Lethal Effects (LCt₅₀)

After reviewing the available animal lethality data, CDEPAT proposed a human LCt₅₀ estimate of 10,000 mg-min/m³ following percutaneous exposure to GB vapor, assuming light clothing and exposure durations of 30 to 50 min for the soldiers. The existing LCt₅₀ estimate is 15,000 mg-min/m³ (CDEPAT 1994).

The Army's proposed estimate is supported by an LCt₅₀ of 9,700 mgmin/m³ in monkeys exposed to hot temperatures (80–95°F) and moderate relative humidity (35% to 55%) (Oberst et al. 1952). On the basis of the monkey and human studies, a lethal Ct (concentration × time) for humans was estimated to be slightly higher than 12,800 mg-min/m ³ (McGrath et al. 1951). Silver (1953) estimated the LCt₅₀ to be about 15,000 mg-min/m³; the estimate was based on studies of McGrath et al. (1951) who investigated the inhibition of cholinesterase (ChE) in monkeys and men exposed to GB. The subcommittee believes that, on the basis of available data, 10,000 mg-min/m³ is a conservative estimate of the human LCt₅₀.

The preliminary studies involved exposure to the right forearm, and data from these studies were used to determine the whole-body exposures. Therefore, the subcommittee concludes that CDEPAT's LCt₅₀ estimate of 10,000 mg-min/m³ for GB is scientifically valid.

ECt₅₀ for Threshold Effects

CDEPAT's proposed ECt₅₀ estimate for threshold (minimal) effects following percutaneous exposure to GB vapor is 1,200 mg-min/m³, assuming light clothing and exposure durations of 30 to 50 min. There is no existing ECt₅₀ estimate for threshold effects (CDEPAT 1994).

The Army's proposed estimate of 1,200 mg-min/m³ is based on human data using the most appropriate study (McGrath et al. 1951). Exposures of 190 to 1,010 mg-min/m³ (concentrations of 21 to 92 mg/m³; durations of 9 to 11 min) resulted in ChE levels of 95% to 108% of baseline; all subjects were asymptomatic, supporting a no-effect level of < 1,000 mg-min/m³ (McGrath et al. 1951). Humans exposed at 1,255 to 1,850 mg-min/m³ (concentrations of 81 to 109 mg/m³; exposure durations of 11.5 to 20 min) had ChE activities ranging from 31% to 90%. Two of nine individuals were asymptomatic, and the other seven experienced sweating that persisted for a minimum of 24 hr and a maximum of 30 days (McGrath et al. 1951). Therefore, the subcommittee concludes that CDEPAT's proposed ECt₅₀ estimate for threshold effects is scientifically valid.

Lethal Effects (LCt₅₀)

CDEPAT's proposed LCt₅₀ estimate following inhalation exposure to GB vapor is 35 mg-min/m³, assuming minute volumes of 15 liters and exposure durations of 2 to 10 min. The existing LCt₅₀ estimate is 70 mg-min/m ³ (CDEPAT 1994).

The LCt₅₀ data for inhalation exposure for several animal species (mouse, rat, primate, dog, rabbit, cat, and pig) provide an LCt₅₀ estimate for humans of 60 mg-min/m³ for 10-min exposures. The average ratio (of LCt₅₀ for GA, GB, and GF) for 10-min and 2-min exposures was calculated to be 0.6 (CDEPAT 1994) and that ratio was also supported by a classified study. Using a factor of 0.6 to estimate the 2-min LCt₅₀ from the 10-min LCt₅₀, CDEPAT obtained a value of 35 mg-min/m ³ (60 × 0.5 35).

Human data from the Adamek Report (as cited in Wills and DeArmon 1954) showed deaths in four of four subjects exposed at 4 mg/m³ for 10 min (a Ct (concentration × time) of 40 mg-min/m³). Data were available for 48 other subjects, all of whom received some type of post-exposure therapy. Using data from exposed and unexposed individuals, the authors calculated an LCt₅₀ of 24 mg-min/m³ (Wills and DeArmon 1954). However, on the basis of the 100% lethality observed in humans exposed at 40 mg-min/m³, the subcommittee recommends that the CDEPAT's proposed LCt₅₀ estimate of 35 mg-min/m³ be lowered. The subcommittee also recommends that further research be conducted to establish the LCt ₅₀ estimate for inhalation with a greater degree of confidence.

ECt₅₀ for Severe Effects

CDEPAT's proposed ECt₅₀ estimate for severe effects following inhalation exposure to GB vapor is 25 mg-min/m³, assuming minute volumes of 15 liters and exposure durations of 2 to 10 min. The existing ECt ₅₀ estimate is 35 mg-min/m³ (CDEPAT 1994).

