2—
Review of Acute Human-Toxicity Estimates for GA (Tabun)

GA (Tabun or ethyl n-dimethylphosphoramidocyanidate) is an organophosphate nerve agent and is a colorless, volatile liquid. The physical and chemical properties, toxicokinetics, and toxicity of GA 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, and percutaneous liquid exposures. Only four toxicity end points were considered—lethality in animals, incapacitation, changes in cholinesterase (ChE) activity, and ocular changes in men and monkeys. The subcommittee's assessment of the scientific validity of CDEPAT's proposed human-toxicity estimates for GA is discussed below.

Percutaneous Vapor Exposure

Lethal Effects (LCt50)

CDEPAT's proposed LCt50 estimate for percutaneous exposure to GA vapor is 15,000 mg-min/m3, assuming that soldiers are wearing light clothing



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--> 2— Review of Acute Human-Toxicity Estimates for GA (Tabun) GA (Tabun or ethyl n-dimethylphosphoramidocyanidate) is an organophosphate nerve agent and is a colorless, volatile liquid. The physical and chemical properties, toxicokinetics, and toxicity of GA 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, and percutaneous liquid exposures. Only four toxicity end points were considered—lethality in animals, incapacitation, changes in cholinesterase (ChE) activity, and ocular changes in men and monkeys. The subcommittee's assessment of the scientific validity of CDEPAT's proposed human-toxicity estimates for GA is discussed below. Percutaneous Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for percutaneous exposure to GA vapor is 15,000 mg-min/m3, assuming that soldiers are wearing light clothing

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--> and are exposed for 30 to 50 min. The existing LCt50 is 20,000 mg-min/m 3 (Wood 1949). The original human vapor exposure estimate corresponding to an LCt 50 was 20,000 mg-min/m3 but appears to have been established without supporting data or scientific rationale. LCt50 data from animal studies varies with species (CDEPAT 1994). For example, exposure of dogs and guinea pigs to GA vapor for 10 min resulted in a higher LCt50 value (approximately > 6,100 mg-min/m3) than exposure of mice for the same time (2,500 mg-min/m3). The LCt50 for the monkey was estimated to be 5,000 to 9,000 mg-min/m3 for exposure durations of 132 to 305 min (Krackow and Fuhr 1949). The LCt50 in rabbits for exposure durations of 120 to 282 min was estimated to be > 20,000 mg-min/m3 (Marquand and Kethley 1946). The rabbit LCt50 was > 20,000 mg-min/m3 (Marquand and Kethley 1946). However, the mouse, guinea pig, and dog studies involving exposure durations of 10 min and the monkey and rabbit studies involving exposure durations of > 120 min (120 to 305 min) are not applicable in deriving LCt50 values for humans. Krackow and Fuhr (1949) exposed 16 men at Cts (concentration × time) of 520 to 2,000 mg-min/m3 for 10 to 40 min. The men used gas masks and wore only shorts, socks, and shoes. The exposure caused a slight decrease in ChE activity. The authors concluded that such exposure was safe at Cts as high as 2,000 mg-min/m3. Those human data provide support for CDEPAT's proposed LCt50 estimate of 15,000 mg-min/m3. The subcommittee concludes that the proposed estimate is scientifically valid. ECt50 for Threshold Effects ECt50 for threshold (minimal) effects is the vapor exposure that would result in a significant ChE inhibition (< 15%) but without any identifiable adverse biological consequences. CDEPAT's proposed ECt50 estimate for threshold effects of percutaneous exposure to GA is 2,000 mg-min/m3 for exposure durations of 30 to 50 min in moderate temperatures. CDEPAT's confidence in this estimate is relatively high and is based on significant ChE inhibition (CDEPAT 1994). There is no existing ECt50 estimate for threshold effects (CDEPAT 1994). Changes in ChE activity have been reported in men and monkeys after percutaneous vapor exposure. The human data indicate that a slight but

