Appendix B
Previous Applications of the Coburn-Forster-Kane Equation to Predict Carboxyhemoglobin Levels Resulting from Varying Carbon Monoxide Exposures

The Army uses the Coburn-Forster-Kane (CFK) equation to calculate carboxyhemoglobin (COHb) levels from measured carbon monoxide (CO) air concentrations. It was pointed out in the committee’s first report (NRC 2008) that the use of COHb levels for assessing the risk of exposure to CO and the use of the CFK equation have a solid scientific basis. However, due to CO released by firing weapons during combat operations or battlefield training sessions, army personnel can be exposed in the confined environment of the vehicle cabin to these very high pulsatile spikes of CO, each lasting for a few seconds. Because this distinctive pattern of intermittent exposures to pulsatile spikes of relatively high concentrations of CO is unusual, the use of the CFK equation for this exposure scenario is further reviewed by the committee.

The CFK equation was originally developed by Coburn and his colleagues (Coburn et al. 1965) for the study of the endogenous production of CO. It has been widely validated and adopted to predict the COHb levels in humans exposed to CO under various conditions (Peterson and Stewart 1970, 1975; Tikuisis et al. 1987a,b, 1992). The COHb values determined experimentally generally agree well with the theoretical values predicted using the CFK equation. The exposure regimens of some of these studies to validate the CFK equation are discussed here so that the criteria for application of the CFK equation for assessing Army personnel exposed to CO can be substantiated or refined.

Before the CFK equation was formulated by Coburn et al. in 1965, many attempts were made by others to describe the CO concentration in the body mathematically. Several of these regression equations, together with the CFK equation, were tested for goodness of fit by Peterson and Stewart (1970) in their large-scale CO study in which human test subjects were exposed to concentrations (1 to 1,000 ppm), including the range reported by the Army. The authors concluded that the CFK equation provided the best fit to the experimental COHb data. In this study, Peterson and Stewart also included an intermittent or discontinuous exposure regimen of 3 h and 1 h of CO exposure separated by a 2-h non-exposure period, and another exposure regimen in which CO concentration gradually increased from ambient level to 1,000 ppm in a 2-h period and was held at this level for another hour. According to the authors, the agreement between the experimental COHb data and the values predicted by the CFK equation were “astonishingly good.”

Peterson and Stewart (1975) carried out another large human study consisting of a series of 50 experiments in which male and female subjects were exposed to various CO concentrations (50 to 200 ppm) for various exposure durations (0.33 to 5.25 h) while they exercised at rates ranging from sedentary to 300 kilopond meters per minute (kpm/min). Using data for individual body weights and heights, the blood volumes and resting lung diffusivity for CO for all 22 subjects were estimated. The baseline (non-exposed) COHb level and hemoglobin value of each subject were measured. Of these 22 subjects, 15 par-



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Appendix B Previous Applications of the Coburn-Forster-Kane Equation to Predict Carboxyhemoglobin Levels Resulting from Varying Carbon Monoxide Exposures The Army uses the Coburn-Forster-Kane (CFK) equation to calculate carboxyhemoglobin (COHb) levels from measured carbon monoxide (CO) air concentrations. It was pointed out in the com- mittee’s first report (NRC 2008) that the use of COHb levels for assessing the risk of exposure to CO and the use of the CFK equation have a solid scientific basis. However, due to CO released by firing weapons during combat operations or battlefield training sessions, army personnel can be exposed in the confined environment of the vehicle cabin to these very high pulsatile spikes of CO, each lasting for a few seconds. Because this distinctive pattern of intermittent exposures to pulsatile spikes of relatively high concentra- tions of CO is unusual, the use of the CFK equation for this exposure scenario is further reviewed by the committee. The CFK equation was originally developed by Coburn and his colleagues (Coburn et al. 1965) for the study of the endogenous production of CO. It has been widely validated and adopted to predict the COHb levels in humans exposed to CO under various conditions (Peterson and Stewart 1970, 1975; Ti- kuisis et al. 1987a,b, 1992). The COHb values determined experimentally generally agree well with the theoretical values predicted using the CFK equation. The exposure regimens of some of these studies to validate the CFK equation are discussed here so that the criteria for application of the CFK equation for assessing Army personnel exposed to CO can be substantiated or refined. Before the CFK equation was formulated by Coburn et al. in 1965, many attempts were made by others to describe the CO concentration in the body mathematically. Several of these regression equa- tions, together with the CFK equation, were tested for goodness of fit by Peterson and Stewart (1970) in their large-scale CO study in which human test subjects were exposed to concentrations (1 to 1,000 ppm), including the range reported by the Army. The authors concluded that the CFK equation provided the best fit to the experimental COHb data. In this study, Peterson and Stewart also included an intermittent or discontinuous exposure regimen of 3 h and 1 h of CO exposure separated by a 2-h non-exposure period, and another exposure regimen in which CO concentration gradually increased from ambient level to 1,000 ppm in a 2-h period and was held at this level for another hour. According to the authors, the agreement between the experimental COHb data and the values predicted by the CFK equation were “as- tonishingly good.” Peterson and Stewart (1975) carried out another large human study consisting of a series of 50 experiments in which male and female subjects were exposed to various CO concentrations (50 to 200 ppm) for various exposure durations (0.33 to 5.25 h) while they exercised at rates ranging from sedentary to 300 kilopond meters per minute (kpm/min). Using data for individual body weights and heights, the blood volumes and resting lung diffusivity for CO for all 22 subjects were estimated. The baseline (non- exposed) COHb level and hemoglobin value of each subject were measured. Of these 22 subjects, 15 par- 32