In the absence of adequate data on GB for this effect, CDEPAT's proposed estimate is based on the assumption that the ratio of ICt₅₀ (incapacitation dose for 50% of a given population) and LCt₅₀ is about 0.7. The ratio is supported by a study conducted in monkeys (Cresthull et al. 1957). The proposed ECt₅₀ estimate of 25 mg-min/m³ was calculated by multiplying the LCt₅₀ of 35 mg-min/m³ by 0.7, which equals 25 mg-min/m³. The subcommittee believes this approach is reasonable. However, the subcommittee recommended that the LCt₅₀ for inhalation exposure be lowered; therefore, the ECt₅₀ should be lowered correspondingly. The subcommittee recommends that further research be conducted to establish the ECt₅₀ for severe effects with a greater degree of confidence.

ECt₅₀ for Mild Effects

CDEPAT's recommended ECt₅₀ estimate for mild effects (miosis or rhinorrhea) after exposure to GB vapor is 0.5 mg-min/m³, assuming exposure durations of 2 to 10 min. That estimate is independent of minute volume. The existing ECt₅₀ estimate is 2 mg-min/m³ (CDEPAT 1994). A question that needs to be addressed is the degree of miosis and rhinorrhea that should be used to estimate the ECt₅₀ for mild effects. The data listed in the CDEPAT report do not support CDEPAT's (1994) conclusion that ''Review of other human data indicated that miosis and rhinorrhea probably occur in at least 50% of the population at GB doses of ≤ 1.0 mg-min/m³." Further, some reports suggest that neither miosis nor rhinorrhea occurred at 0.5 mg-min/m³. The threshold symptoms appear to occur at exposures of approximately 2 mg-min/m³. Thus, the ECt₅₀ value could be slightly higher (because of a steep dose-response curve) for the nerve agents.

The subcommittee concludes that CDEPAT's estimate of 0.5 mg-min/m³ is not supported by the available data, which indicate that the value is higher; therefore, the subcommittee recommends that the proposed estimate be raised. The subcommittee also recommends that further research be conducted to establish the ECt₅₀ for mild effects with a greater degree of confidence.

Lethal Effects (LD₅₀)

CDEPAT's proposed LD₅₀ estimate for percutaneous exposure to GB liquid on bare skin is 1,700 mg for a 70-kg man. That estimate is the same as the existing estimate (CDEPAT 1994). The proposed value was calculated using a ratio of ChE₅₀ inhibition levels in rabbits (whole blood) to ChE₅₀ inhibition levels in humans (red blood cells) (CDEPAT 1994). In rabbits, a reduction of 88.8% ChE resulted in 53% deaths. In humans, ChE₅₀ inhibition was based on exposure of bare skin and was estimated to be between 350 and 400 mg for a 70-kg man. One of three subjects who died was exposed to a concentration of 20 mg of GB liquid under one layer of serge plus one layer of flannel and showed a 96% inhibition of ChE. The two other subjects showed 82% and 87% ChE inhibition but had no clinical symptoms. On the basis of the limited and inconsistent data in humans, the subcommittee concludes that the degree of confidence in CDEPAT's estimate is low. The subcommittee recommends that the proposed LD ₅₀ estimate of 1,700 mg for a 70-kg man be considered an interim value until further research is done. The subcommittee also recommends that further research be conducted to establish the LD₅₀ estimate with a greater degree of confidence.

ED₅₀ for Severe Effects

CDEPAT's proposed ED₅₀ for severe effects after percutaneous exposure to GB liquid on bare skin is 1,000 mg for a 70-kg man. There is no existing toxicity estimate for GB via this route (CDEPAT 1994).

Data are not sufficient to estimate the human ED₅₀ for severe effects after percutaneous exposure to liquid GB, and there are few estimates. The proposed estimate of 1,000 mg per a 70-kg man is based on data assuming that the ID₅₀-to-LD₅₀ ratio of 0.6 is valid. The data were extrapolated from relative similarities in ChE inhibition in pigs and humans; the human LD₅₀ was estimated to be 2,500 mg for a 70-kg man, and the ID₅₀ was estimated to be 1,500 mg for a 70-kg man (Silver 1953). Thus, the ratio of 0.6 (1,500 mg for a 70-kg man to 2,500 mg for a 70-kg man = 0.6) was used to estimate the ED₅₀ for severe effects from percutaneous liquid exposure to GB (Reutter et al. 1992). The subcommittee supports CDEPAT's proposed ED₅₀ estimate of 1,000 mg for a 70-kg man (0.6 × 1,700 1,000) as an interim value. The subcommittee recommends that further research be conducted to establish the ED₅₀ estimate for severe effects with a greater degree of confidence.