic effects. As a result, the Army prepared a report titled Assessment of Combined Health Effects of Hydrogen Cyanide and Carbon Monoxide at Low Levels for Military Oc- cupational Exposures that provides guidance on assessing combined exposures to low levels of CO and HCN (Bazar 2006). CO is assessed as an individual chemical in the Army’s HHA using the Coburn-Forster-Kane (CFK) equation (Smith et al. 1996) for predicting the percentage of carboxyhemoglobin (COHb) in blood. %COHb t = %COHb 0 (e-t/A ) + 218 (1 - e -t/A ) + [1/B + PI CO /1,316], & A = M Vb [O 2 Hb] (1/D L CO + (PB - PH 2O )/VA )/ Pc O 2 , & B = [1/D L CO + (PB - PH 2O )/VA ], where t = time (minutes); 0 = beginning of exposure; PI CO = partial pressure of CO in inhaled air; M = equilibrium constant for the reaction CO + O2Hb → COHb + O2 ; Vb = blood volumn; DL CO = pulmonary CO diffusing capacity; PB = barometric pressure; PH 2O = partial pressure of water; & VA = alveolar ventilation rate; and PcO 2 = mean O2 tension in the pulmonary capillary blood. A DOD 1981 military standard established the Army’s COHb limits of 5% for aviation crew members to protect against visual adverse effects and 10% for other effects. The 5% level was considered a safe level for healthy young people and had previously been used by the American Conference of Gov- ernmental Industrial Hygienists (ACGIH) (DOD 1972; Smith et al. 1996). Adverse motor neuron effects, such as decreased coordination, were not present when COHb was below 10% of hemoglobin (ACGIH 2002). The exposure criterion for HCN is the current ACGIH Threshold Limit Value (TLV) ceiling of 8 

Introduction 4.7 parts per million (ppm) to minimize the potential for headache; nausea; nasal, throat, and pulmonary irritation; and enlargement of the thyroid gland, which can result from low-concentration exposure (ACGIH 2001). In addition to the individual threshold levels, the Army uses the following hazard quotient (HQ) approach, which assumes the effects of CO and HCN at low levels are additive. An HQ equal to or greater than 1.0 indicates an overexposure. COHb % 15 - min avg. HCN (ppm) + = HQ. 10% 4.7 ppm To determine whether the air quality inside armored-vehicle cabins can meet the exposure guide- lines under deployed conditions, the Army test fires the vehicles’ weapons and measures the concentra- tion of potentially harmful gases resulting under various operational scenarios. When an armored vehicle is first tested, no personnel are usually in the cabin and weapons are fired remotely. Before, during, and after firing, air is sampled remotely from the crew compartments and concentrations of specific gases are measured. Subsequent testing involves weapons firing by personnel within the vehicle cabin followed by air sampling and analysis (Bazar and Kluchinsky 2008; M. Bazar CHPPM, personal commun., September 23, 2008). To evaluate the stream of test data, the Army calculates COHb levels at the end of each data interval (3 or 5 seconds) using the instantaneous CO concentrations and the COHb concentration from the end of the previous interval. The 15-minute (min) HCN average is based on a running average calculated at the end of each data interval. The 15-min HCN average concentration is used because HCN exposures have been observed to be transient and to clear quickly after a round is fired. CO concentrations exhibit a spike when a round is fired and also quickly decline, but COHb begins to accumulate in the blood of ex- posed subjects after several rounds. In addition to evaluating test data, the Army provides predictions for proposed training and opera- tional scenarios. The predictions are used for adjusting the proposed firing rates and patterns to keep weapons-emissions exposure below the specified levels or for verifying the need to use personnel protec- tive equipment. The predictions are based on the worst-case scenario of CO exposure levels per round (expressed in parts per million–minutes) from the proposed hatch-position and ventilation configuration. The buildup and decay of COHb is calculated over the course of the scenario. The HQ is then calculated with the highest estimated COHb value and the highest value of the 15-min running HCN average from the relevant scenario. In summary, to assess the potential for health effects of CO and HCN combined exposures at low levels, the Army first determines if either or both of the limits of 10% COHb or 4.7-ppm HCN are ex- ceeded. If so, the scenario fails and the HQ calculation is not needed. If COHb and HCN are within ac- ceptable limits, then the HQ calculation is performed; the scenario fails if the HQ equals or exceeds 1.0. The method used allows the HQ results to be consistent with the single results. In 2005, the Department of Defense (DOD) requested that the National Research Council assess (NRC) the Army’s proposed guidance for assessing the adverse effects resulting from the combined si- multaneous exposures to low levels of CO and HCN in weaponized armored vehicles. The NRC was asked to prepare two reports. In response, the NRC convened the Committee on Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations under the oversight of the Committee on Toxicology to assess the Army’s proposed guidance. The committee’s Statement of Task is presented in Box 1-1. THE COMMITTEE’S INITIAL REPORT In its initial report (NRC 2008), the committee evaluated the Army’s proposed guidance on using the HQ approach as part of its HHAs of military systems. The committee concluded in its initial report 9 

