6—
Review of Acute Human-Toxicity Estimates for VX

VX (O-ethyl-S-[2(diisopropylamino)ethyl]methylphosphonothioate) is an organophosphate nerve agent. It is less volatile than G-nerve agents, a property that might significantly affect its role in chemical warfare. The physical and chemical properties, toxicokinetics, and toxicity of VX 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 a few end points were considered—lethality in animals, changes in cholinesterase (ChE) activity in humans and animals, incapacitation, ocular toxicity, and rhinorrhea. The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for VX is discussed below.

Percutaneous Vapor Exposure

Lethal Effects (LCt50)

CDEPAT's proposed LCt50 estimate for percutaneous exposure to VX vapor is 150 mg-min/m3 assuming exposure durations of 30 to 50 min and moderate temperatures. There is no existing LCt50 estimate (CDEPAT 1994).



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--> 6— Review of Acute Human-Toxicity Estimates for VX VX (O-ethyl-S-[2(diisopropylamino)ethyl]methylphosphonothioate) is an organophosphate nerve agent. It is less volatile than G-nerve agents, a property that might significantly affect its role in chemical warfare. The physical and chemical properties, toxicokinetics, and toxicity of VX 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 a few end points were considered—lethality in animals, changes in cholinesterase (ChE) activity in humans and animals, incapacitation, ocular toxicity, and rhinorrhea. The subcommittee's assessment of the scientific validity of CDEPAT's human-toxicity estimates for VX is discussed below. Percutaneous Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for percutaneous exposure to VX vapor is 150 mg-min/m3 assuming exposure durations of 30 to 50 min and moderate temperatures. There is no existing LCt50 estimate (CDEPAT 1994).

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--> The potency of VX is enhanced by increased ambient wind speed and aerosol particle size. Those factors are more noticeable with VX than with the other nerve agents because of the relatively low volatility of VX. The recommended percutaneous estimates for VX vapor are for no wind and for aerosol particles of < 2 µm diameter (CDEPAT 1994). The estimates also take into consideration the areas of the body that are probably the most sensitive to VX, the head and neck, which are highly likely to be exposed to vapor (Bramwell et al. 1963; Sim 1962). The most relevant human and animal studies for generating human LCt 50 estimates are discussed below. The percutaneous toxicity of VX vapor was investigated in mice and goats. The exposure duration was uncertain for goats (values were given, but uncertainty was associated with them) and unreported for mice (Koon et al. 1960). The LCt50 was 11.5 mg-min/m3 for mice and 100 to 150 mg-min/m3 for clipped goats (Koon et al. 1960). The LCt50s for clothed, depilated rabbits at 0-mph and 8-mph wind speeds were 814 mg-min/m3 and 35 mg-min/m3, respectively (Cresthull et al. 1963). The values for unclothed rabbits at 0-mph and 8-mph wind speeds were 28 mg-min/m3 and 8.3 mg-min/m3, respectively (Cresthull et al. 1963). Krackow (1956) studied the toxicity of VX in depilated rabbits. On the basis of his data, he proposed an LCt50 of 124 to 180 mg-min/m3. Animal data indicate that the highest observed LCt50 for no wind is 100 to 150 mg-min/m3 (Koon et al. 1960). Human estimates vary from 6 to 3,600 mg-min/m3 for various exposure conditions (Koon et al. 1960), and the human estimate depends on wind speed and particle size. Higher wind speed and larger particle size are more effective in producing toxicity of VX. The more credible animal studies estimated the LCt50 to be between 280 and 300 mg-min/m3. CDEPAT estimated a LCt50 for percutaneous VX vapor of 150 mg-min/m3 (slightly more protective given the sensitivity of the head region). The subcommittee agrees with CDEPAT's evaluation that the degree of confidence in that estimate is low. The subcommittee recommends that CDEPAT's proposed LCt50 estimate be considered an interim value until further research on VX is conducted to establish the LCt50 estimate with a greater degree of confidence. ECt50 for Severe Effects CDEPAT's proposed ECt50 estimate for severe effects from percutaneous

