6
Appropriateness of Measurement of Blood or Air Levels of Cyanide

The question has been asked if blood cyanide levels would be a more appropriate biomarker of toxicity risk than ambient air cyanide levels. It should first be noted that there is little human data for non-lethal endpoints with good measurements of either air or blood levels (reviewed in ATSDR 2006; NRC 2002). Most of the data on these gases are old and based on chronic occupational exposures to low levels of airborne hydrogen cyanide. In most of these reports symptoms were either absent or minor in nature. There are considerable data on blood cyanide levels in lethalities, primarily from fire victims where carbon monoxide was also present. Most authorities conclude that whole blood cyanide levels >1 mg/L may cause major symptoms or lethality, although reported levels in deaths have ranged from 0.4 to 230 mg/L (Rehling 1967). In summary, there is not good human data relating either blood levels or air levels to relevant endpoints of interest in the present situation.

That said there appear to be several reasons to think that measurement of air levels is a better benchmark to use in assessing the combined toxicity of cyanide and carbon monoxide in a hazard quotient model. First, measurement of hydrogen cyanide in air can apparently be done in real time as judged by the data presented by the military. There are no reported rapid or simple methods for the determination of cyanide in biological fluids (ATSDR 2006). Second, using blood cyanide levels as a biological marker for sub-lethal effects is complicated by the rapid metabolism of cyanide in vivo. The initial half-life of cyanide in humans is estimated to be 20-60 minutes (ATSDR 2006). When levels are very high, as in potentially lethal exposures, there is an initial rapid decline followed by a slow terminal elimination with half-lives ranging from 19-66 hours for the terminal phase (ATSDR 2006). Thus timing of blood sampling would be crucial in interpreting the results. Cyanide undergoes first pass metabolism that further complicates the interpretation of blood levels. Third, there is a problem with which blood fraction to use in analysis. Whole blood (WB) samples are more stable than plasma or serum samples, where there can be a significant decline in cyanide levels in stored samples over a period of hours (Alarie 2002; Ballantyne 1976). In WB most cyanide resides within the red blood cell. Thus WB levels may be a poorer marker of toxicity if obtained before equilibrium has been reached between the plasma cyanide and red blood cell cyanide (Alarie 2002). Plasma cyanide levels appear to correlate better with clinical effects, but suffer from the stability problem, even if stored at appropriate temperature. In any case virtually all authorities recommend that cyanide levels be measured as soon as possible after collection in order to avoid declining values. This would create a significant logistical problem if blood levels were to be used as the biomarker.

Finally it should be noted that factors other than acute environmental exposure may influence cyanide levels measured in blood. The most important of these is smoking history. There are numerous reports in the literature documenting variable increases in cyanide in blood as a result of smoking (Cailleux et al. 1988). There are also reports of increased blood cyanide levels in some populations whose diet includes large proportions of certain cyanogenic foods (Mlingi et al. 1992).



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6 Appropriateness of Measurement of Blood or Air Levels of Cyanide The question has been asked if blood cyanide levels would be a more appropriate biomarker of toxicity risk than ambient air cyanide levels. It should first be noted that there is little human data for non-lethal endpoints with good measurements of either air or blood levels (reviewed in ATSDR 2006; NRC 2002). Most of the data on these gases are old and based on chronic occupational exposures to low levels of airborne hydrogen cyanide. In most of these reports symptoms were either absent or minor in nature. There are considerable data on blood cyanide levels in lethalities, primarily from fire victims where carbon monoxide was also present. Most authorities conclude that whole blood cyanide levels >1 mg/L may cause major symptoms or lethality, although reported levels in deaths have ranged from 0.4 to 230 mg/L (Rehling 1967). In summary, there is not good human data relating either blood levels or air levels to relevant endpoints of interest in the present situation. That said there appear to be several reasons to think that measurement of air levels is a better benchmark to use in assessing the combined toxicity of cyanide and carbon monoxide in a hazard quotient model. First, measurement of hydrogen cyanide in air can apparently be done in real time as judged by the data presented by the military. There are no reported rapid or simple methods for the determination of cyanide in biological fluids (ATSDR 2006). Second, using blood cyanide levels as a biological marker for sub-lethal effects is complicated by the rapid metabolism of cyanide in vivo. The initial half-life of cyanide in humans is estimated to be 20-60 minutes (ATSDR 2006). When levels are very high, as in potentially lethal exposures, there is an initial rapid decline followed by a slow terminal elimination with half-lives ranging from 19-66 hours for the terminal phase (ATSDR 2006). Thus timing of blood sampling would be crucial in interpreting the results. Cyanide undergoes first pass metabolism that further complicates the interpretation of blood levels. Third, there is a problem with which blood fraction to use in analysis. Whole blood (WB) samples are more stable than plasma or serum samples, where there can be a significant decline in cyanide levels in stored samples over a period of hours (Alarie 2002; Ballantyne 1976). In WB most cyanide resides within the red blood cell. Thus WB levels may be a poorer marker of toxicity if obtained before equilibrium has been reached between the plasma cyanide and red blood cell cyanide (Alarie 2002). Plasma cyanide levels appear to correlate better with clinical effects, but suffer from the stability problem, even if stored at appropriate temperature. In any case virtually all authorities recommend that cyanide levels be measured as soon as possible after collection in order to avoid declining values. This would create a significant logistical problem if blood levels were to be used as the biomarker. Finally it should be noted that factors other than acute environmental exposure may influence cyanide levels measured in blood. The most important of these is smoking history. There are numerous reports in the literature documenting variable increases in cyanide in blood as a result of smoking (Cailleux et al. 1988). There are also reports of increased blood cyanide levels in some populations whose diet includes large proportions of certain cyanogenic foods (Mlingi et al. 1992). 16

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Appropriateness of Measurement of Blood or Air Levels of Cyanide In summary, there seems to be no compelling reason why blood measurements of cyanide would be a better predictor of toxicity than measurement of ambient air levels. The added difficulties associated with the measurement and interpretation of blood cyanide levels would suggest that this measurement should not be selected as a routine monitoring methodology. 17