title: Evaluating the validity and applicable domain of the toxic load model: impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide.
abstract: The ten Berge model (or "toxic load" model) is often used to estimate the acute toxicity for varying combinations of inhaled concentration and duration. Expressed as C(n) × t = toxic load (TL), TLs are assumed constant for various combinations of concentration (C) and time (t). Experimental data in a recent acute inhalation study of rats exposed to time-varying concentrations of hydrogen cyanide (HCN) supported the validity of the toxic load model except under very brief, discontinuous, high concentration exposures. In the present investigation, experiments were conducted to extend the evaluation of the applicable domain of the model for acute lethality of HCN in the rat (cumulative exposure range of 2900-11,000 ppm min). The lethality of HCN over very short (< 5 min) durations of high concentrations did not conform to the toxic load model. A value of n=1.57 was determined for uninterrupted exposures ⩾ 5 min. For 30-min exposures, the presence or absence of a gap between two exposure pulses of different concentrations, the relative duration, relative height, and the ordering of the pulses (low then high, vs. high then low) did not appear to have a meaningful impact on the toxic load required for median lethality.
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Naval Medical Research Unit Dayton, Wright Patterson Air Force Base, OH 45433, United States. Electronic address: lisa.sweeney.3.ctr@us.af.mil.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sweeney
authors.affiliation: U.S. Army Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Sommerville
authors.affiliation: Leidos, Linton, IN 47441, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Channel
authors.affiliation: CAMRIS, Naval Medical Research Unit Dayton, Wright Patterson Air Force Base, OH 45433, United States.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Sharits
authors.affiliation: CAMRIS, Naval Medical Research Unit Dayton, Wright Patterson Air Force Base, OH 45433, United States.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Gargas
authors.affiliation: CAMRIS, Naval Medical Research Unit Dayton, Wright Patterson Air Force Base, OH 45433, United States.
authors.forename: Chester P
authors.initials: CP
authors.lastname: Gut
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005740:Gases; D006856:Hydrogen Cyanide / Q000008:administration & dosage / Q000633:toxicity*; D019570:Inhalation Exposure; D007928:Lethal Dose 50; D008297:Male; D008962:Models, Theoretical; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D005740:Gases; D006856:Hydrogen Cyanide
keywords: Acute lethality; Hydrogen cyanide; Non-constant concentrations; Nose-only inhalation; Pulsed exposures; Toxic load model