5—
Review of Acute Human-Toxicity Estimates for GF

GF (cyclohexyl methylphosphonofluoridate) is an organophosphate nerve agent. The physical and chemical properties, toxicokinetics, and toxicity of GF 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 for percutaneous liquid exposures. Only a few toxicity end points were considered; they include lethality and cholinesterase (ChE) inhibition in humans and animals. The subcommittee's assessment of the scientific validity of CDEPAT's proposed human-toxicity estimates for GF is discussed below.

Percutaneous Vapor Exposure

Lethal Effects (LCt50)

CDEPAT's proposed LCt50 estimate for percutaneous exposure to GF vapor is 2,500 mg-min/m3, assuming exposure durations of 30 to 50 min and



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--> 5— Review of Acute Human-Toxicity Estimates for GF GF (cyclohexyl methylphosphonofluoridate) is an organophosphate nerve agent. The physical and chemical properties, toxicokinetics, and toxicity of GF 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 for percutaneous liquid exposures. Only a few toxicity end points were considered; they include lethality and cholinesterase (ChE) inhibition in humans and animals. The subcommittee's assessment of the scientific validity of CDEPAT's proposed human-toxicity estimates for GF is discussed below. Percutaneous Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for percutaneous exposure to GF vapor is 2,500 mg-min/m3, assuming exposure durations of 30 to 50 min and

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--> moderate temperatures. The existing estimate is 15,000 mg-min/m3 (CDEPAT 1994). In a study conducted with rhesus monkeys, 10 animals each weighing 2.7 to 5.9 kg were exposed to GF vapor. An LCt50 value of 10,000 mg-min/m3 was reported (McGrath et al. 1953). It is important to note that the animals were clipped, allowing for maximum skin exposure. Exposure durations varied from 31 to 345 min with an average atmospheric concentration of 105 mg/m3. Animals were exposed until they died. That type of exposure is a serious limitation of the study, because exposure until death necessarily results in higher LCt50 values. Had animals been exposed to lower vapor Cts (concentration X exposure time) and followed for 24 to 48 hr, the LCt50 might be lower. CDEPAT proposed lowering the existing estimate of 15,000 mg-min/m3 to 2,500 mg-min/m3. The subcommittee agrees with CDEPAT's proposal to lower the estimate, but it believes that insufficient evidence was provided for lowering the estimate to 2,500 mg-min/m3. Therefore, the subcommittee recommends that CDEPAT's proposed estimate of 2,500 mg-min/m3 serve as an interim value until further research is done. The subcommittee also recommends that a study be conducted at different exposure levels and observations made 24 to 48 hr after exposure to obtain data to more accurately determine the LCt50. ECt50 for Threshold Effects CDEPAT's proposed ECt50 estimate for threshold (minimal) effects from exposure to GF is 300 mg-min/m3, assuming exposure durations of 30 to 50 min and moderate temperatures. There is no existing ECt 50 estimate for threshold effects (CDEPAT 1994). No human or animal data are available for estimating the ECt50 for threshold effects (CDEPAT 1994). The proposed estimate is based on the assumption that GD and GF are equipotent (Cullumbine et al. 1954). The subcommittee believes that, in the absence of adequate data on GF exposure of humans and animals, CDEPAT's approach of assuming equipotencies for GF and GD and thus proposing the same ECt50 estimates is reasonable. The subcommittee recommends that CDEPAT's proposed estimate of 300 mg-min/m3 serve as an interim value until further research on GF is conducted to establish the ECt50 estimate with a greater degree of confidence.

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--> Inhalation Vapor Exposure Lethal Effects (LCt50) CDEPAT's proposed LCt50 estimate for inhalation exposure to GF vapor is 35 mg-min/m3, assuming exposure durations of 2 to 10 min, moderate temperatures, and minute volumes of 15 liters. There is no existing LCt50 estimate (CDEPAT 1994). No data are available concerning the toxicity of GF in humans following inhalation exposures, and the animal data are insufficient for deriving an LCt50 estimate (CDEPAT 1994). LCt50 studies were conducted in rats and monkeys. The LCt50s for male and female Wistar rats exposed for 1 min were 181 mg-min/m3 and 110 mg-min/m3, respectively (Callaway and Blackburn 1954). In a study using 44 rhesus monkeys, the LCt50 was determined for 2-min and 10-min durations. The reported LCt50s for GF were 130 mg-min/M 3 and 75 mg-min/m3 for 2-min and 10-min exposures, respectively (Cresthull et al. 1957). These studies are considered inadequate for deriving human LCt50 estimate. The proposed estimate of 35 mg-min/m3 is based on the assumption that GF is as potent as GB or GD (CDEPAT 1994). That assumption is supported by animal studies (Cresthull et al. 1957) that show that GF, GB, and GD have equal potencies for this effect via inhalation vapor exposures (CDEPAT 1994). The subcommittee recommends that the proposed LCt50 estimate for GF be lowered to correspond to that recommended for GB. The subcommittee also recommends that further research on GF be conducted to establish this estimate with a greater degree of confidence. ECt50 for Severe Effects CDEPAT's proposed ECt50 estimate for severe effects from inhalation exposure to GF is 25 mg-min/m3, assuming exposure durations of 2 to 10 min, moderate temperatures, and minute volumes of 15 liters. There is no existing ECt50 estimate (CDEPAT 1994). No data are available on severe effects in humans, and the studies on severe effects following inhalation exposures in animals are inadequate. In the absence of data in humans and animals, CDEPAT's proposed estimate of 25 mg-min/m3 is based on the assumption that GF is as potent