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--> exposure to VX vapor is 25 mg-min/m3, assuming exposure durations of 30 to 50 min and moderate temperatures. There are no existing ECt50 estimates (CDEPAT 1994). In one study in humans, a spirometer mouthpiece was used for breathing; a clip was placed over the nose, and the eyes were kept closed (Bramwell et al. 1963). Percutaneous exposure of the head and neck to VX vapor at a rate of 1 mg-min and a temperature of 32°C resulted in miosis in almost all subjects even though the eyes were closed (Bramwell et al. 1963). The ECt50s were 0.7 to 25.6 mg-min/m3; exposure durations were 15 to 24 min and concentrations ranged from 0.23 to 5 mg/m3. In one or more trials, five of eight individuals experienced local flushing (transient redness) over the face and neck. After 24 hr of exposure, the ChE activity ranged from 37% to 108% of baseline. Nausea, vomiting, cold sweats, and pallor were also observed. The effective dose for 50% inhibition of ChE activity was 27 mg-min/m 3 (Bramwell et al. 1963). This study did not identify a no-observed-adverse-effect level (NOAEL). Because the subcommittee's degree of confidence in the proposed ECt 50 estimate is low to moderate, the subcommittee recommends that the estimate of 25 mg-min/m3 for severe effects serve as an interim value until further research on VX is conducted to establish the ECt50 estimate with a greater degree of confidence. ECt50 for Threshold Effects CDEPAT's proposed ECt50 estimate for threshold (minimal) effects from percutaneous exposure to VX vapor is 10 mg-min/m3, assuming exposure durations of 30 to 50 min and moderate temperatures. There is no existing ECt50 estimate for threshold effects (CDEPAT 1994). In one human study, exposures investigated for severe effects produced adverse effects at the highest exposure level, which was 25.6 mg-min/m 3 (Bramwell et al. 1963). At this exposure level, approximately 50% ChE inhibition occurred. This study did not identify a NOAEL. The subcommittee's degree of confidence in the proposed estimate is low because a true NOAEL was not established. The subcommittee recommends that the proposed estimate be considered an interim value until further research on VX is conducted to establish the NOAEL.

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--> Inhalation Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for inhalation exposure to VX vapor is 15 mg-min/m3, assuming exposure durations of 2 to 10 min, minute volumes of 15 liters, and moderate temperatures. The existing LCt 50 estimate is 30 mg-min/m3 (CDEPAT 1994). There are a few reports on VX that provide definitive data about human inhalation toxicity. Most studies are in animals and often do not specify the duration of exposure. CDEPAT's proposed human-toxicity estimates considered effects produced from inhalation exposures as well as from percutaneous vapor exposures. Bramwell et al. (1963) reported that the ECt50 for ChE inhibition following percutaneous vapor exposure to VX was 27 mg-min/m3; one subject experienced systemic effects from vapor exposure at 25.6 mg-min/m3. Bramwell et al. (1963) also reported a mean ChE inhibition of 26% in humans exposed to VX vapors by inhalation at 2.6 to 3.6 mg-min/m3 for 1.5 min. Studies performed in the rat reported LCt50 values for 1 min, 5 min, and 10 min at exposures of 17 mg-min/m3, 8 mg-min/m3, and 9 mg-min/m 3, respectively (Krackow 1956). The vapor toxicity of VX was also investigated in mice for whole-body or head-only exposures (Koon et al. 1960). For a 10-min exposure, the LCt50 for whole-body exposure in mice was 4 mg-min/m3. The LCt 50 value for head only exposure was 13.6 mg-min/m3. The LCt50 value reported for goats was 9.2 mg-min/m3 (Koon et al. 1960). In deriving the human-toxicity estimates for inhalation, CDEPAT assumed that the dose delivered to the target tissue is greater for inhalation than for percutaneous vapor exposure. Although humans tolerated (26% ChE inhibition) 3.6 mg-min/m3 via inhalation for 1.5 min, higher exposures were not used. The subcommittee agrees with CDEPAT's evaluation that degree of confidence in the proposed estimate of 15 mg-min/m 3 is low to moderate. The subcommittee recommends that CDEPAT's proposed estimate of 15 mg-min/m3 be lowered. The subcommittee also recommends that research on VX be done to establish the LCt50 estimate with a greater degree of confidence.

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--> ECt50, for Severe Effects CDEPAT's proposed ECt50 estimate for severe effects is 10 mg-min/m 3, assuming exposure durations of 2 to 10 min, minute volumes of 15 liters, and moderate temperatures. The existing ECt50 estimate for severe effects is 25 mg-min/m3. In one study, the ICt50 (exposure level producing incapacitation in 50% of a given population) for VX was estimated to be 13 mg-min/m 3 (Howd et al. 1986). That estimate was based on ChE inhibition in humans and animals. The available data to derive an ECt50 for severe effects are insufficient. CDEPAT used the ratio of ICt50/LCt50 of 0.7 to 0.8 to derive the ECt50 for severe effects. The rationale for using this ratio is unclear. The subcommittee's degree of confidence in the CDEPAT's proposed ECt50 estimate of 10 mg-min/m3 is low. Thus, the subcommittee recommends that the proposed ECt50 estimate for severe effects of 10 mg-min/m3 serve as an interim value until further research on VX is conducted to establish the estimate with a greater degree of confidence. Ect50 for Mild Effects CDEPAT's proposed Ect50 estimate for ocular effects or rhinorrhea in humans is 0.09 mg-min/m3, assuming exposure durations of 2 to 10 min and moderate temperatures. The existing estimate is the same (CDEPAT 1994). Exposures of the head and neck of humans to VX vapor for 1.5 to 6 min resulted in Ect50 values of 0.6 to 6.4 mg-min/m3, respectively (Bramwell et al. 1963). Transient respiratory signs occurred after exposure, but no systemic effects were observed. A vapor dose of 5.5 mg-min/m3 produced a 70% ChE inhibition. Some miosis occurred after exposure. Rhinorrhea was reported in all but one subject. The effects of wind speed on the miotic potencies of VX in humans and rabbits were also studied. A definite relationship was observed between impaction velocity on the cornea (exposure that reduces pupil size by 90%) and the Ect90. On the basis of the available data, the subcommittee concludes that the Ect50 estimate of 0.09 mg-min/m3 for ocular effects is scientifically valid.

