4—
Review of Acute Human-Toxicity Estimates for GD (Soman)

GD (Soman or 1,2,2-trimethyl propyl methylphosphonofluoridate) is an organophosphate nerve agent. It is a colorless, volatile liquid. The physical and chemical properties, toxicokinetics, and toxicity of GD are discussed in detail by CDEPAT (1994), Marrs et al. (1996), and Somani (1994). Human-toxicity estimates have been derived for percutaneous vapor exposures, vapor inhalation exposures, and percutaneous liquid exposures. Only a few toxicity end points were considered (for example, lethality in animals and incapacitation). The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for GD is discussed below.

Percutaneous Vapor Exposure

Lethal Effects (LCt50)

CDEPAT's proposed LCt50 estimate following percutaneous exposure to GD vapors is 2,500 mg-min/m3, assuming that soldiers are wearing light clothing, temperatures are moderate, and exposure durations are 30 to 50



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--> 4— Review of Acute Human-Toxicity Estimates for GD (Soman) GD (Soman or 1,2,2-trimethyl propyl methylphosphonofluoridate) is an organophosphate nerve agent. It is a colorless, volatile liquid. The physical and chemical properties, toxicokinetics, and toxicity of GD are discussed in detail by CDEPAT (1994), Marrs et al. (1996), and Somani (1994). Human-toxicity estimates have been derived for percutaneous vapor exposures, vapor inhalation exposures, and percutaneous liquid exposures. Only a few toxicity end points were considered (for example, lethality in animals and incapacitation). The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for GD is discussed below. Percutaneous Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate following percutaneous exposure to GD vapors is 2,500 mg-min/m3, assuming that soldiers are wearing light clothing, temperatures are moderate, and exposure durations are 30 to 50

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--> min. There is no existing LCt50 estimate for exposures to percutaneous vapor (CDEPAT 1994). No human data on GD are available for this effect. LCt50 values derived from studies in monkeys range from 1,750 to 28,000 mg-min/m3 (Cresthull 1957). Because data on the effects of percutaneous exposure to GD vapor are extremely limited and are insufficient for developing human-toxicity estimates, CDEPAT recommended that estimates for GD be based on toxicity information on GB, assuming that GD is 4 times more potent than GB. This assumption is supported by empirical evidence in dogs and rabbits, showing that the percutaneous potency of GD vapor is at least 2 times and maybe 5 times that of GB (Van de Wal and Zeffert 1970). The subcommittee concludes that the approach used by CDEPAT to estimate the LCt50 of GD is scientifically valid and defensible, because (1) GD and GB belong to the same class of chemicals (organophosphates) and are structurally similar, and (2) animal data support the assumption that GD is 4 times more potent than GB. On the basis of the available data, the subcommittee concludes that the CDEPAT's LCt50 estimate of 2,500 mg-min/m3 is scientifically valid. ECt50 for Threshold Effects CDEPAT's proposed estimate for the ECt50 for threshold (minimal) effects after percutaneous exposure to GD vapor is 300 mg-min/m3, assuming light clothing, exposure durations of 30 to 50 min, and moderate temperatures. There is no existing toxicity estimate for threshold effects from exposure to percutaneous vapor (CDEPAT 1994). No human data are available to estimate this effect level. In deriving the ECt50 for threshold effects, CDEPAT assumed that GD vapor is 4 times more potent than GB vapor (CDEPAT 1994). This assumption was based on a report (Cullumbine et al. 1954) showing that the LCt 50 for GD was 4 times lower than GB. However, CDEPAT has a low degree of confidence in this estimate because of insufficient data. The subcommittee agrees with CDEPAT's approach of basing the ECt50 estimate for GD on toxicity data from GB and assuming that GD is 4 times more potent than GB. The subcommittee also agrees with CDEPAT that the confidence in the ECt50 estimate is low to moderate because of sparse data on both compounds. The subcommittee recommends that CDEPAT's proposed estimate of 300 mg-min/m3 serve as an interim value