Combined Exposures to HCG and CO in Army Operations: Final Report BOX 1-1 Statement of Task An ad hoc committee under the oversight of the standing Committee on Toxicology (COT) will assess potential toxic effects from combined exposures to low-levels of carbon monoxide (CO) and hydrogen cyanide (HCN). In its first report, the committee will evaluate the U.S. Army’s proposed guidance on as- sessing combined exposures in Health Hazard Assessments (HHAs) of military systems. The ad hoc committee will specifically determine the following in its first report: Does the hazard presented from combined exposure to HCN and CO at low levels warrant their combined assessment or is the individual assessment of each chemical sufficiently protective and, if the combined exposure assessment of HCN and CO is warranted at low levels, is the hazard quotient approach, discussed in the Army’s technical context section, a reasonable method of as- sessment? Should it be modified or improved (that is, the use of a blood HCN benchmark instead of the ACGIH TLV-C1)?1 In its second report, the committee will address the following: Is the approach discussed in the technical context section of the Army’s proposed guidance appropriate or should an alternative assessment method be developed and validated through either field or laboratory study? Provide recommendations for making improvements in the Army's proposed methodology for assessing these combined exposures. The committee will also provide recommendations that will yield more precise measure- ments of gases, which might be useful in hazard assessment, and recommend approaches for de- veloping exposure-limit guidelines for combined exposures to these chemicals. ____________________ 1 ACGIH TLV-C refers to a Threshold Limit Value ceiling issued by the American Conference of Govern- mental Industrial Hygienists. that the toxic effects of CO and HCN are likely additive, and, therefore, the effects presented from com- bined exposures to these chemicals should be assessed as a mixture and not individually. The literature (for example, Levin et al. 1987, 1988; Chaturvedi et al. 1995) indicates that the toxic effects of inhaled CO and HCN are additive at lethal and incapacitating levels. However, for expo- sures occurring at lower and varying concentrations over periods of several weeks to perhaps several years, it is not known whether military personnel, while also in the presence of other combustion gases, may experience similar additive effects. Although a number of reports on the interaction of HCN and CO have been done and the potential interaction has been well recognized in respect to fires, the human litera- ture is not helpful in defining adverse blood concentrations of HCN alone or in combination with CO. In most cases, the exposures were very high and/or the measurements of exposure, particularly to HCN, were questionable. Animal studies mostly used high levels of HCN that were greater than 100 ppm or high levels of CO that were in the range of one to several thousand parts per million compared with low levels of interest with HCN at less than 5 ppm or CO at less than 100 ppm. Furthermore, available studies do not address subtle effects, such as decrements in performance, that are relevant to setting guidelines for human exposure. Although guidelines for limiting exposure to CO and HCN have been published by gov- 10 

Introduction ernmental and professional groups, they have the same limited databases, especially for the interaction. Therefore, the possibility that independence or subadditive responses may occur cannot be discounted. However, in light of the weak database of relevant studies, the committee agrees that assuming an additive response is the most reasonable approach. In assessing the toxic effects 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. Therefore, the committee concluded that until further findings suggest otherwise, the Army’s use of the HQ approach or hazard index is reasonable in establishing exposure limits for personnel simultaneously exposed to CO and HCN. The committee stated that the HQ should be used for calculating the risk of adverse effects from exposure to CO and HCN combined. The approach involves assessment of CO exposure using the CFK equation. The CFK equation has not, however, been evaluated in environments with rapidly changing CO concentrations, such as in the air within crew compartments of armored vehicles. Therefore the committee recommended that the Army assess the validity of the CFK model in that context. Regarding HCN, the committee considered available evidence of HCN toxicity and the appropri- ateness of measurements of blood or air concentrations of HCN in the HHA. The committee identified several reasons why measurement of air concentrations is a better benchmark to use (for example, the lack of reported rapid or simple methods for the determination of HCN in biologic fluids). Also, there seemed to be no compelling reason why blood measurements of HCN would be a better predictor of ad- verse effects than measurement of ambient air concentrations. The added difficulties associated with the measurement and interpretation of blood HCN concentrations indicated that this measurement should not be selected as a routine monitoring method. Therefore, the committee concluded that the Army’s use of air concentrations of HCN, rather than blood HCN concentrations, in the HHA is reasonable. Also, the committee recommended that the Army conduct further neurologic studies on sensory and motor per- formance at low concentrations of HCN and CO. In addition, the committee recommended that the Army consider concurrent exposures to other chemicals that may have additional effects on the armored-vehicle crew. THE COMMITTEE’S FINAL REPORT The exposure information provided to the committee by CHPPM focused mainly on CO. As noted in the committee’s initial report, the Army reported that exposures to HCN appear to be low most of the time, indicating that HCN may not contribute substantially to the HQ calculation for HCN and CO. As a result, the committee focused much of its consideration on CO with the understanding that actual exposures involve a multi-chemical mixture. In the committee’s final report, Chapter 2 discusses whether there is a role for the use of portable multi-agent monitors to assess the armored-vehicle environment during varied operations. Chapter 3 discusses the types of experiments needed to answer whether the CFK equation is valid (1) for assessing COHb levels at low and or spiking levels of CO or (2) under conditions of rapid changes in ventilation. Appendix B reviews past assessments of using the CFK equation for estimating various exposure concentrations, durations, and conditions. Appendix C provides details on methods for addi- tional experiments recommended by the committee to assess the CFK equation. Chapter 4 discusses whether there is dose-related performance degradation resulting from expo- sure to CO. Chapter 5 discusses whether there is dose-related performance degradation resulting from combined exposures. Chapter 6 discusses the potential for other deleterious end points of these exposures. Each of the chapters also recommends studies that may provide useful information for developing expo- sure limit guidelines for combined exposures. Chapter 7 presents considerations for the Army as it moves forward in developing exposure guidelines. The chapter also considers environmental factors that might modify responses to CO exposure that are not currently taken into account by the Army, and it discusses whether computational models could be used to assess the effect of multiple exposures. 11