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--> significant reduction in ChE activity occurs after percutaneous vapor exposures above 1,000 mg-min/m3 (Krackow and Fuhr 1949). Data are also available that indicate that men wearing only shorts, socks, and shoes and using gas masks could be safely exposed (that is, without degradation in performance) to vapor doses as high as 2,000 mg-min/m 3 (Krackow and Fuhr 1949). Masks were used to avoid exposures via inhalation and to protect against ocular effects. On the basis of the human data, the subcommittee concludes that CDEPAT's proposed ECt50 estimate of 2,000 mg-min/m3 is scientifically valid. Inhalation Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for inhalation exposure to GA vapor is 70 mg-min/m3, assuming exposure durations of 2 to 10 min and minute volumes of 15 liters. The existing LCt50 value is 135 mg-min/m3 (CDEPAT 1994). The LCt50s estimates for GA vary with time. In one study, they were 4 mg-min/m3, 8 mg-min/m3, and 16 mg-min/m3 for exposure durations of 48, 40, and 19 min, respectively (Wills and DeArmon 1954). Questions about the accuracy of those data and the longer exposure time make those data inappropriate for calculating human-toxicity estimates for a 2- to 10-min exposure. Other estimates of the LCt50 for humans ranged from 400 to 500 mg-min/m3 (Welchman 1946). However, the rationale and justification for making such estimates are obscure. A number of animal studies using a variety of species have been conducted to establish LCt50 values following inhalation exposure to GA vapor. Unfortunately, most of those studies were conducted over 50 years ago, and few details concerning the exposure and monitoring aspects of the study were recorded. In general, the LCt50 values for GA ranged from 135 to 500 mg-min/m3 for exposures of 10 min or less. CDEPAT's estimates were largely based on studies using rhesus monkeys in which the LCt50s were 135 and 187 mg-min/m3 for 2-min and 10-min exposures, respectively (Cresthull et al. 1957). The poor quality of the animal data used in estimating the LCt50 provides little confidence in the ability to predict the human LCt 50. Existing human data are also inadequate for estimating LCt50 values. Thus,

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--> CDEPAT based its proposed LCt50 estimate for humans primarily on the assumption that GA is probably about 0.5 times as potent as GB (HEC 1960). The subcommittee accepts CDEPAT's approach of assuming that GA is 0.5 times as toxic as GB in deriving its LCt50 estimate for this route. The subcommittee recommends that the LCt50 estimate for GA be lowered, as was done for GB by the subcommittee. The subcommittee also recommends that further research be conducted to establish the LCt50 estimate with a greater degree of confidence. ECt50 for Severe Effects CDEPAT's proposed ECt50 estimate for severe effects following inhalation exposure to GA is 50 mg-min/m3, assuming exposure durations of 2 to 10 min and minute volumes of 15 liters. CDEPAT's degree of confidence in this estimate is moderate. There is no existing toxicity estimate for ECt50 for severe effects following inhalation of GA vapors (CDEPAT 1994). CDEPAT's proposed ECt50 estimate of 50 mg-min/m3 was derived on the basis of the study by Cresthull et al. (1957), which indicated that the ratio of the incapacitation vapor dose (ICt50) to the LCt50 is about 0.75. The reported ICt50s for 2-min and 10-min exposures were 102 and < 180 mg-min/m3, respectively. The subcommittee believes that CDEPAT's approach of estimating the ECt50 for severe effects is reasonable in its assumption that the ratio of ICt50 to LCt50 is 0.75. The subcommittee recommends that CDEPAT's estimate of 50 mg-min/m3 be lowered to correspond to the lowered estimate for LCt50 until further research is conducted to establish the ECt50 for severe effects with a greater degree of confidence. ECt50 for Mild Effects CDEPAT's proposed ECt50 estimate for mild effects (miosis or rhinorrhea) following exposure to GA vapor is 0.5 mg-min/m3, assuming a 2-min to 10-min exposure period. The Army's existing ECt50 estimate for mild effects is 0.9 mg-min/m3; the duration of exposure was 5 min (Mumford 1950). Human data are available that indicate that the proposed ECt50 esti-

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--> mate could be greater than 0.5 mg-min/m3. At concentrations of 0.7 mg-min/m3 and exposure periods ranging from 2 to 10 min, GA could be detected by smell (Udhe and Moore 1945). However, the number of volunteers detecting the odor was not specified. Tightness of the chest was also observed at exposures of 0.7 mg-min/m3 (Udhe and Moore 1945). In the same study, tightness of the chest and miosis, with impaired vision, occurred at doses ranging from 3.2 to 30 mg-min/m 3 (Udhe and Moore 1945). At higher vapor doses, those effects were accompanied by severe eye pain, headaches, nausea, and vomiting. On the basis of the review of the available data, the subcommittee concludes that CDEPAT's proposed estimate of 0.5 mg-min/m3 can be raised. The subcommittee recommends that further research be conducted to establish the ECt50 estimate with a greater degree of confidence. Percutaneous Liquid Exposure Lethal Effects (LD50) CDEPAT's proposed LD50 for percutaneous exposure to GA liquid on bare skin is 1,500 mg for a 70-kg man. The proposed LD50 estimate does not differ from the existing estimate (CDEPAT 1994). LD50 values reported for animals ranged from 1 mg/kg for mice to 30 to 50 mg/kg for dogs. However, it is difficult to use those data for predicting the human LD50 estimate because many of the animal studies involved the use of depilated animals (animals whose hair was removed chemically, thus making them more susceptible to toxic effects of chemicals) and others tested only crude material. The proposed LD50 estimate for men was based on animal data without the use of uncertainty factors to account for inter-species variability. Thus, the subcommittee concludes that the proposed LD50 value for humans is not scientifically defensible because it is based on the use of limited animal data without the use of uncertainty factors. The subcommittee recommends that the proposed estimate be lowered until further research is conducted on GA to establish an LD50 estimate With a greater degree of confidence. ED50 for Severe Effects CDEPAT's proposed estimate for the ED50 for severe effects (that is,

