3
A Brief Review of Hydrogen Cyanide and Carbon Monoxide Toxicity

Data on sublethal exposures and time to incapacitation for HCN and CO gases alone and combined are available for experimental animals and humans. However, data addressing subtle differences (e.g. attention deficits, decreases in hand and eye coordination, and decreases in fine movements) in performance, relevant to setting guidelines for human exposure, are sparse. For HCN, inhalation toxicity studies that involve human exposures are old, often anecdotal, and lack analytically measured concentrations. Human exposures with measured concentrations are limited to occupational reports, but these studies lack correlation between exposure concentrations and symptoms. Animal studies were generally conducted at high concentrations and also lack good dose-response information (Lam and Wong 2000; NRC 2002). Few studies measured cyanide concentration in the blood.

Concentrations of CO that produce incapacitation are extremely high, and it is difficult to correlate exposure concentrations with COHb formation. Data for combined exposure to HCN-CO involve laboratory animal studies and were generally conducted at high concentrations, i.e., concentrations that produce incapacitation or death. Recent inhalation studies, considered relevant to setting human exposure guidelines for military unique occupational exposures, i.e., performance degradation rather than incapacitation or death, are reviewed below.

HYDROGEN CYANIDE

Selected occupational monitoring studies show that exposures have been to concentrations up to an average of 10 ppm (Hardy et al. 1950; Maehly and Swensson 1970; El Ghawabi et al. 1975). Although many of these studies did not address health effects, symptoms that were reported appeared attributable to the long-term effect of cyanide on the thyroid gland. In animal studies, times to incapacitation for the monkey ranged from 8 to 19 minutes at concentrations of 156 to 100 ppm, respectively (Purser et al. 1984). A concentration of 60 ppm for 30 minutes had only a non-biologically significant depressive effect on the central nervous system of monkeys (Purser 1984). For the rat, incapacitation (EC50 for loss of righting reflex) occurred at 10 minutes at an exposure concentration of 170 ppm (Levin et al. 1987) and, in another study, at 5 minutes at 184 ppm and at 35 minutes at 64 ppm (Chaturvedi et al. 1995; see also Crane et al. 1989; Sanders et al. 1994). Respective blood cyanide concentrations in the Chaturvedi et al. (1995) study were 2.3 and 4.2 μg/mL. In a third study, incapacitation of rats exposed to 95 ppm HCN occurred at 44 minutes (Hartzell et al. 1985a,b). Lethal (LC50) values in the rat range from approximately 500 ppm for a 5-minute exposure to 100-140 ppm for a 60-minute exposure (NRC 2002).

There are studies that show that HCN can be absorbed through the skin, with effects up to and including lethality. For that reason, the ACGIH has used a skin notation since 1961, stating that a significant fraction of the total absorbed dose of HCN can occur via this route to produce systemic effects. However, the committee concludes that exposure from this route of exposure is not likely to be significant



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3 A Brief Review of Hydrogen Cyanide and Carbon Monoxide Toxicity Data on sublethal exposures and time to incapacitation for HCN and CO gases alone and combined are available for experimental animals and humans. However, data addressing subtle differences (e.g. attention deficits, decreases in hand and eye coordination, and decreases in fine movements) in performance, relevant to setting guidelines for human exposure, are sparse. For HCN, inhalation toxicity studies that involve human exposures are old, often anecdotal, and lack analytically measured concentrations. Human exposures with measured concentrations are limited to occupational reports, but these studies lack correlation between exposure concentrations and symptoms. Animal studies were generally conducted at high concentrations and also lack good dose-response information (Lam and Wong 2000; NRC 2002). Few studies measured cyanide concentration in the blood. Concentrations of CO that produce incapacitation are extremely high, and it is difficult to correlate exposure concentrations with COHb formation. Data for combined exposure to HCN-CO involve laboratory animal studies and were generally conducted at high concentrations, i.e., concentrations that produce incapacitation or death. Recent inhalation studies, considered relevant to setting human exposure guidelines for military unique occupational exposures, i.e., performance degradation rather than incapacitation or death, are reviewed below. HYDROGEN CYANIDE Selected occupational monitoring studies show that exposures have been to concentrations up to an average of 10 ppm (Hardy et al. 1950; Maehly and Swensson 1970; El Ghawabi et al. 1975). Although many of these studies did not address health effects, symptoms that were reported appeared attributable to the long-term effect of cyanide on the thyroid gland. In animal studies, times to incapacitation for the monkey ranged from 8 to 19 minutes at concentrations of 156 to 100 ppm, respectively (Purser et al. 1984). A concentration of 60 ppm for 30 minutes had only a non-biologically significant depressive effect on the central nervous system of monkeys (Purser 1984). For the rat, incapacitation (EC50 for loss of righting reflex) occurred at 10 minutes at an exposure concentration of 170 ppm (Levin et al. 1987) and, in another study, at 5 minutes at 184 ppm and at 35 minutes at 64 ppm (Chaturvedi et al. 1995; see also Crane et al. 1989; Sanders et al. 1994). Respective blood cyanide concentrations in the Chaturvedi et al. (1995) study were 2.3 and 4.2 µg/mL. In a third study, incapacitation of rats exposed to 95 ppm HCN occurred at 44 minutes (Hartzell et al. 1985a,b). Lethal (LC50) values in the rat range from approximately 500 ppm for a 5-minute exposure to 100-140 ppm for a 60-minute exposure (NRC 2002). There are studies that show that HCN can be absorbed through the skin, with effects up to and including lethality. For that reason, the ACGIH has used a skin notation since 1961, stating that a significant fraction of the total absorbed dose of HCN can occur via this route to produce systemic effects. However, the committee concludes that exposure from this route of exposure is not likely to be significant 9

