GB toxicity reassessed using newer techniques for estimation of human toxicity from animal inhalation toxicity data: New method for estimating acute human toxicity (GB)

Abstract

Estimated human inhalation toxicity values for Sarin (GB) were calculated using a new two independent (concentration, exposure time), one dependent (toxic response), non-linear dose response (toxicity) model combined with re-evaluated allometric equations relating to animal and human respiration. Historical animal studies of GB toxicity containing both exposure and fractional animal response data were used to test the new process. The final data set contained 6621 animals, 762 groups, 37 studies and 7 species. The toxicity of GB for each species was empirically related to exposure concentration (C; mg m(-3)) and exposure time (T; min) through the surface function Y = b0 + b1 Log10C + b2 Log10T or Y = b0 + b2 Log10C(n)T where Y is the Normit, b0, b1 and b2 are constants and n is the 'toxic load exponent' (Normit is PROBIT - 5). Between exposure times of 0.17 and 30 min, the average value for n in seven species was 1.35 +/- 0.15. The near parallel toxic load equations for each species and the linear relationship between minute volume/body weight ratio and the inhalation toxicity (LCt50) for GB were used to create a pseudo-human data set and then an exposure time/toxicity surface for the human. The calculated n for the human was 1.40. The pseudo-human data had much more variability at low exposure times. Raising the lower exposure limit to 1 min, did not change the LCt50 but did result in lower variability. Raising the lower value to 2 min was counterproductive. Based on the toxic load model for 1-30 min exposures, the human GB toxicities (LCt01, LCt05, LCt50 and LCt95) for 70 kg humans breathing 15 l min(-1) were estimated to be 11, 16, 36 and 83; 18, 25, 57 and 132 and 24, 34, 79 and 182 mg x min m(-3) for 2, 10 and 30 min exposures, respectively. These values are recommended for general use for the total human population. The empirical relationships employed in the calculations may not be valid for exposure times >30 min.

Inhalation toxicity in mice exposed to sarin (GB) for 20–720 min

“…the lct 50 varies directly as the product of concentration and exposure time (lct 50 = CT; Haber, 1924) at the 720-min exposure (Table 7). A similar divergence occurs at shorter exposure times (Bide et al, , 2004a. Using Haber's rule to estimate the toxicity of GB is clearly unacceptable.…”

“…high concentration, very short (1-30 s) exposures. In the literature, only one of the 10 identified historical studies involving GB toxicity to mice contained data for exposures of >10 min (Bide et al, , 2004a. The compilation of historical data has provided a reasonable set of toxicity data for 0.17-30 min exposures.…”

“…In these early experiments, many exposure times were short (1-30 s) to demonstrate the lethality resulting from a massive attack and incapacitation from a single breath. The result was that very few data were generated for exposures of >10 min (Bide et al, , 2004a. When the literature concerning nerve agents was re-examined in preparation for the 1991 Gulf War and following the terrorist use of sarin (GB) in Tokyo (Okumura et al, 1996(Okumura et al, , 1998a, one of the main data gaps identified was the absence of data concerning the toxicity of the nerve agents at exposure times of >15 min (Bide et al, , 2004aMioduszewski et al, 2000Mioduszewski et al, , 2001Grotte and Yang, 2001).…”

“…The result was that very few data were generated for exposures of >10 min (Bide et al, , 2004a. When the literature concerning nerve agents was re-examined in preparation for the 1991 Gulf War and following the terrorist use of sarin (GB) in Tokyo (Okumura et al, 1996(Okumura et al, , 1998a, one of the main data gaps identified was the absence of data concerning the toxicity of the nerve agents at exposure times of >15 min (Bide et al, , 2004aMioduszewski et al, 2000Mioduszewski et al, , 2001Grotte and Yang, 2001). Information concerning the toxicity of chemical warfare agents at these longer exposure times is critical for: (i) Setting limits for first responders functioning near an incident where contamination levels can be low and variable, and exposures of many hours are encountered.…”

“…However, information concerning the toxicity of GB (and other nerve agents) from longer exposures of 1-12 h is critical for all personnel who must work in or close to low-level concentrations of chemical for extended periods and for all personnel, dressed in Individual Protective Equipment, who need to know when, and if, it is safe to take off these cumbersome garments.The data presented for the toxicity of GB to mice for whole-body exposures of 20 min to 12 h are intended to form part of an ongoing, multi-species effort aimed at establishing toxicity estimates for humans for these longer exposure times: (v) All personnel, dressed in Individual Protective Equipment, who need to know when, and if, it is safe to take off these cumbersome garments.At exposure times up to 30 min the toxicity of GB in several species (Bide et al, , 2004a follows an empirical relationship (tenBerg, 1986;Yee, 1996;Yee et al, 1998), referred to as the 'toxic load model' and characterized by the equivalent planar surface equationsinvolving the exposure time T explicitly. Here, Y is the PROBIT value, C is the exposure concentration, T is the exposure time, n(= b 1 /b 2 ) is the 'toxic load exponent' and b 0 , b 1 and b 2 are experimentally derived regression coefficients (empirical constants).…”