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--> Percutaneous Liquid Exposure Lethal Effects (LD50) CDEPAT's proposed LD50 estimate for percutaneous exposure to VX liquid on bare skin is 5 mg for a 70-kg man. The existing estimate is 10 mg for a 70-kg man (CDEPAT 1994). No human studies have been conducted for this effect and route of exposure. Most of the animal studies do not take into account the sensitivity of various areas of the human body to dermal penetration by toxicants. Animal data indicate that CDEPAT's proposed estimate of 5 mg for a 70-kg man is too high because it underestimates the potency of VX liquid on bare skin. Studies have shown the LD50s in clipped rabbits, pigs, and guinea pigs to be 0.02 mg/kg (1.4 mg for a 70-kg man), 0.12 mg/kg (8.4 mg for a 70-kg man), and 0.077 mg/kg (5.4 mg for a 70-kg man), respectively (Wiles and Shaw 1960). No uncertainty factors were applied when extrapolating from animal data to compensate for the variability associated with dermal penetration of various areas of the human body. Thus, the subcommittee concludes that CDEPAT's proposed estimate of 5 mg for a 70-kg man (0.07 mg/kg) for percutaneous exposure to VX liquid is too high. The subcommittee also recommends that the proposed estimate be lowered. The subcommittee recommends that further research be conducted to establish the LD 50 estimate with a greater degree of confidence. ED50 for Severe Effects CDEPAT's proposed ED50 estimate for severe effects from percutaneous exposure to VX liquid is 2.5 mg for a 70-kg man. The existing estimate is 5 mg/70-kg man (CDEPAT 1994). There are no human data and few animal data for this end point by this route of exposure. A study in rabbits showed that the ratio of Ict50 to LD50 for VX is O.5 (Manthei and Callahan 1991). Therefore, in the absence of adequate human or animal data for severe effects via percutaneous exposure to VX liquid, the ratio was used to derive the ED50 for severe effects. The subcommittee agrees with this approach. The subcommittee recommends that CDEPAT's ED50 estimate of 2.5

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--> mg for a 70-kg man be lowered because of the subcommittee's recommendation for lowering the LD50 estimate. The subcommittee also recommends that further research on VX be conducted to establish an ECt50 estimate with a greater degree of confidence. Conclusions and Recommendations The subcommittee's conclusions concerning the scientific validity of CDEPAT's proposed human-toxicity estimates for VX are summarized Table 6-1. Eight human-toxicity estimates, instead of the seven proposed for the other organophosphate agents, were calculated for VX; an ECt50 for severe effects from percutaneous vapor exposure was also calculated. Of the eight human-toxicity estimates for VX proposed by CDEPAT, the subcommittee concludes that only one estimate is appropriate for protecting soldiers and is scientifically valid. The subcommittee recommends that four estimates serve as interim values until further research is conducted, and three estimates are to be lowered. The subcommittee recommends that further research be conducted on VX to establish the human-toxicity estimates with a greater degree of confidence.

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--> TABLE 6-1 Evaluation of Human-Toxicity Estimates for VX     Human-Toxicity Estimates for VX     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for VX Rationale for Subcommittee's Evaluation LCt50a Percutaneous, vapor None 150 mg-min/m3 Proposed estimate should be considered an interim value Degree of confidence in data is low to moderate; further research recommended   Inhalation, vapor 30 mg-min/m3 15 mg-min/m3 Proposed estimate should be lowered Degree of confidence in data is low to moderate; further research recommended ECt50b Threshold effects Percutaneous, vapor None 10 mg-min/m3 Proposed estimate should be considered an interim value Degree of confidence in data is low; a no-observed-adverse-effect level (NOAEL) was not defined; further research recommended Severe effects Percutaneous, vapor None 25 mg-min/m3 Proposed estimate should be considered an interim value Degree of confidence low to moderate; further research recommended   Inhalation, vapor 25 mg-min/m3 10 mg-min/m3 Proposed estimate should be considered an interim value Insufficient data; further research recommended Mild effects Inhalation, vapor 0.09 mg-min/m3 0.09 mg-min/m3 Proposed estimate is scientifically valid Available human data support the proposed estimate LD50c Percutaneous, liquid 10 mg/70-kg man 5 mg/70-kg man Proposed estimate should be lowered Animal data indicate that the proposed estimate is too high; furthermore, no uncertainty factor used in lieu of variability associated with dermal penetration of various regions of body; further research recommended

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-->     Human-Toxicity Estimates for VX     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for VX Rationale for Subcommittee's Evaluation ED50d Severe effects Percutaneous, liquid 5 mg/70-kg man 2.5 mg/70-kg man Proposed estimate should be lowered The ED50 is based on the ID50e/LD50 ratio; the subcommittee recommends that the LD50 be lowered, therefore, the ED50 should be lowered correspondingly; 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.