Impact of non-constant concentration exposure on lethality of inhaled hydrogen cyanide

• Published in: Toxicological sciences 2014-03, Vol.138 (1), p.205-216
• Main Authors: Sweeney, Lisa M, Sommerville, Douglas R, Channel, Stephen R
• Format: Article
• Language: English
• Subjects: Animals; Chemical Warfare Agents - toxicity; Dose-Response Relationship, Drug; Hydrogen Cyanide - toxicity; Inhalation Exposure - analysis; Lethal Dose 50; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Time Factors; Toxicity Tests, Acute
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kft277

The ten Berge model, also known as the toxic load model, is an empirical approach in hazard assessment modeling for estimating the relationship between the inhalation toxicity of a chemical and the exposure duration. The toxic load (TL) is normally expressed as a function of vapor concentration (C) and duration (t), with TL equaling C(n) × t being a typical form. Hypothetically, any combination of concentration and time that yields the same "toxic load" will give a constant biological response. These formulas have been developed and tested using controlled, constant concentration animal studies, but the validity of applying these assumptions to time-varying concentration profiles has not been tested. Experiments were designed to test the validity of the model under conditions of non-constant acute exposure. Male Sprague-Dawley rats inhaled constant or pulsed concentrations of hydrogen cyanide (HCN) generated in a nose-only exposure system for 5, 15, or 30 min. The observed lethality of HCN for the 11 different C versus t profiles was used to evaluate the ability of the model to adequately describe the lethality of HCN under the conditions of non-constant inhalation exposure. The model was found to be applicable under the tested conditions, with the exception of the median lethality of very brief, high concentration, discontinuous exposures.