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--> as GD and GB (CDEPAT 1994) in monkeys and other species by the inhalation route. That assumption is supported by animal studies that show that GF, GB, and GD are equipotent for this effect via inhalation vapor exposures (Cresthull et al. 1957; CDEPAT 1994). In the absence of adequate data on GF for severe effects, the subcommittee recommends that CDEPAT's proposed ECt50 estimate be lowered to correspond to lowered estimates for GB and GD until further research on GF is conducted to establish the estimate with a greater degree of confidence. ECt50 for Mild Effects CDEPAT's proposed ECt50 estimate for ocular effects from exposure to GF is 0.2 mg-min/m3, assuming exposure durations of 2 to 10 min and moderate temperatures. There is no existing ECt50 estimate (CDEPAT 1994). No data are available on the ocular toxicity of GF in humans or experimental animals. The proposed estimate is based on the assumption that GF and GD are equipotent (Cullumbine et al. 1954). The subcommittee agrees with CDEPAT's approach. The subcommittee recommends that CDEPAT's ECt50 estimate for ocular effects be raised to correspond to the recommended raised estimate for GD until further research is conducted on GF to establish this estimate with a greater degree of confidence. Percutaneous Liquid Exposure Lethal Effects (LD50) CDEPAT's proposed LD50 estimate for percutaneous exposure to GF vapor is 350 mg for a 70-kg man, assuming exposure at moderate temperatures. There is no existing LD50 estimate (CDEPAT 1994). Limited human data are available, and the data that are available suggests a fourfold variation in ChE inhibition. Studies have been conducted in rabbits and pigs to determine the LCt50 of GF liquid after percutaneous exposure. In one study (Marzulli et al. 1952), rabbits were exposed at four levels. A similar protocol was used for pigs. The LD50 in rabbits was 1.3 mg/kg (91 mg for a 70-kg man); the LD50 in pigs was 16.5 mg/kg (1,155 mg for a 70-kg man). On the basis of the rabbit data, CDEPAT concluded that liquid GF poses a serious threat to soldiers in a moderate climate. The proposed LD50 estimate assumes that GF and GD are equipotent

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--> (Cullumbine et al. 1954). The subcommittee believes that, in the absence of adequate data, the use of this assumption is a reasonable approach. The subcommittee recommends that CDEPAT's estimate of 350 mg for a 70-kg man be considered an interim estimate until further research on GF is conducted to establish this estimate with a greater degree of confidence. ED50 for Severe Effects CDEPAT's proposed ED50 estimate for severe effects from percutaneous liquid exposure to GF is 200 mg for a 70-kg man, assuming exposure durations of 2 to 10 min and moderate temperatures. There is no existing ED50 estimate (CDEPAT 1994). In the absence of adequate human and animal data on the severe effects following percutaneous exposure to GF liquid, CDEPAT (1994) assumed that GD and GF are equipotent. The subcommittee concludes that the approach used by CDEPAT (1994) to derive the ED50 is reasonable and recommends that the proposed estimate be considered an interim value until further research on GF is conducted to establish this estimate with a greater degree of confidence. Conclusions and Recommendations The subcommittee's conclusions concerning CDEPAT's proposed estimates for GF are summarized in Table 5-1. Of the seven acute human-toxicity estimates for GF proposed by CDEPAT (1994), the subcommittee agrees that the estimates are not scientifically valid or appropriate for protecting soldiers. Four estimates are recommended to serve as interim values until further research is conducted, one estimate should be raised, and two estimates should be lowered. The subcommittee recommends that further research be conducted to establish estimates with a greater degree of confidence.

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--> TABLE 5-1 Evaluation of Human-Toxicity Estimates for GF     Human-Toxicity Estimates for GF     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GF Rationale for Subcommittee's Evaluation LCt50a Percutaneous, vapor 15,000 mg-min/m3 2,500 mg-min/m3 Proposed estimate should serve as an interim value Rationale for the CDEPAT estimate not supported by data; further research recommended   Inhalation, vapor None 35 mg-min/m3 Proposed estimate should be lowered In the absence of adequate data, proposed estimate based on assumption that GF, GD, and GB are equipotent; approach is reasonable; because LCt50 for GB was recommended to be lowered, proposed value for GF should be lowered correspondingly; further research recommended ECt50b Threshold effects Percutaneous, vapor None 300 mg-min/m3 Proposed estimate should serve as an interim value Proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; further research recommended Severe effects Inhalation, vapor None 25 mg-min/m3 Proposed estimate should be lowered In the absence of adequate data, proposed estimate based on assumption that GF, GD, and GB are equipotent; approach is reasonable, because ECt50s for severe effects for GB and GD were recommended to be lowered, proposed value for GF should be lowered correspondingly; further research recommended

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-->     Human-Toxicity Estimates for GF     Toxicity Type Route and Form of Exposure Existing Estimates CDEPAT's Proposed Estimates Subcommittee's Evaluation of Proposed Estimates for GF Rationale for Subcommittee's Evaluation Mild effects Inhalation, vapor None 0.2 mg-min/m3 Proposed estimate should be raised In the absence of adequate human or animal data, the proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; because ECt50 for mild effects for GD was recommended to be raised, proposed value for GF should be raised correspondingly; further research recommended LD50c Percutaneous, liquid None 350 mg for 70-kg man Proposed estimate should serve as an interim value In the absence of adequate human or animal data, proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; further research recommended ED50d Severe effects Percutaneous, liquid None 200 mg for 70-kg man Proposed value should serve as an interim value In the absence of adequate human or animal data, the proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; 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.