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--> until further research is conducted to establish the ECt50 estimate for thresh-old effects with a greater degree of confidence. Inhalation Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed estimate for the LCt50 following inhalation exposure to GD vapor is 35 mg-min/m3, assuming exposure durations of 2 to 10 min, minute volumes of 15 liters, and moderate temperatures. The existing toxicity estimate is 70 mg-min/m3. CDEPAT's proposed estimate for the LCt50 is based on the assumption that GD and GB are equipotent. The equipotency of GD and GB via inhalation is supported by recent data reported by Schoene et al. (1985). The subcommittee agrees with CDEPAT's approach of basing the LCt50 estimate for GD on toxicity data from GB for reasons previously stated. The subcommittee also agrees with CDEPAT's conclusion that the confidence in the LCt50 estimate is low because the data on both compounds are sparse. Because the subcommittee recommends lowering the LCt50 estimate for GB, it also recommends that the estimate for GD be lowered correspondingly. The subcommittee recommends that further research be conducted to establish the LCt50 estimate with a greater degree of confidence. ECt50 for Severe Effects CDEPAT's proposed estimate for ECt50 for severe effects following inhalation exposure to GD vapor is 25 mg-min/m3, assuming exposure durations of 2 to 10 min, minute volumes of 15 liters, and moderate temperatures. The existing toxicity estimate is 35 mg-min/m3, (CDEPAT 1994). The inhalation data needed to develop an estimate for the severe effects of GD are insufficient. CDEPAT assumed that the potencies of GD and GB via the inhalation route are comparable and proposed identical toxicity estimates. The subcommittee agrees with CDEPAT's approach of basing the ECt50 estimate for GD on toxicity data from GB, because (1) GD and GB belong to the same class of chemicals (organophosphates) and are structurally similar, and (2) animal data support the assumption that GD is equipo-

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--> tent to GB for severe effects via the inhalation route (CDEPAT 1994). The basis of this assumption is a study by Cresthull et al. (1957) in which the ratio of ICt50 to LCt50 for GB was 0.7. Because GB and GD have similar structures and similar modes of action, CDEPAT assumed that the ratio of 0.7 for GB would also hold true for GD. However, the subcommittee concludes that the confidence in the ECt50 value is low because of sparse data on both compounds. The subcommittee recommends that CDEPAT's proposed estimate of 25 mg-min/m3 be lowered to correspond to the subcommittee's recommendation for lowering the ECt50 for GB until further research is done to establish the estimate with a greater degree of confidence. ECt50 for Mild Effects CDEPAT's proposed estimate for ECt50 for mild (ocular and/or nasal) effects for GD is 0.2 mg-min/m3, assuming exposure durations of 2 to 10 min and moderate temperatures. This local effect is not affected by minute volume. There is no existing ECt50 estimate for GD (CDEPAT 1994). Sufficient human data are not available to calculate an ECt50 for mild effects following ocular exposure to GD. One study in which rabbits were exposed under identical conditions to GB and GD showed that GD is a 2.5-times more potent miotic agent than GB via inhalation exposure (Callaway and Dirnhuber 1971). Thus, in deriving the ECt 50 estimate for GD, CDEPAT assumed that GD is 2.5 times more potent than GB for ocular effects (Callaway and Dirnhuber 1971). The subcommittee agrees with CDEPAT's approach of assuming that the ocular toxicity of GD is 2.5 times greater than that of GB. The subcommittee also agrees with the conclusion of CDEPAT that the confidence in the ECt50 estimate is low because of sparse data on both compounds. In addition, because the subcommittee recommends raising the ECt50 for GB, it concludes that the estimate for GD should be raised correspondingly for ocular effects until further research is done to establish the estimate with a greater degree of confidence. Percutaneous Liquid Exposure Lethal Effects (LD50) CDEPAT's proposed estimate for the LD50 value is 350 mg for a 70-kg