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Appendix B ticipated in several exercise levels and their alveolar ventilation rates (6.2-17 liters per minute [L/min]) were measured. All of these individual variables were used for the calculation of COHb values using the CFK equation; the affinity constant, M, was assumed to be 218 and the endogenous CO production rate to be 0.007 milliliters per minute (mL/min) for all subjects. Peterson and Stewart concluded that the CFK equation predicts COHb concentrations equally well for sedentary subjects and exercising individuals; during exercise, the alveolar ventilation rate changed by a factor of 2.5 from the sedentary level but did not alter the fit of the CFK equation to the experimental data. The authors further noted that the work rate (300 kpm/min) for this level of exercise is equivalent to the work rate of an individual who consumes oxygen at 10 L/min or to the work rates of many industrial workers. The CFK equation also predicts val- ues for men and women equally well. To test the goodness of fit of the CFK equation to predict COHb for other exposure scenarios, Peterson and Stewart extrapolated from these experimental data with CO con- centrations of 8.7, 25, 35, 50, 200, 500, and 1,000 ppm and concluded that the CFK equation fit the result- ing data very well. From these observations and the results of their previous studies investigating discon- tinuous or intermittent CO exposures, Peterson and Stewart concluded, “Even though the CFK equation has not been completely tested at all levels of all parameters (and such testing is, in fact, impossible), pre- sent indications are that it describes uptake and excretion of CO extremely well. This equation even ap- pears suitable for summing (integrating) long-term exposures to varying concentrations of CO in air.” If the CFK equation is valid for predicting COHb in CO-exposed subjects, then an exposure to x ppm (concentration) for y minutes will produce the same COHb level as that produced by an exposure to y ppm for x minutes. This hypothesis was tested by Tikuisis et al. (1987a) on 11 nonsmoking men ex- posed to two exposure regimens, both of which gave the same total concentration (c) × exposure time (t) values of 37,500 ppm-min. In regimen I, the subjects were exposed to five sessions of 1,500 ppm for 5 min per session; each pair of sessions was separated by 3 min. In regimen II, each session consisted of exposure to 7,500 ppm for 1 min; sessions were separated by 7 min. The COHb values measured for regimens I and II were 11.46 ± 0.41% and 11.13 ± 0.45%, respectively. These values agreed well with the values (11.63 ± 0.59% and 11.46 ± 0.49%) predicted using the CFK equation. However, Tikuisis et al. stressed the importance of using the subject’s alveolar ventilation rate in the CFK equation. Having the same objective as the Army about assessing exposures of personnel to CO in armored vehicles, Tikuisis and colleagues at the Canadian Defense and Civil Institute of Environmental Medicine (DCIEM) exposed test subjects to CO in a series of experiments that simulated the environment in an ar- mored vehicle during weapons firing (that is, CO concentrations were transient and their peak was as high as 4,000 ppm). The test subjects were at rest and exposed to varying concentrations of CO in a symmetric stepwise fashion beginning with 500 ppm for 60 seconds (sec), followed by steps of 1,000, 2,000, 4,000, 2,000, and 1,000 ppm CO for 30 sec each and ending with 500 ppm for 60 sec (Tikuisis et al. 1987b). The transient exposure gave the subjects a nominal CO dosage of 6,000 ppm-min in a 4.5-min period. The second series of experiments included exercise patterns to imitate the workload of soldiers in armored vehicles before or during CO exposures. The overall results showed that the exposures raised the subjects’ COHb saturation from 1.7% to 17.3%. The CFK equation was solved using parameters (such as affinity and alveolar ventilation) used by the DCIEM or those recommended by the National Institute of Occupa- tional Safety and Health (NIOSH). Tikuisis et al. (1987b) concluded that when DCIEM values were used with the CFK equation, the predicted values compared favorably (regression coefficient, b = 1.04) with the measured COHb data, but when the NIOSH values were used, the CFK equation significantly (b = 1.28) overpredicted the COHb concentrations. This review shows that the CFK equation has been validated for various exposure concentrations, durations, and conditions. All of these validation studies collectively show that the values predicted by the CFK equation agree well with experimental data. However, the above studies used inspired CO concen- trations in excess of those found in armored-vehicle cabin air. Further experimentation, as described in Chapter 3 and Appendix C, is needed to assess whether the CFK prediction equation is valid (1) at low and or spiking levels of CO or (2) under conditions of rapid changes in ventilation. 33

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Combined Exposures to HCG and CO in Army Operations: Final Report REFERENCES Coburn, R.F., R.E. Forster, and P.B. Kane. 1965. Comparison of the physiological variables that determine the blood carboxyhemoglobin concentration in man J. Clin. Invest. 44(11):1899-1910. NRC (National Research Council). 2008. Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations: Initial Report. Washington, DC: The National Academies Press. Peterson, J.E., and R.D. Stewart. 1970. Absorption and elimination of carbon monoxide by inactive young men. Arch. Environ. Health 21(2):165-171. Peterson, J.E., and R.D. Stewart. 1975. Predicting the carboxyhemoglobin levels resulting from carbon monoxide exposures. J. Appl. Physiol. 39(4):633-638. Tikuisis, P., F. Buick, and D.M. Kane. 1987a. Percent carboxyhemoglobin in resting humans exposed repeatedly to 1,500 and 7,500 ppm CO. J. Appl. Physiol.63(2):820-827. Tikuisis, P., M.D. Madill, B.J. Gill, W.F. Lewis, K.M. Cox, and D.M. Kane. 1987b. A critical analysis of the use of the CFK equation in predicting COHb formation. Am. Ind. Hyg. Assoc. J. 48(3):208-213. Tikuisis, P., D.M. Kane, T.M. McLellan, F. Buick, and S.M. Fairburn. 1992. Rate of formation of carboxyhemoglo- bin in exercising humans exposed to carbon monoxide. J. Appl. Physiol. 72(4):1311-1319. 34