Physiologically based pharmacokinetic modeling of hydrogen cyanide levels in human breath

Abstract

Hydrogen cyanide (HCN) is a potent and fast-acting toxin increasingly recognized as an important cause of death in fire victims. Prompt diagnosis and treatment of cyanide poisoning are essential to avoid fatalities. Unfortunately, there are at present few rapid diagnostic methods. A noninvasive methodology would be to use HCN in exhaled air as a marker for systemic exposure. To explore this possibility, we developed a preliminary physiologically based pharmacokinetic model. The model suggests that breath HCN levels following inhalation exposure at near-lethal and lethal conditions are 0.1-1 ppm, i.e., one to two orders of magnitude higher than the background breath level of about 0.01 ppm in unexposed subjects. Hence, our results imply that breath analysis may be used as a rapid diagnostic method for cyanide poisoning.

Evaluating the validity and applicable domain of the toxic load model: Impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide

“…With regard to hydrogen cyanide in particular, the elimination half-life in exhaled air for humans was 15.6 ± 3.9 min (Stamyr et al, 2008), similar to the rat blood cyanide half-life reported by Leuschner et al (1991), suggesting the impact of ''gaps'' of toxicokinetics might be similar. Stamyr et al (2014) recently used physiologically based pharmacokinetic modeling of HCN lethality from human case reports with times to death ranging from $7 to 60 min to derive a toxic load exponent of 2.4. This human value is slightly higher than the value of 1.6 for rats (derived herein) and the value of 2.1 for monkeys derived by the National Research Council (2002).…”

Breath biomarkers in toxicology

“…Some examples are ingestion of volatile foods or substances (Beauchamp et al 2010;Traucher et al 1996), breath diagnosis of life-threatening hydrogen cyanide (HCN) toxicity in victims of fire (Stamyr et al 2015), alcohol and ethylene glycol poisoning (Johanson 2000;Walsh and Macleod 1983;Eder et al 1998), carbon monoxide exposures (Cunnington and Hormbrey 2002), and toluene abuse (Garriott et al 1981).…”

Possibilities and limitations of intravital imaging

“…First, pharmacokinetic modelling can be improved by intravital imaging. PBPK modelling is of high relevance for simulation of compound concentrations in blood or organs (Golubovskaya et al, 2015[9]; Stamyr et al, 2015[20]; Widera, 2015[24]; Ghallab, 2015[5]) as well as for interspecies extrapolation (Thiel et al, 2015[21]). However, current PBPK models consider individual organs as single compartments (Schug et al, 2013[19]; Mielke et al, 2011[14]).…”