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

Abstract

Sweeney, Lisa M.; Summerville, Douglas R.; Channel, Stephen R.; Sharits, Brian C.; Gargas, Nathan M.; and Gut Jr., Chester P., "Evaluating the validity and applicable domain of the toxic load model: Impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide" (2015). 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 P5 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.

Acute toxicity when concentration varies with time: A case study with carbon monoxide inhalation by rats

“…The validity of the toxic load models for extrapolation from constant exposures to time-varying exposures is being tested by comparing outcomes from rat studies with standard (constant) profiles with outcomes from studies where rats are exposed to time varying concentrations. In a previous series of experiments using hydrogen cyanide (HCN), we concluded that as long as continuous exposures lasted 5 min or longer, the toxic load model was consistent with the outcomes of variable-concentration exposures with and without gaps (brief [30% of total duration] periods with no exposure) (Sweeney et al, 2014(Sweeney et al, , 2015. No definite conclusions could be made about the toxic load model concerning shorter exposures (less than 5 min) due to probable breath-holding on the part of the rats.…”

“…As noted above, the current experiments and analyses build off of previous efforts in which HCN was used as the test chemical (Sweeney et al, 2014(Sweeney et al, , 2015. The current effort was a departure from the previous efforts in that a different test chemical was used.…”

“…As discussed previously (Sweeney et al, 2014(Sweeney et al, , 2015, two approaches have been proposed for the calculation of toxic loads under non-constant conditions. The duration-averaged (DA) approach uses the time weighted average concentration raised to the toxic load exponent, and multiplied by t: TL DA ¼ (Cavg) n  t. The integrated approach uses TL ¼ !C n dt.…”

“…For simple scenarios like those in this study, the integrated approach is equivalent to a piecewise (PW) approach, with TL PW ¼ (C1) n  t1 þ (C2) n  t2 where C1, C2, t1 and t2 and the concentrations and durations of the two pulses. The relationship between TL DA and TL PW (derived in Sweeney et al, 2015) is described in the following equation, where f ¼ gap duration (fraction of total duration: 0, 0.33 or 0.67), CR ¼ concentration ratio for pulses (C1/C2), DR ¼ duration ratio for pulses (t1/t2), and n ¼ toxic load exponent.…”

“…The toxic load of the high concentration LC 50 pulse in the two-pulse scenarios was more consistent with the TL 50 values of the single pulse profiles than TL DA or TL PW . A larger data set for HCN with nine different twopulse profiles (minimum continuous exposure duration of 5 min, to exclude exposures influenced by breath holding; Sweeney et al, 2014Sweeney et al, , 2015 was further evaluated, and it was determined that the toxic loads for the high concentration median lethal pulse alone were consistent with the TL 50 values from the single pulse exposures (Supplementary Data, Figure S-3).…”