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Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations so as to be considered in the development of allowable concentrations used in the hazard index calculation. Guidelines for human exposure to HCN have been developed by several agencies. Following a review of the literature on occupational exposures, a National Research Council Subcommittee concluded that a 1-hour exposure to HCN at 8 ppm should cause no more than mild headache in healthy adults (Lam and Wong 2000). The American Conference of Governmental Industrial Hygienists Ceiling value, a concentration that should not be exceeded during any part of a working exposure, is 4.7 ppm (ACGIH 1996). The National Institute for Occupational Safety and Health (NIOSH) short-term exposure limit is also 4.7 ppm, and the Immediately Dangerous to Life and Health (IDLH), a 30-minute exposure, is 50 ppm (NIOSH 2005). The Occupational Safety and Health Administration Permissible Exposure Limit (OSHA) is 10 ppm (NIOSH 2005). A guideline value considered safe for the general public includes the 1-hour Acute Exposure Guideline Level-1 (AEGL-1) of 2.0 ppm (NRC 2002). CARBON MONOXIDE Data on correlations between exposure concentrations and levels of blood COHb are lacking. A number of sources including Coburn and Forman (1987), WHO (1999), and EPA 2005 reviewed COHb levels in the blood of smokers and symptoms in healthy adults associated with COHb levels in the blood. A physiologic background concentration of 0.5-0.8% is due to endogenous formation. A concentration of 5% COHb may be found in one pack/day smokers, and concentrations of 10-15% in two and three pack/day smokers. Up to 10% COHb has no appreciable effect except shortness of breath on vigorous exertion. Concentrations of 10-20% may result in symptoms such as headache. As concentrations of COHb increase from 30 to 70%, successive symptoms reported are headache, fatigue, dizziness, confusion, unconsciousness, and possibly death. A concentration of 80% COHb is rapidly fatal. Clinical studies with humans indicate that a COHb of about 34-56% are not lethal in healthy adults EPA 2005. CO levels in homes are usually lower than 9 ppm, but may range up to 30 ppm in homes with wood stoves. Levels inside motor vehicles are generally around 9-25 ppm, but may range up to 35 ppm EPA 2005. In a study with cynomolgus monkeys exposed to 900 ppm CO, no signs of intoxication occurred during the first 20-25 minutes (corresponding to COHb of about 16-21%) (Purser and Berrill 1983). At 25 minutes, the animals’ performance in a behavioral test was significantly decreased. At 30 minutes the monkeys were lying down. In rodent studies, incapacitation in rats exposed to CO occurred at 5 and 35 minutes at concentrations of 5706 and 1902 ppm, respectively. Blood COHb values were 81 and 71%, respectively (Chaturvedi et al. 1995). Hartzell et al. (1985a,b) reported a higher value, incapacitation at 8000 ppm at 5.1 minutes. Blood levels were not reported. Lethal (LC50) data in the rat ranges from a 5- minute value of 10,000-14,000 ppm to a 60-minute value of approximately 4000 ppm EPA 2005. Guidelines for human exposure to carbon monoxide include the following: ACGIH 8-hour TLV- TWA of 25 ppm; NIOSH 8-hour TWA of 35 ppm and IDLH of 1200 ppm; OSHA PEL of 50 ppm; 1- hour Emergency Response Planning Guidelines (ERPG-1) of 200 ppm; and the NRC Emergency Exposure 1-hour Guidance Level of 400 ppm. 10