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--> man, or 5 mg/kg. The existing LD50 estimate for GD following percutaneous liquid exposure is the same (CDEPAT 1994). The available animal-toxicity data are insufficient for estimating the human LD50 for percutaneous exposure to GD liquid with any degree of confidence. The most often quoted estimate is 350 mg for a 70-kg man, an estimate based on a study by Cullumbine et al. (1954) investigating the effect of percutaneous exposure of rabbits to GD liquid. The rabbit is more sensitive to GD liquid than any other nonhuman species (Henry 1989). The reported LD50s in animals range from < 1 to 14 mg/kg (< 70 to 980 mg for a 70-kg man). Given this wide range in LD50 values, the subcommittee's degree of confidence in CDEPAT's proposed estimate of 350 mg for a 70-kg man is moderately low. The subcommittee recommends that CDEPAT's proposed estimate serve as an interim value until further research is conducted to establish this estimate with a greater degree of confidence. ED50 for Severe Effects CDEPAT's proposed estimate for the ED50 for severe effects following percutaneous exposure to GD liquid on bare skin is 200 mg for a 70-kg man or approximately 3 mg/kg. There is no existing ED50 estimate for GD (CDEPAT 1994). The available data are insufficient for estimating the human ED50 for severe effects (incapacitation, prostration, collapse, and convulsion) after percutaneous exposure to GD liquid. Data on exposure of pigs indicate that the slopes for lethality and severe effects are parallel and that the ID50-to-LD50 ratio is about 0.8 (Manthei et al. 1988; CDEPAT 1994). Other data suggest that the ratio is approximately 0.6 (Reutter et al. 1992). On the basis of the more conservative ratio of 0.6, CDEPAT derived the human-toxicity estimate of 3 mg/kg (5 mg/kg (LD50) × 0.6 = 3 mg/kg). In the absence of adequate human data or animal data on GD for this effect, the subcommittee accepts CDEPAT's approach of using the ID50-to-LD50 ratio of 0.6 to derive the ED50 estimate. The subcommittee's degree of confidence in CDEPAT's proposed estimate is low to moderate because of the insufficient data. The subcommittee recommends that the proposed estimate serve as an interim value until further research is conducted to establish this estimate with a greater degree of confidence.

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--> Conclusions and Recommendations The subcommittee's conclusions concerning CDEPAT's proposed estimates for GD are summarized in Table 4-1. Of the seven human-toxicity estimates for GD proposed by CDEPAT to protect soldiers from the toxic effects of CW agents, the subcommittee agrees that one estimate is scientifically valid. The subcommittee recommends that two of the estimates be lowered, and three be considered interim estimates. It also concludes that one estimate should be raised.

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--> TABLE 4-1 Evaluation of Human-Toxicity Estimates for GD     Human-Toxicity Estimates for GB     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GB Rationale for Subcommittee's Evaluation LCt50a Percutaneous, vapor None 2,500 mg-min/m3 Proposed estimate is scientifically valid Proposed estimate based on assumption that GD is 4 times more toxic than GB for percutaneous exposure   Inhalation, vapor 70 mg-min/m3 35 mg-min/m3 Proposed estimate should be lowered Proposed estimate based on the assumption that GD and GB are equipotent via this route; subcommittee recommends that LCt50 estimate for GD be lowered to correspond to lowered estimate for GB; further research recommended ECt50b Threshold effects Percutaneous, vapor None 300 mg-min/m3 Proposed estimate should serve as an interim value In the absence of adequate human or animal data, proposed estimate based on assumption that GD is 4 times more toxic than GB for percutaneous exposure; further research recommended Severe effects Inhalation, vapor 35 mg-min/m3 25 mg-min/m3 Proposed estimate should be lowered In the absence of adequate human or animal data, proposed estimate based on assumption that potenies of GD and GB are comparable; ECt 50 estimate for GD should be lowered to correspond to the lowered estimate for GB; further research recommended Mild effects Inhalation, vapor None 0.2 mg-min/m3 Proposed estimate should be raised In the absence of adequate human or animal data, proposed estimate based on assumption that GD is 2.5 times more potent than GB for miotic effects; subcommittee recommends that the LCt50 estimate for GD be raised to correspond to the recommended raised estimate for GB; further research recommended

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-->     Human-Toxicity Estimates for GB     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GB Rationale for Subcommittee's Evaluation LD50c Percutaneous, liquid 350 mg for 70-kg man 350 mg for 70-kg man Proposed estimate should serve as an interim value Because of wide range of LD50 values in animals, subcommittee's confidence in the proposed estimate is low; CDEPAT's proposed estimate of 350 mg for 70-kg man should serve as an interim value; further research recommended ED50d Severe effects Percutaneous, liquid None 200 mg for 70-kg man Proposed estimate should serve as an interim value In the absence of adequate human or animal data, proposed estimate was derived using the ID50e/LD50 ratio of 0.6; the subcommittee recommends that CDEPAT's proposed estimate serve as an interim value; further research recommended a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. e ID50: Liquid dose causing incapacitation in 50% of the exposed population.