Acute inhalation toxicity of carbon monoxide and hydrogen cyanide revisited: Comparison of models to disentangle the concentration × time conundrum of lethality and incapacitation

Abstract

Contemporary emergency response planning guidelines are stratified to consider the threshold for serious toxicity and/or impairment of escape, relative to the potentially lethal level above this threshold and the lower level at which individuals should not experience or develop effects more serious than mild irritation. While harmonized testing guidelines and risk assessment paradigms are available for the quantification of thresholds for lethality or establishing no adverse effect levels, the quantification of ‘impairment of escape’ appears to be a more elusive goal. Approaches were explored in context with CO and HCN in past experimental combustion toxicology studies to estimate the time available for escape. This point of departure (POD) was compared with the non-lethal threshold (LC01) and one third thereof from published recent acute inhalation studies in rats examining the Cxt-matrix of both CO and HCN. The findings from this analysis suggest that the rat delivers the most consistent data. However, it remains challenging yet to bridge the behavioral variables of human behavior typical of escape to any surrogate animal model. For the asphyxiant gases examined, the PODs characterizing ‘impairment of escape’ were difficult to distinguish from those indicative of impending death. No specific modeled carboxyhemoglobin (COHb) level could be linked to onset of incapacitation. In summary, the higher ventilation of rats (kg body weight adjusted) renders this species even more susceptible than heavy breathing humans. LCt01 × 1/3 values derived from the comprehensive Cxt matrix of rat inhalation studies are considered to be most suitable and robust to estimate the human equivalent threshold (POD) of ‘impairment of escape’.