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--> incapacitation in 50% of animals, or ID50) following acute percutaneous exposure to GA liquid on bare skin is 880 mg for a 70-kg man. There is no existing ED50 estimate (CDEPAT 1994). Because of the lack of human or animal data on GA for severe effects, the ED50 was derived by assuming that the ratio of ID50 to LD50 is 0.6 (CDEPAT 1994). The assumption that the ratio is 0.6 is based on a study using weanling pigs in which the ratio of ID50 to LD50 for GB was 0.6 (Silver 1953). CDEPAT assumed the same ratio for GA because GA and GB belong to the same class of compounds. The subcommittee believes that the CDEPAT approach is reasonable. The subcommittee recommends that CDEPAT's estimate of 880 mg for a 70-kg man, based on the ID50-to-LD50 ratio of 0.6, be lowered to correspond to the lowered estimate for LD50 until further research is done to establish the ED50 estimate with a greater degree of confidence. Conclusions and Recommendations The subcommittee's conclusions concerning CDEPAT's proposed human-toxicity estimates for GA are summarized in Table 2-1. Of the seven human-toxicity estimates for GA proposed by CDEPAT, the subcommittee agrees that two estimates are scientifically valid for protecting the soldier and recommends that four be lowered and one raised. The subcommittee also recommends the need for additional research to establish human-toxicity estimates with a greater degree of confidence.

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--> TABLE 2-1 Evaluation of Human-Toxicity Estimates for GA     Human-Toxicity Estimates for GA     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GA Rationale for Subcommittee's Evaluation LCt50a Percutaneous, vapor 20,000 mg-min/m3 15,000 mg-min/m3 Proposed estimate is scientifically valid Proposed estimate supported by human data   Inhalation, vapor 135 mg-min/m3 70 mg-min/m3 Proposed estimate should be lowered Because of inadequate data on GA for this route, CDEPAT derived the estimate by assuming that GA is 0.5 times as toxic as GB; approach reasonable but estimate should be lowered because of recommended lowering of LCt50 for GB for this route; further research recommended ECt50b Threshold effects Percutaneous, vapor None 2,000 mg-min/m3 Proposed estimate is scientifically valid ChE inhibition data used for proposing new recommendation Severe effects Inhalation, vapor None 50 mg-min/m3 Proposed estimate should be lowered CDEPAT's proposed estimate based on a study that indicated the ratio of ICt50e/LCt50 is 0.75; that assumption used to establish ECt50 for severe effects; the subcommittee recommends that the ECt50 estimate be lowered to correspond to the lowered estimate for LCt50; further research recommended Mild effects Inhalation, vapor 0.9 mg-min/m3 0.5 mg-min/m3 Proposed estimate should be raised Human data show that humans can tolerate higher exposures; further research recommended

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-->     Human-Toxicity Estimates for GA     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GA Rationale for Subcommittee's Evaluation LD50c Percutaneous, liquid 1,500 mg for 70-kg man 1,500 mg for 70-kg man Proposed estimate should be lowered No uncertainty factors used in lieu of limited animal data for proposed estimate; further research recommended ED50d Percutaneous, liquid None 880 mg for 70-kg man Proposed estimate should be lowered In the absence of adequate human or animal data for this effect, CDEPAT established the estimate by assuming ID50f/LD50 ratio of 0.6 to estimate ED50; the subcommittee recommends that the ED50 estimate be lowered to correspond to the lowered estimate for LD50; 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 ICt50: Vapor exposure that produces incapacitation in 50% of the exposed population. f ID50: Liquid dose causing incapacitation in 50% of the exposed population.